AP1A - Polycyclic aromatic compounds - Google Patents

Polycyclic aromatic compounds Download PDF

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Publication number
AP1A
AP1A APAP/P/1984/000003A AP8400003A AP1A AP 1 A AP1 A AP 1A AP 8400003 A AP8400003 A AP 8400003A AP 1 A AP1 A AP 1A
Authority
AP
ARIPO
Prior art keywords
propanediol
methyl
amino
methy
thy
Prior art date
Application number
APAP/P/1984/000003A
Other versions
AP8400003A0 (en
Inventor
Kenneth Walter Bair
Original Assignee
The Wellcome Foundation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GB838313571A priority Critical patent/GB8313571D0/en
Priority to US06/499,813 priority patent/US4530800A/en
Priority to DE8484105584T priority patent/DE3473141D1/en
Priority to NO841954A priority patent/NO157416C/en
Priority to JP59099655A priority patent/JPS59225149A/en
Priority to EP84105584A priority patent/EP0125701B1/en
Priority to EG315/84A priority patent/EG17595A/en
Priority to GB08412485A priority patent/GB2140416B/en
Priority to GR74735A priority patent/GR82278B/el
Priority to IE120384A priority patent/IE58416B1/en
Priority to MC841705A priority patent/MC1595A1/en
Priority to CA000454514A priority patent/CA1222750A/en
Priority to DK242284A priority patent/DK242284A/en
Priority to ZA843708A priority patent/ZA843708B/en
Priority to EP84105585A priority patent/EP0125702B1/en
Priority to ES532512A priority patent/ES8603376A1/en
Priority to JP59099656A priority patent/JPS59225150A/en
Priority to IL71854A priority patent/IL71851A/en
Priority to NZ208168A priority patent/NZ208168A/en
Priority to HU841886A priority patent/HU197875B/en
Priority to PH30683A priority patent/PH22265A/en
Priority to AU28098/84A priority patent/AU572509B2/en
Priority to SU843744951A priority patent/SU1535377A3/en
Priority to KR1019840002647A priority patent/KR910000854B1/en
Priority to PT78586A priority patent/PT78586A/en
Priority to CS364584A priority patent/CS273314B2/en
Priority to DD84263086A priority patent/DD223439A5/en
Priority to FI841966A priority patent/FI85263C/en
Priority to DE8484105585T priority patent/DE3465296D1/en
Priority to PL1984254244A priority patent/PL145420B1/en
Priority to PL1984247759A priority patent/PL144294B1/en
Priority to PL1984254245A priority patent/PL145421B1/en
Application filed by The Wellcome Foundation Ltd filed Critical The Wellcome Foundation Ltd
Priority to APAP/P/1984/000003A priority patent/AP1A/en
Priority to US06/661,802 priority patent/US4719049A/en
Priority to US06/661,803 priority patent/US4719236A/en
Priority to US06/661,674 priority patent/US4720587A/en
Publication of AP8400003A0 publication Critical patent/AP8400003A0/en
Priority to ES540161A priority patent/ES540161A0/en
Priority to ES540160A priority patent/ES8604487A1/en
Priority to US06/725,157 priority patent/US4719047A/en
Application granted granted Critical
Publication of AP1A publication Critical patent/AP1A/en
Priority to SU853947162A priority patent/SU1466648A3/en
Priority to SU853982431A priority patent/SU1447277A3/en
Priority to US07/102,275 priority patent/US4820873A/en
Priority to AU13052/88A priority patent/AU599215B2/en
Priority to SG223/89A priority patent/SG22389G/en
Priority to HK450/89A priority patent/HK45089A/en
Priority to CY1486A priority patent/CY1486A/en
Priority to JP2144246A priority patent/JPH0684336B2/en

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    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
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    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
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    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

Biocidal (particularly antitumour active) compounds of the formula (1),

Description

The present invention relates to polycyclic aromatic alhano! derivatives v/hich have been found to have biocidal activity. More specifically tne invention concerns aminoalkanol derivatives containing a polycarbocychc aromatic ring svstsm, methods for the synthesis thereof, pharmaceutical formulations thereof, novel intermediates therefor, pharmaceutical formulations thereof and their use as oiocidal agents, particularly antitumour agents.
t
Razz. Chim. Ital., 93, 118, ;1Ηό31 describes the creoarafion of 2oheny Imethy lamino-2-methy 1-1,3-propanedioI but no antitumour activity is disclosed for this compound. Two analogues of nitracrine '1-ai tro-R-(',3'di methyl am inop ropy Dam i no'acridine) containing 2-a.mi.na-2-me thy 1-1,3-propanediol and tris (hydroxymethyl)methylamine groups are disclosed in Arzneim Γorsch Drug Res. 3211,1013,(1982) as having antitumour’activity in murine screening svstems.
'Ie have now discovered a class of novel polycarbocyclic aromatic alkancl derivatives which have biocidal activity. Accordingly, in a first aspect, e present invention provides a comnound of the formula (I):
R ' a
or a monomethyl or monoetnvl ether ther°of, the compound of formula (1' including its ethers containing no more than 2 8 carbon atoms in total, n- an ester or salt thereof;
BAD ORIGINAL
AJR/TJM/DC12/25th April 1984
D388 A
optionally substituted by one or two substituents which taken together contain not more than four carbon atoms in total and which are the same or different and are selected from halo: cyano; ^alkyl or ^alkoxy each optionally substituted by hydroxy or 2θΙ'<οχ3'> substituted^ 2alkyl or Cj 2alkoxv: a group SfO^R^ wherein n is an integer 0,1 or 2 and is C. 9 alkyl optionally substituted by 6 7 hydroxy or C, ~ alkoxy; or Ar is optionally substituted by a group NR R 6 7 containing not more than 5 carbon atoms wherein R° and R are the same or different and each is a Cj alkyl group or NR^R? forms a five or six membered heterocyclic ring optionally containing one or two additional hetero atoms;
R* is C. -, alkyl substituted by hydroxy; ., ,
- C'
R is hydrogen, Cj alkyl or hydroxymethyl;
4
R and R are the same or different and each is hydrogen, methyl or ethyl;
I 2 3 a
R , R , R and R taken together containing not more than five carbon atoms; or the group:
p
AP o 0 0 0 0 1
AJR/TJM/DCl2/25th April 1984 bad original &
R388 A
Pc wherein -C-C- is a five or six membered saturated carbocyclic ring containing two or three hydroxy grouDs; θ
R is hydrogen, methyl or hydroxymethyl;
10
R and fv are the same or different and each is hydrogen or methyl;
R^ is hydrogen, hydroxy, methyl or hydroxymethyl;
9 10 11
R , R , R , R1 and the -C-C- ring taken together containing less than seven carbon atoms.
Preferably, when Ar is 1- or 9- anthracenvl, the aromatic ring system is substituted.
Preferably Ar is 6-chrysenyl or 3- or 7-fluoranthenyl.
Particularly suitable substituents for the aromatic ring include Cj alkyl or Cj 2 . alkoxvl each optionally substituted by chloro, hydroxy or methoxy; or a group
SIO) or chloro, imidazolyl, morphQlino, cyano, bromo. ^referred substituents n 12 12 are chloro, 2-chIoroethyl or OCH^CH^R wherein Rv is hydrogen, hydroxy or methoxy or a group 5(O)nCHj wherein n is the integer Ο, 1 or 2. The substituents may be attached to any appropriate position on the aromatic ring. Preferably when Ar is substituted, this is by one substituent only.
Suitably
R* is or
wherein
R13 is C^OH, CH(CH3)0H or CH2CH2OH,
RlZ| is hydrogen, Cj^alkyl, or CH20H
R-1^ is hydrogen or methyl.
Preferably R^ is CH20H or CHCCH^JOH. Suitably R^ is hydrogen, methyl, ethyl or CH^OH.
AJR/TJM/DCi2/25th Apr'd 1984 bad
B388 A
Preferably the grouo:
P* 20H
IS
OH wherein R^ is hydrogen or methyl and is hydrogen, methyl or ethvl, preferably methyl.
Salts included within the scope of the present invention are those of compounds of formula U) and ethers and esters th^peof.
Esters and non pharmaceutically acceptable salts of the compounds of formula (I) are useful intermediates in the preparation of compounds of the formula (I) and pharmaceutically acceptable salts thereof, and are therefore within the scope of the present invention. Thus, salts of the compounds of the formula '1' useful in the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and orqanic acids such as isethionic, maleic, malonic, succinic, salicyclic, tartaric, lactic, citric, formic, lactobionic and pantothenic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, · benzenesulfonic, p-toluenesulfonic and naphthalene-2-sulfonic acids; ascorbic and amino acids, such as glycine. Suitable salts include hydrochlorides, methane and ethanesulfonates, lactates, citrates and isethionates. Pharmacologically and pharmaceutically acceptable salts are preferred, particularly those that are soluble in solvents suitable for parenteral administration, for example hydrochlorides, methanesulphonates and isethionates.
O o
o
O
CL <
Esters of compounds of formula (I) are derived from acids knov/n to those skilled in the art to be suitable for ester formation, and are conveniently those derived from & alkanoic acids, for example acetic acid, propionic acid, n-butyric acid and iso-butyric acid.
A JR/TJM/DC12/25th April 1984 bad ORIGINAL
3388 A
The esters may be formed from all, or only some, of the hydroxy groups contained in the compounds of formula (I).
Specific compounds within the scope of formula (I) include, for example
2-((6-Chryseny lrnethyl)amino)-2-methyl-1,3-propanediol,
- ((9 - A nthracenylmethyDami no)-2-methyl -1,3-propanediol,
2-((1-AnthracenylmethyBami no)-2-methyl - 1,3-propanediol,
2-((10-Chloro-9-anthracenvlmethy 1)-amino)-2-methyl-1,3-propanediol,
2-((10-Bromo-9-anthracenylmethyl)amjno)-2-methyl -1,3-propanediol,
2-Methyl-2-((lO-methyl-9-anthracenyImethyl)amino)-1,3-propanediol,
2-Methyl-2-((10-methyl thio-9-ant hracenylmethyDamino)-1,3-propanediol,
2-((10-(2-Chloroethyl)-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol,
-((10-Hydroxy me thy 1)-9- anthraceny!methyl)amino)-2 -methyl -1,3-prop’anediol,
10-((1,1 -Bis)hydroxymethy!)ethylamino)methy 1-9-anthracene-carbonitrile,
2-Methyl - 2-((i0-methy!sulfinyl-9-anthraeenylmethyl;am!no)-1,3-propanediol,
2-((10 - Met noxy - 9-ontnracenylmethyl)amino'i-2 - methyl -1,3-propanediol,
2-((10 -Bromo-1 -anthracenvlmethy I )ami no)-2-methyl - 1,3-propanediol,
-((4,10-Di chloro-9-anthracenyl methyl'iami no''· - 2 - me thy 1-1,3 - propanediol,
2-((4,3-Dichloro-9-anthracenyImethyl)amino)-2-methyl -1,3-propanediol,
2-((2,l0-Dichloro-9-anthracenylmethyI)amino)-2- me thy 1-1,3-propanediol,
- ((3,lO-Dichloro-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol,
BAD ORIGINAL
AJR/TJM/DCl2/25th April 1984
Β38Θ A
2-(( 3-E luoranthr y lme thy l)a mi no)-2-methy 1-1,3-propanediol,
2-Methyl-2-((2 -triphenylenylmethyl)amino>-1,3-propanediol,
2-((4-Chloro-9-anthracenylmethyl}amino)-2-methyl-i,3-propanediol,
2-((2-Chloro-9-anthracenylmethy Damino)-2-methyl-1,3-propanediol,
- ((10-E thy 11 hi o-9-anthracenylmethy Kami no'-?-me thy 1-1,3-propanediol,
2-(( lO-(2-Hydroxyethylthio)-9-anthraoenyl met hyl'aminol-2-methy 1-1,3-propanedioI,
2-(( 10-Chloro-9-ant hracenvl met hv Ba mi no 1-2-hydroxy me thy!-1,3-propanediol,
2-((7-rluorantheny!me thy I/amino^-methyl-1,3-propanediol,
2-((i0-(2-Hydroxyethyloxy)-9-anthracenylmethyDamino-2-methy 1-1,3-propanediol,
2-((l(J-Ethoxy-9-anthracenylmethy I )amino)-2-methyl-1,3-propanediol,
2-((6-Chryseny Imethyl 'ami no)-2-hydroxy met hy 1-1,3-propanediol,
2-((6-Chry senylme thy l)amino)-2-e thy 1-1,3-propanediol, »
2-Hydroxymethyl-2-((3-f!uoranthens Imethyl 'amino'- 1,3-propanediol,
2-Ethy 1-2-(( 3-fluorantheny Imethyl )ami no-1.3-d ropanediol,
- ,(10-chi oro-9-anthracen.y Imethyl'a mi no'-2-ethyl-1,3-propanediol bad original
AJR/TJM/DCl2/25th April 19H0
Ί
Β388 A
2-((3-chloro-9-anth*acenylmethyl)amino-2-methy '-1,3-propanediol, (+-) (2R*., 3S*)-2-((6-chrysenylmethyI)amino)-2-methyl-l,3-butanediol, > .
' 2-l(2-etbyl-9-anthracenylmethyl)amino)-2-methyl-1,3-propanediol and
2-((3-ethyl-.9-anth(acenylmethyl)amino)-2-methyl-1,3-propanediol, * .
(+-) (2R*,. 3_S*)-2-((-9-anthracenylmethyl)amino)-2-nnethyl-l,3-butane^iol,
--- . / . (.+-) (2T^*, 3R*)-2-(((6-chpysenyl)methy[)amino)-2-rnethyI-l,3-butanediol, « 1 ' ’
2- (((6-chryseny I )methyl)a mi no)-2-ethoxy methyl- 1,3-propanediol,
3- methoxf-2-((i(6-chrysenyl)methyl)amino)-2-methyl-l-propanol,
3-methoxv-2(((3-f!uorantheny))methy!)amino'-2-methvl-l-propanol, ·,, i . ' >Λ , (+-H2R*,'?S*}-,2-(l((3-fluoranthenyI)methyl)amino)-2-methyl-l,3-butanediol,
2-ethoxy methyl-2-((( 3-fluoranthenyDmet by I )amino)-l,3-propanediol, *
12-(((9-arithracenyDme&hyl)amino)-2-ethoxymethyl-i,3-propanedioI, '
2-^-((6-cht5’sepylm^thyl)aminftiil-a,3-a-cyclohexanediol ' i, / : ' ;
2-8-ll3-1fluorqnthenyTmethyl)amind)-J«-a;3-a-cyclbhexanediol x r ’ ' ' ' s » ' f ' ί )2--((6-chrysenyimethyl)annino)-2-isopropyl-1,3-propanediol
2-((3-fluoranthenylmethyDamino)-2-isopropyl-1,3-propanediol
2-((6-chryseny lmethyI)apnmo)-2-me thy 1-1,4-butanediol ♦
2-((3-fluoranthenyImethyl)amino)-2-methyl-i,4-butanedioI
2-(((10-chloro-l-anthracenyl)methy!)amino)-3-methyl-2,5-pentanediol
2-(((10-chi oro-1 - ant hracenv DmethyBa mi no'-2-me thy 1-1,3-propanediol h'1eso-3-((6-chrysenylmethyDamino)-2,4-pentanedio!
2-((6-crhs^senylmethyl)ami no)- 1,3-propanediol 2-((( 12-ethyl-6-chryseny I )methv Damino'-2-me thy I -1,3-propanediol 2-(((10-(2-methoxy ethoxy)-9-anthraceny!)me thy Da mi no)-2-me thy I-1,3-prbpa.nediol 2-methyl-2-(,((10-morpholino-9-anthracenyl)methy!)ami no)-1,3-propanediol 2-((9-anthracenylmethyl)amino)-3-methoxy-2-methy!-l-propanol 2-((( l2-chloro-6-chrysenyI)methyl)amino)-2-methyl- 1,3-propanediol 2-((9-anthracenylmethyl)amino)-2-isopropyl-l,3-propanediol
AJR/TJM/DC12/25th April 1984
BAD ORIGINAL
F3388 A
2-l(9-anthracenylmethyI)amino)-2-methyl-l,4-butanediol
2-((310-(1 H-im i da zol-l-y 1)-9-anthraeenyl)me thy Da mi no)-2-me thy 1-1,3-propanediol 2-(9-ethy!-3- fluoranthenyl)methy!)amino)-2-methyl-l,3-propanediol 2-(((l2-ethoxy-6-chrysenyl)methy !)amino)-2-methyl-l,3-propanediol (Ια, 2β, 3a)-2-(9-anthracenylmethy!)amino-l,3-cyclohexanediol
2-(((4-chloro-l0-hydroxv ethoxy )-9-anthracenyl)me thy l)amino)-2- me thy!-l,3-propane diol (+-X2R *, 3R S* 4R*)-3-(6-ChrysenvImethyl)amino)-3-methy 1-2,Spentanediol 2-Methy !-2-(((l0-methy lsuIfonyl-9-anthracenyDmethyDamino'!-l,3-prqc?aTiediol and salts and esters thereof.
O o
o o
c
bad original
AJR/TJM/DCl2/25th April 1980
3388 A
Of these specific examples of compounds of formula (I), the most preferred compounds are 2-((0-chrysenylmethy!)amino)-2-methyI-l,3-propanediol, 2-((3f!uoranthenylmethyI)amino-2-methy)-l,3-propanediol, 2-((10-(2-hydroxyethyloxy)9-(anthracenylmethyl)amino)-2-methyl-I,3-propanediol.
The compounds of formula (I) and their ethers, esters and salts thereof may be prepared by any method known in the art for the preoaration of compounds of analogous structure. Thus the compounds of formula (I) may, for examole, be
X ' ' prepared by any of the methods defined below.
