IE47633B1 - Novel anthracene-9, 10-bis-carbonyl hydrazones and derivatives - Google Patents

Novel anthracene-9, 10-bis-carbonyl hydrazones and derivatives

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Publication number
IE47633B1
IE47633B1 IE2342/78A IE234278A IE47633B1 IE 47633 B1 IE47633 B1 IE 47633B1 IE 2342/78 A IE2342/78 A IE 2342/78A IE 234278 A IE234278 A IE 234278A IE 47633 B1 IE47633 B1 IE 47633B1
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IE
Ireland
Prior art keywords
hydrogen
bis
carbon atoms
compound according
anthracene
Prior art date
Application number
IE2342/78A
Other versions
IE782342L (en
Inventor
Keith Chadwick Pearl River Ny Us Murdock
Frederick Emil Ridgewood Nj Us Durr
Ralph Gassing Pearl River Ny Us Child
Jun Stanley Albert Stony Point Ny Us Lang
Ving Jick Airmont Ny Us Lee
Yang I Nanuet Ny Us Lin
Original Assignee
American Cyanamid Co
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Filing date
Publication date
Priority claimed from US05/943,908 external-priority patent/US4235996A/en
Priority claimed from US05/947,976 external-priority patent/US4187373A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of IE782342L publication Critical patent/IE782342L/en
Publication of IE47633B1 publication Critical patent/IE47633B1/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Abstract

The invention provides novel anthracene -9,10-bis-carbonyl- hydrazones and derivatives thereof useful as antibacterial agents, for inhibiting the growth of transplanted mouse tumors, and for inducing the regression and/or palliation of leukemia and related cancers. The novel compounds are represented by the formula: wherein A, B and C form an anthracene or a 9,10-dihydro anthracene nucleus, Z is a trivalent moiety of the formulae: wherein n is 0, 1, 2 or 3 and R is hydrogen, alkyl having up to 4 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, phenyl or benzyl; R1 is hydrogen or alkyl having up to 4 carbon atoms; R2 is hydrogen, alkyl having up to 4 carbon atoms, phenyl or monovalent moieties of the formula: wherein m is 2, 3, 4 or 5, R7 is amino anilino, hydrazino, monohydroxyalkylamino having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear a hydroxy group, alkylamino having up to 4 carbon atoms, dialkylamino where each alkyl group has up to 4 carbon atoms, cycloalkylamino having from 3 to 6 carbon atoms, benzylamino, alpha - phenethylamino, beta -phenethylamino 2-furfurylamino, 3-furfurylamino, alpha - thenylamino, beta -thenylamino, alpha - pyridylmethylamino, beta - pyridylmethylamino, gamma - pyridylmethylamino, indanylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-methyl-piperazino, alkoxy having up to 4 carbon atoms or alkylthio having up to 4 carbon atoms, X is oxo, thioxo, imino or alkylimino having up to 4 carbon atoms, and Y is oxy, thio or a divalent group of the formula: wherein R8 is hydrogen, alkyl having up to 4 carbon atoms or monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear a hydroxy group; R3, R4, R5 and R6 are each individually selected from the group consisting of hydrogen, halogen, hydroxy, nitro, amino, sulfonamido, alkyl having up to 4 carbon atoms and alkoxy having up to 4 carbon atoms; and R3 and R4 which they are attached form a phenyl group provided that in that case R1 is hydrogen and R2 is wherein m and R8 are as defined above and the pharmacologically acceptable acid-addition and quaternary ammonium salts thereof.

Description

This invention relates -to new organic compounds and, more particularly, is concerned with novel anthracene-9,10-bis-carbonyl -hydrazones which may be represented by the following general formula: (I) wherein A, B and G form an anthracene or a 9,10-dihydroanthracene group; R^ is hydrogen or alkyl having up to 4 carbon atoms; R is hydrogen, alkyl having up to 4 carbon atoms, phenyl 2 or a moiety of the formulae: — C-—C-Y wherein m is 2, 3, 4, or 5, Ry is amino, anilino, hydrazino, monohydroxyalkylamino having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group, alkylamino having up to 4 carbon atoms, dialkylamino wherein each alkyl group has up to 4 carbon atoms, cycloalkylamino having from 3 to 6 carbon atoms,'benzylamino, α-phenethylamino, 0-phenethylamino, 2-furfurylamino, 3-furfurylamino, α-thenylamino, B-thenylamino, a-pyridyjigethylamino, β-pyridylmethylamino, γ2 -pyridylmethylamino, indanylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-methylpiperazino, alkoxy having up to 4 carbon atoms or alkylthio having up to 4 carbon atoms, X is oxo (0=), thioxo (S=) or imino (R'-N= wherein R' is hydrogen or alkyl having up to 4 carbon atoms) and Y is oxy (-0-), thio (-S-) or a divalent group of the formula: wherein R is hydrogen, alkyl having up to 4 carbon atoms or mono8 hydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear an hydroxy group; group consisting of hydrogen, halogen (F, Cl, Br, I), hydroxy, nitro, amino, sulfonamido, alkyl having up to 4 carbon atoms and alkoxy having up to 4 carbon atoms and and R^ together with the carbon atoms to which they are attached form a fused benz ring provided that in that case R, is hydrogen and R2 is J-^m -C- N-Rg wherein m and Rg are as defined above,and the 20 pharmacologically acceptable acid-addition and quaternary ammonium salts thereof.
The hydrazono substituents pendant from the anthracene-9, 10-bis-carbonyl nuclei may be the same or different and may be in the syn or anti form. Additionally, where the hydro25 gen atoms or other substituents at positions 1, 4, 5 and 8 of the anthracene nucleus cause restricted rotation of the bonds extending from Cg and C1Q of the anthracene nucleus, then the entire units -CH=N-N^Rl at the Cg and Cjq positions may be either cis (both extending out from the same face of the anthracene 30 nucleus) or trans (extending out from the opposite faces of the anthracene nucleus). Nuclear magnetic resonance data for the hydrochloride product of Example 3 gives strong evidence for a mixture of rotational isomers at 29° (shows four peaks for -N(CH3)2: § 3.02, 3.05, 3.18 and 3.20) but at 85°C. the four had coalesced to a sharp singlet at 3.20 (in D2O). The quadruplet reappears on cooling. Thin layer chromatography at 24°C. shows two spots, as also do the S products of Examples 7, 8 and 14. Ultra violet absorption data were obtained on the products of Examples 3 and 4 which indicate that the double bonds proximate to the anthracene ring system have been jforced out of the plane of that system.
A preferred embodiment of the present invention consists of compounds which may be represented by the following structural formula: n-nh-c—Y wherein m, Y, R^, R^, Rg, Rg, A, B and C are as hereinabove defined.
The novel compounds of the present invention are obtainable as yellow crystalline materials having characteristic melting points and absorption spectra and which may be purified by reerystallization from common organic solvents such as lower alkanols, dimethylformamide, tetrahydrofuran and methyl isobutyl ketone .
The organic bases of this invention form non-toxic acid-addition and quaternary ammonium salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with one or more equivalents of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like. Quaternary ammonium salts may be formed by reaction of the free bases with one or more equivalents of a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. The organic reagents employed for quaternary ammonium salt formation are preferably lower alkyl halides. However, other organic reagents are suitable for quaternary ammonium salt formation, and may be selected from among a diverse class cf compounds including benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate ethyl tol’uenesulfonate, allyl chloride, methallyl bromide and crotyl bromide. For purposes of this invention the free bases are equivalent to their non-toxic acid-addition and quaternary ammonium salts. The acid-addition and quaternary ammonium salts of the organic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene, and the like.
The novel compounds of the present invention are useful as antimicrobial agents and possess broad-spectrum antibacterial activity in vitro against a variety of standard laboratory microorganisms as determined by the standard agar well diffusion assay. In this assay, the minimal inhibitory concentration (MIC) was determined by using twofold dilutions of the compound in nutrient agar. One ml. of each dilution was placed £n a sterile Petri dish; 9 ml. of nutrient agar was added to each dish. Five-hour cultures of the indicated _2 organism in Trypticase Soy Broth were diluted 10 in nutrient broth. This dilution of each culture was transferred to the •surface of the plates by using a Steers replicating device. After incubation at 37°C. for 24 hours, the MIC was recorded as the lowest concentration of the compound which-completely inhibits the macroscopic growth of each organism. The MIC of typical compounds of the present invention against the indicated organisms are set forth in Tables I and II below.
TABLE ιη ιη ο «—r ΓΊ Ο ΓΊ ο rl ιη σ ιη ιη 1 I 1 1 ιη rl ΓΊ ο ιη Η ί 1 1 ί ιη ΓΊ ο ιη ι 1 I ΙΛ ΓΊ ΓΊ ιη rl ιη ί 1 ιη ΓΊ ΓΊ ΓΊ - - ιη ιη ο ιη ο ο ο ΓΊ ΓΊ ο ιη rl ι-Ι ΓΟ ΙΟ υ ο S ιη rl Η U α § φ Ui CO ο ΓΊ «3* CO «3* ιη *3* rl Ο rl U U Ε·) «Σ ΓΊ Η ε ♦Η Φ S' ο Ρί 01 01 σ» Φ 01 ω φ φ φ ο 01 •Η 2 Φ β rl φ ο 0 Ό Φ φ φ rl •rl Η β •rl Μ σ θ’ ω C < Ή X α 0 0 0 er •Η φ > Μ •Η £ 0) β U CM Φ rl 3 •Η Μ Φ 01 Φ 0 φ U Φ X - 0 01 ϋ β φ Φ β 0 3 14 α σ φ ϋ ϋ Φ φ rl 0) ο ϋ X •Η φ S Φ φ ϋ η ϋ α r-4 > β rl 0 0 φ υ Η 0 1—4 0 X Ή Φ 01 b Φ > χ 0 Μ •Η φ 0 β X ρ Η Φ 01 φ 73 . 0 α φ Φ • X A X α Ε φ Μ X ϋ .Φ 0 φ rl 4-1 X C Μι rl X ω Φ ω W ω ω CM CM ω Φ >5 Φ 7? γ·I Φ X Φ 0 73 X •rl Μ Μ Φ 0 □ rl •Η X 73 ϋ Φ 0 β Η Φ 73 υ > Φ X tl •rl Ω X β Φ φ β 1 •rl σ «—« 7J rf φ •rl ·. 73 β ΟΝ Ή Φ Ν β U-J Φ CP 0 X ρ4 Φ Μ 73 C Φ r—· Φ 0 ϋ β Ν •Η 0 0 Φ ε rl Ν X φ •rl Φ μ 01 φ 7J •rl Φ·Η Ό 0 Μ Ό»ΰ ο >, *^Χ Ο ·Η Μα 73 Χ~* •rl · ^· οχ 'φ’ό —* —4 £ ‘3 73 χ •η ο £43 β φ Να β C 9« £2^ I JJ W Ci Η < X ι Ο Οσ» r-t •Hy_j ΰε gg S,N τ?Φ ££ Χ71 Φ£· £5 a? •rd CS 42^ φ >* C I Φ™ ri I r P o CN a£ I τ! r-l Π ON * — Ol - *-*O O i—l 01 i—I i—l i—l Ui » Ή ·· * «. ’r-i Η « σ\ on h ca M U Φ O X 73 Ο «Η •r! >vrl X βΧ 6 X φ rl Φ —* β >1 01 01 >» β ·Η ·Η Φ ·Η Φ Λ •Η Ό •Η ·Η Φ Φ ^ετί73 45 Ή >ι > X H X X Φ >% Φ Φ ε CM 73 73 I ΗΗ Ui ΓΊ Φ Φ •HI XX 43 Ο Ο Ο Φ υ 43 X CO U >4 Φ >ι Φ Φ η χ υ υ Φ Ή ·Η Η Μ 73 73 χ X Φ φ X Φ β β α £4 φ φ < ι σ υ I νο Φ Φ ο *. U Μ rl ιη X χ - % X X σΐΊ· c C ι ι r-4 ΓΊ fO *3· in kO o cm o tn m m © 1 w cm cm ci H Minimal Inhibitory Cone. (meg./ml. in I ο I © ι t * t-1 fi in ci ο · I in ι I I I I I H cm > © lfi a o o υ ε* in r-i O o ϋ «4 § CM ϋ tn r- g CO § in σι tn Ul ω fl fi 3 0 QJ 0 O Ul fS fl QJ fi C rl fl U 0 IQ ε ρ 0 0 rH •H fi •rl & 3 IT rr co c •rl fl 0 fl 0 0 υ CT fl g ρ •r4 ε Ul fi fl» Ul Ul & 0 r-f 3 •rl ρ y 3 fl 0 0 P 0 o g ϋ 0 ϋ fi fl fl fi 0 fi p U σ •rl o ϋ 0 fl fl U) ρ ϋ O fi •rl fl 3 fl QJ υ 0 ϋ Λ fl > fi fi 0 CJ fl. υ r4. 0 0 0 Λ •r| 0 Ul ε fl fi 0 P •rl fi 0 XI .rt Q p 0 Ul QJ τί o 0. 0 0 4= fi fi 3 ϋ a P fi ϋ 0 0 0 >, fi ' fi fi Ul f—1 ρ Ul •τ* ω w ω M ft CM fl i V} •rl *3 •rl 4J •rl u 0) 4J fi Ό •rl Ά o •H U •3 >v fi •rl 0 Q *0 -rl U flj <ΰ 0 -P •rl 0 W U CJ Ό «Η Ό >1 >-rl fi JZV •r| 4J Ο Φ a 0 -r| Ό ε ο-h 0 •rl Ρ P CQfl 0 0 fi »3 fi Λ •H •H -rl 0 Ό ϋ Ω 0 •rl fl P rl 0 nJ QJ Ό •r). $4 O r-1 XS ϋ Ο Μ □ C 0 ν -π -ri x: x: nJ Ό nJ ·Η □ >, Ό -H -rl Q Of •H g fi k o g *rt fl 0 *3 γΉ N fi Ό > I fl ©-rl x: < I U > fl Q q K fl fi Ρ XJ >, u +j nJ QJ μ x: o qj a •Ρ ·Η 6 fi >1 U Φ Λ I -Η .C pt».' •Η 1 1 flJ Ό cn w «—» rf 1 -rl’H 0 fl co fi Xi C X ·» >1 0 i-fr-ir-i •3 fi XJ ο O fl fl ί -P r-f rl >t O fl •r| ·Η ·Η J3 ·Η < S p Ρ -Ρ Ό | -Ρ -P 0 0 O QJ -rl -rl S C fi C C •rl 0 - •H 0 0 tJ ϋθ7 N fi fi 0 fl fl >t >, fi Mw •Η Ό Ό »H Λ η Ά *r| *r| rH -fi QJ fl fl >1 fi Λ »0 >1 >1 P < O >,£££ ι c 43 4J+14JO n Q) QJ QJ C «Η N ό e ε to * a r| **-* *·* I Ο p fl W Vi © fl χ -Η ·Η r-f tu >. 0ΛΛ *· θ£ XJ QJ QJ σ» UGG —— > fl ·Η ·Ρ 0 0 | Ο r| ι-l C fi OJ r| 5>j Si’H O | ffl p p Ο N fl 0 fi Λ >1 A -rl fl 4J -P ft Ρ κ occ tnflj o O flj < rl > N fl | I fi fl O O X r-l f£j 45 fl fl -P Sh-p •fi - - CJ fi £ C σ> σ\ £ fi κ rtj ’—•'—'Ή 0 ι I I I QEn © - - I — pmp Z in * * - *··*<-H 07 ro H 25 CQ £} r-l CM <*» O' in ID The antibacterial spectrum in terms of the concentration required to inhibit the growth of various typical bacteria was determined in standard manner by the agardilution streak-plate technique for the following compounds in Table III. A Steers multiple inocula replicator was used with incubation at 37eC. for 18 hours in Mueller-Ninton agar. The results for 7.12-bis-(2imidazolin-2-ylhydrozone)benz[a]anthracene-7,12-dicarboxaldehyde dihydrochloride, a typical compound of this invention, are set forth in Table III as the minimal inhibitory concentration (MIC) in micrograms per milliliter.
