Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~4Z439
FIELD OF THE INVENTION
; This invention relates to new organic chemical com- pounds, to their preparation and to pharmaceutical compo-
sitions çontaining such compounds. The compounds de-
scribed herein are useful antiviral agents which inhibit
or inactivate viruses by their administration to either
an infected qr to a non-infected host.
~-
BACKGROUND OF THE INVENTION
There is a growing body of information that viruses
play a vital role in a broad range of diseases, some of
which represent the most serious of man's ills. Arthritis~
juvenile arthritis, diabetes, Hodgkin's disease and various
immunological diseases and degenerative diseases of the
central nervous system have been linked to viruses as
the causative agents.
At present, the control of virus infecttons is
primarily achieved by means of immunization vacc;nes.
' ~
- WJS:dw . 1-
.
M-677
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For examp 1 e, po 1 i omye 1 i tisl sma 1 1 pox, meas 1 es and i nf 1 uenza
are well recognized diseases in which viral vaccines have
proven effective. In general, however, viral vaccines
have had only a moderate success in animal prophylaxis.
Each vaccine acts primarily against a specific virus and
is not heterophilic in the protection it offers. Hence~
vaccines do not provide a practical solution against
the wide array of infectious viruses, even where limitedg
as for example, solely to respiratory viruses.
One approach to the control of virus-related diseases
and, particularly to the spread of such virus diseases, ;
has been to search for mediclnal agents or chemothera- -
peutic agents which are capable of inhibiting the growth
of viruses, thereby preventing the spread of disease as
well as preventing further damage to cells and tissues ~`
of the animal host which have not as yet been infectedO ;
Heretoforeg only a limited number of virus infections
such as smallpox, Asian influenza and herpes~keratitis
have been susceptible to prevention by chemical antiviral
agents. Sulfonamides and ant;biotics which hàve revo--
lutionized the treatment of bacterial infections have
substantially no effect upon virus infections. Certain
infections caused by large v;ruses, such as iymphogranuloma
venereum, psittacosis and trachoma have been successfully
treated using antibiotics and sulfa drugs. However~ the
majority of infections have not been respons;ve to attack
by chemotherapeutic agents. Thus, it can be seen that
there is a need for new chemotherapeutic agents which are
effective against a broad range of virus diseases9 and
which at the same time, are non-toxic to the;host.
: ., ~' ' - : ' - :
: .' . ' , , :
M-677
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~ ~ Z ~ 39
As a result of a long series of investigations,
applicants have discovered a novel class of antiviral
agents which are bis-basic ether derivatives of 9-sub-
stituted phenanthrene and which also include their
corresponding 10-oxa and 10-aza derivatives. A more
descriptive designation for these compounds in accord-
ance with Chemical Abstracts nomenclature would be to
describe them as bis-basic ether derivatives of 9-phenan-
throl, 6(5H)-phenanthridinone and 6H-dibenzo[b,d]pyran-
10 6-one. These compounds are effective against a wide
spectrum of viral infections and are useful in treating
such infections either prophylactically or therapeutically.
U.S. Patent 3,592,819 is the closest art known to
applicants and discloses certain bis-basic ethers and
thioethers of various substituted fluorenesJ 9-fluorenols
and 9-fluorenones useful as antiviral agents. Certain
of the bis-basic ethers described therein serve as
starting materials for the preparation of some of the
compounds of the present invention.
The bis-basic ethers described and claimed herein,
however, are derived from a totally different and chemi-
cally unrelated 6,6,6 tricyclic aromatic ring system which
differs substantially from the fluorene nucleus. To
applicants' knowledge the compounds described and claimed
herein are novel compounds which have not been previously
described nor reported in the literature. AdditionallyJ
applicants are unaware of any previously reported bis-basic
derivatives of 9-phenanthrol, 6(5H)-phenanthridinone or
6H-dibenzo[b~d]pyran-6-one which possess antiviral
30 activity. The compounds described herein possess a wide
-3-
: . ,
. . .. . , : . . .
,. . ~ ... . : :
:-: . , -
M-677
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spectrum of antiviral activity in varying degrees which
could not have been predicted from a knowledge of the
present state of the art.
SUMMARY OF THE INVENTION
' ', ~
This invention relates to new derivatives of 9-sub-
stituted phenanthrene and to their related 10-oxa and 10-aza
congeners, to their methods of preparation, compositions ~ -~
thareof, and to their usefulness as pharmaceutical agents. : :
More particularly, the compounds of the present invention
are 2,7-bis-basic ethers of 9-phenanthrol or 9-lower
alkoxyphenanthrene, 3,8-bis-basic ethers of 6(5H)-phenan-
thridinone and 3,8-bis-basic ethers of 6H-dibenzo[b,d~pyran-
6-one which are useful in the prevention or inhibition
of viral infections. Still more particularly, the com-
pounds of the present in~/ention may be represented by ~
the following general formulas: ~.
R
,-R1 ~ o-(CH2)n-
~N-(CH2)n-O
and R1`
~-R1 ~ O-(CH2)n-N \ R '
R ~N-(CH2)n O ~ Y
OR2
( I l ) -
wherein n is an integer of from 2 to 6; R and Rl are each
selected from the group consisting of hydrogen, lower alkyl
,~ 4
''!~ _
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3~
having from 1 to 6 carbon atoms, cycloalkyl having from
3 to 6 carbon atoms, alkenyl having from 3 to 6 carbon
atoms in which the unsaturation is in a position other
than the 1-position of the alkenyl group, and when R and
R1 are taken toge~her with the nitrogen atom to which they
are attached represent the pyrrolidinylJ piperidino or
morpholino radical; Z is selected from the group consist-
ing of oxygen, imino and methylene; Y is nitrogen or
methylidene; and R2 is selected from the group consisting
of hydrogen or lower alkyl having from 1 to 4 carbon
atoms. The expression methylene is intended to refer to
the -CH2- radical, whereas the expression methylidene
is intended to refer to the -CH= radical.
The compounds represented in formulas (I) and (Il)
above include both the free base form as well as the
pharmaceutically acceptable acid addition salts thereof.
In generalJ the salts of these compounds are crystalline
materials which are soluble in water and various hydro-
philic organic solvents, and which, in comparison to their
free base forms, generally exhibit higher melting points
and an increased stability.
It should be noted that the bis-basic ether side
chains appear in the same relative configuration for the
9-substituted phenanthrene, 6(5H)-phenanthridinone and the
6H-dibenzo[b,d]pyran-6-one series of compounds. However,
due to the difference in numbering systems as shown below,
the compounds of the present invention are designated as
2,7-bis-basic ethers for the phenanthrene series of com-
pounds~ whereas they are designated as 3,8-bis-basic ethers
in both the phenanthridine and 6H-dibenzo[b,d]pyran series
-5-
-
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2~3~3
of compounds.
~:' ~3 ~33
8 9 6 7 6
Phenanthrene Phenanthridine 6H-Dibenzo[b,d]pyran
The 2,7-bis-basic ethers of 9-methoxyphenanthrene (V)
are prepared via a ring enlargement of the related 2,7-
bis basic ethers of fluoren-9-one (Il 1)3 which are found
described in U.S. Patent 3,592,819. This series of re-
actions can best be illustrated by means of the following
reaction scheme in which the symbols n, R~ R~ and R2 have
the values previously assigned.
,-Rl O Rr
\N-(cH2)n-o ~O-(CH2)n-N~
( I I 1)
C H 2 N2-~
10 ,'Rl ~ O-( CH2)n-N ~ ,
~ R ~N-(CH2)n-O ~ . :~
O ~ ,
,-RI ~ O-(CH2)
` R /N-(CH2)n-O
OH
~IV)
, . ; , . . . : . . . .
