Note: Descriptions are shown in the official language in which they were submitted.
z6~49L 02JB/87
B~ 18957/77
This invention relates to new pyranoquinolinone derivatives,
composi~ions containing them and methods -for thsir prepa~ation.
~cording to our invention ~e provide compounds of formula I,
R
8 Rg
in which an adjacent pair of R5, R6, R7 and R8 form a chain
-COCH= OE-0-, and the remainder of R5, R6, ~ and R8, which
may be the same or different, each ~epresent hydrogen, hydrox~,
-) ~ alkyl, halogen~ alkenyl, alkoxy, or - ~ ~ in which ~ and ~ ,
which are the same or different, are each hydrogen or alkyl,
Rg is-hydrogen, alkyl, alkenyl or phenyl-alkyl, and :~
E is -COOH, a 5-tetrazolyl group or an (N-tetrazol-5-yl~
car~oxamido group,
and pharmaceutically acceptable derivatives thereof.
According to our invention we also provide a p~ocess for ~he
production of a compound of ~ormula I, or a pharmaceutically
acceptable derivative thereo~, which comprises,
(a~ producing a compound of formwla I in which E is -CCC~I by
se~ectively hydrolysing or oxidising a compound of formula II,
,;, " ,'.
'' ' ': ,, : ,'
,, :~, ~` :
03/B/87
- 3 - ..
R
R6a~
R8a Rg
S in which Rg is as defined above,
R5a, ~a, R7a and R8a have the sa~e significances as R5,
R6, R7 and R8 above, save 1:han an adjacen,t pair of R5aJ R6a, R7a
i,
- and ~a may represent a chain of ~ormula -OOCH-C~Dl)O, and
one or both of D and Dl represents a group hydrolysable or
oxidisable to a ~ group, and the other may represent a -COOH
grou~ 9
~b) producing a co~olmd o:f fonmlla I ~n which E is -COCH by
cyclising a con~pound of fo~la III or IVJ -~
~5b
1- ~b III
Rg
Rb
~0 5
R6b ~ ~COC~I
R7b ~ ~ COOH
~8b Rg
25or all ester of ei~er thereo~,
-- 3 -- -
04/B/87
4 -
.
in which Rg is as defined above,
R5b, ~ b, ~ ~nd ~ have the sam~ significances as R5, R6,
'~ R7 and ~ abo~e, save that an adjacent pair of R5b9 R6b7 R7b an~
~b may represent ~he pair of groups -H and -O-C~GOOH)=CH-oOOH,
(c~ producin$ a compound of formula I in which E is -COOH by
cyclising a compound of formula V,
:, .
~ ~ R5c o
lo .J~;J~, co~ V
:~` ' R8C Ig
`~
or an ester thereof,
m which Rg is as defined above,
.~ .
~C9 ~C, R7c and R8c have ~he s2me signi~icances as R5~ Rs,
. 15 ~ and ~ above sa~e that an adjacent pair of R5c, ~ c5 R7c and
~ c, instead of forming a chain -COCH=C(oOOH)-O-~ represent the
: pairs of groups: _ _
ti~ - ~ OO-COR~' or -OOCH=CtOOOH)-NLlL2, or a sui~able
; derivative thereof; and -CM or a halogen atom, or
(ii) -H and -O-C(~OR")=CH-OOR"
~" represents -CM~ or a group which is hydrolysable thereto,
and L2 ~hich may be the same or different are each
hydrogen, aryl or alkyl9 or together form a saturatea or
unsaturated alkylene chain, and
M represents hydrogen or an al~ali metal,
05/B/87 ;
6~ .
- 5 -
: and if necessary or desired hydrolysing the group -COR", to :
a group -COOM,
~d) con~ersion of a compound of for~ula Vl,
d ~ ~ O
E Vl
d Rg
or an ester thereof,
in which Rg and E are as defined above,
R~d, R6d, R7d and R8d have the same significances as R5, R6,
1?7 and R8 above save that an adjacent pc.ir of R~d, R6d, R7d and
d ~ay represent ~he chain -C(~o)CH=cE-o-,
at least one of the pairs of groups ~ and Rlo together
15 forn a =S or together ~orm an -S(~)nS- chaLn in which n is 2
or 39 .~nd the other pair ~ , ~ O may lepresent =0,
~o a corresponding compound of formu~a I,
~ (e3 selecti~ely removing the group5 A and B from a compound o~
- ~ormula VII; ~ e O
~ e ~ - H VII
R8~ Rg
or an ester thereof~
in which Rg and E are as defined above,
~ 5 -
r~ ' .
,,, , , ,.' , .
06/B/&7
,
=~_
.
R5e, R6e, R7e and R8e have the same si ~ -~icances as R5, R6,
and ~ above save ~hat an adjacen pair of R5e, R6e, ~ e and
e may represent a chain -00CHA-CBE-0-7
in at least one o~ the pairs of groups A and B both A and B .
~; 5 a~e hydrogen, or one of A and B is hydrogen and the o~her is
halogen OT hydroxy9 and the o~her pair A5 B may together form a
douhle bond,
(f) producing a compound of ~ormula I in which F. is -COOH by .
- ~yclising a compound of ~ormula VIII,
~ ~CiOIl VIII
or an es~er thereof~
in which Rg is as def m ed abuv~ f, R6f~ R7f and ~ f have
the same significances a~ R5, R63 R7 ~nd R8 above save~hat an
adjacent pair of R5f, ~Of, ~ f and ~ f, ~ tead of forming a chain
-COCH=C(COCH)-O-, represen~ ~he pai~ of groups -CoCH(S0 ~ 0~-
CH(OH)-oOOR" and -CM,
~" and ~ are as defined above, and
~ 0 represents an alkyl C 1 to 10 group,
(g) producing a compound of formula I in which E is a 5-tet~azolyl
group by reacting a corresponding compound of formula I in which
E is -CN.
,, , , , , ~ - ,
07/B/87
-- 7 --
with an azide in a solvent which is inert under the reaction
: conditions,
(h) producing a compound of formula I in which E is an (N-tetra-
zol-5-yl)carboxamido group by reaGting a corresponding compound
; 5 of formula I in which E is -COOH, or an acid halide, ester or
mixed anhydride thereof,
with 5-aminotetrazole, or
(i) producing a pharmaceutically acceptable salt of a compound
of formula I, by treating a compound of formula Ic,
13
R7~ ~ ~ X
R~j Rg
in which Rg is as defined above,
R5j~ ~6i, R7j and R8j have the same significances as R5, R6,
R7 and R~ above, save that an adjacent pair of R5j, R6j, R7j and
R8j may form a chain -O-C(X)=CHCO-, and
X is a 5-tetrazolyl group, an (N-tetrazol-5-yl) carboxamido
group, a carboxylic acid group (or an ester thereof, or another
salt thereof), a nitrile group, an acid halide group or an amide
group,
with a compound containing an available pharmaceutically
acceptable cation and capable of converting the group X to a
pharmaceutically accep-table salt of group E,
and if neeessary or desired hydrolysin~ the ester of the
compolmd of formula I and/or converting the compound of
formula I to a pharmaceutically aceeptable derivative thereof.
- 7 -
' ''; :; : . : '
07/B/87
- 7a -
In process (a) the group D may be, for example an ester,
acid halide, amide or a nitrile group, which may be hydrolysed
to a -COOH yroup. The hydrolysis may be carried out using
conventional techniques, for example under mildly basic
conditions, e.g. using sodium carbonate, sodium hydroxide,
sodium bicarbonate, or under acidic conditions, e.g. a mixture
of aqueous dioxan and hydrochIoric acid, or hydrogen bromide in
acetic acid. The hydrolysis may be carried out at a temperature
of from about 25 to 120C depending on the compounds used.
~lternatively the ~roup D may be an alkyl, e.g. a lower alkyl
such as methyl, a hydroxymethyl, an aralkenyl, e.g. styryl, an
acyl, e.g. a lower alkanoyl such as acetyl, or a formyl group. -;
The oxidation may be carried out using conventional techniques ~;-
which do not otherwise modify the molecule to such an extent
that the yield of the desired product is uneconomical, for
example an . . . . . . . . . . . . . . . . . . . . . . . . . .
- 7a -
..... ,:
..~ .
"
... ..
08/B/87
64~4
alkyl or a hydroxy~e~hyl group may be oxidised using selenium
: dioxide, e.g. under re1ux in aqueous dioxan; or chromic acid,
- e.g. under reflux in aqueous acetic acid. Aralke~yl groups may
be oxidised using~ ~or ex ~ le neutral o~ alkaline potassium ~:
5 pe~manganate in aqueous ethanol, and aey7 groups may be oxidised :
using, for example c~romic acid or a~ aqueous hypochlorite, e.g. .
sodium hypochlorite. The formyl group may be oxidised using,
. for example ~hromic acid or silver oxide.
In process Cb) ~he eyclisation may ~e carried out by treating
the compound of formula III or IY, with a cyclising agent, for
example a dbhydra~ing agent such as chlorosulphonic, sulphuric
o~ polyphosphoric acid. The reaction is preferably car~ied out
under anhydrous conditions and may be carried out at a temperature
of from abou~ 25 to 150, and preferably from 75 to 150C~ We
have found that isomerisation of *he maleic acid der;vative of
foxmula rv to the corTesponding fumarîc ad d derivati~e of . ...
formNla III *akes place when polyphosphoric acid is used to
cyclise ~hese co ~ unds to a compound of ~ormula 1, ~hus enabling
a satisfactory yield of the compound of formula I to be obtained
from a ~ facie unsatlsfactory mixbure of s~mpounds of
fo~mulae III and rv. Compounds of formula III ma~ also be cyclised
by subjecting the compound to an ele~ated temperature, e.g. of from
200 to 250C, optio~ally in the presence of a hi~h boiling solYent
which is inert under ~he reaction conditions, e.g. diphenyl e.~her~
: 25 When one of the groups is -oM the ~yclisation of p~ocess
-- 8 ---
09/~/87
:~ - 9 - :
tc)ti) may be carried out by heating, or under basic or neu~raI
conditioDs. It is however preferred to carry out the cyclisation
in ~he presence of an acid~ e.g hydrochloric acid, and in a
solvent which is inert under the reacti~n conditions, e.g ethanol~
The reaction may be carried out at from about 20~ to 150C The .
group -COR" is preferably an ester group, e.g R" may be a lower
alko~y group. When one of the groups is COCH=C~COOH3-NLlL2 the
deriva~ive o~ the -COOH group may be a group -CONLlL2 in which L
and L2 are as defined above. It is preferred that Ll and L2 are
hyd~ogen~ phenyl, alXyl C 1 to 6 or together form a 4 or 5
- membered alkylene chain, e.g. together with the nitrogen atom
foTm a piperidine ringO When one of the gro ~ s is halogen the
- cyclîsation mar be carTied out in a solvent which is inert und~er
the reac~îon conditîons, pre~erably a high boiling polar solven~; -
e~g pyridine, dimethyl~ormamide or hexamethylphssphoramide. The
: neactîo~ is preferably carried out wn~h ~he aid ~f a strong base,
~or example a~ alkali m~tal-hydride, e.g sodium hydride~ me ~~- ~ -
eaction is prefera~ly carried ou~ at a temperature of from about
80 *o 200C, In ~he absenre of ~ree oxygen, e.g under an inert
atmosphere .such as nitrogen. ~-
lhe cyclisation of process (c~ (ii) may be carried out by
treating the compound of ~ormula V wqth a cyclising agent7 for
example a dehydrating agent such as chlorosulphonic~ polyphosphoric
or sulphuric acid. The reaction is pre~eTably carried out under
anhydrous conditions and may be carried out at a temperature o~
- 9 -
....... , . . ~ . ~
. : ~ . . ... ~ ~
:: :
10/B/87
rom 0 to 1Q0C. Alternatiyely cyclisation may be achieved by
converting the free carboxy groups of ~he co~pound of formula V
to acyl halide groups and subjeting the resulting acyl halide *o
an intramolecular Friedel-Crafts reaction.
In processes (d), when ~ and ~ O together forn a cha m -S-
( ~ 3~-S-, ~he conve~sion may comprise oxidative hydrolysis and
may be carried out in an aqueous polar organic solvent, for
example aqueous ethanol, acetone or tetrahydrofuran. The
oxidati~e hydrolysis may be carried ou~ in the presence of an
oxidising agent, for example mercuric chloride, an N-halosuccin-
imide such as N-brono- or N-chloro-succinimide, a per acid such
as periodic acid; or ~-toluenesulphonchloramide or a salt
- thereof. When mercuric chloride is used the reaction may b~
carried out in the presence o a base, e.g. mercuric oxide,
cadmi~n carbonate or calcium carbonate. N-halosuccinimides may
be used alolle or in the presence of a sil~r salt, e.g. silver
perchlorate, or sll~er nitrate. The reaction ~ay conveniently
be carried out at a temperature of from abou~ 15 to 100C.
When ~ and ~ 0 together form a =S group the conversion may
co~prise (oxidative) hrdrolysis and may be carried out in the
presence of a heavy metal compound, e.g a compound of group Ib~
IIb or IIIb of the Periodic Table of Mendeleef, as catalyst.
Suitable compounds include mercury, ~hallium and sil~er compounds,
e.g. mercury (II) acetate or chloride, ~hallium (III~ trifluoro-
acetate, or silver oxide. The reaction may be carried out in the
` '' ' ' " ' ~
' '' ' ' ~
ll~B/87
presence o water and an organic sol~ent system such as acetone-
acetic acid9 alkanols,-tetrahydrofuran/methanol, or tetrahydro-
furan. Alternatively the ~eaction ma~ be carried out by alkylation
~ollawed by hydroly~is. In such cases the reaction may be ef~ected
5 by (i) an alkyl halicle or sulphonate (e.g. methyl iodide~J in a
moist solvent, e.g. acetone, (ii~ an alkylfluorosulphonate and
water m sulphur dioxide, or (iii) a trialkyl oxonium fluoroborate
followed by aqueous sodium hydroxide.
