Note: Descriptions are shown in the official language in which they were submitted.
- 1 -
This invention relates to tricyclic compounds useful
in medicine, to the preparation of such compounds, to forum-
ceutical formulations and other presentation forms containing
such compounds and the preparation thereof, to the use of the
compounds in medicine, and to novel intermediates for the said
compounds and the preparation thereof.
This Application is a divisional of Canadian Patent
Application, Serial No. 426,692j filed on April 26, 1983.
The present invention more particularly relates to
the novel tricyclic compounds of formula (I):
X~[~X2~ (1)
I
,
as hereinafter defined, which are of value in both human and veterinary
medicine in enabling an increase in oxygen liberation from oxyhaemoglobin.
Human hemoglobins are composed of four palpated (glob in) chains
which together comprise the hemoglobin tetramer; each chain surrounds
a porphyrin molecule (hem) containing a central iron atom to which oxygen
is reversibly bound. When a graph is plotted of the percentage saturation
of hemoglobin with oxygen (ordinate) against the partial pressure of oxygen,
sometimes called the oxygen tension (abscissa) a characteristic sigmoid
curve is obtained, the oxygen-dissociation curve. A displacement of the
curve to the left of the "normal" position would indicate an increase in
the affinity for oxygen of the hemoglobin, a lower oxygen tension then
being required to produce a given percentage saturation, while conversely
a displacement to the fight would indicate a reduced oxygen affinity and
hence a requirement for a higher oxygen tension for a given percentage
saturation. It follows that upon displacement of the curve to the right
there is a reduction in the percentage of oxyhaemoglobin present at any
given oxygen tension and hence an increased liberation of oxygen upon a
fall in tension to any given level.
The compounds of formula (I), as hereinafter defined, induce an in
vitro right-displacement of the oxygen-dissociation curve
a) of fresh whole human blood and
b) of whole human blood subjected to a procedure (incubation overnight
at 37C) producing changes similar to those seen in blood stored for extended
periods by transfusion services and the like (vise infer).
MC/JAH/20th April.
I, .
. i
The compounds thus have applications both in viva and in vitro in
circumstances where it is desirable to provide a more effective delivery
of oxygen to the tissues of the (eventual) recipient.
In viva applications for the compounds include the following, many
of which may be together classed as the relief or amelioration of conditions
wherein the delivery of oxygen to the tissues is impaired, i.e. wherein there
is tissue hypoxia:
-the treatment of shock
-the treatment of cardiac ischaemia,for example after myocardial
10 infarction (coronary thrombosis), and the relief of suckle thereto such
as angina pocketers
-the treatment of cerebral ischaemia and of cerebrovascular accidents
in general
-the relief of intermittent claudication
-the treatment of placental insufficiency in graved females
-the treatment of certain anemic conditions and in particular pathological
anemia in preterm infants
-the treatment of the micro vascular complications of diabetes Maltese
-the treatment of hypovolaemic anemia of trauma (the so-called
"missing blood syndrome")
-as an adjunct to anesthesia in cardiac bypass surgery, in particular
in patients having compromised respiration
-applications in which a pathological tissue or invading organism
is made more sensitive to treatment by increasing the partial pressure
of oxygen in its environment, for example:
MC/JAH/20th April.
~LZZ93~L
_ 4 -
the radio sensitization of tumors as an adjunct to deep X-ray
therapy, with or without concomitant hyperbaric oxygen treatment,
the treatment of infections of oxygen-sensitive parasites, for
example, anaerobic bacteria.
Thus in one aspect of the invention there is provided
a sterile, sealed vessel containing an anti-coagulant and a non-
toxic amount of a tricyclic compound of formula (I), as defined
above, or a pharmacologically acceptable salt thereof.
In a particular embodiment the sealed vessel contains
human erythrocytes and effective amounts of the anti-coagulant
and the non-toxic compound or salt.
In another aspect of the invention there is provided
a method for maintaining the oxygen-delivery capacity of stored
human erythrocytes in which the cells a admixed, prior to
their transfusion into a recipient, with a non-toxic,
maintenance-effective amount of the compound (I) or acceptable
salt thereof.
In still another aspect of the invention there-is
provided a method for prolonging the useful storage life of
stored human erythrocytes which comprises admixing the cells
prior to their transfusion into a recipient, with a non-toxic,
prolongation-effective amount of the compound (I) or accept-
able salt thereof.
aye
- pa -
A major in vitro application for the compounds is in the field of blood
storage. As is well known there is an ever-present need for human blood
by medical services throughout the world for use in a wide variety o, life-suppor-
live measures. For the majority of recipients whole blood is the only accept
table material as although a number of alternatives have been proposed,
none has been found to be a completely satisfactory substitute. The collection,
storage and distribution of blood is generally catered for by specialist trays-
fusion services or blood banks" as exemplified by the National Blood Trays-
fusion Service in the United Kingdom. The effective and economic operation
10 of such agencies is however in large measure governed by the fact that
whole blood or, more correctly, the red blood cells (erythrocytes) therein,
even when stored as customarily at 4C, have a very limited "shelf-life"
generally accepted as I days after removal from the donor By the end
of this period they are considered unsuitable for transfusion and are discarded
and there has been considerable research into methods for prolonging the
useful life of stored red blood cells and thus reducing the wastage due to
"out-dating".
A particular feature of the aging of red blood cells during storage
is a progressive left-displacement of the oxygen-dissociation curve associated
us with a fall in intracellular levels of 2,~-diphosphoglycerate (DUG), the earthier-
~Z~93~4
cites' natural right-displacement effecter. As previously indicated a
left-displacement is associated with the hemoglobin having an increased
affinity for oxygen and hence aging cells exhibit a progressive decline
in their ability to deliver oxygen to the peripheral tissues following
transfusion. Although this property is gradually restored within the
recipients body as DUG levels recover, the initial deficiency is of
literally vital significance as the prime reason for transfusing red
blood cells (as distinct from just plasma) is generally the immediate
prevention or reversal of tissue hypoxia (vise swooper). The present
compounds, in displacing the oxygen-dissociation curve to the right,
are of value not only on maintaining the oxygen-delivery capacity of
stored red blood cells, thus improving their quality and providing
improved oxygen-delivery in the immediate post-transfusion period, but
also in prolonging their useful storage life.
In formula (I), as set forth above,
X is a carboxyl or 5-tetrazoLyl group
X is carbonyl or ethylene
X3 is hydroxyl or a group -X4(CnHzn)X5
where
X is oxygen or Selfware
X lo hydrogen or a group ox
where
X is hydrogen, alkanoyl of 1 to 4 carbon atoms or a group ~(CmH2m~X7
why
X is hydrogen or a group - OX
where
X is hydrogen or alkanoyl of 1 to 4 carbon atoms and
~2z~3~
m and n are each, independently, an integer from 1 to 4,
together with salts thereof,
provided that when X is a group ox then n is always greater
than 1 and X4 and X5 are attached to different carbon atoms
and that when X7 is a group ox then m is always greater than 1
and no single carbon atom in the radical -(C H )- it attached to two
- m Em
oxygen atoms.
As herein understood, the 5-tetrazolyl group us that having the
structural formula
.--' I
_ N
which thus embraces both tautomeric forms thereof respectively identi-
liable as 5-/1H/ tetrazolyl and 5~/2H/-tetrazolyl~
When m and/or n is 3 or 4 the moieties -(CmH2m)- and -(C Ho Jo can
be linear or branched.
In the salts of the compounds of formula tip the biological
activity resides in the tricyclic (anion) moiety and the identity of
the cation is of less importance although for use in medicine it is
preferably pharmacologically acceptable to the eventual recipient
Suitable salts include ammonium salts, alkali metal salts such as
sodium and potassium salts, alkaline earth salts such as magnesium
and calcium salts, and salts formed with organic bases, for example,
~2293~
amine salts derived from moo-, dip or troweler alkyd) or (lower
alkanol)amines such as triethanolamine and diethylaminoethylamine,
and salts with heterocyclic amine such as piperidine, pardon,
piperazine and morpholine.
As a class of compounds within formula (I) may be mentioned
those wherein:
x1 is a carboxyl or 5-tetrazolyl group
X is carbonyl or ethylene
X3 is hydroxyl or a group -X4~CnH2n)X5
where
X us oxygen or Selfware
X is hydrogen or a group ox
why
x6 is hydrogen or alkanoyl of 1 to 4 carbon atoms and
n is an integer from 1 to 4,
together with salts thereof,
provided that when X is a group ox then n is always greater
than 1 and X4 arid X are attached to different carbon atoms
As subclasses of compounds within formula (I) may be mentioned
those wherein:
(;) x1 is 5-tetrazolyl and salts thereof
(j;) x2 is carbonyl
(iii) X3 is a group -X4(CnH2 )X5
(iv) X is oxygen
(v) X is hydrogen
~Z2~3~
(vi) X5 is a group ox where X is hydrogen, i.e. X5 is
hydroxyl
tvii) n is 2 or 3.
- Two further classes of compounds within formula (I) respectively
comprise those wherein
(a) X1 is 5-tetrazolyl, x2 is carbonyl and X3 us -O(CnH2n)H; and
(by X1, x2 and X3 are as herein before defined, provided that
X is other than -O(CnH2n)H when X1 and x2 are respectively 5
tetrazolyl and carbonyl;
together with salts thereof.