M-677
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39
R
(cH2)n-o~ $J o-(cHz)n-N\
._ . ......
CH2N2
R
¦ ( R /N~(CH~)n~ ~ O-(CH2)n-
OCH3
(V) , .
R2N2 R
rR1\ ~ O-(CH2)n-N\R J
R ~N-(CH2)n-O ~ R2
t I I )
The 3,8-bis-basic ethers of 6(5H)-phenanthridinone
~VI) are prepared via a hydrazoic acid ring expansion using
the 2,7-bis-basic ethers of fluoren-9-one (111) in the -
presence of a strong mineral acid. This reaction can be :
illustrated by the following general reaction scheme in
which the symbols n~ R and R1 have the same values pre- .
viously assigned:
.,.~
- ~ . . .
-, ~ .
:, . .
M- G ~7
~4;~
, ' ~1 R l"
R ~N-(CH2)n-O~ (CHz)n-~.
( I I I )
NaN3
~(CII: )n~N \
( V 1 )
The 3,8-bis-basic ethers of 6H-dibenzo[b,d]pyran-6- ~ :
one (X) can be prepared by means of a peractd or peroxide
ring expansion of the related 2,7-bis(w-haloalkyl)ethers :
of fluoren-9-one (Vll) in the presence of a strong mineral
acid. The 3,8-bis(w-haloalkyl)ethers of 6H-dibenzo[b,d]
pyran-6-one (Vlli) so prepared are subsequen~iy condensed
with an amine (IX) to form the desired 3,8-bis-basic -
ethers of 6H-dibenzo[b,d]pyran-6-one (X). Th;s reaction
sequence can be illustrated by the following genera1
reaction scheme in which the symbols n, R and R1 have the
values previously designated and the symbol Hal is
chlorine, bromine or iodine.
~ _ .
.
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3~
O
~al-(CH2)n~ ~r -( CH2) n-Ha 1 + H22 ~---
(Vll)
Strong
Acid
~ O- ( CH2 ) n-Ha 1
-\ ~N-H + Hal-(~H2) -O ~ ~~~~~ ;
(IX) (Vlll)
R
L ~o-(cH8) ~ ~
(X, ~..... ~
To achieve an antiviral effect the compounds of this
invention are administered to a suitable host using a
variety of compositions. Such compos~tions-may be admin~
istered either prior to inf~ctiong as~a prophylactic use
or treatment, or they may be administered subsequent to
infection of the host as a curative use or tr~eatment.
A wide variety of compositions are also included with-
in the scope of the present invention~ Thus, the instant
compounds may be applied externally or topically directiy
- at the situs of infection, or they may be administered
internally or systemically, irrespective of whether the
treatment is prophylactic or curative in na~ure. In either
_g_
.. . . .................... . . .... :
.. ... ... ..
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event, replication of the infectious virus is inhibited
or preyented with the concomitant result that the variou~
disease symptoms characteristic of the pathogenic viral
infection are either diminishecl or no longer present~
DETAILED DESCRIPTION OF THE INVENTION
As can be seen from general formulas (I) and (Il)
above, the compounds of the present invention encompass
bis-basic ethers in which each side chain is linked to a ~ ;
benzenoid portion of the tricyclic nucleus. More spe-
cificallyg these side chains are linked at the 2 and 7_
positions in the phenanthrene series and at the corre-
sponding ~ and 8-positions in the phenanthridine and
6H-dibenzo[b,d]pyran seriesO It can be further seen that
the side chains consist essentially of a basic amino
function at the terminal end of the chain, an ether
bridging group at the proximal end of the chain with the
basic amino function separated from the ether group by
an alkylene chain of prescribed length. `~
The basic amino function represented by the symbol
-N ~R `~ can be a primary, secondary or a tertiary amino
group. Preferablyy each amino group ;s a tertiary amine
The symbols R and R1 represent either hydrogen or a lower
alkyl group. The term lower alkyl as used herein with
regard to the basic amino function relates to groups
having from 1 to 6 carbon atoms. Illustrative of such
groups can be mentioned both straight or branched chain
alkyl radicals such as: methyl~ ethyl, n-propyl, iso
propyly n~butyl, sec-butyl, isoamyl, n-pentyl and
- 1 0 -
., ~ ~ -..
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n~hexyl. When R and R~ each represent lower alkyl, a
preferred subgenus ;s formed.
Each R and Rl can also represent a cycloalkyl group
having from 3 to 6 carbon atoms. Illustrative of such
groups are the cyclopropyl~ cyclobutyl, cyclopentyl and
cyclohexyl radicals.
The symbols R and R1 also represent an alkenyl group
having from 3 to 6 carbon atomsO In addition to the un-
saturation which must be present, this unsaturation must
be in a position other than the 1-position of the alkenyl
group in order to prevent hydrolysis from occurringO
lllustrative of such groups are the allyl~ 3-butenyl and '~
the 4-hexenyl radicals.
R and R~ may also be joined with the nitrogen atom
to which they are attached to represent various saturated ~,
monocyclic, heterocyclic radicals. Typical of such hetero~
cyclic groups are the 1-pyrrolidinyl9 piper;dino or '~
morpholino radicals~ Compounds containing these groups
are,readily prepared and typify saturated monocycl iC9
heterocyclic radicals which are generally useful in
lieu of the dilower alkylamino groups present in the
compounds of this InventionO
The alkylene chain separating the basic amino function
from the tricyclic ring consists of from 2 to 6 carbon
atoms and can be either a straight or branched alkylene
chain. the alkylene chain must separate the adjacent
oxygen atom from the terminal amino nitrogen by at least
2 carbon ato~s9 i.e.9 the ether oxygen and amino nitrogen
cannot share the same carbon atom of the alkylene group.
Each of the alkylene groups can be the same or dtfferent~
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~ 4Z4~
preferably, however, both alkylene groups are the same.
Illustrative of such groups are ethylene, propylene,
1,3-propylene, butylene, 1,4-butylene, 2-methyl-1,4-but~
ene, pentamethylene, 3-methyl-1,5-pentylene`and hexameth~
ene.
Illustrative of the base compounds of the present
invention represented by generic formula (I) can be men- `~
tioned: 398-bts(4-piperidinobutoxy)-6(5H)-phenanthridinone,
2,7-bis[2-(diethylamino)ethoxy]-9-phenanthrol, 3,8-bis~3~
(N-cyclohexyl-N-methylamino)propoxy]-6H-dibenzo[b,d~pyran-
6-one, ~,8-bis[2-(diisopropylamino)ethoxy]-6(5H)-phenan-
thridinone, 398-bis[2-(diisopentylamino)ethoxy]-6H-dibenzo
[b,d]pyran-6-one and 2,7-bls[2-(diallylam;no)ethoxyJ-g-
phenanthrolO '~
It must also be recognized that compounds of formula ~ ~
(i) in which a hydrogen atom Is avallable adjacent to the ~ ~ -
keto function are capable of forming the corresponding
enol tautomers. Thus, in both the phenanthrene and the ~
6H-phenanthridone seriesg the compounds of the present ;~-
invention may also be represented by the general formula
(IA) which is tautomeric with the corresponding keto Form
as illustrated below.
.
