CA1121815A - Dimeres d'alcaloide de catharantus pontes - Google Patents

Dimeres d'alcaloide de catharantus pontes

Info

Publication number: CA1121815A
Authority: CA; Canada
Prior art keywords: vlb; desacetyl; formula; reaction; compounds
Prior art date: 1978-05-15
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired

Application number

CA000374565A

Other languages

English (en)

Inventor

Robert A. Conrad

Koert Gerzon

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Eli Lilly and Co

Original Assignee

Eli Lilly and Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1978-05-15

Filing date

1981-04-02

Publication date

1982-04-13

1978-05-15 Priority claimed from US05/905,667 external-priority patent/US4199504A/en

1981-04-02 Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co

1981-04-02 Priority to CA000374565A priority Critical patent/CA1121815A/fr

1982-04-13 Application granted granted Critical

1982-04-13 Publication of CA1121815A publication Critical patent/CA1121815A/fr

Status Expired legal-status Critical Current

Links

239000000539 dimer Substances 0.000 title abstract description 5
229930013930 alkaloid Natural products 0.000 title description 11
241000208328 Catharanthus Species 0.000 title description 4
150000003797 alkaloid derivatives Chemical class 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 17
150000001540 azides Chemical class 0.000 claims abstract description 11
150000004985 diamines Chemical class 0.000 claims abstract description 11
UKTNDLHXQNQKBH-UHFFFAOYSA-N 2,3-dihydro-1h-indole;1h-indole Chemical compound C1=CC=C2NCCC2=C1.C1=CC=C2NC=CC2=C1 UKTNDLHXQNQKBH-UHFFFAOYSA-N 0.000 claims abstract description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 2
241000863480 Vinca Species 0.000 abstract description 5
230000000174 oncolytic effect Effects 0.000 abstract description 3
125000005392 carboxamide group Chemical class NC(=O)* 0.000 abstract 2
239000003795 chemical substances by application Substances 0.000 abstract 1
229910052757 nitrogen Inorganic materials 0.000 abstract 1
125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 50
JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 48
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
238000006243 chemical reaction Methods 0.000 description 21
238000000034 method Methods 0.000 description 12
239000000243 solution Substances 0.000 description 11
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 11
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
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238000002360 preparation method Methods 0.000 description 8
239000000047 product Substances 0.000 description 8
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 7
LPGWZGMPDKDHEP-GKWAKPNHSA-N Leurosine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@]6(CC)O[C@@H]6[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C LPGWZGMPDKDHEP-GKWAKPNHSA-N 0.000 description 7
125000005518 carboxamido group Chemical group 0.000 description 7
-1 chloracetyl group Chemical group 0.000 description 7
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 7
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JXLYSJRDGCGARV-KSNABSRWSA-N ac1l29ym Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-KSNABSRWSA-N 0.000 description 6
150000001408 amides Chemical class 0.000 description 6
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239000003814 drug Substances 0.000 description 6
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125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
239000011541 reaction mixture Substances 0.000 description 6
JXLYSJRDGCGARV-PJXZDTQASA-N Leurosidine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-PJXZDTQASA-N 0.000 description 5
241000699670 Mus sp. Species 0.000 description 5
239000002253 acid Substances 0.000 description 5
OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 5
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230000008020 evaporation Effects 0.000 description 4
235000010288 sodium nitrite Nutrition 0.000 description 4
238000011282 treatment Methods 0.000 description 4
NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 3
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
239000002246 antineoplastic agent Substances 0.000 description 3
239000012442 inert solvent Substances 0.000 description 3
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VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 3
229960004355 vindesine Drugs 0.000 description 3
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
240000001829 Catharanthus roseus Species 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
125000002252 acyl group Chemical group 0.000 description 2
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WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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IFGMHVGAHYXLIZ-UHFFFAOYSA-N methyl 11-acetyloxy-12-ethyl-4-(17-ethyl-16,17-dihydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl)-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate Chemical compound OC1C(CC)(O)CN(CCC=2C3=CC=CC=C3NC=22)CC1CC2(C(=O)OC)C1=CC(C23C(C(C(OC(C)=O)C4(CC)C=CCN(C34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC IFGMHVGAHYXLIZ-UHFFFAOYSA-N 0.000 description 2
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238000000921 elemental analysis Methods 0.000 description 1
230000003203 everyday effect Effects 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
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229940049920 malate Drugs 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
230000036210 malignancy Effects 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
125000005341 metaphosphate group Chemical group 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
229940095102 methyl benzoate Drugs 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
238000002156 mixing Methods 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 1
MUNVQRULTAETOU-UHFFFAOYSA-N n-[2-(2-aminoethyldisulfanyl)ethyl]formamide Chemical compound NCCSSCCNC=O MUNVQRULTAETOU-UHFFFAOYSA-N 0.000 description 1
PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
230000007135 neurotoxicity Effects 0.000 description 1
231100000228 neurotoxicity Toxicity 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
238000011275 oncology therapy Methods 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
201000008968 osteosarcoma Diseases 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
229940049953 phenylacetate Drugs 0.000 description 1
WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
229950009215 phenylbutanoic acid Drugs 0.000 description 1
239000000843 powder Substances 0.000 description 1
KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
238000000746 purification Methods 0.000 description 1
YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
229940116351 sebacate Drugs 0.000 description 1
CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
150000003334 secondary amides Chemical class 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
NGDIAZZSCVVCEW-UHFFFAOYSA-M sodium;butyl sulfate Chemical compound [Na+].CCCCOS([O-])(=O)=O NGDIAZZSCVVCEW-UHFFFAOYSA-M 0.000 description 1
239000007787 solid Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
238000011287 therapeutic dose Methods 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
229950003670 vinrosidine Drugs 0.000 description 1
229940071104 xylenesulfonate Drugs 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA000374565A 1978-05-15 1981-04-02 Dimeres d'alcaloide de catharantus pontes Expired CA1121815A (fr)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CA000374565A CA1121815A (fr)	1978-05-15	1981-04-02	Dimeres d'alcaloide de catharantus pontes