Table III Test Organism MIC Staphylococcus aureus, OSU 75-2 16 Staphylococcus aureus, Q 74-11 8 Staphylococcus aureus, St. Paul (NYC 78-1) 8 Enterococcus, SM 77-15 8 The novel compounds of the present invention also possess the property of inhibiting the growth of transplanted mouse tumors as established by the following tests. Lymphocytic leukemia P388 test The animals used are mice all of one sex, weighing a minimum of 17 g. and all within a 3 gram weight range.
There are 5 or 6 animals per test group. The tumor transplant is by intraperitoneal injection of 0.1 ml. or 0.5 ml. of dilute ascitic fluid containing 10S cells of lymphocytic leukemia p388. The test compounds are administered intraperitoneally on days one, 5 and 9 (relative to tumor inoculation) at various doses. The animals are weighed and survivors are recorded on a regular basis for 30 or 60 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals are calculated. The positive control compound is 5-fluorouracil, The results of this test with representative compounds of the present invention appear in Table IV below. The criterion for efficacy is.T/C x 100=^-125%. '10 o O μ C Φ X ϋ μ U Φ ιη cm rn σι H in co r* in Ν Η Η H rH CM t XJ1 cm cm co in in rt co ιο in χ* rt CM I I 10 cm φ μ* o in co m ι© in Η Η Η Η H c m 10 > M rl ·Η > Ό > <0 gss (0 in σ ο o in rtr-ooit'CM rH CM rt rH O • rd rH ιη ο ιη ο ο ιη ο ω γ* ιο CM CM Η rH rd ο in o in o © r*. co io id CM <-H rd 1-H rd © rH tr Φ X W'x 0 Q tr| in r» in p- rt so rt rH o o o in cm »~h ° CM rH CM 10 rt rH Ο rH Lymphocytic Leukemia P388 Te3t Φ •d ι μ O 0 H rH *43 σι ϋ Ο μη μ Ο *2 -Κ j? 0) «Η β Ό ο Ν Φ β υ μ >ι Ό Χί >1 Φ Χί »0 Η Η >1 Λ ( Κ ΓΜ Ο I Λ β μ •rl β rd υ Ο ·Η Ν Ό β 0) _ β •rl φ β ϋ •d β ι μ CM XJ μ W β *d β tf I Ο μ μ β ο υ •rl ϋ β μ β ο μ § rH ft I in •d μ •μ •rl S a •C •rl rH si ω ttl Efl —*·Η in m •h o od ο n c o a o r4 fi t»O AS? 4J-rf C Ό < I ni o fi rH *d -T3 cn .rf β I β - 2 rH &» *«d rH *X3 rH •d ϋ β μ μ ό Ό >* >ιΛ Λ-ri rH 13 >1 β Φ •d 13 13 >ι •d x; ε •Η Ό M rH β ft M I 0 CM μ 1 μ 0 β μ 0 13 •d >ιΌ Χί φ β β μ φ μ □ φ β μ μ 1 43 10 μ * fi in β rd μ χρ Ο 13 0 0 »» rH *d μ 2 rH *. μ μ γΗ ‘-όι ο β ft U) rd 0 1 •d ΜΗ υ ιη tf 0 0 μ μ β Ο U -Fluorouracil 60 146-236 π Lymphocytic Leukemia P388 Test o — ο «3 KO KO KO ft β QJ CO rt ΙΠ CM ΙΠ rt CM ’ 1 τρ cm σκ in rt CM tp p- o in rt ft rt CM LD ΙΠ ^3* rt CM ft co in τρ t KO CM © rt P- Tp 1 KD CM ft ft ft KO CM CM CM ft ft ft ko U 0 Tf Tp TP ft ft ft •Et — ft C fi rt > w in ο o tn o o rt © rt o o rt ftft >1 OS P- KO TP tP η o r* kd ft σκ in cm r> cn in ft ω m Q S3 — ft CM CM ft ft ft CM CM CM ft ft ft ft w CM KD 00 KO CM KO co rt CM KO CO Cp m r-i in r* CM ft rt > in cm ft rt r- 0 Λί OJ \ in cm rt ft o o o • » « · rt rt ft o o O rt cm vo rt ft o o o z Q O' CM ft KO KO CM ft KO E 0 X“\ 0 ft ft fi •ri fi -|J •fi ft ft β 0 fi 0 0} 3 0 0 fi Ό 0 C Ό >ft N >Ι·Η »b Ό rt Ό tJ «4 Q fi •Η O ft ft 0 V ft ft >1 0 Ό >i & fi JS fi Ρ Π3 λ τ’ +i >a Ό GJ >i ω >t g > c £ Λ *3 js Β F 0 ‘—’ft ft -fi '—ft 0 « Ω , rt 0 0 Ω H X E ft £ J3 —‘ 0 ft § QJ V Λ >1 0 0 u fi fi fi ι fi fi 0 ft rt CM 0 ft ft Π3 0 1 ft »0 •η 0 b’d fi fi u a fi fi JS rt 0 ft C <4) +> fi C r-4 ft +) 3 ft fi cn ft ο ο ω ft 5 51 •ri pH ft 0 U Nfi 0 ? 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QJ «fi Ό °3 — fi 0 0 fi Λ ° y N fi fi υ fift Ό »3 >i I Λ CM ft ft >i * . ι r CM ι I 0 fi fi ft 0 ft 0 o fi N fi fi JS Ό 4J •gs ft I—» I fi CM »— — N 0 fi ft 0 ffl Λ ft fi fi § fi fo I rt I I 0 0 fi fi »3*3 ΛΛ ft ft »3 *3 I CM 0 ft >3 * >1 r js — X fi 0 fift 'fi *3 >< I JS CM ftft >1 * I r CM I 1 0 fi fi ft 0 ft υ o fi N fi fijS i0 4J ft r ε « ai 0 ft r-. 3 fi ft o t fift 0 0 fi 3 fi 4J — N 0 ft +> fi 0 fi ft fo fi 0 η ai Λ 1 0 O CO J3 0 rt u ft ft ο fi fi Lymphocytic leukemia L1210 test The procedure is the same as for the Lymphocytic leukemia P388 test except that the tumor transplant consists of lymphocytic leukemia L1210 inoculated at a concentration of 103 cells/mouse with a mean survival time being calculated and the test compound is administered only on day one. The results of this test with a representative compound of this invention appear in Table V below. The criterion for efficacy is T/C x 100 125%.
Lymphocytic Leukemia L1210 Test T/C x 100 (Percent) u· ro r- r* ro ro ro ro ro ro ip i co rd rd rd rd rd rd Median I Survival 1 (Days) cm ro u* co ro *3* * « · « · · · © rd Ο Ο Ο Γ* M* rd rd rd rd rd rd O' rtx Vl\ 0 · O tr © © ro ro ro © © O ro CM rd © rd CM Compound a) Ό ‘rl I k o 0 rd rd *x ro ϋ 0 < rt X Ό rd rd rt ι κ ro o l X β k •rd rt rd ϋ rd 0 id *H N *0 0 rt rt fl τι β y •rd <11 β g ϋ 0 •rd rt rd k Ik 0 0 ss n ns pa. •H nJ 0 1 £Q I_r> m - I Melanotic Melanoma B16 The animals used are C57BC/6 mice, all of the same sex, weighing a minimum of 17 g. and all within a j g. weight range. There are normally 10 animals per test group. A one5 -gram portion of melanotic melanoma B16 tumor is homogenized in 10 ml. of cold balanced salt solution and a 0.5 ml. aliquot of the homogenate is implanted intraperitoneally into each of the test mice. The test compounds are administered intraperitoneally on days one through 9 (relative to tumor inoculation) at various doses. The animals are weighed and survivors are recorded on a regular basis for 60 days. The median survival time and the ratio of survival time for treated (T)/control (CJ animals are calculated. The positive control compound is -fluprouracil given as a 20 mg./kg. injection. The results of this test with representative compounds of the present invention appear in TableVI below. The criterion for efficacy is T/C x 100 .> 125%.
Melanotic Melanoma B16 Melanotic Melanoma B16 © © X rd β rt rd CM rd ro cm © r* ro rd κ u CM rd © ro Γ* r*· d* cm ro k CM CM rd rd rd rd rd rd rd ϋ rt \0< fi “ rd fi nJ — in © in o © ro ro © *3« © - rt > w rd Ή r· ro cm t·* CO o © ro cm Γ* CO Ό > nJ ro ro ro rd CM ro CM CM CM rd CM QJ fi Q S rt co σ rt X in r* ro W X ' o ro rd o o © CM ro ro rd O © Q & CM rd CM ε X 1 0 0 k ι rt -*O Id fi rt >i fi-rj fi X QJ ifi 0 id fi-H N Q rt T3 rt k rt •η rt Ό Ό . rd cn >1 >1 * •Πτ! »σ rd QJ fi >, β >tO rt x 3 X rd E -fi 0 X rt ·— ο) Ρή rt κ n ix Ss g o •d κ 0 H x X 0 υ >1 k rt k I rt fi Ό CM O QJ >i I id ΗΛ fi Ό r*1 ' •rl QJ k CM * rd fi Λ rd 0 •rd X 1 rt •d N □ 0 fi η Ό 0 rt rt rt 3 ·—‘id rt »0 k k 1 Μ Ό k •rd X rt ©id 0 rt g -k o rd X «rl p Id fi k . 0 rd k ι rti rt 0 0 <Λ —. fi 0 0 CM 1 TJ k rt ·— 0 Ό k rt *-* O »d X rd • rd >1 X rd W rd »0 fi Cu rd *d X c fo id * 0 n * k *d υ I tt σι -fi u ro im +i a u ro ro σ» m o r* ro u* tn CM CM CM rd σι ro u· r* oo ip ip CM rd CM ro rd © ro I Ud rd 0 rt κ <—· o rt X fi k O rt N o rt ή k Ό ro rt £lfi Λ QJ ι-H O NnJ -2 I H? d Λ sZ I -fi o fi fi·Ή nJ -g Η I g Ο o g N rd Ό rt - >» Ό σ\ ·© Ή I X EHa •rl >j rd I X QJ O CM X Ίί k rt >ι X w ex •η ι oj Λ CM Ό co rd in CM rd •rl O rt k rt o k O rt rd fo I in o — Ο 44 r-4 fi Φ χ υ μ υ φ ΕΜ~ ©mom© Ο Γ»Ο Η> m Οί (Ν OJ Η > © rM •e rM © M· © p* © Ol rM rM oi rM -^ © m © rM co © m rM Ol rM rM rM m in rM fi fi — ra > w Η Ή TJ > fi φ μ Ω S ω ο m m m co © m m m οι rM rn m o © rM oi m m xr m rM m rM O r> oi in ο o m o © o in r-j © © m tr m m οι rM Melanotic Melanoma B16 © Φ44 « X · Ω © ε © m οι η m m oi © m rM o o © ιη η rM m oj © m rM rM O OI in rM m tn oi rM tfrlOOQ μ ο ι rM 0 λ μ Ο *3 I Ol 43 •H UM Q 0 Φ — TJ Φ tn firfi Ο Φ Ν XJ fi rM U fi •3 X >10 43 43 rM M >1 fi I o Ol ‘.M I *3 fi Φ •«Μ fi Φ υ fi μ >3 43 •μ 44 β c φ •μ fi *3 I I Ή οι ο μ '-’rM 0 (fl *· rM •μ © xj tt ι u ♦μ υ fi μ μ ο «-Μ •μ μ «Ρ •μ c φ c >1 Φ τί *σ •μ ·μ rM »3 >ιθ ‘3 φ μ ε >ι '-'Χί (0 ·μ •μ Ω 43 Φ Φ C C Φ·μ rM TJ >,·μ μ fi fi 3 C © J tn © 43 rM -Ρ * Φ © 6 ·— I I m Ζμ ii * ·μ <ΜΑ γΜ •μ υ fi μ ο μ § I m ο Φ rM Ό •μ ·μ μ μ UJ ο •μ rM C Χ3 Φ 0 C Ο >iH Τ3 Χ3 Η >t rM 43 !μ·μ Φ — Sg w ·μ •μ *3 Λ ·μ Φ fi fi fi Φ 9 Η © &S ΛΛ 44 44 fi Φ < ε ι ·<μ ο TJ rM I -m © “ —·‘ rM rM (fl *·μ H43 μ C U -Fluorouracil Melanotic Melanoma ~B16 MelanoticMelanoma B16 x 100 rcent) r* in c* h σ» to xr m* HPPH CO to rp 192 150 129 168 1 O © CO rp © in rt rt d rp rp rP r> co fi O 0 Vfa fi fi fl in © © © © tn o in © © in O O O O o fl > ω fi fi Sh Π3 > fl m co in *3* rt rt d d fi co d ri in d rt d d rp co CM cm m d H ci cn rt rt © fi o rt oc so w Oi 0 fi in in W X a · rt © rt fi o o d © rt © © rt © rt rp o © Q CP ε rl d fi d rP rt 4) nJ ι | •rp © >1 © >1 1 P rlfi rp »fi 0 0 P fi cn nj 00 Ό nJ fi >i 0 X 0 *«« 0 fi 0 0 *0 dl Ό fi P fi >1 fi >1 Ό Ό Ofi N 0 0 fi N 0 1 >1 O fi fl Ό nJ Ό fi fi p fl P rP -Ό »tj fl Ό nJ 07 X I 0 fi 0 X! 0 *->nj rd Λ >1 P 1 10 rp fi >1 P I fl 0 >i fi fi 0 0 CM U CM 0 Μ *o fl fi 2 fi *3 •H 0 fi nJ fi 0 P fl flX g fl fi fi fi >1 0 o 0 0 0 0 fi fi Gi e N U fl fl N U fl fl fi p Nfl o Ό P Ό P 1 u u •r| fi •Sfi •rlfi g fi CM fi ι nJ •5 a β OJ 1 § 1 fl •rl fi fi d ι fi fi 0 fi **· o fi —*© •rl 0 0 •rl 0 fl U 0 fi ϋ N fl 0 fi ·. 0 fl •rp - 0 fl nJ P fl Α σι nJ 1 1 fi P fi A 07 nJ I 1 ή P s *3 fi fi fi P fi fi 0 P 0 η η ρ 0 § s 0 ·>, p 0 P P P 0 fi P •n fl fi P ±5 nJ fi 0 0 0 nj rP 0 0 rt o 0 0 P >i*C p fi rd >lX! P fi P fi 0 XJ ϋ •P rp ΛΛ O fi A *— fi fi fi S'H 0 fi fa 1 U-H 0 fi fa 0 » fi fa i *o p n 1 Ό P 0 | fi 07 0 1 © Ν 1 Ό υ in rd 1 Ό u in CQ I U Ο —- © μ Η β φ X ϋ k U Φ Xfe co in γί μ tn co co in μ in Median Survival J (Days) © in ρ o tn in Η o in cm io in μ μ γί γί μ γί χ“<» • Dl Φ 44 W \ 0 · Q 5» ε ιη ιη γί μ μ ο © © ΓΊ Compound β k Λ μ β β Γ-Ί β Ν β 5 μ 0 Φ* β 0 Μ β φ k Ό *0 >1 >ιΛ £ Φ HTJ > μ 1 β ΓΊ X •Η k μ « μ ο ο μ Μ μ υ β Ό β Ό I k μ γί 3 SH 0 μ *» μ k I Γ* 0 0 γί 1 k 3 *-* φ μ μ ω β 3 fe μ Φ οι η ϋ · υ ιη The novel compounds of the present invention exhibit antibacterial activity when tested according to the following procedure. The antibacterial spectrum, in terms of the concentration required to inhibit the growth of various typical bacteria, was determined in a standard manner by the agar-dilution streak-plate technique. A St?ers multiple inocula replicator was used with incubation at 37°C. for 18 hours in Mueller-Ninton agar. The results for typical compounds of this invention are set forth in Table VH below as the minimal inhibitory concentration in micrograms per milliliter.