Preferred compounds within formula (I) are
C2~50
chemically named 2-ethoxy-6-(5-tetrazolyl)xanthone, together with salts
thereof, and on particular
HO (SHEA 2 I;
O ~/~ N
NUN
~Zz93~!4
chemically named 2-(2-hydroxyethoxy)-6-(5-tetrazolyL)xanthone,
together with salts thereof
Where the compounds of formula (I), as above defined, include
an asymmetric center the said formula should be understood to include
all optical isomers embraced thereby and mixtures thereof.
The compounds of formula (I) and their salts may be prepared by
those methods known in the art for the synthesis of compounds of
analogous structure and in thus regard reference is made by way of
illustration only, to the following standard texts:-
(i) "Protective Groups in Organic Chemistry" Ed JAW McOmie,Plenum Press (1973), ISBN 0-306-30717-0;
(ii) "Compendium of Organic Synthetic Methods" Ed IT. Harrison
and S. Harrison, Wiley-Interscience, Vol. I ~1971) IS8N 0-471-35550-X,
Vol. II (1974~IS8N 0-471-35551-8 and Vol. III ted. LO Hegedus and
L. Wade) (1977) ISBN 0-471-36752-4; and
(iii) Rhodes "Chemistry of Carbon Compounds" second edition,
Elsevier Publishing Company.
/
/
~L2~2~3~
. . 'I
(1) One method, applicable to both the xanthenes (X2 is ethylene) and
the xanthones (X2 is carbonyl) within formula (I), comprises cyclization
5 in the presence of a base of a compound of formula (II)
~3~,~x2~ (If)
wherein X1, x2 and X3 are as defined in formula (I) and one of z1 and z2
is hydroxyl or an ester thereof and the other is a leaving atom or group.
Amongst suitable leaving atoms/groups are halo (for example sheller),
vitro and sulphinyl while appropriate bases include alkali metal alkoxides
10 such as sodium rnethoxide and sodium ethoxide.
(2) The xanthones may also be prepared by cyclization in the presence of
a Lewis or pro tonic acid of a compound of formula (III)
Lowe X~lx l (III)
MC/JAH/20th April.
I
1 .
wherein X1 and X3 are as defined in formula (I) and I is a carboxyl group,
a derivative thereof or a formal group.
Suitable identities for Z3 as carboxyl group derivatives include cyan,
carbamyl and chlorocarbonyl. Suitable Lewis acids include aluminum tracheal
ride, ferris chloride, phosphorus oxychloride and boron trifluoride while
preferred pro tonic acids are polyphosphoric (tetraphosphoric) and sulfuric
acids. The reaction is preferably effected at a temperature in the range
20 to 160C.
(3) A further preparation of the xanthones comprises selective oxidation
of the corresponding xanthene also within formula (I).
A suitable selective oxidizing agent comprises oxygen in the presence
of Briton B (tetramethylammonium hydroxide) and pardon.
(4) Conversely, the xanthenes may be prepared by selective reduction of
the corresponding xanthone within formula (1).
Suitable selective reducing agents include zinc and an acid, for example
acetic or hydrochloric acid and zinc amalgam and concentrated hydrochloric
acid (the Clemmensen reduction).
(5) The compounds of formula (I? wherein X1 is 5-tetrazolyl may be prepared
by the reaction with hydrazoic acid or a salt thereof or with nitrous acid,
as appropriate, of a compound of formula (IV)
My jJAH/2ûth April
^ trade Mark
~LZZ~3~
OX
Z
wherein x2 and I are as defined in formula (I) and Z4 is a 5-tetrazolyl
group precursor as herein defined.
When hydrazoic acid or a salt thereof is employed the 5-tetrazolyl
group precursor is a group of formula
--C = N
16 15
wherein Z5 and z6 together form a bond (nitrite), Z5 is hydrogen or alkyd
of 1 to 4 carbon atoms and z6 is alkoxy of 1 to 6 carbon atoms (imidoester),
alkylthio of 1 to 6 carbon atoms (imidothioester), hydrazino (amidrazone),
or amino (amidine) or Z5 is hydroxyl and z6 is amino (amidoxime). The
reaction is desirably effected in a polar aprotic liquid medium, for example
lo dimethylsulphoxide, dimethylformamide, hexamethylphosphoramide, dimethylace-
tumid, N-methyl-2-pyrrolidone, sulpholane and acetonitrile and mixtures
thereof, and preferably with a hydrazoic acid salt such as sodium or ammonium
a ides
MC/JAH/20th April.
.
3~4
13
When nitrous acid is employed the 5-tetrazolyl group precursor is
also a group of formula
-- C _ N
z6 z5
wherein Z5 is hydrogen or alkyd of 1 to 4 carbon atoms and ;z6 is hydrazino
~amidrazone), or Z5 is hydrogen and z6 is amino (amidine). In the latter
case selective reduction of the initially formed notarization product, with
or without prior isolation and using an agent such as sodium amalgam, is
required to provide the 5-tetrazolyl end product.
(6) The compounds of formula (I) wherein X1 is carboxyl may be prepared
by hydrolysis of a compound of formula (V)
Zoo (V)
wherein x2 and X3 are as defined in formula (I) and Z7 is a carboxyl group
precursor as herein defined.
Suitable identities for Z7 include cyan, trichloromethyl and a group
Casey where z8 is a leaving, preferably nucleophilic atom or group such
as halo, trichloromethyl, alkoxy of 1 to 6 carbon atoms and optionally-substi-
tuned amino.
MC/JAH/20th April.
~2~3~
.
The hydrolysis may be effected by heating with either a dilute aqueous
mineral acid, for example sulfuric or hydrochloric acid, optionally in the
presence of an organic acid such as acetic acid, or with a base such as an
alkali metal hydroxide or alkoxide, for example aqueous sodium or potassium
5 hydroxide, sodium methoxide and sodium ethoxide.
It will be appreciated that the basic conditions appropriate to cyclization
of a compound of formula (II) (vise (1) swooper) will also effect hydrolysis
of a group Z7 as defined in formula (V) and that the former synthetic approach
may hence be extended to include, where necessary, a combined ("one-pot")
10 cyclization/hydrolysis procedure. The starting material for method (1)
may thus more generally be represented by formula (Ill)
I x I (ha)
z2 z1 ye
wherein x2 and X3 are as defined in formula (I), one of z1 and z2 is hydroxyl
or an ester thereof and the other is a leaving atom or group and ye is a
group X1 as defined in formula (I) or a carboxyl group precursor as herein
15 defined.
to) The carboxyl compounds of formula (I) may also be prepared by selective
oxidation of a compound of formula (VI)
My H/2ûth April.
, .
2 2 I 3 I!
`- X2 lo
TV
wherein x2 and X3 are as defined in formula (I) and Z9 is alkyd or alkanoyl
of 1 to 6 carbon atoms.
Alkyd identities for Z may be oxidized with agents such as acid or
alkaline aqueous potassium permanganate, an aqueous dichromate salt such
5 as sodium or potassium dichromate in the presence of acetic acid, oxygen
in the presence of a catalyst such as a cobalt, manganese or vanadium salt
or oxide and chromium trioxides with for example acetic or sulfuric acid
while oxidation of an alkanoyl group may be effected by means of an agent
such as nitric acid, an aqueous dichromate salt such as sodium or potassium
dichromate in the presence of acetic acid, an aqueous salt of hypobromous
or hypochlorous acid in the presence of a base and chromium trioxides with
for example acetic or sulfuric acid.
It will be appreciated that the formation in this manner of the carboxyl
identity for X1 may, if desired, be effected in association with the conversion
15 of a xanthene precursor to a xanthone end-product (vise (3) eye) the
two procedures being conducted either sequentially or simultaneously (as
a "one-pot" reaction) depending upon the identity of the selective oxidizing
agent(s) employed The starting material for the oxidative preparation
of the compounds ox formula (I) may thus generally be represented by formula
20 (VII)
MC/JAH/20th April.
l~Z~3~
(Ill)
wherein x2 and X3 are as defined in formula (I) and ye is a group Al as
defined in formula (I) or alkyd or alkanoyl of 1 to 6 carbon atoms, provided
that when x2 is carbonyl then ye is always alkyd or alkanoyl.
(8) The carboxyl xanthenes of formula (I), i.e. where X1 is carboxyl and
5 x2 is rnethylene, may be prepared by carooxylation of a compound of formula
(VIII)
X Jo SHEA
¦ O I I O ¦ (VIII)
._ . ,
wherein X3 is as defined in formula (I) and zoo is halo, preferably broom
or idea.
This may be effected by for example reacting the compound (VIII)
10 in ethereal solution with either lithium or magnesium, in the latter case
to yield the appropriate Grignard reagent, and then contacting the mixture
with gaseous or solid carbon dioxide.
(9) A further synthetic approach comprises conversion of a compound of
formula (IX)
MC/OAH/20th April.
I
I Al (IX)
wherein X1 and x2 are as defined in formula (I) and z11 is a group convertible
to a group X also as defined in formula I).
Compounds wherein X3 is hydroxyl may be prepared by hydrolysis
of a suitable precursor, for example by reaction with water of a corresponding
diazonium salt (Z11 is -NOAH where W is an anion such as chloride, bromide
and hydrogen sulfite), the latter being prepared by the action of nitrous
acid on the amine (Z11 is amino). The diazonium salts may also be converted
to the corresponding alkylthio end-products (wherein X4 is Selfware and
X5 is hydrogen) by reaction with an appropriate potassium alkyd xanthate
and sequential decomposition of the successively formed diazoxanthate
and aromatic xanthate by warming in a faintly acidic cuprous medium (the
Lockhart synthesis). The alkylthio compounds may also be prepared by
alkylation of the corresponding they'll (Z11 is Marquette) which may be obtainedby for example alkaline hydrolysis of the previously mentioned aromatic
xanthates.
