JP2003513079A - Heterocyclic cytotoxic agent - Google Patents

Abstract

(57) SUMMARY The present invention provides a compound of formula (I). Here, R ₁ -R ₈ and AG have any of the meanings defined herein. Moreover, the present invention provides a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising a compound of formula (I), the present invention also provides a process for preparing a compound of formula (I), and the present invention also provides a process for preparing a compound of formula (I) Provided are intermediates useful for preparing compounds of formula (I), and the present invention also provides therapeutic methods for treating cancer using compounds of formula (I).

Description

Detailed Description of the Invention

GOVERNMENT FUND The invention described herein is supported by the United States Government and is a National
Grant No. CA39662 awarded by al Cancer Institute
Was made under. The US Government has certain rights in this invention.

BACKGROUND OF THE INVENTION DNA-topoisomerases are enzymes present in the nucleus of cells where they catalyze the cleavage and recombination of DNA strands, which control the topological state of DNA. Recent studies also suggest that topoisomerases are also involved in the regulation of template supercoils during RNA transcription. There are two major classes of topoisomerases in mammals. DNA-topoisomerase-I catalyzes the change in the topological state of double-stranded DNA by undergoing a transient single-strand break-bond cycle. In contrast, mammalian topoisomerase II induces D by the occurrence of transient enzymatic cross-linking double-strand breaks, followed by strand passage and recombination.
Change the topology of NA. Mammalian topoisomerase II is further classified into type IIa and type IIb. The antitumor activity associated with the topoisomerase toxin factor is related to its ability to stabilize the enzyme-DNA cleavable complex. This drug-induced stabilization of the enzyme-DNA complex effectively converts the enzyme into a cytotoxin.

[0003] Several clinically used antineoplastic agents have potent activity as mammalian topoisomerase II poisons. These include the following: adriamycin, actinomycin D, daunomycin, VP-16, and VM-26 (teniposide or epipodophyllotoxin). In contrast to the number of clinical and experimental drugs that act as topoisomerase II poisons, there is currently only a limited number of drugs identified as topoisomerase I poisons. Camptothecin and its structurally related analogs are among the most thoroughly studied topoisomerase I venoms. In recent years, bibenzimidazole and terbenzimidazole (Chen e
t al. , Cancer Res. 1993, 53, 1332-1335; S
un et al. J. Med. Chem. 1995, 38, 3638-36
44; Kimet al. J. Med. Chem. 1996, 39, 992-
998), certain benzo [c] phenanthridine and protoberberine alkaloids and their synthetic analogs (Makhey et al., Med. Che.
m. Res. 1995, 5, 1-12; Janin et al. J. Med
． Chem 1975, 18, 708-713; Makhey et al. , B
ioorg. & Med. Chem. 1996, 4, 781-791), as well as the fungal metabolite, bulgarein (Fujii et al., J. Biol. Che.
m. 1993, 268, 13160-13165) and a signature pin (Ya
mashita et al. , Biochemistry 1991, 30,
58385845) and indolocarbazole (Yamashita et.
al. , Biochemistry 1992, 31, 12069-12075.
) Was identified as a topoisomerase I poison.

The exceptional topoisomerase poisoning observed with coralyne, nitidine, 5,6-dihydro-8-desmethylcoraline and related analogs has been the result of some recent studies in its structural features. Promoted. This feature is related to their ability to specifically act as Topoisomerase I or Topoisomerase II (Gatto et al., Cancer.
Res. 1996, 56, 2795-2800; Wang et al. , Ch
em. Res. Toxicol. 1996, 9, 75-83; Wangeta a.
l. Chem. Res. Toxicol. , 1993, 6, 813-818).
. A common feature associated with all three of these agents is that they have 3 in their structure.
The presence of a phenylisoquinolinium moiety.

[0005] Despite some of these compounds having similar potency as camptothecin as a topoisomerase I poison or VM-26 as a topoisomerase II poison, they were found to be mild cells. It had only toxic activity. Less directly linked to its ability as a topoisomerase poison is
In part due to the fact that these drugs do not appear to be as effectively absorbed as either camptothecin or VM-26. The presence of a quaternary ammonium group
It seems to impair cellular uptake. It may be necessary to subject the quaternary ammonium parent compound to hydrolysis followed by dehydration or cyclodehydration to allow phytotoxicity such as coralin and nitidine to be effectively transported.
This may explain the relatively poor antitumor activity observed in vivo with agents such as coralin or nitidine.

[0006] Currently, there is a need for additional agents that are useful for treating cancer.

SUMMARY OF THE INVENTION Applicants have discovered compounds that exhibit inhibitory activity against topoisomerase I and / or topoisomerase II, and compounds that are effective cytotoxic agents against cancer cells, including drug resistant cancer cells. . Therefore, the present invention provides the following formula (I):

[0008]

[Chemical 11] Provided is a compound, or a pharmaceutically acceptable salt thereof.

[0009]   Where A is N or CR₃And   B is N or CR_sAnd   D is NR_eOr CR_aR_bAnd   E is NR_fOr CR_cR_dAnd   F is N or CR_tAnd   G is N or CR₆And   R₁, R₂And R₃Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₁And R₂Are together
Is methylenedioxy, and R₃Is hydrogen, (C₁-C₆) Alkyl, (C₃ -C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_g R_h, COOR_k, OR_m, Or halo; or R₂And R₃Together
Is methylenedioxy, and R₁Is hydrogen, (C₁-C₆) Alkyl, (
C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, N
R_gR_h, COOR_k, OR_m, Or halo;   R₆, R₇And R₈Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₆And R₇Are together
Methylenedioxy, and R_gIs hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C_l-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₇And R₈Are together
Methylenedioxy, and R₆Is hydrogen, (C₁-C₆) Alkyl, (C₃−
C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR _h , C (= O) R_k, COOR_k, OR_m, Or halo;   Each bond represented by ----- is either individually present or absent;   R_aAnd R_bIs a bond between the 11-position and the 12-position represented by -----
If not, each independently hydrogen or (C₁-C₆) Alkyl; or
When a bond between the 11-position and the 12-position represented by ----- is present, R_aIs water
Elementary or (C_l-C₆) Alkyl, and R_bDoes not exist;   R_cAnd R_dIs a bond between the 11-position and the 12-position represented by -----
When not present, each independently hydrogen or (C₁-C₆) Alkyl; or-
When a bond between the 11-position and the 12-position represented by ----- is present, R_cIs hydrogen
Or (C₁-C₆) Alkyl, and R_dDoes not exist;   R_eIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_eIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   R_fIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_fIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   Each R_gAnd R_hAre independently hydrogen, (C₁-C₆) Alkyl, (C₃-C₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, (C₁-C₆) Alkanoyl, Ali
Aryl, aryl (C₁-C₆) Alkyl, aryloxy, or aryl (C₁
-C₆) Alkoxy; or R_gAnd R_hAnd the nitrogen they attach to
Together with pyrrolidino, piperidino, morpholino, or thiomorpholino
Yes;   Each R_kAre independently hydrogen, or (C_l-C₆) Alkyl; and   Each R_mIndependently, (C₁-C₆) Alkanoyl, aryl, or ant
(C₁-C₆) Is alkyl;   Each R_sAnd R_tAre independently hydrogen, methyl, nitro, hydroxy, amine
No or halo;   Where R₁, R₂, R₃, R₆, R₇, R₈, Or R_kAny of (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Alkoxy is required
Optionally substituted on the carbon with 1, 2 or 3 substituents, which substituents are:_mHydro
Kishi, halo, NR_nR_p, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Al
Selected from Koxy; where each R_nAnd R_pAre independently hydrogen, (C₁
-C₆) Alkyl, (C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy,
Or (C₁-C₆) Alkanoyl; or R_nAnd R_pIt joins
Together with nitrogen, pyrrolidino, piperidino, morpholino, or thiomorpho
Reno;   Where any aryl is optionally hydroxy, halo, nitro, tri
Fluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, and (C₁-C₆) Select from alkoxy
Substituted with 1, 2 or 3 substituents;   However, 2 or less of A to G contain nitrogen.

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.

The present invention also provides a method of inhibiting cancer cell growth. The method comprises the step of administering to a mammal suffering from cancer an amount of a compound of formula (I) effective to inhibit the growth of the cancer cells.

The present invention also provides a method of inhibiting cancer cell growth. The method is by contacting the cancer cells in vitro or in vivo with an amount of a compound of claim 1 effective to inhibit the growth of the cancer cells.

The present invention is also preferably for use in medical treatment, preferably cancer (eg
Formula I compounds for use in treating solid cancers) as well as the use of compounds of Formula I for the manufacture of a medicament useful for the treatment of cancers (eg solid cancers).

The present invention also provides the processes and novel intermediates disclosed in this invention that are useful in preparing the compounds of this invention. Some of the compounds of formula I are
Are useful in preparing other compounds of

K. W. Gopinath et al. , Indian J .; Chem. ，
1958,504-509 discloses the preparation of 2,3,8,9-tetramethoxy-5,6-diazachrysene and 2,3-8,9 bismethylenedioxy-5,6-diazachrysene. Therefore, the compounds of the present invention are preferably 2,3,8,9
Compounds of -tetramethoxy-5,6-diazachrysene and 2,3-8,9-bismethylenedioxy-5,6-diazachrysene may be excluded.

The compound of the invention is preferably A is CR ₃ ; B is CR _s ; E is C
When R is R _c R _d ; F is CR _t ; and G is CR ₆ , compounds of formula (I) in which D is NR _e may be excluded.

The compounds of the invention may also preferably exclude compounds in which R ₁ -R ₃ and R ₆ -R ₈ are each hydrogen.

The compounds of the invention may also preferably exclude 9-hydroxy-2,3,8-trimethoxydibenzo [c, h] cinoline.

Preferably, for compounds of formula I, one of R ₂ and R ₈ is hydrogen, methyl,
Is nitro, hydroxy, amino, fluoro or chloro; or at least one of R ₂ and R ₈ forms part of methylenedioxy.

[0020]   (Detailed explanation)   The following definitions are used unless otherwise indicated.

Halo is fluoro, chloro, bromo or iodo. Alkyl, alkoxy, alkenyl, alkynyl and the like refer to both branched and straight chain, but references to individual radicals (eg, “propyl”) refer to branched isomers (eg, “isopropyl”) Aryl only means a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about 9 to 10 ring atoms in which at least one ring is aromatic.

The specific values enumerated below for radicals, substituents, and ranges are for illustration only; they are defined elsewhere for radicals and substituents and for other values in the defined range. Is not excluded.

[0023] Specifically, (C ₁ -C ₆₎ alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, pentyl, a 3-pentyl, or hexyl, obtained; (C ₃ - C ₆₎ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and is obtained,; (C ₁ -C ₆₎ alkoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, pentoxy, 3 - pentoxy or hexyloxy obtained,; (C ₁ -C ₆₎ alkanoyl, acetyl, propanoyl, butanoyl, and is obtained pentanoyl or hexanoyl; aryl is phenyl, may be indenyl or naphthyl.

Specifically, R ₂ or R ₇ is hydroxy, methoxy, benzyloxy, amino, hydroxymethyl, aminomethyl, aminocarbonyl, methoxycarbonyl, trifluoromethyl, 3-aminopropoxycarbonyl, or 2-hydroxy. It can be ethyl.

Specifically, R ₃ can be hydrogen.

Specifically, R _s and R _t are each hydrogen.

A specific group of compounds is the compound of formula I: embedded image or a pharmaceutically acceptable salt thereof.

[0028]

[Chemical 12]   Where A is N or CR₃And   B is N or CR_sAnd   D is NR_eOr CR_aR_bAnd   E is NR_fOr CR_cR_dAnd   F is N or CR_tAnd   G is N or CR₆And   R₁, R₂And R₃Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₁And R₂Are together
Is methylenedioxy, and R₃Is hydrogen, (C₁-C₆) Alkyl, (C₃ -C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_g R_h, COOR_k, OR_m, Or halo; or R₂And R₃Together
Is methylenedioxy, and R₁Is hydrogen, (C₁-C₆) Alkyl, (
C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, N
R_gR_h, COOR_k, OR_m, Or halo;   R₆, R₇And R₈Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₆And R₇Are together
Methylenedioxy, and R_gIs hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C_l-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₇And R₈Are together
Methylenedioxy, and R₆Is hydrogen, (C₁-C₆) Alkyl, (C₃−
C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR _h , C (= O) R_k, COOR_k, OR_m, Or halo;   Each bond represented by ----- is either individually present or absent;   R_aAnd R_bIs a bond between the 11-position and the 12-position represented by -----
If not, each independently hydrogen or (C₁-C₆) Alkyl; or
When a bond between the 11-position and the 12-position represented by ----- is present, R_aIs water
Elementary or (C_l-C₆) Alkyl, and R_bDoes not exist;   R_cAnd R_dIs a bond between the 11-position and the 12-position represented by -----
When not present, each independently hydrogen or (C₁-C₆) Alkyl; or-
When a bond between the 11-position and the 12-position represented by ----- is present, R_cIs hydrogen
Or (C₁-C₆) Alkyl, and R_dDoes not exist;   R_eIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_eIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   R_fIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_fIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   Each R_gAnd R_hAre independently hydrogen, (C₁-C₆) Alkyl, (C₃-C₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, (C₁-C₆) Alkanoyl, Ali
Aryl, aryl (C₁-C₆) Alkyl, aryloxy, or aryl (C₁
-C₆) Alkoxy; or R_gAnd R_hAnd the nitrogen they attach to
Together with pyrrolidino, piperidino, morpholino, or thiomorpholino
Yes;   Each R_kAre independently hydrogen, or (C_l-C₆) Alkyl; and   Each R_mIndependently, (C₁-C₆) Alkanoyl, aryl, or ant
(C₁-C₆) Is alkyl;   Each R_sAnd R_tAre independently hydrogen, methyl, nitro, hydroxy, amine
No or halo;   Where R₁, R₂, R₃, R₆, R₇, R₈, Or R_kAny of (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Alkoxy is required
Optionally substituted on the carbon with 1, 2 or 3 substituents, which substituents are:_mHydro
Kishi, halo, NR_nR_p, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Al
Selected from Koxy; where each R_nAnd R_pAre independently hydrogen, (C₁
-C₆) Alkyl, (C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy,
Or (C₁-C₆) Alkanoyl; or R_nAnd R_pIt joins
Together with nitrogen, pyrrolidino, piperidino, morpholino, or thiomorpho
Reno;   Where any aryl is optionally hydroxy, halo, nitro, tri
Fluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, and (C₁-C₆) Select from alkoxy
Substituted with 1, 2 or 3 substituents;   Provided that 2 or less of A to G include nitrogen; and   However, R₂And R₈At least one of hydrogen, methyl, nitro, hydroxy
, Amino, fluoro or chloro; or R₂And R₈At least one of
One forms the part of methylenedioxy. Preferably, this particular group of compounds
Wherein the compound of formula I is 2,3-8,9 bismethylenedioxy-5,6-
Diazachrysene; not R₁-R₃And R₆-R₈Are not each hydrogen.