TABLE vrr 0 3 0 ϋ 0 ϋ in ft l Ρ» KO KD kd 0 P- ft tn in fi Pl Pl a? s χ·· 4J ω • c ft H • 0 σ 3 o 0 g 0 ft ft 0 ω 3 1 0 3 fi 03 co c 0 0 cu r> TP co ο fi KD Pl PJ •η 3 . a ft ft •μ JS fi +> X ε a Cu ω z; 0 fi fi ft -U 4J fl fl fi 0 Cn ϋ ω fi fl ω O 0 3 u 0 4J 0 in >, 0 0 ft 0 fi. 0 3 ft co £-< 0 0 fi 1 CM TP +> fi τρ co KD CM ft >1 3 ρ» ft JS JS fi ft a a 45 fi fl JJ H ω ft fi. 0 E 3 ft 0 fl 0 PJ ft 0 0 | s 0 3 in co 0 01 Ρ» co CO fi Pl Pl CM >1 3 P ft ft ft JS fi ω a o fi jj co 1 1 fi1 fi fl TS β Ό fl I •rt > ft >1 Q fi ft 1 JS ft 1 JS tt fl 0 0 fi 0 0 fi fi fi tt fi TS N fi TS fi 0 flO ft fi TS ft TS fi Ό >i rt Ό >irt >iM· •rt 45 X •rt45 X rj r- E'rt 0 E’rt 0 TS ft ΰ ft TS JS •rt TJ 43 c >1 fl1 1 y 1 1 fi 3 1 fl Ν o rt CM © fi 0 cm ι *-ft 0 *-ft 0 Π I o I —rt I -ft £ eft ω © ts 0 © TS 0 ft * qj ft I fi ft 1 fi u rlinU 43— β JJo fl fi 0 1 >1 1 fi fi J fi fi TS tt 0 JS o X5Ort rt rt ω XO rt X 0 fi fi TS Ό *3 0 « c 0 N rt 0 ft >tft 43· rt 45 45 rt 4^ rrt ε js a P fi «Ρ ft fi ft JS •rt-rt X • fi TS fl fi TS fl 0 1 TS 0 E >4 rt E >4 rt o pi ι ja ftJS 1 •rt 45 1 rt —© μ a ft o Ω ft O TS 1 H 3 t >lft 1 >4-1 >1 0 *. 0 TP 1 * τρ ( ·. JS •pi cn - Pl © ft m ι ό ft I 1 Η 1 1 Ό The novel compounds of formula (I) and their pharmacologically acceptable acid-addition and quaternary ammonium salts would be expected to show activity against a'broad range of cancer diseases, and especially blood cancer diseases such as leukemia, in standard test animals at doses substantially below toxic levels. The modes contemplated for administration are essentially parenteral and intraperitoneal.
Solutions of the active ingredient as a free base or salt can be prepared in water or in water suitably mixed with, for example, surfactants. The preferred compound, where m is 2 and γ is imino in formula (II) , is slightly soluble in water. It can, for example, be converted to an acetate having. a pH in aqueous solution of about 7.4 which, on analysis, shows about one acetic acid residue per anthracene nucleus.
A diacetate may also be produced having a pH in aqueous solution of about 6.2. The diacetate is soluble in water to the extent of about 400 milligrams per milliliter of water.
The base or various salts may be made more soluble by the addition of surfactants such as hydroxypropylcellulose to the composition. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical compositions can be in forms suitable for injectable use, which forms include sterile aqueous solutions or dispersions and sterile powders for the extemporanous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a I solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liguid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the reguired particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can b'e brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, ’followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumer25 ated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile30 filtered solution thereof.
As used herein, pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coat34 tings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, its use in the present compositions is contemplated. Supplementary active ingredients can also be incorporated into the inventive compositions.
It is especially advantageous to formulate compo10 sitions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique character istics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated, the particular condition and its severity; the particular form of the active ingredient and the route of administration. A 30 daily dose of from about one to about 100 mg./kg. of body weight given singly or in divided doses of up to 5 times a day embraces the effective range for the treatment of most conditions for which the novel .compounds are effective and substan tially non-toxic. For a 75-kg. subject, this translates into between about 75 and about 7500 mg./day. If the dosage is divided, for example, into 3 individual dosages, these will g range from about 25 to about 2500 mg. of the active ingredient.
The preferred range is from 2 to about 50 mg./kg. of body weight/day with about 2 to about 30 mg./kg./day being more preferred .
The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for example, contain 'the principal active ingredient in amounts ranging from about 0.1 to about 400 mg., with from about one to about 30 mg. being preferred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 400 mg./ml. of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of ad20 ministration of the said ingredients.
Regression and palliation of cancers are attained, for example, using intraperitoneal administration. A single intravenous dosage or repeated daily dosages can be administered. Daily dosages up to about 5 or 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administrated is a sufficient amount to aid regression and palliation of the leukemia or the like, in the absence of 3° excessive deleterious side 'effects of a cytotoxic nature to the hosts harboring the cancer. As.used herein, cancer means blood malignancies such as leukemia, as well as other solid and non-solid malignancies such as the melanocarcinomas, lung carcinomas and mammary tumors. By regression and palliation is meant arresting or retarding the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence of treatment.
Most of the novel compounds of the present invention may be readily prepared as set forth in the following reaction scheme: wherein A, B, C, Rj., Rj' ®3' R4' ®5' R6 are as hereinabove defined.
In accordance with the above reaction scheme, an appropriately substituted 9,10-anthracenedialdehyde III is reacted with a hydrazine derivative of the formula: HjN-NR^R to provide the 9,10-anthracene-bis-hydrazones (I). The reaction is carried out in a lower alkanol in the presence of an acid such as hydrochloric, hydriodic or acetic (or glacial acetic acid may be used as the sole solvent) usually at the reflux temperature of the reaction mixture.
Other reaction procedures are as follows.
R is H or lower alkyl, R' is lower alkyl and R^ is -C-Rn or wherein I 7 II I 2 X Ν—Y X, Rj, Y and m are as defined before.
In accordance with the reaction scheme a mixture of the anthracene derivative and 2 to 2.5 molar equivalents of this amine in a lower alkanol is heated to 50-120° for 2 to 10 hours to give the desired product. (2) In accordance with the above scheme a mixture of the anthracene and 2 molar equivalents of the methylthiourea in a lower alkanol is heated to 50-120° for 2 to 10 hours to give the desired product.
The starting 9,10-anthracenedialdehydes may be obtained commercially or prepared in accordance with any one of the reaction schemes denominated (A), (B) and (C) below wherein A, B, C, Rg, Rj, Rg and Rg are as hereinabove defined.
(VI) In accordance with the above reaction scheme, the anthracene derivative (IV) suspended in dioxane and concentrated hydrochloric acid and saturated with HCl, is treated with paraformaldehyde at the reflux temperature for 2-6 hours to obtain the 9,10-bis-(chloromethyl)anthracene derivative (V). This 9,10-bis-(chloromethyl)anthracene, suspended in dry dimethyl sulfoxide under nitrogen at room temperature, is treated with sodium in ethanol and worked up as described in tha examples to obtain the desired 9,10-anthracene dicarboxaldehyde (VI). 47633' (Β) (VII) OSi{CH3)3 OSi (CH3) (VIII) (CH3)-Sio (CH3) 3 SiO C'HN(CH3)2 CHN(CH3)2 (IX) CHO CHO (X) In accordance with the above reaction scheme, the dihydroxyanthraciuinone (VII) is treated with trimethylsilyl chloride in dry tetrahydrofuran in the presence of triethylamine to obtain the trimethylsilyloxy derivative (VIII). The latter compound is then dissolved in tetrahydrofuran and treated with an anhydrous diethyl ether-hexane solution cr [α-lithio-a-(N,N-dimethylamino)methyl]diphenyIphosphine oxide at room temperature to obtain the bis-enamine (IX) which, without isolation, is hydrolyzed by the addition of a 90¾ formic acid solution to give the hydroxy substituted 9,10R-y -anthracenedicarboxaldehyde (X).
(XI) (XII) R6 In accordance with the above reaction scheme, the anthracene derivative (IV) is heated with excess vinylene carbonate under reflux for about 10-24 hours to give the cyclic carbonate (XI) in which D and E are 0, S or NH, F is =0, =S, =NH or cyclohexyl and R? and Rg are H, alkyl or aryl. Hydrolysis of the cyclic carbonate (XI) with aqueousethanolic potassium hydroxide at 70o-75oC. for about 1-4 hours produces a diol (XII) which in turn is treated with lead tetraacetate in acetic acid at 20°-35<,C. for about 10 minutes to 2 hours to give the 9,10-anthracenedicarboxaldehyde (VI).
Other methods for the preparation of the intermediate dialdehydes are as follows. ι, I In accordance with the above reaction scheme, the anthraquinone (XIII) is treated with dimethylsulfonium methylide (or dimethyloxosulfonium methylide) in dimethylsulfoxide at 1040°C to obtain the dispiro [oxirane-2,9'(10Ή)-anthracene-10',2 oxirane] (XIV). The latter compound is rearranged with lithium bromide (or lithium perchlorate, boron trifluoride, magnesium bromide, trifluoroacetic acid and methanesulfonic acid) in organic solvent to obtain the 9-formyl-10-hydroxymethylanthracene (XV). The 9-formyl-10-hydroxymethylanthracene is then oxidized with 0chloranil(or dichlorodicyano-1,4-benzoquinone, dimethylsulfoxide, diethyl azodicarboxylate, lead tetracetate, nickel peroxide, manganese oxide#chromium trioxide and selenium oxide) in an organic solvent at 20°-100° to obtain the 9,10-anthracenedicarboxaldehyde (XIV).. (2) XIII } XVI In accordance with the above reaction scheme, the anthraquinone of formula XIII is treated with dimethylsulfoxide dianion in dimethylsulfoxide atl0-40°C to obtain the 9,10dihydro-9,10-(methanothiomethano)anthracene-9,10-diol 12-oxide (XVII). The latter compound is treated with acetic anhydride and then with 88% formic acid to obtain the 9,10-anthracenedicarboxaldehyde (XVI).
VI The 9,10-dimethylanthracene (XVIII) in a solution of acetic acid, acetic anhydride and sulfuric acid is cooled to 0-10°C and treated with 2 molar equivalents of chronium trioxide to obtain the tetraacetate (XIX) which is then hydrolyzed at 20°-50oC with a sodium carbonate solution to obtain the dialdehyde (VI).
Other oxidized agents such as selenium dioxide and ceric ammonium nitrate may be used for the oxidation. '3 R R.
R O=C-R XXI XXII R in the above is H, alkyl or GOOCHor COOH.
In accordance with the above scheme a mixture of the anthracene and an excess of the acetylene is heated without solvent or with an organic solvent such as xylene to 50° to 150° for 2 to 20 hours tp give the adduct (XX).
The adduct in a solvent such as ether or dioxane is treated with osmium tetroxide in the presence of pyridine at 10°-60° for 12 hours to 2 days and then with mannitol to obtain the cis glycol XXI. Compound XXI is then treated with lead tetra-acetate in acetic acid at 20-60° for 1 to 5 hours to give dicarbonylanthracene XXII. When R is COOH, compound XXII is heated in quinoline or pyridine at 100-180° to obtain the 9,1O-anthracenedicarboxaldehyde XVI.
The invention will be described in greater detail in conjunction with the following specific examples.
Example 1 Bis(2-imidazolin-2-ylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydroehloride The 2-hydrazino-2-imidazoline monohydrochloride, described in U. S. Patent No. 3,931,152, is converted to the dihydroehloride by treatment with ethanol and concentrated hydrochloric acid. A suspension of 3.45 g. of the 2-hydrazino-2-imidazoline dihydroehloride and 2.34 g. of 9,10-anthracenedicarboxaldehyde in 100 ml. of ethanol is stirred and heated under reflux for two hours. The mixture is cooled and the solid is collected and washed with ethanol giving the desired product as a crystalline orange solid, m.p. 288°-289°C. (dec.).
Example 2 .
Bis(dimethylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydroehloride A suspension of 4.68 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol containing 2.40 g. of unsymmetrical dimethylhydrazine and two drops of glacial acetic acid is stirred under reflux for two hours. The mixture is filtered while hot. The filtrate deposits the desired producf as an orange solid, m.p. 177°-178’C.
Example 3 Ν,Ν-Dimethylglycine(9,10-anthrylenedimethylidyne)dihydrazide dihydroehloride A suspension of 4.68 g. of 9,10-anthracenedicarboxaldehyde and 6.14 g. of Ν,Ν-dimethylglycyl hydrazide hydrochloride in 200 ml. of ethanol is stirred and heated under reflux for two hours. After the mixture is cool, the orange solid is collected and washed twice with ethanol. A turbid solution of this solid in 400 ml. of hot methanol is filtered, • the filtrate is concentrated to 150 ml. and 150 ml. of diethyl ether is added. After standing overnight, the Orange solid is collected and washed with acetone. A turbid solution of this solid in 200 ml. of methanol is chromatographed on silica gel, eluting with methanol. The eluate is allowed to stand 4 hours as it deposits a small amount of the solid, yellow free base [m.p. 276°-279° (dec.)] of the desired product. The filtrate from the yellow solid is evaporated giving an orange solid.
A turbid solution of the orange solid in 150 ml. of hot metha10 nol is filtered, concentrated to 50 ml., partly cooled, seeded and gradually diluted with 50 ml. of diethyl ether. The solid which separates is collected by filtration and washed with ethanol giving the desired dihydrochioride product as an orange solid, m.p. 277®-279°C. (dec.).
Example 4 ' l,l'-[9,10-Anthrylenebis(meth-ylidynenitrilo)]diguanidine dihydrochioride A suspension of 3.51 g. of 9,10-anthracenedicarboxaldehyde and 4.08 g. of aminoguanidine bicarbonate in a mix20 ture of 100 ml. of ethanol and 5.4 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for two hours. The mixture is cooled and the solid is collected, washed four times with cold ethanol and dried, giving the desired product as an orange powder, m.p. 298°-301°C.