The hydroxyl compounds may also be prepared from precursors having
as z11 a group ooze which is convertible to hydroxyl. Suitable identities
for the moiety z12 include alkyd, for example alkyd of 1 to 4 carbon atoms
and in particular methyl, ethyl, isopropyl and t-butyl; aralkyl such as bouncily;
azalea such as alkanoyl, in particular alkanoyl of 1 to 6 carbon atoms, for
MC/JAH/20th April.
AL 2
. I
- example acutely; and tetrahydropyranyl. Such groups may be removed, i.e.
replaced by hydrogen, by methods standard in the art. Thus removal of
an alkyd group may be effected using for example magnesium iodide or
sodium thiocresolate, by heating with aluminum trichloride in zillion or
(at reduced temperatures) by use of an agent such as boron trichloride or
tribromide in a medium such as dichloromethane; an azalea group may be
removed by base hydrolysis; an alkyd group and tetrahydropyranyl may be
removed by acid hydrolysis, for example using hydrogen bromide in acetic
acid; and hydrogenolysis (for example using a palladium charcoal catalyst)
may be used to remove an aralkyl group.
It will be appreciated that certain of the above-described conditions
for removal of an alkyd group will also be suitable for effecting cyclization
as described in (2) swooper and that hence the hydroxyl xanthones of formula
(I) may be prepared by a "one pot" cyclization/dealkylation of the alkoxy
compounds of formula (III) (wherein X4 is oxygen and X5 is hydrogen).
Alkoxy compounds may be prepared by alkylation of the corresponding
hydroxyl compound, for example by use of an alkyd halide or dialkyl sulfite
and an alkali such as an alkali metal hydrides or carbonate.
The hydroxyl compounds may be converted to the corresponding hydroxy-
alkoxy compounds (wherein X4 is oxygen and X5 is hydroxyl) by for example
reaction with the appropriate alkaline oxide or carbonate and the hydroxy-
alkylthio compounds (wherein X4 is Selfware and X5 is hydroxyl) may be
similarly prepared from the corresponding they'll ~Z11 is Marquette); when
in the said starting materials X1 is carboxyl the latter group may be simultaneously
MC/JAH/20th April.
I
to
esterified by this procedure, the desired end-product then being obtained
by selective hydrolysis thereof (vise (6) swooper). The end-products wherein
X5 is alkanoyloxy (i.e. x6 is alkanoyl) may be prepared from the corresponding
hydroxyalkoxy or hydroxyalkylthio compounds, as appropriate, by conventional
5 alkanoylation procedures and the latter may be obtained by hydrolysis of
the former.
In the preparation of the compounds of formula (I) by the above-described
methods it will be understood that where the groups X1 and X3 are formed
prior to the complete formation of the desired end-product it may in some
instances be desirable to protect said groups from reaction in the final
synthetic step(s), and subsequently regenerate them by appropriate deprotection
procedures, using techniques well known in the art; alternatively the formation
of X1/X3 may advantageously comprise the final step in the synthetic sequence.
The compounds of formula (I) may be isolated as the acids or as salts
thereof and it will be appreciated that the said acids may be converted
to salts thereof, and the reverse, and the salts converted to salts formed
with other cations, by techniques well-known and conventional in the art.
Thus, those salts which are not themselves pharmacologically acceptable
are of value in the preparation of the parent carboxyl or 5-tetrazolyl acids
and of pharmacologically acceptable salts thereof.
When the preparative procedures herein described provide a mixture
of optical or other isomers of a compound of formula (I) or of an intermediate
thereto, the individual isomers may be separated by appropriate conventional
techniques.
MC/JAH/20th April.
.
293~
The compounds the formula (I), as above defined, may be used in both
human and veterinary medicine in circumstances such as those previously
identified where it is desirable to provide a more effective delivery of oxygen
to the tissues of the (eventual) recipient. When administered in viva the
compounds may be used both on a regular maintenance basis and for the
relief or amelioration of acute crisis states.
For in viva use the compounds may be administered to the human
or non-human recipient by a route selected from oral, parenteral (including
subcutaneous, intradermal, intramuscular and intravenous) and rectal.
The size of an effective dose of a compound will depend upon a number
of factors including the identity of the recipient, the precise condition
to be treated and its severity and the route of administration and will multi-
mutely be at the discretion of the attendant physician or veterinarian.
An effective dose will generally be in the range 1 to 500 mg/kg Baudot
of recipient per day, more generally in the range 10 to 250 mg/kg Baudot
per day and most often in the range 25 to 100 mg/kg Baudot per day,
a particularly suitable dose being 50 mg/kg Baudot per day (all doses
calculated as the carboxyl or 5-tetrazolyl acid of formula (I); for salts the
figures would be adjusted proportionately). The desired dose is preferably
presented as between two and four sub-doses administered at appropriate
intervals throughout the day. Thus where two sub-doses are employed each
will generally be in the range 0.5 to 250, more generally 5 to 125 and most
often 12.5 to 50 my (acid)/kg Baudot with an optimum of 25 my (acid)/kg
Baudot.
MC/JAH/20th April.
~2~3~
Al
A daily dose for a human being weighing of the order of 50 kg will
thus generally be in the range 50mg to 259 (acid), more generally in the
range 500 my to 12.59 (acid) and most often in the range 1.259 to 59 (acid)
and may be conveniently presented as two equal unit sub doses of 25mg
to 12.59 (acid), more generally 250mg to 6.259 (acid) and most often 0.6259
to 2.59 (acid). Optimally a human daily dose is 2.59 (acid) conveniently
presented as two unit sub-doses each of 1.259 (acid). For veterinary use,
for example in the treatment of non-human mammals such as cats, dogs,
cattle, sheep, pigs and horses, the above-recited doses would be increased
or decreased at the discretion of the veterinarian having regard to the weight
and identity of the recipient.
While it is possible for the compounds of formula (I) to be administered
as the raw chemical it is preferable to present them as a pharmaceutical
formulation preparation. The formulations of the present invention, for
human or for veterinary use, comprise a compound of formula (I), as above
defined, together with one or more acceptable carriers therefore and optionally
other therapeutic ingredients. The carrier(s) must be 'acceptable' in the
sense of being compatible with the other ingredients of the formulation
and not deleterious to the recipient thereof.
:20 The formulations include those suitable for oral, parenteral (including
subcutaneous, intradermal, intramuscular and intravenous) and rectal ad minis-
traction although the most suitable route may depend upon for example the
condition and identity of the recipient. The formulations may conveniently
be presented in unit dosage form and may be prepared by any of the methods
well known in the art of pharmacy. All methods include the step of bringing
into ask- ration the compound of formula (I) (the active ingredient) with
MC/JAH/2ûth April.
93~
.
the carrier which constitutes one or more accessory ingredients. In general
the formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into the desired
5 formulation.
Formulations of the present invention suitable for oral administration
may be presented as discrete units such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient; as a powder
or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous
10 liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The active ingredient may also be presented as a bonus, elixir or paste.
A tablet may be made by compression or mounding, optionally with
one or more accessory ingredients. Compressed tablets may be prepared
-- by compressing in a suitable machine the active ingredient in a free-flowing
15 form such as a powder or granules, optionally mixed with a binder, lubricant,
inert delineate, lubricating, surface active or dispersing agent. Mpulc'ed tablets
may be made by mounding in a suitable machine a mixture of the powdered
compound moistened with an inert liquid delineate. The tablets may optionally
be coated or scored and may be formulated so as to provide slow or controlled
f70 release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous
sterile injection solutions which may contain anti-oxidants, buffers, bacteria-
stats and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile suspensions
MC/JAH120th April,lg82.
31 I
13
which may include suspending agents and thickening agents. The formulations
may be presented in unit-dose or multi-dose containers, for example sealed
ampules and vials, and may be stored in a freeze-dried (Iyophilized) condition
requiring only the addition of the sterile liquid carrier, for example water
for injections, immediately prior to use. Extemporaneous injection solutions
and suspensions may be prepared from sterile powders, granules and tablets
of the kind previously described.
Formulations for rectal administration may be presented as a suppository
will the usual carriers such as cocoa butter and polyethylene glycol.
Preferred unit dosage formulations are those containing a daily dose
or unit daily sub-dose, as hereinabove recited, or an appropriate fraction
thereof, of a compound of formula (I).
-- It should be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include other agents
conventional in the art having regard to the type of formulation in question,
for example those suitable for oral administration may include flavoring
agents.
The compounds of formula (I) may also be presented as depot formulations
of the kind known in the art from which the active ingredient is released,
over a prolonged period, once the formulation is in place within the body
of the recipient.
MC/~AH/20th April.
I 4
- I
A further application for the compounds of formula (I) is the extractor-
portal treatment of blood from the (generally human) patient. As one possibility
such treatment may be conducted in a batch-wise manner by removing
an appropriate volume of blood, admixing it with the compound and transfusing
the treated blood back into the patient. As an alternative possibility the
treatment may be on a continuous basis, analogous to the well-known tech-
piques for haemodialysis, whereby for a period of time blood is continuously
withdrawn admixed with the compound and passed back into the patient.
Both procedures should be conducted under sterile conditions and may be
repeated as often as necessary. An effective blood concentration of a compound
of formula (I) will generally be in the range 0.1 my to 50 my, more generally
in the range û.5 my to 25 my and most often in the range 1 my to 10 my,
with an optimum concentration of 3 my.
