Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
  • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms

Definitions

• This invention describes the use of compounds that are used in combination with taxol to control cancerous growths and tumors.
• Protein kinase inhibitors and related compounds are combined with taxol and taxol related compounds and the combination of compounds exhibits powerful potentiating effects when used to treat cancer.
• Many of the compounds are protein kinase inhibitors, other compounds achieve similar effects but are not necessarily protein kinase inhibitors.
• Taxol was first isolated from the baric of the western yew, Taxus brevifolia, and identified as an antitumor agent in 1971 by Wani, et al. Recently, phase ⁇ clinical trials with taxol have shown it to be one of the most exciting chemotherapeutics available. Taxol has proven effective in drug-refractory ovarian cancer (McGuire, et al., 1989), and has shown a 56% objective response rate in metastatic breast cancer (Holmes, et al., 1991). In addition, there is reason for hope that taxol may be effective in many other types of cancers.
• Taxol has faced many obstacles. Taxol's poor solubility required that it be administered in the vehicle Cremophor EL (polyethylated castor oil), which led to a high incidence of hypersensitivity reactions. It is not clear whether these reactions are caused by the vehicle or the drug, but it was found that using longer drug infusions (Weiss, et al., 1990) and anti-allergic regimens (Rowinsky, et al., 1990) reduced the incidence of such reactions. In addition, there are inherent problems in producing sufficient quantities of taxol. Extraction from the bark of the extremely slow growing western yew using present methods cannot meet the demand for taxol. Cultivation of the western yew may take years to establish, synthesis of the complex taxol molecule will be difficult andNor very expensive. Alternative sources of taxol or a taxol substitute or a taxol additive would therefore be highly desirable.
• Taxol has been shown previously to be toxic to tumor and leukemia cells inoculated in mice, including L-1210, P388 and P-1534 leukemia cells and Walker WM-256 carcinosarcoma, sarcoma 180 and Lewis lung tumor cells (Wani et al., 1971). It has also been shown to be toxic to cultured human HeLa cells (Schiff et al., 1979 ) and CHO (Chinese hamster ovary) cells (Cabral et al., 1981). This evidence of toxicity to rodent and human tumor cells in vitro and to tumor bearing mice in vivo predicted that taxol would be an active chemotherapeutic agent and led to clinical trials in human cancer patients.
• Taxotere is a taxol type compound that has also been shown to have powerful antitumor activity. Bissery et. al, Cancer Research 51, 4845-4852, Sept. 15, 1991. Since taxol is now known to be an effective chemotherapeutic agent, a co-treatment that increases the toxicity of taxol on cancer or transformed cells, such as CHO cells, would be likely to increase the chemotherapeutic effect of taxol in cancer patients or to allow smaller doses of taxol to be administered. Quantities of taxol available are extremely limited.
• J63 295-589-A, J62 155-284-A, and J62 155-285-A disclose stausporine related compounds.
• R j is -H, -(C r C 4 alkyl), -C(0)-(C j -C 4 alkyl), -NH 2 , -C(0)-NH 2 , -CH 2 CH 2 -N(R ) 2 , wherein RJ.J is -H or -(C j - alkyl,
• R 2 is -H, or R 2 and R 3 taken together are (O)
• R 3 is -H, -OH or R 2 and R 3 taken together are (O)
• R 4 is -H, -OH, -NH 2 , or -0-(C r C 4 alkyl)
• R 5 is -OH, -0-(C r C 4 alkyl), or -0-C(0)-(C r C 4 alkyl)
• R 6 is C 6 -C U alkyl), -(C 3 -C 10 cycloalkyl), -(CH 2 ) n CH 2 N(R 6 . 1 ) 2 , wherein R 6 .
• R 8 is -Cl, -Br, -H, -CH 3 , -CH 2 OH, -OH,' -0-(C r C 4 alkyl), -N(R 8 .! 2 , or -NHC(0)-NH(R 8 . 1 ), wherein R g .
• j is -H or -(C r C 4 alkyl) wherein n is 0-5 with the proviso that: a) when R 2 or R 3 is -OH then R j is H, b) when R j , R 2 , R 3 , R 4 , and R 7 all equal H and R 5 is OH then R 6 does NOT equal -(CH 2 ) 5 CH 3 , c) when R j , R 4 , and R 7 all equal H, and R 2 combined with R 3 is (O), and R 5 is OH , then Rg does NOT equal -(CH 2 ) 5 CH 3 . d) when R 4 is -OH, -NH 2 , or -0(C j -C 4 alkyl), then R 4 and Rg are the same.