~hen both A and B are hydrogen process (e) is a
dehydrogenation and may be carried out by oxidation using a nald
oxidising agent~ ~or example selenium dioxide, palladium blac~
chloranil, lead tetraacetate or triphenyl nethyl pe~chlorate.
Alternatively the dehydI~genation of a compound of formwla VII in
which both A and B are hydrogen may be carried out indirectly by
15 halogenation ~ollo~ed by dehydTohalogenation, e.g. by treatment
with N~brom~succinimlde or pyridim um bromade perbromide ~o yield
a compound of fo~mula VII in which A is halogen and B is hydro~en,
~hich is subsequen~ly dehydrobromanated. I~hen one of A and B i5
hydroxy ~he dehydration may be catalysed by an acid, e~gO sulphuric
or oxalic acid; a base, e.g. potassium hydroxide; or a salt,
e.g. potassium hydrogen sulphate; or N b~omosuccinimide. The
reaction may be carried out in a solvent which is mert under
the reaction conditions7 e.g. a halogenated ~ydroca~bon, xylene,
or glacial acetic acid. The reaction may be carried out at an
elevated temperat-ure, e.g. ~rom 20 to 150C.
. .
,
12/B/87
12 ~L~L2 6~
The cyclisa~ion o~ process (f3 may be carried out in a
solvent which is inert under the reac~ion conditions9 e.g.
diethyl e~her or benzene. The reaction may also, if desired, be
carried ou~ in the presence of a Lewis acid, e.g. boron
5 trifluoride. The reaction is preferably carried out at a
temperature of from 10 to 120~ in presence of an organic base,
.g. piperidene.
Suitable solvents which are inert under the reaction conditions
of process (g) include those in which both the reagents are soluble,
e.gO N,N-dimethylformamide. Other solvents which may be mentioned
include dimethylsulphoxide, tetrahydro~uran~ diethyl glycol and
ethyl me~hyl glycol. The reaction is pre~erably car~ied out at a
temperature of from about 20 to 130C ~or from about 1 to 20 hours~
~he azide used in ~he reaction is preerably ammonium or an alkali
15- metal azide, e.g. sodium or lithium azide~ but other azides, e.g.
alumlnium azid~ or the azides of nitrogen cont ~ ng bases9 eOg.
m~no-, di-, tri-, and tetra- me~hyl- ammonium, anilinium~ _
mDrpholinium and piperidinium azides, may also be used i~ desired.
Where an azide other ~han that of an alkali metal is used ~his
~0 azide may be pTepared in the reaction m~xture by double decomposition.
The ~eaction ma~ desired, be carried ou~ in the presence of an
~lectron acceptor, e.g. aluminium chloride, boron trifluoride,
ethyl sulphonic acid or benzene sulphonic acidO As an alternati~e
to the reaction con~;tions se~ out above, the reaction may be
carried out using hydrazoic acid ~hydrogen azide) at a temperature
- 12 -
- .,
.
` , ;
.
', "~ ~'
13~B/87
~2~
- 13 -
of from about 20 to 150C in a suitable solvent~ under greater
than abmospheric pressure. When an azide other than hydrazoic acid
is used, e.g. sodium azide, the product of the reaction will be
the corresponding tetrazole salt. This salt may rea~ily be
converted to the free acid by treatment with strong acid, e.g.
hydrochloric acid. ;
In process Ch3 the anhydride is preferably a mixed anhydride
o such a ~ype that it will cleave preferentially, to give the
desired chromone carboxamidotetrazole, as the major product when
reacted wi~h the S-aminotetrazole. Examples of suitable acids
from which the mixed anhydride may be derived are sulphonic
acids e~g. benzene sulphonic acid, sterically hindered carboxylic
-~` acids, e.g. pivalic, iso~aleric, diethylacetic or triphenylacetic
acid, and alkoxy formic acids, e.g. a lower alkoxy formic acid
such as ethoxy or isobutoxy formic acid. When an acid halide is
used it ma~ co~veniently be an acid chloride. The reaction is
preerably carried ou~ under anhydrous conditions in a solvent
which will not react wi~h either the S-an~note~razole or the
mLxed ~ydride or acid halide~ e~g. pyridine or dimethylfo~mamide.
; 20 H~we~er when the reaction is carried out in a non-basic sol~ent7
e.g. dimethyl~ormamide, an adequate proportion of an acid
- acceptor, e.g. triethylamine, should also preferably be present.
The reaction is preferably carried out at a temperature of from
about -15 to ~20~C. When an ester is used we pre~er to use a
lower alkoxy ester and to carry out the Teaction in a solvent
- 13 -
- - - -:
,
~4/~/~7
6~ :
- 14 -
which is inert under the reaction conditions, e.g. glacial acetic
acid, at a temperature of from about 100 to 150C. When a
compound of formula I m which ~ is -C~OH is used as startLng
ma~erial the reaction may be carried out by heating ~he compound
of formula I and the 5-aminotetrazole in a solvent which is ineTt
under the reaction conditions, e.g. dimethylacetamide9 at a
temperature of ~rom 100 to 200C. Alternatively the reaction
may be carried out in ~he presence of a condensation agent, e.g.
N,N'-carbonyl-diimidazole or dicyclohexyl carbodiimide, in an
ap~otic solYent, e.g. dimethylfo~mlmide~ at a temperature o from
about 10 to 40C.
The starting materials Eor process tb) may be made by reacti~g
l a compound of formula IX,
Rsb
R~b
^ ~b
in which R~ ~b, R6b~ ~b and ~b a~e as defined abovep with
a compound of formula X,
Da-C-C-Da X
,~ ,
in which Da is an ester group~ ~
to produce a mixture o~ compounds of formulae XI and XII,
, .. _, .. , ,. , , ; ,, ,; , ; ~
:- ,. , - .
:- .:
.. .
~, ,: : , :,
.. ..
. . .
, :
:,:
15/B/87
~ 15 ~ 64~L :
R5b R b
R b X~)~`N~ Da R b ~3" N 3~~a
~8b ~ Rg
in which Rg, Da, ~b, R6b, R7b and ~ b are as defined aboYe. :
lhe compounds of formula XI and XII may be hydrolysed to give ~:
compounds of formulae rv and III. Alternatively the groups Da :
In the compounds of ~o~mulae XI ~nd XII may be converted using
conventional techniques kn~wn ~ se, to other groups D and the
resulting compounds cyclised, using thQ same conditions as -for
process ~b3 above, to yield a co~pound of formula II. As a further
and preferred alternative the compounds of formula XI and XII may
be cyclised, using the same conditions as for process ~b~ above,
to give a compound of formul~ II in ~hich D is an ester group, and
the resulting compound of ~ormula II is used itself in process (a),
or the D group con~erted to another gr~up Dg e.g an acid halide,
amide or nitrile group, using techniques knolYn ~ se.
The ~nara~e isom~r of fo~la XII (or ~e corresponding
compound ~n which D~ has been converted to D3 is the only isomer
which can cyclise to give the required compounds of ~ormula II.
The propo~ti~n o~ ~he ~Yo isomers may be ~eadily determined by
: nuclear ~agnetic resonnance spectrosccpy and ~e have found ~hat,
in general, ~he desired fumaric acid derivative is only a minor
proportion of the mixLure of isomers obtaîned from the reaction.
- 15 -
'~ ' ' "'. ' i~ ~ '
.. , ~ , " " :
. '~ '
16/~/87
16
The compounds Of formula V, in ~nich an adjacent pair of R5c,
R6c, R7c and R8c represent ~e groups -COC~12COCOR" and ~(~ or .
halogen~ may he made by reacting a compound of formula XIII~
S 6g ~ O H XIII
, - R~g ~g
or an ester ~hereof,
in which Rg is as defined above j
and ~g, ~g~ R7g and R~g have ~he same significances as R5,
and RB above, save that an adjacent pair of R5g~ R6g~ R7g and
R8g, instead of forming a -COCH=CHtCOOH)-0- chain, represent the ~:
~ groups -COCH3 and ~1; or halogen~ in ~l~ch M is as defined above,
; 15 with a compound o formula XIV~
RtCZ-C~R" xrv ~. ...... .`
:; in whi~h R~ is as de:fined above,
R9 is a suit~ble leaving grouP, e.g an alkoxy, halo, amino~
alkylamino, slibstituted zmLnO (a.g an arylsulphonylamino grol~?)
or substituted alkylamino group, reactive with the carbanion of
the -COCH3 group of the compound of formula XIII, and
-each Z is a carbonyl oxygen atom, or one Z may represent two
halogen atoms and the other a carbonyl oxygen atom,
and if necessary hydrolysing the resulting compound to a
: ....
:~
....
.: ., ~
''~ ' " .. , '' , ,
17/B/87
~Z6~
compound of formula V. The preferred compounds of formula XIV
are dialkyl oxalates, e.g. diethyl oxalate.
Compounds of formula V bearing a -COCH=C(COOH)-NLlL2 group,
or a derivative thereof, may be made from known compounds in one
or more steps using processes known per se.
The Compounds of formula II may be made as described above
or by a process analogous to process (c)~i).
Alternatively the compounds of formula II may, for example
in the case of the acid halide, the amide and the nitrile, be
made from compounds of formula I using conventional techniques,
e.g. reaction of an ester of the compound of formula I with
ammonia to produce the amide, followed by dehydration of the
amide to form the nltrile.
The compounds of formula V carrying substituents -H and
-O-C(COR''~=CH-CORI' may be made by xeacting a compound of
formula XV,
R h O
R6h ,~N ~L COOH XV
7h
R8h R
:~ g
or an ester thereof,
in which Rg is as defined above, and R5h, R6h, R7h and R8h
have the same significances as R5, R6, R7 and R8 above, save that
an adjacent pair of R5h, R6h, R7h and R8h, instead of forming a
-COCH=C(COOH)-O~ chain, O . . . . . . . . . . . . . . . . . . . .
~ 17 -
,. ; ,, ",. .. ..
.
.
,,
18/B/87
6~
- 18 -
Tepresent ~he groups -H and -OH,
with a dialkyl acetylene dicarboxylate, Ln co~ventional
manner, followed i.f necessary by hydrolysis of the reaction
product.
S Compounds o formula VIII may be made by reacting a compound
of formul~ XV~,
R5i o
R7i~ COOH
. Rg
or an ester thereof,
:1 in which Rg is as defined above7
i and R8i have the same significances as R59 ~ ,
R7 and ~ -above, save that an adjacent pair of R5i, R6i, ~i and
R8i, mstead of formcng a chain -COCH-C(COOH~-O-,i~epYesent the
.~ . .
pai~ of gTOUpS -OH and -COC~Alkyl,
with a methyl alkyl sulphoxide anion, e.g. the anion of
dimethyl sulphoxid~,
~:. 20 and ~eacting the resulting _-hydroxy-2~a1ky1sulphinyl c pound
with glyoxalic ad d or an ester ~hereof.
:.~, .The ompounds of formula I in l~hich E is -CN may be made by
dehydrating the corresponding pyranoquinolinone amide using, ~or example,
phosphorus oxychloride, as dehydrating agent. The reaction is
preferably carried out using at least one molar equivalent of
- 18 -
, ~ , , , , ~
, " : " . .-
:: ~ : , .,
',.".: ., :: ."
l~/B~87
2~
- 19 - -
dehydrating agent per mole of the pyr~noquinolinone amide. Where the
dehydrating agent reacts with one of ~ , R6, ~ or R8 ~e.g. a
substituent comprising an -OH group) suficient dehydrating agent
should be used to satisfy the side reaction as well as the main
reaction. The reaction may, if desired, be carried out in the
presence of an acid binding agent, e.g. triethylamm e, The Teaction
may be carried out in the presence of a solvent, e.g. N,N-dime~hyl-
~orm~mide, dimethyl sulphoxide, pyridine, benzene or hexamethyl
phosphoramade, or an excess of the dehydrating agent may be used
~; 10 as the reaction medium. The reaction may be carried out at a
temperature o from about 0 to 200C depending on the dehydrating
agent used. When phosphorus oxychloride is used a temperature
of from 0 to 100C is preferred.
The chromone amide starting materials may be made by
reacting a corresponding pyranoquinol~nonè ester ~ith ammonia, using
techniques con~entional in the production of amides rom esters9
e.g. using an alkanol as solvent at a temperature of 0 to 120C.
Conpo~ds of ~rnwlae VI, VII, IX, XIII~ XIV, XV and XVI are
- either known or may be made from Xnown COmpQUlldS using conventional
techniques known ~ s~.
The processes as described above may produce ~he compouna of
.
- form~la I or a ~erivative thereo. It is also within ~he scope
of this inventio~ to treat any derivative so produced to liberate
the ~ree compound of formula I, or to convert one derivative into
another.
lg - .
,,~.
.'~
. "~ - :
20/BJ87
~ ~Z~
- ~0-
l~e compounds of formula I and the interm~diates therefore
may be isolated from ~hei~ reaction nuxtures using con~entional -
~echniques.
: Pharmaceutically acceptable derivatives of the compounds of
~rmula I include pharmaceutically acceptable sal~s, and ~hen E
is a -CCOH group, esters and amides of the 2-carboxylic acid group.
Sui~able salts mclude ammonium, alkali ne~al (e.g sodium, potassium
and lithium~ and alkaline earth metal (e.g, calcium or magnesium)
salts~ and salts with suitable organic bases; e.g. salts with :
hydroxylamine, lower alkylamines such as methylamine or ethylamine,
with substituted lower alkylammes, e.g hydroxy substituted
alkylamines such as tris~hydroxymethyl)me~lylamine, or with simple
- nocyclic nitrogen heterocyclic compo~nds, e.g piperidine or
morpholine. Suitable esters include simple lower alkyl esters,
e.g the ethyl ester, esters derived ~rom alcohols containLng basic
groups, e.g di-lower alkyl amino substituted alkanols such as the
~-(diethylamino)-ethyl ester,-and acyloxy alkyl esters, e.g a lower
ac~loxy-low~r alkyl ester such as the pi~aloyloxym~thyl ester, or a
bis-ester derived ~rom a di-hydroxy compound~ e.g a di~hydroxy-lower
alkyl3 ether~ e.g ~he bis-2-oxapropan-1,3-diyl ester. The
pharmaceutically acceptable acid additio~ sal~s of the basic esters9
and also of those compounds in which one of ~ , R6, ~ and R8 is a
group ~ ag the hydroch~oride, the hydrobromide, the oxalate,
the maleate or the flmarate sal~s; m~y also be used. The esteTs
~ay be made by convent;onal t~c ~ ques, e.g esteri~ication or
- 20 ~
21/BJ87
21 ~ 6~41'
transesterification. The amides may be9 for example, unsubstituted
or mono- or di- C 1 to 6 alkyl amides and may be made by
con~entional techniques, e.g reaction of an ester of the
corresponding acid with ammonia or an app~opriate amine.