.
For in vitro use in the storage of red blood cells as previously described
15 the compounds are conveniently admixed with the cells in the vessel in
which the latter are collected and stored; this conventionally takes the
form of a bottle or bag of sufficient size to hold the customary whole blood
unit (circa 450 ml.) together with an Alcott of anticoagulant. A compound
may be brought into contact with the cells at any appropriate point between
20 their collection from the donor and their transfusion (together with the
compound) into the recipient. As one possibility therefore the compound,
in association with the anticoagulant, is present within the bottle or bag
when the latter is "ready for use", the admixture occurring upon entry of
the blood, while in an alternative approach the compound is added to cells
25 already held within the bottle/bag, for example immediately subsequent
to collection or just prior to use transfusion). The compounds may be used
MC/JAH/20th April.
~22~33~9~
in Lucy fashion whether the cells are stored in the form of whole blood or
as a packed cell mass (when the plasma is held separately) and, in the latter
case, whether transfused resuspended in plasma or in a plasma substitute.
The effective concentration of a compound, in whole blood volume
in a bottle or bag as above described, will generally be in the range 0.1 my
to 50 my, more generally in the range 0.5 my to I my and most often
in the range 1 my to 10 rum, with an optimum concentration of 3 my.
Although the precise weight of compound required will vary with its identity
a standard size bottle/bag tide swooper) will require circa 0.59 (calculated
10 as the acid) to provide the optimum 3 my concentration.
The compounds of formulae (II) to (IX) as herein before defined may
be-prepared by those methods known in the art for the synthesis of compounds
of analogous structure and in particular, inter alias by methods analogous
to those taught herein in respect of the compounds of formula (I) using
20 appropriate starting materials and conditions as herein before described.
It will be understood from the foregoing description that this invention
may comprise any novel feature described herein, principally but not exclusively
f r example:
(a) Compounds of formula (I) as herein before defined and salts thereof.
(b) Methods as herein before described for the preparation of compounds
according to (a) eye, together with the compounds when so prepared.
(c) Compounds of formula (I) as hereinoefore defined and pharmacologic
gaily acceptable salts thereof for use in the medical treatment of a mammal
and in particular a human being.
MC/JAH/20th April.
aye
Al,
(d) Compounds of formula (I) as hereinbeFore defined and pharmacologic
gaily acceptable salts thereof for use in a mammal, in particular a human
being, to provide a more effective delivery of oxygen to the tissues.
(e) Compounds of formula (I) as herein before defined and pharmacologic
gaily acceptable salts thereof for use in a mammal, in particular a human
being, in the relief of tissue hypoxia.
(f) A pharmaceutical formulation comprising a treatment-effective
amount of a compound of formula (I) as herein before defined or a pharmacolo-
jackal acceptable salt thereof together with an acceptable carrier therefore
(9) A method for the preparation of a formulation according to (f)
- eye comprising admixture of the active ingredient, as defined, with the
carrier therefore
(h) A method for providing a more effective delivery of oxygen to
the tissues of a mammal, in particular a human being, comprising administering
to a mammal in need thereof a non-toxic, treatment-effective amount
of a compound of formula (I) as herein before defined or a pharmacologically
acceptable salt thereof.
(i) A method for the relief of tissue hypoxia in a mammal, in particular
a human being, comprising administering to a mammal in need thereof a
non-toxic, treatment-effective amount of a compound of formula (I) as
herein before defined or a pharmacologically acceptable salt thereof.
(j) A method for maintaining the oxygen-delivery capacity of stored
mammalian red blood cells comprising admixing said cells, prior to their
MC/J~H/2ûth April.
~ZZ~3~4
27
transfusion into a recipient mammal, with a non-toxic, maintenance-effective
amount of a compound of formula (I) as herein before defined or a pharmacologic
gaily acceptable salt thereof.
(k) A method for prolonging the useful storage life of stored mammalian
red blood cells comprising admixing said cells, prior to their transfusion
into a recipient mammal, with a non-toxic, prolongation-effective amount
of a compound of formula (I) as herein before defined or a pharmacologically
acceptable salt thereof.
(l) A method according to (j) or (k) swooper wherein the red blood cells
are human in origin.
(m) A sterile, sealed vessel containing an anticoagulant and a non-toxic
amount of a compound of formula (I) as herein before defined or a pharmacologic
gaily acceptable salt thereof.
(n) A sterile, sealed vessel containing mammalian, in particular human,
red blood cells, an effective amount of an anticoagulant and a non-toxic
amount of a compound of formula (I) as herein before defined or a pharmacologic
gaily acceptable salt thereof.
(o) Novel compounds of formulae (II) to (IX) as herein before defined,
methods for their preparation as herein before described and the compounds
when so prepared.
MC/JAH/20th April.
I
A large number of tricyclic structures have been described
in the literature as active in mammals and in in vitro mammalian
preparations as inhibitors of allergic reactions associated with
reagin;c antibodies of the kind responsible for asthma in man, see
for example Wok. patent spec;f;cat;ons nos. 1,414,621; 1,447,031;
1,447,032; 1,452,891; 1,458,185 and 1,458,186; such compounds
have thus been proposed for use in the treatment or prophylax;s
of mammalian allergic conditions such as asthma and other allergic
chest conditions, hay fever (allergic runts conjunctivitis,
urticaria and eczema.
Formula (I) as herein defined is believed to lie outside of
the disclosures of all this art.
Japanese patent Cook no. 16821/82 (laid open to public
inspection on Thea January 1982) describes a drug for treating
;mmunodeficiency diseases of mammals, e.g. man, comprising, as
an effective ingredient, a compound represented by general formula:
wherein R represents a hydrogen atom or a lower alkoxy group and A
represents an oxygen atom or a sulfonyl group, or a salt thereof;
specifically recited immunodefic;ency diseases are cancer, rheumatism,
~93~4
clue
auto immune disease, hepatitis nephritis and infectious disease.
The Japanese document identifies only three specific compounds
within the general formula therein set forth, each said compound
being acknowledged as previously disclosed in the literature and
suggested for use in the treatment or prophyLaxis of asthma and
related allergic conditions. These three compounds are:
(A): 3-(1H-tetrazol-5-yl)thioxanthone-10,10-dioxide
(B): 7-methoxy-2-(1H-tetrazol-5-yl)xanthone
(C): 2-(1H-tetrazol-5-yl)xanthone.
The Japanese document thus identifies no specific compound
that was not previously specifically disclosed in the literature
and the subject invention-is presented-a's'the''finding of a "new
use" for the said "old" compounds.
None of the compounds identified in the Japanese document
as (A), tub and (C) is within formula (I) as herein defined
The following Examples are provided in illustration of the
present invention and should not be construed as in any way constituting
a limitation thereof. All temperatures are in degrees Celsius.
. ` . I
Example 1
7-Methoxyxanthone-3-carboxylic acid
A. 2-(4-Methoxyphenoxy)terephthalic acid
Sodium metal (11.5 9) was dissolved in methanol (250 ml) and to this
solution was added 4-methoxyphenol (62.1 g). The methanol was thoroughly
removed by rotary evaporation and the residual sodium salt dissolved in
dim ethyl sulphoxide. Dim ethyl 2-nitroterephthalate (107.6 9) was added and the
mixtul~ stirred and heated at 120 for 2.5 h. The dark resulting solution was
hydrolyzed by boiling under reflex with a solution of sodium hydroxide pellets
(70 9) in water (500 ml) and ethanol (800 ml) for 2.5 h. The solution was
acidified by pouring into excess iced hydrochloric acid and the precipitated 2-
(4-methoxyphenoxy~terephthalic acid was filtered off, washed with water and
dried at 90 in vacua to give 125.0 9, mop. 280~283.
The following compounds were prepared similarly:
2~4-Ethoxyphenoxy)terephthalic acid, mop. 280-281 from 4-ethoxyphenol
prepared by the method of McElvain and Englehardt, _. Amer. Chum. So.,
(19~ 66, 1080.
2-(4-Propoxyphenoxy)terephthalic acid, mop. 279-281 from 4-
propoxyphenol prepared by the method of Klarmann7 Guts and Shternov, J.
Amer. Chum. Sock (1932), 54, 298.
2-(4-lsopropoxyphenoxy)terephthalic acid, mop. 261-263, from acetic
acid, from 4-isopropoxyphenol prepared by the method of Klarmann, Guts and
Shternov, J. Amer. Chum. Sock (1932), 54, 298.
2-(4-Methylthiophenoxy)terephthalic acid mop. 294-296 from methanol,
from 4-(methylthio)phenol.
B. 7-Methoxyxanthone-3-carboxylic acid
2-(4-Methoxyphenoxy)terephthalic acid (90.0 9) was boiled under reflex with
phosphorus oxychloride (900 ml) far 2 h. The cooled reaction mixture was
IvlC/JAH/21st April.
31 ~Z~5~3~
cautiously decomposed by adding to water, controlling the temperature at 40-
50 by ice addition. The precipitated 7-methoxyxanthone-3-carboxylic arid
was filtered o if, washed with water, and recrystallized from
dimethylformamide (after drying at 80 in vacua mop. 301-302).
Found: C, 66.73%; H, 3.70%. C15H1005 requires C, 66.67%; H, 3.73%.
The following compounds were prepared similarly:
E 7-Ethoxyxanthone-3-carboxylic acid mop. 286-289 ~unrecrystallised).