, ,~
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lL~4'~39
R l`,
~Rl ~J ~(CH2)n~N\ R '
, N- ( C 112 ) " - H
( I)
O- ( C H2 ) n - N
R ,N-(CH2)n-O
OH
(IA)
In the above representation, it is understood that the
symbol Y is limited to nitrogen and the.CH. group only . Where
the oxygen atom is present,as in the-6H-dibenzo[b,d]pyran
series of compoundsg there is, of course, no~ enoi.îzable
hydrogen available and the compounds exist only in their
keto form. It is further understood that the~compounds in
the phenanthrene and phenanthridine series are li.kely to
be mixtures of tautomeric forms, the compositions of which
are dependent upon such factors as the nature of the tri-
cyclic nucleus, the various side cha;ns present and the
environment surrounding the molecule as a whole. In the
case of the phenanthrene series, the enol or phenolic
form predominatesO
The enol form can be stabil;zed by a replacement of
the enol hydrogen in this position with a lower alkyl
group as represented by the symbol R2. Thus~ the 6 and/or
9-lower alkyl ethers exist only in compounds of the
phenanthrene and phenanthridine series respectively, wherë-
as the 6H-dibenzo[b,d]pyran series of compounds exist
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only as 6-keto compounds and do not form the corresponding
6-lower alkyl ethers. Illustrative of the base compounds
of the present invention represented by general formula
(li) there can be mentioned: 2,7-bis[2-(diethylamino)
ethoxy]-9-methoxyphenanthrene, 2,7-bis[3~ pyrrolidinyl)
propoxy~-9-propoxyphenanthrene, 2,7-bis[2-(cyclohexylamino)
ethoxy]-9-methoxyphenanthrene, 2,7-bis[4-(diallylamino)
butoxy]-9-methoxyphenanthrene~ 3,8-bis[2-(diethylamino)
ethoxy]-6-methoxyphenanthridine and 398-bis[4-(dimethyl-
amino)butoxy]-6-ethoxyphenanthridine.
The expression "pharmaceutically acceptable acld
addition salts" is Intended to apply ~o any non-toxic
organic or inorganic acid addition salts of the base com-
pounds represented by formulas (I) and (Il). Illustrative
inorganic acids which form suitable salts include hydro-
chloric, hydrobromic, sulfuric and phosphoric a~ids as ;
well as acid metal salts such as sodium monohydrogen
orthophosphate and potassium hydrogen sulfate. Illustra-
tive organic acids which form suitable salts include the
mono, di and tricarboxylic acids. Illustrative of such
acids are,ifor example, acetic, propionic, glycolic,
lactic, pyruvic9 malonic, succinic, glutaricg fumaricg
malicg tartaric, citric~ ascorbicg maleic, hydroxymaleic
benzoic, p-hydroxybenzoicg phenylacetic, cinnamic,
salicylic, 2-phenoxybenzoic and sulfonic acids such as
methanesulfonic acid and 2-hydroxyethanesulfonic acid~
Either the mono or the di-acid salts can be formed, and
such salts can exist in either a hydrated or a sub
stantially anhydrous form.
In general the compounds of the present Tnvention
-14-
, . , - . . ,, . :
.. . - . .. , , ... . . . . . ~,.
, : . . . .
.. : . . . :...... ~ , .. .
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3LV4~39
are prepared From various 2,7-disubstituted-9-fluorenone
precursors which are more fully described in U.S. Paten~
3,592,~19. The preparation of the instant compounds
involv~s various ring expansions of the g-fluorenone
nucleus to form the corresponding g-substituted phenan-
threne, 6(5H) phenanthridlnone and 6H-dibenzo[b,d]pyran-
6-one rings. More particularly, the reaction with diazo-
methane results in the formation of the 2,7-bis bas;c
ethers of 9-methoxyphenanthrene; the reaction with
hydrazoic acid results in the formation of 3,8-bis basic
ethers of 6(5H)-phenanthridinone; whereas the reaction with
peracids or hydrogen peroxide results in the formation of
the 3,8-bis basic ethers of 6H-dibenzo[bgd]pyran 6-one.
Cyclic aliphatic ketones are known to ring expand
with diazomethane-to form larger cyclic aliphatic ketonesO
This reaction may also be conducted in some instances with
aromatic ketones, producing a variety of homologous ring-
enlarged ketones in addi~ion to the formation of enols,
enol ethers and ethylene oxidesO Thusg for example,
Schultz et alg J. Am. Chem SocO 62g 2902-4 (1940)
reported the reaction of diazomethane with fluorenone to
yield 5% of 9-phenanthrol, 30% of 9-methoxyphenanthreneg
1.5~ of di-9-phenanthryl etherg an unknown substance and
30~ of unchanged fluorenoneO In additiong substituents
on the aromatic ring are known to change the ratio of the
various products obtained as well as to give rise to
additional isomericJ homologous ketones and side productsO ;
Thus, the application of the diazomethane reaction to the
2,7-bis-basic ethers of 9-fluorenone could not have been
predicted and is not without difficultyO
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The reaction is most frequently conducted by treat-
ment of a methanolic solution of the carbonyl containing
compound with an ethereal solution of diazomethane, either
in the presence or absence of a catalyst. Alternatively,
a solution of the carbonyl compound in methanol is
treated with nitrosomethylurethane in the presence of a
base. The diazomethane can be prepared either ex situ
or in situ. Generally, applicants prefer to generate the
diazomethane ex situ and to co-distill t-he diazomethane
so produced with ether into a methanolic solution of the
carbonyl containing compound. Suitable inert solvents
which may also be utilized include such solvents as
dioxane, benzene, toluene, chloroform and methylene
chloride with ether-methanol being the solvent combination
of choice. Additionally, methanol has been shown to have
a high catalytic activity for dia~omethane ring expansion
reactions. Catalysts which may be usefully employed in
this reaction include trace amounts of metal salts such ;~
as zinc chloride or lithium chloride. A minimum of 2
equivalents of diazomethane are generally employed, one
equivalent providing for the ring expansion, whereas the
other equivalent competes with the starting material to
form the corresponding 9-methoxyphenanthrene ethers (V).
In addition to a variety of side products which are
formed, some of the intermediate 2,7-bis basic ethers of
9-phenanthrol (IV) also remain. The intermediates are
readily separated from the reaction mixture in the form
of their sodium salts. The 9-lower alkoxyphenanthrene
derivatives (II), other than the 9-methoxyphenanthrene
~o derivatives, are prepared, in turn, by the reaction of the
-16-
B
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~ 4 ~ ~ 3~
9-phenanthrols (IV) with other lower diazoalkanes.
Due to the complex and wide variety of side reactions
possible, no more than 8 equivalents of diazomethane are'
useful in the preparation of the 2,7-bis-basic ethers
g-methoxyphenanthreneO The reaction proceeds exothermall~
and is conducted at room temperature or below. The re-
action takes place at a temperature range of from about
-50C. to ambient temperatur-es with a temperature of 0C.
conveniently preferred. The reaction can be conducted
for a period ranging anywhere from about,one hour to about
seven days.
- The 9-phenanthrol derivatives~ which are also formed
in the diazomethane ring expansion reaction,are readily
freed of their nonacidic materials by extraction with
chloroform from a strongly alkaline reactlon mixture.