1. The reduction of a compound of formula (II):
Ar - CH = N - C
OH (Π)
4 wherein R to R are as hereinbefore defined or an appropriately protected derivative thereof, followed by deprotection where appropriate. The conditions and reagents for such a reaction are well known to those skilled in the art and any such conditions/reagents may be employed. The reduction conveniently is carried out by a metal hydride such as lithium aluminium hydride, sodium borohydride or sodium cvanoborohydride, or by catalytic hydrogenation conveniently by hydrogen in the presence of a meta! catalyst such as palladium or platinum or equivalent reagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed., paaes 819820, McGraw Hill, Hew York, 1977. The reduction is suitably carried out with the compound of the formula (II) in solution in an inert solvent or mixture of solvents compatible with the reducing agent at a non-extreme temperature, for example between 0° and 8O°C and conveniently at room temperature.
In the case of lithium aluminium hydride and like reagents suitable solvents include ethers (for example tetrahyrofuran, diethylether and dimethoxyethane) optionally in the presence of a hydrocarbon co-solvent (for example toluene, benzene, or hexane).
A3R/TJM/DC12/25th April 1984 bad original d
3380 A
In the case of sodium borohvdride and like reagents, suitable solvents include alcohols (for example ethanol, methanol or isopropanol) optionally in the presence of a hydrocarbon co-solvent (.for example toluene, benzene or hexane), or an ether co-solvent (for example diethylether or tetrahydrofuran).
In the case of sodium cyanoborohvdride and like reagents, suitable solvents include those described for sodium borohvdride and the reaction is suitably carried out in the presence of an acid conveniently glacial acetic acid as outlined in, for example, R. Hutchins et al, Organic Preparations and Procedures International, 11, 201, 11979). ·'
In the case of catalytic hydrogenation, suitable solvents include alcohols (for example methanol and ethanol optionally in the presence of a hydrocarbon solvent (for example toluene or benzene) or an ether co-solvent (for example diethyl ether or tetrahvdrofuran) in the presence of an acid (for example glacial acetic acid or ethanolic hydrochloric acid) or in glacial acetic acid.
I
X
Protected derivatives of compounds Of formula (II) aipe conveniently used when lithium aluminium hydride is employed as the reducing agent. Convenient protecting groups are compatible with the reducing agent utilized and are readily removed under nondestructive conditions; for example benzyl, tetrahydropyrany 1, and isopropylidene ethers.
It is often convenient not to isolate the comDOund of the formula ill) but to react a compound of the formula (III’ ,vith a compound of the formula GV):
OH (IV)
AP 0 0 0 0 0 1 wherein Ar and R to R are as hereinbefore defined, and reduce the compound of
BAD ORIGINAL fi
A JR/TJM/DCl2/23th April i98u
3388 A formula (II) so formed jn situ. The reaction of the compounds of the formulae (III) and (IV) is again suitably carried out using conditions and reagents which are well known to those skilled in the art, for example in the presence of an acid, such as a sulfonic acid, i.e. p-toluenesulfonic acid, in an appropriate inert solvent, such as an aromatic hydrocarbon, for example toluene, with azeotropic removal of water followed by treatment with the reducing agent in an appropriate solvent, suitably ethanol or methanol. Alternatively, compounds of formula (II) formed under equilibrium conditions in appropriate solvents are reduced jn situ with an appropriate reducing agent, suitably sodium cyanobrohvdride. The coTrnpound of the formula (III) may be in the form of a protected aldehyde, for example an acetal, which liberates the aldehyde function under the reaction conditions.
In turn, a compound of formula (HI) can be synthesised by reacting the appropriate polycyclic aromatic hydrocarbon with a formylating agent such as that generated by the reaction between SnCl^ and C^CHOCHj or equivalent reagents, for example, according to the method A.Reiche et. al. Chem. Ber. 93, 88 (1960), or with other standard formylating reagents/procedupes known to the art, for example; the Gatterman-Koch reaction (CO/HC1/A1C1 j/CuCl), the Gatterman reaction (HCN/HCl/ZnC^), and the Vilsmeier reaction (POCI-j/PhN(Me)CHO, or POCl-j/Me^NCHO) (J. March, vide supra pages 494-497).
The compounds of the formula (III) may also be prepared from an appropriate polycyclic aromatic hydrocarbon substituted by a suitable functional group such as CH^OH, CHBr^, N or methyl, and converting this functional group to an aldehyde group by methods well known to those skilled in the art.
Where the polycyclic aromatic ring bears substituents, the compound of formula (III) may be prepared by a variety of methods known in the art of organic chemistry depending on the nature of the substituent on the polycyclic ring. Tor example if the substituentts) is a halogen, the starting materials may be prepared by direct treatment of the polycyclic aromatic hydrocarbon with a halogenating agent (e.g. Cl^, Br^, or SQ^Cl^) or indirectly by such routes as the Sandmever reaction (D.T. Idoury, Chem. Rev. 42, 213 (19^8)). If the substituent(s) is alkyl, the polycyclic aromatic hydrocarbon may be reacted with the appropriate reagents under FriedelCrafts reaction conditions (P.Gore, Chem. Rev. 53 229, (1955)).
AJR/TJM/DC12/25th April 1984
ORIGINAL
B388 A
The compounds of the formula (IV) also may be prepared by methods known in the art, for example by the reaction of compound NO^CH^R^ with an appropriate aldehyde, conveniently acetaldehyde or formaldehyde, (as in B.M.Vanderbilt and H.3. Haas, Ind. Eng. Chem. 32, 34 (1940)) followed by reduction (as outlined in T. March, vide supra 1123-1126) conveniently by hydrogen in the presence of a metal catalyst, for example a platinum containing catalyst, in an appropriate solvent, conveniently glacial acetic acid.
2), The reduction of a compound of the formula (V):
ArCONH _ c __-
OH
I wherein Ar and R to R are as hereinbefore defined qpd the hydroxy groups are optionally protected, followed by deprotection of the hydroxy groups where appropriate. The reduction may be carried out by standard reducing agents known for carrying out this type of reduction, for example, a hydride such as lithium aluminium hydride in an inert solvent, such as an ether, i.e. tetrahvdrofuran at a non-extreme temperature, for example, at between 0° and 1OO°C and conveniently at the reflux temperature of the ether.
The compound of the formula (V) may be formed by the reaction of the appropriate 3cid ArCOOH, or’a suitable reactive acid derivative thereof, for example, an acid halide, in an inert solvent with an amine of the formula (IV' in which the hydroxy groups are optionally protected; for example when the compound of the formula (IV) is a diol, by an isopropyledene group. The compound of the formula (V) so formed is suitably reduced jri situ and deprotected where appropriate to a compound of the formula (I). The compounds of the formula ArCOOH can be prepared by methods well known to those skilled in the art.
AP 0 0 0 0 0 1
BAD ORIGINAL
AJR/TJM/DCl2/25th April 1984
338« A
3) The reaction of a compound ArCh^L , wherein Ar is as hereinbefore defined and L is a leaving group, with a compound of the formula (IV) as hereinbefore defined. Suitable leaving groups are those defined by J. March, vide supra pages 683 and 895, and include halogens, such as chlorine and bromine, and sulphonic acid derivatives such as p-toluenesulfonate. The reaction is suitably carried out in an appropriate solvent, such as a dipolar aprotic solvent or alcohol at a non-extreme temperature, for example between 50° and 150° conveniently between 50 and 100°. The compounds of the formula ArCH^L can be prepared by methods well known to those skilled in the art.
There is therefore provided, as a further aspect of the invention, a method for the preparation of a compound of formula (I) comprising any method known for the preparation of analogous compounds, in particular those methods defined in (1) to (3) hereinabove. In a yet further aspect, the invention provides novel intermediates involved in the preparation of compounds of the formula (1).
The compounds of formula (I) hav’e^biocidal activity in that they are toxic to certain living cells that are detrimental to mammals, for example, pathogenic organisms and tumour cells. This toxicity to pathogenic organisms has been demonstrated by activity against viruses (eg,, Herpes simplex i/vero), bacteria (eg., Mycoplasma smeqmatis and Streptococcus Pyogenes) fungi (e.g., Candida albicans) protozoa (eg., Eimeria tenella) and helminths (eg., Nippostronqylus brasiliensis). The antitumour activity of compounds of formula (I) has been shown in a number of recognized screens and primarily by the activity against ascitic P388/0 leukaemia. The activity, against ascitic tumours, including P388/0, is evidenced by reduction of tumour cell number in mammals, for example mice bearing ascitic 'tumours, and their consequent increase in survival duration as compared to an untreated tumour-bearing group. Antitumour activity is further evidenced by measurable reduction in the size of certain solid tumours following treatment of mice with the compounds of this invention compared to an untreated tumour-bearing control group. Thus, compounds of formula J) have been shown to be active against murine tumours, lymphocytic leukaemia P38B/U, lymphocytic leukaemia L1210, melanotic melanoma Bl6, P8i5 mastocytoma, MDAY/D2 fibrosarcoma, colon 38 adenocarcinoma, M5076 rhabdomyosarcoma, and Lewis lung carcinoma.
BAD ORIGINAL s
AJR/TJM/DCl2/25th April 1984
Β388 A
Activity in one or more of these tumour tests has been reported to be indicative of antitumour activity in man (A. Goldin et. aj in Methods of Cancer Research ed. V.T. DeVita. Jr., and H. 3usch, 16 165, Academic 3ress, N.Y. I97q).
There are sublines of P3B8/O which have been made resistant to the following clinically useful agents; cytosine arabinoside, doxorubicin, cycloDhosphamide, Lphenylalanine mustard, methotrexate, 5-fIuorouracil, actinomycin D, cis-platin, and bis-chloroethylnitrosourea. Compounds of formula (I) show potent activity against those drug-resistant tumours using the test procedure for P388/0 above.
Compounds of formula 'J) have aiso been found to be active against human tumour cells in primary cultures of gastric, pancreatic, mesothelioma, myeloma, and colon cancers. {As used herein cancer is to be taken as synonymous with malignant tumour or more generally tumour unless otherwise noted). This is a procedure in which the prevention of tumour cell colony formation, i.e., tumour cell replication, by a drug has been shown to correlate with clinical antitumour activity in man
J (D.D. Von Hoff et al, Cancer ChemotheTapy and Pharmacology 6, 265 (1980); S. Salmon and D.D. Von Hoff, Seminars in Oncology, ¢3, 377 (b98l).
Compounds of formula (I) which have been found to have antitumour activity intercalate in-vitro with DNA. This property is determined by viscometric methods using the procedure of V/.D. Wilson et al, Nucleic Acids Research 4, 2697, (1954), and a log P as calculated by the method of C. Hansch and A. Leo Γη Substituent Constants for correlation analysis in Chemistry and 3iology, John Wiley and Sons, New York 1979, lying in the-range between -2 and -2.5.
The invention further provides a method for the treatment of tumours in animals, including mammals and especially humans, which comorises the administration of an effective, non-toxic amount of the compound of formula (I), an ether or ester thereof, or an acid addition salt thereof.
Tnere is further provided as a further, or alternative, aspect of the invention, a compound of formula (I) for use in therapy, for example as an antitumour agent.
The amount of compound of formula (I) required to be effective as a biocidal agent will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, the nature of the formulation; the mammal's body weight, surface area, age and genera! condition; and the particular compound to be
bad original ji
AJR/TJM/DCl2/25th April 1WW
3388 Λ administered. A suitable effective antitumour dose is in the range of about 0.1 to about 120 mg/kg bodyweight, preferably in the range of about 1.5 to 50 mg/kg for example 10 to 30 mg/kg. The total daily dose may be given as a single dose, multiple doses, e.q., two to six times a day or by intravenous infusion for a selected duration. For example, for a 75 kg mammal, the dose range would be about 8 to 9000 mg per day, and a typical dose would be about 2000 mg per day. If discrete multiple doses are indicated, treatment might typically be 500 mg of a compound of formula I given 4 times per day in the form of a tablet, capsule, liquid (e.q, syrup) or injection.
* V
Whilst it is possible for the active compound (defined herein as compound of formula I or ether, ester or salt thereof) to be administered alone as the raw chemical it is preferable to present the active compound in a pharmaceutcal formulation. Formulations of the present invention, for medical use, comprise an active compound together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The present invention therefor, further provides a pharmaceutical formulation comprising a compound of formula (I) (in the form of the free base, ether, ester or a pharmaceutically acceptable acid addition salt thereof) together with a pharmaceutically acceptable carrier therefor. There is also provided a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) or an ether, ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
Whilst the antitumour activity of the compounds of formula (I) is believed to reside in the free base, it is often convenient to administer an acid addition salt of a compound of the formula (I).
The formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration.
ftp 0 (J 0 0 0 1
AJR/TJM/DC12/25th April 1984
BAD ORIGINAL
Β38Θ A
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.
Formulations of tne present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount, of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound-in a free-flowing form such as a powder or granules, optionally mixed with a binder , lubricant, inert-diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar for example sucrose to which may also be added any accessory ingredient. Such accessory ingredients) may include flavourings, an agent to retard crystallisation of the sugar pr an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol or sorbitol.
F ormulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter.
Formulations suitable for parenteral administration conveniently comprise a sterile aoueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula that is isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in
AJR/TJM/DCl2/25th April 1984
BAD ORIGINAL
B388 A distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the isethionate and methane sulphonate salts and preferably the latter.
In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredients selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
The following Examples are provided by the way of illustration of the present invention and should in no way be construed as a limitation thereof. All temperatures indicated are in degrees Celsius.
General Comments
All solvents were reagent grade and,used without further purification with the following exceptions. THE was dried b/ distillation from^Na/K alloy under nitrogen (N?) and used immediately. Toluene (PhCH-j) was distilled from CaH^ under and stored over 3A molecular sieves. Chemicals used were reagent grade and used without purification unless noted. The full name and address of the suppliers of the reagents and chemicals is given when first cited. After this, an abbreviated name is used.
Dreparative HPLC was carried out on a Waters rTep LC/Svstem 500A machine using two 500 g silica gel (.0102) cartridges unless otherwise noted. Plugs of SiO7 used for purifications were flash chromatography silica gel (E. Merck, silica gel 60, 230-400 mesh). An appropriate volume sintered glass funnel was filled approximately 3/4 full with the SiO? and packed evenly by tapping the outside of the funnel. A peice of filter paper was then placed on top of the SiC7 and a solution of the materia! to be purified applied evenly on the too. Gentle suction through a filter flask moved the eluting solvent through the plug rapidly. The appropriate size fractions were combined as needed and further manipulated.
Satisfactory elemental analyses were obtained for all exemplified compounds of the formula (I). Where elemental analyses were performed on the intermediates or starting materials, these elements analysed for are indicated eg (C, Η, N) or (C, H,
AJR/TJM/DCl2/25th April 1984 ,
BAD ORIGINAL £
I 0 0 0 0 0 dV
3388 A ,ί
Cl) etc. In all of the abovementioned analyses, the experimentally determined valves were within - 0.4% of the calculated valves.
Preparation of Starting Materials
A. 6-Chrvsenecarbaldehvde — ' . .-- - - —
To a 5L 3-neck flask equipped with overhead mechanical stirrer, thermometer, condenser, and nitrogen line was added chrysene (Eastman Kodak Co., Rochester,
N. Y. 14650, 100 g, 0.438 mole) and o-dichlorobenzene (2500 mL). The liquid was warmed until all the large chunks of solid dissolved ( 80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl^ (Aldrich Chemical Co., Milwaukee, Wis. 53201, 98%, 228.2 g, 0.876 mole, 102.4 mL), was added in one portion. No temperature change occurred. Keeping the pot temperature below 5° a, a-dichloromethyl methyl ether (Aldrich, 70.48 g,
O. 613 mole, 55.45 mL) was added dropwise over 1 hour. The resulting suspension was warmed slowly to 40° over hours and further stirred for 16 hours. Considerable HC1 gas evolution occurred during the warjming and the early part of the reaction at 40°. The reaction was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H^O. After 4 hours the layers were separated and the organic layer filtered, dried with anhydrous Na^SO^ (Mallinckrodt Co., St. Louis, Mo., 100 g) and filtered again. The clear yellow solution was split into 2 portions and passed through 500 g plugs of flash chromatography silica gel (E.Merk, siHca gel 60, 230-400 mesh) using toluene as the eluting solvent with 500 mL fractions. This separated unreacted chrysene., ( 3 g) from the aldehyde and a more polar product. Tractions containing the aldehyde were combined and the toluene removed. Crystals formed during this process and were removed periodically by filtration. After drying in a vacuum oven (at 60°) final vield of 6-chrysenecarbaldehyde was 89.46 g (79.7%) mp = 167-196°.
E xample B
I0-Msthylthio-9-anthracenecarbaldshyde
The procedure of V. Rogovik et al., Zh. Org. Khim. 3, 1315 (1969) was modified in the following way: A 2L 3-neck flask fitted with stirring bar, condenser, additional
AJR/t JM/DC12/25th April 1984 bad ORIGINS
B388 A funnel, thermometer, N2 inlet, and bubbler was charged with 10-chloro-9anthracenecarbaldehyde (Aldrich, 28.0 g, 0.116 mul), and DME (Aldrich, 1 L). The solid dissolved when the reaction mixture was warmed to 60°. The addition funnel was filled with a solution of Na2S (Mallinckrodt, 28 g, 0.116 mol) in 30 mL of H2O. This solution was added rapidly to the flask causing a considerable amount of spattering as the purple thiolate formed. The reaction mixture was stirred at 65° for 45 minutes, then cooled to 30° (ice bath). CH^I (Aldrich, 27.36 g, 0.193 mol) was then added to the flask dropwise over 5 minutes. The colour of the solution changed from deep purple to yellow after 3 hr. After 15 minutes, 1 L of H20 was added to the reaction mixture. The yellow solid that formed was collected by filtration, dissolved in hot toluene, (500 mL) dried (MgSO^), and filtered through Celite (Trade Mark). Most of the volume of toluene was removed and the resultant oil swirled with hexane (200 mL) to give a bright yellow solid. The material was dried at 50° affording 25.04 g (86%) of lO-methylthio-9-anthracenecarbaldehyde mp 98.5-99°, (C,H,S).