Example 5 Bis(l,4,5,6-tetrahydro-2-pyritnidinylhydrazone) of 9,10-anthracenedicarhoxaldehyde dihydrochioride 2-Hydrazino-l,4,5,6-tetrahydropyrimidine monohydroiodide (U. S. Patent No. 3,931,152) is converted to the di30 hydrochloride by treatment with excess Dowex-2X8 (a strongly basic anion exchange resin in the hydrochloride form). The aqueous filtrate, upon being’acidified with excess concentrated hydrochloric acid, gives the dihydrochioride salt. A mixture of 5.61 g. of the dihydrochloride and 3.51 g. of 9,10-anthracenedicarboxaldehyde in 100 ml. of ethanol is stirred and heated under reflux for two hours, then filtered. The chilled filtrate deposits a solid which is collected and washed three times with ethanol, giving the desired product as yellow crystals, m.p. 215°-230°C. (dec.).
Example 6 Bis(4,5,6,7-tetrahydro-lH-l,3-diazepin-2-ylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydroiodide A mixture of 7.6S g. of 2-hydrazino-4,5,6,7-tetrahydro-lH-1,3-diazepine hydroiodide (U. S. Patent No. 3,931,152), 3.51 g. of 9,10-anthracenedicarboxaldehyde and 7.57 ml. of 4N ethanolic hydrogen iodide, allowed to react as in Example 5, gives the desired product as an orange solid, m.p. 301-302’C. (dec.).
Example 7 1,1'-[9,10-Anthrylenebis(methylidynenitrilo)bis-3-benzylguanidine dihydroiodide A mixture of 216 g. of thiosemicarbazide and 360 g. of iodomethane in 2.4 litres of absolute ethanol is heated under reflux for two hours and then allowed to cool overnight giving colorless crystals of S-methylisothiosemicarbazide hydroiodide. A mixture of 11.65 g. of this product and 10.9 ml. of benzylamine in 25 ml. of absolute ethanol is heated under reflux at 100°C. for one hour. The mixture is chilled and seeded and the product, 1-amino-3-benzylguanidine monohydroiodide, is collected as colorless crystals.
A suspension of 2.34 g. of 9,10-anthracenedicarboxaldehyde, 5.92 g. of 1-amino-3-benzylguanidine monohydroiodide and 5.8 ml. of 3.47N ethanolic hydrogen iodide in 100 ml. of ethanol is stirred and heated under reflux for two hours, allowed to cool overnight, and the solid is collected and washed three times with diethyl ether giving the desired product as a-yellow solid, m.p. 279e-282°C. (dec,).
Example 8 1,1'-[9,10-Anthrylenebis(methylidynenitrilo)]bis(3-cyclo5 hexylguanidine) dihydroiodide A solution of 2.8 g. of l-amino-3-cyclohexylguanidine hydroiodide [W. G. Finnegan, R. A. Henry, E, Lisker, J. Org. Chem., 18, 779 (1952)] and 2.34 g. of anthracene-9,10-dicarboxaldehyde in 200 ml. of ethanol and 20 ml. of acetic acid is heated under reflux for 18 hours and filtered . hot. The filtrate is evaporated to yield 5.0 g. of an orange solid. This is recrystallized from ethanol-ether to give the title compound? m.p.^>300°C.
Example 9 j Bis (2-iinida2olin-2-ylmethylhydrazone) of 9,10-anthracenedicarboxal.dehy de dihydroiodide A solution of 48.8 g. of 2-methylthio-2-imidazoline hydroiodide and 10.0 g. of methylhydrazine in 200 ml. of ethanol is heated at reflux for several hours, clarified and then cooled at -10°C. The precipitate is collected, washed with diethyl ether and dried, giving 2-(1-methylhydrazino)-imidazoline hydroiodide.
A suspension of 5.08 g. of 9,10-anthracenedicarbox'aldehyde, 10.2 g. of 2-(1-methylhydrazino)imidazoline hydro25 iodide and 12.1 ml. of 3.47N ethanolic hydrogen iodide in 135 ml. of ethanol is heated under reflux with stirring for two -hours. The mixture is allowed to stand overnight and the solid is collected and washed three times with acetone giving the desired product, m.p. 298°-300°C. (dec.).
Example 10 1,l·1-(9,10-Anthrylenebis(methylidynenitrilo)]bis-.5-mothylguanidine dihydroiodide A suspension of 3.05 g. of 9,10-anthracenedicarboxaldehyde, 5.63 g. of l-amino-3-methylguanidine hydroiodide [Kirsten et al., J.A.C.S. 58, 800 (1936)] and 7.50 ml. of 3.47 ethanolic hydrogen iodide in 100 ml. of ethanol is heated under reflux with stirring for two hours and then chilled overnight. The mixture is evaporated to dryness, 40 ml. of methanol is added and the mixture is placed in an ice bath for 15 minutes. The solid is collected and washed three times with methanol giving the desired product, m.p. 247°-265°C. (dec.).
Example 11 9,10-Anthracenedicarboxaldehyde bis(thiosemicarbazone) A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 3.65 g. of thiosemicarbazide in 250 ml. of absolute 15 ethanol containing 2.0 ml. of glacial acetic acid is heated on a steam bath for 24 hours, allowed to cool and then let stand overnight. The solid is collected, washed with absoluti ethanol, dried and recrystallized from aqueous dimethylformamide giving the desired product as orange crystals, m.p. 275' 20 ~277°C.
Example 12 9,10-Anthracenedicarboxaldehyde disemicarbazone A mixture of 2.34 g, of 9,10-anthracenedicarboxaldehyde, 4.46 g. of semicarbazide hydrochloride and 5.44 g. 25 of sodium acetate in 250 ml. of absolute ethanol is heated at reflux for 24 hours, cooled and allowed to stand at room temperature. The solid is collected and recrystallized from a mixture of dimethylformamide and dimethylsulfoxide giving the desired product as yellow crystals, m.p. 300°C.
Example 13 1,1' - (9,10-Anthrylcncdimethylidync)bis-3-thiocarbohydrazide A mixture of 2.34 -g. of 9,10-anthraccnedicarboxaldehyde and 4.25 g. of thiocarbohydrazide in 250 ml. of abso49 lute ethanol containing 2.0 ml. of glacial acetic acid is • refluxed for' 24 hours and then allowed to stand at room temperature. The solid is collected, washed with ethanol, dried and recrystallized from dimethylformamide giving the desired product, m.p. 252°-258eC. (dec.).
Example 14 3,3'- [9,10-Anthrylenebis(methylidynenitrilo)]bis thiocarbazimidic acid dimethyl ester dihydroiodide A mixture of 2.34 g. of 9,10-anthracenedicarboxal10 dehyde and 4.66 g. of S-methylthiosemicarbazide hydroiodide in 250 ml. of absolute ethanol containing 2.0 ml. of glacial acetic acid is heated on a steam bath for 24 hours, cooled and allowed to stand for several hours. The solid is collected, washed with ethanol, dried and recrystallized from a mixture of dimethylformamide-ethanol-diethyl ether and petroleum ether giving the desired.product as red-orange crystals, m.p. 225<’-227°C. (dec.).
Example 15 9,10-Anthracenedicarboxaldehyde bis(methylhydrazone) A suspension of 4.68 g. of 9,19-anthracenedicarboxaldehyde and 1,84 g. of methyl hydrazine in 200 ml. of ethanol containing 2.0 drops of glacial acetic acid is stirred and heated under reflux for 1.5 hours. The mixture is cooled and the solid is collected and washed with ethanol giving the desired product as orange needles, m.p. 172°-174°C. (dec.) Example 16 Ν,Ν''- [9,10-Anthrylcnedimethylidyne)bis [N* ,N'.-dimethylethylenediamine] A suspension of 4.68 g. of 9,10-anthracenedicarbox30 aldehyde and 5.29 g. of Ν,Ν-dimethylethylenediamine in 100 ml. of toluene is stirred and heated under reflux for 30 minutes collecting by-product water in a Dean-Stark trap. The solu50 tion is filtered and concentrated to 25 ml. Upon cooling, the reaction mixture gives a semi-solid mixture which is thoroughly macerated and dispersed in 75 ml. of petroleum ether (b.p. 35°-60eC.). The solid is collected and washed with petroleum ether giving the desired product as yellow leaflets, m.p. 108e-109°C.
Example 17 1,1[9,10-Anthrylenebis(methylidynenitrilo)]bis-1-methylguanidine dihydrobromide IO A mixture of 2.3 g. of 9,10-anthracenedicarboxaldehyde, 3.4 g. of 1-amino-l-methylguanidine dihydrobromide, 200 ml. of ethanol and 1.3 ml. of 7.4 N HBr in ethanol was heated and stirred under reflux for 17 hours. The mixture was filtered hot to give 4.5 g. of product; m.p. 324°-325°C. .15 (dec.).
Example 18 1,1'-[9,10-Anthrylenebis)methylidynenitrilo)]bis[3,3-dimethyiguanidine] dihydroiodide A mixture of 4.60 g. of 1-amino-3,3-dimethylguani20 dine hydroiodide [Finnegan et al., J. Org. Chem. 18 779 (1953) 2.34 g. of 9,10-anthracenedicarboxaldehyde and 5.04 ml. of 4N ethanolic hydrogen iodide in 100 ml. of ethanol is stirred and heated under reflux for two hours, then allowed to cool. The orange solid is collected and washed with ethanol, giving the desired product, m.p. 320“-322aC.
Example 19 1,1'-[9,10-Anthrylenebis(m_e thylidynenitrilo)]bis[1,3-dimethyl-guanidine] dihydroiodide A solution of 10.4 g. of Ν,Ν'-dimethylthiouroa in 50 ml. of ethanol-is treated with 14.5 g. of methyl iodido and heated under reflux for 70 minutes. The solution is filtered hot and cooled to give S-methyl-N,N'-dimethylisothiourea hydroiodide, m.p. 209°-212°C.
A solution of 17.5 g. of S-methyl-Ν,Ν'-dimethylisothiourea hydroiodide in 20 ml. of ethanol and 10 ml. of water is treated with 10 ml. of hydrazine hydrate and heated under reflux for 20 minutes. The mixture is cooled and the product is collected and washed with ethanol-water (2:1) and ether to give 13 g. of product. This is recrystallized from 150 ml. of boiling ethanol by adding water just to complete solution followed, by cooling to give l-amino-2,3-dimethylguanidine hydroiodide, m.p. 296°-298°C. Reaction of this salt according to the procedure of Example 18 followed by recrystallizatiob from water gives the title compound as an orange solid, m.p. 281e-283°C.
Example 20 1,1'-[9,10-Anthrylenebis(methylidynenitrilo)]bis[3-(2-hydroxyethyl) guanidine dihydroiodide A solution of 11.6 g. of s-methylthiosemicarbazide hydroiodide and 3.2 ml. of ethanolamine in 50 ml. of ethanol -0 is heated under reflux on a steam bath for 3 hours. The solution is cooled and treated with 15 ml. of 8N ethanolic HCl cooled and diluted with diethyl ether to give a thick gum.
The supernatant is decanted and the residue is dissolved in 60 ml. of hot ethanol, treated with about one ml. of water and cooled. A 'small amount of a solid is removed by filtration and the filtrate is treated with more ethanolic HCl to give a viscous gum. The supernatant is decanted, the residue (4.8 g.) is dissolved in 65 ml. of ethanol and treated with 1.9 g. of 9,10-anthracenedicarboxaldehyde and heated under reflux for 2,5 hours. The solution is filtered and cooled to give 1.7 g. of product. This product is recrystallized from 15 ml. of dimethylformamide (yield 1.0 g.) and then slurried in 6 ml. of *Cellosolve to give 450 mg. of an orange crystalline product; m.p. 234°-235°C.
Example 21 1,1'-(9,10-Anthylenebis)raethylidynenitrilo)bis[3-(2-hydroxy-propyl)guanidine] dihydroiodide A solution of 32.0 g. of 1-(2-hydroxypropyl)imidazolidine-2-thione and 15 ml. of methyl iodide in 250 ml. of j5 isopropanol is stirred and heated under reflux for four hours, then cooled at -10°C. The precipitate, collected and washed with cold isopropanol and then with diethyl ether, is 1-(2-hydroxypropyl)-2-(methylthio)-2-imidazoline hydroiodide m.p. 114°-116eC. A solution of 30.2 g. of this salt and 5.2 ml. of hydrazine hydrate in 200 ml. of isopropanol is heated under reflux for four hours, filtered, then cooled at -10eC. The resulting precipitate, collected and washed with cold isopropanol and then with ether, is 2-hydrazino-l-(2-hydroxypropyl)-2-imidazoline hydroiodide, m.p. 140“-142C. A mixture of 2.86 g. of this salt, 1.17g. of 9,10-anthracenedicarboxaldehyde and 2.5 ml. of 4N ethanolic hydrogen iodide, allowed to react as in Example 18 gives the title compound as a yellow solid, m.p. 249e-251eC. (dec.).
♦Cellosolve is a Trade Mark Example 22 Bis-( 5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-y1 hydrazone) of ' 9,10-anthracenedicarboxaldehyde dihydrobromide A mixture of 26.4 g. of hexahydro-4-hydroxypyrimidine-2-thione and 30 ml. of ethyl bromide in 250 ml. of ethanol is stirred and heated under reflux for seven hours. Decolorizing charcoal is added, the solution filtered, cooled and diluted with 1 1. of ether. A Mick oil separates. The mother liquor is discarded and the oil dried in vacuo. A mixture of 22.8 g. of the residue with 100 ml. of 95% ethanol and 5 ml. of hydrazine is stirred and heated under reflux for five hours as ethanethiol is evolved. The solution is evaporated to dryness in vacuo and the residue is dissolved in a boiling mixture of 100 ml. of isopropanol and 100 ml. of •methanol. Decolorizing charcoal is added, the hot solution filtered, then cooled at -10°C. The resulting precipitate is collected and washed with cold 2-propanol and with ether. It is then recrystaliized from isopropanol-methanol (1:1), using decolorizing charcoal, giving 2-hydra2ino-5-hydroxy-3,4,5,6-tetrahydropyrimidine hydrobromide, m.p. 167°-169°C. A mixture of 1.19 g. of this salt and 1.32 g. of 9,10-anthracenedicarboxaldehyde in 40 ml. of ethanol and 0.95 ml. of 7.4 N ethanolic hydrogen bromide is allowed to react as in Example 18 to give the desired product as an orange-yellow solid. i ' Example 23 Ι,Ι1-[9,10-Anthrylenebis)methylidynenitrilo)]bis-(3-(2-di. ’ methylaminoethyl)guanidine] fcetrahydroiodide A mixture of 216 g. of thiosemicarbazide and 360 g. of iodomethane in 2.4 litres of absolute ethanol is heated under reflux for 22 hours and then allowed to cool overnight, giving colorless crystals of S-methylthiosemicarbazide hydroiodide. A mixture of 11.65 g. of this product and 4.41 g. of N,N-dimethylethylenediamine in 25 ml; of absolute ethanol is heated under reflux at 10Q°C. for one hour. The mixture is cooled, diluted with ether and chilled. The product, 1-amino-3-(2-dimethylaminoethyl)guanidine hydroiodide, is collected as a colorless solid. A suspension of 2.34 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of absolute ethanol containing 5.46 g. of the guanidine salt and 5.8 ml. of 3.47N ethanolic hydrogen iodide is stirred and heated under reflux for two hours. The mixture is allowed to cool, finally at 0°C., and the desired solid product is collected by filtration.