The 9-phenanthrol derivatives which remain in the aqueous
medium may then be removed by neutralization of the
aqueous medium to a pH of about 9-10, and subsequently
extracting the neutralized rnedium with chloroformO
The 9-phenanthrols so obtained can then be etherified
by reacting with a lower diazoalkane to form the
corresponding 9-lower alkoxy phenanthrene ethers~
The preparation of the 398-bis-baslc ethers of 6(5H)
phenanthridinone (VI) is achieved via a modification of
the so-called Schmidt reaction. Essentially, as applied
here, this method inserts a hetero nitrogen atom via a
ring expansion into the five membered fluoren-9-one ring
using hydrazoic acid in the presence of a strong mineral
acid such as sulfuric acid to form the six-membered
~0 heterocyclic ring of 6~5H)-phenanthridone. Hydra20ic
'
-17- -
' . ' ' ! . ' ~ ' ' ' . ' ' ' . ' : '
acid is ~nown to react with simple cyclic ketones to
form ring enlarged cyclic amides or lactams. Thus, for
example, cyclohexanone reacts with hydrazoic acid yielding
caprolactam. However, to applicants' knowledge, the
use of hydrazoic acid on a 9-fluorenone nucleus containing
a bis-basic ether side chain has not previously been
reported. Approximately equimolecular quantities of
hydrazoic acid are used inasmuch as an excess of hydrazoic
acid encourages tetrazole formation. The reaction can be
conducted by the addition of a solution of hydrazoic
acid in an appropriate organic solvent to a solution of
the fluoren-9-one. Alternatively, hydrazoic acid can
be generated ln situ by the addition of sodium azide to
the reaction mixture. Due to the extremely hazardous
nature of hydrazoic acid, the use of sodium azide is
preferred, thereby eliminating the necessity for the
isolation of the toxic hydrazoic acid. This reaction is
exothermic in nature, and consequently the reaction
is best conducted by stirring with a suitable means
for cooling. The reaction can be conducted at
temperature ranges of from about -20C. to about 50C.,
and for periods of from about 30 minutes to about one
week. Generally, a temperature of 0C. with a reaction
period of about 1 hour is preferred as a matter of
convenience. If the reaction appears to proceed slug-
gishly, higher temperatures can be advantageously
employed. Due to the rapidity of the reaction with
hydrazoic acid, the reaction is conveniently controlled
by the rate of addition of the hydrazoic acid or sodium
azide to a stirred solution of the 9-fluorenone.
-18-
~' ' .
~ -, ~ ,. .' ' '
. . - , . . .
M-677
derivative dissolved or suspended in a suitable solvent.
Suitable solvents include sulfuric acid, chloroform,
benzen~ dioxane and diethyl ether with trifluoroacetic
acid h~ving been found to be particularly useful.
Generally, sodium azide is added in small increments
to a trifluoroace~ic acid solution of the g-fluorenone
ether derivat;ve, until no further evolution of nitrogen
gas is observed. At this point the reaction is con-
sidered to be complete for all practical purposes. An
acid catalyst is also employed. Any strong acid may be
used with concentrated sulfuric acid being the catalyst
of choice. Isolation of the 3,8-bis basic ethers of
6(5H)-phenanthridinone so prepared is achieved using
standard procedures apparent to those skilled in the art.
An alternative route to the preparation of the 6(5H)-
phenanthridinone ethers is via a Beckmann rearrangement
of the corresponding fluorenone oximes. Moore and
Huntress, J. Am. Chem. Sc. 49, 2618 (1927), have demon~
strated the preparation of 7-nitro-6(5H)-phenanthridinone
by the treatment of 2-n;trofluoren-9-one oxime with
phosphorous pentachloride dissolved in phosphorous oxy- -
chloride. In similar fashion the 3,8-bis basic ethers of
6(5H)-phenanthridinone can be prepared from the 2,7-bis-
basic ethers of fluoren-9-one oxime as illustrated in
the following reaction scheme:
- 19- ~
M- 677
Z~39
N - ~ CHz ~ n - ~ O - ( C H2 ) - N /
POCl3
PCls
NC1 Rl``
~N-(CH2)n-O~JO-(cH2)n-N~ ~ Ç .
Heat ~ . /R
- L ~R~ (CH2)
-(CH2)n-O ~Cl
H20
Rl~
,~R 1 o~ 0~( CH2) n~N \ R ~ ¦
\N-(CH2)n-
~R ~ OH
1~ ..
,
R ~ ~ O- ( C H8 ~ ~ - N
,N_~HZ)n-o H
R O
-20 -
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~)4Z439
The first step in the preparation of the 3,8-bis-
basic ethers o~ 6H-dibenzo[b,d~pyran-6-one involves the
peracid or peroxide oxidation of a 2~7-bis(w~haloalkyl)
ether of fluoren-9-one (Vll) under Baeyer-Villiger
conditions. Essential 1YJ this reaction results ;n a
ring expansion of the five-membered fluoren-9-one ring
with the introduct10n of an oxygen atom to form a
six-membered ring expanded lactone or 6H-dibenzo[b,d]
pyran-6-one nucleus. Thus, the oxidation of a 2,7-bis
(w-haloalkyl~ ether of fluoren-g-one (Vll), found
described in U.S. Patent ~5g2g819~ with a peracid or
hydrogen peroxide in the presence of a strong acid~ such
as sulfuric acid, results in the formation of a ~,8-bis
(w-haloalkyl) ether of 6H-dibenzo[b,d]pyran-6-one (Vlll).
The 6H-dibenzo[bld]pyran (w-haloalkyl) ethe~s so pre-
pared can then be condensed with an amine (IX) to form
the desired 3,8-bis-basic ethers of 6H-dibenzo[bJdJpyran-
6-one (X), the compounds of the present inventionO The -
oxidation reaction is exothermic in nature and the temp-
erature of the reaction mixture may be conveniently
controlled by the rate of additi~n of the oxidizing agent.
The reaction temperatures ~ary from about -20 to 40C.,
with a temperature of about 25~C. being preferred~ ~ -
Reaction times range anywhere from about ~0 minutes to
about one week at the lower temperatures. Large excesses
of peroxide are to be avoided inasmuch as there is always
the hazard o-F peroxide oxidations occurring with explosive
violenc;e. IF significant amounts of peroxide remain upon
completion of the reaction, they can be decomposed using
reducing agents such as sodium bisulfite or ferroùs
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.
M-67rl~
1~4Z~39
sulfate. Generally, a two or three fold excess of hydrogen
peroxide is satisfactory in carrying out the ring expansion.
The reaction is favored by polar solvents and proceeds
in a variety of solvents such as sulfuric acid, acetic
acid or acetic anhydride. The 3,8-bis(w-haloalkyl) ethers
of 6H-dibenzo[b,d]pyran-6-one (Vlll) so prepared are sub-
sequently condensed for the second step in the preparation
of the 3,8-bis basic ethers of 6H-dibenzo[b,d]pyran-6-one
( X ) ~
The condensation reaction of the bis(~-haloalkyl)
ethers (Vlli) with an amine.(IX) can be carrTed out using
a variety of conditions. For example, the ethers can be
heated together with a large excess of amine, the excess
amine serving both as the reaction medium and the hydro-
halide acceptorO This method is particularly suitàble
for those amines which are readily available9 inasmuch.
as any excess amine can be readily removed from the ;~
reaction mixture via distillation at a reduced pressure or
by steam distillation. Alternatively,.the w-haloalkyl
ethers (Vlll) can be heated with an excess of~the amine
in a suitable organic solvent. Suitable organic sol-
vents include benzene, toluene, xylene and chlorobenzene,
lower molecular weight alcohols such as methanolg ethanol -
and isopropyl alcoholg or they may include .lower molec-
ular weight ketones such as acetone and methyl ethyl
ketone. The reaction of these ethers with an amine is
generally promoted by the addition of either~ sodium or
potassium iodide, the iodide being used in either cata-
lytic or stoichiometric amounts. In some casesJ as when
the amine is expensive or in short 5Upp 1 y, it may be
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:
M-677
~042~L39
advantageous to use only two equivalents of the amine for
each equivalent of the ~-haloalkyl ether employed in the
presence of an excess of e i ther powdered sodium or
potassium carbonate as the acceptor for the hydrohalidç
that is ~enerated. In the case of volatile amines the
condensation reaction can best be conducted under pressure
in a suitable bomb or autoclave.