L
Example C lO-(2-Chloroethyl)-9-anthracenecarbaldehyde
AP 0 0 0 0 0 1
Using the Vilsmeier procedure (L.E. Eieser, Org. Syn. Coll. Vol HI, 98 (1955)), 9vinylanthracene (Aldrich) gave i0-(2-chloroethyl)-9-anthraceneearba!dehyde mp 153-159°, (PhCH-j/CH^OH), (C, H, Cl).
Example D . «
A. l,10-Dichloro-9-3nthracenec3rbaldehyde and 4, lO-Dichloro-9-3nthr3cene-carbaldehvde
Using the procedure of V.I. Roqovik et al., Zh. Org. Chim 5, 1315 (1967), 1chloroanthraquinone (Aldrich) gave a mixture of 1,10- and 4,10-dichloro-9anthracenecarbaldehydes. These compounds were separated by preparative HPLC using toluene as the eluting solvent to give 3.05 g (14%) of 1, l0-dichloro-9anthracenecarbaldehyde mp 180.5-183°, (R^ = 0.64, SiO2, PhCH^), (C,H,C1), and 0.59 g (3%) of 4,i0-dichloro-9-anthracenecarbaldehvde mp 167-170°, (R^. = 0.57,
SiO2, PhCH3), (C, H, Cl).
BAD ORIGINAL &
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B388 A
Example E
A. 10-Bromo-9-anthracenecarbaldehyde
This material was made from 9,10-dibromoanthracene (Eastman 20 g, 60 mmol) modifying the procedure of R. Kuhn an H. Fischer, Chem. Ber. 94, 3060 (1961). In this procedure, the reaction mixture was cooled to -78° before the nBuLi was added. The resulting mixture was warmed to RT over 1 hr and then refluxed until the crystalline starting material disappeared. The mixture was then cooled to -78° again before the DME was added (in Qne portion). The flask was warmed to RT and then quenched with 1M HBr (200 mL). The two-phase system was then extracted with (3 x 500 mL). The extracts were combined, dried (MgSO^), filtered, and the solvent removed to give the crude material. This was purified by preparative HPLC using toluene as the eluting solvent. After the solvent was removed 13.06 g (76%) of iO-bromo-9-anthracenecarbaldehyde mp 215-216.5°, (lit, mp 218°, P. Kuhn and H. Fischer, bhem. Ber. 94, 3060 (1961)), (C, H, Br) was obtained.
Example E
4,5-Dichloro-9-3nthracenecarbaldehyde *
1,8-Dichloroanthracene prepared by the method of H.O. House et al. (J. Qrq. Chem. 38, 1167 (1973)), was formylpted by the method outlined in A (except that C^C^ was used as the reaction solvent) to give 4,5-dichloro-9anthracenecarbaldehvde mp 218-220°, (PhCH^/CH^OH), (.C, H, Cl), (lit. 224-226°, E.L. Stoarvn, J. Med. Chem. 17, 563 (1974)).
Example G
Eormvlation of Fluoranthene
Fluoranthene (Aldrich, 100 g, 0.49 mol) was formylated according to the procedure outlined in A (except that was used as the reaction solvent). The crude material was passed through a 1000 g plug of Si02 using toluene as the eluting solvent (3 L). The fractions containing the mixtures of aldehydes were combined
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B388 A and the solvent removed giving 115 g of crude yellow oil. This material was dissolved in 500 mL of CH^Cl^ and diluted to 1 L with hexane. A yellow precipitate formed and this was isolated by filtration. The solid (which is 3fluoranthene-carbaldehyde) was crystallized from CH^C^/hexane and dried at 50° to give 45.7 g of pure material. The filtrate was added to the remaining impure mixture and the solvent removed. The remainder of the material was chromatographed on a 1000 g plug of SiC^ using PhCH^ as eluting solvent. From this mixture, three aldehydes (including more of the 3- isomer) were obtained. The total amounts isolated, identity, and TLC behaviour (SiO^/P^CH^) of these aldehydes are shown below.
I. 3-Fluor ant henecarb aldehyde 68.73 g (61%) mp 103-104.5°, (Rf = 0.27, (C, H), (lit. mp 98-99°, N. Campbell and N.H. Wilson, Chem. and Ind., 1114, (1970).
II. 7-Fluoranthenecarbaidehyde 2.10 g (2%) mp 139-141°, (C, H), R^ = 0.38 III 8-Fluoranthenecarbaldehyde 24.8 g f22%) mp 91.5-93?, (C, H), (R^ = 0.19).
Example H
4-Chloro-9-anthracenecarbaldehyde
1-Chloroanthracene prepared from 1-chloroanthraquinone (Aldrich) by the method of H.O. House et. al. (J. Org. Ch^m. 38, 1167, (1973)) was formvlated by the procedure outlined in A (except that CH^Cl^ was used as the reaction solvent to give 4-chloro-9-an*hraeenecarbaldehyde mp 129-131°, (PhCH^./CH^OH), (C, H, Cl).
I 0 0 0 0 0 dV
Example I lO-Methylsulfinyl-9-anthracene carb aldehyde
A IL round bottom flask fitted with addition funnel and stirring bar was charged with lO-methylthio-9-anthracenecarbaldehyde (example B, 12.0 g, 48 mmol) and 450 mL of CH^CI^· The resulting solution was cooled to 5° with an ice bath. A solution of MCPBA (Aldrich (85%), 9.64 g, 48 mmol) in 350 mL of CH^C^ was then added dropwise to the flask over 1 hr. The reaction mixture was allowed to warm
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B388 A to RT over 1 hr and then was washed with 5% NaHCO-j solution (2 x 500 mL), dried (Na^SCW), filtered, concentrated to 500 mL, and passed through SiC^ (250 g) using toluene (5 L) as the eluting solvent. The desired material was then eluted from the SiO? using EtOAc (2 L) as the eluting solvent. The solvent volume was reduced to 100 mL and then filtered to 700 mL with hexane. The resulting yellow solid was filtered and dried at 50° to give 11.98 g (94%) of 10-methylsulfinyl-9anthracenecarbaldehyde mp 182-184°, (C, H, S).
Example J
2-T riphenylenecarbaldehyde
Using the formylation procedure described in A (except that the reaction temperature was 85°), triphenylene (Aldrich) gave 2-triphenylenencarbaldehyde mp 160-101.5°, (CH2C12/CH3OH), (C, H).
Example K ’ >
lO-Methoxy-9-anthracenecarbaldehyde
A 2 L round bottom flask fitted with distilling head, thermometer, and condenser was charged with 15-crown-5 (Aldrich, 25.89 g, 0.118 mol), NaOCH-j (Aldrich, 7.62 g, 0.141 mol), and CH^OH (50 mL). After 5 minutes 10-chldro-9anthracenecarbaldehyde (Aldrich 28.4 g, 0.118 mol) and 900 mL of dry toluene were added to the clear colourless solution. The solvent was distilled off until the head temperature reached 108° ;300 mL). Additional dry toluene was added to give a total of 1 L volume. The reaction mixture was refluxed for 4 hr, cooled and poured onto a large plug of SiO^ 0-000 g) in a sintered glass funnel. The crude product was chromatographed using toluene as eluent (5 L). The fractions (250 mL) containing the product were combined t = 3 L) and the solvent volume reduced to 500 mL. The shiny golden crystals which formed were filtered to give, after drying at 50°, 15.6 g of material. The volume of the filtrate was reduced to 200 mL and more material fell out of solution and this was filtered and dried to give 6.1 g of additional material. The two crops were combined to give 22.51 g (81%) of 10methoxy-9-anthracenecarbaldehyde which was used without further purification. Recrystallization gave analytically pure material mp 164.5-166.5°, (PhCH-j), (C, H), (lit. mp 165°, J.B. Conant and M. Sramann, J. Amer. Chem. Soc. 50, 2305 (1928)).
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B388 A
Example L
10-E ormyl-9-3nthracenecarbonitrile
A 25 mL 2-neck round bottom flask fitted with thermometer, condenser, inlet and bubbler, and stirring bar was charged with 10-chIoro-9-anthraldehyde (Aldrich, 5g, 21 mmol), CuCN (Fisher Scientific Company, 711 Forges Ave., Dittsburgh, PA, 15219, 2.14 g, 24 mmol), N-methyl-pyrrolidinone (100 mL), DME (15 mL), and bis (triphenylphosphine) palladium dichloride (Eluka, (J.08 g, 01. mmol). The mixture was warmed to 170° and stirred 15 hr under N^· After 1.5 hr, the mixture became homogenous. The reaction was cooled to 70° and poured into a solution composed of 16 g of ΕεΟ^.όΗ^Ο, (Mallinckrodt), 70 mL of 1.0 M HC1 and 400 mL H^O. The resulting mixture was stirred at 60-70° for 1 hr, filtered and a crude orange solid isolated. This material was dissolved in 1 L of hot toluene and passed through a small plug (100 g) of SiO^. The filtrate was then concentrated to 75 mL and diluted with hexane (200 mL). The orange solid which formed was collected by filtration and dried to give 3.17 g (68%) of lO-f0rmyl-9-anthraceRecarbonitrile mp 270-275°, (C, Η, N).
Example M
9.10-Dihydro-9,10-dioxo-1-anthracenecarboxvlie acid
I. 0 0 0 0 0 dV
Benzanthrone (Aldrich, Technical grade) was purified by chromatography on a plug of SiO^ with ^hCH-j as eluent (83% recovery), mp. 172-172.5° (lit. mp. 170-171°, O. Bally and R. Scholl, Ber. 44, 1656 (1911)).
The purified benzanthrone (63.7 g, 0.277 mol) was dissolved in 15 mL of glacial HOAc at 90° and stirred with a mechanical stirrer. After cooling to 80° solid CrOj (Mallinckrodt 200 g, 2 mol) was added in = 5 g portions over about 4 hr. The exothermic reaction maintained the mixture at =80° during this time and CO? was evolved. After CO^ evolution ceased and the reaction temperature fell, the heating mantle was reapplied and the reaction stirred overnight. H^O (1.5 L) was then added to the dark-green solution. The reaction was then filtered to give a deep brown solid which was washed with Ch^OH (200 mL) until the washings were
BAD ORIGINAL ft
AJR/T0M/DC12/25th April 1984
B388 A colourless. The resulting solid was dissolved 2 L of hot methoxyethanol and filtered through Celite (Trade Mark) to remove a black solid residue. The volume of the solution was reduced to =75 mL (some solid formed) and diluted with 100 mL CH^oh to give the product. This material was filtered to give 32.0 g (96%) of golden brown 9,10-dihydro-9,10-dioxo-l-anthracenecarboxylic acid mp 287-289°, (C,H), (lit. mp 293-299°, Chemistry of Carbon Compounds Illb, edited by E.H. Redd, 1919 (1956), Elsevier, New York.
1-Anthracenecarboxylic acid
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 9, i0-dihydro-9,l0-dioxo-l-anthracenecarboxyiic acid (90 g, 0.357 mol), zinc dust (Mallinckrodt, 250 g, 3.82 mol), CuSO^H^O (Mallinckrodt, 5g), and 28% NH^OH (Mallinckrodt, 2500 mL). The mixture was heated slowly until a dark-red solution occurred as the temperature reached 85°. After 3.5 hr the colour of the solution faded to yellow. The reaction was heated, an additional 1 hr, and then cooled and the excess zinc filtered. The filter cake was washed with more NH OH (100 mL) and then discarded. The filtrate was carefully acidified to pH 1 with cone. HO added in portions over 1 hr affording a light-green precipitate which was separated by filtration. The solid was washed with H^O (200 mL) and then recrystallized once from methoxvethanol/^Q (with a small amount of HC1) filtered, and dried at 75° to give 65 g (82%) of 1-anthracenecarhoxylic acid mp 299-250°, (C, H), (lit. mp 295°, Chemistry of Carbon Compounds Illb, edited 'by E.H. Rodd, 1373 (1956), Elsevier, New York).
(1-Anthryl )methanol
To a 500 mL 2-neck flask equipped with condenser, addition funnel with N^ inlet, and stirring bar was added 1-anthracenecarboxy lie acid (6.88 g, 3l mmol) and dry THE (250 mL). To the addition funnel, was added a 1M solution of BH^ in THE (Aldrich, 50 mL, 50 mmol) via a cannula. The BH^ solution was added over 1 hr and the solution stirred overnight at RT. CH^OH was then added until evolution ceased. (5 mL) and then IN HC1 (5 mL) was added to the flask. The solvents were removed and then toluene (100 ml) added to the flask. The toluene was then also removed. The resulting solid was recyrstallized from EtOAc/hexane to give 9.3 g (67%) of (l-anthryl)-methanol mp 129-125°, (C,H), lit 129-125°, 5. Akiyama et al., Bull.Chem. Soc. Jap. 35 (1962)).
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B388 A
1-Anthracenecarbaldehyde
To a 2 L round bottom flask equipped with condenser and magnetic stirring bar was added (l-anthryl)methanol (21.0 g, 0.10 mol, CH^Cl^ (1200 mL) and pyridinium chlorochromate (PCC) (Aldrich, 32.33 g, 0.15 mol). The mixture was then refluxed for 5 hr. The reaction was cooled and then filtered through a 400 g plug of spica gel using toluene as eluting solvent. The first 1 L of solution was collected and concentrated to give 16 g of crude product. This material was purified by preparative HPLC using PhCH^ as eluting solvent. The solvent was removed and the pure material recrystallized from PhCH^/hexane to give 14.Og (67%) of 1anthracenecarbaldehyde mp l30-l3l.5°, (C,H), (lit. mp 126.5-127.5°, P.H. Gore J. Chem. Soc. 1616 (1959)).
Example N (lO-Bromo-l-anthryl)methanol \ 'T
10-Bromo-l-anthracenecarboxylic acid, made from 1-anthracenecarboxylic acid (example M) by the procedure of E. Barnett, J.W. Cook, and H.H. Grainger, Ber. 57 B, 1775 (1924), was reduced with 3H^ in THE by the procedure outlined in 18C to give (lO-bromo-l-anthryl)methano! mp 125-127°, (EtOAc/hexane), (C, H, Br).
10-3 romo-1-anthracene carb al dehvde
---------------- -...- z
Using the procedure outlined in example M oxidation of (lO-bromo-l-anthrvl)methanol with PCC gave lO-bromo-l-anthracenecarbaldehyde mp 134.5-135.5°, (PhCHj/hexane), (C, H, Br).
Example C
AP 0 0 0 0 0 1
2-Chi oro-9-an thracenecarb aldehyde and 3-chloro-9-anthracenecarbal dehvde
2-Chloroanthracene prepared from 2-chloroanthraquinone (Aldrich) by the method of H.Q. House et al. (J. Orq. Chem. 38, 1167 (1973)) was formylated by the procedure outlined in A (except that CH^Gl^ was used as the reaction solvent) to give a (4:1) mixture of 2-chloro and 3-ch!oro-9-anthracenecarbaldehydes (87%). Trituration of the material with CH-jOH gave preferential crystallization of 2AJR/TJM/DCl2/25th April 1984
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B388 A , chloro-9-anthracenecarbaldehyde which after further crystallization (PhCH^/hexane) gave the pure 2-chloro isomer mp 149-150° (C, H, Cl) (lit. 148• 150°, British Patent 1,149,557). The filtrate (R^ = 0.48, SiC^, PhCHj) from the
CH^OH trituration was further purified by preparative HPLC to give pure 3chloro-9-anthraldehyde mp. 122-123.5°, (PhCH^/hexane), (C,H,C1), (Rf = 0.48, SiO2, PhCH3).
Example P
10-E thy lthi o-9-an thracenecarbal delay de
Using the procedure described in Example B lO-chloro-9-anthracenecarbaldehyde (Aldrich) and ethyl iodide (Fisher) gave an oil which solidified to give 10-ethylthio9- anthracenecarbaldehyde mp 74-75.5° (C, H, S).
Example Q
10- ((2-Hydroxy ethyl)t hi o)-9-anthracenecarbaldehvde
Using the procedure described in example B (except that the alkylation reaction was run for 1 hr at 65°), 10-chloro-9-anthracenecarbaldehyde (Aldrich), and 2iodoethanol (Aldrich) gave 10-((2-hydroxyethyl)thio-9-anthracenecarbaldehyde mp 103-104°, (PhCH^/hexane), (C, H, 5).
Example R ,
2,10-Dichloroanthracenecarbaldehyde and 3,10-dichloro-?-anthracene carbaldehyde
Using the procedure of V.I. Rogovik et at. (Zh. Org. Khim. 5, l3l5 (1967)) 2chloroanthraquinone (Aldrich) gave a mixture ( = 1:1) of 2,10- and 3,10dichloroanthracenecarbaldehydes (68%). A portion of the mixture was separated by preparative HPLC using the shave/recycle technique to give 2,10-dichloro-9anthracenecarbaldehyde mp 175.5-176.5°, (PhCH^), (C, H, Cl), and 3-l0-dichloro-9anthracenecarbaldehyde mp 173.5-175°, (PhCH^), (C, H, Cl). The remainder of the materia! was used as a mixture.
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B388 A
Example S
1O-E thoxy-9-anthr a cenecarb aldehyde
Using the procedure outlined in example K, except that NaOEt (Aldrich) EtOH was used instead of NaOCH^/CH^OH, lO-chloro-9-anthraldehyde (Aldrich) gave 10ethoxy-9-anthracenecarbaldehyde mp 88-90°, (CH^Cl^hexane (C,H).