The compounds o~ -formula I and pha~maceutically acceptable
derivatives thereof are useful because they possess pharmacological
activity in animals; in particular they are useful because they
inhibit the release and/or action of pharmacological mediators
w~ich result from the in viYo combination o certaLn ~ypes of
; 10 antibody and specific antigen, e.g the combination of reaginic
antibody wqth speciic an~igen ~see Exampl~ 27 of British Patent
Specifisation No 1~292,601). The new compounds have also been
found to inte~fare with reflex pathways in experimental animals
and ~an and in particular those reflexes associated with lung
function. In man, both subjective and o~jective changes which
result.from the inhalatîo~ of speci~ic antigen by sensitised sub~ects
a~e inhibited ~y p~ior adm;nistration of the new compounds. Thus
the new compounds are indicated for use in the treatm~nt of
reversable airway ~bstruction and/or to prevent the secretion of
; 20 excess ~ucous. The new compounds are thus indicated or ~he
treatment of allergic asthma, so-called 'intrinsic' asthma tin which
no sensitivity to extrinsic antigen c~n be demDnstrated), bronchitis,
coughs and the nasal and bronchial obstructions associated with ~he
common colds. l~le new compounds may also be of value in the
25 treatment of o~her oond~tions in which an~igen-antibody reactions or -~^
- 21 -
.
.,,
., ~ ,
01/B/30
~ 22 ~ L~L'~6~4
excess mucous secretion are responsible for, or are an adjunct to9
disease, for example, hay fever; certain eye conditions, e.g
trachoma; alimentary allergy, e.g urticaria and atopic ec~ema; cmd
gastrointestinal conditions, for example gastrointestinal allergy,
S especially in children, e.g milk allergy, or ulcerati~e colitis.
For the aboYe mentio~ed uses the dosage administered ~nll,
o course9 vary with the compound employed, the m~de of
~dministration and the treatment desiTed However, in general~
satisEactory ~esults are obtained ~hen ~le compounds are
administered at a dosage of from 0.001 to 50 mg per kg of animal
body weight in the test set out in Example 27 o~ British Patent
Specification No lt292,601. For m~n the indioated total daily
1 dosage is in ~he range o from 0.01 mg to 1,~00 mg preferably from
0.01 mg to 200 mg and more preerably from 1 mg to 60 mg, which
may be administered in divided doses fiom 1 to 6 times a day or
in sus~ained release form. Thus unit (~sage ~orns sui~able ~OT
.
administration (by inhalation or oesophageally~ comprise from
0.01 mg to 50 mg, preferably 0.01 mg to 20 mg and more pre~erably
from 0.01 mg to 10 mg of the compound preferably admixed with a
solid or liquid pharmaceutically acceptable diluent~ carrier or
adjuvant.
. The comFounds o~ formula I, and phaTmaceutically acceptable
derivatives thereof, ha~e the advantage that they are n~re
ef~icacious in certaLn pharmacological mDdels, or a~e longer
acting than compounds of similar structure to the compounds ~f
. :
22 -
' " '~' .' ' , ~ :
1, . .
02/~/30
- 23 -~
formula I. Furthermore the compounds of formula I, and pharma-
ceu-tically acceptable derivatives thereof, are advantageous in
that they are more efficaceous in interfering with reflex
pathways and in inhibiting the ~ecretion of mucous than are
compounds of similar structure to the compounds of formula I.
We prefer each of Ry, R5, R6, R7 and R8, when they contain
carbon, to contain up to 8, and preferably up to 4 carbon atoms~
Specifically we prefer R5, R6, R7 and R8 to be selected from
hydrogen, methoxy, propyl, allyl, methyl, ethyl, chlorine, bromine
and hydroxy. The -COCH=CE-O- chain may be bonded to the benzene
ring in any sense and in any of the adjacent positions R5, R6,
R7, R8. However, we prefer the chain to ~e bonded in the positions
R6 and R7 the -O- part of the chain being in position R7. We also
prefer the group E to be a -COOH group.
According to the invention there is also provided a process
for the produc-tion of a pharmaceut:ically acceptable salt of a
compound of formula I, which compr:ises treating a compound of
formula Ic,
R5j O
R6~ ~ Ic
R8j R .
in which Rg is as defined above,
R5j, R6j, R7j and R8j have the same significances as R5, R6,
R7 and R8 above, save that an adjacent pair of R5j, R6j, R7j and
.,~-
- 23 -
. ~
' ' ' ' ;',~,
,
~3/~/30
- 24 ~
~j ~ay form a chain -O-C~X)=CHCO-, and
X is a 5-tetrazolyl group; an (N-tetrazol-S-yl)carboxamido
group, a carboxylic acid.group ~or an ester thereo~, or another
~alt thereof), a nitrile group, an acid halide group or an amide
s ~roup,
wqth a compound containing an available pharmaceutically
acceptable cation and capable of co~verting the group X to a
Fharmaceutically acceptable salt of an H group.
Compounds capable of converting the group X to a
pharmaceutically acceptable salt of an E group
include compounds, e.g bases and ion exchange resinsS containing
pharmaceuticalIy acceptable cations, e~g sodium~ potassium,
calcium, ammonium and appropriate nitrogen contain;ng organic
cations. In g~neral we prefer to form the pharmaceutically
acceptable salt by treatIng ~he free acid of formula I with an
appropriate base, e.g with an alkaline-earth or alkali metal
. hyd~oxide, carbona*e or biearbonate in aqueous solution or by a --.
m~ta~he~ical process wlth an appropriate salt. When a stronglr
basic compound~is used care should be taken, e~g by keeping the
~0 te~perature suf~iciently l~wS to ensure that the compound o~
fo i a I is not h~drolysed or o~herwise degraded. The
.
phanmaceutically acceptable salt may be recovered from the
reaction maxture by~ for example, solvent precipitation and/or
removal of the solvent by evaporation, e.g by reeze drying.
According to ou~ invention we also provide a pharmaceutical
:~ - 24 - .
~. :
:::;. :: ~ :i:; . . .: "
, : :, .: '
' ~' '. ' :
:'': ., . :. :~
04/B/30
25 -
composition comprising (preferably less than 80~, and more
preerably less than 50% by weight~ of a compound of ~ormula I, or
a pharmaceutically acceptable derivativ~ thereo-f, in combination
~ h a pharmaceutically acceptable adjuvant, diluent or carrier.
Examples of suitable adjuvc~nts, diluents or carriers are:- for
tablets capsules and dragees; microcrystalline cellulose, calcium
phosphate, diatom~ceous ear~h, a sugar such as lactose, dextrose
- or mannitol, talc, stearic acid, StarGh, sodium bicarbonate and/or
gelatin; ~or suppositories, natural or hardened oils or waxes;
and for inhalation compositions, coarse lactose. The compound of
~ormula I; o~ the pharmaceutically acceptable deri~ative thereof,
preferably is m a form having a mass median diam~ter o from 0.01
to lO mQcrons. The compositions may also contain suitable
preserving, stabilising and w~tting agents9 solubilizeTs,
sweetening and colouring agents and ~avourings. The co.~positions
may1 if deslred7 be formulated in sustained release form. We
prefer con~osîti~ns ~ich aIe designed to be taken oesoq?hageally
and to r~lease their contents in the gastrointestinal tract. r~
The 5-tetrazolyl and (N-tetrazol-S-yl)car~oxamido groups are
of orm~1ae XVII and XVIII respecti~ely,
`
XVII - C \ ll CONH~ XVIII
N - N N
. ~ I
H H
, ~ ` .
- 25 -
,
05/~/30
644
- -26 -
The group5 of ormu1ae XVII and XVIII may exist in tautoneric
forms and such tautomeric forms are in d uded within the
defini~ion of the compounds of formula I.
~ le invention is illustrated, but in no way limited by the
following Examples.
le 1
4 6 Dioxo-10 o 1-4H 6H- ano C3,2-~ 7 uinoline-2,8-dicarboxylic acid
9 ~ py / pyr _ c> q -
(a) 4 Acetamido-2-allyloxyacetophenone
4-Acetamado-2-hydroxyacetophenone (19.3g) allyl bromide ~12.1 ml~
and anhydrous po~assium carbonate (21.$g~ were stirred in dry
dimethylformamide (250 ml) at room temperature for 24 hours. The
reaction mixture was poured into water and ~he product was extracted
with e~hyl.acetate. The organic solution was ~hen washed well wi~h
water dried over magnesium sulphate an~ evaporated to dryness. The
su~-title product was obtained as buf coloured solid (20.Sg). The
structure of the product was confirmed b~r N~IR and mass spectroscopy~
tb) ~ =~
The above allyl ether (18.4g) was hea~ed at Z00-210C for 4
hours. 17~1g of the thermally rearranged sub-ti le product was
obtained as brown solid~ Again ~he structure was confirmed by
MR and mass spect~oscopy.
~c) 4-Aceta~ido-Z-hydroxy-3-p~Ey-~acetophenone
The product of step (b~ (17g) was dissolved in glacial acetic
acid and hydrogenated in the presence of Adans catalyst ~til
-~ 25 hydrogen uptake had ceased~ The catalyst was filtered off through
- 26 -
':
06/B~30
2~
- 27 -
a kieselg~r filter and the filtrate was evaporated to leave 13.0g
o allnost colourless solid. The mass and ~IR spectra confilmed
t~e struc~cure of ~he product.
(d) E~2~1 7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carbo~ylate
A n~xture of diefflyl oxalate ~19.3g; 17.9 ml) and the above
product of step tc) (12.4g) in dry ethanol (100 ml~ was added to
a stilTed solution o sodi~ e~oxide in et:hanol (prepared by
dissolving sodi~n (6.1g) in dry ethanol ~200 n~)). The reaction
mLxture was refluxed for 3 ho~s and ~hen poured into dilute
hydrochloric acid and chloro:Eorm. The chloroform layer was separated"
washed with wate~ and dried. The solvent was evapora~ed to leave
a br~: solid which wa~ dissolved in ethanol t3Q0 m~) contai~ing
concentrated hydrochloric acid t3 n~) and the ~ole was reLuxed
~or 1 hour. lhe ~eaction mixture was poured into wa~er and t~he
~: 15 product was extTacted into ethyl acetate which was washed with
~ water aIId dried. l~e solvent was evaporated to leave 10 g of a; sticky solid whiçh had n~ss- and NMR spectra consistent with the
expected product.
~ (e) Eth ~ am mo~4-oxo-8~E~eyl-4H-l-benzopyr
- 20 A solution of the amide of step (d) (lOg) in ethanol ~300 m~)~
contaLning concent~ated hydrochloric acid ~5 ~1), was refluxed
fiDr 8 hours. The Teaction mixture was diluted with water and
extracted into ethyl acetate. The extract was washed ~ith water,
dried and the solvent was evaporated to leave a dark ~rown semi-
25 solid. This was chromatographed o~ a silica gel column, using
~ 27 -
,
,
07~B/30
- 28 ~ 64~
ether as eluant to give 4.8g of the required product whose structure
w~s confirmed by mass and NMR spectral evidence; mp 84 87~C.
~f) 8-Ethoxycarbonyl-2-me~hoxycarbonyl-476-dioxo-10-propyl-4H,6H-
pyranoL3 ,2-g~q linoline
The amino benzopyran of step ~e3 (2.0g) and dimethyl acetylene
dicaTboxylate ~1.24g; 1.01 n~) were refluxed ~n ethanol ~30 ml) -for
26 hours. The reaction maxtllre was cooled to 0C and the insoluble
yellow-brown solid was collected by filtration and washed wqth a
little ethanol and dried to gi~e 2.0g of a product which was a
-mixture of maleic and ~umaric este~s obtained ~y Michael addition
of the amine to the acetylene.
This mixture of esters t2.0g) was treated with polyphosphoric
1-- acid (30 ma~ and heated on the stean bath with stirring for 20
m~nutes. The reaction mix*ure was then poured onto ice and stirred
with ethyl aceta~e. The organic layer w s separated~ washed with
~; water and dried. The solvent was evaporated ~o leave ~6g of a
yel~ow o~an~e solid. P~c~rstallisation of ~is solid from e~yl
aceta~e gave the ~equired product as fluf~y orange needles
np 18Y-1~8~C.
~0 ~al~
F~nd: C~ 62~0~o; H3 5.1%; H, 3.7~0
C2 ~ 9N7 Required: C 62.3~; H, 4.9~; N, 3.6~
(g) ~,6-~ioxo-10-propyl-4H,6H-pyrano~ 2-g7quinoline-2~8-
_carb~n~lic a~d
The above bis ester (2.5g) was ~efluxed w~:h sodium bicarbona~e
, .. .
- 28 -
, , . :,
, .; , : .
:, ' ,
087B/30
- 29 ~ ~L~L~ 44
~1.64g) in e~hanol (100 ml) ~nd water ~50 ml) for 12 hours. The
~hole was poured into water and acidified to precipitate a
gelatinous solid. This was collected by filtration, refluxed
with ethanol and the protluct was separated by centri~ugation (1.4g)
mp 303-304C dec. The s~ructure of the product was confirmed by
mass and Nh~ evidence.