The compounds of the present invention are antiviral
agents. Preferably they are administered to an animal
host to prevent or inhibit viral infections. The term
host refers to any viable biological material or intact
animal including humans which is capable of inducing the
formation of interferon and which serves as a support
means for virus replicationO The host can be of animal ~ i
or mammalian origin. Illustratively such hosts include
birds, mice, rats, guinea pigs, gerb;ls, ferrets, dogs,
cats, cows, horses and humans. Other viable biological
mater;al such as used in the production of vaccines may
also act as a host. Thus, tissue cultures prepared from
organ tissues, such as mammalian kidney or lung tTssue9
as well as tissue cultures prepared from embryo tissue,
such as obtained from amniotic cells or chick allantoic
fluid, have been found to be useful hosts~
The treatment of virus infections for purposes of
the present invention encompasses both the prevention and
the inhibition of characteristic disease symptoms in a
mammalian host susceptible to invasion by a pathogenic
virus. Illustrative of mammalian virus infections which
can be prevented or inhibited by the administration of
~0 the compounds of the present invention are infections
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M- ~77
~ 0~43~
caused by picornaviruses, such as encephalomyocarditis
virus; myxoviruses, such as influenza A2 (Jap/305) virus~
arboviruses; such as Semliki forest virus; the herpes
group of viruses, including herpes simplex; and the po~-
viruses, as for example vaccir~ia IHDo Thus9 for example~
the compounds of the present invent~on when administered
orally or subcutaneously to mice in varying doses either
shortly prior or subsequent to a fatal inoculation of a
neurotropic virus such as encephalomyocarditis virus,
having a LD50 anywhere from 5 to 50J delay or prevent
completely the onset of death. Salts of these compounds
are generally administered in compositions containing
a 0.15% aqueous hydroxyethylcellulose vehicle, whereas
the free base compounds are generally administered in
compositions containing a 10~ aqueous surfactant vehicle
in order to help solubilize the compound. In general~
ten mice are used for each treated group with an additional
20 mice serving as a control group. At the time of
administration the test virus is titrated in order to
determine the potency or LD50 for the particular virus
pool used as a challenge. The control anima`ls are given
a placebo containing the ident;cal volume of vehicle
without, of course, the active ingredient. Because of
the lethal ~ature of the test system employed, the anti-
viral nature of the test compound is dramatically
illustrated by a side by side comparison of the survival
time of treated animals with the untreated control group
of animalsO
Respiratory viruses, such as influenza ~2 ( Jap/305)
~0 virusJ which are also lethal to the test animals employed,
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~ 4 Z ~ 3~
are administered via intranasal instillation. Animals
infected in this manner have the active ingredients
administered in the same manner as the test virus, and
again a side by side comparison is made of the survivors
of the animals ~reated with the untreated control animals.
Inexplicably, a mouse fcltally infected with encephalo-
myocarditis or influenza virus occasionally survives with-
out further treatment. This may be the result of a prior,
interferon induced infection in the mouse9 or perhaps ~
due to some genetic factor or other natural defense mech- '
anism not presently understood. For this reason the
control group selected is of sufficient size as to sta-
tistically reduce to a negligible amount the influence
of such a chancé survivor upon the test results.
The vaccinia test virus is typical of the dermato- ' '
trophic type viruses which respond to treatment with -
compositions containing the compounds of the'instan~ `
Invention. The vaccinia virus generally produces a non-
fatal infection in mice, producing characteristic tail
lesions when the virus is subcutaneously'admi'nistered to
the tail of the mouse. The instant compounds are
adrninistered either orally or'subcutaneous-ly either prior '' ~;~''`
to or subsequent to the vaccinia infectionO Tail lesions
are subjectively scored on the eighth day following
infection against untreated animals which serve as a
control group, The compounds of the present invention
have been found to be effective in varying degrees against
one or all of these test virus systems. ~ -
The mode of activity of the active ingredients of
the present invention is not rigorously defined. Inter
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; ~ ~ - . . , ~ .. ,
M-677
alia, the compounds ~ ~he present invention may induce
the formation of interferon in a viable host. Interferon
is a biological substance of unknown chemical structure,
presumably proteinaceous in nature, which is produced
by host cells in response to a viral infection. The inter
feron so produced acts to induce a virus inhibiting su~
stance, which inhibits in some yet unknown manner the
intracellular replication of the virus without appear-
ing to hav`e any inactivation effect per se upon the virus
itself. A few of the viruses susceptible to interferon
replication inhibition are described in Horsfall and Tamm,
"Viral and Rickettsial Infections of Man'~ 4th Edition
(1965), J.B. Lippincott Company, pp. 328-9.
As previously indicated~ the compounds of the present
invention may be prophylactically administered in order
to prevent the spread of contagious viral diseases or
they may be therapeutically administered to a host already
infected intended for their curative effect. When admin-
istered prophylactically3 it is pre~erred that the admin-
istration be made within 0 to 96 hours prior to theinfection oF the host animal with a pathogenic virusi
When the compounds of the present invention are admin-
istered for their curative effect, it is preferred that
they are admin'istered within about 1 or 2 days following
infection of the host in order to obtain the maximum
therapeutic effect.
The dosage to be administered will be dependent upon
such parameters as the particular virus for which either
treatment or prophyiaxis is desired, the species of animai
~0 involved, its age, health, weight, the extent of infection,
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M-677
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1~?4i~439
concurrent treatmentg if ~ny~ frequency of treatment and
the nature of the effect desired. A daily dose of the
active ingredients will generally range from about 0.1 mg
to about 500 mg per kg of body weight.. Illustratively
dosage levels of the administered active ingredients
for intravenous treatment range from about 0.1 mg to about
10 mg per kg of body weight; for intraperitoneal admin-
istration range from about 0.1 mg to about 50 mg per kg of
body weight; for subcutaneous administration range from
about 0.1 my to about 250 mg per kg of body weight; for
vral administration may be from about 0.1 mg to about 500 ~:
mg per kg of body weight; for intranasal instillation range .
from about 0.1 mg to about 10 mg per kg of body weight; an~
for aerosol inhalatian therapy, the range is generally from
about 0.1 mg to about 10 mg per kg of body weight.
The novel compounds described herein can also be
administered in various differPnt dosage unit forms, e.g.,
oral compositions such as tablets, capsules, dragees, :
lozenges, elixirs, emulsions, clear liquid solutions and
suspensions; parenteral compositions such as intra-
muscutar3 intravenous or intradermal preparations; and
topical compositions, such as lotions, creams or ointments.
The amount of active ingredient contained in each dosage
unit form will, o~ course, vary widely according to the ~.
particular dosage unit employed, the animal host being
treated, and the nature of the treatment, i.e., whether
prophylac~ic or therapeutic in nature. Thus, a particular
dosage unlt may contain ~rom about 2.0 mg to over 3.0 9
of active ingredient in addition to the pharmaceutical
excipients contained therein.
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. . .