Example T
10-(2-hy dr oxethy loxy )-9-an thraceneca rbaldehyde
A 3 L 2-neck flask fitted with thermometer, condenser, stirring bar, N'2 line and bubbler was charged with KOtBu (MCB Manufacturing Chemists. Inc., 2909 Highland Ave, Cincinnati, OH, 43212, 25 g, 0.22 mol), ethyleneglycol (1500 ml) and lO-chloro-9-anthraldehyde (Aldrich, 50 g, 0.207 mol). The mixture was stirred at 100° for 1.5 h. An additional 5 g (45 mmol) of K0_t3u was added and the stirring continued for an additional 075 h. The reaction mixture was cooled and •r poured into 1500mL of cold H^O, stirred for IO minutes’before the precipitate was collected by filtration. The yellow solid was dissolved in 1 L of C^C^ and passed through a 100 g plug of SiO-, using CH^CI^ (9.L). The C^C^ was discarded and the desired materia! eluted with EtOAC (12 L). The appropriate fractions were combined and the solvent removed to give after drying at 50° 10-(2hydroxvethy loxy )-9-anthracenecarbaldehyde 28.82 g (53%), mp 142-144°, (CH2CI9/hexane), (C,H).
Example U
10-Uethv! sulfonyl-9-3nthracenec a rbaldehyde lO-Methylthio-9-anthracenecarbaldehyde (4.50 g, 17.83 mmol’ was dissolved in CH^Cl^ (1OO ml) and cooled to 0° in an ice bath. To the magnetically stirred solution was added dropwise over 15 minutes a solution of m-chloroperbenzoic acid (Aldrich, 85% technical grade, 7.08 g 35.76 mmol) in 250 ml of CH^Cl^· The ice bath was removed and the clear solution stirred for 2 h. The solution was then washed sequentially with 10% Na252O3 solution (500 ml) and satd. Na2OO3 solution (2 x 1OO ml). The solvent was removed and the crude material passed through a small plug of silica gel (200 ml) in a sintered glass funnel using CH2C12 as the eluting solvent (500 ml). The solvent was removed to give the crude product which was recrystallized from CH2Ol2/EtOH to give 10methylsulfonyl-9-anthracenecarbaldehyde mp 216-217° (C,H,S). BAD ORIGINAL
AP o 0 0 0 0 1
B388 A
Example V
10-(2-Methoxy ethoxy )-9-anthracenec a rbaldehvde
KCDtBu (MOB ManufacturingChemists, Inc. 18.2 g, 0.162 mole) in methoxyethanol (1OOO ml) was treated with IO-chloro-9-orthraldehyde (Aldrich, 25 g, O.IO4 mole) and heated at reflux for 2 h. The cooled reaction mixture was diluted with H^O (5 L) and the resulting oil stirred for 2 h until solidification occurred. The filtered solid was chromatographed on a plug of SiO2 (500 g1 using CH^C^ as the eluting solvent to afford 26.9 g (92%) of IO-(2methoxyethoxy)-8-anthracenecarboxaldehyde mp b7-88°, (C,N), (CH^Cl^/hexane), (Rf = 0.16, SiO9, ΟΗ^,ΟΙ^)·
Example W lQ-Morpholino-9-3nthracenecarbaldehyde lO-Chloro-9-anthracene carboxaldefiyde (Aldrich, 25. g, 0.104 mole) in morpholine (MOB, practical, 500 ml) was heatecJ at 55° under for 17 h. The reaction mixture was poured into H^O (2 L). The filtered precipitate was chromatographed on a plug of S1O2 (1 kg) using toluene (4 L) as the initial eluting solvent to remove starting material and byproducts. The orange product band was then eluted with CH2CI2 (2 L) to yield 10.58 g (35%) of 10-morphoIino-9-anthracenecarboxaldehyde mp 182-184° softens 175°), (C,H,N), (Rf = 0.16, SiO2, C^C^)·
Example X _
12-ch lor o-6-chrysenecarb aldehyde
6-Chlorochrysene (Cambridge Chemical. 70 g 0.266 mole) was formvlated according to the procedure outlined in example 1A, except that (2500 ml) was used as the reaction solvent. Chromatography on a plug of S1O2 (1 kg) using EtOAc as the eluting solvent afforded 19.1 g (25%) of 12-chloro-6chrysenecarbaldehyde mp 255-257°, (EtOAc), (Rf = 0.42, S1O2, toluene).
Example Y lOAImidazol-l-y 1)-9-an thracencarbaldehyde
A solution of 10-chloro-9-anthraldehyde (Aldrich, 15 g, 0.062 mole), imidazole (Aldrich, 10.2 g 0.15 mole), and DMF (300 ml) at 55° was treated with KOtBu , , ,,. t BAD ORIGINAL dj# w
B388 A (MCB, 7.9 g, 0.07 mole) and stirred for 30 minutes. The reaction mixture was poured into O.1M NAOH (1500 ml). The filtered precipitate was chromatographed on a plug of Si09 (500 g) using CH^Cl? (3 L) as the initial eluting solvent to remove starting material and by-products. The yellow product band was then eluted with EtOAc (2 L) to yield 12.29 g (73%) of l0-(imidazol-l-yl)-9-anthracenecarbaldehyde mp 194-196°, (C,H,N,), (EtOAc), (Rf = 0.38, SiO?, EtOAc).
Example Z
2-Ethyl anthracene
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 2-ethylanthraquinone (Aldrich, 120g, 0.51 mol), Zn dust (Mallinckrodt, 300 g, 4.59 mol), CaSO^.5 H?O (Mallinckrodt, 3.0 g), and 28% NH^OH (Mallinckrodt, 2800 mL). The temperature was increased until the initial dark red colour had faded (about 6 h). The reaction mixture was then filtered.The filtrate was extracted with EtOAc, and the zinc solid also extracted with EtOAc. The EtOAc solutions were combined and the solvent removed. The residue was refluxed with a mixture of con HOI (10 mL) in n-PrOH (1200 mL) for 2 h. Upon cooling, a solid precipitated which was filtered, washed with abs. EtOH (100 mL) and dried togive 40 g (38%) of 2-ethy!anthracene mp, C,H.
2- and 3-Ethy lanthracene-9-carbaldehyde
2-Ethylanthracene (40 g, 0.194 mol) was formylated according to the procedure outlined in example A, except that CH^Cl^ (500 mL) was used as the reaction solvent. Chromatography over a plug of SiO^ with DhCH^ as the eluting solvent gave 43.68 g (96%· of a mixture of 2- and 3-ethyl-anthracene-9-carbaldehvde.
AP 0 0 0 0 0 1
Example AA
3,5-Diphenvl-7a(7H)-ethoxymethvl-l|-l,3H.5H-oxazolo(3,4-c)oxazole
A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa-Ventron, 34.0 g, 0.85 mol) was washed with dry hexane to remove the oil and suspended in dry DME (300 mL). To the mixture was added a solution of 3,5-diphenyl-lH,3H,5H-
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3388 A oxazolo(3,4-c)oxazole-7a(7H)-methanol (208.2 g, 0.7 mol, prepared by the method of J. Pierce et al JACS 73 2595 (1951)) in dry DMF (300 mL) keeping the reaction mixture between 30-35°. The salt suspension was stirred at RT for 60 min, diluted with dry DMF (200 mL) to facilitate stirring, cooled, then treated with ethyl iodide (Aldrich, excess) at such a rate that the reaction temperature was between 20-35°. The mixture was stirred at RT for 2 h, then cautiously treated with absolute EtOH (30 mL). The resulting mixture was diluted with Εί£θ (2.5 L) and the resulting solids removed by filtration. The solvent was then removed using a rotary evaporator to give 229.5 g of a yellow oil containing both starting material and desired product. A solution of the oil in chloroform was mixed with SiO^ (200 g) and the solvent removed. The solid was then added to a column of SiQ^ g).
Elution with the EtOAc/hexane (1:3.5) gave 139.7 g (61.3%) of 3,5-diphenyl-7a(7H)ethoxymethyl-lH,3H,5H-oxazolo(3,4-c)oxazole. An analytical sample was obtained by recrystallization from hexane, mp of 83.5-85°, (C,H,N). The bulk of the materia! was used without further purification.
2-Amino-2-sthoxymethoxy-l,3-propanediol hydrochloride
7* —
3.5-Diphenyl-7a(7H)-ethoxymethyl-lH,3H,5H-oxazolo(3,4-c)oxazole (136 g, 0.42 mol) was dissolved in 6 N HC1 (400 mL) and the resulting solution stirred 1.5 h at RT. After extraction with Et^O (2x200 mL) to remove benzaldehyde, the aqueous solution was concentrated on a rotary evaporator to give a colourless oil. This was cooled in an ice bath to facilitate cystallization. The solid which formed 'was slurried with cold CH^CN, filtered, then washed with Et^O and dried in a vacuum oven at RT to give 7i g (89%) of 2-amino-2-ethoxymethyl-l,3-propanediol hydrochloride mp 76-79°, (C,H,C1,N).
Example AB
4-Aza-3-hydroxymethyl-3-methyl-l-oxaspiroi4,5)dec3ne
A solution of 2-amino-2-methv!-l,3-propanediol (Aldrich, 303.4 g, 3.0' mol), cyclohexanone (Fisher, 294.5 g, 3.0 mol) and PhCH^ (400 mL) was refluxed for approximately 2 h with azeotropic removal of H^O. The material which crystallized from the PhCH^ on cooling was recrystallized twice from hexane to give 444.4 g of 4-aza-3-hydroxymethyI-3-methyl-l-oxaspiro(4.5)decane (80%) mp 52-54°, (C,H,N).
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AJR/TJM/DC12/25th April 1984
3i
B388 A
4-Aza-3-methoxymethy!-3-methyi-l-oxaspiro(4.5)decane
A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa-Ventron, 75g, 1.9 mol) was washed with dry hexane tc remove the oil and suspended in dry DMF (200 mL). To the mixture was added a solution of 4-aza-3-hydroxymethyl-3-methyl-loxaspiro(4.5)decane (27.8 g, 1.6 mol) in dry DMF (200 mL) keeping the reaction mixture temperature between 30-36°. Small amounts of DMF were added as necessary to facilitate stirring. The mixture was stirred at RT for 1.6 h, then cooled and treated with methyl iodide (Fisher, 234.2 g, 102.7 mL, 1.66 mol) keeping the reaction temperature between 20-30°. The mixture was stirred 2 h at RT and slowly treated with absolute EtDH (40 mL), then diluted with dry Εΐ£θ (3 L). The reaction mixture was filtered and the solvent removed by rotary evaporation. The residue was then fractionally distilled to give 209.7 g (70.3%) of 4-aza-3methoxymethyl-3-methy!-l-oxasprio(4.6)decane as a colourless liquid bp 114°/14 mm, (C,H,N).
I
2-Ami no-3-methoxy-2-me thy 1-1 -propanol
A solution of 4-aza-3-methoxymethyl-3-methyl-l-oxaspiro(4.5)decane (299 g, 1.6 mo!) and 6 N HC1 (500 mL) was refluxed for 60 min. On cooling, two layers formed, the upper one containing cyclohexanone was removed by extraction with Et./D (2x400 mL). The lower aqueous layer was concentrated on a rotary evaporator to give a syrup which then was treated with excess 50% NaOH. The resulting slurry was extracted wi|n Et2O/CH^Cl(2:1, 4x500 mL), then with CH^C^ (500 mL). The solvent was removed by rotary evaporation to give 198 g of pale oil. Fractional distillation of this oil gave I66g (93%) of 2-amino-3methoxymethyl-i-propanol as a colourless oil, bp 94°C/l7 mm, (C,H,M).
Examole AC
Ar0 0 0 0 0 1 lg, 2a, 3a-2-Amino-1,3-cvclohex anediol acetate
This compound was prepared by the method of F. Lichtenthaler (Ser, 96, 851 (1963)), mp 175-177°, (C,H,N), (lit 175-177°, F. Lichtenthaler, Ber. 96, 851 (1963)).
A3R/TJM/DCl2/25th April 1984 bad original A
B388 A
Example AD
2-IsopropyI-2-nitro-l,3-propanediol
A solution of 2-methyl-i-nitropropane (38.7 g, 0.375 mol prepared by the procedure of N. Kornblum, B. Tunbe, and H. Ungnade, J. Am.Chem,Soc., 1954, 76, 3029) and NEt-j (Eastman 3.79 g, 0.0375 mol) in CH-jOH (50 mL) was added dropwise to 37% aqueous formaldehyde solution (Mallinckrodt 76.2 g, 0.938 mol) at a rate such that the reaction mixture temperature did not exceed 30°. After 72 h, the solution was concentrated under vacuum and the residue was dissolved in H^O (250 mL). The solution was continuously extracted for 1 h with CH^C^ (1 L). The CH^C^ solution was dried (MgSO^), filtered, and concentrated to give 53.3 g of 2isopropyl-2-nitro-l,3-propanediol a waxy, white solid (87%); mp 67-72°C (lit. mp 87-88°’ B.M. Vanderbilt and H.B. Hass, Ind. Eng. Chem. 32, 34 (1940). In our hands this procedure failed to give the desired compound).
2-Amino-2-isopropyl-l,3-propanediol acetate
Using the procedure in example AM, 2-isopropyl-2-nitro-i,3-propanediol gave a 98% yield of 2-amino-2-isopropyl-l,3-propanediol acetate mp 155-155.5°. (H.S.
3roadbent et al. J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70-72°)).
Example AE
Ethyl N-benzylidene-L-alaninate
Ethyl N-benzylidene-L-alaninate was prepared according to the general procedure of 3. Stork et al., 0. Org. Chem. 41, 249 (1976), bp 98-lOO°/0.4 mm (lit. l00°/0.3 mm, A. Calcayai et al., Synthesis 445 (1981)).
2-(2-Iodoethoxy) tetrahydro-2H-pv ran
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of iodoethanol (Aldrich, 98 g, 0.57 mol) in Et?!^ (IL) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K^CO} (Mallinckrodt, 5 g) was then added to the reaction mixture and the
AJR/TJM/DCl2/25th April 1984
BAD ORIGINAL
3338 A resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et^O (IL). The organic solutions were combined and concentrated on a rotary evaporator (in a flask washed with 1% NEt-j in H^O). The crude 2-(2-iodoethoxy)-tetrahvdro-2H-pyran ( 100 g, 68.9%) was used without further purification.
Ethyl 2-benzyiideneamino-2-methy 1-4-(( tetrahydrc-2H-pvran-2-vi)oxy)butvrate
A solution of lithium diisopropylamide was prepared by dropwise addition of n-BuLi (Aldrich 1.6 M in hexane, 228 mL, 0.365 mol) to a solution of diisopropylamine (Aldrich, 51.6 g, 0.51 mol) in a mixture of dry THE (700 mL) and dry HMPA (Aldrich, 40 mL) kept at 30-40°. The solution was then cooled to -70° and a solution of ethyl N-benzvlidene-L-alaninate (74.9 g, 0.365 mol) was added dropwise to the solution allowing the reaction mixture to warm to -20° for several min. The resulting red solution was then cooled to -70°.
X
2-(2-Iodoethoxy)tetrahvdro-2H-pvran (98.1 g, 0.383 mqj) was then added to the solution at such a rate that the temperature in the reaction mixture did not rise above -65°. The solution was allowed to warm slowly to RT and stirred for 14 h.
The volume of the solution was reduced to 300 mL by a stream of dry during the last few hours to facilitate the final workup. The reaction was quenched with sat.
NaCl (800 mL) and diluted with Et^O (800 mL). The Et^O was removed and the aqueous layer extracted with hexane (500 mL). The Et^O and hexane layers were combined and dried (Na^SC^). The^solution was filtered and the solvent removed to give 124 g of crude red oil. Bulb to bulb distillation (in 1% aq. NEt^ washed glassware.) (210° bath temoerature/0.3 mm) gave 95 g of ethyl 2-benzylideneamino2-methyl-4-((tetrahvdro-2H-pyran-2-yl)oxy)butyrate which was homogeneous by vpc and gave acceptable NMR and mass spectra. It was stored under in the refrigerator and was used without further purification.
2- Benzvlami no-2-methy 1-4-(( tetrahydropyran-2-yl)oxy)but anol
A solution of ethyl 2-benzylideneamino-2-methyl-4-((tetrahydro-2H-pyran-2yl)oxy)butyrate (100.0 g, 0.3 mol) in THE (100 mL) was added slowly to a suspension of lithium aluminum hydride (Alfa-Ventron, 22.77 g, 0.6 mol) rapidly stirred in dry THE (IL) at such a rate to maintain a gentle reflux. After the addition was
BAD ORIGINAL l ο ο ο ο η <·*ν
AJR/TJM/DC12/25th April 1984
B388 A complete the mixture was refluxed for 4 h. The reaction mixture was cooled and treated successively with H^O (23 mL), 15N NaOH (23 mL) and (45 mL). The solid was removed by filtration and washed with THE (200 mL). The organic layers were combined and concentrated by rotary evaporation to give 2- Benzylamino-2methy!-4-((tetrahydropyran-2-yl)oxy)butanol (81.1 g, 92.0%) as a thick oil which was used without further purification.
2-Benz\ lamino-2-methyl-l,4-butanediol
The crude 2- Benzylamino-2-methyl-4-((tetrahydropyran-2-yl)oxy)butanol (80.1 g, 0.273 mol) was dissolved in 3N HC1 (128 mL). After 5 min the mixture was washed with Et^O (200 mL). The aqueous solution was concentrated by rotary evaporation to give a thick oil which was cooled and basified with excess 50% NaOH. The oily amine which formed was extracted with Et^O (3x200 mL). The Et2O extracts were combined and concentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g (94%) of 2-benzylamino-2-methyl-i,4-butanediol as a pale yellow oil (bp 168170°/0.35 mml(C,H,N).
T
2-Amino-2-methyl-l,4-butanediol hydrochloride
2-Benzylamino-2-methyl-l,4-butanediol (31.08 g, 0.149 moi) was dissolved in 95% EtOH (240 mL) containing Con HC1 (21 mL, 0.25 mol) and 5% Pd/C (10.0 g) and reduced in a Parr apparatus at 40 psi over 37 h at RT. The catalyst was then removed by filtration and the solvent removed by rotary evaporation (bath at 60°) to give 20.91 g of 2-amino-2-methyi-l,4-butanediol hydrochloride (90.2%) as a clear, thick, colourless oil with acceptable NMR and mass spectra. It was used without further purification. This compound has been reported as its acetate salt tG. Cardillo et al., Chem. Comm. 1308, 1982), but no data was given.
