The alkaloids obtainable from Vinca rosea represent one of the most productive areas of chemistry for drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids, obtainable from the leaves of the plant by extraction and purifiable by chromatography, were found to be active. These active antineoplastic alkaloids obtained directly from the leaves of the vinca plant incude VLB (Vinblastine, vincaleucoblastine), vincristine (leurocristine), leurosine (vinleurosine), leurosidine (vinrosidine), leuroformine (formylleurosine) and deoxy VLB "A" and "B" (4'-deoxy VLB and 4'-deoxyleurosidine).
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemists were slow to 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 anticancer 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 only 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 turned out to be active anti-tumor agents. [See U.S. Pat. No. 4,166,810, and Conrad et al. J. Med. Chem., 22, 391 (1979)]. 4-Desacetyl VLB 3-carboxamide (vindesine) is currently being marketed in several European countries as an oncolytic agent. It is said to be effective in treating some vincristine-resistant leukemias in addition to many common neoplasms including germ-cell tumors. Reaction of the 3-hydroxy and 3-ester functions with an isocyanate has produced the corresponding oxazolidinedione derivatives, one of which, the N-chloroethyl derivative--vinzolidine--is currently undergoing a clinical trial. These oxazolidinedione derivatives are disclosed in Miller and Gutowski, RE 30,560, reissued Mar. 31, 1981.
A second area of the molecule which has been modified is the C-4' functionality. A majority of these modifications have been based on the 3',4'-anhydro derivative, makeable both by coupling vindoline and catharanthine via a modified Polonovski reaction--Potier et al. J.C.S. Chem. Comm., 670, (1975)--and by dehydrating VLB or leurosidine--Gutowski and Miller, U.S. Pat. No. 4,029,663. The dehydration reaction produces two exo-double bond isomers in addition to the .DELTA..sup.3',4' -anhydro derivative. Functionalization of any one of these double bonds to form epoxides, diols, etc. has constituted the chief chemical modifications undertaken at C-4'.
The third region of the indole-dihydroindole which has been modified successfully is C-4. In the first place, hydrolysis of the acetoxy group, present in all the above vinca alkaloids, yields active antineoplastic 4-desacetyl derivatives. (Vindesine, a C-3 carboxamide, is a 4-desacetyl derivative.) Secondly, Hargrove, U.S. Pat. Nos. 3,387,001 and 3,392,173 prepared novel 4-acyl derivatives of 4-desacetyl VLB, 4-desacetyl vincristine, etc. Among these new derivatives was 4-chloroacetyl VLB, which compound could be reacted with amines, for example, dimethylamine, to yield a potent anticancer drug, vinglycinate, N,N-di-methyl 4-glycinyl VLB. In a different modification, Wright and Neuss, U.S. Pat. No. 4,122,082, oxidized the 4-hydroxyl of 4-desacetyl VLB to a 4-keto compound, and Thompson, U.S. Pat. No. 4,195,022, reduced this ketone to the 4-epihydroxy (4.alpha.-hydroxy) derivative, also a compound with anticancer activity.
Indole-dihydroindole bridged dimers; i.e., the same or different alkaloid moieties bridged thru the 3-carboxyl via a bis-amide are described in Conrad and Gerzon, U.S. Pat. No. 4,199,504. Otherwise, indole-dihydroindole vinca alkaloid dimers have not been bridged through other positions in the molecule to form vinca tetramers.
VLB and vincristine have been conjugated with proteins to form antigens useful in radioimmune assays. 4-Desacetyl VLB 3-carboxazide (desacetyl vinblastinoic azide) and the corresponding vincristine compound have been the derivatives employed; see Conrad et al., J. Med. Chem., 22, 391 (1979), European Pat. No. 41,935, Abstract 182, FACSS, Oct. 6, 1975, and U.S. Pat. No. 4,203,898 for illustrations of this reaction.