~h) sodium 4,6-dioxo-10~ 4H,6H-E~ran L~3,2-g 7quinoline-
- 2,8-di.carboxylate
The bis acid from step (g) (1.35g) and sodium bicarbonate
(0.661g) in water ~150 ml) were warned and stirred until a clear
solution was obtained~ This solution was filtered and ~he filtrate
was ~r~eze dried to give 1.43g of the required disodium salt~
Analysis
Found: C, 46.1~; H, 4~0%; N~ 2.9
~ 7~ 1NO7Na2 12.5~ ~ 0 requi~ed: Cg 46.1%; H~ 3.8%; N, 3~15
` Ex~ple 2
4~Dioxo- thyl-10-propyl-4H ~ -g 7quinoline-2,8-
car~oxylic acid
~a) 4-tN Acetyl-N~ethyl)~nino-2-allyluxyaoetophenone
~ 20 4-~N-acetyl-N-ethyl~amino-2-hydroxyacetophenone (92~6g), allyl
: bromide (51 m~s~ and anhyd~ous pvtassium carbonate ~90.4g) were
stirred in dry dimethylform~mide ~500 n~s) for 17 hours. The
reaction mixture was poured into water and the produc~ was
ext~acted with e~her. The organic solution was then washed well
with water, dried over magnesium sulphate and evaporated to
- 29 -
' '/ ' ' ~ `" ` ' ' ~ . , ,
09/B/30
- 30 -
dryness. The product ~as obtained as an oil (102.5g). ~he
st~ucture of the product was con~irmed by NMR and mass
spectroscopy.
Cb) 4-~N-A~etyl-N-e~hyl)amm o-~propyl-2-hydroxyacetophenone ,
The allyl ether product of step (a) (lOO.Sg) was refluxed in
diethylaniline (300 nls) for 3 hours. The reaction mnxture was
cooled and poured into dilute hydrochloric acid and extracted
into ether, ~lich latter was washed with dilute hydrochloric acid,
and ~hen with water. The organic solution was extracted with 10
sodium hyd~oxide solution which was then acidified. The
precipitated product was extracted with e~her which was dri~d
-over mag~esiu~ sulp~ate. The resulting ethereal solution was
evàporated ~o dryness to give a yellow-brown oil C78.7g~ This
oil was a n~xture of 4-~N~acetyl-N-ethyl)amino-3-allyl-2-
. .,
hydroxyacetop~enone and 6-QN-acetyl-N-~thyl~amino-3-allyl~2-
hydroxyacetophenone.
This mixture was dissol ~ d in ethanol (500 nls) and glacial
acetic acid ~20 mls) and hydrog~nated ~n the pTesence of Adams
catalyst until hydrogen ~p~ake had c~ased. The catalyst was
~ ,
filte~ed of~ ~hrough kieselguh~ and ~he filt~ate evaporated to
leave 79.9g of brown oil. Ihis brown oil was a mixture and was
separated by hi~h pressure liquid chromatography using
etheT/petroleum ether ~1:1) as solvent to give 44.2g of the
sub-title conpound and 23.8g of 6-~N-acetyl-N-ethyl)amino-3-
propyl-2-hydroxyacetophenone.
- 30 -
, . . .. ~
10/B/30
~%~
- 31 -
(c~ 4-N-Ethylamino-~propyl-2-hydroxyacetophenone
4-(N-Acetyl-N~ethyl)amino-3 propyl-2-hydroxyacetophenone
(44g) was refluxed in 48~ hydrogen bromide in glacial acetic acid
; (100 mls), glacial acetic acid (S00 mls) and water (20 mls~ for
6 hours~ The reaction ~ixture was poured on to ice-water and
extracted with ethyl acetate which was washed with water, sodium
bicarbonate solution, then water again and dried over magnesium
sulphate. The organic solYent was evaporated to dryness to leave
the sub-title compound as a red oil (34g). The structure was
confirmed by NMR and mass spectroscopyO
(d) Me~hyl 6-acetyl-1-ethyl-7-~y_roxy-4-oxG-8-propyl-4H-
uinoline-2~carbo~y_ate
he amine product oL step ~c) (17g) and dime~hacetylenedi-
carboxylate tll.3 mls) were re~luxed ~l e~hanol (300 mls) for 17 hrs.
The reaction mixture was cooled and evaporated to dryness to leave
a deep red oil. Thi5 oil was chromatographed on a silica gel
-~ column using e~her/pe~roleum ether (1:1~ as eluant to give l9.1g
of dimethyl l-t4 acetyl-3-hydroxy-2-propylphenyl~-N-ethylamino-
maleate, m.p. 83~87C.
The maleic ester (Sg) was heated and s~irred in polyphosphoric
acid ClC0 mls) on the steam bath for 10 minutes. The reaction
m~xture was cooled and poured on to a mixture of ice-water and
ethyl acetate. The organic solution was separa~ed-, washed with
water and dried ove~ magnesium sulphate. The solvent was
evaporated ~o dryness to lea~e a pale yellow solid. lhis
- 31 -
'' ~, '
ll/B/30
26~
-- 32 --
product was purified by high pressure liq~id chroma~ography
to give 2.6g of the sub title compound m.pD 121-123C.
An~ysis
Found: C: 65.5~ H; 6.6% N; 4.2~
C18~21N05 Requlred: C~ 65-3~ H; 6~34% N; 4.23%
~e~yl 6-acel~ ethyl-5-hydro~y-4-oxo-4H-quinoline-2-
ca~boxylate was obtained from the purification as a pale yellow
solid (100 mgs).
(e)
qwnoline-2,8-dicarboxylate
The hydroxy keto~e product of step ~d) (l.Og) and diethyl
~!`, oxalate (3.3 mls) in dry dimethylformamide (25 mls) were added to
; ether washed 50% sodium hydride (0.581g~ in dry dimethylformamide
~, . , . ~
C20 mls) and the reaction mixture stirred for 4 hou~s. The
~eaction mdxture was then poured into water,acidîfied and
ext~acted wi~h ethyl acetate, which was then washed wqth water
~nd.dried over magn0sium sulphate. ~he solvent was evaporated
to dryness to give an oil whic~ was dissolved in ethanol ~100 mls)
.~, .
; and concentrated hydrochloric acid ~a few drops) added. The
20 solution was refluxed for 2 hr, cooled~ poured into water and
extracted with.ethyl acetate, which was washed with water and
dried over magnesium sulphate. The solvent was evaporated to
dryness to leave an oil which solidified on trituration with
40-60 petroleum ether (1.2g). The structure of ~he compound was
conirmed by NMR.
- 32 -
t
- 32a - ~ %
~f) ~l~l ~g~quinoline-
' 2~8-diciarb~ lic acid
The abo~e bis ester ~l.Og) and sodium bicarbonate (00787g) in
ethanol (~5 mls) and water ~32 mls~ were ref~uxed for 4 hours. The
5 reaction mixture was poured into water, acidified and the precipitate .;
was collected by filtration &nd dried. The product was purified by
:~x~tula.~,~n.~,wi~ bQ~lihg ethanol9 then twice with boil m g acëtone.
~fter each trituration the mixture was centrifuged and ~he
` supernatent liquid was removed by decantation. The residual solid
was dried to give 0.547g o ~he requi~ed di~acid as a yellow
powder m.p. 298-3~0 dec~ ,
Pound: C: 61.3~ H; S.0% N; 3~6%
.
~'', C1 ~17N07 Required: C: 61.5~ H; 4~6~ N; 3.79
tg) Disodlum 4~6-Dioxo-l-ethyl-lo-propyl- H ~ 3,2-~:7
, 15 quinoline-2,8-dicarboxylate
The abo~e di-acid (4.098g), s~spended in ~ater ,~100 mls) and
was treated with sodium bicar~onate ~1~82g). The ~esul~ing
solu~ion was filtered and the filtrate ~as treated with acetone '~
until co~plete precipitation of the product had occurTed. l~e
required di-sodium salt was il~ered off ~nd dried to give 3~39g
of a pale yellow powder.
~;
' Found: C; 51.1~ H; 4.3~N; 3.0
19~115NNa27R~quired: C: 51.1~ H; 4.1~N; 3.1
2S t6.9~ water)
', ' ,. ':
_ 32a -
1 . ,
... .
. 12/B/30
- 33 ~ L'~6
Exa~ple 3
The ~ollowin~ compounds may also be made by the processes
described abo~e:-
(i) 5-E~hyl-4,8-dioxo-10-propyl-4H,8H-pyrano r2~3-h~7-
q ~loline-2,6-dicarboxylic acid
(ii) 4l10-Dioxo-4H,lOH-pyranoL~,3-~7quinoline-2,8- .
dicarboxylic ad d r
~;. (iii) 10-Bromo-4,6-dioxo-4H,6H-pyrano L3,2-g~7quinoline-
2,8-dicarboxylic acid
` 10 (iv) 5-Hydro2y-4,6-dioxo-10-prow 1-4H,6H-pyrano L 3~2-g,7 .
quQnoline~2,8-dicarboxylic acid
~v) 4,9-Dioxo-4H,9H-pyranoL~2,3-g~7quinoline-2,7-
~- dicarboxylic acid
(vi) 4,10 Dioxo-4HJlOH-pyrano C2,3-~:7quinoline 2,8-dif~N-
~- 15 ~tetrazol-5-yl) 7carboxa~de
.. ~ . -
~vii~ 10-Bromo-4,6-dioxo-2,8-di-(tetrazol-5-yl)-4H,6H-
~, pyranoL~3,2-g~7quinoline.
'
'
.
- 33 -
-
: ;, .,
... .
:
, , , : .: :
,..... .. . .
_ 3a~ _
)~ pp/~r~er~ t!c~r~ S c/o S~tre
'~'^`' Exa~le 4
ne-
2,8_dicarboxy1ate
(a) Methyl-6-acetyl-1-ethyl-5-hydroxy-4-oxo-4~1-quinoline-
2-carboxylate
:
A mixture of di~ethyl acetylene dicarboxylate (13g; 91.5 n~ole)
and 4-e~hylamino-2-hydroxyacetophenone (16.1g, 89.8 mmoles) in
ethanol t250 ml3 was re~luxed on a steambath for 7 hours. The
mixture was cooled before being poured into water. The n~xture
was concentrated by removing some o~ the ethanol and was then
extracted with ethylacetate. The organic extract was washed with
a large volume of water and then was dried (~nhydrous sodium
sulphate). Solvent was rem~ved by evaporation to giYe a light
brown oil. When triturated with petroleum ether/ether mixture a
yellol~ solid was obtained. Both N~ and MS showed it to be
consistent 1~ith *he expected structure.
l~e above dimethyl acetylene dicarboxylate adduc* of
4-ethylamino 2-h~fdroxy acetophenone (5.5g, 17~1 ~moles) was
~yclised by heating with polyphosphoric acid (19Og) for 20
minutes. The dark viscous solutio~ was treated with ice/water
mixture and the resulting suspenLsion w~s extracted with
ethylacetatç. The organic layer was washed with large volume
of water, and this w~s then dried (anhydrous sodium sulphate).
Solvent was removed to give a light brohn solid. ~ ~ and ~
showed this compound to be a mixtuTe, the sub-title compound
- 34 -
I~...~i
' ' ' . ', , ~,, `: ~
6~
- 35
being the main produot. A pure sample was obtained by
chromatography on silica gel using petroleum ether/ether as
eluent. A yellow solid with MP = 155-58C and N~ and
consistent with the desired structure was obtained.
~b) Diethyl 7~ethyl-4?10-dioxo-4H,lOH-pyTanoL~,3-f:7quinoline-
2,8-dicarboxylate
A mixture of the product of step (a) (2.6g~ 8.99 mmoles) ~nd
diethyl oxalate (11 nls, 75.3 mmoles) I~ dry dimethylformamide ~70 mls)
was added to a stirred suspension of 57~ sodium hydride (1.8g,
43.48 mmoles) under nitrogen at room temperature. After addition,
the mixture was left to stir at room temperature for 28 hours.
,~ .
The mixture ~as then acidified with lO~o hydrochloric acid. A
bright yellow precipitate was obtained. The mixture was extracted
wi~h ethyl acetate which was dried and evaporated to gi~re a yellow
solidO This solid was redissolved in an ethanollh~rdrochloric acid
~ixture. This solu~io~ w~s brought to reflux on a steambath for
2 hours and cooled befare pouring into an ice/water mix~ure. The
mixture was extracted ~ith e~hyl acetate, dried, and e~aporated to
give a br~wn oil which ~hen triturated with a petroleum ether/ether
mixture yielded a brow~ solid whose h~ and ~S spectr~ ~ere consistent
with the desired structure.
(c) 7-Ethyl-4710-dioxo-4H,lO~l-pyrano LZj3-f~Tquinoline-
b~ 9~C~-d
O.lN Sodium hydroxide (75ml, 7.4815 mmoles) was added slowly
to a boiling solution of the product of step (b) (1.440g;
- 35 -
- . :: -, ,
:
- 36 -
3.7402 mmoles~ in methanol (50 mls). After addition the mixture was
allowed to reflux for 2 hours, then cooled, and acidified with 10
hydrochloric acid. A light brown precipitate was obtained, which
was iltered and dried In vacuo. ~ and MS were consistent with
the desired structureO
Elemental Analysis: C = 58.8% H = 3.37% N = 4.25%
Found: C = 51.8 H = 4.3 N - 3.7
Containing 11.9~ ~ 0
~d~ Disodium 7-ethyl-4~10-dioxo-4H,lOH-pyrano C~,3- D ~uinoline-
Z,8-dicarboxylate
Excess acetone was added to a solution of the product of step
(c) ~0.755g, 2.2948 mnoles) and sodium bicarbonate ~0.3856g,
4.5892 mm~les) in water (5 mls). A pale yellow precipitate was
obtained and was dried in vacuo. N~ was consistent wqth the
desired structure.
Ele~nental Analysis: C - 51.49~ H = 2.43~ N = 3.75
Found: ~ = 44.1~ H = 3.7~ N = 3~2nO
Containing 14.4~ H20
,
Disodium-9-(3-methylbutyl)-4 ? 6-dioxo-4H/6H-pyTano L3,2-g 7 quinoline-
2,8-dicarboxylate
(a~ Methyl 6-acety~ 7-hydr xy-1-(3-methylbutyl)-4-oxo-4H-quinoline-2-
. ~ .