A particular group of compounds is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R ₁ , R ₂ and R ₃ are each individually hydrogen, or (C ₁ -C ₆₎ alkoxy; or R ₁ and R ₂ together, methylenedioxy (-
OCH a ₂ O-), and R ₃ is hydrogen or (C ₁ -C ₆₎ alkoxy.

[0030]   Another specific group of compounds are the compounds of formula I or pharmaceutically acceptable salts thereof
Yes, here, R₇Or R₈Is (C₁-C₆) Alkoxy; or R ₇ And R_gTogether are methylenedioxy.

Another particular group of compounds are compounds of formula I or a pharmaceutically acceptable salt thereof, wherein R ₇ and R ₈ together are methylenedioxy.

Another particular group of compounds is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the bond represented by ----- is both present.

Another particular group of compounds is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound between the 5- and 6-positions represented by There is no bond.

Another particular group of compounds are the compounds of formula I or pharmaceutically acceptable salts thereof, wherein the bond between the 11 and 12 positions represented by do not do.

Another particular group of compounds is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein both bonds represented by ------ are absent.

Certain compounds of formula I are represented by formulas II, III, IV, V, VI, VII, VIII
, IX or X (FIG. 6). _{Wherein, R 1 -R 8, R a} -R t have the values described herein for compounds of formula I, one of the specific values or preferred values. Compounds of formula II-X may be prepared from available starting materials using procedures known in the art or using procedures similar to those described herein.

Compounds of formula I have the formula XX, wherein R ₁ -R ₈ and AG are as described herein for the corresponding substituents in the compounds of formula I, specific values or preferred values. Have any of the values)

[0038]

[Chemical 13] Can be prepared by subjecting the intermediate of 1) to conditions suitable for the formation of the tetracyclic ring system.
Suitable conditions for forming a tetracyclic ring system are well known in the art. See, for example, Example 1 herein below.

Intermediates of formula XX can be prepared from readily available starting materials using procedures known in the art, or using the procedures described herein illustrated in the figures. Can be prepared.

As illustrated in FIG. 1 and shown in Example 1, reduction of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene provides alcohol 1, which Can be dehydrated to provide dihydronaphthalene 2. Two
Coupling with iodo-nitrobenzene can provide 3, which can be oxidized to provide 4. Reduction of the nitro group provides amine 5, which is a compound of formula XX.

As illustrated in FIGS. 2, 3 and 4 and shown in Example 2, nitration of 4-bromoveratrol under standard conditions provided the nitro compound 7, which It can be converted to tin 8 under normal conditions. The coupling of tin 8 with triflate 9 provides 11 which can be oxidized to provide 12. Alternatively, tin 8 can be combined with triflate 10 to provide 12. Reduction of the nitro group at 12 under standard conditions provides the intermediate of formula XX. As illustrated in FIG. 4, the triflate 9 is 6,7 dimethoxy-2-oxo-1,2,3.
It can be prepared from 4,4-tetrahydronaphthalene by formation of the enol triflate under standard conditions. Triflate 10 can be prepared from 9 by standard oxidation.

Intermediate 16 as illustrated in FIGS. 4 and 5 and as shown in Example 3 is the nitration of readily available 3,4-dimethoxybromobenzene under standard conditions, followed by nitration. It can be prepared by forming the corresponding tin 16. Coupling of triflate 10 and tin 16 under standard conditions can provide the nitro compound 17, which can be reduced to provide the intermediate of formula XX.

Other intermediates of formula XX are prepared using procedures similar to those described herein by selecting the appropriate starting materials to provide the desired intermediate of formula XX. Can be done.

Administration of the compound as a salt may be suitable when the compound is sufficiently basic or acidic to form a stable, non-toxic acid salt or base salt. Examples of pharmaceutically acceptable salts include organic acid salt addition salts that form physiologically acceptable anions (eg,
Tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate). . Suitable inorganic salts may also be formed, including hydrochlorides, lead sulfates, nitrates, bicarbonates, and carbonates.

Pharmaceutically acceptable salts are prepared by reacting procedures well known in the art (eg, a sufficiently basic compound such as an amine with a suitable acid that provides a physiologically important anion). ) And using standard procedures. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) carboxylates can also be prepared.

The compound of formula I can be formulated as a pharmaceutical composition, and administered to a mammalian host (eg, a human patient) in a selected dosage form (ie oral or parenteral, intravenous,
It may be administered in various forms adapted to the intramuscular, topical or subcutaneous route.

Accordingly, the compounds of this invention may be systemically administered (eg, orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or taken directly with the food product of the patient's diet. For the purpose of oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Can be used in. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of compositions and preparations may, of course, vary, and may conveniently be from about 2% to about 60% by weight in a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

Tablets, troches, pills, capsules and the like may also include: Binders such as tragacanth gum, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants. (For example, corn starch, potato starch, alginic acid, etc.); Lubricants (for example, magnesium stearate)
And sweeteners such as sucrose, fructose, lactose or aspartame, or flavors such as peppermint, wintergreen oil or cherry flavors can be added. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials can be present as coatings or otherwise to modify the physical form of a solid unit dosage form. For instance, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course,
Any material used in preparing any unit dosage form should be pharmaceutically acceptable and, in the amounts used, should be nontoxic in a sustained manner. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersants can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Suitable pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions or dispersions or extemporaneous sterile injectable or injectable solutions, optionally encapsulated in liposomes. Mention may be made of sterile powders containing the active ingredient, which are adapted for the preparation. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium. This includes, for example, water, ethanol, polyols (eg glycerol, propylene glycol, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, maintenance of the required particle size in the case of dispersion, or the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents such as, for example, paraben, chlorobutanol, phenol, sorbic acid and thimerosal. In many cases, it will be preferable to include isotonic agents, for example sugars, buffers or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use of agents in the composition that delay absorption such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. It In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are the techniques of vacuum drying and freeze-drying, which contain the active ingredient and any further desired active ingredients presently present in the solution which have been filter-sterilized. To produce a powder of the ingredients of.

For topical administration, the compounds of this invention may be applied in pure form (ie,
They are liquids). However, it is generally desirable to administer it to the skin as a composition or formulation in combination with a dermatologically acceptable carrier. It can be solid or liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends. Here, the compounds according to the invention can be dissolved or dispersed in effective levels, optionally with the aid of non-toxic surfactants. Adjuvant (eg fragrance)
And additional antimicrobial agents may be added to optimize the properties for a given use. The resulting liquid composition can be applied from a suction pad, used to soak in a bandage, or sprayed onto the affected area using a pump-type or aerosol spray.

Thickeners (eg synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose or modified mineral materials) also with liquid carriers for coatable pastes, gels, ointments, soaps and the like. , Can be used for direct application to the user's skin.

Examples of useful dermatological compositions that can be used to deliver compounds of formula I to the skin are known in the art; see, eg: Jacquet.
et al. (US Pat. No. 4,608,392), Geria (US Pat. No. 4
, 992, 478), Smith et al. (U.S. Pat. No. 4,559,1
57) and Wortzman (US Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods for extrapolating effective amounts of humans in mice and other animals are known in the art; see, eg, US Pat. No. 4,938,949.

Generally, the concentration of the compound of Formula I in the liquid composition (eg, lotion) is 0.
It is 1 to 25% by weight, preferably 0.5 to 10% by weight. The concentration in a semi-solid or solid composition (eg gel or powder) is 0.1-5% by weight,
It is preferably 0.5 to 2.5% by weight.

The amount of compound, or active salt or derivative thereof, needed for use in therapy depends on the particular salt selected, as well as the route of administration, the nature of the condition being treated and the age and condition of the patient. It will vary and will ultimately be at the discretion of the attending physician or clinician.

Generally, however, suitable doses will be in the range of about 0.5 to about 100 mg / kg body weight per day, for example about 10 to about 75 mg / kg body weight (eg 1 kg of recipient per day. About 3 to about 50 mg, preferably 6 to 90 mg / body weight
kg / day, most preferably 15-60 mg / kg / day).

The compounds may conveniently be administered in unit dosage form; for example 5-1000 mg per unit dosage form, simply 10-750 mg, most conveniently 50-.
Contains 500 mg of active ingredient.

Ideally, the active ingredient is about 0.5-75 μM, preferably about 1-50 μM,
Most preferably it should be administered to achieve peak plasma concentrations of active compound of from about 2 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.05-5% solution of the active ingredient in saline if necessary, or about 1-
It can be administered orally as a bolus containing 100 mg of active ingredient. The desired blood level is a continuous infusion or about 0 to provide 0.01-5.0 mg / kg / hour.
． It may be maintained by intermittent infusion containing 4-15 mg / kg of active ingredient.

The desired dose may conveniently be presented in single dose or in divided doses administered at appropriate intervals (eg 2, 3, 4 or more divided doses per day). obtain. The divided dose itself may be subdivided into a number of discrete relief spaced doses; for example, by inhalation with an inhaler or by application of drops in the eye.

The ability of the compounds of the invention to effect Topoisomerase I or Topoisomerase II mediated DNA cleavage is determined using pharmacological models well known in the art (eg, a model such as Test A described below). Can be determined.

[0064]   (Test A: Topoisomerase I-mediated DNA cleavage assay)   Human topoisomerase I was transformed into E. coli using the T7 expression system as previously described.
E. coli and isolated as a recombinant fusion protein (Ma
Khey, D.K. et al. , Bioorg. Med. Chem. , 2000,
8, 1-11). Previously reported DNA topoisomerase I from calf thymus
Purified as described (Maniatis, T., et al., J. Mo.
regular Cloning, a Laboratory Manual,
Cold Spring Harbor Laboratory, Cold S
pring Harbor, New York, 149-185). Plasmid
  YepG was also prepared as described by the alkaline dissolution method, followed by phenol removal.
And purified by protein and CsCl / ethidium isopycnic centrifugation (Man.
iatis, T .; Fritsch, E .; F. Sambrook, J .; Mol
Equal Cloning, a Laboratory Manual; C
old Spring Harb or Laboratory: Cold Spr
ing Harbor, NY 1982; pp 149-185).¹⁰². That plastic
End-labeling of the Smid was carried out by digestion with restriction enzymes followed by Kl as previously described.
Achieved by end-weighting with enow polymerase (Liu, LF; Row
e, T. C. Yang, L .; Teway, K .; M. Chen, G .; L. ”
Clearage of DNA by mammalian topoiso
merase II, "J. Biol. Chem. 1983, 258, 1536.
5)¹⁰³. The cleavage assay was performed as previously reported (B. Gatto
et al. Cancer Res. , 1996, 56, 2795-2800). ¹³ . Ink the drug and DNA in the presence of topoisomerase I for 30 minutes at 37 ° C.
I cubted. DNA fragmentation using gel exposure, typically 24 hours after development
We obtained an autoradiogram outlining the extent of. Topoisomerase I-mediated DNA
The value of cleavage is REC (relative effective concentration) (ie 2,3-dimethoxy-8,9
Methylenedioxybenzo [i] phenanthridine)
. This value is arbitrarily assumed to be 1.0. This is the presence of human topoisomerase I
The same can be generated below in the plasmid. Relative intensity is about 10% D
It was based on the relative amount of drug required to induce NA fragmentation. Assay is Dr
． L. F. Liu, Department of Pharmacology,
The University of Medicine and Denist
ry of New Jersey, Robert Wood Johnson
  Medical School, Piscataway, New Jersey
I went under the command of y. Data from Test A for representative compounds of the invention
It shows in Table 1.

[0065]

[Table 1] The cytotoxic effect of the compounds of the invention can be determined using pharmacological models well known in the art (eg, using a model such as Test B described below).

(Test B. Inhibition of cell proliferation: MTT microtiter plate tetrazolinium cytotoxicity assay (RPMI 8402, CPT-K5, U937, U93).
7 / CR cells) Cytotoxicity was determined using the MTT microtiter plate tetrazolinium cytotoxicity assay (MTA) (see below: Chen AY.
et al. Cancer Res. 1993, 53, 133 ₂ ; Mosman
n, T. J. J. Immunol. Methods 1983, 65, 55;
and Carmichael, J. et al. et al. Cancer Res. 19
87, 47, 936). Human lymphoblastoid RPMI 8402 and its camptothecin resistant variant cell line CPT-K5 were transformed into Dr. Toshiwo Andoh (
Anchi Cancer Research Institute, Nago
ya, Japan) (see below: See Andoh, T .;
Okada, K .; "Drugresistance mechanisms o
f topoisomerase I drugs, "Adv. in Phar
macology 1994, 29B, 93). Human U-937 myeloid leukemia cells and U-937 / CR cells are described in Rubin et al. J. Biol. C
hem. 269, 2433-2439 (1994). The cytotoxicity assay was performed using 2000 cells / well in 200 mL of growth medium.
This was done using a 6-well microtiter plate. Cells at 5% C at 37 ° C
Grow in O ₂ and 10% heat-inactivated fetal bovine serum, L-glutamine (2 m
M), penicillin (100 U / mL) and streptomycin (0.1 mg /
mL) in RPMI medium supplemented with regular passages. For IC50 determination, cells were exposed to various concentrations of drug for 3-4 consecutive days, and MTT assay was performed at the end of day 4. Each assay was performed with a control that contained no drug. All assays were performed at least twice in 6 replicate wells. All assays were performed with Dr. L. F. Liu,
Department of Pharmacology, The Uni
rsity of Medicine and Dentistry of N
ew Jersey, Robert Wood Johnson Medica
1 School, Piscataway, New Jersey.