Ex.3: 7-Propoxyxanthone-3-carboxylic acid mop. 261-264 from
dimethylformamide.
Found I 68.84%; H, 4.91%. C17H1405 requires C, 68.46%; H, 4.70%.
Ex.4: 7-(Methylthio)xanthone-3-carboxylic acid mop. 272-275 from acetic acid.
.
Found: C, 62.69%; H, 3.48%; S, 11.15%. C15H10045 requires C, Dow;
H, 3.4~%; S, 11.19%.
Example 5
7-Isopropoxyxanthone-3-carboxylic acid
.
2-~4-Isopropoxyphenoxy)terephthalic acid (1305 9) was boiled under reflex
with thinly chloride for 0.5 h, then ferris chloride (1.0 g) was added and reflex
continued for a further 4.5 h. The excess thinly chloride was evaporated off,
and the residue poured into water. The precipitated product was filtered off,
washed with water, and stirred with excess aqueous sodium bicarbonate solution
at 80-90 for 1.5 h. The solution was acidified to precipitate 7-
isopropoxyxanthone-3-carboxylic acid which was filtered off, washed with
water and dried. It was recrystallized first from dimethylformamide, and then
from acetic acid, mop. 261-263.
Found: C, EYE%; Ho 4.60%. C17H1405 requires C, 68.46%; H, 4.70/~.
MC/JAH/21st April.
3 ~2~3~
Example 6
7-Hydroxyxanthone-3-carboxylic acid
7-Methoxyxanthone-3-carboxylic acid (8.0 9) was boiled under reflex with
a 12% solution of hydrogen bromide in acetic acid (500 ml) for 28 h. The
reaction mixture was poured into iced water and the precipitated product
filtered off, washed well with water, and dried at 100 in vacua to yield 7-
hydroxyxanthone-3-carboxylic acid mop. 349-350.
Found: C, 65.59%; H, ~.14%. C14H805 requires C, 65.63%; H, 3.12%.
Exam mule 7
7-Ethoxyxanthone-3-carboxylic acid
(i) 7-Hydroxyxanthone-3-carboxylic acid (5.0 9) was stirred with a
mixture of an hydrous potassium carbonate (50 9) and deathly sulfite (10.25 ml;
1200 9) in dimethylformamide (150 ml) for 5 h, then allowed to stand at room
temperature for 16 h. The reaction mixture was poured into water and the
residual ethyl ester of 7-ethoxyxanthone-3-carboxylic acid filtered off and
hydrolyzed by boiling with a solution of sodium hydroxide (2.0 9) in water (200
ml) and ethanol (50 ml) for 2 h. The cooled reaction mixture was acidified with
excess hydrochloric acid, and the precipitated acid filters off, washed with
water, and recrystallized from dimethylformamide mop. 287-289.
Found: C, 67.72%; H, 4.40%. C16H1205 requires C, 67-60%; H,
4.26%.
(ii) (A) Methyl 7-hydroxyxanthone-3-carboxylate
7-Hydraxyxanthone-3-carboxylic acid (10.0 9) was boiled under reflex
with methanol (1.5 Iitres) and concentrated sulfuric acid (15 my for 3 h. The
hot ~nlution was filtered, and on cooling methyl 7-hydroxyxanthone-3-
carboxylate crystallized out, and was filtered off and dried, 6.4 g, mop. 268-
270.
MC/JAH/21st April.
33 ~22~3~
(if) (B) 7-Ethoxyxanthone-3-carboxylic acid
Methyl 7-hydroxyxanthone-3-carboxylate (6.9 9) was boiled under reflex
with stirring with ethyl iodide (9.75 9), potassium carbonate (75 9) and acetone
(I lithe) for 4 h. The mixture was filtered while hot and the residue itched
with acetone. The combined filtrate and washings were evaporated to dryness
and the residue dissolved in dichloromethane and washed with water. The
solution was dried and evaporated to give methyl 7-ethoxyxanthone-3-
carboxylate, 3.65 9, mop. 169-171.
The ester (3.6 9) was hydrolyzed by boiling with a solution of sodium
hydroxide (2.0 9) in water (250 ml) and ethanol (50 ml) For 2 h. The resulting
solution was acidified with excess dilute hydrochloric acid, and the precipitated
product filtered off giving 7-ethoxyxanthone-3-carboxylic acid (on recryst-
Alsatian from dimethylformamide mop. 290-291).
Similarly were prepared:
Ex.8: 7-(3-Hydroxypropoxy)xanthone-3-carboxylic acid mop. 245-246 from
acetic acid, from 3-bromo-1-propanol (methyl ester, mop. 161-162 from
methanol).
Found: C, 65.15%; H, 4.56%. C17H1406 requires C, 64.97%; H, 4.49%.
Ex.9: 7-Butox~xanthone-3-carboxylic acid mop. 225-227.
Found: C, 69.09%; H, 5.16%. C18H1605 requires C, 69.22%; H, 5.11%.
Ex.10: 7-Propoxyxanthone-3-carboxylic acid mop. 262-263, from n-propyl
iodide (methyl ester, mop. 151-152).
Example 11
7-(2-Hydroxyethoxy)xanthone-3-carboxylic acid
7-Hydroxyxanthone-3-carboxylic acid (3.0 9), ethylene carbonate (13.0 9)
and tetramethylammonium iodide (0.07 9) were heated together at 170 for oh.
The cooled reaction mixture was diluted with chloroform and the solid residue
filtered off and boiled with a solution of sodium hydroxide (2.0 9) in
MC/JAH/21st April,lg82.
I
ethanol (40 ml) and water (60 ml) for 5 h. The reaction mixture was then
diluted with water, filtered, and acidified with dilute hydrochloric acid, and the
solid product filtered off and recrystallized from boiling dimethylformamide to
yield 7-(2-hydroxyethDxy)xanthone-3-carboxylic acid mop. 265-267.
Found: C, 63.43%; H, 4.11%. C16H1206 requires C, 64.00%; H, 4.03%.
Example 12
7-(2-Hydroxypropoxy)xanthone-3-carboxylic acid
Methyl 7-hydroxyxanthone-3-carboxylate (2.0 9), propylene carbonate
(Lowe) and tetramethylammonium iodide (0.20 9) were heated together at
170 for 4 h. The cooled reaction mixture was then boiled under reflex with a
solution of sodium hydroxide (6.0 9) in water (200 ml) and ethanol (200 ml) for
30 min. The solution was cooled, filtered, and acidified with excess dilute
hydrochloric acid. The precipitated product was filtered off, washed with
water, and reorystallised twice from 95% 2-butanone-5% water mixture to yield
7-(2-hydroxy-propoxy)xanthone-3-carboxylic acid m p. structure
confirmed by proton magnetic resonance spectroscopy).
Found: C, 65.06%; H, 4.54%. C17H1406 requires C, 64.96%; H, YO-YO%.
Example 13
7-(3-Acetoxypropoxy)xanthone-3-carboxylic acid
7-(3-Hydroxypropoxy)xanthone-3-carboxylic acid (8.8 9) was boiled under
reflex with acetic android (200 ml) for 2 h. The resulting solution was
filtered and the excess android evaporated off. The residual solid was
washed with water and dried, then recrystallized from acetic acid to give 7-(3-
acetoxy-propoxy)xanthone-3-carboxylic acid, mop. 236-237.
Found: C, 63.94%; H, 4.51%. ClgH1607 requires C, 64.04%; H, 4 53D/~.
MC/JAH/~lst April.
it
US
Exam mule 14
7-Methoxy-3-(5-Tetraz olyl)xanthone
(A) 7-Methoxyxanthone-~-carboxamide.
7-Methoxyxanthone-3-carboxylic acid (2n.0 g) was boiled under reflex
with thinly chloride t200 ml) for 2 h. The excess thinly chloride was
evaporated thoroughly from the solution and the residual acid chloride added to
0.880 ammonia (200 ml3 with stirring The solid 7-methoxyxanthone-3-
carboxamide was filtered off, washed with water, and dried at 80 in vacua to
give 19.6 9 mop. 2B6-287.
The following asides were prepared similarly:
7^Ethoxyxanthone-3-carboxamide, mop. 311-~14.
7-Butoxyxanthone-3-carboxamide, mop. 222-225.
7-(3-Acetoxypropoxy)xanthone-3-carboxamide, mop. 205-209.
7-(2-Acetoxypropoxy)xanthone-3-carboxamide, mop. 196-198 from acetic
acid.
7-Propoxyxanthone-3-carboxamide, m.p.-272-274.
7-Isopropoxyxanthone-3-carboxamide, mop. 234-239.
7-(Methylthio)xanthone-3-carboxamide, mop. 228-234.
(B) 6 Cyano-2-methoxyxanthone.
7-Methoxyxanthone-3-carboxamide (1.15 9) was added to a stirred solution
of thinly chloride (5.0 ml) in dimethylformamide t25 ml) at 0-5 over about 5
minutes. The reaction mixture was stirred at 0-5 for 1 h., then poured on to
ice. The solid precipitated product was filtered off, washed with water and
recrystallized from dimethylformamide, giving 6-cyano-2-methoxyxanthone,
0.60 9, mop. 254-255.
The following nitrites were prepared similarly:
-Cyano-2-ethoxyxanthone, mop. 204-205, ox dimethylfolmamide.
2-Butoxy-6-cyanoxanthone, mop. 156-157 ox acetic acid.
MC/JAH/21st April.
~2~3
AL
- 2-(3-Acetoxypropoxy)-6-cyanoxanthone, mop. 158-160 ox ethanol.