• a pharmaceutical composition consisting of a pharmaceutically acceptable carrier and an effective amount of FORMULA I A pharmaceutical composition consisting of a pharmaceutically acceptable carrier and an effective amount of the compound of FORMULA I in conjunction with an appropriate dose of taxol or taxol related compounds.
• a method of controlling cancerous growths in mammals which comprises administering a therapeutic or prophylactic dosage of any of the three following groups of compounds in conjunction with an appropriate dose of taxol or taxol related compounds. 1) a compound of FORMULA I, 2) any one of the compounds described in the specification as "Indolecarbazole Type Compounds.”, 3) any one of the compounds described in the specification as "Non-Indolecarbazole Type Compounds.”
• FIG. 1 Isobologram showing potentiating effect of the combination of Taxol plus KT5823.
• the isobologram shows the effectiveness of a combination of 2 drugs for the killing of wild type, 10001a CHO, cells.
• the data line is the solid line with open circle or triangle data points.
• the data line shows the combination of doses which gives an LD 5Q for the cells.
• the diagonal dashed line shows the predicted concentrations of drugs if their combination only had an additive effect. If any data points were above the dashed line that would indicate the combination of compounds had antagonistic effects. Data points below the line indicate the compounds have potentiating or synergistic effects.
• Figure 6 Isobologram showing potentiating effect of the combination of taxol plus tamoxifen.
• Figure 7 Isobologram showing potentiating effect of the combination of taxol plus 2-aminopurine.
• Figure 9. Isobologram showing potentiating effect of the combination of taxol plus chlorpromazine.
• Figure 10. Isobologram showing potentiating effect of the combination of taxol plus
• Figure 14 Isobologram showing potentiating effect of the combination of taxol plus Example B-2.
• Figure 15 Isobologram showing potentiating effect of the combination of taxol plus Example B-3.
• Figure 17. Isobologram showing potentiating effect of the combination of taxol plus Example B-5.
• Figure 18. Isobologram showing potentiating effect of the combination of taxol plus
• Figure 19 Isobologram showing potentiating effect of the combination of taxol plus Example B-7.
• Figure 20 Isobologram showing potentiating effect of the combination of taxol plus Example B-8.
• Figure 21 Isobologram showing potentiating effect of the combination of taxol plus Example B-9.
• Figure 22 Effect of KT5720 and taxol on the growth of MX-1 tumors.
• Figure 23 Table of data showing toxicity of several of the drugs both individually and in combination with taxol on non-tumored mice. (In Vivo Effects)
• the compounds of this invention are of two types.
• the first type are known compounds described here for their usefulness when combined with taxol type compounds and used to treat cancer.
• the second type of compounds are novel compounds described here for the first time. These novel compounds are also useful when combined with taxol type compounds and used for the treatment of cancer. .
• Known Compounds are known compounds described here for their usefulness when combined with taxol type compounds and used to treat cancer.
• novel compounds described here for the first time are also useful when combined with taxol type compounds and used for the treatment of cancer. .
• Taxol and taxotere can be obtained from The National Cancer Institute. The clinical pharmacology of taxol is reviewed by Eric K. Rowinsky and Ross C. Donehower, The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., Vol 52, pp 35-84, 1991. Clinical and preclinical studies with taxol are reviewed by William J. Slichenmyer and Daniel D. Von Hoff, Taxol: A New and Effective Anti-cancer Drug, Anti-Cancer Drugs, Vol. 2, pp 519-530, 1991.
• Taxol and analogs thereof are the subject of various patents including, for example, U.S. Patent Nos. 4,814,470; 4,857,653; 4,942,184; 4,924,011; 4,924,012; 4,960,790; 5,015,744; 5,157,049; 5,059,699; 5,136,060; 4,876,399 as well as PCT Publication No. WO 92/09589, European Patent Application 90305845.1 (Publication No. A2 0 400 971), 89400935.6 (Publication No. Al 0 366 841) and 90402333.0 (Publication No. 0 414 610 Al), 87401669.4 (Al 0 253 739), and PCT Publication Nos. WO 91/17977, WO 91/17976, WO 91/13066, WO 91/13053.
• Lavendustin (B8) is available from Gibco BRL.
• the compound, sangerol-7-neonesperidoside, is available from Apin Chemical Co.,
• Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n- octyl.
• Alkoxy as represented by -0-(C j -Cg alkyl) refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and n-octoxy.