[0067]   Representative data are shown in Tables 2 and 3.

[0068]

[Table 2]

[0069]

[Table 3] * See Figure 11. ⁺ VBS = vinblastine The data in Tables 2 and 3 demonstrate that representative compounds of the present invention function as cytotoxic agents against tumor cell lines, including multidrug resistant tumor cell lines. Therefore, the compounds are useful in treating cancer and can be used to treat tumors that are resistant to other specific chemotherapeutic agents.

Topoisomerase inhibitors also include antibacterial agents, antifungal agents, antigenic animal agents,
It is known to have insecticide and antiviral activity. Thus, the topoisomerase inhibitors of the present invention may also be useful as antibacterial, antifungal, antiprotozoal, insecticide, or antiviral agents. In particular, the compounds of the present invention exhibiting little or no activity as mammalian topoisomerase I, due to the potential for similar molecular mechanisms of action, are highly active and selective antibacterial, antifungal, antiprotozoal agents. It can be an agent, an insecticide, or an antiviral agent. Thus, certain compounds of the present invention may be particularly useful in mammals as systemic, antibacterial, antifungal, antiprotozoal, pesticide, or antiviral agents. The invention also relates to the use of the compounds of the invention for the manufacture of a medicament useful for producing antibacterial, antifungal, antiprotozoal, insecticidal or antiviral agents in mammals. provide.

As used herein, the term “solid mammal tumor” includes the head and neck,
Lungs, mesothelioma, longitudinal wall, esophagus, stomach, pancreas, hepatobiliary system, small intestine, colon, rectum, anus, kidney, uterus, bladder, prostate, urethra, penis, testis, gynecological organ, ovary, breast, endothelium Includes cancers of the system, skin, central nervous system; sarcomas of soft tissue and bone; and melanomas of cutaneous and intraocular origin. The term “hematological malignancies” includes childhood leukemias and lymphomas, Hodgkin's disease, lymphomas of lymphoid and cutaneous origin, acute and chronic leukemias, plasma cell neoplasms, and AIDS-related cancers. The preferred mammalian species for treatment are humans and farm animals.

The present invention is now illustrated by the following non-limiting examples. Here, unless otherwise stated, the melting point is Thomas-Hoover Unimelt.
Determined by capillary melting point meter; column chromatography was performed using SiliTech 32-63m (ICN Biomedical) using the solvent system shown.
s, Eschwege, Ger. ) Is a flash chromatography carried out in (1); radiochromatography means Model 8924 chromat.
otron (Harrison Research, CA); infrared spectral data (IR) is Perkin-Elmer 1600 Fou.
obtained on a Rier conversion colorimeter and reported in cm ^-1 ; proton ( ¹ H N
MR) and carbon ( ^{l 3} C NMR) nuclear magnetic resonance were measured by Varian Gemini.
Recorded on a -200 Fourier transform spectrophotometer; NMR spectrum (
200 MHz ¹ H and 50 MHz ¹³ C) were reported in deuterium solvent as indicated by the chemical shifts reported in the unit downfield from tetramethylsilane (TMS); coupling constants of the protonated form of terbenzimidazole were reported. Reported in Hertz (Hz) with a few drops of CF ₃ COOH by increasing solubility and formation, thereby eliminating tautomeric differences between carbon atoms;
Department of Chemistry at Washingto
n University, St. Louiston, Washington in Mo
University Resource for Biomedical
and Bio-organic Mass Spectrometry; combustion analysis was performed by Atlantic Microlabs, Inc. , Norcr
oss, GA and within 0.4% of theory; compounds 7 and 15 were previously described for 4-bromoveratrol and 4-bromo-1,2- (methylenedioxy) benzene. Prepared by nitration (P
ettit, G.M. R. Piatak, D .; M. J. Org. Chem. , 25
, 1960, 721; Dallacker, F .; Wagner, A .; Z. Na
Tursch. , 1984, 39b, 936).

Example 1 2,3-Dimethoxy-dibenzo [c, h] cinoline (cinno)
line) (6)) 6- (2-aminophenyl) -2,3-dimethoxynaphthalene (5, 70 mg
, 0.25 mmol) in 48% hydrobromic acid (4.25 ml), cooled in an ice-salt bath and stirred with sodium nitrite (0.13 g) in water (2.2 ml). It was treated by dropwise addition. Stirring is continued for 0.5 hours,
Then to the cold solution was added freshly precipitated copper (0.5 g) with stirring. The mixture was slowly warmed to room temperature and left overnight. The solid was filtered off and washed with hot chloroform. The chloroform solution was washed with dilute sodium hydroxide solution, then water, dried (anhydrous Na ₂ SO ₄ ) and rotor evaporated to give the crude product. Chromatography on silica gel with 50:50 hexane: ethyl acetate gave the title compound (13 m
g) was obtained in a yield of 18%; ¹ H NMR (CDCl ₃ ) d 4.11 (3H, s).
), 4.24 (3H, s), 7.37 (1H, s), 7.89-7.94 (2H)
, M), 8.14 (1H, d, J = 8.9), 8.41 (1H, d, J = 8.8).
), 8.61-8.66 (1H, m), 8.75-8.80 (1H, m), 9.
24 (IH, s); ¹³ C NMR d 56.1, 56.4, 104.0, 10
7.3, 112.3, 116.5, 118.5, 121.7, 126.7, 12
8.6, 128.8, 131.1, 131.2, 131.9, 141.5, 14
6.3, 150.9, 151.0.

Intermediate 6- (2-Aminophenyl) -2,3-dimethoxynaphthalene (5) Prepared as follows:

A. 6- (2-nitrophenyl) -2,3-dimethoxy-7,8-dihydronaphthalene _{(3) Pd (PPh 3)} 2 CI 2 (840mg, 1.2mmol) and sodium acetate (200 mg, 2.4 mmol) , 6,7-Dimethoxy-3,4-dihydronaphthalene (2,700 mg, 3.7 m in dimethylacetamide (50 ml).
mol) and 1-iodo-2-nitrobenzene (925 mg, 3.7 mmol)
) Solution was added. The mixture was stirred at 140 ° C. under nitrogen overnight and then concentrated under reduced pressure. Ethyl acetate (60 mL) was added to this residue and washed with distilled water (50 mL). The organic layer was separated and passed through a Celite bed. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was chromatographed to give compound 3 (330 mg) in 29% yield; ¹ H NMR (CDCl ₃ ) d 2.51 (2H, t, J = 8.1), 2.92.
(2H, t, J = 8.1), 3.87 (3H, s), 3.90 (3H, s), 6
． 45 (1H, s), 6.67 (1H, s), 6.73 (1H, s), 7.38
-7.45 (2H, m), 7.54-7.62 (1H, m), 7.88-7.9
3 (1H, m); ¹³ C NMR d 28.5, 28.5, 56.6, 111.
0, 111.7, 124.9, 127.0, 127.1, 128.1, 128.
3, 131.3, 133.3, 135.7, 138.7, 147.9, 148.
9.

[0076]   b. 6- (2-Nitrophenyl) -2,3-dimethoxynaphthalene (4).

6- (2-Nitrophenyl) -2,3-dimethoxy-7,8-dihydronaphthalene (100 mg, 0.32 mmol) was added in toluene to DDQ (109 mg,
Reflux in 0.48 mmol) overnight. Cool to room temperature and filter through a Celite bed. The filtrate was rotovaped and dried to give the crude product. 80:
Chromatography on silica gel with 20 hexane: ethyl acetate gave compound 4 (90 mg) in 91% yield; ¹ H NMR (CDCl ₃ ) d
4.00 (3H, s), 4.01 (3H, s), 7.12 (1H, s), 7.
14 (1H, s), 7.27 (1H, dd, J = 8.4, J = 1.7), 7.4
6-7.62 (3H, m), 7.66 (1H, s), 7.72 (1H, d, J =
8.4), 7.86 (1H, d, J = 8.1); ¹³ C NMR d 56.4,
106.6, 107.1, 124.5, 124.6, 125.9, 127.3,
128.4, 129.3, 129.6, 132.7, 132.7, 133.6,
137.0, 149.9, 150.5, 150.6.

C. 6- (2-Aminophenyl) -2,3-dimethoxynaphthalene (5) 6- (2-Nitrophenyl) -2,3-dimethoxynaphthalene (70 mg, 0
． 23 mmol) in ethyl acetate (45 ml) with a palladium catalyst (activated carbon 20 m
40% by weight of 40-45 lb. / Sq. in. Hydrogenated overnight. The solution was passed through a Celite bed and the catalyst washed with ethyl acetate (3x
10 ml). Compound 5 (60 mg) was obtained in 99% yield by concentration under reduced pressure; ¹ H
_{NMR (CDCl 3) d 4.02 (} 3H, s), 4.04 (3H, s), 6.
82 (1H, d, J = 8.0), 6.85-6.93 (IH, m), 7.16 (
1H, s), 7.18 (1H, s), 7.20-7.26 (2H, m), 7.4.
7 (1H, dd, J = 8.3, J = 1.6), 7.78 (1H, d, J = 8.8)
), 7.80 (1H, s); ¹³ C NMR d 56.4, 106.6, 106.
． 9, 116.1, 119.2, 126.1, 126.8, 127.3, 128
． 3, 128.7, 128.9, 129.9, 131.2, 135.8, 144
． 3, 150.2, 150.3.

Compound 2 was prepared from readily available starting materials using standard procedures as illustrated in FIG.

Example 2: 2,3-Dimethoxy-8,9-methylenedioxy-dibenzo [c
, H] Cinoline (14)) 6- (2-amino-4,5- in acetic acid (2 mL) and concentrated hydrochloric acid (0.3 mL).
Methylenedioxyphenyl) -2,3-dimethoxy-naphthalene (13,40m
g, 0.13 mmol) was cooled to 0 ° C. and a solution of sodium nitrite (1.
Diazotized with 0.09 g) in 5 mL. The diazonium solution was slowly warmed to room temperature and left overnight. Water (50 mL) was added to this red solution with some settling. The resulting mixture was extracted with ethyl acetate, washed with dilute sodium hydroxide, then with water, dried (anhydrous Na ₂ SO ₄ ) and rotor evaporated to give the crude product. Chromatography on silica gel with 40:60 hexane: ethyl acetate gave 50% of the title compound (20 mg).
Obtained in yield; ¹ H NMR (CDCl ₃ ) d 4.09 (3H, s), 4.2 ₂ (
3H, s), 6.24 (2H, s), 7.31 (1H, s), 7.80 (1H,
s), 7.95 (1H, s), 8.00 (1H, d, J = 9.2), 8.13 (
1H, d, J = 8.9), 9.14 (1H, s); ¹³ C NMR d 56.5.
, 56.9, 98.1, 102.9, 104.6, 107.5, 107.9, 1
17.1, 119.6, 120.6, 126.8, 128.5, 131.7, 1
41.9, 145.6, 150.2, 151.2, 152.1.

The intermediate 6- (2-amino-4,5-methylenedioxyphenyl) -2,3 dimethoxynaphthalene (13) was prepared as follows.

A. 6,7-dimethoxy-3,4-dihydro-2-naphthalene triflate (
9) 6,7-Dimethoxy-2-tetralone (250 mg, 1 in THF (5 mL)
． 2 mmol) was cooled in an ice bath and stirred for 0.5 h in THF (5 mL).
Of sodium hydride (60% by weight, 75 mg, 1.9 mmol) was added to the suspension. Then a solution of N-phenyltrifluoromethanesulfonimide (500 mg, 1.4 mmol) in THF (5 mL) was added and the reaction was stirred at 0 ° C. for 9 min.
Stir for hours. After concentration under reduced pressure, the residue was chromatographed with 80:20 hexane: ethyl acetate to give compound 9 (300 mg) in 73% yield; ¹ H
NMR (CDCl ₃ ) d 2.66 (2H, t, J = 8.5), 3.00 (2
H, t, J = 8.4), 3.86 (3H, s), 3.88 (3H, s), 6.4
0 (1H, s), 6.62 (IH, s), 6.68 (1H, s); ¹³ C NMR
d 27.1, 28.9, 56.5, 111.3, 111.7, 115.9,
118.7, 122.3, 124.0, 126.0, 148.2, 148.9,
149.3.

[0083]   b. 6,7-Dimethoxy-2-naphthalene triflate (10).

6,7-Dimethoxy-3,4-dihydro-2-naphthalene triflate (200
mg, 0.59 mmol) was refluxed in toluene (30 mL) with DDQ (166 mg, 0.73 mmol) overnight, cooled to room temperature and filtered through celite bed. The filtrate was concentrated under reduced pressure to obtain a crude product. Chromatography on silica gel with 80:20 hexane: ethyl acetate gave compound 10 (1
90 mg) was obtained with a yield of 95%; ¹ H NMR (CDCl ₃ ) d 4.00 (
6H, s), 7.10 (1H, s), 7.12 (1H, s), 7.21 (1H,
dd, J = 8.9, J = 2.5), 7.58 (1H, d, J = 2.5), 7.7
1 (1H, d, J = 8.9) ¹³ C NMR d 56.4, 106.6, 106
． 6, 109.7, 116.1, 117.9, 118.2, 122.5, 128
． 9, 129.0, 129.8, 146.6, 150.9, 151.3.

C. 6- (4,5-methylenedioxy-2-nitrophenyl) -2,3-dimethoxynaphthalene (12) tetrakis (triphenylphosphine) palladium (0) (40 mg) and copper bromide (8 mg) were mixed with THF ( 6,7-Dimethoxy-2-naphthalene triflate (160 mg, 0.48 mmol) and trimethyl (3,4) in 20 mL).
-Methylenedioxy-6-nitrophenyl) tin (8,187 mg, 0.57 m
mol) solution. The mixture was stirred at room temperature for 0.5 hours and then refluxed under nitrogen for 18 hours. After cooling, THF was rotovaped and ethyl acetate (50 ml) was added to the residue. The solution was washed with water (30 mL). The organic layer was separated and passed through a Celite bed to remove suspended particles.
The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel with 70:30 hexane: ethyl acetate to give a mixture of two compounds having the same Rf value. This mixture may be separated after the hydrogenation step.