Polyphosphoric acid ~50 ml) was added to E-dimethyl 2- ~N-(4-
acetyl-3-hydroxyphenyl)-N-~3-methylbutyl)amino~7-but-2-ene-1,4-
- 36 ~
~f~
- 37 -
dioate, (10089g) and the resultin~ viscous dar~ red oil ~as stirred
on a steambath for ten mlnutes9 then poured into an iced l~rater/
ethyl acetate mixture and stirred vigorously ~or one hour. The
~esulting moxture ~as extracted into ethyl acetate? dried using
magnesium sulphate, iltered and the volatiles were removed m vacuo
af~ording a mixture (8.0g) of the required sub-title eo~pound and
methyl 6-acetyl-S-hydroxy-1-(3-methylbutyl)-4-oxo-4~-quinoline-2-
carboxyla~e.
~ eparation of the isomers was achie~ed using column chromatography
wi~h sIlica gel as the stationary phase and eluting primarily with
ether~ then chlorofonm. This process removed some of the unwanted
isomerJ the required sub-title compound being adsorbed on the
silica-gel. The silica gel was removed from the column, refluxed
with ethyl acetate, filtered o~ and ~he filtTate evaporated
yiélding a cTude sample of the required sub-title compound ~2.7g).
This was further purifled us m~ high pressure liquid chromatgraphy
affording 0.5g o the sub-title compound. MP 108-110C.
Anal~is
Found: CJ 65.4~0: H, 6.3~o: N~ 3.9~
C18H21N03 Requires: C, 55.3~: H~ 6.3~0: N, 4~2~o
N~ spectroscopy and mass spectroscopy con~inmed the structure.
(b) Diethyl-9-(3-meth~lbu~yl)-4~6-dioxo-4H~6H-pylano L3,2-g 7quinolin~-
2,8-dica boxylate
A solution o the product o~ step (a~ (2~3g) and diethyl o~alate
(~.5 ml) in dry dImethyl-Eormamide (60 ml3 was adde~ to a stirred
- 37 -
~;
, ~ , ., ' ;
- 38 -
suspension of ether waslled sodium hydride (0~65g) in dry
dLmethylformamide ~75 ml) under nitrogen. I~e whole was then
stirred at a~bient *emperature for t~en~y four hours9 then
poured into iced water and extracted into ethyl acetate. This
solution was dried using magnesium sulphate, filtered and volatiles
removed in vacuo, affording an oil.
To this oil was added saturated ethanolic hydrogen chloride
t300 ml) and the whole heated under reflux for two hours, then poured
into iced water and ex*racted into ethyl acetate, which was washed
with water, saturated aqueous sodium chloride solution and then dried
using magnesium sulphate. The organic solution was filtered and
Yolatiles were removed in acuo. The resulting oil was subjected
to column ~hromatography with silica gel as the statio~ary phase and
diethyl ether as eluan~ affording a solid, ~hich was triturated with
light petroleum ether>w~shed with a little ether, and dried undeT
reduced pressure oYer phosphorus pentoxide at 100C for three hours
yielding l.Zg of sub-title co~p~und. MP 149-150C.
Analysis
Found: C, 64.2~: H, 6.0~: N, 3.0
C23H2~i!107 Requi~es: C, 64O6~i~ H, 5.9~: N~, 3.3~
NMR a~ectroscopy a~d mass spectroscopy confi~med ~e structure.
~c~ 9 (3-Methylbutyl) -4 ~6-dioxo-4H,6H-pyranoL~3,2-~7quinol~
di~ic acid
The product of step ~b) (l.OOOg) was dissolved in methanol ~150 ml)
and heated to re~lux. 0.1 M NaCH (46.8 ml) was then added and the whole
-- 38 --
~ 1
6~
heated at re1ux for ~hree minutes. The soluti~n was cooled,
acidified, and the precipitated product collected and dried under
reduced pressure over phosphorus pentoxide at 80C for ~o hours, and
then at 100C for one and one half hours, affording the sub-title
compound (0.7g) MP 302-304C.
Analysis
Found: C, 59.7~: H, 4.9~: N, 3.5
ClgH17N07 Requires: C, 59.7~: H, 4.6%: N, 3.6
2.9~ H20
Hemihydrate requireso C, 60,0~: H, 4.5%: N, 3.7~
(d) Disodium-9-~3-methylbutyl)-4~6-dioxo-4H~6H-pyTanoL 3~2-g~7quinoline-
2,8-dicarboxylate
- The product of step (c) 2.9% H20 (0.5g) was suspended in
distill~d water (100 ml). Sodium bicarbonate ~0~243g) was added
and the whole mixture was shaken vigoIously. The r~sulting solution
was filteTed and freeze drled a~fording 0.7 g o~ the title compoundi
.
Found: C, 45.4~: H, 5.2~: N, 2~g5
C19H15NNa207 Requires: C, 45.4~: ~, 4.9~: N, 2.8%
17.Z~ H20
NMR spectroscopy confirmed the structure.
.
- 3~ -
" ~, "
.~
,6~
- 40 -
a~ple 6
Disod;um 7-(3-me~ylbutyl)-4~lo-dioxo-4H?loH-pyTan-o--c223-fJ quinoline-
2 ~-dicarboxy~
(a) N-(3-Methoxyphenyl)-N (3-methylbutyl)ethanoamide
Sodium hydride ~14.4gm) was washed with dry ether, then suspended
in dry di~ethylformamide CloO ml) under dry nitrogen. N-t3-Methoxy-
phenyl)ethanoan~de ~74.3g~ was dissolved in dry dimethylform3mide
(400 ml) and added to ~he NaH suspension. The resulting suspension
was cooled to 0C and stirred until hydrogen evolu~ion ceased.
3-~lethylbutylbromQde ~88.5g) was then added dropwise and the whole
stirred at room temperature for two hours The mixture was then
poured in~o water containing a little ethanol, extracted into ether,
washed l~th water~ dried UsiIIg magr~esium sulphate, filtered and the
volatiles were removed in vacuo. The resulting oil was subjected
to a vacuum distillation~ accepting the raction at 126~146C and
0.5 mm Hg p~essure3 yleldin~ 9S.5 gm o~ the sub-title compound. N~
spectroscopy and ~ss sepctroscopy confilmed the stru~ture.
~b) N-t3-Hydroxyphenyl)-N-~3-methylbutyl)ethanoamide
To a stirred solution of the product of step ~a) (10.8g) in
d~y dichloroethane ~100 ml) at -70C was added borontribromide (1~.4g).
The tempera~ure was allowed to rise to room temperature and the
mixture was stirred at this temperature ~or 12 hours, then poured
into water, extracted into chloroform, dried using magnesium sulphate~
iltered and the ~olatiles were removed în ~acuo, afording (10.4g)
o the sub-title compound. NMR spectroscopy and mass spectrDscopy
. ~,. .
: .. . : ,. .
.. ,~ :
- 41 -
confirmed the structure.
(c) N-Acetyl-N-(3-methylbutyl) aminophenyl-ethano te
To the product of step (b) ~92.2g) in dry *oluene ~2L~ was
added acetyl chloride (49.1g) and pyridine (2 ml). The resulting
solution was re~luxed for five hours, poured into water and the
organic layer ~Tas separated, ~ashed with more water, dried using
magnesium sulphate9 filtered and the volatiles were removed in
vacuo, aEforalng (102g) of the sub-title compound.
N~R spectroscopy and mass spectroscopy confiTmed the structure.
(d) N-~4-Acetyl-3-hydroxyphen~ N-(3-methy-lbutyl)-ethanoamide
The produc~ of step ~c~ (11.3g) was mixed with aluminium
chloride (18g) and sodium chloride (2~5g) and then heated a* 160C
for two hours. Iced water was added cautiously and the resultm g
nixture was extracted with 10~ sodium hydroxide solution,which was
the~ washed wlth ether. ~e alkaline extracts were acid;fied,
extracted in*o ether, dried using magnesium sulphate, filtered and
the Yolatiles ~ere r ~ Yed in vacuo, af~ording 7.5g o the
sub-title compound.
N~R spectroscopy ~nd ~ss spectroscopy confirmed the structure.
(e) l L ~ 4-~3-methylbutyl)amino-phenyl~7-et~mone
To the product of step (d~ ~49.9g) in gIacial acetic acid ~550 ml~
~as added 48~ aqueous hydrogen bromide solution ~110 ml). The mixture
was ~efluxed for two hours, poured into water and extracted into
diethyl ether. The ether was washed well wqth water, then with
saturated sodiumn bicarbonate solution7 dried using magnesium sulphate,
- 41 -
-
. , ~ ,... . . .
: : ,
:
~ : :
~ 42 -
filtered and finally the volatiles were removed in vacuo, afording
38.0g of the sub-title compoundO
N~ spectroscopy and mass spectroscopy confinmed the structure.
(f~ Iy~ aL~3-hydroxyphenyl)-N-(3-methylbutyl~-
amino-1,4-but-2-enedioate
To the product of step (e~ (38.0g) in ary ethanol (300 ml)
was added dimethyl acetylene dicarboxylate ~31.8g). The resulting
solu~ion was heated under reflux for seven hours, after which time
the volatiles were removed in vacuo, affording ~75 gm) of crude
sub-title compound. The crude sample YaS sub~ected to column
chromatography using silica-gel as the stationary phase and a
1:1 mixture of petroleum ether and diethyl ether as eluant. This
process aforded (41.4 gm) of pure su~-title compound.
~ ~ spectroscopy and mass spectroscopy confirmed the st~ucture
and that of the iso~ric fo~m of the product~
(~ thyl 6-Acetyl-5-hv~rox~ 3-methylbu~y_)-4-oxo-4H-
c- . .
quinolIne-2-carbox~ate
The product of step ~f) ~3.3g) was added to stirred viscous
polyphosphoric acid ~15 ~1~ and the moxture was heated o~ a $team
bath for fifte~n minutes. The whole was then poured onto ~n iced
water~ ethyl acetate ~i~ture and vigorously stirred for one hour.
The organic layer was sepa~ated, washed well wqth water, dried
using magnesium s~lphate~ filtered and Yolatiles ~ere removed m
Ya~lo affo~ding a crude sample ~1.7g3 sub-title conpound, 0.7g of
which was recrystallised from methanol to gi~e 0.3g of the pure
- 42 -
.. ,, ~; i .
,, ~,
, i; , .: ~ .. ~.... . .
.
.. ..
. . . ~
~.
- 43 -
sub-title compound. MP 140-141C.
A~alysis
Found: C, 65~2%: H, 6.5~ N~ 4.1
ClgH21N05 Requires: C, 65~3~o H~ 6~3~o N, 4.2~
N~ spectroscopy and mass spectroscopy confirmed preparation
of the sub-title compound.
Ch) Diethyl 7-(3-met~ylbutyl)-4,10-dioxo-4H,lOH-EyT~c~L~73- D -
quinoline~2,8-dicarboxylate
To sodium hydride ~0~26g)~ which had been washed lnth dry ether,
was added dry dimethylformamide (20 ml) under nitr~gen, with
stirr mg. The product of s~ep tg) (0.9g) and diethyl oxalate
3.18g~ in dry dimethylformamide ~20 ml) were added to the above
N~H suspension and the whole ~s stirred at room temperature ~or
twenty four hours, the~ heated on a steam bath for two hours. The
reaction mixture was cooled, poured into water, acidified and
extracted Lnto ethyl acetate. The organic layer was dried using
m2gnesium sulphate~ il.ered and volatiles were Temoved in va wo.
The residue was dissolv~d in saturated ethanolic HCl ~200 ml) and
re1uxed for 15 ~ tes. The whole ~as poured into water7 extracted
into ethyl acetate and dried. Evaporation gave a sticky solid which
was crystallised from aqueous ethanol to give 0.5g ~f a light bro~n
crystalline solid. This was fur~her purified using c~lumn
chromatography wnth silica gel as the stationary phase and et~yl
acetate as eluant~ affording 0.26g of sub-title compound. MP 144-146C.
- 43 -
.
., : " .' :' ~
.:.
.. .
~.; ~. .
~ 44 - ~L~L
~lysis
Found: C, 64.2~: H, 6.2~: N, 3.37~
C23H25N07 Requ;res: C~ 64.6~: H, 5.84~: N, 3.2g~
N~ spectroscopy and mass spectroscopy confi~med prcparation
of the sub-title compound
(i) 7-(3-Me hylbutyl)-4,10-dioxo-4H,l~H-pyra o L~,3-f~7quinoline-
2,8-dicarboxylic acid
The product of step th) ~0.9lgg~ was dissolved in methanol ~50 ml)
and ~eated to ~eflux. O.lM NaOH ~43 ml) was added and the whole was
refluxed for ive ~anutes. The resulting solution was then acidified
with O.lNHCl and allowed to cool. A yellow solid crystallised out of
solution, was filte~ed off, washed with ether and dried under a
~educed pressure of 0.2 mm Hg at 70C over phosphorus pentoxide,
affording 0.67g of sub-title co~ound.
~nalysis
Found: C~ 55~7~: H, 4.9~: N, 3.0%
ClgH17N07 9.4~ ~ O ~eo~ui,es: C, 55.7~: H, 5~2~: N, 3.4~
Dihydrate R~qui.es: C, 56.0~: Ho 5.16~: N, 3.4%
Dis~dium-7-(3-m thylbutyl)-4,10-dioxo_4H,lOH_pyrano L~,3- V -
quinoline-2~8-dicarboxylate
l~e product of step ~i) 9~4~ H20 (005568g) was suspended in
distilled wrater ~40 ml). Solium bicarbonate tO.~3g) was then added
~nd the whole vigorously shaken until solution was achievedD The
solution was then filtered, and the filtrate freeze-dried3 to give
0~59g of the title compound.
- 44 -
g~
, :, ,, , . ,:
, . . ,. . : .
,
; .: ,, ~, , :
. i : , " .,
,:; '., . ~,,
64~
- 45 -
Analysis
Fo~d: C, 46.7%: H, 407% N, 2.8~
ClgH15NNa207 Requires: C, 46.7~o H, 4~7~ N, 2~8Co
14.9% H20
N~R spectroscopy confirmed preparation of the ti~le
con~ d.