Example AE lO-Chloroanthracene-l-carboxylic acid
1-Anthroic acid (24 g, 0.108 mol) was treated with N-chlorosuccinimide (Aldrich, 24 g, 0.18 mol) in N-methylpyrrolidinone (Eastman, 600 mL) and heated under N^ at 90° of 1.5 h. The reaction mixture was diluted with 3.5 L H^O filtered, dried, and the precipitate recrystallized from EtOAc to afford 16.41 g (59%) of 10chloroanthracene-l-carboxylic acid mp 257-277°, (C,H,C1).
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ORIGINAL
B388 A
Ethy! 10-chloroanthracene-1-carboxylate
10-Chloroanthracene-l-carboxylic acid (17.3 g, 0.0679 mol), con H^SO^ (1.0 mL), and abs. EtOH (500 mL) was refluxed for 3 days using 9 S molecular sieves in a Soxhlet extractor to remove H^O. The solvent was removed and then partitioned between EtOAc and satd. NaHCOy The solvent was then removed from the organic layer to give 19.86 g (77%) of ethyl lO-chloroanthracene-l-carboxvlate, which was used without further purification.
lO-Chloro-l-anthracenemethanol
A solution of ethy! lO-chloroanthracene-l-carboxylate (19.86 g, 0.052 mol) in THE (300 mL) was treated with LiBH^ (Alfa-Ventron, 1.19 g, 0.052 mol) and refluxed for
h. The reaction mixture was poured into ice water and acidified with HC1 to pH2. The solid was filtered, washed with H^O (500 mL), air dried and then chromatographed on a plug of SiO2 (500 g) using EtOAc as the eluting solvent. The 1 solvent was removed by rotary evaporation to give a solid, which was crystallized from CCl^ to give 10.3 g (81%) of 10-chloro-l-anthracenemethanol mp 138-190°, (C,H,C1).
10-Chloroanthracene-I-carbaldehyde
10-Ch!oro-l-anthracenemethanoI (8.8 a, 0.036 moi) was dissolved in OH^Ol^ (ZOO mL) and treated with BaMnO, (Aldrich, 15 g, 0.059 mol) for 3 days and briefly brought to reflux. The reaction mixture was filtered, and the filtrate reduced to dryness. The residue was chromatographed by preparative HPLO using PhCH^ as the eluting solvent to give 6.0 g (69%) of slightly impure lO-chloroanthracene-lcarboxaldehyde, which was used without further purification.
I 0 0 0 0 0 dV
Example AG
3-Nitro-2,9-pentanediol
A solution of nitromethane (Aldrich, 73.3 g , 1.2 mol) and acetaldehyde (Eastman,
158.6 g, 3.6 mol) was cooled in a ice bath. H2O (80 mL) and Ca(OH)2 (0.90 g) were then added to the flask. The mixture was stirred under for 0 h, neutralized with CO2 and filtered. The filtrate was extracted continuously with CH2C12 (IL) for 6 h. The CH^C^ extract was concentrated under vacuum to give 119.6 g (77%) of AJR/TJM/DCl2/25th April 1989 BAD 0RIGINAL
B388 A crude 3-nitro-2,4-pentanediol, a pale yellow syrup. This material was unstable and was used without further purification. Z. Eckstein and T. Urbanski, Roczniki Chem. 26, 571 (1952), also report the synthesis and isolation of this product as a crude material.
, J.
(2 a,4 g, 5g,ba )-4,6-P i me thyl-5-nitro-2-phenyl-1,3-dioxane
A solution of the crude mixture of 3-nitro-2,4-pentanediols (115 g 0.77 mol) from above, benzaldehyde (Fisher 8l.7 g, 0.77 mol) and p-toluenesulfonic acid (Fisher 1.28 g) in benzene (400 mL) was refluxed for 1.5 h with azeotropic removal of H^O· After removal of the solvent under vacuum, the crude product (a complex mixture) was dissolved in abs. FtOH (150 mL). After 36 h, the crystals that had formed (RT) were collected and dried to give yield 25.8 g, of a 5:1 mixture (based on NMR) of desired product and another isomer (C,H,N). Pure 2a,4a,5a,6a-4,6-dimethyl-5nitro-2-phenyl-l,3-dioxane was obtained after recrystallization from abs. FtOH mp
117.5- 118° (C,H,N).
meso-3-Amino-2,4-pentanediol acetaffe v
Prepared from (2a,4a,5a,6a)-4,6-dimethyl-5-nitro-2-phenyl-i,3-dioxane as described for example AM except that the temperature was 50°C and subsequently recrystallized from 95% FtOH to give meso-3-amino-2,4-pentanediol acetate mp
108.5- 109.5°, (C,H,N).
Example AH l2-Fthyi-6-chry sene carb aldehyde
6-Fthylchrysene (Cambridge Chemical, Inc. 60 g, 0.234 mol) was formylated according to the procedure outlined in example A, except that U000 mL) was used as the reaction solvent. The crude material was chromatographed on a plug of SiO^ (1 kg) using PhC'H^ as the elutinq solvent, affording 50.38 g (76%) of l2-ethyl-6-chrysenecarbaldehyde mp 138-139°, (C,H).
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B388 A
Example Al
10-( lmidazol-l-yl)-9-anthracenecarb aldehyde
A solution of 10-chloro-9-anthraldehyde (Aldrich, 15 g, 0.062 mol), imidazole (Aldrich, 10.2 g, 0.15 mol) and DME_(300 mL) at 55° was treated with KOtBu (MCB, 7.9 g, 0.07 mo!) and stirred for 30 min. The reaction mixture was poured into 0.1M NaOH (1.5 L). The filtered precipitate was chromatographed on a plug of SiO^ (500 g) using (3 L) as the initial eluting solvent to remove starting material and by-products. The yellow product band was then eluted with EtOAc (2 L) to yield (after removal of solvent and drying) 12.29 g (73%) of l0-(imidazoI-l-yl)-9anthracenecarbaldehvde mp 194-196°, (C,H,N), (EtOAc).
Example AJ
12-Ethoxy chrysene-6-carbaldehyde
X
6-Ethoxychrysene (Cambridge Chemical. Inc., 48 gr 0.176 mol) was formylated according to the procedure outlined in example A, except that CI-^CI? (1000 mL) was used as the reaction solvent. After isolation, the crude material was chromatographed on a plug of SiO^ (500 g) using as the eluting solvent to give after removal of solvent and drying 33.7 g (64%) of l2-ethoxychrysene-6carbaldehyde mp 173.5-176°, (C,H).
Example AK
4-Chloro-lO-(2-hydroxvethoxy-9-anthracenecarbaldehvde
AP 0 u u u o 1
An isomeric mixture of 1-chloro- and 4-chloro-9-anthraldehvdes (36.8 g, 0.133 mol) in ethylene glycol (1000 mL) and THE (200 mL) was treated with KOtBu (MOB, 12.5, 0.11 mol) and heated at 80° for 14 h. The reaction mixture was poured into Η^,Ο (2 L). The precipitate was filtered, washed with H^O (500 ml) sucked dry, then chromatographed on a plug of silica (500 g) using CH^C^ as the intial eluting solvent to remove starting material and by-products. The desired product was then eluted with EtOAc to give, after removal of solvent and recrystallization from EtOAc, 3.0 g (7.5%) of 4-chloro-l0-(2-hydroxyethoxy)-9-anthracenecarbaldehyde mp 141-145°, (C,H,C1).
A JR/TJM/DC12/25th April 1984 bad original $
B388 A
Example AL
Eormvlation of 3-ethyIf luoranthene
3-Ethylfluoranthene (Cambridge Chemical Inc., 70 g , 0.304 mol) was formylated according to the procedure outlined in 1A, except that CH^C^ U L) was used as the reaction solvent. Chromatography on a plug of SiO^ (1 kg) yielded three partially purified products, each of which was rigorously purified by preparative HPLC using PhCH^ as the eluting solvent. Each of the three products were isomeric mixtures as described below.
a) 3- and 4-Ethylfluoranthene-7-carbaldehyde, 5.0 g (6%), (Rf=0.55, SiO^ PhCH^), (C,H).
b) 4-Ethylfluoranthene-3-carbaldehvde and 3-ethy lfluoranthene-2-carbaldehyde,
4.7 g (6%), Rf=0.49, SiC>2, PhCH^), (C,H).
r
c) 3- and 4-Ethylfluoranthene-8-carbaldehyde, 47.3 g (60%), (Rf=0.38, SiO2, PhCH3), (C,H).
d) 4-Ethylfluoranthene-3-carbaldehyde
The mixture b (4.7 g) was recrystallized twice from C^Cl^/hexane to yield 1.83 g (2% from 3-ethyIfluoranthene) cd 4-ethylfluoranthene-3-carbaldehvde mp 113.5116°, (C,H).
Example AM
3-Methyl-3-nitro-2,4-pentanediol
Solid NaOH (Mallinckrodt, 286 mg, 7.15 mmol) was added to a solution of 3-nitro-2butanol (Aldrich, 59.6 g, 0.50 mol) and acetaldehyde (Eastman 132 g, 1.50 mol) in anhydrous DM5O (MCB, 100 mL). The reaction was stirred under N2 for 5 days. Glacial acetic acid (0.5 mL) was then added to the solution. The solvent was then removed by rotary evaporation, (45°C bath temperature) to give a yellow liquid. This was diluted with H2O (200 mL) and extracted with CH2C12 (5x200 mL). The combined CH2C12 extracts were washed sequentially with H2O (50 mL) and sat.
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B388 A
NaCl (50 mL), dried (MgSO^) and filtered. Volatile components were removed from the filtrate under vacuum (first at aspirator vacuum and at 0.1 mm (bath temperature of 50-135°)) leaving a viscous yellow liquid (53.0 g, 64%). This was mixed with EtOAc/hexane (1:1) (50 mL) and subjected to flash chromatography on SiO2 (1.5 kg, Merck silica gel 60 230-400 mesh) using 11 L of EtOAc/hexane (i:l) as the eluting solvent and collecting 500 mL fractions. Appropriate fractions were combined and the solvent removed by rotary evaporation to give a total of 43.5 g (53%) of the diastereomeric mixture of 3-methyi-3-nitro-2,4-pentanediols (two meso forms and a d, 1 pair, easily distinguished by NMR in OMSO-d^).
(+-)-(2R*,3R5,4R*)-3-Hitro-3-metbyl-2,4-pentanediol and meso-3-Nitro-3-methyl2,4-pentanediol
The chromatographic process described above gave partial separation of the diastereomers. The early fraction (500 mL) gave 13.1 g of one of the meso-3-nitro3-methyl-2,4-pentanediols as a colourless solid mp 60-61° (C,H,N). The remaining
Ί fractions were combined to give 38.3^ of the isomeric mixture containing both the r meso- and d, 1-compounds. Recrystallization from EtOAc/hexane (300 mL, 2:1) gave 27.8 g of a 4:1 ratio of ( + -)-(2R*,3RS,4R*)-3-nitro-3-methyl-2,4-pentanediol and the other of the meso-3-nitro-3-methyl-2,4-pentanediols mp 79-86° (C,H,N). These two materials were then used without further purification.
(*-)-(2R*,3RS,4R*)-3-Amino-3-methy 1-2,4-pentanediol acetate
I 0 0 0 0 0 dV
To a solution of 3-methyI-3-nitro--2,4-pentanediol (16.3 g, 0.1 mol; the 4:1 mixture of d,i pair to one meso form described above) in 95% EtOH (150 mL? was added glacial acetic acid (19 mL) and 10% Pd/C (2.0 g, MCB). The reduction was carried out in a Parr apparatus at 50 psi of during a 70 h period at RT, the catalyst was removed by filtration through a Millipore (TM) filter and the solvent was removed under vacuum (RT, 2 days). The viscous, colourless syrup was dissolved in abs. EtOH (30 mL). While slightly warm, the solution was made cloudy by adding anhydrous Et^O (100 mL) and was then placed in a refrigerator. Colourless crystals formed over two days which were filtered, washed with Et^O and dried in a vacuum oven (at RT). The yield of pure (*-)-(2R*,3R5,4R*)-3-amino-3-methyl-2,4pentanediol acetate (as shown by NMR in DMSO-d&) was 12.8 g mp 110.5-112° (C,H,N). USSR patent 521,272 (CA 85: 177498) mentions 3-amino-3-methyl-2.4pentanediol as an intermediate but no synthetic details, physical properties, or stereochemistry was presented in the abstract.
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AJR/TJM/DCi2/25th April 1984
5388 A meso-3-Amino-3-methyl-2,4-pentanediol acetate
Using the procedure described above meso-3-methyl-3-nitro-2,4-pentanediol(undetermined configuration) gave meso-3-amino-3-methy!-2,4-pentanediol acetate (53%), mp 137-138°, (C,H,N).
Example AN (+-) (2R*,3S*)-2-Methy!-2-nitro-l,3-butanediol (A) and (+-) (2R*,3R*)-2-Methyl-2-nitro-l,3-butanediol (B)
To a mixture of 2-nitro-l-propanol (Aldrich, 63.0 g, 0.60 mol) and acetaldehyde (Eastman, 39.6 g, 0.90 mol) cooled in an ice bath under N^ was added cold h^O (40 mL) and calcium hydroxide (200 mg). The mixture was allowed to warm to RT over 2 h and then stirred for 68 h. The resulting solution was neutralized with excess solid CC^. The mixture was stirred Tor 1 h before filtration through a Millipore (TM) filter. The filtrate was then concentrated under vacuum at 35°. The residue, a viscous syrup which partially crystallized on drying under vacuum (0.1 mm, RT, 48 h), was triturated with cold Et20 (35 mL). Solid white crystals which formed were collected by filtration, washed with cold EtzO (3 x 15 mL) and dried under vacuum (0.1 mm, RT) to give 34.1 g of material, judged by NMR to be diastereomer A (purity >97%, racemic). After recrystallization, the diastereomeric purity Xvas >99%, mp 78.5-81° (lit. 78°; cf. Beil 1, 482 in Henry, Bull.Soc.Chim.Fr.[3J 15, 1224), (C,H,N).
The original filtrate (including wash) was concentrated under vacuum to a pale yellow liquid which was subjected to flash chromatography as follows: The sample was mixed with hexane: EtOAc (2:1, 100 mL) and added to a column of dry silica gel 60 (1500 g, Merck, 230-400 mesh). The column was eluted with hexane:EtOAc (2:1, 12 L) then hexane:EtOAc (1:1, 6 L) while 500 mL fractions were collected. Appropriate fractions were combined. Pure product was found in the final 8 L; yield, 38.7 g of viscous syrup, judged by NMR to be a 1:1 mixture of the two racemic diastereomers (A and B), (C,H,N).
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BAD ORIGINAL ft
B388 A
This and another batch of the 1:1 diastereomeric mixture (prepared as described above) were combined (67 g, total) and subjected to successive liquid-liquid partitioning between and EtOAc to give pure samples ( 99% on the basis of
NMR and HPLC (Hamilton PRP-1 column using 3.5% aqueous acetonitrile as the mobile phase)) of _A (24.9 g, k'=4.3, C,H,N) and 8 (±5.8 g, k'=2.1, C,H,N, a colourless, viscous liquid).
(+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane and (+-X2R*,45 *,55* )-4,5-dimethyl-5-nitro-2-pheny I-1,3-dioxane
The relative configurations of the two diastereomeric pairs (A and B) were assigned on the basis of comparative NMR analysis of the respective cyclic acetals derived from benzaldehyde. Thus, _A (1.49 g, 0.01 mol) and benzaldehyde (Mallinckrodt,
1.06 g, 0.01 mol) were condensed in benzene in the presence of a catalytic amount of p-toluenesulfonic acid with azeotropic removal of water (according to the method of H. Piotrowska, B. Serafin and. T. Urbanski, Tetrahedron 109, 379 (1963)).
7*
After successive washing with sat. NaHCO-j solution, drying (MgSO ), and removal of the benzene by rotary evaporation, a pale yellow obtained. A solution of this product in ethanol at O°C provided an oil isolated by decanting the mother liquor and drying under vacuum (0.1
The yield was 1.48 g (62%) of (+-) (2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl1,3-dioxane (C,H,N). '
Similarly prepared from B and benzaldehyde was (+-) (2R*,4S*,5S*)-4,5-dimethyl5-nitro-2-phenyl-l,3-dioxane (74%) (C,H,N).
( + -) (2P*,3R*)-2-Amino-2-methyl-1.3-butanediol acetate
Prepared from (+-) (2R*,3R*)-2-methyl-2-nitro-l,3-butanediol as described for example AM (97%) (C,H,N) mp 117-121°.
(+-) (2R* ,3S* )-2-Amino-2-methyl-l,3-butanediol acetate
Prepared from (+-) (2R*,3S*)-2-methyl-2-nitro-l,3-butanediol as described for AM (93%) (C,H,N) mp 163-165°C.
BAD ORIGINAL uM filtration, solid was which was mm, RT).