D. 6- (2-amino-4,5-methylenedioxyphenyl) -2,3-dimethoxynaphthalene (13).

6- (4,5-Methylenedioxy-2-nitrophenyl) -2,3 dimethoxynaphthalene (25 mg, 0.071 mmol) in ethyl acetate in a palladium catalyst (10 wt% on activated carbon, 20 mg). 40-45 lb. in (40 mL). / S
q. in. Hydrogenated overnight. The solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (3 x 10 ml). The crude product was obtained by concentration under reduced pressure. 60: 4
Chromatography with 0 hexane: ethyl acetate gave compound 14 (1
5 mg) was obtained in a yield of 66%; ¹ H NMR (CDCl ₃ ) d 4.01 (3
_{H, s), 4.0 2 (} 3H, s), 5.91 (2H, s), 6.40 (1H, s
), 6.73 (1H, s), 7.13 (1H, s), 7.15 (1H, s), 7
． 39 (1H, dd, J = 8.2, J = 1.8), 7.72 (1H, s), 7.
74 (1H, d, J = 8.5); ¹³ C NMR d 56.4, 98.3, 10.
1.2, 106.6, 106.8, 110.7, 120.5, 126.3, 12
7.0, 127.3, 128.5, 129.9, 135.7, 138.9, 14
1.1, 148.0, 150.1, 150.3.

The intermediate trimethyl (3,4-methylenedioxy-6-nitrophenyl) -tin (8) in subpart c above was prepared as follows.

E. Trimethyl (3,4-methylenedioxy-6-nitrophenyl) tin (8
).

A mixture of hexamethylditin (3 g, 9.2 mm) in anhydrous THF (30 mL).
ol), 4-bromoveratrol 7 (Pettit, GR; Piatak,
D. M. J. Org. Chem. , 25, 1960, 1.6 g, 6.1 mmol
) And Pd (PPh ₃ ) 4 (200 mg) were heated to reflux under nitrogen for 10 hours. After cooling to room temperature, THF was evaporated and methylene chloride (30 mL) was added to the residue. To this mixture was added aqueous potassium fluoride (7.0M,
2 mL) was added dropwise with vigorous stirring. The mixture was passed through a Celite bed and the filtrate washed with brine. The methylene chloride layer was dried (anhydrous Na ₂ SO ₄ ), filtered, and evaporated under reduced pressure. The residue was chromatographed through 100 g of silica gel with 1: 6 ethyl acetate: hexane to give 8 in 65% yield; ¹ H NMR (CDCl ₃ ) d 0.32 (9
H, s), 6.12 (2H, s), 7.04 (1H, s), 7.82 (1H, s)
); ¹³ C NMR (CDC1 ₃ ) d −6.8, 103.3, 105.8, 1
14.5,137.2,147.9,149.4,153.4; HRMS theory _{(C 10 H 13 NO 4 Sn} -CH 3): 315.9632; Found: 315.963
8.

Example 3: 2,3,8,9-Tetramethoxy-dibenzo [c, h] cinoline (19) 6- (2 in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). -Amino-4
, 5-Dimethoxyphenyl) -2,3-dimethoxynaphthalene (18) (11 m
g, 0.033 mmol) was cooled to 0 ° C. and diazotized with 0.026 g) in 0.5 mL of sodium nitrite. The diazonium solution was slowly warmed to room temperature and left overnight. Water (30 mL) was added to this red solution with some sediment. The resulting mixture was extracted with ethyl acetate, washed with dilute sodium hydroxide solution, then water, dried (anhydrous Na ₂ SO ₄ ) and rotor evaporated to give the crude product. Chromatography on silica gel with 40:60 chloroform: ethyl acetate gave 44% of the title compound (5 mg).
Obtained in yield; ¹ H NMR (CDCl ₃ ) d 4.09 (3H, s), 4.18.
(6H, s), 4.23 (3H, s), 7.31 (1H, s), 7.74 (1H
, S), 8.00 (1H, s), 8.01 (1H, d, J = 8.5), 8.20.
(1H, d, J = 8.9), 9.15 (1H, s); ¹³ C NMR d 56.
5, 56.9, 99.9, 104.5, 107.9, 109.5, 116.9,
118.5, 118.9, 127.0, 128.4, 131.6, 141.8,
144.6, 151.1, 151.2, 152.0, 153.9.

The intermediate 6- (2-amino-4,5-dimethoxyphenyl) -2,3 dimethoxynaphthalene (18) was prepared as follows.

A. Trimethyl (3,4-dimethoxy-6-nitrophenyl) tin (16) Hexamethylditin (3 g, 9.2 mmol) in anhydrous THF (30 ml),
4-Bromo-1,2- (methylenedioxy) benzene 15 (Dallacker
, F. Wagner, A .; Z. Natureforsch. , 1984, 39b
, 936, 1.6 g, 6.1 mmol) and Pd (PPh ₃ ) 4 (200 mg
) Was heated to reflux under nitrogen for 10 hours. After cooling to room temperature, THF was evaporated and methylene chloride (30 mL) was added to the residue. In this mixture,
Aqueous potassium fluoride (7.0 M, 2 mL) was added dropwise with vigorous stirring. The mixture was passed through a Celite bed and the filtrate washed with brine.
The methylene chloride layer was dried (anhydrous, Na ₂ SO ₄ ), filtered and concentrated under reduced pressure.
The residue was chromatographed on 100 g of silica gel with 1: 6 ethyl acetate: hexane to give 16 in 70% yield; mp 115-117 ° C; ¹ H.
NMR (CDCl ₃ ) d 0.32 (9H, s), 3.94 (3H, s),
3.99 (3H, s), 7.03 (1H, s), 7.88 (1H, s); ¹³ C
NMR (CDCl ₃ ) d 7.2, 56.7, 107.7, 117.3, 13
4.0, 146.8, 149.8, 154.1; HRMS theoretical value (C ₁₁ H ₁₇ N
_{O 4 Sn-CH 3):} 329.9937; Found: 329.9939.

B. 6- (4,5-Dimethoxy-2-nitrophenyl) -2,3-dimethoxynaphthalene (17) Tetrakis (triphenylphosphine) palladium (0) (80 mg) and copper bromide (16 mg) in THF (25 mL) 6,7-Dimethoxy-2-naphthalene triflate (10,220 mg, 0.655 mmol) and trimethyl (3,4-dimethoxy-6-nitrophenyl) tin (16,220 mg, 0.
64 mmol). The mixture was stirred for 0.5 hours at room temperature and then refluxed under nitrogen for 32 hours. After cooling, THF was rotovaped and ethyl acetate (50 ml) was added to the residue and the solution was washed with water (30 ml). The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel with 60:40 hexane: ethyl acetate to give compound 17; ¹ H NMR (CDCl ₃ ) d 3.95 (3H, s), 3.99 (6H, s), 4.01 (3H, s)
, 6.86 (1H, s), 7.12 (1H, s), 7.14 (1H, s), 7.
23 (1H, dd, J = 8.4, J = 1.8), 7.56 (1H, s), 7.6
1 (1H, d, J = 1.7), 7.70 (1H, d, J = 8.4); ¹³ C NM
Rd 56.4, 56.9, 106.7, 107.0, 108.3, 114.
4, 124.9, 125.7, 127.0, 129.0, 129.5, 132.
2, 134.6, 141.6, 148.4, 150.4, 152.7.

[0095]   c. 6- (2-amino-4,5-dimethoxyphenyl) -2,3-dimethoxy
Naphthalene (18)   6- (4,5-dimethoxy-2-nitrophenyl) -2,3-dimethoxynaphth
Tarene (12 mg, 0.03 mmol) was added to palladium (10% by weight on activated carbon).
10-mg) under catalyst 40-45 lb. / Sq. in. With ethyl acetate (20m
Hydrogenated in 1) overnight. This solution is passed through a Celite bed and the catalyst is converted to acetic acid.
Wash with ethyl (3 x 10 ml). Concentration under reduced pressure gave a crude product. 65: 3
Chromatography with 5 hexane: ethyl acetate gave almost 100%
Compound 18 (11 mg) was obtained with a yield of;¹1 H NMR (CDCl₃) D 3.
84 (3H, s), 3.89 (3H, s), 4.01 (3H, s), 4.02 (
3H, s), 6.41 (1H, s), 6.80 (1H, s), 7.14 (1H,
s), 7.15 (1H, s), 7.43 (1H, dd, J = 8.4, J = 1.6)
), 7.75 (1H, d, J = 1.5), 7.75 (1H, d, J = 8.4); ¹³ C NMR d 56.4, 57.2, 101.3, 106.6, 106.8.
, 115.2, 119.9, 126.2, 126.8, 127.3, 128.5.
, 129.9, 135.7, 138.0, 142.7, 149.8, 150.1
, 150.3.

Example 4: 2,3,8-Trimethoxydibenzo [c, h] cinoline (60)
) 6- (2-Amino-4-methoxyphenyl) -2,3-dimethoxynaphthalene (32) (12 mg, 0.039 mmol) was dissolved in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). The solution was cooled in an ice bath and diazotised by the dropwise addition of a solution of sodium nitrite (0.026g in 0.5ml water).
The resulting diazonium solution was slowly warmed to room temperature and left overnight.
To the resulting red solution containing some precipitate, 30 ml water was added and the mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined and washed first with dilute sodium hydroxide solution, then with water and brine.
The ethyl acetate extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was subjected to column chromatography on silica gel at 40: 6.
Purification with 0 hexane: ethyl acetate gave pure 4 (5 mg) in 40% yield; m
p 244-246 ° C; IR (KBr) 2919, 1619, 1507, 138.
8, 1292, 1277, 1204 cm ⁻¹ ; UV (MeOH) 292, 266,
216 nm; ¹ H NMR (CDCl ₃ ) δ 4.10 (6 H, s), 4.22 (
3H, s), 7.32 (1H, s), 7.54 (1H, dd, Je = 9.1, J
2 = 2.6), 8.04-8.08 (2H, m), 8.28 (1H, d, J = 8)
． 9), 8.49 (1H, d, J = 9.1), 9.16 (1H, s); ¹³ C N
MR δ 56.33, 56.52, 56.92, 104.36, 107.93,
108.92, 116.88, 117.08, 119.48, 123.51, 1
24.54, 127.14, 128.42, 132.46, 141.77, 14
8.52, 151.12, 151.40, 160.45; HRMS (EI) theoretical value (C ₁₉ H ₁₆ N ₂ O ₃ ) m / z: 320.1161; found value: 320.0384.
.

[0097]   Intermediate compound 32 was prepared as follows.

A. 6- (4-Methoxy-2-nitrophenyl) -2,3-dimethoxynaphthalene (29) Tetrakis (triphenylphosphine) palladium (0) (60 mg) and copper bromide (10 mg) in THF (20 ml). 6,7-Dimethoxy-2-trifluoromethanesulfonyloxynaphthalene 10 (150 mg, 0.45 mm
ol) and trimethylnitroaryltin 26 (140 mg, 0.45 mmo
The solution of l) was added at room temperature and stirred for 0.5 hours. The mixture was then refluxed under N ₂ for 36 hours. After cooling, THF was evaporated and ethyl acetate (30 ml) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure.
The residue was chromatographed with a 70:30 mixture of hexane: ethyl acetate to give 29 (60 mg) in 43% yield; ¹ H NMR (CDC
l ₃ ) δ 3.92 (3H, s), 4.01 (3H, s), 4.02 (3H, s)
), 7.12-7.26 (4H, m), 7.397.46 (2H, m), 7.6.
1 (1H, d, J = 1.7), 7.71 (1H, d, J = 8.4); ¹³ C NM
R (CDCl ₃₎ δ 56.42,106.64,106.98,109.50
, 119.23, 124.83, 125.89, 127.20, 129.02,
129.38, 129.60, 133.53, 150.25, 150.42, 1
59.46; HRMS (EI) theoretical value (C ₁₉ H ₁₇ NO ₅ ) m / z: 339.11.
07; Found: 339.1108.

B. 6- (2-amino-4-methoxyphenyl) -2,3-dimethoxynaphthalene (32). 6- (4-Methoxy-2-nitrophenyl) -2,3-dimethoxynaphthalene 29 (18 mg, 0.053 mmol) as a catalyst on carbon (10 mg) on 1
40-45 lb. with 0% palladium. / Sq. in. With ethyl acetate (20
ml) overnight. The reaction solution was passed through a celite bed and the catalyst was washed with ethyl acetate (10 ml x 3). The crude product was obtained by concentration under reduced pressure. Chromatography of this residue with 60:40 hexane: ethyl acetate gave 32 (14 mg) in 85% yield; ¹ H NMR (CDCl ₃ ) δ 3.
． 83 (3H, s), 4.01 (3H, s), 4.03 (3H, s), 6.37
(1H, d, J = 2.5), 6.45 (1H, dd, J1 = 8.3, J2 = 2.
4), 7.12-7.16 (3H, m), 7.42 (1H, dd, J1 = 8, 4)
, J2 = 1.7), 7.72-7.77 (2H, m); ¹³ C NMR δ 55.
72, 56.40, 101.56, 104.79, 106.59, 106.78.
, 121.49, 126.36, 126.81, 127.24, 128.47,
129.89, 131.98, 135.55, 145.28, 150.01, 1
50.25, 160.49; HRMS (EI) theoretical value (C ₁₉ H ₁₉ NO ₃ ) m / z
: 309.1365; Found: 309.1355.

[0100]   Intermediate compound 26 used in subpart a above was prepared as follows.