2-(2-Acetoxypropoxy)-6-cyanoxanthone, mop 139-140 ox methanol.
6-Cyano-2-propoxyxanthone, mop. 166-167 ox dimethylformamide.
6-Cyano-2-isopropoxyxanthone, mop. 145-146 ox aqueous dimethylformamide.
6-Cyano-2-(methylthio)xanthone, mop. 209-210 ox aqueous dimethylformamide.
(C) 2-Methoxy-6-(5-tetrazolyl)xanthone.
6-Cyano-2-methoxyxanthone (12.6 9) was heated with sodium aside ~3.41
g) and ammonium chloride (2.95 9) in dimethylformamide (100 ml) at 125 for 6
h. The reaction mixture was diluted with water and acidified with excess
hydrochloric acid. The precipitated 2-methoxy-6-(5-tetra7O1yl)xanthone was
filtered off, washed with water, and recrystallized from dimethylformamide,
decomposes above 300.
- Found: C, 60.82%; H, 3.45%; N, 18.91%.
Clown requires C, 61.22%; H, 3.42%; N, 19.04%.
Similarly were prepared: -
E_: 2-Ethoxy-6-(5-tetrazolyl)xanthone.
Decomp. 272-274 from dimethylformamide.
Found: C, owe; H, 3.94%; N, 18.20%.
C16H12N4O3 requires C, 62.33%; H, 3.92%; N, 18.17%.
~:x.16: 2-Propoxy-6-(5-tetrazolyl)xanthone
Decomp. 272-273 from dimethylformamide.
Found: C, 63.39%; H, 4.37%; N, 17.15%.
C17H14N4O3 requires C, 63.35%; H, 4.38%; N, 17.38%.
MC/JAH/21st April.
12~3~J~
Ex.17: 2-Butox~-6-(5-tetrazolyl)xanthone
Decomp. 249-25D from dimethylformamide.
Found: C, 64.37%; H, 4.71%; N, 16.54%.
C18H16N4O3 requires C, 64.28%; H, 4.79%; N, 16.66%.
Ex.18: 2-Isopropoxy-6-(5-tetrazolyl)xanthone
Decomp. 263-265 from 2-methoxyethanol.
Found: C, 63.27%; H, 4.37%; N, 17.25%.
C17H14N4O3 requires C, 63.35%; Ho 4.35%; N, 17.39%.
Ex.19: 2~Methylthio)-6-(5-tetrazolyl)xanthone
Mop. 253-255 from aqueous 2-methoxyethanol.
Found: C, 58.34%; H, 3.23%; N, 17.97%; S, 10.29%.
Clown requires C, 58.06%; H, 3.22%; N, 18.06%; S, 10.32%.
Example 20
2-(3-Hydroxypropoxy) 6-(5-tetrazolyl)xanthone
2-(3-Acetoxypropoxy)-6-cyanoxanthone (3.25 9), sodium aside (~.66 9),
ammonium chloride (0.57 9) and dimethylformamide (50 ml) were heated
together at 125 for 5 h. The reaction mixture was poured into water, and
made alkaline with sodium hydroxide solution. The solution was extracted
twice with chloroform to remove unchanged nitrite, and then acidified with
hydrochloric acid to precipitate crude 2-(3-acetoxypropoxy)-6-(5-
tetrazolyl)xanthone, 2.85 9, mop. 240 (decomposes).
The Aztecs compound (1.5 I was boiled under reflex with sodium
hydroxide (3.0 9) in water (30 ml) for 1.5 h., and the solution acidified with
hydrochloric acid. Thy precipitated solid was filtered off and recrystallized
MC/JAH/21st April.
;~2~3(}~
I
from dimethylformamide to yield 2-(3-hydroxypropoxy)-6-(5-
tetrazolyl)xanthone mop. 270 (decomposes).
Found: C, 60.37%; H, 4.27%; N, 16.72%.
C17H14N4O4 requires C, 60.35%; H, 4.17%; N, 16.56%.
Similarly prepared was:
Ex.21: 2-(2-Hydroxyproooxy)-6-(5-tetrazolyl)xanthone
Mop. 250 (decomposes).
Found: C, 60.08%; H, 4.21%; N, 16.62%.
C17H14N4O4 requires C, 60.35%; H, 4.17%; N, 16.56%.
Example 22
7-MethoxYxanthene-3-carboxylic acid
7-Methoxyxanthone-3-carboxylic acid (10.0 9) was reduced by the
Clemmensen method, using zinc amalgam prepared from zinc powder ~100 g)
and mercuric chloride (8.0 g), in acetic acid at ambient temperature. The
product, 7 methoxyxanthene-3-carboxylic acid, was obtained by
chromatography on silica gel, eluding with 5% methanol in chloroform, and had
mop. 259-261.
Found: C, 70.41%; H, 4.78%. KIWI requires C, 70.3û%; H, 4.72%.
Preparation ox sodium salts
7-Methoxyxanthone-3-carboxylic acid sodium salt (En. lay
7-Methoxyxanthone-3-carboxylic acid (32.9 9) was heated with a solution
of sodium bicarbonate (10.08 9) in water (1 lithe), the solution filtered and
evaporated to dryness. The residual solid was ground to a powder and dried in
MCtJAH/21st April.
I
vacua over calcium chloride to give the sodium salt, analyzing for 0.25 mole
water of crystallization.
Found: C, 60.61%; H, 3.22%. C15HgNaO5Ø25 H20 requires C, 60.72%;
H, 3.23%.
The following sodium salts were similarly prepared from the fully
characterized free carboxylic acids or tetrazoles. The number of moles of
water of crystallization may vary for different preparations of the same sodium
salt according to the conditions of drying and exposure to atmospheric
moisture:
7-Ethoxyxanthone-3-carboxylic acid Sodom salt (Ex.2a)
Freeze dried, MindWrite.
Found: C, 59.43%; H, 3.52%. Clown requires C, 59.26%; H,
4.04%.
7-Propoxyxanthone-3-carboxylic acid sodium salt tweaks)
Freeze dried, MindWrite.
Found: C, 60.49%; H, 4.12%. C17H13NaO5.H2O requires C, 60.35%; H,
4.47%.
7-lsopropoxyxanthone-3-carboxylic acid sodium salt (Ex.5a)
Freeze dried, MindWrite.
Found: C, 59.72%; H, 4.00%; Loss on drying at 120, 4.94%.
C17H13NaO5.H2O requires C7 60.35%; H, 4.47%; HO, 5.33%.
7-~Methylthio)xanthone-3-carboxy to acid sodium salt (Ex.4a)
Freeze dried, MindWrite.
MCGEE sty April.
;~2g3~9~
`" 40
Found: C, 55.6}%; H, 3.21%; 5, Dow; Loss on drying at 120%, 4.78%.
C15Hg Noah requires C, 55.20%; H, 3.4D%; 5, 9.82%; HO, 5.52%.
7-Hydroxyxanthone-3-carboxylic acid sodium salt (Ex.6a)
Dried at room temperature in vacua; dehydrate.
Found: C, 53.67%; H, 2.79%. C14H7NaO5.2H2O requires C, 53.50%: H,
3.53%.
7-(2-Hydroxyethoxy)xanthone-3-carboxylic acid sodium spa (Exile)
Dried at room temperature; sesquihydrate.
Found: C, 54.93%; H, 3.92%. Clown requires C, 55.02%;
H, 4.04%.
- 7-(3-Hydroxypropoxy)xanthone-3-carboxylic acid sodium salt (Ex.8a)
Dried at 80 in vacua/ hemihydrate.
Found: C 55.68%; H, 3-64%- C17H13N4NaO4Ø5H2O q
55.29%; H, 3.82%.
2-Methoxy-6-(5-tetrazolYl)xanthone sodium salt (Ex.14a)
Dried at 80 in vacua, exposed to air at room temperature. Tetrahydrate.
Found: C, 46.44%; H, 4.34%; N, 14-58%- C15HgN4NaO3.4H2O require
C, 46.4û%; H, 4.41%; N, 14.43%.
2-Ethoxy-6-(5-tetrazolyl)xanthnne sodium salt (Ex.15a)
Dried at 80 in vacua, exposed to air at room temperature. MindWrite.
F d: C 55 34%; H, 4.00%; N, 16-11%- C16HllN4NaO3.H2O r q
C, 55.17%; H, 3.76%; N, 16.08%.
MC/OAH/21st April.
I
Al
2-Propoxy-6-(5-tetrazolyl)xanthone sodium salt (Ex.16a)
Dried at room temperature, 2.25 hydrate.
Found: C, 53.15%; H, 4.36%; N, 14.65%. C17H14N4NaO3. OWE
requires I 53.05%; Ho 4.58%; No 14.56%.
2-lsopropoxy-6-(5-tetrazolyl)xanthone sodium salt (Ex.18a)
Freeze dried, 3.5 hydrate.
Found: C, 50.13%; H, aye%; N, 13.36%; loss on drying at 120, 14.77%.
C17H13N4NaO3.3.5H2O requires C, 50.12%; H, 4.95%; N, 13.75%; HO,
15.48%.
2-(Methylthio)-6-(5-tetrazolYl)xanthone sodium salt (Ex.lga)
Freeze dried, trihydrate.
Found: C, 46.69%; H, 3.74%; N, 14.31%; S, 8.11%; loss on drying at 120,
13.81%. C15HgN4NaO2S.3H2O requires C, 46.63%; H, 3.91%; N, 14.50%; S,
8.3~%; HO, 13.99%.