Example 24 4-Morpholinecarboximidic acid, 2,2'-(9,10-anthryleneclimethyIidyne)hydrazide dihydroiodide A solution of 4.65 g. of 4-morpholinethiocarboxamide IW. G. Finnegan, et al., J. Org. Chem. 18, 779 (1952)] and 4.54 g. of iodoinethane in 50 ml. of ethanol is allowed to stand 48 hours at room temperature, then diluted with 250 ml. of ether to give a colorless crystalline precipitate of methyl 4-morpholinethiocarboximidate hydroiodide. .A solution of 5.76 g. of this product and 1.1 g. of hydrazine hydrate in ethanol is heated under reflux for about 2 hours and then treated with 2.1 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol and 2 ml. of glacial acetic acid by heating under reflux for 3.5 hours. The solution is filtered and then evaporated to give an orange solid which is recrystai!ized from ethanol-ether to give the title compound, m.p. 280°C.
Example 25 1,1^-(9,10-Anthrylenebis(methylidynenitrilo)]bis[3-(3-dimethylaminopropyl)-2-ethylguanidine) tetra' hydrochloride Solid (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (3.82 g.) is added gradually with stirring to an ice-cooled solution of 1.00 g. of hydrazine hydrate in 75 ml. of water. The mixture is stirred for an hour without further cooling, chilled, strongly basified by the gradual addition of sodium hydroxide solution, then extracted with ether. The ether is dried over magnesium sulfate, filtered and evaporated. A solution of the residue in 100 ml. of ethanol is combined with 3 ml. of 8N ethanolic hydrogen chloride and 2.34 g. of 9,10-anthracenedicarboxaldehyde, the resulting suspension is stirred and heated under reflux for two hours, then allowed to cool. The desired product separates after the addition of ether and is collected by filtration.
Example 26 1,1'- [9,10-Anthrylenebis(methylidynenitrilo)]bis25 biguanide tetrahydrochloride A suspension of 3.36 g. of finely pulverized cyanoguanidine in 50 ml. -of ethanol containing 2.00 g. of hydrazine hydrate is stirred and heated with an oil bath at 50°C. for five hours. After addition of 4.68 g. of anthracene 9,1030 -dicarboxaldehyde and 15.0 ml. of 8N ethanolic hydrogen chloride the stirring and heating were continued for 15 hours After the mixture had cooled the solid was collected by [ filtration and recrystallized from ethanol-water to give the desired product as an oran'ge solid.
Example 27 9,10-Anthracenedicarboxaldehyde bis(2-pyridylhydrazone) A suspension of 4.68 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol containing 4.37 g. of 2-hydrazinopyridine and 2 drops of acetic acid is stirred and heated under reflux for two hours, then allowed to cool. Collection by filtration and washing with ethanol gives the desired product as an orange solid, which sinters from 267°C. to 272°C. (dec.).
Example 28 9,10-Anthracenedicarboxaldehyde bis[(4-hydroxy-6-methyl-2-pyriniidinyl) hydrazone] The procedure of the preceding example applied to 5.61 g. of 2-hydrazino-4-hydroxy-6-methylpyrimidine gives 10.0 g. of crude product as an orange solid which is purified by recrystallization from dimethylformamide.
Example 29 9,10-Anthracenedicarboxaldehyde bis[(2-dimethylamino-ethyl)hydrazone] A suspension of 4.68 g. of anthracene-9,10-dicarboxaldehyde in 100 ml. of ethanol containing 4.13 g. of [2-(dimethylamino)ethyl]hydrazine (Elslager et al., J. Med. Chem.
I, 493 (1964)] containing two drops of acetic acid is stirred and heated under reflux for two hours. The resulting solution is filtered, concentrated, allowed to cool to 45?C., diluted with petroleum ether, then allowed to cool further at 5°C.
The desired product separates as an orange solid and is collected by filtration.
’ Example 30 Ν,Ν- [9,10-Anthrylenebis(methylidynenitrilo)Jdiacetamidine dihydrochloride A mixture of 4.68 g. of 9,10-anthracenedicarboxaldehyde and 4.38 g. of acetimidrazone hydrochloride [Neunhoeffer~ et al., Ann. 760, 102 (1972)] in 100 ml. of ethanol containing 5.0.ml. of 8N ethanolic hydrogen chloride is heated under reflux with stirring for two hours, then allowed to cool. Collection by filtration and washing with cold ethanol affords the desired product as an orange solid.
Example 31 Dibutyl 3,3'-(9,10-Anthrylenedimethylidyne)bis fthio carbazimidate dihydroioaide] A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 5.0 of S-butylisothiosemicarbazide hydroiodide in 250 ml. absolute ethanol which contained 2 ml. of glacial acetic acid is heated at reflux for 24 hours, then cooled to room temperature. The crude product was isolated and recrystaliized from dimethylformamide to yield 3.0 g. of orange-red crystals.
Example 32 Dibenzyl 3,3'-(9,10-Anthrylenedimethylidyne)bis' [thiocarboximidate dihydrochloride) A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 5.0 g. of S-benzylisothiosemicarbazide in 250 ml. of ethanol was treated as for the dibutyl ester to give the title compound.
Example 33 9,10-Anthracenedicarboxaldehyde bis(4,4-dimethylthiosemicarbazone) A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 3.0 g. of 4,4-dimethylthiosemicarbazide in 250 ml. absolute ethanol containing 2.0 ml.· glacial acetic acid is heated at reflux for 24 hours and then allowed to cool to room temperature. The crude solid is isolated by filtration yield 1.83 g. of orange-red crystals.
Example 34 4,Methy1-(9,10-anthrylenedimethylidyne)dihydrazide of 1-piperazinecarbothioic acid A mixture of 3.0 g. of 9,10-anthracenedicarboxaldehyde bis(thiosemicarbazone) and 25 ml. N-methylpiperazine was heated at 130°C. in an oil bath for 9 hours, then cooled to room temperature. The excess piperazine was removed under vacuum, the residual solid recrystallized twice from agueous dimethylformamide to yield 1.0 g. of orange-red crystals.
Example 35 l»l'-[9,10-Aathrylenebis(ethylidynenitriol)]diguanidine dihydroehloride A suspension of 2.28 g. of 9,10-anthracenedicarbonitrile and 5.0 g. of methylmagnesium iodide in a solution of 50 ml. of ether and 50 ml. of toluene is heated to under reflux for 8 hours. The reaction product is collected, resuspended in ether and treated at -10°C. with a mixture of ice and ammonium chloride. The ether layer is dried over MgSO^ and then saturated with hydrogen chloride to obtain the bis-ketimine dihydroehloride.
A solution of 3.33 g. of the bis-ketimifie dihydrochloride, 2.72 g. of aminoguanidine bicarbonate and 1.6 g. of sodium acetate in 100 ml. of ethanol is heated under reflux for 10 hours. The mixture is cooled and filtered to obtain the desired compound.
Example 36 1,1'[9,10-Anthrylonobis(phenylethylidyncnitrilo)]dxguanidine dihydroehloride A suspension of 2.28 g. of 9,10-anthraconodicarbo59 nitrile and 6.0 g. of benzylmagnesium bromide was treated as in the preceding example to obtain the bis-ketimine dihydrochloride. A solution of 4.87 g. of this bis-ketimine dihydrochloride was treated as in the preceding example to obtain the title compound.
Example 37 Bis(2-imidazolin-2-ylhydrazone) of 9,10-anthracenediacetaldehyde dihydroehloride A mixture of 2.56 g. of 9,10-anthracenediaceton.i10 trile [J.A.C.S. 77, 2845 (1955)], 3.46 g. of 2-hydrazino-2-imidazoline dihydroehloride and 1.6'4 g. of sodium acetate in 50 ml. of 50% ethanol is reduced in the presence of 1.5 g. of Raney nickel. until 2 molar equivalents of hydrogen are absorbed. The mixture is heated to boiling and filtered to remove the Raney nickel. The filtrate is evaporated to a small volume and cooled to give the. desired product.
Example 38 l.l'-re-Methyl-g^O-anthrylenebis(methylidynenitrilo) ] diguanidine dihydroehloride A suspension of 2.48 g. of 2-methy1-9,10-anthracenedicarboxaldehyde (Example 51) and 2.72 g. of aminoguanidine bicarbonate in 100 ml. of ethanol and 3.6 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for 2 hours. The mixture is cooled and the title compound is col25 lected by filtration.
Example 39 1,1*-[2,3,6,7-tetramethoxy-9,10-anthylenebis)methylidynenitrilo) 1 diguanidine dihydroehloride A suspension of 3.54 g. of 2,3,6,7-tetramethoxy30 -9,10-anthracenedicarboxaldehyde [C.A. 66, 2405n (1967)] and 2.72 g. of aminoguanidinc bicarbonate in 100 ml. of ethanol and 3.6 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for 18 hours. The mixture is cooled and the title compound [m.p. 314°C. (dec.)] is collected by filtration.
Example 40 1,1'-[Ethyl-9,10-anthrylenebis(methylidynenitrilo)] diguanidine dihydrochioride A suspension of 2.72 g. of 2-ethyl-9,10-anthracenedicarboxaldehyde (Example 53) and 2.72 g. of aminoguanidine bicarbonate in 100 ml. of ethanol and 3.6 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for 2 hours. The mixture is cooled and the title compound is collected by filtration.
Example 41 [Bis(2-imidazolin-2-ylhydrazone)] of 2-chloro-9,10-anthracenedicarboxaldehyde dihydrochioride A reaction mixture comprising 1.34 g. of 2-chloro-9,10-anthracenedicarboxaldehyde and 1.73 g. of 2-hydrazinoimidazoline dihydrochioride in 80 ml. of ethanol is refluxed for two hours, and filtered while hot. After cooling, the solution deposited 0.7 g. of the desired product as orange crystals, m.p. - 280°C.
Example 42 1,1'-[2-Nitro-9,10-anthrylenebis(methylidynenitrilo)1 diguanidine dihydrochioride A suspension of 2.8 g. of 2-nitro-9,10-anthracenedicarboxaldehyde and 2.72 g. of aminoguanidine bicarbonate in 100 ml. of ethanol And 3.6 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for 2 hours.
The mixture is cooled and the title compound is collected.
Example 43 1,1'-[2,6-Dihydroxy-9,10-anthrylcnobis(mothylidynenitrilo) ]diguanidine dihydrochioride ι A suspension of 2.66 g. of 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde (Example 57) and 2.72 g. of aminoguanidine bicarbonate in 100 ml. of ethanol and 3.6 ml. of-8N ethanolic hydrogen chloride is stirred and heated under reflux for 2 hours. The mixture is cooled and the title compound is collected by filtration.
Example 44 1,1'- [2,6-Dimethoxy-9,10-anthrylenebis(methylidynenitrilo)]diguanidine dihydrochloride 10 A suspension of 2.94 g. of 2,6-dimethoxy-9,10-anthracenedicarboxaldehyde (Example-58) and 2.72 g. of aminoguanidine bicarbonate in 100 ml. of ethanol and 3.6 ml. of 8N ethanolic hydrogen chloride is stirred and heated under reflux for 2 hours. The mixture is cooled and the title compound is collected.
Example 45, ' Bis(2-imidazolin-2-ylhydra2one) of 2,6-diacetoxy-9,10-anthracenedicarboxaldehyde dihydrochloride A suspension of 3.5 g. of 2,6-diacetoxy-9,10-anthracenedioarboxaldehyde (Example 59) and 3.46 g. of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml. of ethanol is stirred and heated under reflux for 2 hours. The mixture is cooled and the product is collected.
Example 46 Bis(2-imidazolin-2-ylhydrazone) of 2-hydroxy-9,10-anthracenedicarboxaldehyde dihydrochloride .
A suspension of 2.5 g. of 2-hydroxy-9,10-anthracenedioarboxaldehyde (Example 60) and 3.46 g. of 2-hydrazino-230 -imidazoline dihydrochloride in 100 ml. of ethanol is stirred and heated under reflux for 2 hours. The mixturcr is cooled and the product is collected by filtration. - 47633 Example 47 Bis(2-imidazolin-2-ylhydrazone) of l,2-dihydroxy-9,10-anthracenedicarboxaldehyde dihydrochloride A suspension of 2.66 g. of l,2-dihydroxy-9,10g -anthracenedicarboxaldehyde (Example 61) and 3.46 g. of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml. of ethanol is stirred'and heated under reflux for 2 hours. The mixture is cooled and the product is collected.
Example 48 2.0 Bis(2-imidazolin-2-ylhydrazone) of 1,4-dihydroxy-9,10-anthracenedicarboxaldehyde dihydrochloride A suspension of 2.66 g. of l,4-dihydroxy-9,107 -anthracenedicarboxaldehyde (Example 62) and 3.46 g. of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml. of ethanol is stirred and heated under reflux for 2 hours. The mixture is cooled and the product is collected.
Example 49 Bis(2-imidazolin-2-ylhydrazone) of 2-amino-9,10-anthracenedicarboxaldehyde dihydrochloride 2o A suspension of 2.5 g. of 2-amino-9,10-anthracenedicarboxaldehyde (Example 63) and 3.46 g. of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml. of ethanol is stirred and heated under reflux for 2 hours. The mixture is cooled and the compound is collected by filtration.
Example 50 2-Chloro-9,10-anthracenedicarboxaldehyde A solution of 15.0 g. of 2-chloroanthracene in 60.8 g. of vinylene carbonate is heated under reflux for 20 hours. The excess vinylene carbonate is removed by vacuum distillar tion. The residue, a brown solid, is recrystallized from methylene chloride-methanol to give 2-chloro-9,10-dihydro-9,10-ethanoanthraceno~ll,12-diol cyclic carbonate, m.p. 200°-230°C.
A mixture of 12.0 g. of this cyclic carbonate and 9.2 g. of potassium hydroxide in 100 ml. of water and 12 ml. of-ethanol is heated at 75° for 2 hours. The mixture is evaporated under reduced pressure to a volume of 50 ml. and then treated with 400 ml. of water. The crystalline product is collected and recrystallized from toluene to give 2-chloro-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, m.p. 195°-210°C.
To a suspension of 2.73 g. of this diol in 70 ml. of acetic acid at 35°C. is added potassium 8.8 g. of lead tetraacetate during a 5-minute period. The reaction mixture is stirred at 35°C. for another two hours to give 1.5 g. of an orange crystalline compound. Evaporation of the mother liquor gives another 0.5 g. of compound. The two crops are combined and recrystallized from 50. ml. of toltfehe to give 2-chloro-9,10-anthracenedicarboxaldehyde, m.p. 193°-1969C.
Example 51 2-Methyl-9,10-anthracenedicarboxaldehyde Thirteen grams of 2-methylanthracene is converted to 2-methy1-9,10-anthracene-dicarboxaldehyde by the three step process described for the 2-chloro analog in Example 50.
Example 52 l-Chloro-9,10-anthracenedicarboxaldehyde Fifteen grams of 1-chloroanthracene is converted to l-chloro-9,10~anthracened'icarboxaldehyde by the’ three step process described in Example 50.
Example 53 2-Ethyl-9,10-anthracenodicarboxaldehydo Fourteen grams of 2-ethylanthracene is converted to 2-ethy1-9,10-anthraccncdicarboxaldohydc by the three step process described in Example 50, • Example 54 9,10-Bis(chloromethyl)-2-methylanthracene A mixture of 35 ml. of dioxane and 6 ml. of concentrated hydrochloric acid is saturated with hydrogen chloride gas. Then, 4.5 g. of 2-methylanthracene and 3.8 g. of 95% paraformaldehyde is added. The mixture is stirred slowly and heated under reflux while hydrogen chloride gas is introduced for 2 hours. The mixture is stirred and heated under reflux for 3 hours longer and then allowed to stand at room temperature for 16 hours. The yellow solid is collected by filtration, washed with dioxane, and dried to give the title compound.