[0101]   c. Trimethyl (4-methoxy-2-nitrophenyl) tin (26)   Hexamethylditin (1.0 g, 3.1 mmol) in anhydrous THF (20 ml)
), 4-methoxy-2-nitrobromobenzene 23 (0.5 g, 2.16 mmo
l) and Pd (PPh₃) 4 (60 mg) mixture was heated under nitrogen to a thin layer
Reflux until chromatography showed no starting material present. To room temperature
After cooling, the THF was evaporated and methylene chloride was added to the residue. this
Aqueous potassium fluoride (7.0 M, 1.0 ml) was added to the mixture with vigorous stirring.
It was added dropwise. The mixture is passed through a Celite bed and the filtrate is filtered.
Washed in. The methylene chloride layer was dried (anhydrous Na₂SO_Four), Filter, and
The solution was concentrated under reduced pressure. Mix the residue with hexane: ethyl acetate 95: 5
Chromatographed on product to give 26 (260 mg) in 38% yield.
Mp 93-5 ° C .;¹1 H NMR (CDCl₃) Δ 0.32 (9H, s), 3
． 89 (3H, s), 7.21 (1H, dd, J1 = 8.0, J2 = 2, 6),
7.57 (1H, d, J = 8.0), 7.86 (1H, d, J = 2.6);¹³C
NMR (CDCl₃) Δ-7.1, 56.7, 107.7, 117.3, 133
． 9, 146.8, 149.6, 154.1; theoretical HRMS (EI) value (C_TenH ₁₅ NO₃Sn-CH₃) M / z: 301.9839; found: 301.9832.

The starting material 4-bromo-3-nitroanisole (23) was prepared from Aldrich
Purchased from the Chemical Company (Milwaukee, WI) [5344-78-5].

Example 5: 2,3,9-trimethoxydibenzo [c, h] cinoline (61) 6- (2-amino-5-methoxyphenyl) -2,3-dimethoxynaphthalene (33) (60 mg) , 0.20 mmol) in acetic acid (1.5 ml) and concentrated hydrochloric acid (
0.3 ml). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.12 g in 1.2 mL water). The resulting diazonium solution was slowly warmed to room temperature and left overnight. To the resulting solution with some precipitate was added 50 ml water, then extracted with ethyl acetate (40 ml x 3). The organic layers were combined and washed first with dilute sodium hydroxide solution, then with water and brine. It was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with 35:65 hexane: ethyl acetate to give pure 5 (16 mg) in 26% yield; mp 215-217 ° C; IR (KBr
) 2987, 1617, 1504, 1486, 1394, 1277, 1231,
1167 cm ⁻¹ ; UV (MeOH) 288, 262, 232 nm (log ε = 4)
． 71, 4.66, 4.58); ¹ H NMR (CDCl ₃ ) δ 4.07 (3H
, S), 4.09 (3H, s), 4.22 (1H, s), 7.29 (1H, s)
, 7.46 (1 H, dd, J, = 9.1, J2 = 2.6), 7.72 (1 H,
d, J = 2.5), 7.99 (1H, d, J = 8.9), 8.20 (1H, d,
J = 9.0), 8.60 (1H, d, J = 9.1), 9.17 (1H, s); ¹³ C NMR δ 56.31, 56.51, 56.90, 100.27, 104.
61, 107.73, 117.00, 118.66, 121.31, 124.2.
5, 126.98, 129.09, 131.40, 133.34, 141.76.
, 143.70, 151.23, 151.31, 161.95; HRMS (EI
) Theoretical value (C ₁₉ H ₁₆ N ₂ O ₃ ) m / z: 320.1161; measured value: 320.11
44.

[0104]   Intermediate compound 33 was prepared as follows.

A. 6- (5-Methoxy-2-nitrophenyl) -2,3-dimethoxynaphthalene (30). Tetrakis (triphenylphosphine) palladium (0) (80 mg) and copper bromide (6 mg) were combined with 6,7-dimethoxy-2-trifluoromethanesulfonyloxynaphthalene 10 (200 mg, 0.60 mmol) in THF (25 ml).
) And trimethylnitroaryltin 27 (200 mg, 0.64 mmol)
Was added to the solution at room temperature and stirred for 0.5 hours. The mixture was then refluxed under N ₂ overnight. After cooling, THF was evaporated and ethyl acetate (30 ml) was added to this residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was chromatographed with a 75:25 mixture of hexane: ethyl acetate to give a mixture of two compounds with similar Rf values.
This mixture was used for the next step without further purification.

[0106]   b. 6- (2-amino-5-methoxyphenyl) -2,3-dimethoxynaphtha
Ren (33)   Crude 6- (5-methoxy-2-nitrophenyl) -2,3-dimethoxynaphtha
Ren 30 (100 mg, about 90% pure) was used as a catalyst on carbon (30 mg) 1
40-45 lb. with 0% palladium. / Sq. in. With ethyl acetate (40m
Hydrogenated in 1) overnight. The reaction solution is passed through a Celite bed and the catalyst
It was washed with ethyl acetate (10 ml x 3). The crude product was obtained by concentration under reduced pressure. This
Chromatograph the residue in 50:50 with a hexane: ethyl acetate mixture.
-Treated to give 33 (66 mg); mp 158-160 ° C; IR (KBr)
3408, 3354, 2936, 1633, 1499, 1249, 1166cm ^-1 ;¹1 H NMR (CDCl₃) Δ 3.57 (2H, s), 3.79 (3H, s)
), 4.01 (3H, s), 4.03 (3H, s), 6.77-6.84 (3H)
, M), 7.15 (1H, s), 7.16 (IH, s), 7.45 (IH, dd)
, J, = 8.3, J2 = 1.8), 7.75-7.79 (2H, m);¹³C N
MR δ 56.34, 56.42, 106.59, 106.85, 114.8.
0, 116.35, 117.41, 125.99, 126.81, 127.32.
, 128.73, 129.42, 129.82, 135.75, 137.89,
150.19, 150.32, 153.25; HRMS (EI) theoretical value (C₁₉H ₁₉ NO₃) M / z: 309.1365; found: 309.1375.

[0107]   Intermediate compound 27 was prepared as follows.

[0108]   c. 3-Methoxy-6-nitrobromobenzene (24)   Nitrous acid (70%, 5 ml) was placed in a 25 ml round bottom flask. Then, dense
Sulfuric acid (4 ml) was added dropwise with stirring. Add this mixture to the flask in an ice bath.
Cooling was maintained during the addition by adding the rusco by dipping. Then
, 3-methoxybromobenzene (4 g, 21.5 mmol) was added dropwise.
. The reaction mixture was then heated to 50 ° C. and stirred for 5 hours. After cooling
The mixture was poured into 100 ml of cold water and then extracted with ethyl acetate (3
0 ml x 3). Combine the organic layers and wash with water (50 ml x 4) and
Wash with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and
And concentrated under reduced pressure. This crude product was washed with 95: 5 hexane: ethyl acetate to give a crude product.
Purified by column chromatography. The first compound eluted from the column is
Yield 24% with 3-methoxy-4 nitrobromobenzene (1.2 g); ¹ 1 H NMR (CDCl₃) Δ 3.96 (3H, s), 7.17 (1H, dd,
J1 = 8.6, = 1-9), 7.24 (1H, d, J = 1.9), 7.75 (1
H, d, J = 8.6);¹³C NMR δ 57.34, 117.58, 124
． 00, 127.41, 129.05, 142.26, 154.02. Column?
The second compound eluted from it was 24 (1.5 g, 30% yield); 43-
45 ° C;¹1 H NMR (CDCl₃) Δ 3.89 (3H, s), 6.91 (1H
, Dd, Jl = 9. l, J2 = 2.7), 7.21 (1H, d, J = 2.7),
7.98 (1H, d, J = 9.1);¹³C NMR δ 56.68, 114.
02, 117.29, 120.61, 128.46, 163.23.

D. Trimethyl (3-methoxy-6-nitrophenyl) tin (27) Hexamethylditin (2 g, 6.13 mmol) in anhydrous THF (20 ml).
, 3-Methoxy-6-nitrobromobenzene 24 (0.70 g, 3.0 mmo
A mixture of l) and Pd (PPh ₃ ) 4 (100 mg) was heated at reflux under nitrogen until thin layer chromatography showed no starting material. After cooling to room temperature, THF was evaporated and methylene chloride was added to the residue. Aqueous potassium potassium fluoride (7.0 M, 1.5 ml) was added dropwise to this mixture with vigorous stirring. The mixture was passed through a Celite bed and the filtrate washed with brine. The methylene chloride layer was dried (anhydrous Na ₂ SO ₄ ), filtered, and the solution concentrated under reduced pressure. The residue was chromatographed with a mixture of 500: 8 hexane: ethyl acetate to give 27 (200 mg) in 21% yield; ¹ H NMR (CDCl ₃ ) δ 0.34 (9H, s. ) 3.91 (3H,
s), 6.92 (1H, dd, J, = 9.1, J2 = 2.7), 7.13 (1H
, D, J = 2.8), 8.33 (IH, d, J = 9.1); ¹³ C NMR δ.
-7.09, 56.23, 114.22, 122.38, 127.03, 143
． 62, 146.84, 164.05.

Example 6: 9-Hydroxy-2,3,8-trimethoxydibenzo [c, h]
Cinoline (34)) 9-benzyloxy-2,3,8-trimethoxydibenzo [c, h] cinoline, 42, (5 mg, 0.012 mmol) was added to 26 lb. / Sq. in. Hydrogenated overnight in ethyl acetate (25 ml) with 10% palladium on carbon (1.5 mg). The solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 ml x 3). A crude product was obtained by concentrating the ethyl acetate solution under reduced pressure. Fifty
Chromatography using a mixture of hexane: ethyl acetate: methanol :: 45: 5 as the eluting solvent gave compound 34 (3 mg) in 76% yield; ¹
1 H NMR (DMSO-d ₆ ) δ 4.00 (3H, s), 4.10 (3H, s)
4.12 (3H, s), 7.66 (IH, s), 8.02 (2H, s), 8.
21 (in, d, J = 8.4), 8.38 (IH, d, J = 8.9), 8.96
(1H, s); ¹³ C NMR δ 55.9, 56.4, 103.1, 103.
8, 108.5, 109.1, 117.4, 117.8, 118.0, 125.
7, 128.1, 131.3, 140.4, 143.8, 150.5, 150.
7, 151.3, 152.4; HRMS (EI) theoretical value (C ₁₉ H ₁₆ N ₂ O ₄ ) m /
z 336.111; found: 336.1109.

Example 7: 9-Benzyloxy-2,3,8-trimethoxydibenzo [c,
h] Cinoline (42)) 6- (2-amino-5-benzyloxy-4-methoxyphenyl) -2,3-
Dimethoxynaphthalene 41 (35 mg, 0.084 mmol) was added to acetic acid (0.6
5 ml) and concentrated hydrochloric acid (0.13 mL). The solution was chilled on ice and diazotized by the dropwise addition of a solution of sodium nitrite (0.052 g in 0.52 mL water). The reaction mixture was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution with some sediment was added 50 ml water and the mixture was extracted with ethyl acetate (30
ml x 3). The organic layers were combined and washed first with dilute sodium hydroxide and then with water and brine. The organic layer was dried with anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with 20:80 hexane: ethyl acetate to give 42 (24 mg) in 67% yield; mp 244-246 ° C .; IR (K
Br) 2935, 1621, 1507, 1466, 1307, 1269, 123.
4, 1206, 1168 cm ⁻¹ ; ¹ H NMR (CDCl ₃ ) δ 4.07 (3H
, S), 4.14 (3H, s), 4.21 (3H, s), 5.40 (2H, s).
, 7.25 (1H, s), 7.37-7.60 (5H, m), 7.91 (1H,
d, J = 9.0), 7.97 (1H, s), 8.01 (1H, d, J = 9.0)
, 9.11 (1H, s); ¹³ C NMR δ 56.48, 56.86, 56.
91, 71.64, 101.69, 104.43, 107.82, 109.58.
, 116.84, 118.19, 118.81, 126.95, 127.97,
128.34, 128.90, 129.34, 131.51, 136.31, 1
41.61, 144.52, 151.00, 151.14, 152.31, 15
2.93; HRMS (EI) theoretical _{(C 26 H 22 N 2 O} 4) m / z: 426.158
0; found: 426.1577.

[0112]   Intermediate compound 41 was prepared as follows.

A. 5-bromo-2-methoxyphenol (35) 50 ml in CH ₂ Cl ₂ for 5-bromo-2-methoxybenzaldehyde (2.
4 g, 11.2 mmol) in m-chloroperbenzoic acid (70-75%, 7
g, 28.4 mmol pure m-CPBA) was added and the mixture was stirred at ambient temperature for 2 days. The reaction was quenched with aqueous saturated NaHCO ₃ solution,
Then, it was extracted with ethyl acetate (50 ml × 3). The organic extract was dried over anhydrous sodium sulfate and filtered through a silica gel bed. Evaporation of this solution gave compound 35 (2.1 g) in 92% yield; mp 62-6.
4 ° C .; ¹ H NMR (CDCl ₃ ) δ 3.87 (3H, s), 6.71 (1H,
d, J = 8.6), 6.97 (1H, dd, J1 = 8.6, J2 = 2.4), 7
． 07 (1H, d, J = 2.4); ¹³ C NMR δ 56.59, 112.3.
6, 113.75, 118.33, 123.29, 146.37, 146.98.
.

B. 3-Benzyloxy-1-bromo-4-methoxybenzene (36) 5-Bromo-2methoxyphenol, 35, (2.0 g, 10 mmol) and α-bromotoluene (2.6 g, 15.4 mmol) in CH _3. CN (30 ml
) And acetone (25 ml) in potassium carbonate (2.1 g, 15.2).
mmol). The resulting mixture was heated to reflux under nitrogen for 18 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite bed.
The acetone was removed under reduced pressure and 50 ml ethyl acetate was added to the residue. The ethyl acetate solution was washed with water, brine, dried over anhydrous Na ₂ SO ₄ ,
It was then evaporated under reduced pressure. The residue was chromatographed with 90:10 hexane: ethyl acetate mixture to give compound 36 (2.77 g) 96.
% Yield; mp 70-71 ° C .; ¹ H NMR (CDCl ₃ ) δ 3.86 (
3H, s), 5.12 (2H, s), 7.77 (1H, J = 9.2), 7.04
−7.08 (2H, m), 7.33-7.48 (5H, m); ¹³ C NMRδ.
856.66, 71.68, 113.04, 113.54, 117.71, 12
4.47, 127.91, 128.58, 129.13, 136.91, 149
． 45, 149.50; HRMS (EI) theoretical value (C ₁₄ H ₁₃ O ₂ Br) m / z:
292.00099; found: 292.00085.