2-(2-Hydroxypropoxy)-6-(5-tetrazolYl)xanthone sodium salt (Ex.21a)
Dried at 80 in vacua, MindWrite.
F undo C 53 96%; H, 4.0Q%; N, 14.58%. C17H13N4NaO4.H2O q
C, 53.97%; H, 4.07%; N, 14.81%.
2-(3-Hvdroxypropoxy)-6-(5-tetrazolyl)xanthone sodium salt (Ex.20a)
Dried at 80 in vacua, one-third hydrate.
Found: C, 58.68%, H, 3.64%; N, 15.14%. C17H13N4NaO4. OWE
requires C, 55.74%; H, 3.76%; N, 15.29%.
MC/JAH/21st April.
- ~Z2~3~
Example 23
7-t2 Acetoxyethoxy)xanthone-3-carboxylic acid
7-(2-Hydroxyethoxy)xanthone-3-carboxylic acid (4.0 g) was boiled
under reflex with acetic android (200 ml) for 3 h. The solution
was evaporated to dryness and the residue recrystallized from
acetic acid to yield 7-(2-acetoxyethoxy)xanthone-3-carboxylic acid,
mop. 248-2490C.
Found: C, 63.08%; H, 4.18%. C18H1407 requires C, 63.16~; H, 4.12%
Example 24
2-t2-Acetoxyethoxy)-6-(5-tetrazoLyL)xanthone
PA) 7 ~2-Acetoxyethoxy~xanthone-3-carboxamide
. _
7-(2-Acetoxyethoxy)xanthone-3-carboxylic acid (3.4 9) was boiled
under reflex with thinly chloride (50 ml) for 2 h. The resulting
solution was evaporated to dryness and the residual acid chloride
added to ice-coLd concentrated ammonia solution with stirring. After
2 h the aside was filtered off and dried, yielding 3.3 9, mop. 230-2320C.
(B) 2-(2-Acetoxyethoxy)-6-cyanoxanthone
The aside from step (A) (3.3 g) was added to a solution of thinly
chloride (7 my in dimethylformamide (5Q ml) at -10~. The mixture was
stirred at ice-bath temperature for 3 h, then poured into iced water.
The precipitated nitrite was filtered off, washed with water, and dried
to Yield 2.9 g, mop. 194-196C.
:3LZ~S~3~9~
(C) 2-(2-Acetoxyethoxy)-6-(5-tetraZOlYl~xanthone_
The cyanoxanthone from step (B) (2.9 9), sodium aside (0.61 93,
ammonium chloride (0.53 9) and dimethylfor~amide(50 ml) were heated
together at 125 for 8 h. The reaction mixture was poured into an
iced aqueous solution of hydrochloric acid (excess) and the product
filtered off and dried. Recrystallization from dimethylfo ~amideyielded
the title compound,m.p. 216-218C
Found: C, 58.96%, H, 3.84%, N, 15.01%. C18H14N405 requires C, 59-02%C
H, 3.85%; N, 15.29%.
Example 25
2-(2-Hydroxyethoxy)-6-(5-tetrazolyl)xanthone
2-(2-Acetoxyethoxy)-6-(5-tetrazolyl)xanthone (1.0 9) was boiled under
reflex with a solution of sodium hydroxide t2.0 9) in water t20 ml)
for 2.5 h. The solution was cooled and poured into excess aqueous
hydrochloric acid and the precipitated product filtered off washed
with water, and dried. Recrystallization from dimethylformamide gave
the title compound, mop. 270C.tdecomposes).
Sodium salt text 25 a )
The free tetrazole (13.45 y) was dissolved by warming with a solution
of sodium bicarbonate (3.48 93 in water (150 my The cooled solution
was filtered, extracted once with chloroform, and evaporated to
dryness. The residue was dried at room temperature in vacua over
phosphorus pent oxide to yield 2-(2-hydroxyethoxy)--6-(5-=tetrazoly~)-
xanthone sodium salt dehydrate. Found: C, 50~46%; H, 3.79%; N, 14.52%~
C16H15N4NaO6 requires C, 50.26~; H, 3.95%; N, byway%.
44
1~2Z93
Example 26
2-C2-(2-Hydroxyethoxy)ethoxy]xanthone-6 carboxyl;c acid
.. . .
7-Hydroxyxanthone-3-carboxylic acid (75.0 9), ethylene carbonate
(3Z5 9) and tetrabutylammonium iodide (1.75 9) were heated together
with stirring for 5 h. The cooled reaction mixture was diluted with
ethanol and the solid residue filtered off and boiled with sodium
and water (1.0 L)
hydroxide (175 9) in ethanol (1.0 for 4 h. The mixture was filtered,
and the filtrate diluted with water (2.0 l) and acidified with
dilute hydrochloric acid. The solid product was filtered off,
washed with water and recrystallized from 2 methoxyethanol, mop. 188~C.
Analysis
Cafe% 62.78 4.68
Found% 62~52 4.73
En _ 26 a
The above product acid (1 9) was boiled with sodium bicarbonate (0.244 9)
in water (200 ml); the cooled solution was filtered and freeze dried
to yield the sodium salt as a pale yellow solid, mop. greater than
350C.
Example 27
2 (2-~utyryloxyethoxy)xanthone-6-carboxylic acid
2-(2-~ydroxyethoxy)xanthone-6-carboxylic acid t10 9) was reflexed with
us
" ~Z~93~
butyric android (250 my) for 2 h. The resultant solution was
evaporated and the residue triturated with ether. Recrystallization
from dimethylformaMide/water gave the title carboxylic acid, mop.
237-241C.
Analysis
C H
Cafe% 64.~6 4.89
Found% 65.05 4.87
En. aye
The corresponding sodium salt was obtained as a pale yellow solid,
mop. greater than 350Cn
Example 28
2-C2-(2-Acetoxyethoxy)ethoxy]xanthone-6-carboxylicc acid
2-[2-t2-Hydroxyethoxy)ethoxy]xanthone-6-carboxylicc acid ~10 9) was
reflexed in acetic android (150 ml) for 2 h. The resultant solution
was evaporated and the residue triturated with ether. Recrystallization
from methanol gave the product as yellow crystals, mop. 199-200C.
Analysis
C H
Cafe% 62.17 4.69
Found% 62.û8 4.63
~93
En. 28 a
The corresponding sodium salt was obtained as a pale yellow solid,
mop. greater than 350C.
Example 29
2-t2-Butyryloxyethoxy)-6-(S-tetrazolyl)xanthone
(A) 2-(2-Butyryloxyethoxy)xanthone-6-carboxamide
2-(2-Butyryloxyethoxy)xanthone-6-carboxylic acid t8.0 g) was reflexed
with thinly chloride (100 ml) for 1 h. The resultant solution was
evaporated to dryness and the residual acid chloride added portions
to ice-cold 0.880 ammonia solution with stirring. After 2 h the solid
was-filtered-off and washed with water Recrystallization from 2-
methoxyethanol gave the indicated product, mop. 205-2070C.
Analysis
C H N
Cafe% 65.û3 5.19 3.79
Found% 65.35 5.18 3.67
(B) 2-(2-Butyryloxyethoxy)-6-cyanoxanthone
Thinly chloride (10 ml) was added drops to a stirred suspension of
the carboxam;de from step (A) (5.22 g) in dimethylformamide (100 ml)
at -10C. The mixture was kept at ice bath temperature for 1 h, then
poured into iced-water. The solid precipitate was filtered off and
recrystallized from glacial acetic acid yielding the title cyanoxanthone,
mop. 145-147C.
I
Z~3
(C) Z-(2-Butyryloxyethoxy)~6-(5~tetrazolyl)xanthone
The cyanoxanthone from step (B) (4.17 go, sodium aside (0.82 9)
ammonium chloride Tao 9) and dimethylformamide (100 ml) were
stirred together at 120C for 8 h. The cooled mixture was poured
into iced 2 M hydrochloric acid, warmed to OKAY for 10 minutes,
cooled and filtered. The resultant solid was rerrystallised from
water yielding
dimethylformamide~the title xanthone, mop. 207-2090C.
Analysis
C H N
Cowlick 60.90 4.61 14.22
Found% 60.93 4.55 14.12
En. 29 a
The corresponding sodium salt was obtained as a pale yellow solid,
mop. 275-2800C.(decomp.).
Example 30
2-(Ethylthio)xanthone-6-carboxylic acid
-
(~) Diethyl-2-(4-ethylthiophenoxy)terephthalate
Sodium metal (3.4 9) was added over 20 minutes to a stirred solution
of 2-(4- ethylthiophenoxy)terephthalic acid (10 9) in hexamethyl-
phosphoramide (100 ml) at 100C under dry nitrogen. After 2 h the
mixture was cooled and treated with ethyl iodide (20 ml) with ice bath
cooling to maintain the temperature below 450C. After a further 30
:~2~3~L
minutes the mixture was poured into water and ether extracted. The
organic extracts were washed with brine, dried over magnesium sulfite
and evaporated. Chromatography of the residual oil over silica,eLuting
with chloroform/60-80 petrol ~2:3, v/v) and C8 Zorba reverse phase
HPLC eluding with methanol/water (7:3, v/v) gave the product as an oil.
(B) 2-(4-Ethylth;ophenoxy)terephthalic acid
The divester from step (A) (1.9 9) was boiled under reflex with a
solution of sodium hydroxide (5.6 9) in water (70 ml) and ethanol
(30 ml). After 2 h the mixture was cooled and diluted with water
(100 ml). Acidification with concentrated hydrochloric acid yielded
the product acid which was filtered off and dried, mop. 282-284C.