AJR/TJM/DCl2/25th April 1984
B388 A
Example 1
B. 2-((6-ChrvssnylmethyDami no)-2-methyl-1,3-propanediol hydrochloride
To a 2 L Erylenmeyer flask was added 6-chrysenecarbaldehyde (21.2 g, 82.7 mmol) from example A, 2-methyl-2-amino-l,3-propanediol (Aldrich, 9.13 g, 86.8 mmol), p-toluenesulfonic acid. H^O (Eastman, 0.5 g, 2.5 mmol), and 500 mL of toluene. The mixture was warmed to reflux for a few minutes and H^O ( 2-3 mL) was driven off. The resulting golden coloured solution was allowed to cool room temperature, diluted with 500 mL of absolute EtOH and stirred overnight. NaBH^CN (Aldrich, 95%, 2.5i g, 42 mmol) was added to the reaction. After it was dissolved, a indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M g-HCl in absolute EtOH every l5 minutes. After 3 days the indicator turned green then yellow and voluminous white precipitate was present in the flask.. To the flask v/as then added 10 mL of 1M g-HCl in absolute EtOH. The reaction was diluted tg 4 with absolute ether and stirred for 1 hour. The precipitate was then filtered through a medium porosity glass fritted funnel and pressed dry. The filter cake was washed thoroughly with 5x250 mL portions of 20% HC1, pressed dry and then washed with 4x500 mL portions of CH^C^, pressed and sucked dry. The solid was dissolved in 1400 mL of absolute EtOH. 1 mL of 1M g-HCl in absolute EtOH and 5 g of Calgon (Trade Mark) brand of activated charcoal were added and the mixture boiled and filtered through a pad of Oelite (Trade Mark of John Manville Co.) brand of filter-aid. The clear yellow solution was concentrated to 500 mL and diluted to 2 with absolute Et?O.
Further crystallisation (2x) from ΟΗ^ΟΗ,'Εί^Ο mixtures (1/3' gave 18.07 g (57.2%) mp = 241-243° (dec' of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride.
AJR/TJM/DC12/25th April 1984
BAD ORIGINAL
3388 A
Examples 2-49
Using methods analogous to that described in Example 1 and utilising the appropriate aldehyde and aminoalkanol starting materials, the following compounds of formula (I) were orepared in the form of their hydrochloride salts (all compounds analysed correctly for the assigned structures):
Comoound Ar R RZ R.Solv. M.P.°
7 lO-Cl-9-An Eh2OH CH3 M/EE 268-269(d)
3 9-An EH2OH ch3 M/EE l39-140(d)
4 10-SMe-9-An CH20H CH3 E/EE 225-226(d)
5 lO-(2-CH CH?Cl)-9-An CH20H CH3 E/EE 229-23it,d)
6 4,10-Cl-9-An CH oh ch3 E/EE 26l-262td)
7 1/4H2O 10-CH OH-9-Απ EH20H CH3 E/EE 2O9-21O(d)
8 1/2H2O 10-Me-9-An ch2oh CH3 E./EE >300(d)
9 lO-Br-9- An EH20H- CH2 M/EE 263-264(d)
10 10-Cl-9-An CH2OH C2H5 M/EE 252-254 O
11 4,5-Cl-9-An CH OH CH E/EE 239.5-240.5(^
12 3-F! CH20H cH; M/EE 262-265.5(,d) θ O
13 4-01-9-An CH20H CH3 E/EE 225-226(d) o
14 10-S0CH3-9-An CH20H CH3 E/EE ' 266-268(d) Π
15 2-Tr CH20H CH3 E/EE 207-208.5(d)
16 10-0Me-9-An CH OH ch3 E/EE 173-174(d)
17 lO-CN-9-An CH20H ch3 M/EE 307-308
18 10-Br-l-An CH20H CH, E/EE 225-226.5(d)
19 1-An CHqQH CH, E/EE lH9-19Kd'
20a 2-Cl-9-An CH.,0H z. CH? M/EE 265-266(d)
b 3- El-9-An CH OH ch3 ΓΗ/ΕΕ 268-269. d)
21 2-5Et-9-An CH,,QH CH3 E/EE 2OI-2O2(d)
22 2-SCH?CHzOH-9-An CH,?OH X. ch3 E/EE 199-2QOkd)
23 IO-Ci-9-An CH2OH ch2oh E/EE 251-254(d)
24 3,10-CI-9-An CH?0H ch3 M/EE 3O3-3O4(d)
25 2,10-Cl-9-An ch2oh ch3 M/EE 3O5-3O6(d)
26 6-Ch ch2oh ch2oh M/EE 238-239(d)
27 6-Ch ch2oh C2H5 E/EE 241-243(d)
28 3-E1 ch2oh ch20h M/EE 24O-241(d)
29 3-Π CH2OH o2h5 M/EE 25O-252(d)
30 10-0Et-9-An “H?0H
ch3 E/EE 229-23O(d)
JM/RC' 12 ?‘-‘h Ar.-i! !984 BAD ORIGINAL
B388 A
31 7-FI
32 l/2H 0 lO-CH2CHOH-9An
33 lO-SO2CH3-9-An
34 3-Cl-9-An
35 2- Et-9-An 3- Et-9-An
*36 6-Ch
37 6-Ch
38 3-F1
*39 9/20 3-F1
*40 9-An
*41 6-Ch
*42 3-F1
*43 i/3H2O 6-Ch
*44 3-F1
*45 i/3 EtOH 6-Ch
*46 Π/20Η20 3-F1
47 l/4H20 lO-CH2CH2OCH3-9-An
48 11/20 H20 lO-lm-9-An
49 9-An
ch2oh ch3 M/EE 2O4-2O6(d)
ch2oh CH3 E/EE l79-l8l(d)
CH2OH ch3 M/EE 238-239(d)
CH2OH ch3 M/EE 268-289(d)
CH2OH ch3 E/EE 203-205(d)
CH2OH ch3 E/EE
CH2OH CH2OEt M/EE 230-232(d)
CH2OCH3 CH3 E/EE 233-234(d)
CH2OCH3 ch3 E/EE 222-223(d)
CH?OH CH2OEt E/EE 179-180
CH2OH CH2OEt E/EE 176.5-178.5
CH2OH CH2OEt M/EE 280-282(d)
CH2OH i-pr M/EE E/EE 258-260(d) 223-
CH2OH i-Pr E/EE 223.5(d) 216-2l7(d)
CH2CH2OH ch3 E/EE 233-
>· CH2CH2OH CH3 E/EE 235(d) 210-
CH2OH CH3 E/EE 212(d) 182-
CH2OH CH3 183(d) E/EE '212-
CH2OCH3 CH3 E/EE 215(d) 214-2l5(d)
In 3II compounds;
3 4 R = R = H 1
In examples 41 _r. .p and 42, y represent R-C- RJ 1
Key: An - anthracenyl
FI = fluoranthenyl
Tr = triphenylenyl
Ch = chrysenyl
R.Solv = recrystallisation solvent
Im = imidazol-yl
wM&oO'SSIflfc
HO
Et = ethyl i-fr - iso-propvl
M/EE = methanol/diethvl ether
E/EE - ethanol/diethyl
B388 A ♦ In these instances the aminoalkanol starting material was in the form of a hydrochloride salt which was neutralised with an eguimolar amount of methanolic sodium methoxide and, after warming, the solvent was removed by rotary evaporation before the reductive amination was carried out as described in example 1.
** In these instances the aminoalkanol starting material was in the form of an acetate which was reacted with an equimolar amount of sodium methoxide in methanol and, after warming, the solvent was removed by rotary evaporation before the reductive amination was carried out as described in example 1.
x.
•r ►
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AJR/TJM/DCl2/25th April 1984
8388 A xample 50
2-((6-Chrysenylmethyl)amino)-2-methyl-l,3-propanediol methanesulfonate
To a 12 L round bottomed flask equipped with overhead stirrer, condenser, thermometer, and Dean-Stark trap was addded chrysene-6-carba!dehyde (Cambridge Chemical Inc., 202 E. Smith St., Milwaukee, Wl, 53207, 260 g, 1.01 mol), 2-amino-2-metbyl-l,3-propanediol (Aldrich, 213 g, 2.03 mol), ptoluenesulfonic acid monohydrate (Aldrich, 20.8 g, 0.104 mol) and 3.8 L of PhCH^. The mixture was stirred at reflux with removal of H^O for 2 h (or until no further H^O was collected). The mixture was cooled to RT and diluted with 3.8 L of absolute EtOH. Solid sodium borohydride (MCB, 46 g, 1.22 mol) was added in portions to the stirred mixture with the temperature maintained at 25-30° by external cooling. After the addition was completed, the reaction was stirred an additional 3 h at RT. The reaction mixture was then concentrated under vacuum to a volume of 800 mL keeping the flask temperaturemt 40° or less. The slurry was diluted with Ho0 (6 L) and cooled to 5°.
The solid was removed by filtration and washed with H^O (2x1.5 L).* The solid was then suspended in a mixture of 5D3A (US Industrial Chem. Co., 2.5 L) and methanesuifonic acid (Alfa Ventron, 107.2 g, 1.12 mol). The resulting solution was filtered and diluted with 5 L of PhCH^. After crystallization overnight at RT the mixture was cooled at 5° for 1 h and filtered. The solid was washed with PhCH^ '100 mL) and dried to give 417 g (93%) (after a second crop obtained from the filtrate was added) of 2-(15Chryseny 1 me thy !)amino)-2-methy!-l,3-propanedioI methanesul fonate mp 239-240° (dec), (C,H,N,S).
2-((6-Chrysenylmethyl)amino)-2-methy I-1,3-propanediol
To a rapidly stirred solution of 2-((6-Chrysenylmethyl)amino)-2-methyl-l,3propanediol hydrochloride from example 1 (20 g, 52.36 mmol) in a mixture of CH-jOH) (200 mL) ahd H^O (800 mL) was added dropwise over 10 min a 1M NaOH solution (55 mL). The resulting white precipitate was filtered and washed with warm H^O (4x500 mL) and then with Et£O (1 L), sucked dry and placed in a vacuum oven overnight. A total of 17.43 g (96.4%) of 2-((6Chrysepv.lmethvl)amino)-2-methy!-l,3-propanediol mp 200-202°, (C,H,N) αχη ORIGINAL ft
April 1984
B388 A
C. 2-((0-Chrysgnylmethyl)amino)-2-me thy 1-1,3-propanediol lactate
A mixture of 2-((6-Chrysenylmethyl)amino)-2-methyl-l,3-propanediol free base (50B) (,3.45 g, 10 mmol) and lactic acid (Fisher, 85% liquid,
1.04 g, 10 mmol) in CH-jOH (500 mL) vzas brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH^OH/Et^O) 3 times to give 1.84g (42.2%) of 2-((6-chrysenyImethyI)amino'-2methyl-1,3-propanediol lactate mp 163-164°, (C,H,N).
D. . 2-((6-Chry5enylmethyl)amino)-2-methyl-l,3-orooanediol citrate
A mixture of 2-((6-Chrysenylmethy!)amino'-2-methyl-l,3-propanediol free base (50B) (3.45 g, 10 mmol) and citric acid (Sigma, 1.92 , 10 mmol) in CHjOH (500 mL) was warmed until it dissolved then filtered through a glass fritted funnel. The solvent was then removed to give a crude white solid.
This was boiled with abs. EtOW (2x300 mL) and filtered to give a white solid. This was then recrystallized 2x (CH^OH/Et2O) filtered and dried overnight in a vacuum oven to give 1.24 g of 2-((6-Chrysenylmethyl)amino)2- methyl-1,3-propanediol citrate mp 146-151°, (C,H,N).
E. 2-((6-Chryssnylmethyl)amino)-2-methyl-l,3-propanediol-hydroxyethanesulfonate
2-((6-Chrysenylmethyl)amino)-2-methyl-l, 3-propanediol methanesulfonate (10.0 g, 26.63. mmol) was neutralized with IN NaOH (30 mL) in CH^OH/H?O (200/800 mL) as in procedure ID. The white solid which formed was filtered, washed successively with warm ^0 (3x500 mL), CH-^OH (200 mL), and Et?O (2x500 mL), sucked semidry and then resuspended in CH^DH (500 mL). To this was added a 0.43 aqueous solution of 2-hydroxyethanesu'ionic acid (30 mL). Slight warming gave a solution which was then filtered. The * Note: In the subsequent procedures referring to this method, the particular example was suspended in either abs. EtOH or CH^OH then methanesulfonic acid was added. After slight warming and filtration, the resulting solution vzas diluted with Et^O, hexane, or PhCH^. The precipitate which formed then was filtered and then recrystallized to give the desired compound.
bad ORIGINAL $
AJR/TJM/DCl2/25t' '984
3388 A solvent was removed b> rotary evaporation to give a wet white solid. This was triturated with dry Et2O to give 2-((6-Chrysenylmethyl)amino)-2-methyl-i,3propanediol 2-hydroxyethanesulfonate, (C,H,N,S).
Examples 51 - 66
Using methods analogous to that described in example 50A, the following compounds of formula (I) were preoared in the form of their methanesulfonate salts (all compounds analysed correctly for the assigned structures):
Compound Ar P? R2 P.Solv. M.P.°
51 lO-Cl-9-An CH2OH ch3 M/EE 234-235(d)
52 lO-SMe-9-An Ch2OH CH3 E/EE 193-I94(d)
53 l0-(2-CH2CH2Cl)-9-An CH2OH CH3 E/EE 210-210.5(d)
54 4,5-Cl-9-An ch2oh CH3 M/EE 252-253(d)
55 4_Cl-9-An X CH2OH ch3 M/EE 223-233.5(d)
56 2-Tr CH^H ch3 M/EE 259-26l(d)
57 3/4H20 lO-morpholino-9-An ch2oh CH3 E/EE l59-160(d)
58 l2-Et-6-Ch CH2OH ch3 E/EE 189-192(d)
59 l/3H20 12-C1-6-CH CH2OH CH3 E/EE 233-233.5(d)
60 12-OC2H5_6-Ch ch2oh CH3 E/EE 202-204(d)
61 l/3H20 4-CI-10-(2-OCH2CH2OH)-9-An ch2oh ch3 P/EE ' l56-158(d)
1/10 i-PrOH
62 4-Et-3-cl CH?OH CH3 E/hex 198-199(d)
*63 6-Ch Ch2OH H M/EE 208-209(d).
*64 ' 9-An ch2oh iPr ' E/EE 192-I94(d)
65 9-An ch2ch2 ohch3 ΕΈΕ 2 12-21 3.d'·
66 9-An see below M/EE 25l-252td‘
* Key as for examples 2 to 49 with the addition that p/t_E refers to an isopropanol/tirthyl ether solvent mixture and E/hex refers to an ethanol/hexane solvent mixture. In example 66 R represents a cyclohexanediol-ring
BAD ORIGINAL
AJR/TJM/DC12/25th Aoril 1984
3388 A
In these instances the aminoalkanol starting material was in the form of a hydrochloride salt which was neutralised with an equimolar amount of methanolic sodium methoxide and, after warming, the solvent -was removed by rotary evaporation before the reductive amination was carried out as described in example 1.
Example 67
2-((6-Chrysenylmethyl)amino)-2-methyl-l,3-propanediyl diacetate
A mixture of 2-((6-chrysenyimethyl)amino)-2-methyl-l,3-propanediol hydrochloride (5.0 g, 13.1 mmol) and acetylchloride (Aldrich, 5.0 mL, 70.3 mmol) were refluxed in dry THF (200 mL) under N2 for 12 h. The reaction mixture was poured into saturated NaHCO^ (500 mL) and extracted with EtOAc (3x500 mL). The EtOAc layers were combined, dried (k^CO-j) and filtered to give a slightly yellow clear liquid. The solvent was removed to give an off-white, solid. This was recrvstallized 3x from PhCH^/hexane (1:1). After filtration and dryjng, 3.67 g (65.2%) of 2-((6chrysenylmethyl)amino)-2-methyl-l,3-propanediyl diacetate was obtained mp 136137.5°, (C,H,N).
Example 68 h1eso-3-('6-Ohrysenxlmethy Da mi no)-2,4-pentanediol methanesulfonate
-x
To a round-bottomed flask was added meso-3-amino-3-methyl-2,4-pentanediol acetate (570' and an equimolar amount of sodium methoxide (MOB.’1 and CH^OH (100 mL). After warming to aid solution, the solvent was removed by rotary evaporation, and after addition of chrysene-6-carhaldehyde the reaction run following the normal reductive amination procedure outlined in example 50A to give meso-3-(((6-chry sen ylme thy Dam i no)-2,4-pentanediol methanesulfonate mp 221-223), (CH3OH/Et2O), (C,H,N,S).
AP o 0 0 0 0 1
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JR/TJM/DCl2/25th April 1984
B388 A
Examples 69 and 70
2-6-((3-Eluoranthenylmethyl)amino)-I-a,3-g-cyclohexanediol methanesulfonate and
2-3-((6-Chrysenylmetbyl)3mino)-l-a,3-g-cyclohexanediol methanesulfonate
Using the procedure in example 50B, compound 42 was converted to its free base. Addition of an equivalent of methanesulfonic acid (Alfa-Ventron 99.5%) followed by recrystallization (EtOH/Et^O) gave 2-6-((3-fluoranthenylmethyl)amino)-i-a,3g-cyclohexanediol methanesulfonate, mp 214-216° (d), (C,H,N,S). 2-6-((6chrysenylmethyl)amino-i-a,3-g-cyclohexanediol rnethanesulphonate, mp 280-281° (d), C,H,N,S) was prepared from the corresponding hydrochloride in similar manner.
Example 71 ( + -)-(2R*.3RS,4R*)3-((6-Chrysenylmethyl)amino)-3-methyl-2,5-pentanediol methanesulfonate V
To a round-bottomed flask was added (+-)-(2R*,3R5,4R*)3-amino-3-methyl-2,4pentanediol acetate and an equimolar amount of sodium methoxide (MCB) and CH^OH (100 mL). The solvent was then removed by rotary evaporation and after addition of chrysene-6-carbaldehyde, the reaction run following the normal reductive amination procedure outlined in example 1 to give (+-)-(2R*,3RS,4R'i)3((6-GhrysenylmethyI)amino)-3-methyl-2,5-pentanediol methanesulfonate mp 192183° (.dec). kEtOH/Et2O), (C,H,N,S^.
Example 72 (--) (2R*,35*)-2-((6-Chrysenylmethyl)amino)-2-methyl-l,3-butanediolhydrochloride
1/3H2O
To a round-bottomed flask was added (+-)-(R*,S*)-2-amino-2-mcthvl-l,3butanediol acetate and an equimolar amount of sodium methoxide (MCB) and UH^OH (100 mL). After warming, the solvent was removed by rotary evaporation, and after addition of chrysene-6-carbaldehyde the reaction run following the normal reductive amination procedure outlined in example 1 to give (+-)(2R*,3S*)2-((6-chrysenylmethyl)amino)-2-methyi-l,3-butanediol hydrochloride. l/3 h^O mp 238-239° (dec), (EtOH Et2O), (C,H,C1,N).