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US905,667		1978-05-15
US05/905,667 US4199504A (en)	1978-05-15	1978-05-15	Bridged cathranthus alkaloid dimers
CA327,351A CA1114816A (fr)	1978-05-15	1979-05-10	Dimeres pontes d'alcaloides de catharantus
CA000374565A CA1121815A (fr)	1978-05-15	1981-04-02	Dimeres d'alcaloide de catharantus pontes

Publications (1)

Publication Number	Publication Date
CA1121815A true CA1121815A (fr)	1982-04-13

Family

ID=27166231

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000374565A Expired CA1121815A (fr)	1978-05-15	1981-04-02	Dimeres d'alcaloide de catharantus pontes

Country Status (1)

Country	Link
CA (1)	CA1121815A (fr)

1981
- 1981-04-02 CA CA000374565A patent/CA1121815A/fr not_active Expired

Legal Events

Date	Code	Title	Description
1999-04-13	MKEX	Expiry

Publication	Publication Date	Title
US4166810A (en)	1979-09-04	Derivatives of 4-desacetyl VLB C-3 carboxyhydrazide
CA1067073A (fr)	1979-11-27	Derives amides de la vinblastine, de la leurosidine et de la leurocristine, et autres alcaloides dimeriques connexes
US4199504A (en)	1980-04-22	Bridged cathranthus alkaloid dimers
CA1082179A (fr)	1980-07-22	Amides derives du vlb, de la leurosidine, de la leurocristine et d'autres alcaloides dimeres
CA1121815A (fr)	1982-04-13	Dimeres d'alcaloide de catharantus pontes
US4191688A (en)	1980-03-04	Amides of leurosine, leuroformine, desacetylleurosine and desacetylleuroformine
US4096148A (en)	1978-06-20	Oxazolidinedione derivatives of Vinca alkaloids
KR840002164B1 (ko)	1984-11-24	빈카로이코블라스틴 유도체의 제조방법
US3954773A (en)	1976-05-04	4-Desacetoxyvinblastine
US4160767A (en)	1979-07-10	Vinca alkaloid intermediates
USRE30561E (en)	1981-03-31	Vinca alkaloid intermediates
CA1127153A (fr)	1982-07-06	Dimeres pontes d'alcaloide de catharantus
USRE30560E (en)	1981-03-31	Oxazolidinedione derivatives of Vinca alkaloids
US4159269A (en)	1979-06-26	Preparation of oxazolidinedione derivatives of Vinca alkaloids
GB1596235A (en)	1981-08-19	4'-deoxyvinca alkaloids
US4122081A (en)	1978-10-24	5'-Hydroxyleurosine and related compounds
CA1168231A (fr)	1984-05-29	20'-hydroxyvinblastine et composes apparentes
US5043336A (en)	1991-08-27	Cyclic imide derivatives of 4-desacetyl VLB c-3 carboxhydrazide
KR810001453B1 (ko)	1981-10-22	인돌-디하이드로인돌 카복스 아마이드 이량체의 제조방법
IE42132B1 (en)	1980-06-04	Novel derivatives of vinblastine,vincristine and leurosidine
US4362664A (en)	1982-12-07	Vinblastine oxazolidinedione disulfides and related compounds
KR790000810B1 (ko)	1979-07-12	빈브라스틴 유도체의 제조방법
KR820001240B1 (ko)	1982-07-07	4-데스 아세틸 vlb c-3카복스하이드라지드의 항종양 유도체 제조방법
US4175080A (en)	1979-11-20	Process of producing 5'-hydroxyleurosine and related compounds
CS214793B2 (en)	1982-05-28	New method of making the dimeric disulphides of indol-dihydroindole derivatives genus vinca connected by the bridge