.:
.
- 45 - .
. ~,
: , ,........ ~ .
.,
.,.~
....
.. , . : .~ :,:
, . . ..
07/B/25
-46 -
Example 7
Disodium 5~m~hoxy-4,7-dioxo-4H ? 7H-pyranoL~,2-~7quinoline-2,9
dica~boxylate
~a) N~(3-Acetyl~2-hydro~y-4-m~thoxyQhenyl~acetamide
1-~3-~mino-2-hydroxy-6-n~ho~y-phenyl)ethanone (12.9g) was
added to a mixture of acetic acid ~3 mls) and water (20 m~s) and
heated to 60C. Acetic aRhydride (9.5 mls) was then added and
the ~hole heated on a steam bath for ~hirty minutes. The reaction
mixture was poured into water and extracted into ether, which was
1~ dried using magn~sium sulphat~, and after filt~ation the volatiles
WeTe ~emoved in vacuo7 affording a golden b~own:solid which was
triturated wqth chloroform and dried under reduced pressure,
yielding 3.7g of the sub t;tle compound, mp 160-162C.
~b) Ethyl 8-~mmo-6-metho~y-4-ox~ 4H~l-benzoEy~ 2-carbox~l te
: 15 Sodium (1.4g) was reacted wnth ethan~l (150 m~s3. me ~esultant
solu~ion was cooled and sti~red vigorously, and to this solution was
added a slurry of the product o~ step ~a) (305g) and Methyl oxalate
~5.4 mls) in ethanol (50 n~s)~ The maxture was heated under reflux
for three hours, poured into water ~nd the aqueous solution w~s
extracted into ethyl aceta~e, which was washed with a little water
and dried using magnesium sulphate. After filtration the solvent was
reved in vacuo. Ihis procedure yielded an oil to which was added
_
comcentrated hydrochloric acid (3 mls) and ethanol ~100 mls). This
solution was heated undeT reflux overnight. The volatiles were
rem~ved in vacuo, to a~ford the sub title compound (2.3g). N~M.R.
_ ~6
,
08/B~25
-47 ~
and M~ss Spectroscopy confl~m~d the structure.
(c) Dimethyl N-(5-methoxy-2-e~t~oxycarbonyl-4-oxo-4H~ enzopyran-
8-yl)-2-amino~but-2-en~ -dioate
To ~he product of step Cb~ C2-3g) was added ethanol (20~ mls)
and dimethyl ace~ylene di~arboxylate (1.3 mls). The whole was
heated under reflux ~or bwenty hur hours. The v~latiles were ~hen
remDved in vacuo to aford a sticky yellow-orange solid ~hich was
triturated with a petroleum ether-diethyl ether mixture. The
~ resulting solid was ~iltered under reduced pressure affording
; 10 (1.8gn) of the sub-title compound. N.M.R. Spectroscopy and M~ss
Spectroscopy confirmed ~he structure.
(d) Methyl 2-ethox~carbony_1-5-metho -4,7-dioxo-4H,7H-pyranoL~3
: q~inoline-9-c~Iboxyla~e
To refluKIng diphenyl ether (5C) mls) was ad~ed the product of
step k~ (1.8gm). R~fluxing was cc~ltinued for five minutes, and
~he moxture was then all~wed to coo].. Light petroleum e~her was
added an~ the precipitated p~oduct was filtered under Teduced
p~essu~e, and w~shed wi~h a ll~tle diethyl ether, affording l.Og
of crud~ sub title compound. This solid was tIiturated wi~h a
n~xture o~ hot ethyl ace~ate ana chloro~o~m, filtered under reduced
pressure and dr~ed. The ma~erial was recrystallised fr~m toluene,
and dried in vacuo at 89C over phosphorous pentoxide for ~our hours,
- ~esulting in 0.2g of the sub title compound, mp ~60-261C.
. -47-
'. ' l~
. ~, ~ "
:,
.
09/B/25
-48- ~L~L~ 9
~e~ 5iMethoxy-4~7-dioxo-4H~7H-py~a~oL~?2-~;7quinoline-2
dicarboxylic acid
To a stir~ed suspension of methyl 2-ethoxycarbonyl-5-m~thoxy-
4~7-dioxo-~H97H-pyræno C3~2~h~ quinoline-9-carboxylate ~2g) in ~
glacial acetic acid (16 mls~ was added concentrated hydrochloric
acid (4 mls). The whole was hea~ed on a steam bath for two hours,
cooled and the result~nt solid was ~iltered off under reduced
pressure. me solid was washed with acetic acid and ether, End
~hen dried under reduced pressure o~er phospho~us pentoxide ~nd
sodium hydroxide at 80C, yielding ~O.~g) of the sub-title-compound,
mp 294-6C ~dec).
Analysis
.~ Found: C, 49.1; H9 3.4; N, 3.6
N08.9~6% ~ 0 Requires: C, 49~1; H, 3.5; N~ 3,8~
NMR spectroscopy and mass SpeCtl~SC~py con~irm the structure.
~f) D~s~dium 5-methoxy-4?7-dioxo-4H~7H-pyrano r3~2-h 7quinoline-
. 2~9-dica~boxylate
: 5-M~hoxy-4,7-di~xo-4H~7H-pyranoL~3,2-h 7quinoline-2,9-
dicarbo~ylic acid (0.~231g~ was suspended in distilled wa~er (50 nl5).
Sodium bica~bonate ~0~286 gm) was added, and the ~hole was vigorously
shaken. me resul~ant solu~ion was ~iltered and the filtrate was
~reeze dried, afording (0.6g) of ~he title compound.
Analysis
Found: C, 41.07; H, 2.7; N, 3.3%
25~5H7NNa208.14.4~ ~ 0 RequQr~s: C, 41.07; H, 3.1; N, 3.2
-48 -
. ,~,
, ~ ,
10/~/25
%~
-49 ~
~ . .
4,6-Dioxo-10- &r~p-2-e~yl)-4H,6H-pyranoL~,2-g7 qui ine-2
dicaTb xylic acid
(a) Eth~l 7-~mino-4-oxo-8-~pro~-2-enyl)-4H-benz~y~an-2-carboxylate
:
1-(4-A~ety1amino-2-hyd~oxy-3-~prop-2-enyl)-phenyl~ethanone
(20g) and diethyl oxalate (30.95g; 28.7 ml) w~re added to a
previously fo~ed solution of sodium ethoxide (~rom add;tion of
sodium ~9.7g) to dry ethanol (243.4 ml)) with stirring.
The Teac*ion mixture was stirred und0r neflux ~or 3 hours,
cooled and then poured into wa*er. The precipi*ated product was
- extracted into chlorof~rm, dried and evaporated to dryness unde~
reduced pressure. The yell~w residual solid was dissolved in
fresh, dry ethanol (324.5 ml)~ concentrated hydrochloric acid
(3.25 ml) added and the reaction mi~;ure refluxed for 17 houTs.
The ~lole w~s poured ~nto water (1.5 litre3, extracted into ethyl
ace~ate, washed with water and dried ov~r magnesium sulphate. The
solvent was evaporated to d~yness and the rssidue tritura~ed wi~h
40-60 p~troleum ether to give 19.6g of brown crystall me solid~ A
l.Og sample of the crude product was recrystallised from ethanol to
give ~ crystalline solid, mp 142.5-143C.
~b~ Dime~y~l_N-~2-ethoxyca o~yl-4-oxo-8-~pr~p 2-enyl)-4H-l-
benzopyTan-7-yl)-2-aminobut-2-ene-1~4-dioate
Th0 ploauct vf step ta~ (18.6g) and dimethylacetylene-
dicaTboxylate (11.95g; 10.86 ml) in e~hanol (148 ml) were refluxed
together for 17 hours. The reaction mLxture was cooled to 10C and
-49 -
ll/B/25
50 ~
the precipitate was collec*ed by filtration, washed with a little
ethanol and dried to give 15q8g of product. A O.9g sample was
recrystallised from ethanol to ~e a crystalline solid, mp 148-148.5C.
` (c) Ethyl 8-me~hoxycarbonyl-4,6-dioxo-lO-(prop-2-enyl) 4H,6H-
~
The product of step Cb) tl4.0g) was added to diphe~yl ether
(200 ml) under r~lux wnth stirTing~ The ~eaction mixture was
~efluxed ~o~ a further 5 minutes, cooled and poured into 60-80
petroleum ether (2.0 1). The precipita~ed product was collected by
filtration, dried and lecrystallised fr~m ethyl acetate to gi~e 3.5g
of yellow solid.
(d3 476-Dioxo-10-~pr~p-2-enyl~-4H~H~-pyrano ~3 9 2- ~ quinoline-
298-~icarb~ lic acid
The product of step (c) was hydrolysed by ~he method of
Example 3(c) ~o afford the title con~und. Structure was confirmed
by N.M.R.
Example 9
4,10-Di~xo-4H~OH-pyrano~,3-hJ qu~loline-2,8-dicarboxylic acid
(a) E*hyl 5-ami~o-4-oxo-4H-benzopyran-2-ca~bo~ylate
E~hyl 5-nitro-4-oxo-4H~benzopyTan-2-caTboxylate tlOg, 38.022 mmolcs)
in ethanol ~250 mls) was added ~o 5~ Pd/C ~lg) in ethanol t50 m~) în
: a hydrogenation v~ssel. I~o drops of concentra$ed hydrochloric acid
were then added to the above m~xture. The mixture ~as ~hen
hydrogenated at 3 atmospheres pressure at rD~m tem~erature for 2 hours.
The ca~alyst was filtered of~ through a filter aid ~hich was
: -50-
.. . s . . ..
- , , , .,., ~.
,: . , ,
,
. . .
, " '
12/B/25
~2~
-- 51 --
washed ~th ~hloro~orm. The filtrate wæ evapo~ated to give a
yellaw solid ~8.1g9 91.5~. NMR and m~ss spectra confirm2d that
; the desired c~mpound had been made.
~h~ 8-E~hoxy~a~bonyl-2-methoxy ca~bo~n~l-4,10-dioxo-4H~lGff-pyrano-
r ~ -~uinollne
The product of step (a~ ~6.1g, 26.1~ Dle) and dimethyl
ace*ylene-dica~boxylate (llg; 77.46 mm~le) were heated ~n e~hanol
(180 ~il) fo~r 7 hours. The ~eaction nL~xture was cooled and was
:: diluted wi~ water. Half of ~he original v~lw~ of ethanol was
10 nemoved an~ the concentrated mdxtNre was. extracted with ethyl
acetate. ~e org mic layer was washed ~h a la~ge volume of
water, dried and evaporated to give a yellow solid (8.5g, S6~).
lhe solid ~8.5g, 22.66 ~ole) WclS added sl~wly to p~eheated
diphenyl e~er (90 n~, 240C) ~der N2 wi~:h stirring. A~ter
15 addition th~ n~xture was brought to ~reflux or 15 ~utes. Ihe
n~x~e was ~led and poured into pet~leum et31er (4~6bc,
200 n~) to give ~e slibtitle p~oduct as a li~ht grey solid
(4g, 51.3~ 166-7~)C.
(c) 4,1~Dioxo-4H,l~H-Er~,3-h~ inol~e-2,8-dicaTbo~ylic aci_
SoditDn hydroxide solution (O.lN, 58.,27 ml; 5.8267 ~nDle3 was
added slowly to a boiling methanolic solutio~ of tihe product of
s~p ~b). After additiorl, ~e reaction was heated to reflux for
25 nanu~es. me mixture was cooled and was acidified with dilute
hydro~hloric acid (10~) ~o give a very fine precipi~ate, lhis was
25 filtered off and was collected as a light bro~ solid and d~ied
_ 51 _
.~ .
13/B/25
-- 52 --
in vacuD ove~ P205 at 70C o~e~ ht to give the sub-title p~ uct
6:17g) m~ 200C.
~lysis
Found: C3 50~91 H" 2.78; N, 4.12
8.8~ H2û Rsquires: C, 50~9 H, 3.1; N, 4.2%
~d) sodi~n 4~lo-dioxo-4H?loH~o~?3-hJquin~li~e-2~8
dicarbo~rlate
;
~ e product of step (c) tO.4117g, 1.2462 ~nole) was dissolved
wit~h sodium bicarbo~ate (0.20~4g~ 2.4922 Dmole3 in water (30 ml).
10 lhis was filtered to ~emwe ally insoluble particles. The solutio~
was ~hen freeze d~ied to give 1~he s~ title product as a bro~
solid (0.4137g~.
~alysis
Found: C, 41.82; H, 2.96; N, 3.44~
14~14~ ~ O ~equires: C~ 41.82; ~, 2.82; ~, 3.49%
(a) 3-Ethox~ca~bonyl-10-h~dro ~ -8-methcxycarbanyl-1-oxo-lH-pyran _
D,~f71 1 w
: Ethyl 6-amino-4-oxo-4H-l-benz~pyran-2~carboxy1ate ~3.9g; 1607 mo~le~
2U in ethanol (70 ml) and dimethylacetylene-dica~boxylate (2.84g; 20 mm~le~
were heated under reflux for 2 h~s. The solu~ion was cooled ~nd the
solvent rem~ved on the rotary evaporator to give a green solid.
The solid w~s added all at ance to re~luxing diphenylether ~50 ~1)
and heating was continued ~or 25 nins. The mixture was allowed to
cool and then poured ~nto a mixture of diethylether (25 ml) and
- ~2 -
.,
:;
;:
' ' . ' ' , ,, . ~ ~ ~ , . i
,
14/~2~
~2~
~ 53 -
petroleum eth~r ~bp 40-60) (40 ml) and ~he br~wn solid was
filtered off and recrystallised from chloroform to giYe the title
compound as a dark green solid (2.9g ; 50.6~)5 mp 247-8.5.
~b) _sodium 10-hyd~ l-oxo-lH-p~ oL~3,2-f~7quinoline-
3~8-dicarboxylate
The product of step ~a) was hydrolysed by the method of
Ex3~ple 5 ~d) to afford the disodium salt.