AJR/TJM/DC12/25th Aoril 1984 bad OFttGlNAU
B388 A
Example 73 (+-) (2R *,3S * )-2-((9-Anthracenylmethyl)aminoU2-methyl-l,3-butanediolhydrochloride
Following the procedure outlined for example 73 anthracene-9-carbaldehyde (Aldrich) and (+-)-(R*,S*)-2-amino-2-methyl-l,3-butanediol acetate gave (+-) (2R *,3S * )-2-((9-Ant hraceny 1 me thy l)amino)-2-me thy I-1,3-but anediol hydrochloride
H2O mp 216-217° (dec), (EtOH/Et2O), (C,H,C1,N).
Example 74 (+-)-(2R*,3R*)-2-((6-Chrysenyl)methyl)amino)-2-methyl-l,3-butanediolhydrochloride
Using the procedure outlined for example 73 chrysene-6-carbaldehyde and ( + -) (2R*,3R*)-2-amino-2-methyl-l,3-butahediol acetate -(40E) gave (+-)-(2R*,3R*)-2((6-Chrvsenyl)methyl)amino)-2-methyl-l,3-butanediol h/drochloride, mp 236-237.5 (dec), (CH3OH/Et2O), (C,H,C1,N).
Example 75 ( + -'-(2R~lt,25*)-2-(((3-fluoranthenvl)methyl,)amino'i-2-methyl-l,3-butanediol hydrochloride
Using the procedure outlined for example 73, fluoranthene-3-oarbaldehyde and (+X2R* ,3S*?-2-amino-2-methyl-l,3-butanediol acetate gave (--)-(2R* ,2S*)-2-(((3fluoranthenyl)methyl)amino)-2-methyl-l,3-butanedioI hydrochloride mp 242-243° kdec), EtOH/Et2C, (C,H,C1,N).
Example 76 (+-) (2R ♦,35 * )-2-((6-Chry seny 1 me thy l)amino)-2-methyl-1.3-but anediol methanesulfonate
Using the reductive amination procedure outlined in example 50A the two intermediates in example 73 gave (+-) (2R*,35* •-2-((6-Chrysenylmethyl)amino)-2methyl-l,3-butanediolmethanesulfonate mp 220-221° (dec), (EtOH/Et2O), ijR/T^‘/DCl2/25 th April 1984
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Ar u v u U 0 1
3388 A
Example 77
Antitumour Test Results for 2-((6-chrysenylmethyl)amino)-2-methyl- 1,
3-propanediol
Methods for evaluating the antitumour activity of these compounds are essentially those used in the Tumour Panel by the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, A.Goldin, et al., Methods in Cancer Research, Vol. XVI, p. 165, Academic Press (1979). Some modifications, in dose level and schedule have been made to increase the testing efficiency.
Lymphocytic Leukemia P388/0 Test
CD2-E^ mice, of the same sex, weighing within a 3 gram range surrounding 20 g, are used for this test. Control and test animals are injected intraperitoneally with a suspension of 10^ viable P388/0 tumor cells on day 0. In each test several dose levels which bracket the LD^g for the compound are»evaluated; each dose level group contains 6 animals. The test compounds are prepared either in physiologic saline containing 0.05% Tween 80 or distilled water containing 5% dextrose and are administered intraperitoneally on days 1,5 and 9 relative to tumour implant. Doses are on a mg/kg basis according to individual animals' body weights. The day of death for each animal is recorded, the median identified for each group and the ratios of median survival time for treated (T)/control (C) groups are calculated. The criterion for activity is T/C,xx 100 >120%. The results of several tests are summarised in Table I below.
AJR/TJM/DCl2/25th April 1984
BAD ORIGINAL
B388 A
Compound
Table I
Optimal Dosage (mg/kg)
T/C x 100% (Excluding 30 day
Survivors)
1 121 + 280
3 150 + 130
19 77 + 204
2 425 + 228
9 450 + 200
8 94 + 160
4 110 V + 262
5 l30 T w- + 225
7 165 + 170
17 387 + 190
14 45 +220
16 120 +220
18 300 +225
6 - 300 + 204
11 300 + 204
25 450 +210
24 600 + 200
12 90 + 270
15 84 +200
13 200 +215
20a 150 + 170
21 281 + 145
22 440 + 145
23 277 +140
32 160 + 300
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AJR/TJM/DCl2/25th April °84
5b
B388 A
Lymphocytic Leukemia L1210 Test
The protocol for this test is identical with that for P388/0 except that the number of L1210 cells implanted on day 0 is 10^/mouse. The mouse strain used is CD2-F^, and the criterion for activity is T/C x 100 >125%. Results, of Ll2l0 testing are summarised in Table II below.
Table II
Compound Optimal Dosage T/C x 100%
of Example (mg/kg) (Excluding 30 Day Survivors)
1 K 120 + 252
«' * 4 110 + 194
5 150 + 217
3 Malanotic Melanoma Bi6
B6C3-F^ mice of the same sex, weighing within a 3 gram range surrounding 20 g, are used for this.test. A suspension of Bl6 cells is prepared from a. non-necrotic portion of solid tumour tissue obtained from a passage mouse. One gram of tumour is homogenised in 9 mL ice-cold Earle's salts solution and filtered through 100 mesh screen to remove debris. 0.5 mL of the resulting brei is injected intraperitoneally to each animal. Dosing is carried out as in the P388/0 and L1210 tests. Days of death are recorded for a 60 day period and T/C ration calculated as in the P388/0 and L1210 tests. The results of 3l6 testing are summarised below in Table III.
AjR/TJM/DC12/25th April 1984
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B388A
Compound of Example
Table III
Optimal Dosage (mg/kg)
T/C x 100% (Excluding
Day Survivors)
100
110
130
300 + 146 + 143 + 146
-200
-216
AP o 0 0 0 0 1
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B388A
M5076 Sarcoma Test
This sarcoma arose as a solid tumour in the ovary of a C57B1/6 mouse and was subsequently converted to the ascitic form for intraperitoneal use. The protocol for this test is identical with that for P388/0, the B6C3-E^ mouse strain is used and the criterion for activity is T/C x 100 > 125%. Results of M5076 testing are summarized in Table below.
Compound
Table. M5076 Screening Data
Optimal Dose (mg/kg)
T/C x l00%*
105 + 168 + 162 λ
X.
T * Excluding 30 Day Survivors
Colon 38 Carcinoma Test
This chemically-induced tumour arose in a C57Bl/6 mouse and is maintained as a solid tumour in that mouse strain. The subcutaneously growing solid tumour is aseptically excised from passage mice and placed in sterile saline. The tumour is trimmed free of visible necrotic and connective tissue, then divided into 2-3 mm cubes. A cube is implanted subcutaneously in the ventral thoracic region with a sterile trochar on day 0. In each test several dose levels which bracket the LD^^ for the compound are evaluated. Ten animals are included in each dose level group and 30 in the untreated control group. The test compounds are prepared either in physiolgic saline containing 0.05% Tween 80 or distilled water containing 5% dextrose and are administered intraperitoneally on days 1, 5 and 9 after tumour implant. Doses are on a mg/kg basis according to individual animals' body weights. At day 20 the animals are sacrificed and the longest (L) and the shortest (W) dimensions of each tumour measured with vernier calipers. Tumor weight is 100 calculated from the formula L(W)2/2. The criterion for activity isT/C x < 42%. The results of Colon 38 testing are summarized below.
AJR/TJM/DCl2/25th April 1984 ffiP QRlGlNAt57
Compound
Optimal Dose (mg/kg)
T/C x 100%
120 36
150 38
65 23 ‘ Lewis Lung Carcinoma Test
This tumour arose spontaneously in the lung of a C57B1/6 mouse and is maintained by subcutaneous passage in the strain. The solid tumour is excised aseptically and placed in sterile saline. Pieces of viable tumour tissue are minced finely with scissors and forced through a 200 mesh stainless steel screen to disaggregate the tumour cells into a suspension. 10^ viable cells are injected intravenously into the tail vein of 3D-F, mice of the same sex weighing 20-3 grams. In each test several dose levels which bracket the LDzq fbr the compound are evaluated. Ten animals are included in each dose level group and 20 in the untreated control group. The test compounds are prepared and administered as in the P388/0 protocol. The day of death for each animal is recorded, the median identified for each group and the ratios of median survival time for treated (T)/controI (C' groups are calculated. The criterion for activity is T/C x 100 > 140%. The results of Lewis lung testing are summarized in Table below.
ft η η η n
Compound <
Optimal Dosage (mq/kg)
T/C x 100%
105 +191
85 +222
AJR/TJM/DCl2/25th April 1984 bad OB’°,NAL
B338 A
Example 78 : Herpes si^-oles l/vero Test
Antiviral testing against Herpes simplex l/vero v/as done using plaque inhibition methods as outlined in P. Collins and D. j. Bauer, Proc. N.Y. Acad. Sci. 284, 49 (1977) and by plaque reduction methods as outlined in P. Collins and D.J. Bauer, J. Antimicrobial Chemotherapy 2i Supplement A, 73 (1977). The column headings labelled Score, Toxicity, and Zone of Inhibition refer to the plaque inhibition screen while the IC^g heading to the plaque reduction screen.
Table Results of Antiviral Screening Against herpes simplex l/vero
A
lund No. Score T oxicity IC50
2 -4 Y 1.60
n ‘x
3 -3 T·
24 -4 Y
4Z -4 Y 12
48 -2 Ϋ 23.3
A. Score : Ό = no inhibition, -1 = 1.25% inhibition, -2 = 26-50% inhibition -3 = 51-75% inhibition, -4 = 76-lOU% inhibition
Example 79 : Candida albicans Test
Antifungal testing against Candida albicans (CN 1863) was done with slight modifications using a combination of broth and agar dilution assays as outlined in Laboratory Handbook
AJR/TJM/DCl2/25th April 1984 bad ORIGINAL
3308 A of Medical Mycology, Chapter 6, pages 441-446, M.R. McCinnis, Academic Press, New York, NY, 1980.
Table Results of Antifungal Testing Against Candida albicans (CN 1863)
Compound No. MIC t,mg/L) >50 >50
100
Μ·..—I! !,!.......... , ..........—
Medium : Wellcotest sensitivity test agar plus 7% lysed Horse blood :>
Example 80 5
Antibacterial Screening
Antibacterial testing against Mycoplasma smegmatis (S3264) and Streptococcus pyogenes (CNlO) was done with skght modifications using standard agar dilution assays as outlined in Manual of Clinical Microbiology Second Ed., E.H. Le.nette, E.H. Spaulding and J.P. Truant Eds., American Society for Microbiology, Washington, DC,1974.
Mr
Table Results of Antibacterial Testing Against Streptococcus pyogenes (CNlO)
Compound No. MIC imq/L)
1 10
AjR/TJM/DCi2/25th April 1984
BAD ORIGINAL ft
Β388 A
Example 8l : Mycoplasma smeqmatis Test
Antibacterial Screening Against Mycoplasma smegmatis (.532
Compound No. MIC (mg/L)
3 <5
1 <10
58 10
Example 82 : Trichomonas vaginalis Test ►
Antiprotozoal testing against Trichomonas vaginalis was done using methods outlined by R.M. Michaels in Advances in Chemotherapy _3j 39-108(.1968).
Table Results of Antiprotozoal Testing Against Trichomonas vaginalis (in vitro)
Compound No. (mg/L) Dose Result^
8 40 .4
7 40 .4
(Stenton or Modified Diamond's medium)
A. Screen Code 0 = no inhibition, -1 = 1-25% inhibition, -2 = 26-50% inhibition, -3 = 51-75% inhibition,
-4 = 76-100% inhibition.
A JR/T JM/DCi2/25th April 1984
BAD ORIGINAL
B388 A
Example 83 : Nippostronqylus brasiliensis Test
Anthelmintic testing against Nippostronqylus brasiliensis was done using methods outlined in D.C. Jenkins, R. Armitage, and T. S. Carrington, Zeitschrift for Parasitenkunde 63, 261-269 (1980)
T able
Results of Anthelmintic Screening Against Nippostronqylus brasiliensis (Immature free living stages)
Compound of Example No. MIC (mg/L)
8 50
3 >50
2 >50
Example 84 : Eimeria tenella Testing
Antiprotozoal testing against Eimeria tenella was done using methods outlines in V.S. Latter and D. Wilson, Parasitology 79, 169 (1979)
I 0 0 0 0 0 AV
Table XIII : Results of Antiprotozoa Screening Against Eimeria tenella (in vitro)
Compound of Example No. Dose (mg/L) Result'3'
12 0.31 .4
3 1.25 .4
A. Screen Code 0 = no inhibition, -1 = 25% inhibition, -2= 26-50% inhibition, 3=51-75% inhibition, -4=76-100% inhibition AJR/TJM/DCi2/25th April 1984
BAD ORIGINAL
B388 A * .
Example 85 : LD^gTests u —
Table : LD^g Values for Selected Compounds (IP single dose - CD - 1 Male Mouse)
Compound No. LD5g (mk/kg)
12 82
1 140
4 100
3 160
2 X 250
32 110 ►
Example 86: Γormulation Examples
A, TABLET
Compound oLFormula I (as hydrochloride) Pregelatinised Corn Starch Sodium Starch Glycolate Magnesium Stearate
500.0 mg 60.0 mg 36.0 mg 4.0 mg
The Compound of formula (I) is finely ground and intimately mixed with the powdered excipients, pregelatinised corn starch and sodium starch glycolate. The powders are wetted with purified water to form granules. The granules are dried and mixed with the magnesium stearate. The formulation is then compressed into tablets weighing approximately 600 mg each.
AJR/T3M/DCl2/25th April 1984
BAD ORIGINAL
B383A
B. TABLET
Compound of formula (Il 500.0 mg
Corn Starch 70.0 mg
Lactose 83.8 mg
Magnesium Stearate 4.2 mg
Polyvinylpyrrolidone 14.0 mg
Stearic Acid 28.0 mg
The Compound of formula (I) is finely ground and intimately mixed with the powdered excipients, corn starch and lactose. The powders are wetted with a solution of polyvinylpyrrolidone dissolved in purified water and denatured alcohol to form granules. The granules are dried and mixed v/ith the powdered stearic acid and magnesium stearate. The formulation is then compressed into tablets weighing approximately 700 mg each.
τ »
C. CAPSULES
Compound of formula (I) Corn Starch Magnesium Stearate
500.0 mg 50.0 mg 3.0 mg *
The finely divided Compound of formula (Il is mixed v/ith powdered corn starch and k
wetted with denatured alcohol to density the powder. The dried powder is mixed with stearic acid and filled into hard-shell gelatin capsules.
AP 0 0 0 0 0 1
AJR/TJM/DC12/25th April 1984
BAD ORIGINAL ft
B388 A
Jr
D. SYRUP
Compound'of formula (I)
Ethanol
Glycerin
Sucrose
Flavouring Agent Colouring Agent Preserving Agent Purified Water .
250.0 mg 250.0 mg 500.0 mg
3,500.0 mg q.s. q.s.
0.1%
q.s. to 5.0 ml
The Compound of formula (1) is dissolved in the ethanol, glycerin, and a portion of the purified water. The sucrose and preserving agent are dissolved in another portion of hot purified water, and then the colouring agent is added and dissolved.
The two solutions are mixed and cooled before, the flavouring agent is added.
Purified water is added to final volunle. The resulting syrup is throughly mixed, τ
E. IV INJECTION
Compound of formula (I) Glycerin Preservative Hydrochloric Acid or Sodium Hydroxide Water for Injection
5.0 mg
q.s. for isotonicity 0.1% . as needed for pH adjustment
q.s. to 1 ml
The compound of formula (,1) and preservative is added to the glycerin and a portion of the water for injection. The pH is adjusted with hydrochloric acid or sodium hydroxide. Water for injection is added to final volume and solution is complete after thorough mixing. The solution is sterilised by filtration through a 0.22 micrometer membrane filter and aseptically filled into sterile 10 ml ampoules or vials.
BAD ORIGINAL
AJR/TJM/DC12/25th April 1984 t·-' 6': ,
•z z^jni'p’i s+R
-13388 A
Haims idh.·
1. A compound of the formula (I):
(I)
Ar - CH.NH - C - R^ 1 3
I
OH or a monomethyl or monoethyl ether thereof, the compound of formula (I) including its ethers containing not more than 28 carbon atoms in total, or an ester of salt thereof;
wherein Ar is selected from the group comprising:
@2^> ;
I ο Ο Ο Π n J»* optionally substituted by one or two substituents which taken together contain not more than four carbon atoms in total and which are the same or different and are selected from halo; cyano; C^ ^alkyl or ^alkoxy each' A £·' optionally substituted by hydroxy or C. -alkoxy; halo substituted C. -alkyl or
5
Cj 2θϋ<θχγ; a group S(O)nR wherein n is an integer 0,1 or 2 and R is Cj alkyl optionally substituted by hydroxy or C. - alkoxy; or Ar is optionally 6 7 substituted by a group NR R containing not more than 5 carbon atoms wherein R^ and R? are the same or different and each is a Cj -j alkyl group or NR6r7 forms a five or six membered heterocyclic ring optionally containing one or two additional hetero atoms;
r! is Cj j alkyl substituted by hydroxy; BAD ORIGINAL r2 is hydrogen, Cj_3 alkyl or hydroxymethyl;

Claims (10)

1. A compound of the formula (I):
Ar - CH-NH - C - R2 2 ( (I)
R4— C —R3 1
OH or a monomethyl or monoethyl ether thereof, the compound'of formula (I) including its ethers containing not more than 28 carbon atoms in total, or an ester of salt thereof;
wherein Ar is selected from the group comprising:
optionally substituted by one or two substituents which taken together contain not more than four carbon atoms in total and which are the same or different and are selected from halo; cyano; ^alkyl or ^alkoxy each optionally substituted by hydroxy or C. ?alkoxy; halo substituted C. ?alkyl or
C, 2alkoxy; a group S(O)nR wherein n is an integer 0,1 or 2 and R is Cj 2 alkyl optionally substituted by hydroxy or C, - alkoxy; or Ar is optionally 6 7 substituted by a group NR R containing not more than 5 carbon atoms wherein R^ and R? are the same or different and each is a C, , alkyl group or 6 7
NR R forms a five or six membered heterocyclic ring optionally containing one or two additional hetero atoms;
R1 is C,_3 alkyl substituted by hydroxy; oRjQ1NAL r2 is hydrogen, Cj.j alkyl or hydroxymethyl;
-2B388 A and are the same or different and each is hydrogen, methyl or ethyl; r\ r2, R^ and R4 taken together containing not more than five carbon atoms;
or the group:
R'
I
- C
R
OH is
OH wherein -C-C- is a five or six membered saturated carbocyclic ring containing two or three hydroxy groups;
g
R is hydrogen, methyl or hydroxymethyl;
9 IO
R and R are the same or different and each is hydrogen or methyl;
R·^ is hydrogen, hydroxy, methyl or hydroxymethyl;
8 9 10 11
R , R , R , R and the -C-C- ring taken together containing less than seven carbon atoms.