Example 55 2-Methyl-9,10-anthracenedicarboxaldehyde To a stirred suspension of 2.6 g. of 9,10-bis-(chloromethyl) -2-methylanthracene in 50 ml. of dimethyl sulfoxide (dried over calcium hydride) under nitrogen at room temperature is added slowly a solution prepared by adding 3.0 g. of 2-nitropropane to a solution of 0.5 g. of sodium in 30 ml. of ethanol. The reaction mixture gradually changes from yellow to dark orange and becomes homogenous. At this point (2.5 to 3.0 hours) the mixture is_filtered into 200 ml. of ice-water. The orange precipitate is collected and redissolved in methylene chloride which is then extracted with water. The methylene chloride solution is dried over MgSO^ and evaporated to dryness to give the title compound.
Example 56 1-Methy1-9,10-anthraccnodicarhoxaldehyde 1-Methylanthracenc (4.5 g.) is converted to 1-methyl-9,10-anthraccne dicarboxaldehydc by the procedure described for the 2-methyl derivative.
' Example 57 2,6-Dihydroxy-9,10-anthracenedicarboxaldehyde A.suspension of 2.4 g. (0.01 mole) of 2,6-dihydroxy anthraquinone in 100 ml. of dry tetrahydrofuran containing 2.1 g. of triethylamine is treated with 2.2 g. of trimethylsilyl chloride and allowed to react until the anthraquinone dissolves. The triethylamine hydrochloride is filtered off and the remaining solution of silated anthraquinone is used as is in the following reaction.
In a dry system protected from moisture and under an atmosphere of argon, the solution of 0.01 mole of silated anthraquinone in tetrahydrofuran at room temperature is treated slowly with a solution of 0.02 mole of [α-lithio-a-(N,N-dimethylamino)methyl]diphenylphosphine oxide [Peterson, J.
Am. Chem. Soc. 93, 4027 (1971)] in anhydrous ether-hexane.
The reaction is allowed to proceed'for two hours maintaining the temperature at room temperature with an ice bath.
The solution of the enamine is hydrolyzed at room temperature by the addition of 20 ml. of 90% formic acid solution. The reaction mixture is filtered, washed with water, dried and recrystaliized from toluene giving 2,6-dihydroxy-9,10-anthracene dialdehyde.
Using well-known procedures, 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde can be converted to the 2,625 -dialkoxy- and 2,6-diacyloxy- derivatives.
Example 58 2,S-Dimethoxy-9,1O-anthracene-dicarboxaldehyde A suspension of 2.66 g. (0.01 mole) of 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde in 100 ml. of toluene is treated with 0.02 mole of petroleum ether-washed sodium hydride and is warmed gently with stirring until evolution of hydrogen ceased. The cooled reaction mixture is then treated with 0.02 mole of petroleum ether-washed sodium hydride and is warmed gently with stirring until evolution of hydrogen ceases. The cooled reaction mixture is then treated with 2.84 g. (0.02 mole) of methyl iodide and is stirred at 40°C. overnight, then is heated to reflux, filtered hot to remove the sodium iodide and allowed to cool giving crystals of 2,6-dimethoxy-9,10-anthracenedicarboxaldehyde.
Example 59 2,6-Diacetoxy-9,10-anthracenedicarboxaldehyde A solution of 2.66 g. (0.01 mole) of 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde in 100 ml. of hot glacial acetic acid is treated with 2.5 g. (0.025 mole) of acetic anhydride. The mixture is stirred, heated on a steam for one hour, then allowed to cool yielding crystals of 2,6-diacetoxy-9,10-anthracenedicarboxaldehyde.
Example 60 2-Hydroxy-9,10-anthracenedicarboxaldehyde A suspension of 2.24 g. (0.01 mole) of 2-hydroxy anthraquinone in 100 ml. of dry tetrahydrofuran containing 1.05 g. {0.01 mole) of triethylamine is treated with 1.1 g. (0.01 mole) of trimethylsilyl chloride and allowed to react until the anthraquinone dissolves. The triethylamine hydrochloride is filtered off and the remaining solution of silated anthraquinone is used as is in the following reaction.
In the same system as described for the 2,6-dihydroxy analog, a solution of-0.01 mole of the silated 2-hydroxy-anthraquinone in tetrahydrofuran is treated slowly with a solution of 0.01 mole of the same lithio anion. The reaction is allowed to proceed for two hours at room temperature. This solution of the enamine is hydrolyzed at room temperature by addition of 20 ml. of 90Ϊ formic acid solution. Tho reaction mixture is filtered, washed with water, dried and recrystallized from toluene giving 2-hydroxy-9,10-anthracene dicarboxaldehyde.
Example 61 1,2 Dihydroxy-9,10-anthracenedicarboxaldehyde Starting with 2.4 g. (0.01 mole) of 1,2-dihydroxyanthraquinone and using the same three-step procedure described above for the 2,6-dihydroxy analog, there is obtained l,2-dihydroxy-9,10-anthracene dicarboxaldehyde as colorless crystals from toluene.
Example 62 ' r,4-Dihydroxy-9,10-anthracenedicarboxaldehyde Starting with 2.4 g. (0.01 mole) of 1,4-dihydroxy anthraquinone and using the same three-step procedure as for the 2,6-dihydroxy analog, there is obtained 1,4-dihydroxy-9,10-anthracene dicarboxaldehyde as crystals from toluene.
' Example 63 2-Amino-9,10-anthracenedicarboxaldehyde Starting with 2.3 g.. (0.01 mole) of 2-aminoanthraquinone and following the same procedure as described for the 2-hydroxy analog, there is obtained 2-amino-9,10-anthracenedicarboxaldehyde .
Example 64 '9,10-Anthracenedicarboxaldehyde A solution of 2.38 g. (0.01 mole) of cis-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol [Newman et al., J. Am. Chem. Soc., 77, 3789 (1955)) in 50 ml. of glacial acetic acid was stirred magnetically at 30°-35eC. and treated portionwise with 8.9 g. (0.02 mole) of lead tetra-acetate or until a blue color persisted v/ith starch-iodide test paper. The reaction mixture was stirred for two hours and the so-formed orange crystals were removed by filtration and recrystallized from methylene chloride giving 1.5 g. (65%) of orange needles, m.p. 245°-247°C.
Example 65 [9,10-Anthrylenebis(methylidynenitrilo)Ibis[3-furfurylguanidine] dihydrochloride A mixture of 1.0 g. of 9,10-anthracenedicarboxaldehyde, 2.0 g. of 1-amino-3-furylguanidine dihydrochloride and 100 ml. of ethanol is heated under reflux for 1.5 hours.
• The solution is evaporated to give a glassy residue which is ground and triturated with diethyl ether to give an orange powder weighing 2.0 g.; m.p. 135°-140°C. (dec.).
Example 66 1,1'-[9,10-Anthrylenebis(methylidynenitrilo)Ibis [3(2-thenyl)guanidine] dihydrochloride A mixture of 2.0 g. of 0.96 g. of 9,10-anthracenedicarboxaldehyde, 2.0 g. of 1-amino-3-thenylguanidine dihydrochloride, 75 ml. of ethanol and 0.3 ml. of concentrated HCl is heated under reflux for 2.5 hours. The solution is cooled and filtered to remove a small amount of solid and then evaporated to dryness. The residue is evaporated three times with methanol and then dissolved in a small amount of methanol and treated with a large amount of diethyl ether to give a gummy solid. The supernatant is decanted and the residue is slurried with more ether to obtain a yellow solid; yield 2.2 g.; m.p. 190e-200°C. (dec.).
Example 67 1,1[9,10-Anthrylenebis(methylidynenitrilo)]bis[2,3-diisopropylguanidine] dihydroiodide A mixture of 4.0 g. of l-amino-2,3-diisopropyl .guanidine hydroiodide, 1.6 g. of 9,10-anthracenedicarboxaldehyde, 100 ml. of ethanol and 2 ml. of 4N ethanolic hydrogen iodide is heated under reflux for 4 hours. The mixture is ι /.47633 filtered hot to remove a little solid and the filtrate is concentrated to the appearance of an orange crystalline product.
The suspension is cooled and filtered to give 4.4 g. of product; m.p. 278a-280°C.
Example 68 1,1' - [9,10-Anthrylenebis(methylidynenitrilo)lbis13- (l-indanyl)guanidine] dihydroiodide A solution of 1.14 g. of 9,10-anthracenedicarboxaldehyde and 3.1 g. of l-amino-3(l-indanyl)guanidine in 50 ml. of ethanol containing 3 ml. of 4N ethanolic HI is heated under reflux for 3 hours and then cooled overnight to give 2.3 g. of orange crystalline product; m.p. 262°-263°C.
Example 69 1,1'- [9,10-Anthrylenebis(methylidynenitrilo]bis[3- (4-pyridylmethyl)guanidine] tetrahydro.iodide A mixture of 2.3 g. of 9,10-anthracenedicarboxaldehyde, 6.4 g. of l-amino-3-(4-pyridylmethyl)guanidine, 9.0 ml. of 4N HI and 100 ml. of ethanol is heated under reflux for 3 hours and cooled to give 6.3 g. of solid. 3.9 g. of this product is slurried-'in 160 ml. of ethanol which is brought to boiling, treated dropwise with water until solution occurrs. This is treated with a little *Darco, filtered and cooled to give 2.2 g. of product; m.p. 235°-240aC. (dec.).
Example 70 2-Methyl-9,10-anthracenedicarboxaldehyde A mixture of isomers of 2-methy1-11,12-dihydroxy-9,10-ethano-anthracene weighing 2.1 g. is dissolved, in 45 ml. of glacial acetic acid and is treated at room temperature with 7.45 g. of lead tetraacetate until a starch-iodide test is positive. After 2-3 hours at room temperature followed *Darco is a Trade Mark by cooling there is deposited orange crystals, which are collected by filtration and recrystallized from methylene chloride-methanol giving 1.1 g. of orange crystals melting at 162°-164’C.
Example 71 Bis(2-imidazolin-2-ylhydrazone] of 2-methyl-9,10-Anthracenedicarboxaldehyde dihydrochloride monohydrate A solution of 2.2 g. of 2-methy1-9,10-anthracenedicarboxaldehyde in 150 ml. of boiling n-propanol is treated with 3.1 g. of 2-imidazolin-2-ylhydrazine. The solution is boiled and concentrated over the course of 2 hours to 100 ml., whereupon it is filtered to clarify and cooled. After long standing there is deposited 2.2 g. of orange crystals melting at 300°-302°C.
The free base of the above product may be obtained as red-orange crystals by basifying the mother liquor with aqueous sodium bicarbonate solution, m.p. 295°-298°C.
Example 72 l,4-Dimethoxy-9,10-anthracenedicarboxaldehyde A mixture of isomers of l,4-dimethoxy-ll,12-dihydroxy-9,10-ethano-anthracene weighing 10 g. is dissolved in 150 ml. of glacial acetic acid at 50°C. and treated portionwise with 30 g. of lead tetraacetate. After 2 hours at. 50’C., the solution is filtered to remove insoluble materials and cooled yielding orange crystals, which are filtered, washed with glacial acetic acid and dried, m.p. 208°-212°C.
I 7 6,3 3 Example 73 Bis[1,4-Dimethoxy-bis(2-imidazolin-2-ylhydrazone)] of-9,10-Anthracenedicarboxaldehyde dihydroehloride A solution of 1.7 g. of l,4-diraethoxy-9,10-anthracene dicarboxaldehyde in 100 ml. of n-propanol is treated with 2.06 g. of 2-imidazolin-2-ylhydrazine and boiled for 2 hours while concentrating to 50 ml. The hot solution is filtered to give a yellow solid which is washed with n-propanol and dried, m.p. 300a-305oC.
Example 74 Bis(2-imidazolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde A suspension of 2.74 g. of 2,6-difluoro-9,10-anthracenedicarboxaldehyde (Example 75) and 3.46 g. of 2-hydrazino-2-imidazoline dihydroehloride in 10.7 ml. of ethanol is stirred and heated under reflux for 3 hours. The mixture is cooled and the product is collected by filtration.
Example 75 2,6-Difluoro-9,10-anthracenedicarboxaldehyde g. of 2,6-difluoroanthracene is converted to 2,6-difluoro-9,10-anthracenedicarboxaldehyde by the three-step process described in Example 50.
Example 76 Bis(2-imidazolin-2-ylhydrazone) of 2,3-dimethy1-9,10-anthracenedicarboxaldehyde A suspension of 2.7 g. of 2,3-dimethyl-9,10-anthracenedicarboxaldehyde (Example 77) and 3.46 g. of. 2-hydraaino-2-imidazoline dihydroehloride in 100 ml. of ethanol is stirred and heated under reflux for 3 hours. The mixture is cooled and the product is collected. 7 6 3 3 Example 77 2.3- Dimethy1-9,10-anthracenedicarboxaldehyde g. of 2,3-dimethylanthracene is converted to 2,3-dimethy1-9,10-anthracenedicarboxaldehyde by the three-step process described in Example 50.
Example 78 Bis(2-imidazolin-2-ylhydrazone) of 2,6-dichloro-9,10-anthracenedicarboxaldehyde dihydrochloride A suspension of 3.03 g. of 2,6-dichloro-9,10-anthracenedicarboxaldehyde and 3.46 g. of 2-hydr.azino-2-imidazoline dihydrochloride in 100 ml. of ethanol is heated under reflux for 3 hours and cooled'to give the title compound.
Example 79 2,6-Dichloro-9,10-anthracenedicarboxaldehyde g. of 2,6-dichloroanthracene is converted to 2,6-dichloro-9,10-anthracenedicarboxaldehyde by the three-step process described in Example 50.
Example 80 Bis(2-imidazolin-2-ylhydrazone) of 1,4-dimethy1-9,10-anthracenedicarboxaldehyde dihydrochloride A suspension of 2.6 g. of 1,4-dimethyl-9,10-anthracenedicarboxaldehyde and 3.46 g. of 2-hydrazino-2-imidazoline dihydrochloride in 100 ml. of ethanol is heated under reflux for 2 hours and cooled to give the title compound.
Example 81 1.4- Dimethyl-9,10-anthracenedicarboxaldehyde g. of 1,4-dimethylanthracene is converted to 1,4-dimethy 1-9,10-anthracenedicarboxaldehyde by the three-step procedure described in Example 50.
Example 3¾ 9,10-Dihydro-9,10-anthracenedicarboxaldehyde A mixture of 21.3 g. of vinylene carbonate (redistilled to give a colorless liquid 71°-73’C., 28 nun.) and 4.4 g. of dry anthracene is heated at reflux (165°-170°C.), under ni5 trogen for 20 hours and then vacuum distilled (62°-64°C., 17 mm.), leaving 10.2 g. of tan residue. This residue is taken up in 100 ml. of methylene chloride, treated with charcoal and filtered. The filtrate is treated with 100 ml. of methanol and cooled giving colorless crystals of cis-9,10-dihydro-9,1010 -ethanoanthracene-ll,12-diol, cyclic carbonate (m.p. 260°-262°C.) A mixture of 5.6 g. of cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate, 4.9 g. of potassium hydroxide, 6.4 ml. of water and 53 ml. of ethanol is stirred at 70*-75’C. for 2 hours. The resulting two layer system is filtered. The filtrate is diluted with twice its volume of water and cooled producing colorless crystals of cis-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol (m.p. 202°-204°C.).