~ysiS
~4~ 5NNa~U706.11~ ~ 0 requires: C 45.74% H 2.1~ N 3.8%
10~ound: C 45.74% H 2.45~ N 3.6
~1
Disodium 4,1C-dioxo-4H-loH-yyranoL~93-f 7quinol ~ -2,8-dicarboxylate
:~ .
: (a) thyl 7-amono-4-oxo-4H-l-benzo~ an-2-carboxylate
A solutio~ of sodium m~tal, (18.4g, 0.8 gatom), in dry ethanol
(1200 ma), was tTeated with N-(4-acetyl-3-hydroxyphenyl~acetamide,
(30.88g, 0.16 le~. This mixture was stirTed for 15 m ms then
diethyl ocalate, (58.4g, 5403 ml, 0.4 mole), was add~d dropwise
over 30 monsO ~he resulting mixture w~s heated and stirred at
60C for 2 hrs, allowed to c~l and poured into a mnxture of chlorofo~m
(60~ m~), conc HK~ (85 ml), and water (2000 ml). The organic layer
was isola~ed and combined with a chloro~DTm wash of ~he aqueous
layer. The conbined chlor~onm extracts were washed well with water
then evaporated to dryness. The residue was taken into ethanol
(4(~ ml), ~nd conc. HCl (10 ml~, was added. The soluti~n was
Z5 heated at reflux for 30 minutes ~hen eYaporated to dIyness4 The
. .~;
~ 3 -
''~ ' ~ , ;
. . . ..
. . . .. .. .
., ~ . .
, ,, , :; , ,~ : .
, . .
.
15/B/25
- 5~ -
residue was treated ~ ~h ether and ethanol was added d~o ~ se until
the residue began to solidify. Insoluble material was filtered o~f,
washed again with e~her and the Tequired sub-title produc~ was
recovered æ a brown solid (20.5g)9 ~55~), mp 192-194~ NMR and
m~ss spectra confirmed ~he structure.
~b) Dimethyl N ~2-ethoxyca~bony~-4-oxo-4H-l-benzopyran-7-~l~-2
amLno-bu~-Z-ene-dioate
A solution of the product of step (a) ~4~2g, 0.018 mole), and
dime~hylac0tylenedica~boxylate5 ~7.68g, 6.6 ml, 0.054 mole), in
e~hanol (200-ml), was heated ~t re~lux for 3~ hrsO Solvent was
evap~rated off and the residue was tritu~ated nth ether. Insoluble
ma~erial was filtered off and washed with e~her to give the required
product as a buff coloured solid (4.3g), (64~), mp 147-51. NMR and
mass spectra confirmed the structure.
(c) 2-E~h~ ca~bonyl-8-me~h~xycarbcnyl-4~10-dioxo 4H,lOH-pyrano-
L ~,3-f~7quinoline
Diphenyl ether ~140 ml), was heated to 240C and the pnoduct
- of step ~b) ~3.85g~ 0.01027 mole), was added quickly but in small
porti~ns. The resulting soluti~n was heated at re~lux for S minutes
then all~wed to cool, when a gel-like precipitate ~.ormed. This was
~ddea to a nixture of ~ther and 40-60 petroleum ether and allowed
to stand. Insoluble material was filtered off, washed well with e~her
and dried in vacuo to lea~e the required prod~lct as a pale br~w~
p~wder (3.25g), 92~9 mp 239-411 The structure was confirmed by NMR
and m~ss spectra.
~ 54 -
, ~ , ;
, . ..
: '
01/B/49
- g5 -
~d) Lisod ~
A solution o the product of step (c) ~0.517g, 1.506 mmDle) in
methanol (lOO ml), was stirred and heated at reflux during the dropwise
addition of 0.1015M sodium hydroxide solution (29.7 ml, 3.012 ~mole)~
The addition was complete after 15 minutes. After contmum g at
reflux for 5 minutes the mnxture was evaporated to d~yness, the residue
was ~edissolved in water. This soluton was filtered and ~he filtrate
was swamped with acetone. Ater standing overnight the precipitated
solid was filtered o ff, washed wnth acetone and dried in vacuw .~o
leave the required disodium salt as ~ da~k yellow p~wder (0.45g),
86.5~. The structuTe was coni~med by NMR spectrum and elemental
analysis:
Found~ C, 44.36~ : H, 2.18~ : N, 3.54
requiTed for C14H5NNa27-2~ C, 44.1~ : H, ~.38% : N, 3.67
'~
. '
.l - 55 -
, , ,
.,,; ~ ,
: .
~" . ; ,
,~ . .
.
2~
EXAMPLE 12
(~) 2-(2-Carboxy-8-methyl-4-oxo-~4~q--nolin-7-ylo~y-but-2-en
1,4-dioic acid
-
Dimethyl acetylenedicarboxylate (12~3 ml) was added dropwise to
3-amino-2-methylphenol (12.4g) in ethanol (100 ml), at room temperature.
AfteT 0.5h, N-benzyltrinethylammonium hydroxide (0.5 ml), and dimethyl
acetylenedicarboxylate (12.3 ml~ were added, and the reaction mixture
was refluxed for 4h. The solution was cooled, poured into chloroform
(500 ml) and washed wi~h water (5 x 200 ml). The chloroform layer was
dried over magnesium sulphate, and concentrated in vacuo to give a
dark oil, to which was added polyphosphoric acid (70g~. The whole was
stirred on a steam bath for 0.5h, then poured onto ice and extracted
wnth ethyl acetate (2 x 200 ml)~ The organic extracts were combined,
dried over magnesium sulphate and concentrated in vacuo to give a dark
oil (27.4g~. This oil was dissolved in ethanol (200 ml) which contained
sodium hydroxide (12g) in water (100 ml), and refluxed for 5h. The
clear solution was cooled, the ethanol removed by distillation in vacuo,
and the residue ~as ~cidified with S-_-hydrochloric acid, to give on
standing overnight the sub-title compound (12.7g). N.m.r. and i.r.
spectra were consistent with the proposed structure.
~b) 10-Methyl-4,6~dioxo-4H,6H-pyranof~3,2-g 7quinoline-2,8-
dicarboxylic acid
The product of step ~a) above (5.8g; 17.4 mole) was added
portionwise to chlorosulphonic acid (20 ml) with stirring while cooling
in an ice bath. The mixture was allowed to warm to ro~n temperature
and stirred for 1 hour, ~hen it was added dropwise to a mixture of ice
and water with rapid stirr mg. The brown solid was filtered off and
recrystallised fr~n dimethylfornEunide to y;eld a light brown crystalline
solid (2.82g; 51~) containing 1 molar equivalent of d~nethylformamide
.
of crystallisation, m.p. = 302.
56 -
.. . .
, ~ :. . :
;,.. . . .
- 57 -
EXAMPLE 13
4,6-Dioxo-10-propyl-4H,6H pyr~ano[3,2-g]quinoline-2,8-
dicarboxylic acid
.
The title compound may be made by the process of the
invention, the diethyl ester thereof having an m.p. of 211 -
212C.
~ .
",
~: ~ - 57
'
:~`
' ' ' ' '' ':
~245/74 _ 58 -
ExamDle 14
6-Amino-7,10-dihydro-5-methoxy-4,7-dioxo-4H-pyrano[3,2-hJ-
quinoline-2,9-dicarboxylic acid
(a) Diethyl 7,10-dihydro-5-methoxy-6-nitro-4,7-dioxo-4H-
pyrano~3,2-h]quinoline-2,9-dicar~oxylate
Diethyl 7,10-dihydro-5-methoxy-4,7-dioxo-4H-pyrano-
~3,2-h]quinoline-2,9-dicarboxylate (0.82g) was dissolved
in a mixture of concentrated sulphuric acid ~5ml) and
concentrated nitric acid (lml) and heated at 75C for 36
hours. The mixture was poured into water (lOOml), and the
precipitate was collected, and dried to afford the title
compound (O.llOg) as a brown powderO The structure was
confirmed by n.m.r. and mass spectroscopy.
(b) Diethyl 6-amino-7,10-dihydro-r~-methoxy-4,7-dioxo-4H-
p~rano-[3,2-h]quinoline-2,9-dicarboxylate
The product of step (a) (0.105g) was dissolved in
glacial acetic acid (5ml) and`hydrogenated over 5% Pd/C
catalyst at 1 atmosphere and room temperature until
hydrogen uptake ceased. Filtration removed the catalyst
and dilution with water afforded a yellow precipitate
` which was collected and dried. Separation by high
pressure liquid chromatography afforded the sub-title
compound (0.033g) as an off-white solid. The structure
was confirmed by n.m.r. and mass spectroscopy.
- 58 _
, ~,
,:
,, ,'' , ~ :
4245/74 ~ 59 ~ ~ ~ ~26~
(c) 6-Amino-7,10-dihydro~5-methoxy-4,7-dioxo-4H-pyrano-
[3,2-h]quinoline-2,9-dicarboxylic acid
The product of step (b) (0.03g) in glacial acetic acid
~lml) was treated with 48~ aqueous EIBr (2 drops) and
refluxed 18 hours. The reaction mixture was poured into
water (lOml) and an o~f-white solid was filtered off.
Drying aforded the title compound (0.018g).
NMR~ DMSO 3~95t3H,s); 6.95(lH,s); 7.4(lH,s); 9.6(brs-4H).
Example 15
10-Bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-g]quinoline-
2,8-dicarboxylic acid
~,
(a) Diethyl 10-bromo-6,9-dihydro-4,6-dioxo-4H-pyrano-
[3,2-~quinoline-2,8-dicarboxylate
Ethyl 7-amino-8-bromo-4-oxo-4H-l-benzopyran-2-carboxy-
late (5.3g) and dimethyl acetylenedicarboxylate (3.35g) in
methanol (50ml) were heated under reflux for 18 hours. ;~
The solvent was evaporated ln vacuo, and the oil residue
was poured into refluxing diphenyl ether (150ml) in one
portion. After 10 minutes continued refluxing, the
mixture was cooled and poured into petroleum ether
-;
(40-60C, 1 litre). The precipitated solid was
collected, washed with petroleum ether and dried. The
- solid was separated into its components by high pressure
~ liquid chromatography, and the sub-title compound was
- 25 obtained as a fluffy yellow solid (0.28g). The structure
- 59
.
,.
42~5/7~ ~ 60 ~ ~ 6
was confirmed by n.m.r. and mass spectroscopy.
(b) lO-~romo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-g)-
~__noline ~,8-dicarboxylic acid
The product of step (a) (0.279) was heated under
reflux in glacial acetic acid (5ml) containing 48% HBr (lO
drops) for l8 hours; the reaction mixture was then poured
into water (lOOml) and the precipitate was collected.
Drying afforded the title compound (O.llg) as an amorphous
powder.
NMR ~DMSO: 6.gS(lH,s); 7.0¦l~,s); 8.6(l~,s).
Example_15
N,N'-Di-(tetrazol-5-yl)-9-(but 3-enyl)-6!9-dihydro-4-oxo-
10-propyl-4H-7~yrano[3!2-g]quinoline-2,8-dlcarboxamide
(a) 6-Acetyl-3-~but~3-enyl)amino-2~ Ey~ y~
lS 6-Acetyl-3-acetylamino-2-propylphenol (23.5g) was
added to a stirred solution of lithium diisopro~pylamide
(2l.49) in dry tetrahydrofuran (SOOml) under a nitrogen
~` atmosphere at 0C. After stirring for 2 hours, but-3-
enylbromide (13.5g) was added. The reaction was allowed
Y~ 20 to warm to ambient temperature, and was then left for 72
hours.
The solvent was evaporated in vacuo, and concentrated
-~ hydrochloric acid (lOOml), water (lOOml) and glacial
~- acetic acid (50ml) were added. This mixture was heated
under reflux for 18 hours, then cooled, basified with
,
~ 60
,
,
: ~ ~
: . , ,
:" ~' '. , ~ :::
' : .,, ~, , :
26~
4245/74 ~ 61
ammonia, and ether extracted. Drying and evaporation
yielded the sub-title compound (19.7g). The structure was
confirmed by n.m.r. and mass spectroscopy.
(b) Methyl 6-acetyl-1-(but-3-enyl)-1,4-dihydro-7-hydroxy-4-
oxo-8-propylquinoline-2-carboxylate
The product of step (a) (19.5g), dimethyl acetylenedi-
carboxylate (13.5g~ and methanol (lOOml) were heated under
reflux for ~4 hours and then the solvent was evaporated
in vacuo. The residue was added to stirred polyphosphoric
acid ~l50ml) heated to 95C. After 2 hours the reaction
was poured into ice (1 litre) and ether exracted. The
ethereal extract was washed well with dilute hydrochloric
acid, brine and sodium bicarbonate solution, and then
dried. Evaporation afforded a gum which solidified r
partially. The solid was collected and shown to be the
sub-title compound (3.39~ by n.m.r. and mass spectroscopy.
(c) 9-~But-3-~nyl)-6,9-dihydro-4-oxo-10-propyl-4H-pyrano-
~3,2-g]quinoline-2,8-dicarboxYlic acid
:
.
The product of step (b) (3.2g) was added to a solution
20of sodium (l.lSg) in dry ethanol (50ml) and diethyl
oxalate (3~5g) was added. After stirring at room temper-
ature for 18 hours, gaseous hydrogen chloride was passed
; into the ice-cooled mixture until saturated. The mixture
was heated to reflux for 1 hour, then evaporated, and the
25residue was taken up into glacial acetic acid (50ml) and
,
61
, ,, , : ~ ................................ ,, :
,
4245/7~ - 62 ~ Z~ ~ ~
48% aqueous HBr (lml). The mixture was heated to reflux
overnight, then cooled and poured into water (1 litre).
Filtration and drying afforded a fawn solid (1~8g) which
was shown to be the sub-title compound by n.m.r. and mass
spectroscopy.
(d) N,N'-Di(tetrazol-5-yl~-9-(but 3-enyl)-6,9-dihydro-4-
oxo-10-propyl~4~-p~rano~3,2-~quinoline-2,8-dicarboxamide
The product of step (c) (1.759), thionyl chloride
(1006g) dichloroethane (20ml) and dry dimethyl formamide
(1 drop) were heated under reflux for 4 hours. On cooling
a precipitate appeared which was collected and dried
in vacuo.