• (C 3 -C 10 )cycloalkyl refers to a radical of a saturated cyclic hydrocarbon which includes alkyl-substituted cycloalkyl, such as cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3 diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Each of these moieties may be substituted as appropriate.
• Both organic and inorganic acids can be employed to fo ⁇ n non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
• Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, methanesulfonic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
• These salts are readily prepared by methods known in the art.
• the compounds of this invention can be made in accordance with the processes described in the PREPARATIONS AND EXAMPLES for the preparation of novel compounds and illustrated in the GENERAL REACTIONS and the REACTIONS OF CHART A and CHART B.
• the compounds of the present invention will normally be administered by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, mesylate, methanesulfonate, or sulfamate salt, in association with a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, mesylate, methanesulfonate, or sulfamate salt
• Taxol, taxotere and related compounds should be administered from .001 mg kg to 10 mg kg, preferably between .05 mg/kg to 5 mg/kg for intravenous administration.
• the compounds to be combined with taxol should be administered in the same dosage range.
• the precise dosage will be apparent to an ordinarily skilled physician or pharmacologist talcing into account factors such as the age, weight, sex, and medical condition of the patient being treated. Also relevant is the potency of the particular compound and its ability to potentiate the effects of taxol. The potency of the compounds are indicated by the standard tests described below.
• Ri is -H, -(C r C 4 alkyl), -C(0)-(C r C 4 alkyl), -NH 2 , -C(0)-NH 2 , -CH 2 CH 2 -N(R 1 . 1 ) 2 , wherein RJ_J is -H or -(C j -C 4 alkyl),
• R 2 is -H, or R 2 and R 3 taken together are (O),
• R 3 is -H, -OH or R 2 and R 3 taken together are (O),
• R 4 is -H, -OH, -NH 2 , or -0-(C r C 4 alkyl),
• R 5 is -OH, -0-(C r C 4 alkyl), or -0-C(0)-(C r C 4 alkyl),
• R 6 is -(C 6 -C 12 alkyl), -(C 3 -C 10 cycloalkyl), -(CH 2 ) n CH 2 N(R 6 . 1 ) 2 , wherein R 6 1 is -H, or -(C j -C alkyl),
• R 7 is -H, or -NH 2 ,
• R g is -Cl, -Br, -H, -CH 3 , -CH 2 OH, -OH, -0-(C r C 4 alkyl),
• Rg. j is -H or -(C j -C alkyl) wherein n is 0-5 with the proviso that: a) when R 2 or R 3 is -OH then R j is H, b) when R j , R 2 , R 3 , R 4 , and R 7 all equal H and R 5 is OH then R 6 does NOT equal -(CH 2 ) 5 CH 3 , c) when R j , R , and R 7 all equal H, and R 2 combined with R 3 is (O), and R 5 is OH , then R does NOT equal -(CH 2 ) 5 CH 3 . d) when R 4 is -OH, -NH 2 , or -O- C j -C ⁇ alkyl), then R 4 and R g are the same.
• Preferred Compounds are those, referring to the compound of
• taxol is known to be an effective chemotherapeutic agent, for example in the treatment of ovarian cancer
• any co-treatment that increases the toxicity of taxol on cancer cells, such as CHO cells would be likely to increase the chemotherapeutic effect of taxol in cancer patients or to allow smaller doses of taxol to be administered.
• the compounds of this invention synergize with taxol to produce tumor cell toxicity at lower doses than taxol alone, this requires the conclusion that the compounds will be effective in synergizing with taxol in killing tumor cells in human cancer patients. Additional studies that evaluate the compounds effects on human breast call MX-1 tumors, described below also support this conclusion.
• the compounds of this invention are • therefore useful for the same cancers for which taxol has been shown active, including human ovarian tumors, mammary tumors, and malignant melanoma, lung tumors, gastric tumors, colon tumors, head and neck tumors, and leukemia.
• human ovarian tumors, mammary tumors, and malignant melanoma lung tumors, gastric tumors, colon tumors, head and neck tumors, and leukemia.
• the clinical pharmacology of taxol is reviewed by Eric K. Rowinsky and Ross C. Donehower, The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., Vol 52, pp 35-84, 1991.
• Clinical and preclinical studies with taxol are reviewed by William J. Slichenmyer and Daniel D. Von Hoff, Taxol: A New and Effective Anti-cancer Drug, Anti-Cancer Drugs, Vol. 2, pp 519-530, 1991. Cell
• the parental CHO line, 10001a is a subclone of the CHO line Pro "5 (Stanley et al., 1975).