A mixture of 2.38 g. of ’cis-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 40 ml. of glacial acetic acid at room . temperature is treated portionwise with 4.8 g. of lead tetraacetate, with stirring over a period of 10 minutes. The mixture is cooled to 15°C. and the solid which forms is collected by filtration, washed once with glacial acetic acid, then thoroughly with water giving the desired product as colorless grains, m.p. 144e-146’C.
Example 83 Cis-l,4-Dimethoxy-.9,10-dihydro-9,10-anthracenedicarboxaldehyde One gram of l,4-dimethoxy-9,10-dihydro-9,10-cthanoanthracene-11,12-diol, is suspended in 30 ml. of an aqueous solution containing 0.77 g. of potassium periodate and one ml. of ethanol. After stirring at room temperature for 24 hours the insoluble material is removed by filtration, washed well with water and dried leaving a yellow product, m.p. 129°-132°C.
Example 84 Bis(2-imidazolin-2-ylhydrazone)-9,10-dlhydro-9,10-anthracenedicarboxaldehyde A mixture of 2.36 g. of 9,10-dihydro-9,10-anthracenedicarboxaldehyde and 3.46 g. of 2-hydrazinoimidazoline dihydrochloride in 200 ml. of n-propanol is boiled on a hot plate for 1 1/2 hours, concentrating the volume.to 100 ml. The mixture is cooled and allowed to stand overnight, giving a solid which is collected by filtration, washed with n-propanol and dried.
A 0.4 g. portion of this solid is recrystallized from water giving the desired dihydrochloride product as colorless flakes, m.p. 258e-262»C.
Example 2-Chloro-9,10-dlhydro-9,10-anthracenedicarboxaldehyde A solution of 15.0 g. of 2-chloroanthracene in 60.8 g. of vinylene carbonate is refluxed for 20 hours and then vacuum distilled. The residue is recrystallized from methylene chloride-methanol giving cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate as gray crystals, m.p. 200e-230’C.
A mixture Of 12.0 g. of cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate, 9.2 g. of potassium hydroxide, 12 ml. of water and 100 ml. of ethanol is heated at 75°C. for 2 hours and then evaporated in vacuo to 50 ml. The concentrate is diluted with 400 ml. of water and the resulting solid is collected by filtration. This solid is recrystaliized from toluene, decolorizing with a small amount of charcoal, giving colorless crystals of cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, m.p. 195β-210°Ο.
To a solution of 2.7 g. of cis-2-chloro-9,10-dihydro -9,10-ethanoanthracene-ll,12-diol in 20 ml. of acetic acid at room temperature is added 5.0 g. of lead tetraacetate (contain· ing 10% acetic acid) portionwise. The mixture is stirred for 10 minutes, cooled in an ice-water bath and the crystals which form are collected by filtration and washed with cold acetic acid, giving the desired product as off-white crystals, m.p. 113*-115°C.
Example 86 2-Chloro-bis (2-iniidazolin-2-ylhydrazone) -9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride A reaction mixture comprising 0.7 g. of 2-chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.88 g. of 2-hydrazinoimidazoline dihydrochloride in 20 ml. of n-propanol is refluxed for one hour, during which time about 10 ml. of n-propanol is removed through a reflux condenser. The mixture is cooled and ether is added giving the desired product as yellow crystals, m.p. 190®C. (dec.).
Example 87 l-Chloro-9,lO-dihydro-9,10-anthracenedicarboxaldehyde A mixture of 29.5 g. of 1-chloroanthraeene and 126 g. of vinylcarbonate is reacted as described in Example 4, giving tan crystals of cis-l-chloro-9,10-dihydro-9,10-ethanoanthracene· -11,12-diol, cyclic carbonate, m.p. 242’-250°C.
A reaction mixture comprising 27.9 g. of cis-l-chloro-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate, 21.4 g. of potassium hydroxide, 28 ml. of water and 230 ml. of ethanol is heated at 75°C. for 2 hours and then evaporated in vacuo to 80 ml. The residue is dissolved in 500 ml. of chloroform. The chloroform solution is washed with three 70 ml. portions of water and decolorized with charcoal. The chloroform is removed and the yellow residue is dissolved in 150 ml. of toluene. On cooling the product cis-l-chloro-9,10~dihydro-9,10-ethanoanthraeene-ll,12-diol is collected as colorless crystals, m.p. 180°-182°C.
To a solution of 0.54 g. of cis-l-chloro-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol in 5 ml, of acetic acid at 35®C. is added 1.0 g. of lead tetraacetate, portionwise. The mixture is stirred for 10 minutes, cooled in an ice-water bath and the crystals which form are collected by filtration and washed with cold acetic acid, giving the desired product as colorless crystals, m.p. 144'-146eC.
Example 38 1-Chloro-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochioride A reaction mixture comprising 3.7 g. of l-chloro-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 4.64 g. of 2-hydrazinoiraidazoline dihydrochioride in 100 ml. of n-propanol is re77 fluxed for one hour, during which time about 50 ml. of n-propanol is removed through a reflux condenser. The mixture is cooled and ether is added giving the desired product as yellow crystals, m.p. 200*C. (dec.).
Example aq 2-Methyl-9,lO-dihydro-9,10-anthracenedicarboxaldehyde A 10 g. portion of 2-methylanthracene in 50 ml. of vinylene carbonate is heated to reflux under nitrogen for 20 hours. The excess vinylene carbonate is removed by vacuum distillation (55°C.,'11-12 mm.) and the residue is taken up in 100 ml. of methylene chloride, filtered and triturated with three times its volume of methanol. The product, cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate is recovered in its syn and anti forms as cream colored crystals, (m.p. 225°-227eC. and 183°-185eC.).
A 2.8 g. portion of one of the syn and anti forms of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate (m.p. 225°-227°C.) in a mixture of 2.5 g. of potassium .carbonate, 2.3 ml. of'water and 27 ml. of ethanol is stirred at 70°C. for 2 hours. The mixture is treated with three times its volume of water giving the corresponding syn or anti form of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol as pale yellow crystals, (m.p. 227°-228°C.).
A 7.4 g. portion of the other syn or anti form of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol cyclic carbonate (m.p. 183°-185eC.) in a mixture of 6.15 g. of potassium hydroxide, 8.1 ml. of water and 70 ml. of ethanol is reacted as described immediately above giving the corresponding syn or anti form of* cis—2—methyl— 9,10—dihydro— 9,10— sthanoanthracene-11,12-diol as a cream colored solid, (m.p. 153°-156°C.) 4763 A 2.5 g. portion of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol [obtained above as yellow crystals (m.p. 227*-228*C.)) la suspended in 100 ml. of an aqueous solution containing 2.14 g. of sodium periodate and one ml. of eth5 anol. The mixture is stirred at room temperature for 2 hours and the solid is collected by filtration, washed with water and dried giving the desired product as a pale yellow solid, m.p. 125»-126»C.
Example 90 2-Methyl-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydroehloride A mixture of 1.9 g. of 2-methy1-9,lO-dihydro-9,10-anthracenediearboxaldehyde and 2.63 g. of 2-hydrazinoimidazoline dihydroehloride in 150 ml. of n-propanol is heated to boil· ing and concentrated to about 50 ml. over the course of 1-2 hours, filtered while hot and then cooled. A 2-3 ml. portion of acetone and 200 ml. of ether are added giving a precipitate which is collected by filtration giving the desired product as a yellow solid, m.p. 210*-220*C. (dec.). ,. 4 7 6 3 3 Example 91 2,3-Dimethyl-9,10-dihydro-9,10-anthracene’dicarboxaldehyde A mixture of 35.4 g. of vinylene carbonate and 8.5 g.
S of 2,3-dimethylanthracenela) is heated at reflux under nitrogen for 20 hours. The cooled solution is treated with 100 ml. of methanol, warmed , decolorized with charcoal, filtered and cooled giving 7.1 g. of colorless crystals (m.p. 207°-212°C.) of 2,3-dimethy1-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate.
A mixture of 6.4 g. of 2,3-dimethyl-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate,· 5 g. of potassium hydroxide, 6.6 ml. of water and 60 ml. of ethanol is stirre'd at room temperature for 56 hours. The formed pre15 cipitate is filtered, dissolved in glacial acetic acid and precipitated with excess water giving 4.0 g. of colorless 2,3-dimethy1-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, (m.p. 240°-245°C.).
A suspension of 0.3 g. of 2,3-dimethyl-9,10-dihydro20 -9,10-ethanoanthracene-ll,12-diol in 10 ml. water and 0.1 ml. of ethanol is treated with 0.243 g. of sodium periodate and stirred at 20° for 2.5 hours. The formed solid is filtered, washed with water and dried giving 0.2 g. of 2,3-dimethyl-9,10-dihydro-9,ΓΟ-anthracene dicarboxaldehyde, (m.p. 113°-117°C.). (a) Jaylord, N. G., Stepan. V., Collect. Czeck. Chem. Comm. 39,1700(1974).
Example 9? 2.3- Dimethyl-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydroehloride A mixture of 0.2 g. of 2,3-dimethy1-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 0.3 g. of 2-hydrazinoimidazoline dihydroehloride in 30 ml. of _n-propanol is boiled for 2 hours while concentrating to 10 ml. The yellow solution is treated with 0.5 ml. of acetone and 20 ml. of ether giving a yellow precipitate which was filtered, washed with acetone and dried leaving 0.15 g. of product (m.p. 285e-290eC.).
Example 93 1.4- Dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde A mixture of 4.12 g. of 1,4-dimethylanthracene and 17.2 g. of vinylene carbonate is refluxed under nitrogen for 18 hours, cooled, treated with four volumes of methanol, stirred and cooled. . The formed crystals are filtered, washed with methanol and dried leaving 5.45 g. of colorless 1,4-dimethy1-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate (m.p. 225°-245eC.).
A mixture of 4.4 g. of 1,4-dimethy1-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate, 3.45 g. of potassium hydroxide, 4.5 ml. of water and 40 ml. of ethanol is stirred at 20® for 16 hours. The two layered mixture is filtered through *Celite and treated with four volumes of water giving 3.8 g. of colorless l,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol (m.p. 158°-160°C.).
*Celite is a Trade Mark A mixture of 1.5 g. of l,4-dimethyl-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol and 1.22 g. of sodium'periodate in 50 ml. of water and one ml. of ethanol is stirred for two hours at 20°. The formed solid is filtered, washed with water and dried leaving 1.45 g. of l,4-dimethyl-9,10-dihydro-9,10-anthracenedicarboxaldehyde (m.p. 159°-160eC.).
Example 94 1,4-Diroethyl-bis(2-imidazolin-2-ylhydrazone)-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride 10 ' A mixture of 1.15 g. of 1,4-dimethy1-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 1.53 g. of 2-hydrazinoimidazoline dihydrochloride in 50 ml. of _n-oropanol is boiled and concentrated to 20 ml. over the course of two hours. The resulting solution was treated with one ml. of acetone and 75 ml. of ether • 15 giving a pale yellow precipitate which was filtered off, washed with acetone and dried leaving 1.8 g. of product, m.p. 230°-235°C. dec.
Example 95 Cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate, syn and anti isomers Fifteen grams of 1,4-dimethoxyanthracene is refluxed under nitrogen with 55 g. of vinylene carbonate for 16 hours.
The excess vinylene carbonate is removed under vacuum (55eC./12 mm.) and the residue is slurried in chloroform and filtered retaining 13 g. of a mixture of yellow and colorless crystals. On boiling this mixture with methylene chloride and filtering there is left 10.5 g. of colorless crystals, m.p. 283°-285°C. of one syn or anti isomer of the product.
The other syn or anti isomer is obtained from the 30 original chloroform filtrate by precipitation with methanol and I recrystallizing from a mixture of methylene chloride and methanol giving 5 g. of colorless crystals, m.p. 255°-260°C. Both isomers show the same infra-red spectrum, analyze correctly and show a depressed mixed melting point (238e-245°C.).
Example 96 Cis-1,4-dimethoxy-9,lO-dihydro-9,10-ethanoanthracene-ll,12-diol, syn and anti isomers A mixture of 10.5 g. of cis-1,4-dimethoxy-9,10-dihydro-9,10-ethanoanthracene-ll,12-diol, cyclic carbonate, m.p. 283e-285eC., and 8.5 g. of potassium hydroxide, 12 ml. of water and 85 ml. of ethanol is stirred at room temperature for 16 hours. The formed.solid is filtered, washed with water and dried leaving 5.0 g. of one of the isomers of the product m.p. 187°-188’C.
The other syn/anti isomer is obtained in the same manner from 4.0 g. of the corresponding cyclic carbonate, m.p. 238e-245°C., giving 2.1 g. of product, m.p. 183e-185°C. Both isomeric diols show the same infra-red spectrum, analyze correctly and show a depressed mixed melting point, m.p. 155°-158°C.
Example 97 Bis-(2-imidazolin-2-ylhydrazone)-1,4-dimethoxy-9,10-dihydro-9,10-anthracenedicarboxaldehyde dihydrochloride A mixture of 1.5 g. of l,4-dimethoxy-9,10-dihydro-9,10-anthracenedicarboxaldehyde and 1.8 g. of 2-hydrazino-225 -imidazoline dihydrochloride in 100 ml. of jy-propanol is boiled and concentrated to 50 ml. over the course of two hours. The cloudy solution is clarified by filtration and then is basified with saturated sodium bicarbonate solution and diluted with three volumes of water yielding 1.5 g. of the free base as a yellow solid, m.p. 235°-240’C. The dihydrochloride salt of the t product is obtained by dissolving 1 g_. of the free base in 40 •ml. of n-propanol and treating with 1 ml. of 7N anhydrous hydrochloric acid in ethanol. The solution is concentrated to an oil and recrystallized from n-propanol giving 0.3 g. of a color5 less dihydrochloride salt m.p. 250°-255eC.
Example 98 Bis(2-imidazolin-2-ylhydrazone)-7,12-dihydro-benz[a]anthracene dicarboxaldehyde A 1.43 g. portion of 7,12-dihydro-benz[a]anthracene5 -7,12-dicarboxaldehyde [Neuman & Din, J. Org. Chem. 36, 966 (1971)] is dissolved in 100 ml. of boiling n-propanol. This solution is treated with 1.73 g. of 2-hydrazinoimidazoline dihydrochloride and the boiling is continued for 3 hours. The mixture is clarified by filtering while hot. The cooled filtrate produces an orange solid which is removed by filtration, washing with n-propanol. The combined filtrate and n-propanol washings is concentrated to 1/2 its volume, diluted to 200 ml. with water and basified with saturated aqueous sodium bicarbonate solution. The resulting gummy solid hardens and is then ]_5 washed with water, collected by filtration, taken up in methanol and precipitated with water, giving the desired product as the base, m.p. 190°-195°C. This base is converted to its dihydrochloride salt by dissolving in n-propanol, treating with 6N hydrochloric acid in n-propanol and cooling. The dihydrochlor20 ide salt melts at 245e-250°C.
Example 99 ,12-*Dihydro-5,12-benz[b]anthracene dicarboxaldehyde A mixture of 7.0 g. of benz[b]anthracene and 26 g. of vinylene carbonate is heated at reflux under nitrogen for 20 hours. The excess vinylene carbonate is removed by vacuum distillation (57°C./9 mm.) and the residue is taken up in 25 ml. of methylene chloride and filtered. The filtrate is treated with twice its volume of methanol and then cooled, producing a tan solid and a mother liquor which .is saved. This solid is re10 crystallized from 60 ml. of 1,2-dichloromethane, collected by filtration, washed with methanol and saved. The mother liquor (saved above) is concentrated giving a gummy solid which is recrystallized from a' mixture of methylene chloride and methanol giving a gray solid which is combined with the above solid and recrystallized from ethyl acetate with charcoal treatment giving 5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-aiol, cyclic carbonate as colorless rods. A mixture of 1.3 g. of the eye lie carbonate, 1.05 g. of potassium hydroxide, one ml. of water -4-7633 and 15 ml. of ethanol is stirred at 60°-65°C. for 2.hours. The mixture is diluted with 1-2 volumes of water, filtered and the solid is washed with water and dried giving cis-5;12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol as a colorless solid.