C. 3-benzyloxy-4-methoxy-6-nitrobromobenzene (37) 3-benzyloxy-1-bromo-4-methoxybenzene, 36, (1 g, 3
． 4 mmol) was dissolved in 50 ml acetic acid in a 100 ml round bottom flask and cooled with an ice bath at 0 ° C. 2.5 ml nitrous acid (70% in 6 ml acetic acid
) Was added dropwise. The reaction mixture was slowly warmed to room temperature. After 3 hours no starting material was detected by thin layer chromatography. The crude product was obtained by evaporation of acetic acid. It was filtered through a short silica gel column with 80:20 hexane: ethyl acetate mixture to give 3-benzyloxy-4-methoxy-6-nitrobromobenzene (1.15 g) in quantitative yield. ; Mp 134-
135 ° C; IR (KBr) 2946, 1577, 1518, 1468, 1382
, 1329, 1266, 1211 cm ^-1 ; UV (MeOH) 246, 212 nm
(Log ε = 3.91, 4.13); ¹ H NMR (CDCl ₃ ) δ3.93 (
3H, s), 5.19 (2H.s), 7.17 (1H, s), 7.38-7.4.
5 (5H, m), 7.57 (1H, s); ¹³ C NMR δ 56.99, 71.
98, 107.69, 109.74, 118.73, 127.98, 129.1.
1, 129.36, 135.50, 142.42, 149.18, 152.44
HRMS (EI) theoretical value (C ₁₄ H ₁₂ NO ₄ Br) m / z: 336.9950;
Found: 336.9941.

D. Trimethyl (3-benzyloxy-4-methoxy-6-nitrophenyl)
Tin (38) Hexamethylditin (2 g, 6.13 mmol) in THF (40 ml), 3
-Benzyloxy-4-methoxy-6-nitrobromobenzene 37 (1.4 g,
A mixture of 4.14 mmol) and Pd (PPh ₃ ) 4 (200 mg) was heated to reflux under nitrogen for 2 days. After cooling to room temperature, THF was evaporated and methylene chloride was added to this residue. To this mixture was added aqueous potassium fluoride (7
． (0 M, 1.5 ml) was added dropwise with vigorous stirring. The mixture was passed through a Celite bed and the filtrate washed with brine. Dry the methylene chloride layer (
Anhydrous Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. Residue 90:
Chromatography with 10 hexane: ethyl acetate mixtures yields 38 (
1.16 g) was obtained in 66% yield; mp 81-83 ° C; IR (KBr) 29.
08, 1569, 1518, 1454, 1318, 1275, 1215 cm ^-1 ;
UV (MeOH) 248, 214 nm (log ε = 4.08, 4.21); ¹
1 H NMR (CDC13) δ 0.27 (9H, s), 3.97 (3H, s),
5.29 (2H.s), 7.04 (1H, J = 9.2), 7.36-7.44 (
5H, m), 7.91 (1H, s); ¹³ C NMR δ-7.17, 56.75,
71.59, 108.01, 119.55, 127.80, 128.85, 12
9.31, 123.64, 136.42, 146.89, 150.18, 153
． 25; HRMS (EI) theoretical value (C ₁₇ H ₂₁ NO ₄ Sn) m / z: 408.02
58; Found: 408.0243.

E. 6- (5-benzyloxy-4-methoxy-2-nitrophenyl) -2,
3-Dimethoxynaphthalene (39) Tetrakis (triphenylphosphine) palladium (0) (200 mg) and copper bromide (20 mg) in THF (40 ml) 6,7-dimethoxy-2trifluoromethanesulfonyloxy-naphthalene 10 (500 mg). , 1.49mmo
1) and trimethylnitroaryltin 38 (950 mg, 2.25 mmol)
) Was added at room temperature and stirred for 0.5 hours. This mixture is then added to 2
Reflux under N ₂ for days. After cooling, THF was evaporated and ethyl acetate (
30 ml) was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was chromatographed with a mixture of 70:30 hexane: ethyl acetate mixture to give 39 (230 mg) in 35% yield; mp 151-153.
° C; IR (KBr) 2962, 1608, 1573, 1508, 1416, 13
30, 1275, 1254 cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ 3.98 (3
H, s), 3.99 (3H, s), 4.01 (3H, s), 5.20 (2H.s).
), 6.94 (1H, s), 7.10 (1H, s), 7.14 (1H, s), 7
． 18 (1H, dd, J1 = 8.4, J2 = 1.8), 7.36-7.43 (5
H, m), 7.54 (IH, d, J = 1.5), 7.56 (IH, s), 7.6
8 (IH, d, J = 8.3); ¹³ C NMR δ 56.37, 56.95, 7
1.69, 106.69, 106.99, 108.67, 116.35, 124
． 91, 125.78, 127.00, 128.00, 128.87, 129.
00, 129.23, 129.53, 131.81, 134.49, 136.1.
5, 141.89, 148.95, 150.41, 151.85; HRMS (E
I) the theoretical value _{(C 26 H 23 NO 6)} m / z: 445.1525; Found: 445.1
355.

F. 6- (2-amino-5-benzyloxy-4-methoxyphenyl) -2,
3-dimethoxynaphthalene (41).

[0119]   Compound 39 (50 mg, 0.112 mmol) was added to 30 lb. / Sq. in.
On carbon (hydrogenated over 15 mg with 10% palladium as catalyst for 16 hours).
It was The solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 ml x 3
) Was washed with. A crude product was obtained by concentrating the ethyl acetate solution under reduced pressure. Karamuk
Chromatography was performed using a 35:65 hexane: ethyl acetate mixture as the eluting solvent.
Used to give two compounds. Higher Rf on thin layer chromatography
The compound of high quality was isolated as compound 41 (34 mg, 73%); IR (K
Br) 3446, 2932, 1610, 1509, 1461, 1421, 125
4 cm^-l;¹1 H NMR (CDCl₃) Δ 3.90 (3H, s), 4.01 (3
H, s), 4.02 (3H, s), 5.08 (2H.s), 6.42 (1H, s)
), 6.87 (1H, s), 7.12 (IH, s), 7.15 (1H, s), 7
． 33-7.48 (6H, m), 7.71-7.75 (2H, m);¹³C NM
Rδ856.40, 56.42, 56.48, 73.07, 101.48, 10
6.59, 106.78, 119.09, 119.96, 126.24, 126
． 78, 127.29, 128.16, 128.20, 128.45, 128.
90, 129.86, 135.56, 138.19, 138.88, 141.7.
0, 150.07, 150.30, 150.92; HRMS (EI) theoretical value (C ₂₆ H_{twenty five}NO_Four) M / z: 415.1784; Found: 415.1775.

The compound with lower Rf was converted to 6- (2-amino-5-hydroxy-4-methoxyphenyl) -2,3-dimethoxynaphthalene (40) (6 mg, 16%).
IR (KBr) 3432, 2937, 2364, 1625, 1,
508, 1459, 1252, 1232 cm ^-1 ; UV (MeOH) 238, 20
8 nm; ¹ H NMR (CDCl ³ ) 83.88 (3H, s), 4.01 (3H,
s), 4.02 (3H, s), 6.40 (1H, s), 6.85 (1H, s),
7.12 (1H, s), 7.15 (IH, s), 7.41 (1H, dd, J, =
8.4, t-7); 7.73 (1H, d, J = 1.5), 7.74 (1H, d,
J = 8.3); ¹³ C NMR δ 56.40, 100.47, 106.59,
106.82, 116.90, 121.07, 126.29, 126.83, 1
27.25, 128.47, 129.85, 135.50, 137.17, 13
9.05, 147.11, 150.06, 150.27.

[0121]   Example 8: 2-Methoxy-8,9-methylenedioxydibenzo [c, h] si
Norin (43)   6- (2-amino-4,5-methylenedioxyphenyl) -2-methoxynaphth
Tarene 46 (170 mg, 0.58 mmol) was added to acetic acid (4.5 ml) and concentrated.
It was dissolved in hydrochloric acid (0.9 ml). The solution was cooled in an ice bath, and sodium nitrite was added.
Diazotization by the dropwise addition of a solution of thorium (0.36 g in 3.6 mL)
It was The resulting diazonium solution is slowly brought to room temperature and left for 1 day
did. 50 ml of water was added to the resulting red solution containing some sediment, and
The mixture was extracted with ethyl acetate (30 ml x 3). Combine the organic layers and
Washed with dilute sodium hydroxide solution first, then water and brine.
. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure.
It was This crude product was purified on silica gel using 50:50 hexane-ethyl acetate.
Purified by column chromatography to obtain pure 43 (20 mg) with 11% yield.
Mp 258-260 ° C; IR (KBr) 2922, 1611, 14
97, 1465, 1414, 1370, 1272, 1201cm^-1UV (Me
OH) 286, 228 nm (log ε = 4.72, 4.41);¹H NMR (
CDCl₃) Δ 4.01 (3H, s), 6.23 (2H, s), 7.30 (1
H, J = 2.6), 7.48 (1H, dd, J1 = 9.1, J2 = 2.6), 7
． 75 (1H, s), 7.95 (1H, s), 8.00 (1H, d, J = 9.2)
), 8.19 (1H, d, J = 9.1), 9.62 (1H, d, J = 9.2); ¹³ C NMR δ 56.01, 97.95, 102.88, 107.48, 10
8.31, 119.09, 119.61, 119.71, 120.57, 125
． 89, 126.56, 132.26, 134.59, 142.52, 145.
88, 150.21, 152.14, 160.16; theoretical HRMS (EI) value (
C₁₈H₁₂N₂O₃) M / z: 304.0848; found: 304.0843.

[0122]   Intermediate compound 46 was prepared as follows.

A. 6- (4,5-Methylenedioxy-2-nitrophenyl) -2-methoxynaphthalene (45) Tetrakis (triphenylphosphine) palladium (0) (120 mg) and copper bromide (20 mg) in THF (30 ml). 2-Bromo-6-methoxynaphthalene (0.3 g, 1.27 mmol) and trimethyl (3,4-methylenedioxy-6-nitrophenyl) tin, 62, (0.45 g, 1.37 mmol) in
) Was added at room temperature and stirred for 0.5 hours. The mixture was then refluxed for 16 hours under N ₂ . After cooling, THF was evaporated and 50 ml ethyl acetate was added to this residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue is 80
Chromatography with hexane: ethyl acetate 20:20 gave the desired product 45 (0.29 g) in 71% yield; mp 165-167 ° C; IR (
KBr) 2911, 1609, 1520, 1482, 1429, 1393, 13
44, 1257, 1199 cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ 3.94 (3
H, s), 6.14 (2H, s), 6.88 (1H, s), 7.16-7.21.
(2H, m), 7.31 (1H, dd, J1 = 8.5, Je = 1.9), 7.4
7 (1H, s), 7.67-7.77 (3H, m); ¹³ C NMR δ 855.8.
9, 103.45, 105.92, 106.19, 111.69, 119.86.
, 126.90, 127.02, 127.55, 129.23, 130.09,
133.76, 133.85, 134.48, 143.38, 147.52, 1
51.47,158.62; HRMS (EI) theoretical _{(C 18 H 13 NO 5)} m / z
: 323.0794; found: 323.0788.

B. 6- (2-amino-4,5-methylenedioxyphenyl) -2-methoxynaphthalene (46) 6- (4,5-methylenedioxy-2-nitrophenyl) -2-methoxynaphthalene 45 (260 mg, 0 .81 mmol) and 40-45 lb. / Sq. i
n. Hydrogenated overnight in ethyl acetate (35 ml) using 10% palladium on carbon (70 mg) as a catalyst. The reaction solution was passed through a celite bed and the catalyst was washed with ethyl acetate (10 ml x 3). The ethyl acetate solution was concentrated under reduced pressure to obtain a crude product. The residue was chromatographed with 75:25 hexane: ethyl acetate mixture to give 46 (180 mg) in 76% yield; mp 130-132 ° C; IR (KBr) 3463, 3372, 2874, 1
631, 1494, 1441, 1389, 1260, 1187 cm ^-1 ; UV (M
eOH) 234 nm (logε = 4.73 ); 1 H NMR (CDC1 3) δ
3.56 (2H, s), 3.95 (3H, s), 5.92 (2H, s), 6.4
0 (1H, s), 6.75 (1H, s), 7.177.22 (2H, m), 7.
51 (1H, dd, J, = 8.5, J2 = 1.6), 7.73-7.82 (3H
, M); ¹³ C NMR δ655.84, 98.33, 101.25, 106.1.
1, 110.71, 119.66, 120.30, 127.79, 128.27
, 128.61, 129.60, 129.91, 133.95, 135.11,
138.95, 141.17, 148.05, 158.29; HRMS (EI).
Theoretical value (C ₁₈ H ₁₅ NO ₃ ) m / z: 293.1052; found value: 293.105.
1.

[0125]   Intermediate compound 62 was prepared as follows.

C. Trimethyl (3,4-methylenedioxy-6-nitrophenyl) tin (6
2) A mixture of hexamethylditin (1 g, 3.1 mmol), compound 16 (0.7 g, 2.9 mmol) and tetrakis (triphenylphosphine) palladium (100 mg) in THF (20 ml) under nitrogen for 10 hours. Heated to reflux. After cooling to room temperature, THF was evaporated and methyl chloride (30 ml) was added.
) Was added to the residue. Aqueous potassium fluoride (7.0 M, 1 ml) was added to this mixture.
) Was added dropwise with vigorous stirring. Pass this mixture through a Celite bed,
Then the filtrate was washed with brine. Dry the methylene chloride layer (anhydrous Na ₂ SO ₄ ).
, Filtered and evaporated under sterilization. The residue was chromatographed with 95: 5 hexane: ethyl acetate to give 62 (0.5 g) in 54% yield; ¹ H NMR (CDCl ₃ ) δ. 0.32 (9H, s), 6.12 (
2H, s), 7.04 (1H, s), 7.82 (1H, s); ¹³ C NMR (C
DCl ₃₎ δ -6.94,103.27,105.82,114.76,13
7.19,147.90,149.36,153.36; HRMS (EI) theoretical _{(C 10 H 13 NO 4 Sn} -CH 3) m / z: 315.9632; Found: 315.
9638.