• the line was maintained in alpha-MEM Earle's Salts supplemented with 2 mM glutamine, 100 units/ml penicillin, 100 ⁇ g ml streptomycin and 10% fetal bovine serum. All cell lines were maintained at 37°C in 5% C0 2 in a humidified incubator. Periodically, the cell lines were tested for mycoplasma and always found to be free of infection.
• DMSO dimethylsulfoxide
• MTT Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide as described by Mosmann, 1983.
• MTT dissolved in PBS at 2 mg ml was added to the plates already containing growth medium to give a final concentration of 0.2 mg/ml in each well. Plates were then incubated for 3 hours. The medium containing MTT ⁇ drug was then aspirated off and 100 ⁇ l/well isopropanol acidified with 0.04 N HCl was added. Plates were shaken for 5 minutes and absorbance was read at 570 nm on a Bio-tek EL 312e Bio-kinetics microplate reader.
• Percent growth for 10001a cells was determined by dividing the absorbance reading at each drug dilution by the reading in control wells. LD 5Q s for each compound were determined to be the concentration of drug at which a 50% inhibition in cell growth was obtained. Potentiating effects from the combination of compounds on 10001a cells was determined by graphing the combinations of drugs which gave LD 50 s in the form of an isobologram (Kallman, 1987 and Brunden, 1988).
• FIGURES 1-21 demonstrate the effectiveness of combinations of compounds with taxol on the killing of wild type cells.
• FIGURE 4 is included in the series to show how a compound with no potentiating effect behaves.
• the isobologram shows the effectiveness of a combination of 2 drugs for the killing of wild type, 10001a CHO, cells.
• the data line is the solid line with open circle or triangle data points.
• the data line shows the combination of doses which gives an LD 50 for the cells.
• the concentration of taxol is plotted against the concentration of drag.
• the diagonal dashed line shows the predicted concentrations of drugs if their combination only had an additive effect If any data points were above the dashed line the date would indicate the combination of compounds had antagonistic effects. Data points below the line indicate the compounds have potentiating or synergistic effects. Compare the isobologram in FIGURE 4, showing NO potentiating effect to the other isobolograms.
• the compounds have been tested in mice.
• Compound KT5720 has been tested on tumored mice and compounds KT5926 and KT5720 have been tested in non-tumored mice.
• FIGURE 22 shows the effect of KT5720 both separately and in combination with taxol in tumored mice.
• Human breast cell MX-1 tumors were implanted subcutaneously as 2 mm cubes in athymic mice. Mice were dosed every day for five days with drugs or vehicle control. The vehicle used was 2% dimethylacetamide, 10% emulphor, 88% saline. Animals received 12.5 mg/kg taxol (shown in figure as solid circle data points), 25 mg/kg KT5720 (shown in figure as open triangle data points), 12.5 mg/kg taxol + 25 mg/kg KT5720 (shown in figure as solid triangle data points), or vehicle alone (shown in figure as open square data points).
• Tumor burden was measured every two or three days starting with day 5 and volume was calculated.
• FIGURE 22 the size of the tumor in millimeters is plotted against time in days. Eight mice were used per dose group. Results are graphed with standard errors. The results show that there was no effect of KT5720 alone on inhibition of growth of the tumor cells. Taxol, at 12.5 mg/kg, has a modest effect on reducing the tumor burden in these mice. The combination of KT5720 plus taxol clearly show a potentiation of the taxol effect by the addition of KT5720. In summary, KT5720 has no effect by itself, but in combination with taxol, at the dosage tested, it causes a dramatic inhibition of tumor growth.
• FIGURE 23 shows the effects of compounds KT5926 and KT5720 on non-tumored mice.
• the compounds When the compounds are combined with taxol and then administered to non-tumored normal mice they show a dramatic amount of toxicity. There was no lethality at the doses shown when these drugs were given individually. This means that there are strong synergistic effects with the compounds in vivo.
• the combination of drugs will be effective in tumor bearing mice and as a cancer treatment for humans. See FIGURE 23 - IN VTVO EFFECTS. This figure provides a table of data showing the toxicity of several of the drags combined with taxol as compared to the individual administration of the drugs on non-tumored mice.
• synergistically effective amounts will vary depending on the particular types of individual to be treated taking into consideration various conditions including age, weight type of cancer treated, stage of disease, etc. Effective amounts can be readily determined by routine experimentation.