M-677
~0~2439
The novel compounds described herein can be employed
in conjunction or admixture with additional organic or
inorganic pharmaceutical excipients. Suita'ble solid
ex~ipients include gelatin, lactose, starches, magnesiu~
stearate and petrolatum. Suitable liquid excipients ~
include wa~er and alcohols such as ethanol, benzyl alcohol
and the polyethylene alcohols either with or without
the addition of a surfactantO In general~ the preferred
liquid excipients particularly for injectable prep-
arations, include water, saline solution, dextrose andglycol solutions such as an aqueous propylene glycol or
an aqueous solution of polyethylene glycolO Liquid prep~. ' -
arations to be used as sterile injectable'solutions
will ordinarily contain from about 0.5% to about 25~
by weight, and preferably from about 1% t.o about 10~ .
by weight, of the active ingredient in solutionO In
certain topical and parenteral preparationsl various '
oils are u~ilized as carriers or excipients.. Illustrative
of such oils are mineral oils~ glyceride i!s. such as
20 ' lard oil, cod liver oil, peanut oil, sesame oil, corn
oil and soybean oil. . . '.
-A suitable method of administrat'ion for the compounds
of the present invention is orally either in:a soiid dose
form such as a tablet or capsule, or in a liquid dose form
such as an elixir, suspension, emulsion or.syrup. Ordi-
narily the active ingredient comprises from about 0.5%
to about 10~ by weight of an oral liquid compositionO
In such compositions, the pharmaceutical carrier is
generally aqueous in natureJ as for example,:aromatic ':
water, a sugar-based syrup or a pharmaceutical'mucilage.
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M-677
~ 342439
for insoluble compounds suspending agents may be added
as well as agents to control viscosity, as for example,
magnesium aluminum silicate or carboxymethylcellulose.
Buffers, preservatives9 emulsifying agents and other
excipients can also be added.
For parenteral administration such as intramuscular
intravenous or subcutaneous administration, the proportion
of active ingredient ranges from about 0.05% to about 20%
by weight, and preferably from about 0.1~ to about 10%
by weight of the liquid COmpOSitiQn. In order to minimize
or eliminate irritation at the site of injection, such
compositions may contain a non-lonic surfactant having
a hydrophile-lipophile balance (HLB) of from about 12
to about 17. The quantity of sùrfactant in such formu~
lations ranges from about 5% to about 15~ by weight. The -
surfactant can be a single component having the above
idèntified HLB, or a mixture of two or more components
having the desired HLB. Illustrative of surfactants
useful in parenteral formulations are the class of
polyoxyethylene sorbitan fatty acid ethers as, for example,
sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
The concentration of active ingredient contained in these
various parenteral dosage unit forms varies over a broad
range and comprises anywhere from about 0.05% to about
20% by weight of the total formulation, the remaining
component or components comprising liquid pharmaceutical
excipients previously mentioned.
The active ingredients of the present invéntion can
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1t~4~39
also be admixed directly with animal feeds or incorpo-
rated into the drinking water of animals. For most
purposes, an amount of active ingredient is used which
provides from about 0.0001~ to about 0.1% and preferably
from abou-t 0.001% to about 0.02~ by weight of the active
ingredient based upon the total weight o~ feed intake~
The active ingredients can be admixed in anima1 feed
concentrates, suitable for use by farmers or livestock
growers for incorporation in appropriate amounts with
the final animal feeds~ These concentrates ordinarily .
comprise ~rom about 0.5% to about 95% by weight of the
active ingredient compounded with a finely divided solid
carrier or flour, such as wheat~ corn9 soybean or
cottonseed flour. Depending upon the particular animal
to be fed~ nutrients and fillers may also be added such
as ground cereal, charcoal~ fuller's earth, oyster shells
and finely divided attapulgite or bentoniteO ..
The active ingredients of the present invention can
be packaged in a suitable pressurized container together ~ .
with an aqueous or volatile propellant for use as an
aerosol. A suitable discharge valve is fitted to an. -
opening in the container from which the active ingredi-
ents may be conveniently dispensed in the form of a spray,
liquid, ointment or foamO Additional adjuvants such as
co-solvents, wetting agents and bactericides may be
employed as necessary~ Normally, the propellant used is
a liquified gaseous compound, preferably a mixture oF low
molecular weight fluorinated hydrocarbons. These halo-
alkanes are preferred bacause of their compatibility with
the active ingredients of the present invention, and be~
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M-677
~ V4Z~39
cause they are non-irritating when applied to skin surfac~s.
Other useful propellants include ethylene oxide, carbon
dioxide, propane and nitrogen gas.
The invention described herein is more particularly
illustrated by means of the following specific examples:
EXAMPLE I
.
2,7-Bis[2 (diethylamino)ethoxy]fluoren-9-one
dihydrochloride
A solution of [2-(diethylamino)ethyl]chloride obtained
from 1505 9 (0.09 mole) of ~2-(diethylamino)ethyl]chloride
hydrochloride in 100 ml of toluene (dried over molecular
sieves) is added to a mixture of 6.4 g (0.03 mole) of
2J7-dihydroxy-fluoren-9-one and 3.3 g (o.o6 mole) of
sodium methoxide in 200 ml of toluene (dried over molecular
sieves). The resulting mixture is heated to its reflux
temperature with stirrTng for a period of 3 hours. Upon
cooling, the mixture is filtered to remove the precipi
tated sodium chloride~ The toluene solution is washed
3 times with water, once with saturated sodium chlorid~
solution and dried over anhydrous magnesium sulfate~
This mixture is fiitered and the filtrate acidified to
Congo Red with ethereal hydrogen chloride. The solid
which precipitates is filtered, recrystallized from
butanone with sufficient methanol being added to effect
solution~ and the product dried at 100C. for 2~ hours
under vacuum: m.p. 235-7C., ~ma 269~ and E 1~m 16000
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M-677
439
EXAMPLE 1l
?,7-Bis~2-(diethylaminolethoxyl-9-methoxyphenanthrene
A solution of 11.7 9 (0.028 mole) of 2,7-bis[2-
(diethylamino)ethoxy]fluoren-g-one in 20 ml of ether and
50 ml of methanol is stirred and treated with approxi-'
mately o.o8s mole of diazomethane which is co-distilled
into the reaction mixture at 10-28C. with diethyl
ether. The reaction mixture is stirred at room tempera-
ture for 24 hours and most of the volatile materials
are removed in vacuo. The residue is treated with a
dilute solution of sodium hydroxide and extracted'several
times with ether. The combined ether extracts are washed
with water, dried over anhydroùs sodium~-sulfate, treate'd '
with charcoal, filtered and the product converted to -
its hydrochloride salt by treatment with ethereal HCl.
This salt is then dissolved in 200 ml of ethanol and
treated with 3.8 9 of G;rards Reagent T to allow for the
subsequent removal of any unreacted starting material.
The resulting solution is refluxed for 3 hours, treated
with 203 ml of a 5% sodium hydroxide solution and
extracted with etherO The combined ether extracts are
washed with water, dried and most of the volatile
material removed. The resulting residue is~dissolved -~
in 40-60C~ petroleum ether, filtered, placed on an
alumina'chromatographic column and eluted with 40-60Co
petroleum ether. The initial eluate is collected, the
volatiles removed and the 2,7-bis[2-(diethylamino)ethoxy]-
9-methoxyphenanthrene so obtained is recrystallized from
40-60C~ petroleum ether and again from pentane solution,
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M-677
~042~39 ~
m.p. 63-5C., ~mae~H 259, and E 1~ 1590. -
Following essentially the same procedure, but sub-
stituting for the 2,7-bis[2-(diethylamino)ethoxy~
fluoren-g-one above) the appropriate molar equivalent
quantities of 2J7-bis[2-(dibutylamino)ethoxy]fluoren-9~
one, 2~7-bis[2-(diisopropylamino)ethoxy]fluoren-9-one~ -
2,7-bis[3-(dimethylamino)propoxy]fluoren-9-one and
2,7-bis[3-(dibutylamino)propoxy]fluoren-9-one, the
following compounds are obtained: 2,7-bis[2-(dibutyl-
amino)ethoxy]-g-methoxyphenanthrene, 2~7-bisC2-(diisopropyl-
amino)ethoxy]-9-methoxyphenanthrene, 2,7-bisC~-(dimethyl-
amino)propoxy]-g-methoxyphenanthrene and 2,7-bis[3-
(dibutylamino)propoxy]-g-methoxyphenanthrene3 respectlvely.