2. A compound according to claim 1 wherein Ar is 6-chrysenyl, 7-fluoranthenyl or substituted 1- or 9- anthracenyl.
3. A compound according to either claim 1 or 2 wherein Ar is substituted by C^ 2 alkyl or C 9 alkoxyl each optionally substituted by chloro, hydroxy or l-Z 3 methoxy; or a group 5(0) R or chloro, imidazolyl, morpholino, cyano or n I2 bromo. Preferred substitutents are chloro, 2-chIoroethyl or 0CH~CH„R
12 Z wherein R is hydrogen, hydroxy or methoxy or a group S(O)nCH3 wherein n is the integer Ο, 1 or 2. . .
APOOOOO 1
BAD ORIGINAL ft
AJR/KMS/25.04.84
-3B388 A
4. A compound according to any one of claims 1 to 3 in which wherein is CH^OH, CH(CHj)OH or Cb^Cb^OH;
R14 is hydrogen, C -.alkyl, or CH-OH;
15 Z
R is hydrogen or methyl.
A compound according to any one of claims 1 to 4 in which „1
CH2OH
4 3
R - C - RJ
OH is — C - R
I
H - C - R I
OH wherein R1^ is hydrogen or methyl and R16 is hydrogen, methyl or ethyl.
6. A compound of the formula (I) according to claim 1 selected from the group comprising:
2-((6-Chrysenylmethyl)amino)-2-methyl-l,3-propanediol, , \‘y ·
2-((9-Ant hracenylmethyDami no)-2-methyl-1,3-propanediol,
2-((1-Anthracenylmethyl)amino)-2-methyl-1,3-propanediol,
AJR/KMS/25.04.84
BAD ORIGINAL ft
-4B388 A
2-((10-Chloro-9-anthraceny Imethy 1)-amino)- 2- methyl -1,3-propanediol,
2-((10-Bromo-9-anthraceny Imethy Damino)-2-methy I-1,3-propanediol,
2-Methyl-2-((10-methyl-9-anthraceny Imethy Damino)-1,3-propanediol,
2-Methyl -2-((10- methylthio-9 -anthraceny Imethy Damino)-1,3-propanediol,
2-((10-(2-Chloroethy 1)-9-anthraceny Imethy Damino)-2-methyl-1,3-propanediol,
2-((10-Hydroxymethyl)-9-anthracenylmethyl)amino)-2-methy 1-1,3-propanediol,
10-((1,1-Bis)hydroxymethyl)ethylamino)methyl-9-anthracene-carbonitrile,
2-Me thy 1-2 -((10 - methy lsulf inyl -9- anthraceny Imethy Damino'1-1,3 -propanediol,
2-((10-Methoxy-9-anthracenylmethyl)amino)-2-methy 1-1,3-propanediol,
2-((10-Bromo-1-anthraceny Imethy l)3mi no)-2-methy I-1,3-propanediol,
2-((4,10-Dichloro-9-anthracenylmethyl)amino)-2-methy] -1,3-propanediol,
2-((4,5-Dichloro-9-anthraceny Imethy Damino)-2-methy 1-1,3-propanediol,
2-0,2,lO-Dichloro-9-anthraceny Imethy Damino)-2-methy 1-1,3-propanediol,
2-((3,10-Dichloro-9-anthraceny Imethy Damino)-2-methy 1-1,3-propanediol,
2-((3-Eluoranthrylmethyl)amino)-2-methy 1-1,3-propanediol,
2-Methy 1-2-((2-triphenyleny Imethy Damino)-1,3-propanediol,
2-((4-Chloro-9-anthracenylmethyI)amino)-2-methyl-l,3-propanediol,
2-((2-Chloro-9-anthracenyImethyI)amino)-2-methyl-l,3-propanediol,
2-(( 10-E thy lthio-9-anthraceny Imethy l)a mino)-2-me thy 1-1,3-propanediol,
2-((10-(2-Hydroxy ethyl thio)-9-anthraceny Imethy Damino)-2-methy 1-1,3-propanediol,
APOOOOO 1
AJR/KMS/25.04.84
BAD ORIGINAL
-5B388 A
2-((10-Chloro-9-anthracenylmethyDamino)-2-hydroxymethyl-l,3-propanediol,
2-((7-F luorantheny 1 methy Da mi no)-2-methy 1-1,3-propanediol,
2-((lO-(2-Hydroxyethyloxy)-9-anthracenylme thy Dam ino-2-methy I-1,3-propanediol,
2-((lO-Ethoxy-9-anthracenylmethyI)amino)-2-methyl-l,3-propanedioI,
2-((6-Chrysenylmethyl)amino)-2-hydroxymethy l-l, 3-propanediol,
2-( (6-Chrysenyl me thy Dam ino)-2-ethyl-1,3-propanediol,
2-Hydroxymethyl-2-((3-fluoranthenylmethyl)amino)-l,3-propanedioI,
2-E thy l-2-((3-fluoranthenylmethyl)amino-l, 3-propanediol,
2-((l0-chloro-9-anthraceny ImethyDa mi no)-2-e thy 1-1,3-propanediol
2-{(3-chloro-9-anthraeenylmethyl)amino-2-methy 1-1,3-propanediol, (+-) (2R*, 3S*)-2-((6-chrysenylmethyI)amino)-2-methyl-l,3-butanediol,
2-((2-ethyl-9-anthracenlymethy l)a mi no)-2-methyl-1,3-propanediol and
2-((3-ethyl-9-anthracenly me thy Damino)-2-methyl- 1,3-propanediol, (+-) (2R*, 3S*)-2-((9-anthracenylmethyl)amino)-2-methyl-l,3-butanediol, (+-) (2R*, 3R*)-2-(((6-chrysenyl)methyDamino)-2-methyl-l,3-butanediol,
2- (((6-chrysenyl)methy Darn ino)-2-stnoxy me thy l-l,3-propanediol,
O, ,
3- methoxy-2-(((6-chrysenyI)methyl)amino)-2-methyl-l-propanol,
3-methoxy-2(((3-fluoranthenyl)methyl)amino)-2-methy 1-1-propanol, (+-) (2R*, 2S*)-2-(((3-fluoranthenyl)methyDamino)-2-methyl-l,3-butanedioI,
2-ethoxymethy]-2-(((3-fluoranthenyl)methyDami no)- 1,3-propanediol,
AJR/KMS/25.04.84
BAD ORIGINAL
-6B388 A
2-(((9-anthracenyI)methyl)amino)-2-ethoxymethyI-l,3-propanediol,
2-B-((6-chrysenylmethyl)amino)-l-a,3-a-cyclohexanediol
2-B-((3-fluoranthenylmethyl)amino)-l-a,3-a-cyclohexanediol
2-((6-chrysenylmethyI)amino)-2-isopropyl-l,3-propanediol
2-((3-fluoranthrenylmethyI)amino)-2-isopropyI-l,3-propanediol
2-((6-chrysenylmethyl)amino)-2-methyl-l,4-butanediol
2-((3-fluoranthenylmethyI)amino)-2-methyl-l,4-butanediol
2-(((lO-chloro-l-anthracenyl)methyl)amino)-3-methyl-2,5-pentanediol
2-(((lO-chloro-l-anthracenyl)methyl)amino)-2-methy 1-1,3-propanediol
Meso-3-((6-chrysenylmethyl)amino)-2,4-pentanediol
2-((6-chrysenylme thy Garni no)- 1,3-propanedio!
2-(((12-e thy 1-6-chr y seny I )methy l)amino)-2-me thy 1-1,3-propanediol
2-((( i0-(2-methoxyethoxy)-9-anthraceny!)methyl)amino)-2-me thy 1-1,3-propanediol
2 - me thy 1-2-(((10-morphol ino-9-anthracenyl)me thy l)amino)-l,3-propanediol
2-((y-anthracenylmethyl)amino)-3-methoxy-2-methyl-l-prop'ianol
2-(((l2-chloro-o-chrysenyl)methyI)amino)-2-methy 1-1,3-propanediol
2-((9-anthracenylmethyl)amino)-2-isopropyl-l,3-propanediol ”
2-((9-anthracenylmethyl)amino)-2-methyl-l,4-butanediol
2-((( lO-(lH-imidazoI-l-yl)-9-anthracenyl)me thy l)a mi no)-2-methyl-l,3-propanediol
2-(4-e thy l-3-fluoranthenyl)methyl)amino)-2-methyI-,3-propanediol AJR/KMS/25.04.84 BAD ORIGINAL i000004V
-7B388 A
2-(((.12-ethoxy-6-chrysenyI)methyl)amino)-2-methyl-l,3-propanediol (la, 23, 3a)-2-(9-anthracenylmethy])amino-l,3-cyclohexanediol
2-(((4-chloro-lO-hydroxyethoxy/-9-anthracenyl)methyI)amino)-2-methyl-l,3-propanediol
2-M e t hy 1-2-(((10-me t hylsulfonyl-9-anthracenyl)me thy Damino-1,3-propanediol (+-X2R*,3RS*,4R*)-3-(6-Chrysenylmethyl)amino)-3-methyl-2,5-pentanediol and salts and esters thereof.
7. 2-((fe-chrysenylmethyl;amino)2—2-methyl-i,3-propanediol or a salt or ester thereof.
8. Hydrochloride, methanesulfonate, ethanesulfonate, lactate, citrate or isethionate salt of a compound of the formula (I) according to any of claims 1 to 8.
9. A pharmaceutical formulation comprising a compound of the formula (I) or an ether, ester or salt thereof according to any one of claims 1 to 8together with a pharmaceutically acceptable carrier therefor.
1(1. A pharmaceutical composition according to claim 11, that comprises a sterile aqueous solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) according to any one of claims 1 to 6, that is isotonic with the blood of the recipient.
11. A method for the preparation of a pharmaceutical formulation which comprises bringing into association a compound of formula (I) or an ether, ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
bad original
AJR/KMS/25.04.84
-8B388 A ll. A method for the preparation of a compound of the formula (I) according to any one of claims 1 to 7, which comprises:
(i) the reduction of a compound of formula (II):
R
I
Ar - CH = N - C - R‘
R4 C - R* (II) wherein R^ to R^ are as hereinbefore defined, or an appropriately protected derivative thereof, followed by deprotection where appropriate;
(ii) the reduction of a compound of the formula (V):
ArCONH - C - R
R4 - C - R3 (V)
OH
1 4 wherein R to R are as hereinbefore defined and the hydroxy groups are optionally protected, followed by deprotection of the hydroxy groups where appropriate, or ·. A ’ ‘ (iii) the reaction of a compound Ar CH2 L, wherein Ar is as hereinbefore defined and L is a leaving group, with a compound of the formula (IV):
NK
C
R
OH
1 4 wherein R to R are as hereinbefore defined.
13. A novel chemical intermediate of the formula (II), (IV), (V) as hereinbefore defined or of the formula ArCHLCHO wherein Ar is as hereinbefore defined.
APAP/P/1984/000003A 1983-05-17 1984-07-16 Polycyclic aromatic compounds AP1A (en)

Priority Applications (47)

Application Number Priority Date Filing Date Title
GB838313571A GB8313571D0 (en) 1983-05-17 1983-05-17 Chemical compounds
US06/499,813 US4530800A (en) 1983-05-17 1983-06-01 Perylene derivatives
DE8484105584T DE3473141D1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
NO841954A NO157416C (en) 1983-05-17 1984-05-16 ANALOGY PROCEDURE FOR PREPARING POLYCYCLIC AROMATIC ALKANOL DERIVATIVES WITH BIOCID EFFECT.
JP59099655A JPS59225149A (en) 1983-05-17 1984-05-16 Pesticidal polycyclic compound, intermediate, drug containing same and use as medicine
EP84105584A EP0125701B1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
EG315/84A EG17595A (en) 1983-05-17 1984-05-16 Aromatic biocidal compounds,their sunthesis and intermediates therefor,formulations containing them,and their use in medicine
GB08412485A GB2140416B (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
GR74735A GR82278B (en) 1983-05-17 1984-05-16
IE120384A IE58416B1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
MC841705A MC1595A1 (en) 1983-05-17 1984-05-16 DERIVATIVES OF POLYCYCLIC AROMATIC ALKANOLS WITH BIOCIDAL ACTIVITY
CA000454514A CA1222750A (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
DK242284A DK242284A (en) 1983-05-17 1984-05-16 POLYCYCLIC AROMATIC COMPOUNDS, MANUFACTURING THEREOF AND THEIR INTERMEDIATES
ZA843708A ZA843708B (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
EP84105585A EP0125702B1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
ES532512A ES8603376A1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds.
JP59099656A JPS59225150A (en) 1983-05-17 1984-05-16 Pesticidal fragrant compound, synthesis and intermediate therefor, drug containing same and use as medicine
IL71854A IL71851A (en) 1983-05-17 1984-05-16 Polycyclic aromatic alkanol derivatives,their preparation and pharmaceutical compositions containing them
NZ208168A NZ208168A (en) 1983-05-17 1984-05-16 Polycyclic aromatic alkanol derivatives and pharmaceutical compositions
HU841886A HU197875B (en) 1983-05-17 1984-05-16 Process for producing polycyclic aromatic amino-alcanol derivatives and pharmaceutical compositions containing themas active components
PH30683A PH22265A (en) 1983-05-17 1984-05-16 Biocidal polycyclic aromatic amino alkanol derivatives
AU28098/84A AU572509B2 (en) 1983-05-17 1984-05-16 Polycylic aromatic alkanol derivatives with anti-tumour activity
SU843744951A SU1535377A3 (en) 1983-05-17 1984-05-16 Method of producing derivatives of aromatic aminoalcohols or their pharmaceutically acceptable salts
KR1019840002647A KR910000854B1 (en) 1983-05-17 1984-05-16 Process for the preparation of aromatic biocidal compounds
PT78586A PT78586A (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
CS364584A CS273314B2 (en) 1983-05-17 1984-05-16 Method of polycyclic aromatic alkanol derivatives preparation
DD84263086A DD223439A5 (en) 1983-05-17 1984-05-16 PROCESS FOR THE PREPARATION OF ALKANOL DERIVATIVES
FI841966A FI85263C (en) 1983-05-17 1984-05-16 FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA POLYKARBOCYKLISKA AROMATISKA ALKANOLDERIVAT OCH NYA MELLANPRODUKTER.
DE8484105585T DE3465296D1 (en) 1983-05-17 1984-05-16 Polycyclic aromatic compounds
PL1984254244A PL145420B1 (en) 1983-05-17 1984-05-17 Method of obtaining novel substituted polycarbocyclic aromatic amine alkanoles
PL1984247759A PL144294B1 (en) 1983-05-17 1984-05-17 Method of obtaining novel polycyclic aromatic compounds
PL1984254245A PL145421B1 (en) 1983-05-17 1984-05-17 Method of obtaining novel substituted polycarbocyclic aromatic amine alkanoles
APAP/P/1984/000003A AP1A (en) 1983-05-17 1984-07-16 Polycyclic aromatic compounds
US06/661,802 US4719049A (en) 1983-05-17 1984-10-17 Anthracene derivatives
US06/661,803 US4719236A (en) 1983-05-17 1984-10-17 Perylene derivatives
US06/661,674 US4720587A (en) 1983-05-17 1984-10-17 Fluoranthene derivatives
ES540161A ES540161A0 (en) 1983-05-17 1985-02-06 A METHOD FOR PREPARING ACID POLYCLIC AROMATIC DERIVATIVES
ES540160A ES8604487A1 (en) 1983-05-17 1985-02-06 A METHOD FOR PREPARING ACID POLYCLIC AROMATIC DERIVATIVES
US06/725,157 US4719047A (en) 1983-05-17 1985-04-22 Anthracene derivatives
SU853947162A SU1466648A3 (en) 1983-05-17 1985-08-30 Method of producing polycyclic aromatic derivatives of alkanole or its monoalkyl c sub one - c sub two ether or acid salt thereof
SU853982431A SU1447277A3 (en) 1983-05-17 1985-12-02 Method of producing polycyclic aromatic derivatives of alkanol or salts thereof
US07/102,275 US4820873A (en) 1983-05-17 1987-09-28 Pyrene derivatives
AU13052/88A AU599215B2 (en) 1983-05-17 1988-03-11 A novel chemical intermediate of the synthesis of aromatic biocidal compounds
SG223/89A SG22389G (en) 1983-05-17 1989-04-08 Polycyclic aromatic compounds
HK450/89A HK45089A (en) 1983-05-17 1989-06-01 Polycyclic aromatic compounds
CY1486A CY1486A (en) 1983-05-17 1989-12-08 Polycyclic aromatic compounds
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