• n-hexanol Rg is -(CH 2 ) 5 CH 3
• Rg is -(CH 2 ) 5 CH 3
• An equal weight amount of solid KCN is added and the reaction mixture is stirred for an additional 18 to 144 hours at temperatures ranging from room temperature to 125 degrees.
• the reaction mixture is poured into ethyl acetate and the ethyl acetate solution is extracted with water.
• the organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to dryness under high vacuum at temperatures ranging from 35° to 70°C to near dryness.
• HPLC Altex Ultrasphere-ODS 0.5 micron, 4.6 mm X 25 cm, (35:65 wate ⁇ acetonitrile; 2 ml/minute).
• Example A-l (Rg is -O- (CH 2 ) 2 CH 3 , Rg is -(CH 2 ) 5 CH 3 ), from the starting material KT-5926.
• Example A-l is named:
• HPLC data was run as follows: HPLC: Altex Ultrasphere-ODS 0.5 micron, 4.6 mm X 25 cm, (35:65 wate ⁇ acetonitrile; 2 ml/minute) rt is 18.69 minutes for Example A-l; rt is 3.63 minutes for KT 5926.
• Example B-1 is named:
• KT252a 0.032 mmol
• n-heptanol Rg is -(CH 2 )gCH 3
• the reaction mixture is allowed to stir at room temperature until dissolution is complete.
• 15 mg of KCN is added and the reaction mixture is stirred for an additional 96 hours.
• the reaction mixture is poured into 20 ml of ethyl acetate and the ethyl acetate solution is extracted with water. The organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to dryness under high vacuum at 59°C to near dryness.
• 15 ml of hexane is added to the residue and the resulting solids are allowed to sit, under hexane, for 24 hours.
• Example B-1 The solids are filtered and washed well with hexane and dried at 40°C to give 7.8 mg of Example B-1.
• Mass Spec, theory predicts 552.2498 mass units; Measured: 552.2484.
• Example B-2 (Rg is -(CH 2 ) 7 CH 3 ), is named:
• Example B-2 Using procedure B only substituting n-octanol (Rg is -(CH 2 ) 7 CH 3 ) in the reaction described above, and stirring at room temperature for 120 hours, gives Example B-2, as an amber solid.
• Mass Spec, theory predicts 566.2655 mass units; Measured: 566.2652.
• Example B-3 Using procedure B only substituting n-nonanol (Rg is -(CH 2 ) g CH 3 ) in the reaction described above, and stirring at room temperature for 144 hours, gives Example B-3, as an amber solid.
• Mass Spec, theory predicts 580.2811 mass units; Measured: 580.2819
• Example B-4 Using procedure B only substituting 3-heptanol (Rg is -CH(CH 2 CH 3 )((CH 2 ) 3 CH 3 ) in the reaction described above, stirring at 110 degrees for 144 hours, gives Example B-4, as an amber solid.
• Example B-6 (Rg is -CHCH 3 (CH 2 ) 5 CH 3 ), is named:
• Example B-6 Using procedure B only substituting 2-octanol (Rg is -CHCH 3 (CH 2 ) 5 CH 3 ) in the reaction described above, stirring at 100 degrees for 96 hours, gives Example B-6, as an amber solid.
• Example B-7 Using procedure B only substituting 2-nonanol (Rg is -CHCH 3 (CH 2 ) 6 CH 3 ) in the reaction described above, stirring at 100 degrees for 96 hours, gives Example B-7, as an amber solid.
• Mass Spec, theory predicts 580.2811 mass units; Measured: 580.2797.
• Example B-8 (Rg is -(CH 2 ) 2 OCH 2 CH 3 ), is named:
• Example B-8 Substituting ethoxyethanol (Rg is -(CH 2 ) 2 OCH 2 CH 3 ) in the reaction described above, and stirring at room temperature for 96 hours, followed by 50 degrees for 24 hours, gives Example B-8, as an amber solid.
• Example B-9 (Rg is -CH(cyclo-CH 2 ) 5 ), is named: 9,12-Epoxy-lH-diindolo(l,2,3-fg:3' ⁇ ',r-kl)pyrrolo(3,4-i)(l,6)benzodiazocine-
• Example B-9 Substituting cyclohexanol (Rg is -CH(cyclo-CH 2 ) 5 ) in the reaction described above, stirring at 80 degrees for 18 hours, gives Example B-9, as an amber solid.
• Mass Spec, theory predicts 536.2185 mass units; Measured: 536.2169.

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