' :
EXAMPLE lll
?,7-Bis(~piperidinopropox~)
fluoren-9-one dihYdrochlorlde
A mixture of 63.6 9 (0.30 mole) of 2J7-dihydroxy-
~luoren-9-one, 188 9 (0.95 mole) of 1-(3-chloropropyl)
piperidine hydrochloride, 132 9 (2.0 mole) of 85%
potassium hydroxide in 900 ml of toluene and 300 ml of
water is refluxed with vigorous stirring for 20 hoursO
The layers are separated upon cooling and the organic
layer is washed 3 times with water, once with a saturated
solution of sodium chloride and dried over anhydrous
magnesium sulfate. The mixture is filtered and the
solvent removed tn vacuo. The residue is taken up in
isopropyl alcohol and acidified to Congo Red with
ethereal hydrogen chloride. The solid which precip;tates
~3-
~ - - - , . i . .. . .. . . .. . .
M-677
Canada
4'~439
ts filtered, recrystallized from a mixture of 3 parts
isopropyl alcohol to 1 part methanol, and the 2,7-bis
(3-piperidinopropoxy)fluoren-9~one dihydrochloride so
prepared ts dried at 100C. for 24 hours under vacuum,
m.p. 279.5-80.5C., ~Hax 270, and E 1~m 1370.
EXAMPLE IV
9-Methoxy-2,7-bis(3-piperidinopropox~)
phenanthrene
A solution of 4.7 g (0.01 mole) of 2,7-bls(~-piper-
idinopropoxy)fluoren-9-one in methanol is stirred and
treated with approximately o.o8s mole of diazomethane by
co-distillation with ether into the reaction mixture at
a temperature of -15~ to -31C. The reaction mixture is
allowed to warm slowly to room temperature overnight.
The volatile materials are removed on the s~eam bath
in vacuo and the residue tritura~ed with pentane to
induce crystallization. The resulting solid is dissolved
in a mixture of pentane and ether, washed several times
with a dilute solution of sodium hydroxide, washed with
water, dried over anhydrous sodium sulfate, treated with
charcoal, filtered and most of the volatile solvents
removed from the filtrate. The residue is recrystallized
from pentane and again from a methanol-water mixture to
yield the desired 9-methoxy-2,7-bis(3-piperidinopropoxy)
phenanthrene: m.p. 118.5-9.5C., ~mMaeH 259, and
E 1%m 14~0.
Following essen~ially the same procedure, but sub-
stituting for the 2,7-bis(~-piperidinopropoxy)fluoren-9-
"~
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.. . - ~ .
M-677
Canada
~ 39
one above, the appropriate molar equivalent quantities
of 2,7-bis[2~ pyrrolidinyl)ethoxy]fluoren-9-one or
2,7-bis(4-morpholinobutoxy)~luoren-9-one results in the
formation of 9-methoxy-2,7-bis~2-(1-pyrrolidinyl)ethoxy]
phenanthrene and 9-methoxy-2,7-bis(4-morpholinobutoxy)
phenanthrene, respectively.
EXAMPLE V
~`.
2,,7-Bis~2-(dimethylamino)ethoxyl - '
-9-phenanthrol
A solution of 8.1 9 (0.023 mole) of 2,7-bis[2-
(dimethylamino)ethoxy]fluoren-9-one in 50 ml of methanol
and 25 ml of ether is stirred and treated with 0.5 gram of
finely powdered sodium carbonate. To this mixture is
added 75 g (0.06 mole) of ethyl N-methyl-N-nitrosocarbamate
in 20 ml of methanol over a period of 2 hours. The temp-
erature of this reaction mixture is kept below ~0C. for
a period of 24 hours. The react10n mixture is then freed
of most of the volatile materials In vacuo, dissolved in
an aqueous solution of hydrochloric acid, and extracted
several times with diethyl ether. The resulting aqueous
solution is made strongly alkaline with an aqueous sodium
hydroxide solution and extracted with ether. The remaining
aqueous solution is neutralized to an approximate pH of
10 using a 10~ hydrochloric acid solution and extracted
with ether. Evaporation o~ the combined ether extracts
~n vacuo and recrystallization from a methanol-water
mixture yields the desired 2,7-bis[2-(d1methylamino)
ethoxy]-9-phenanthrol.
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~ Z 4 ~9
Preparation o~ the 9~1Oweralkoxy ethers is
accomplished by further reacting a methanolic solution
of 2,7-bis[2-(dimethylamino)ethoxy]-9-phenanthrol with
a diazoloweralkane, such as diazoe~hane and diazGpro-
pane. The resulting 2,7-bis~2-(dimethylamino)ethoxy]-9-
ethoxyphenanthrene and 2~7-bis[2-(dimethylamino)ethoxy]-9-
propoxyphenanthrene so prepared can be isolated by
removal of ~he volatile materials In vacuo and recrys~al-
izing the residue from aqueous methanol.
EXAMPLE_VI
3,8-Bis~?-(diethylamino)ethoxYl
-6(5H)-phenanthridinone dihydrochloride
Using the product prepared in accordance with Example
1, 10 9 (0.027 mole) of 2,7-bis[2-(diethylamino)ethoxy~
fluoren-9-one dihydrochloride is dissolved in 75 ml of
trifluoroacetic acid and chilled to a temperature of
from 0-5~C. Sodium azide, ~.5 9, is added in increments
with stirring followed by 10 ml of sulfuric acid which is
added in a dropwise fashion. Stirring and cooling is
continued for an additional hour and the solution made
alkaline with an excess of a 20% potassium hydroxide
solution. The basic reaction mixture is extracted
several times with methylene chloride, the extracts are
combined, washed with water, dried over anhydrous sodium
sulfate, filtered and the filtrate evaporated in vacuo.
The residue is dissolved in ether and acidified with -
ethereal hydrogen chloride. RecrystallTzation of the
residue from a mixture of methanol-butanone yielded
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M- 677
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3,8-bis[2-(diethyiamino)ethoxy]-6(5H)-phenanthridinone
as the dihydrochloride salt having a m.p. of 250-2C.,
~EtOH 230, and E 1c~m 885.
Following essentially -~he same procedure but sub-
stituting the appropriate molar equivalent amounts of
2,7-bis(2-piperidinoethoxy)fluoren-9-one dihydrochlorideJ
2,7-bis[3-(dimethylamino)propoxy]fluoren-9-one dihydro-
chloride and 2,7-bis[2-(diallylamino)ethoxy]fluoren-9-
one dihydrochloride for the 2,7-bis[2-(diethylamino)ethoxy]
fluoren-9-one dihydrochloride results in the formation of
the following compounds, respectively: 3,8-bis(2-piper-
idinoethoxy)-6(5H)-phenanthridinone dihydrochloride,
3,8-bis[3-(dimethylamino)propoxy]-6(5H)-phenanthridinone
dihydrochloride and 3~8-bis[2-(dlallylamino)ethoxy]-6(5H)-
phenanthridinone dihydrochloride.