To a solution of 2.6 g. of cis-5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol in 400 ml. of glacial acetic acid at 20°C. is added portionwise 4.4 g. of lead tetraacetate. The reaction is stirred for 45 minutes. The weakly purple colored solid is filtered off, washed with glacial acetic acid and finally water and dried leaving 1.0 g. (m.p. 170°-172°C.) of 5,12-dihydro-5,12-benz[b]anthracene dicarboxaldehyde.
Example 100 Bis(2-imidazolin-2-ylhydrazone)-5,12-dihydro-5,12-benz[b]anthracene dicarboxaldehyde dihydrochloride A mixture of 0.85 g. of 5,12-dihydro-5,12-benz[b]~ anthracene dicarboxaldehyde and 1.04 g. of 2-hydrazinoimidazoline dihydrochloride in 60 ml. of n-propanol is boiled and concentrated to 30 ml. over the course of 2.5 hours. The solution is clarified by filtration and allowed to cool for 48 hours.
The formed dark red crystals of the desired product Yfeigh 0.12 g. and melt at 290°-295°C. More product may be obtained as the free base by diluting the mother liguor with water and basifying with sodium bicarbonate solution.. The formed crude product is recrystallized from methanol giving 0.15 g. of dark red crystals melting at 230°-233°C.
Example 101 7,12-Benz[a]anthracene dicarboxaldehyde A mixture of isomers of 7,12-dihydro- 7,12-benz[a]— anthracene dicarboxaldehyde [Newman & Din, J. Org. Chem. 36, 967 (1971)] is suspended in 75 ml. of glacial acetic acid, treat87 ed with 6 g. o'£ ferric chloride hexahydrate and stirred at room temperature for 3 hours. The remaining yellow solid is filtered off, washed with acetic acid and water leaving the yellow product, m.p. 197°-198°C.
Example 102 Bis(2-imidazolin-2-ylhydrazone)-7,12-benz[alanthracene dicarboxaldehyde dihydroehloride A solution of 0.57 g. of 7,12-benz[a]anthracene dicarboxaldehyde and 0.70 g. of 2-imidazolin-2-ylhydrazine in 50 ml. of n-propanol is boiled and concentrated to 20 ml. over the course of 3 hours. After cooling for 3 days, the formed orange powder is filtered off, washed with n-propanol and dried leaving the product, m.p. 240°-245eC. Dilution of the mother liquor with two volumes of water and basification with sodium bicarbonate solution gives the free base of the product as an orange solid, m.p. 210°-215°C.
Example 103 ,12-Be'nz [bl anthracene dicarboxaldehyde A solution of 5 g. of- 13,14-dihydroxy-5,12-ethanobenz[b]anthracene in 110 ml. of glacial acetic acid is treated all at once with 15.4 g. of lead tetraacetate and stirred at 30e-40°C. for 3 hours. The formed purple solid is filtered, washed once with acetic acid, finally with water, dried and recrystallized from methylene chloride-methanol to give purple needles, m.p. 215e-217°C.
Example M4 Bis (2-imidazolin-2-ylhydrazone)-5,12-benz[b]anthracene dicarboxaldehyde dihydroehloride A suspension of 1.0 g. of 5,12-benztb]anthracene dicarboxaldehyde and 1.2 g. of 2-imidazolin-2-ylhydrazine in 75ml of n-propanol is boiled and concentrated to 50 ml. The formed solid material is filtered from.the hot solution, washed with n-propanoi, retaining the purple coloured product, m.p. 3Z0°-325°C.

Claims (36)

1. ,1’-[9,10-anthrylenebis(methylidynenitrilo)]diguanidine dihydrochioride. 1. A hydrazone compound of the formula wherein A, B and C form an anthracene or 2. Is N_(^H 2 ) m wherein m xs 2 2 il wherein X is methylimino and Ry is -C-R_ methylamino; 1,1'-[9,10-anthrylene-bis(methylidyne nitrilo)Ibis-(2,3-dimethylguanidine)dihydroiodide. 5. The compound according to claim 1, R·,, R„, R c and R, -wherein Rp 2 -U bis(2-imidazolin-2-yl)hydrazone of 9,10-anthracenedicarboxaldehyde dihydroehloride.
2. The compound according to claim 1, wherein Rp Rg, Rp Rg and R g are hydrogen and R. is N_(CH O )_ wherein Y is imino and m is two; 3. ’ ''4’ are hydrogen and R- is X -c!-r 7 Ry i3 dimethylamino; 1,1'-[9,10-anthrylenebis(methylidynenitrilo)]bis-(3,3-dimethylguanidine)dihydroiodide.
3. The compound according to claim 1, wnerein Rp Rg, Rp R g and R g are hydrogen and R, is X wherein X is imino and R, is methylamino; 1,1-[9,10-anthrylenebis(methylidynenitrilo)]bis-3-methylguanidine dihydroiodide. 4. -76 33 4 Jr is two; bis-(2-imidazolin-2-ylhydrazone) of 2-chloro9,10-anthracenedicarboxaldehyde dihydrochloride.
4. The compound according to claim 1, wherein Rp Rg, Rp Rg and R g are hydrogen and R- is X
5. Quaternary ammonium salts. 5.12- dihydro-bis(4,5,6,7-tetrahydro-lH-l,3-diazepin-2-ylhydrazone) of 5,12-benz[bJ anthracene dicarboxaldehyde. 5.12- benz[bjanthracene dicarboxaldehyde. 5 “ ,,u ''6 wherein X is imino and and R- is X 2 ii -C-Rwherein X is imino and Ry is amino;
6. The compound according to claim 1, wherein R,, R 3 , Rp Rg and R g are hydrogen and R 2 ^ 3 ft wherein X is Imino and Ry is hydroxy-C-R 7 ethylamino; 1,1'-[9,10-anthrylenebis(methylidynenitrilo)] bis-[3-(2-hydroxyethyl)guanidine] dihydroiodide.
7. The compound according to claim 1, wherein R-p R^, Rp R g and R g are hydrogen
8. The compound according to claim 1, wherein Rp R 3 , Rp Rg and R g are hydrogen and R 2 is N—(CH 2 ) m wherein Y is imino and m is three; .0. bis(1,4,5,6-tetrahydro-2-pyrimidin-2-ylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydrochioride.
9. The compound according to claim 1, wherein R| is methyl, Rj, Rp R g and R g are hydrogen and R 2 is N_(CH 2 ) m wherein Y is imino -LA and m is two; bis(2-lmidazolin-2-ylmethylhydrazone) of 9,10-anthracenedicarboxaldehyde dihydroiodide. 10. The compound according to claim 1, wherein Rp R 3 , Ry, R g and R g are hydrogen and R, is X v/herein X is imino and 2 II -θΛ Ry is benzylamino; 1,1‘-[9,10“anthrylenebis)methy]idynenitri]o)J bis (3-benzy1gauni di ne)di hy.droi odide. 9,10-dihydro anthracene nucleus; R^ is hydrogen or alkyl having up to 4 carbon atoms; R 2 is hydrogen, alkyl having up to 4 carbon atoms, phenyl or monovalent moieties of the formula: and
10. 5!,12-dihydro-tns(2-imidazolin-2-ylhydrazone) of 10 wherein m is 2, 3, 4 or 5, R? is amino, anilino, hydrazino, monohydroxyalkylamino having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear a hydroxy group, alkylamino having up to 4 carbon
11. The compound according to claim I wherein Rp' R g , Rp Rg and R g are hydrogen and R n is X wherein X is imino and R-, is cyclohexyl 2 4-r 7 amino; 1,1'-[9,10-anthrylenebis(methylidynenitrilo)]bis(3-cyclohexylguanidine)dihydroiodide.
12. The compound according to claim 1, wherein Rp Rg, Rp Rg and R g are hydrogen and R o is X wherein X is imino and R_ is 2-thenyl 2 11 7 aminoj 1,1’- (9,10-anthrylenebis(methylidynenitrilo)]bis[3-(2-thenyl)guanidine]dihydrochloride.
13. 13. The compound according to claim 1, where;n Rp Rg, Rp Rg and R g are hydrogen and Rj is X wherein X is imino and R ? is 4-pyridyl- -$-r 7 methylamino $ 1,1' - [9,10-a.nthrylenebis (methyldiynenitrilo) ] bis [3- (4-pyridylmethyl)guanidine tetrahydroiodide.
14. The compound according to claim 1, wherein Rp Rp Ra and R g are hydrogen, Rg is 2-chloro and R, is N_(CH,) wherein Y is imino and m 15. Claim 1, which comprises reacting a compound of the formula: wherein Rg, R^, Rg and R g and rings A, B and C are as defined in claim 1, with a hydrazine of the formula R. wherein and Rg are as defined in claim 1, and, if desired, forming the pharmacologically acceptable acid-addition and 15 hydrogen, m is 3 and R g is hydrogen; 7,12-dihydro-bis(l,3,4,5tetrahydro-lH-pyrimid-2-ylhydrazone) of 7,12-benz[a]anthracene dicarboxaldehyde.
15. The compound according to claim 1, wherein Rp R g , R^ and R g are hydrogen, R g is 2-methyl and R o is N~(CH,)_ ' * Hi. -c- γ wherein Y is imino and m is two; bis(2-imidazolin-2-ylhydrazone) of 2-methyl-9,10-anthracenedicarboxaldehyde dihydrochloride. 15 atoms, dialkylamino where each alkyl group has up to 4 carbon atoms, cycloalkylamino having from 3 to 6 carbon atoms, benzylamino, a-phenethylamino, S.’-phenethylamino, 2-furfurylamino, 3-furfurylamino, α-thenylamino, β-thenylamino,
16. The compound according to claim!, wherein R5 is 1-hydroxy, Rg is 4-hydroxy, R^, Rg and R^ are hydrogen and Rg is N—(CH 2 > m -H—1 wherein Y is imino and m is two; bis(2-imldazolin-2ylhydrazone) of l,4-dihydroxy-9,10-anthracenedicarboxaldehyde dihydrochloride.
17. The compound according to claim 1, wherein Rj, R^. and R g are hydrogen, Rj and Rg are fluorine, and R and Y is imino; bis-(2-imidazolin-2-ylhydrazone) of 2,6-difluoro-9,10-anthracenedicarboxaldehyde.
18. The compound according to claim 1, wherein Rg and R 4 form a fused benz ring with the carbons at the ortho and meta positions of the anthracene, R g and R g are hydrogen, m is 2 and Rg is hydrogen; bis -(2-lmldazolln-2-ylhydrazone) of 7,12benz[a]anthracene dioarboxaldehyde.
19. The compound according to claim 1, wherein Rj and R^ form a fused benz ring with the carbons at the meta and para positions of the anthracene, R g and R g are hydrogen, m is 2 and Rg is hydrogen; bis(2-imidazolin-2-ylhydrazone) of 5,12benz[b]anthracene dioarboxaldehyde. 20. And para positions of the 9,10-dihydro anthracene, Rg and R g are hydrogen, m is 4 and R g is methyl;
20. The compound according to claim 1, wherein Rg and R^ form a fused benz ring with the carbons at the ortho and meta positions of the anthracene, R5 and Rg are hydrogen, m is 4 and Rg is hydrogen; bis-(4,5,6,7-tetrahydro-lH-l,3-dia2epin2-ylhydrazone) of -7,12-benz [a]anthracene dioarboxaldehyde. 20 α-pyridylmethylamino, β-pyridylmethylamino. 476 33 γ-pyridylmethylamino, indanylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-methylpiperazino, alkoxy having up to 4 carbon atoms or alkylthio having up to 4 carbon atoms, X is oxo, thioxo, imino or alkylimino having up to 4 carbon atoms, and Y is oxy, thio or a divalent group of the formula: | -N-Rg wherein Rg is hydrogen, alkyl having up to 4 carbon atoms or monohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbon atom alpha to the nitrogen atom may not bear a hydroxy group; Rg, R^, Rg and R g are each individually selected from hydrogen, halogen, hydroxy, nitro, amino, sulfonamide, alkyl having up to 4 carbon atoms and alkoxy having up to 4 carbon atoms; and Rg and R^ together with the carbon atoms to which they are attached form a fused benz ring provided that in that case R^ is hydrogen and R 2 is N—•jCH 2 ) m wherein m and Rg are as defined above; or a pharmacologically acceptable acidaddition or quaternary ammonium salts thereof.
21. The compound according to claim 1, wherein Rj and R 4 form a fused benz ring with the carbons at the meta and para positions of the anthracene, R5 and R6 are hydrogen, m is 3 and R g is methyl; bis-(1-methy 1-1,3,4,5-tetrahydro-lH-2-pyrimidylhydrazone) of 5,12-benz fblanthracene dioarboxaldehyde.
22. The compounds according to Claim 1, wherein R3 and R^ form a fused benz ring with the carbons at the ortho and meta positions of the 9,10-dihydro anthracene, Rg and Rg are hydrogen, m is 2 and Rg is hydrogen; 7,12-dihydro-bis(2-imidazolin-25 ylhydrazone) of 7,12-benz [_aj anthracene dicarboxaldehyde.
23. The compound according to claim 1, wherein Rg and R^ form a fused benz ring with the carbons at the meta and para positions of the 9,10-dihydro anthracene; Rg and Rg are hydrogen,’ m is 2 and Rg is hydrogen;
24. The compound according to claim 1, wherein Rg and R^ form a fused benz ring with the carbons at the ortho and meta positions of the 9,10-dihydro anthracene, Rg and Rg are
25. The compound according to claim 1, wherein Rg and Rq form a fused benz ring with the carbons at the meta
26. A compound according to any one of the preceding claims 1 or 17-25, wherein the compound is in the acetic acidaddition salt form.
27. A compound according to Claim 26, wherein the compound is in 5 the diacetate salt form.
28. A compound according to any one of the preceding claims 1 or 17-25, wherein the compound is in the hydrochloric acid-addition salt form.
29. A compound according to any one of the preceding claims 1 or 17-25, wherein the compound is in the maleic acid-addition salt form.
30. A compound according to any one of the preceding claims 1 or 17-25, wherein the compound is in the gluconic acid-addition salt form.
31. A process for the preparation of the compounds according to
32. A process according to claim 31, wherein the hydrazine is reacted in a lower alkanol solvent in the presence of a catalytic amount of an acid at a temperature of 50° to 125°C.
33. A process according to claim 31, wherein the hydrazine is 10 guanyl hydrazine.
34. An antibacterial composition comprising a hydrazone compound according to any one of claims 1 - 30 and a pharmacologically acceptable carrier.
35. A process according to claim 31, substantially as herein15 before described with reference to any one of the Examples herein.
36. A hydrazone compound whenever prepared by a process
IE2342/78A 1977-11-28 1978-11-27 Novel anthracene-9, 10-bis-carbonyl hydrazones and derivatives IE47633B1 (en)

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US05/947,976 US4187373A (en) 1978-10-02 1978-10-02 Novel dihydrobenzanthracene derivatives

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