,. _ .
~` The solid was added to a solution of 5-aminotetrazole
~1.5g) in dry dimethylacetamide t20ml). After 48 hours at
room temperature the mixture was poured into water (150ml)
~ . .
and the precipitated solid was collected. Drying in vacuo
afforded the title compound tO.8g) as an off-white powder.
NMR DMSO: 1.0(3H,t); 1.8(2H,m); 2.2(2H,m); 3.8(4H,m);
4.65(2H,m); 5.3(1H,mi; 7.0(1H,s); 8.5(1H,s); 8.7(1H,s);
10.3(br).
'. .
,
- 62
~,
.. . :,. ; . . ;
. .
...
,, ,: ~:
.. :.
4245/74 ~ 63 ~ ~ 6
9-Ethyl-6,9-dihydro-4,6-dioxo-lO-propyl-4H-pyranoc3~2
-
quinoline-2,8~dicarboxylic acid
-
(a) 6-Acetyl-l-ethyl-1,4-dihydro-7-nydroxy-4-oxo-9-propyl~
quinoline-2-carboxylic acid
Methyl 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-
8-propylquinoline-2-carboxylate (209) was heated under
reflux in glacial acetic acid (150ml) containing 48~
,, .
aqueous HBr (23ml). After 18 hours the mixture was cooled
and poured into water. Ammonia was added until pH3. The
':
precipitate was collected and dried in vacuo, and was
identified as the sub-title compound (14.3g) by n.m.r. and
mass spectroscopy.
(b) 2-Ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-
propyl-4H-pyrano[3~2-~l3gl~9ll~g~=5l5~9~ c acid
The product of step (a) (14.2g) was added to a
solution of sodium (5.2g) in ethanol (200ml), and then
~; diethyl oxalate ~16g1 was added. The mixture was heated
under re~lux for 5 hours then cooled and poured into
chloroform (l litre). The mixture was shaken with dilute
hydrochloric acid (150ml), then the organic phase was
dried and evaporated in vacuo. The residue was dissolved
in ethanol (200ml) containing concentrated hydrochloric
acid (2ml) and refluxed for 18 hours. The solvent was
evaporated, and ~he residue was recrystallised from
63
4245/74 ~4 ~ 26~4
ethanol to afford the sub-title compound (3.2g). The
structure was confirmed by n.m.r. and mass spectroscopy.
(c) 9-Ethyl-6,9-dihYdro-4,6-dioxo-10-propyl-4H-pyrano-
[3,2-g]~inoline-2,8-dicarboxylic acid
The product of step (b) was hydrolysed by the process
of step (a) to afford a product (l.lg) identical with that
of Example 2 by thin layer chromatographic compar i50n .
Example 18
9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano~3,2-g]-
quinoline-2,8-dicarboxylic acid
(a) Methyl~9-ethyl-5,9-dihydro-2-methyl-4,6-dioxo-10-
: propyl-4H-pyrano[3,2-~]quinoline-8-carboxylate
6-Acetyl-l-ethyl-7-hydroxy-4(:LH)-oxo-8-propylquinoline-
~ 2-carboxylic acid (3.15g) was dissolved in dry dimethyl-
-~ 15 formamide (SOml) containing washed sodium hydride ~1.05g)
and then ethyl acetate (4.4g) was introduced. After
stirring overnight gaseous hyarogen chloride was passed
into the mixture with ice cooling until saturated. The
mixture was warmed to 75C for 8 hours, then cooled,
``- 20 poured into water and the mixture was extracted with ethyl
acetate. The organic phase was dried and evaporated and
the residue was chromatographed (SiO2/ethyl acetate) to
provide the sub-title compound (0.8g). The structure was
con~irmed by n.m.r. and mass spectroscopy.
- 64
.
,
. . .
,.,. , ,,' .
4245/74 - ~5
Ib) g-~thyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-
8-dicarboxylic ac_d
The product of step (a) (0.75g) was heated under
reflux with selenium dioxide (1.5g) in glacial acetic acid
(50ml) for 48 hour~. Filtration through "Celite" afforded
a clear filtrate which was treated with concentrated
`~ hydrochloric adid (25ml) and heated under reflux for 12
hours. On cooling and pouring into water a precipitate
was obtained (0.19) which was identical to the product of
Example 2 by thin layer chromatographic comparison.
Example 19
9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-py ano[3,2-g]-
quinoline-2,8~dicarboxylic acid
(a) N-[3-(1,2-dicarboxyethenYloxy~-2~propYlphenyl~-N-ethYl-
2-amino-but-2-ene-1,4-dioic acid
3-Ethylamino-2-propylphenol (17.99), dimethyl acetyl-
enedicarboxylate (359~, potassium hydroxide (0.569), water
(50ml) and ethanol (lOOml) were heated under reflux for 24
hours. Potassium hydroxide (1.659) was added and reflux-
ing was continued for another 24 hours.
Concentrated hydrochloric acid (4ml) was added and the
solvent was evaporated. The residue was dried in vacuo
and extracted into ether. The ether was evaporated to
afford the sub-title compound (3069). The structure was
confirmed by n.m.r. and mass spectroscopy~
~ 65
;..~,
~2~g
~24S/7~ ~ 66
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-~yrano-
_ 2-g]quinoline 2,8-dicarboxylic acid
The product of step ~a) (3.55g) was added in small
portions to chlorosulphonic acid (lOOml) cooled to -78C
with stirring. The solution was allowed to warm slowly to
room temperature and was then warmed to 50C for 1
hour~ The reaction mixture was cautiously poured onto ice
(1 litre) and extracted into ethyl acetate. After drying
f the ethyl acetate was evaporated and the residue was
separated by high pressure liquid chromatography to afford
the title compound ~0.2g) chromatographically idential to
the product of Example 2.
~; Example 20
9-Ethyl-6,9-dihydro-4,6-dioxo-lO-~propyl=4H~pyrano[3-2--~]
~uinoline-2,8-dicarboxylic acid
(a) l-Ethyl-6-(3-carboxy-3-diethy]amino-1-oxo-prop-2-enyl)-
1,4-dihydro-7-hYdroxy-4-oxo-8-propylquinoline-2 carboxylic
.
acid
9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-
[3,2-g~quinoline-2,8-dicarboxylic acid (lg) and diethyl-
amine (5ml) were heated together in an autoclave for 12
hours at 100C, then the volatile materials were evapor-
ated at 60C. The residue was triturated with ether to
afford the sub-title compound (0.78g). Structure was
25 confirmed by n.m.r. and mass spectroscopy.
- 66 -
.. .. .
~3
:
,`. `.... : :
.,
.... ,`
,,.. ` . . .,` . ~ .
~245/74 - 67
(b) 9-Ethyl-6,9 dihydro-4,6-dioxo-lO-propyl-4H-pyrano-
[3,2-g]quinoline-2,8-dicarboxylic acid
The product of step (a) (0.77g) was suspended in
ethanolic hydrogen chloride (20ml) and heated under reflux
for 24 hours. Evaporation of the solvent aEEorded a
residue which was separated by high pressure liquid
chromatography to give the title compound (0.2g) which was
chromatographically identical to the product of Example 2.
~;~ Example 21
9-Ethyl-6,9-dihydro-4,6-di_xo-'0-pro~yl-4H-pyrano-
L3,2-~3quinoline-2,8-d carboxylic acid
(a) Dieth~1_9-eth~1-6,9-dihydro-10-propyl-4,6-dithioxo-4H-
py~ano~3,2-g]quinoline-2,8-dicarboxylate
Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-lO~propyl-4M-
pyrano[3,2-g]quinoline-2,8-dicarboxylate (lOg) and penta-
phosphorus decasulphide (20g) were fused together at
160C for 6 hours, then cooled and the product mixture
was extracted into ethyl acetate. Chromatography (silica
gel/ethyl acetate) afforded the sub-title compound
(5.6g). The structure was verified by n.m.r. and mass
spectroscopy.
(b) 9-EthYl-6,9-dihydro~4,6-dioxo-lO-propyl-4H-pyrano-
[3,2-g]quinoline-2,8-dicarboxylic acid
The diester from step (a) was heated at 100C in
glacial acetic acid (50ml) containing concentrated hydro-
- 67
.. . .
,~
,
; :: , : - .
.. ..
4245/74 ~ 68 ~ ~ ~ Z ~ ~ ~
chloric acid (5ml~ for 24 hours. The acetic acid solvent
was evaporated and the residue was triturated with ether.
The solid residue was dissolved in acetonitrile 150ml)
containing water (lml), and was stirred vigorously with
mercuric cnloride (2g). After 48 hours the solution was
filtered, and the filtrate was diluted with water (250ml)
and then acidified. The precipitated solid was purified
by high pressure liquid chromatography to afford the title
compound (2.1g~ which was chromatographically identical
with the product of Example 2.
Example 22
. ,
9-Ethyl-6,9 dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g)- ~;
., .
quinoline~2,8-dicarboxylic acid
- (a) 9-Ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl- H-
pyrano~3,2-g]quinoline-2L8-dicarboxylic acid
Diethyl 6,9-dihydro-4,6-dioxo~10-propyl-4H-pyrano-
[3,2-glquilloline-2~8-dicarboxylate (5g) in glacial acetis
acid (lOOml) was hydrogenated over Adams catalyst (0~5g)
at 4 atmospheres until hydrogen uptake ceased. The
catalyst was removed and concentrated hydrochloric acid
(5ml) was added~ The solution was refluxed for 24 hours
then evaporated. High pressure liquid chromatography of
the residue gave the sub-title compound (0.9g). The
structure was supported by n.m.r. and mass spectroscopy.
- 68
.,
:: -
:.,: : . ,~
4245/74 ~ 69
r
(b) 9-Ethyl-5,9~dihydro-4,G-dioxo-10-pro~yl-4H-pvrano-
[3,2-g~quinoline-2,8-dicarboxylic acid
.. .
- The product of step (a) (0.85y~ was suspended in
cymene (lOml) and treated with 10~ Pd/C catalyst at reflux
for ~ hours. Filtration and evaporation afforded a gum
which was purified by high pressure liquid chromatography
; to give the title compound (0.15g) chromatographically
identical wlth the product of Example 2.
Example 23
9-Ethyl-6,9-dihydro 4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-
quinoline-2,8-dicarboxylic acid
.
(a3 1-Ethyl-1,4-dihydro-7-hy_r_xy-6-methoxycarbonyl-4-
oxo-8-eropylquinoline-2-carboxylic acid
Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-
pyrano[3,2-gJquinoline-2,8-dicarboxylate (4.279) and
sodium hydroxide (1.69) in water (lOml) were heated to
reflux for 24 hours, then the`water was evaporated and the
residue was suspended in ethanol (SOml) saturated with
hydrogen chloride gas and refluxed for 1 hour. Evaporation
of the solvent afforded a residue which was chromato-
graphed (silica gel/ether) to afford a diester (1.3g)
which was boiled with a solution of sodium hydroxide
(0.139g) in water (20ml). On acidification a precipitate
wa~ formed which was shown to be the desired product
(0.93g) by n.m.r. and mass spectroscopy~
~ 69
~ '
.. ~
,: ''-'" ''' -' ~ ,
6~
~245/74 - 7~ -
,
(b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-pro~yl~4H-pyrano-
[3,2 glquinoline-2,8-dicarboxYlic acid
.-- ,
The product of step ~aj (0.9g) dissolved in dry di-
~ methyl sulphoxide (lOml) was added to a solution of dimsyl
`~ 5 sodium (lg) in dry dimethul sulphoxide (50ml) at 40C
under N2. After 48 hours the reaction mixture was
poured into water (500ml) and ether extracted. Drying and
evaporation afforded a red oil which was suspended in
toluene (20ml) and treated with piperidine (l.lg) and gly-
;~ 10 oxylic acid hydrate (1.5g). After refluxing for 5 hours,
the mixture was cooled, poured into ethyl acetate (lOOml)
and washed with saturated sodium bicarbonate solution.
The sodium bicarbonate solution was acidified and extrac- -
ted with ethyl acetate. Drying and evaporation gave a gum
which was separated by high pressure liquid chromatography
to yive the title compound (0.139) ~hich was identical
chromatographically to the product of Example 2.
Example 24
9-Ethyl-10-propyl-2,3-di-tetrazol 5-yl-4H-pyrano[3,2-~]~
quinoline-4_6(9~)-dione
(a~ 9-Ethy_ 6,9-dihyd o-4/6-dioxo-10-propyl-4H-pyrano-
[3,2-g]quinoline-2/8-dlcarbonitrile
9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-
13,2-g]quinoline-2,8-dicarbonyl chloride (lOg) was added
dropwise to cooled aqueous ammonia solution (lOOml) with
~ 7~
.. . ~ . ~
4245/74 - 71
.~
stirring. The insoluble material ~as collected and washed
well with water, then dried ln vacuo at 80C.
The solid was added to a solution of phosphoryl
chloride (209) in dry dimethyl formamide (lOOml) and
warmed to 60C for 48 hours. The reaction mixture was
cooled and poured into water (1 litre), and extracted into
ether. Drying and evaporation afforded an oil which was
chromatographed (silica gel/ether) to afford the sub-title
compound ~3.79). The structure was supported by n.m.r.
and mass spectroscopyO
(b) 9-Ethyl-10-propyl-2,8-di-tetrazol-5-yl-4H-Pyrano-
; [3,2-g]quinoline-4,6(9H)-dione
The product of step (a) t3.6g~ and ammonium azide
(1.3g) in dry dimethyl formamide (lOOml) were heated to
140C for 16 hours then cooled ancl poured into water.
On acidification a precipitate was obtained which was
chromatographed (silica gel~ethyl acetate) to produce the
title compound ~1.69).
NMR ~DMSO: 1.0(3H,t); 1.1(3XIt); 1.8(2X,m); 3.8(2EI,m);
4.5(2H,m); 7.1(1H,s~; 8.65(1H,s); 8.8(1H,s); 10.1(2Hbrs).
'~ ' `