Example 9: 3-Methoxy-8,9-methylenedioxydibenzo [c, h] cinoline (44) 7- (2-amino-4,5-methylenedioxyphenyl) -2-methoxy Naphthalene 49 (70 mg, 0.24 mmol) was dissolved in acetic acid (2.0 ml) and concentrated hydrochloric acid (0.4 ml). The solution was chilled with ice and diazotized by the dropwise addition of a solution of sodium nitrite (0.16 g in 1.6 mL water). The resulting diazonium solution was slowly warmed to room temperature and left overnight.
To the resulting red solution containing some sediment only 50 ml was added and the reaction mixture was extracted with ethyl acetate (30 ml x 3). The organic layers were combined and washed first with dilute sodium hydroxide solution, then with water and brine.
The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel with 55:45 hexane: ethyl acetate to give compound 44 (60 mg, 83%); mp
259-261 ° C; IR (KBr) 2923, 1612, 1498, 1468,
1234, 1199 cm-1; UV (MeOH) 270, 250, 228 nm (
log ε = 4.68, 4.37, 4.44); ¹ H NMR (CDCl ₃ ) 84.
12 (3H, s), 6.24 (2H, s), 7.37 (1H, dd, J1 = 8.
8, J2 = 2.7), 7.80 (1H, s), 7.88 (1H, d, J = 8.8).
), 7.96 (1H, s), 8.03 (1H, d, J = 9.1), 8.09 (1
H, d, J = 9.0), 9.15 (1H, d, J = 2.7); ¹³ C NMR δ5
6.32, 98.31, 102.93, 104.03, 107.49, 116.
36, 120.40, 120.50, 121.09, 127.96, 130.0
0, 132.54, 133.34, 141.99, 146.10, 150.53
, 152.09,160.28; HRMS (EI) theoretical _{(C 18 H 12 N 2 O} 3) m
/ Z: 304.0848; Found: 304.0852.

[0128]   Intermediate compound 49 was prepared as follows.

[0129]   a. 7-methoxy-2-trifluoromethanesulfonyloxynaphthalene (4
7)   7-Methoxy-2-naphthol (0.75 g, 4. ₃ mmol) in ice-cold sodium hydride in THF (10 ml)
Suspension (60% by weight, 205 mg, 5.1 mmol) and 1.5
Stir for hours. Then N-phenyltrifluorometa in THF (10 ml)
Solution of sulfone imide (1.55 g, 4.34 mmol) and
The reaction mixture was stirred for 9 hours. After evaporating the solvent under reduced pressure, the residue is treated with silica gel.
(4 g) and then mixed with 500; 18 hexane: ethyl acetate
Mattography gave pure 47 (1.19 g) in 90% yield; mp
  34 ° C (lit¹⁰⁰  34 ° C);¹1 H NMR (CDCl₃) 3.93 (3H,
s), 7.13-7.25 (3H, m), 7.65 (1H, d, J = 2.5),
7.77 (IH, d, J = 9.1), 7.83 (1H, d, J = 8.8);¹³C
  NMR δ 55.88, 106.25, 116.13, 117.49, 11
8.52, 120.75, 122.51, 128.34, 129.87, 130
． 72, 135.41, 148.29, 159.39; HRMS (EI) theoretical value.
(C₁₂H₉SO_FourF₃) M / z: 306.0174; Found: 306.0176.

[0130]   b. 7- (4,5-methylenedioxy-2-nitrophenyl) -2-methoxy
Naphthalene (48)   Tetrakis (triphenylphosphine) palladium (0) (120 mg) and
And copper bromide (20 mg) in 7-methoxy-2-trifluore in THF (30 ml).
Rmethanesulfonyloxynaphthalene 47 (336 mg, 1.1 mmol) and
And a solution of trimethylnitroaryltin 62 (300 mg, 0.92 mmol)
To room temperature and stirred for 0.5 hours. Then the mixture was stirred overnight for N.₂under
Refluxed. After cooling, THF was evaporated under reduced pressure and ethyl acetate (3
0 ml) was added to the residue. The solution was washed with water. Separate this organic layer and
The suspended particles were removed by passing through a Celite bed. The organic layer was then washed with brine.
Wash and dry (anhydrous Na₂SO_Four) And evaporated under reduced pressure. This remains
The residue is chromatographed using an 80:20 hexane: ethyl acetate mixture.
Yielded 48 (100 mg) in 34% yield; IR (KBr) 2915,16
27, 1509, 1481, 1425, 1333, 1262, 1218cm^-l; ¹ 1 H NMR (CDC13) δ 3.92 (3H, s), 6.15 (2H, s)
, 6.88 (1H, s), 7.13-7.23 (3H, m), 7.48 (1H,
s), 7.64 (1H, s), 7.74-7.81 (2H, m);¹³C NMR
δ 55.81, 103.47, 105.90, 106.46, 111.60,
119.84, 124.13, 126.07, 128.50, 128.72, 1
29.75, 133.89, 134.97, 136.60, 143.42, 14
7.63, 151.45, 158.61; HRMS (EI) theoretical value C₁₈H₁₃NO _Five   m / z: 323.0794; found: 323.0787.

C. 7- (2-amino-4,5-methylenedioxyphenyl) -2-methoxynaphthalene (49) 7- (4,5-methylenedioxy-2-nitrophenyl) -2-methoxynaphthalene 48 (100 mg, 0 .31 mmol) and 40-45 lb. / Sq.
in. At, hydrogenated overnight in ethyl acetate (35 ml) using 10% palladium on carbon (30 mg) as a catalyst. The reaction solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 ml x 3). The ethyl acetate solution was concentrated to give a crude product. The residue was chromatographed with a 75:25 hexane: ethyl acetate mixture to give 49 (75 mg) in 83% yield; IR (K
Br) 3426, 3366, 2364, 2339, 1629, 1503, 148.
7, 1467, 1233, 1215, 1187 cm ⁻¹ ; ¹ H NMR (CDCl ₃ ) δ3.64 (2H, s), 3.94 (3H, s), 5.92 (2H, s), 6
． 40 (1H, s), 6.76 (1H, s), 7.15-7.20 (2H, m)
, 7.40 (1H, dd, J, = 8.3, J2 = 1.7), 7.75-7.85.
(3H, m); ¹³ C NMR δ 55.83, 98.35, 101.27, 1
06.25, 110.65, 119.35, 120.29, 125.82, 12
7.35, 128.31, 128.72, 129.67, 135.34, 137
． 99, 138.99, 141.17, 148.16, 158.49; HRMS.
(EI) Theoretical value C ₁₈ H ₁₅ NO ₃ ) m / z: 293.1052; Found: 293.
1052.

Example 10: 3-Methoxy-8,9-methylenedioxydibenzo [c, h]
Cinoline (44)) The compound of Example 9 (Compound 44) was also prepared as follows. Lithium aluminum hydride (46 mg, 1.2 mmol) was added to diethyl ether (10
ml) and benzene (10 ml) 54 (74 mg, 0.2 mmol)
) Was added to the stirred solution. The mixture was refluxed and stirred for 1 hour. After cooling to room temperature, excess hydride was washed with 0.05 ml water, 0.05 ml 15% N 2.
It was decomposed with aOH and 0.15 ml of water, and the reaction mixture was filtered through a Celite bed. The crude product was obtained by evaporation of the solvent under reduced pressure. This was purified by column chromatography using a 50:50 hexane: ethyl acetate mixture as the eluting solvent to give compound 44 (46 mg, 75%).

[0133]   Intermediate compound 54 was prepared as follows.

[0134]   a. 4-Methyl-2,3,4,5-tetrabromophenol (50).

P-Cresol (5 g, 46 mmol) was added dropwise to 15 ml (0.29 mol) bromine containing 0.25 g iron scrap at room temperature. During the addition of p-cresol, a small amount of chloroform was occasionally added to facilitate stirring. After 6 hours, the HBr product had precipitated. The residue was dissolved in hot chloroform, washed with aqueous Na ₂ S ₂ O ₃ , washed with NaHCO ₃ , dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography using a 95: 5 mixture of hexane and ethyl acetate to give 3.57 g of 50 (92% yield).
Mp 195-196 ° C. (lit ⁹³ 196 ° C.); ¹ H NMR (acetone-d6) δ 2.71 (3H, s); ¹³ C NMR δ 28.10, 115.
． 20, 127.66, 133.24, 152.19.

B. 4-Methyl-4-nitro-2,3,5,6-tetrabromo-2,5-cyclohexadien-1-one (51).

[0137]   A solution of 1.6 mL of nitric acid (d = 1.52, 70%) in 10 mL of acetic acid was added.
Compound 50 (3.2 g, 7.6 m) in 25 ml of pure acetic acid over 10 minutes.
mol) solution at 10 ° C. The reaction mixture was stirred for 4 hours and then
Then, 30 ml of water was added. Filter the precipitate and with water and heptane
Washed and dried under reduced pressure to give 2.9 g of pure 51 (82% yield); ¹ 1 H NMR (CDCl₃) Δ 2.26 (3H, s); IR (KBr) 1680
(C = O) (lit⁹³).

C. 2-Hydroxy-7-methoxy-1-nitronaphthalene (52) 7-Methoxy-2-naphthol (871 mg, 5 mmol) was dissolved in 40 ml of dry ether. To this solution was added 51 (2.33 g, 5 mmol) as a solid. The color of the solution became progressively red, and finally some dark precipitate with a dark red color adhering to the inner surface of the flask. The reaction was continued for 2.5 hours at room temperature.
Evaporation of this solution gave a crude product. To this residue was added 20 ml methanol / water (80:20). The reaction mixture was filtered and washed with methanol / water (80:20). The filtrate was then evaporated under reduced pressure and column purified. A 90:10 mixture of hexane and ethyl acetate was used as the eluting solvent. Yield was 380 mg (35%); mp 130
^{-131 ℃ (lit 93 130 ℃)} ; 1 H NMR (CDC1 3) δ 3.9 6 (
3H, s), 7.04 (1H, d, J = 9.0), 7.10 (1H, dd, J =
9.0, J = 2.6), 7.6 ₇ (1H, d, J = 8.9), 7.8 ₇ (1H, d
, J = 8.9), 8.3 ₇ (1H, d, J = 2.5); ¹³ C NMR δ 56.
． 03, 104.30, 116.80, 117.28, 124.22, 129.
35, 131.52, 139.59, 160.41, 162.75.

D. 7-Methoxy-1-nitro-2-trifluoromethanesulfonyloxynaphthalene (53) A solution of compound 52 (380 mg, 2.24 mmol) in THF (15 ml) was hydrogenated in chilled THF (10 ml). Sodium (60 wt% in mineral oil, 90 mg, 2.25 mmol) was added and stirred for 0.5 h. Then N-phenyltrifluoromethanesulfonimide (8
00 mg, 2.24 mmol) was added and the reaction was stirred for 8 h at 0 ° C. After concentration under reduced pressure, the residue was chromatographed with 85:16 hexane: ethyl acetate to give triflate 53 (526 mg) containing about 10% N-phenyltrifluoromethanesulfonamide.

E. 6- (4,5-methylenedioxy-2-nitrophenyl) -2,3-dimethoxy-5nitronaphthalene (54) tetrakis (triphenylphosphine) palladium (0) (100 mg) and copper bromide (20 mg) were added. , 7-Methoxy-1-nitro- in THF (30 ml).
2 trifluoromethanesulfonyloxy-naphthalene 53 (366 mg, 1.0
4 mmol) and trimethylnitroaryltin 62 (500 mg, 1.52
(mmol) solution at room temperature and stirred for 0.5 hours. The mixture was then refluxed overnight under N ₂ . After cooling, THF was evaporated and ethyl acetate (3
0 ml) was added to this residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was chromatographed with 70:30 hexane: ethyl acetate mixture to give 54 (160 mg) in 42% yield; mp 187-189 ° C; IR (K
Br) 2925, 1628, 1526, 1487, 1364, 1332, 126.
5, 1230 cm ^-1 ; ¹ H NMR (CDCl ₃ ) δ 3.92 (3H, s), 6
． 19 (2H, d), 6.76 (1H, s), 7.12 (1H, d, J = 2.5
), 7.18 (1H, d, J = 8.3), 7.28 (IH, dd, J1 = 9.0).
, J2 = 2.3), 7.70 (IH, s), 7.85 (IH, d, J = 9.2).
, 7.93 (IH, d, J = 8.4); ¹³ C NMR δ 56.08, 100.
． 59, 103.93, 106.31, 110.70, 121.54, 124.
07, 126.47, 128.71, 129.55, 130.33, 130.9
9, 131.23, 142.83, 148.92, 152.07, 160.68
.

Example 10 The following illustrates a representative pharmaceutical dosage form containing a compound of Formula I (“Compound X”) for therapeutic or prophylactic use in humans.

[0142]   (I) Tablet 1 mg / tablet "Compound X" 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0                               300.0.

[0143]   (Ii) Tablet 2 mg / tablet "Compound X" 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium glycolate starch 15.0 Magnesium stearate 5.0                                 500.0.

[0144]   (Iii) Capsules mg / capsule "Compound X" 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0                                 600.0.

[0145]   (Iv) Injection 1 (1 mg / ml) mg / ml "Compound X" (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N sodium hydroxide solution (Adjust pH to 7.0-7.5) Water for injection 1 ml in appropriate amount.

[0146]   (V) 2 (10 mg / ml) for injection mg / ml "Compound X" (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 01 N sodium hydroxide solution (Adjust pH to 7.0-7.5) Water for injection 1 ml in appropriate amount.

[0147]   (Vi) Aerosol mg / can "Compound X" 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 100.0 Dichlorotetrafluoroethane 5,000.0.

[0148]   The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents and patent documents are incorporated herein by reference as if they were individually incorporated by reference. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many modifications and variations can be made while remaining within the spirit and scope of the invention.

[Brief description of drawings]

[Figure 1]   1-5 illustrate the synthesis of compounds of the invention.

[Fig. 2]   1-5 illustrate the synthesis of compounds of the invention.

[Figure 3]   1-5 illustrate the synthesis of compounds of the invention.

[Figure 4]   1-5 illustrate the synthesis of compounds of the invention.

[Figure 5]   1-5 illustrate the synthesis of compounds of the invention.

[Figure 6]   FIG. 6 illustrates certain compounds of Formula I.

[Figure 7]   7-10 illustrate the synthesis of the present invention.

[Figure 8]   7-10 illustrate the synthesis of the present invention.