EXAMPLE Vl~
3,8-Bis~?~ dimethylamino)ethoxyL
-6H-dibenzo~b,dlpyran-6-one dihydrochloride
A solution of 13.5 9 (0.04 mole) of 2,7-bis(2-chloro-
ethoxy)fluoren-9-one in 100 ml of concentrated sulfuric
acid is slowly reacted with 12 ml of a 30% hydrogen per-
oxide solution at room temperatureO The reaction which
is strongly exothermic is controlled by cooling the
stirred reaction mixture in an ice-water bath~ The cooled
reaction mixture is poured onto 500 ml of an ice-water
mixture and the resulting 3,8-bis(2-chloroethoxy)-6H-dibe~zo
[b,d~pyran-6-one which separates is isolated.
A mixture of 4.6 9 (0.013 mole) o~ 3,8-bis(2-chloro-
-S7-
~ M-677
Z~39
ethoxy)-6H-dibenzo[b,d]pyran-6-one so obtained~ 2 g of
potassium iodide and 100 ml of a l~o~ aqueous dimethyl-
amine solution contained in 50 ml of tetrahydrofuran is
heated in a Parr pressure reactor with stirring at 120C.
for sixteen hours. The reaction vessel is cooled and
most of the volatile materials are removed in vacuo.
The residue is treated with an aqueous sodium hydroxide
solution and extracted with ether. The ether solution
is washed twice with water, once with a saturated
solution of sodium chloride, dried over anhydrous mag-
nesium sulfate and treated with ethereal hydrogen
chloride. The product which separates is then recrys-
talized from a methanol-anhydrous ether mixture to yield
the desired 3,8-bis[2-(dimethylamino)ethoxy]-6H-dibenzo
[b,d]pyran-~-one dihydrochloride.
EXAMPLE Vlll
.
The following Example is illustrative of the anti-
viral activity for the compounds of the present invention.
Thirty mice each weighing approximately 12 to 15 gms
are divided into two groups, a control group containing
20 animals and a test group o~ 10 animals. All of the
animals are challenged with a fatal dose (28LD50) of
encephalomyocarditis virus. The test group of an7mals
are treated both prophylactically and therapeutically
using a parenteral composition containing 3,8-bis[2-
diethylamino)ethoxy]-6(5H)-phenanthridinone dihydro-
chloride as the active ingredient dissolved in an aqueous
solution of 0.15% hydroxyethylcellulose. The compo-
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M-677
439
sition contains the active ingredient in an amount such
that each dosage contains 0.25 ml which is equiva1ent to
a dose level of 50 mg per kg. The control group
receives a subcutaneous placebo containing the same vol4me
of vehicle without, of course, the active ingredient.
Observations over a ten day period show a termination of
all the control animals within a period of from ~ to 5
days, with the treated group of animals surviving for a
- s~atistically longer period of time.
EXAMPLE IX
Preparation of a tablet formulation
An illustrative preparatlon of 10gOOO tabletsg each
containing 100 mg of 3~8-bis[2-(diethylamino)etho~y]-6(5H)-
phenanthridinone is prepared as follows:
Gm.
(a) 3/8-bis[2-(diethylamino~etho~y]
-6(5H)-phenanthridinone ......... 0..... O. 1000
(b) Lactose ....... ;.....,........................... 1000
(c) Starch paste (10% w/v
starch in water) .......................... 100
(d) Starch .................................... 32.5
(e) Calcium stearate ......................... 0 6.5
The active ingredient is uniformly mixed with the
lactose and granulated by the addition of the starch paste.
The granules which form are dried at 120F. for 20 hours
and forced through a No. 16 screen. The granules are
lubricated by the addition of the starch and calcium
stearate and compressed into tablets.-Each tablet so
prepared contains 100 mg of the active ingre~iènt.
,"~
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M-677
39
EXAMPLE X
Preparation of_a ca~ le formulation
An illustrative composition for the preparation of
1000 two-piece hard gelatin capsules, each capsule con-
taining 100 mg of 2,7-bis[2-(diethylamino)ethoxy]-9-
methoxyphenanthrene is prepared as follows:
Gm.
(a) 2,7-bis[2-(diethylamino)ethoxy]
-9-methoxyphenanthrene .................. ~ 100
(b) Corn starch O~ D 150
(c) Magnesium stearate ....... ~............... ...25
(d) 1000 Hard gelatin capsules
The finely powdered ingredients are mixed until
uniformly dispersed and then filled into hard shelled
gelatin capsules of the appropriate size.
In a similar fashion, soft gelatin capsules may be
prepared in which the above composition can be granu-
lated, slugged or directly compressed in a rotary die or ~;
plat~ mold in which the soft gelatin capsule is formed. -~
Alternatively, the above excipients may be omitted and
the active ingredient dispensed as a powder directly
into the soft gelatin capsule.
EXAMPLE Xl
, . _ .
- Preparation of an oral s~up formulation
A 2~ weight per volume syrup of 3,8-bis(4-piperidino-
butoxy)-6(5H)-phenanthridinone dihydrochloride is pre-
- pared in accordance with the usual pharmaceutical
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M-677
~0~2439
techniques which has the following formula:
Gm.
(a) Finely divided 3,8-bis(4-piper-
idinobutoxy)-6(5H)-phenanthridinone
dihydrochloride ....................... ~ 2.0
(b) Sucrose ................................. 33.3
(c) Chloroform .............................. 0.25
(d) Sodium benzoate .......................... 0.4
(e) Methyl p-hydroxybenzoate ............. ,. 0.02
(f) Vanillin ................................ 0.04
(g) Glycerol ............................... 0 1o5
(h) Purified water to 100..0 ml
EXAMPLE Xll
Preparation of ointment formulation
One thousand grams of an ointment for topical appli-
cation containing 1.0% of 3,8-bis[2-(diethylamino)ethoxy]
-6(5H)-phenanthridinone dihydrochloride is prepared from
the following ingredients:
Gm.
-(a) 3,8-bis[2-(diethylamino)ethoxy]
-6(5H)-phenanthridinone dihydro-
chloride ................................. 10
(b) Li~qht liquid pe$rolatum ~................ 250
(c) Wool fat .......;.............................. 200
(d) White petrolatum q.s. ad 1000
The wool fat, white petrolatum and 200 gms of the
- light liquid petrolatum are liquified and held at 110DF.
The active ingredient is mixed with the remaining liquid
petrolatum and passed through a colloid mill. After
: : passing through the mill, the mixture is stirred into the
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1~34243g
melt, and the melt is permitted to cool with continued
stirring until congealed.
EXAMPLE Xlll
Preparation of a parenteral emulsion formulatlo,n
An illustrative composition for an emulsion which
is parenterally injectable is as ~ollows:
Each ml
Contains Ingredients Amount
50 mg ~,8-bis[2-(diethylamino)ethoxy]
-6(5H)-phenanthridinone 1.000 9
100 mg Polyoxyethylene sorbi$an
monooleate 2.000 9
o. oo64 Sodium chloride 0.128 9 ,~
Water for injection q.sO 20.000 ml ,'
The parenteral composition is prepared by dissolving
o.64 9 of sodium chloride in 100 ml of water suitable for
injectionO The polyoxyethylene sorbitan monooleate is
mixed with the active ingredient, and an amount of the
previously prepared aqueous sodium chloride solution
added which is sufficient to bring the total volume to ~'
20 ml. The resulting solution is shaken and autoclaved
for 20 minutes at 110C. at 15 p.s.i.g. steam pressure.
The composition can be dispensed in a single ampule for use
in multiple dosages or it can be dispensed in 10 or 20
individual ampules for use as a single dosage unit~
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