[Figure 9]   7-10 illustrate the synthesis of the present invention.

[Figure 10]   7-10 illustrate the synthesis of the present invention.

FIG. 11   FIG. 11 shows the structures of reference compounds tested herein below.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 31/12 A61P 31/12 33/00 33/00 33/02 33/02 35/00 35/00 43 / 00 111 43/00 111 C07D 491/056 C07D 491/056 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K) E, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, Z, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN , YU, ZA, ZW (72) Inventor Riu, Leroy Phone United States New Jersey 08807, Bridgewater, Fair LaCless Drive 5 (72) Inventor Yu, Younon United States New Jersey 08854, Piscataway, Marvin Leh 127 F term (reference) 4C050 AA01 AA08 BB08 CC17 EE02 FF01 GG01 HH01 4C086 AA01 AA02 AA03 BC40 CB22 MA01 MA04 MA05 MA21 MA23 MA35 MA37 MA52 MA55 MA56 MA66 NA14 ZB26 ZB32 ZB33 ZB35 ZB37 ZB38 ZB37 ZB38 ZB37

Claims (38)

[Claims] 1. The following formula (I): [Chemical 1] Or a pharmaceutically acceptable salt thereof, wherein   A is N or CR₃And   B is N or CR_sAnd   D is NR_eOr CR_aR_bAnd   E is NR_fOr CR_CR_dAnd   F is N or CR_tAnd   G is N or CR₆And   R₁, R₂And R₃Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₁And R₂Are together
Is methylenedioxy, and R₃Is hydrogen, (C₁-C₆) Alkyl, (C₃ -C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_g R_h, COOR_k, OR_m, Or halo; or R₂And R₃Together
Is methylenedioxy, and R₁Is hydrogen, (C₁-C₆) Alkyl, (
C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, N
R_gR_h, COOR_k, OR_m, Or halo;   R₆, R₇And R₈Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₆And R₇Are together
Methylenedioxy, and R_gIs hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C_l-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₇And R₈Are together
Methylenedioxy, and R₆Is hydrogen, (C₁-C₆) Alkyl, (C₃−
C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR _h , C (= O) R_k, COOR_k, OR_m, Or halo;   Each bond represented by ----- is either individually present or absent;   R_aAnd R_bIs a bond between the 11-position and the 12-position represented by -----
If not, each independently hydrogen or (C₁-C₆) Alkyl; or
When a bond between the 11-position and the 12-position represented by ---- is present, R_aIs hydrogen
Is (C_l-C₆) Alkyl, and R_bDoes not exist;   R_cAnd R_dIs a bond between the 11-position and the 12-position represented by -----
When not present, each independently hydrogen or (C₁-C₆) Alkyl; or-
When a bond between the 11-position and the 12-position represented by ----- is present, R_cIs hydrogen
Or (C₁-C₆) Alkyl, and R_dDoes not exist;   R_eIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_eIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   R_fIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_fIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   Each R_gAnd R_hAre independently hydrogen, (C₁-C₆) Alkyl, (C₃-C₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, (C₁-C₆) Alkanoyl, Ali
Aryl, aryl (C₁-C₆) Alkyl, aryloxy, or aryl (C₁
-C₆) Alkoxy; or R_gAnd R_hAnd the nitrogen they attach to
Together with pyrrolidino, piperidino, morpholino, or thiomorpholino
Yes;   Each R_kAre independently hydrogen, or (C_l-C₆) Alkyl; and   Each R_mIndependently, (C₁-C₆) Alkanoyl, aryl, or ant
(C₁-C₆) Is alkyl;   Each R_sAnd R_tAre independently hydrogen, methyl, nitro, hydroxy, amine
No or halo;   Where R₁, R₂, R₃, R₆, R₇, R₈, Or R_kAny of (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Alkoxy is required
Optionally substituted on the carbon with 1, 2 or 3 substituents, which substituents are:_mHydro
Kishi, halo, NR_nR_p, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Al
Selected from Koxy; where each R_nAnd R_pAre independently hydrogen, (C₁
-C₆) Alkyl, (C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy,
Or (C₁-C₆) Alkanoyl; or R_nAnd R_pIt joins
Together with nitrogen, pyrrolidino, piperidino, morpholino, or thiomorpho
Reno;   Where any aryl is optionally hydroxy, halo, nitro, tri
Fluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, and (C₁-C₆) Select from alkoxy
Substituted with 1, 2 or 3 substituents;   Provided that 2 or less of A to G include nitrogen; and   However, the compound of formula (I) is 2,3,8,9-tetramethoxy-5,6-dia.
Zacrysen also has 2,3-8,9-bismethylenedioxy-5,6-diazachrysene.
Not; and   However, in the compound of formula (I), A is CR₃And B is CR_sAnd E is CR_c
R_dAnd F is CR_tAnd G is CR₆And D is NR_eAn expression that is
Not a compound of (I), A compound, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R ₃ is hydrogen. 3. R ₁ , R ₂ and R ₃ are each independently hydrogen or (C _1-
C ₆ ) Alkoxy; or R ₁ and R ₂ together are methylenedioxy and R ₃ is hydrogen or (C ₁ -C ₆ ) alkoxy. . 4. The compound according to claim 1, wherein R ₇ or R ₈ is (C ₁ -C ₆ ) alkoxy; or R ₇ and R ₈ together are methylenedioxy. 5. The R ₇ and R ₈ together are methylenedioxy,
The compound according to claim 1. 6. The R ₂ is hydrogen, methyl, nitro, hydroxy, amino,
The compound according to claim 1, which is fluoro or chloro. 7. The R ₈ is hydrogen, methyl, nitro, hydroxy, amino,
The compound according to claim 1, which is fluoro or chloro. 8. The compound according to claim 1, wherein both of the bonds represented by ----- are present. 9. The method of claim 1, wherein R ₁ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy, or halo; or R ₁ and R ₂ together are methylenedioxy. Compound of. 10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ₂ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy, or halo. 11. The method of claim 1, wherein R ₃ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy, or halo; or R ₁ and R _{3 taken} together are methylenedioxy. The described compound. ． 12. The method of claim 1, wherein R ₈ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy or halo; or R ₇ and R _g together are methylenedioxy. Compound of. ． 13. The compound according to claim 1, wherein R ₇ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy, or halo. 14. The method of claim 1, wherein R ₆ is (C ₁ -C ₆ ) alkoxy, nitro, hydroxy, or halo; or R ₆ and R _{7 taken} together are methylenedioxy. The described compound. 15. The following is Formula II: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 16. A compound of formula III: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 17. The following formula V: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 18. The following Formula VI: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 19. The following Formula VII: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 20. The following Formula VIII: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 21. The following is Formula IX: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 22. The following formula X: embedded image A compound according to claim 1 or a pharmaceutically acceptable salt thereof. 23. The following compound: 2,3-dimethoxy-dibenzo [c, h]
Cinoline (6); 2,3-dimethoxy-8,9-methylenedioxy-dibenzo [
c, h] cinoline (14); 2,3,8-trimethoxydibenzo [c, h] cinoline (60); 2,3,9-trimethoxydibenzo [c, h] cinoline (61)
9-benzyloxy-2,3,8-trimethoxydibenzo [c, h] cinoline (42); 2-methoxy-8,9 methylenedioxydibenzo [c, h] cinoline (43); or 3-methoxy -8,9 Methylenedioxydibenzo [c, h] cinoline (44); or a pharmaceutically acceptable salt thereof. 24. The following compound: 2,3-dimethoxy-8,9-methylenedioxydibenzo [c, h] cinoline (14); or a pharmaceutically acceptable salt thereof. 25. The compound of claim 1, wherein R ₁ -R ₃ and R ₆ -R ₈ are not each hydrogen. 26. One of said R ₂ and R ₈ is hydrogen, methyl, nitro, hydroxy, amino, fluoro or chloro; or at least one of R ₂ and R ₈ forms a methylenedioxy moiety. A compound according to claim 1. 27. 9-Hydroxy-2,3,8-trimethoxydibenzo [c
, H] Cinoline. 28. The following formula I: [Chemical 10]   A is N or CR₃And   B is N or CR_sAnd   D is NR_eOr CR_aR_bAnd   E is NR_fOr CR_cR_dAnd   F is N or CR_tAnd   G is N or CR₆And   R₁, R₂And R₃Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₁And R₂Are together
Is methylenedioxy, and R₃Is hydrogen, (C₁-C₆) Alkyl, (C₃ -C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_g R_h, COOR_k, OR_m, Or halo; or R₂And R₃Together
Is methylenedioxy, and R₁Is hydrogen, (C₁-C₆) Alkyl, (
C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, N
R_gR_h, COOR_k, OR_m, Or halo;   R₆, R₇And R₈Are each independently hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₆And R₇Are together
Methylenedioxy, and R_gIs hydrogen, (C₁-C₆) Alkyl, (C₃-C ₆ ) Cycloalkyl, (C_l-C₆) Alkoxy, nitro, hydroxy, NR_gR_h
, COOR_k, OR_m, Or halo; or R₇And R₈Are together
Methylenedioxy, and R₆Is hydrogen, (C₁-C₆) Alkyl, (C₃−
C₆) Cycloalkyl, (C₁-C₆) Alkoxy, nitro, hydroxy, NR_gR _h , C (= O) R_k, COOR_k, OR_m, Or halo;   Each bond represented by ----- is either individually present or absent;   R_aAnd R_bIs a bond between the 11-position and the 12-position represented by -----
If not, each independently hydrogen or (C₁-C₆) Alkyl; or
When a bond between the 11-position and the 12-position represented by ----- is present, R_aIs water
Elementary or (C_l-C₆) Alkyl, and R_bDoes not exist;   R_cAnd R_dIs a bond between the 11-position and the 12-position represented by -----
When not present, each independently hydrogen or (C₁-C₆) Alkyl; or-
When a bond between the 11-position and the 12-position represented by ----- is present, R_cIs hydrogen
Or (C₁-C₆) Alkyl, and R_dDoes not exist;   R_eIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_eIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   R_fIs a water atom when there is no bond between the 5- and 6-positions represented by -----.
Elementary or (C_l-C₆) Alkyl; or R_fIs represented by -----
Not present when a bond between the 5 and 6 positions is present;   Each R_gAnd R_hAre independently hydrogen, (C₁-C₆) Alkyl, (C₃-C₆ ) Cycloalkyl, (C₁-C₆) Alkoxy, (C₁-C₆) Alkanoyl, Ali
Aryl, aryl (C₁-C₆) Alkyl, aryloxy, or aryl (C₁
-C₆) Alkoxy; or R_gAnd R_hWith the nitrogen to which they bind
Together with pyrrolidino, piperidino, morpholino, or thiomorpholino
Yes;   Each R_kAre independently hydrogen, or (C_l-C₆) Alkyl; and   Each R_mIndependently, (C₁-C₆) Alkanoyl, aryl, or ant
(C₁-C₆) Is alkyl;   Each R_sAnd R_tAre independently hydrogen, methyl, nitro, hydroxy, amine
No or halo;   Where R₁, R₂, R₃, R₆, R₇, R₈, Or R_kAny of (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Alkoxy is required
Optionally substituted on the carbon with 1, 2 or 3 substituents, which substituents are:_mHydro
Kishi, halo, NR_nR_p, (C₃-C₆) Cycloalkyl, or (C₁-C₆) Al
Selected from Koxy; where each R_nAnd R_pAre independently hydrogen, (C₁
-C₆) Alkyl, (C₃-C₆) Cycloalkyl, (C₁-C₆) Alkoxy,
Or (C₁-C₆) Alkanoyl; or R_nAnd R_pIt joins
Together with nitrogen, pyrrolidino, piperidino, morpholino, or thiomorpho
Reno;   Where any aryl is optionally hydroxy, halo, nitro, tri
Fluoromethyl, trifluoromethoxy, carboxy, amino, (C₁-C₆)
Rukiru, (C₃-C₆) Cycloalkyl, and (C₁-C₆) Select from alkoxy
Substituted with 1, 2 or 3 substituents;   However, 2 or less of A to G include nitrogen;   R₁-R₃And R₆-R₈Are not each hydrogen;   However, the compound is 9-hydroxy-2,3,8-trimethoxy-dibenzo [
not c, h] cynoline; and   However, in the compound of formula (I), A is CR₃And B is CR_sAnd E is CR_c
R_dAnd F is CR_tAnd G is CR₆And D is NR_eAn expression that is
Not a compound of (I), An effective amount of the compound, or a pharmaceutically acceptable salt thereof,   Including with a pharmaceutically acceptable diluent or carrier, Pharmaceutical composition. 29. A pharmaceutical composition comprising a compound according to any one of claims 1-27 together with a pharmaceutically acceptable diluent or carrier. 30. A pharmaceutical composition for inhibiting the growth of cancer cells, the compound of any one of claims 1-28 in an amount effective to inhibit the growth of the cancer cells. A pharmaceutical composition comprising. 31. A pharmaceutical composition suitable for contacting a cancer cell in vitro or in vivo, for inhibiting the growth of said cancer cell, comprising the compound of any one of claims 1-28. A pharmaceutical composition comprising an amount effective to inhibit the growth of the cancer cells. 32. A compound according to any one of claims 1-28 for use in medical therapy. 33. The compound of claim 32, wherein the therapy is treating cancer. 34. Use of a compound according to any one of claims 1-28 for the manufacture of a medicament useful in the treatment of cancer. 35. A pharmaceutical composition for producing an antibacterial effect in a mammal in need thereof for treating the antibacterial effect, wherein the compound according to any one of claims 1-28 is used as an anti-bacterial agent. A pharmaceutical composition comprising an amount effective to produce a bacterial effect. 36. A pharmaceutical composition for producing an antibacterial effect in a mammal in need of treatment for the antifungal effect, wherein the compound according to any one of claims 1-28 is used as an anti-bacterial agent. A pharmaceutical composition comprising an amount effective to produce a fungal effect. 37. A method according to any one of claims 1-28, for the manufacture of a medicament useful for producing an antibacterial, antifungal, protozoal, insecticidal or antiviral effect in a mammal. Use of the compound according to the paragraph. 38. Use of a compound according to any one of claims 1-28 for the manufacture of a medicament useful for producing an antifungal effect in a mammal.