(C) 2-~Ethylthio)xanthone-6-carboxylic acid
The terephthalic acid from step (B) (1.3 9) was boiled under reflex
with phosphorus oxychloride (50 ml) for 8 h. The cooled reaction
mixture was cautiously decomposed by adding to water, controlling the
temperature below 80C by ice addition. The precipitated solid was
filtered off, washed with water and recrystallized from d;methylformamide/
water giving the title carboxylic acid, mop. 234-2360C.
Analysis
C H
Cowlick 63.99 4~03
Found% 63.98 4.10
*Trade Mark
aye
En. 30 a
The corresponding sodium salt was obtained as a yellow powder, mop.
greater than 35ODC~
Example 31
2-Ethylthio-6-_5-tetrazolyl)xanthone
(A) 2-(Ethylthio)xanthone-6-carboxamide
2-(Ethylthio)xanthone-6-carboxylic acid (0.65 9) was boiled under reflex
with thinly chloride (50 ml) for 1 h. The resultant solution was
evaporated to dryness and the residual acid chloride added portions
to ice-cold 0.8~0 ammonia solution with stirring. After 2 h the solid
was filtered off and washed with water yielding the product carboxamide
(0.62 9), mop. SKYE.
(B) 2~thylthio-6-cyanoxanthone
Thinly chloride (1.5 ml) was added drops to a stirred solution of
the carboxamide from step (A) (0.55 9) in dimethyLformamide (20 ml)
at 5C. The mixture was kept at ice-bath temperature for 1 h, then
poured into iced water. The solid precipitate was filtered fry dried
and chromatographed on silica eluding with ethylene chloride/60-80
petrol (1:1, v/v) giving the title cyanoxanthone (0.44 9), mop.
159-161C.
(C) 2-Ethylthio-6-(5-tetrazolyl)xanthone
The cyanoxanthone from step (B) (0.42 9), sodium aside (0.102 9),
.
293~
ammonium chloride (0~088 9) and dimethyLformamide t25 ml) were
stirred together at 120C for 10 h. The cooled mixture was poured
into iced 2 M hydrochloric acid, warmed to 800C for 10 minutes,
cooled and filtered The resultant solid was extracted into 5%
sodium bicarbonate solution and washed with ether. Acidification of
the base extracts gave the title compound which was filtered off
and dried, mop. 261-262C.
Analysis
C H N
Cowlick 59.24 3.73 17.28
Found% 59.25 3.76 17.32
En. 31 a
The corresponding sodium salt was obtained as a yellow powder, mop.
335-3360C.
example 32
2-(Methylthio)xanthene-6-carboxylic acid
(A) 2-Methylthio-6-hydroxymethyl~anthene
orate tetrahydrofuran complex (30 ml, 1 M solution on tetrahydrofuran)
was added under dry nitrogen to an ice cold stirred solution o-f 2-
(methylth;o)xanthone-6-carboxylic acid (3 9) in dry tetrahydrofuran
(100 ma After 1 h the mixture was allowed to attain room
temperature and stirred for 12 h. The excess borne was decomposed by
93~
.
addition of ice and the resultant solution extracted with ethyl acetate.
The organic extracts were washed with brine, dried over magnesium
sulfite and evaporated yielding the title compound ~2.39 g) as a white
solid, mop. 151-153C.
(B) 2-(Methylthio)xanthene-6-carboxaldehyde
_
Under dry nitrogen, dimethylsulphox;de (5 ml) was added drops to
a stirred solution of oxalyl chloride (0.89 ml) in ethylene
chloride (S ml) at -600C. After 2 minutes a solution of the xanthene
from step (A) (2.3 g) in dimethylsulphoxide (35 ml) was introduced
drops over 5 minutes whilst maintaining the temperature below -500C
with cooling. After 15 minutes triethylamine (6.20 ml) was added, the
mixture allowed to warm to room temperature and then poured into water.
The mixture was ethyl acetate extracted, the organic layers were
combined, washed with brine, dried over magnesium sulfite and evaporated
yielding the title carboxaldehyde ~1~97 9), mop. 122-123C.
(C) 2-Methylthio-6-cyanoxanthene
A mixture of the carboxaldehyde from step (~) (1.75 g), hydroxylamine
hydrochloride (~.56 g), sodium format (1 9) and formic acid (15 ml)
was reflexed for 1 h. The resultant solution was diluted with water
and ether extracted, the extracts were washed with brine, dried over
magnesium sulfite and evaporated. The residual solid was chromatographed
over silica eluding with chloroform/methanol (98:2, v/v) yielding the
title cyanoxanthene (1.58 9), mop. 142-144C.
~2~3~
so
(D) 2-(Methylthio)xanthene-6-carboxylic acid
The cyanoxanthene from step (C) (0.3 9) was boiled under reflex
with a solution of sodium hydroxide (3 9) in water (10 my) and
ethanol (10 my) for 6 h. The resultant solution was diluted with
water, ether extracted, and acidified with concentrated hydrochloric
acid. The precipitated carboxylic acid was filtered off, washed
with water and dried, mop. 266-2670C.
Analysis
C H
Cafe% 66.20 4.45
Found% 66.24 4.82
En. 32 a
The corresponding sodium salt was obtained as a white powder, mop.
greater than 3OODC.
Example 33
2-Hydroxy-6-(5-tetrazolyl)xanthone
(A) 3-t5-Tetra~olyl)xanthone
3-(5-Tetra2Olyl)thioxanthone-10,10-dioxide sodium salt US patent
specification 1,447,031; 45.0 9) was stirred and boiled under reflex
with 2-normal sodium hydroxide solution for I hours The solution
was acidified by pouring into excess hydrochloric acid solution and
~2SZ3~3~
the precipitated product filtered of and recrystallized from
dimethylformamide to give the title compound (14.95 9), met 2960C.
(decomposes).
Calculated: C, 63.64%, H, 3.05%, N, 21.20%
Found : I, 63.77%, H, 3.Q5%, N, 21.15%
to) 2-Nitro~6-(5-tetrazolyl)xanthorle
3-(5-TetrazoLyl)xanthone (1.0 g) was dissolved in concentrated sulfuric
acid (10.0 ml) and the resulting solution cooled to below 15C. Potassium
nitrate (0.50 9) was added in small portions over 10 min. with cooling
to maintain the temperature between 10 and Canada the reaction mixture
was then stirred at 200C.for 1 hr. The reaction mixture was poured
on to ice and the precipitated product filtered off, washed with water
and recrystallized from d;methylformamide. The crystallized product
was washed with methanol and dried at 156C/2Q mm Hug to yield 0.78 go
met. cay Cathy decomposition.
found : C, 54.11%; H, 2.25%i No 22.60X C14H7N504
requires : C, 54.38%; H, 2.28/'; N, 22.65%.
(C) 2-Am;no-6-~5-tetrazolyl)xanthone
The n;troxanthone from step (~) (1.55 9) was dissolved in a solution
of sodium bicarbonate (0.42 9) in water ~150 ml) with warming. To the
solution was added 10% palladium on carbon catalyst and the solution
hydrogenated at room temperature and atmospheric pressure for 4 ho,
during which time hydrogen uptake was miswords 440 ml. The solution
~2Z93~
, "`, SLY
was filtered and the filtrate acidified with twice-normal hydrochloric
acid solution. The amino-compound was filtered from the warmed mixture,
washed well with water and dried to yield 0.98 9, met. 296 -Cathy
decomposition
Found : C, 56-38%; H, 3.71%, N, 23.58% Clown
requires : C, 56.57%; H, 3.73%, N, 23.56%.
(D) 2-Hydroxy-6-~5-tetrazolyl)xanthone
The aminoxanthone from step (C) (14~4 9) was dissolved in concentrated
sulfuric acid (250 ml) and to the stirred solution at Casey
added in portions sodium nitrite (3.6 9). The solution was then
stirred at 150C.for 1 ho, poured on to ice (2 kg) and water (2.5 l).
The mixture was slowly brought to the boil and boiled under rollicks
for 1 hr. The resulting yellow product was filtered off, washed well
with water and Druid
A sample was purified by chromatography on silica gel~eluting with
chloroform-methanol 3:1 v/v, met.
Found : C, %; H, X; N, 14 No 3
requires : C, 60.00%; H, 2.87%; N, 20.00%~
Exam 34
2 (2-Hydroxyethylthio)-6-(5-tetrazolyl)xanthone
2-Amino-6-(S~tetrazolyl)xanthone (4.60 g) was dissolved by stirring in
concentrated sulfuric acid (80 ml) at Cole in portions, over
so
31L 2 2 AL
10 mint was added sodium nitrite (1.15 9) with cooling to maintain
the temperature at 153C. The mixture was stirred at 153C.for 1 ho,
then poured on to ice The solid diazonium sulfite was filtered
off and washed with a little cold water.
The solid salt was added to a hot (503C) solution of 2-mercaptoethanol
to ml) in water (50 ml) in portions. Vigorous effervescence took place.
The mixture was kept at 503C.for 30 mint then the solid product was
filtered off and washed with water. Flash chromatography of the dried
crude product on silica gel, eluding with chloroform-acetic acid 4:1 TV
followed by recrystallization once from aqueous dimethyLformamide and
twice from 2-methoxyethanol, yielded the title compound, met. Cathy
decomposition), structure supported by nor spectroscopy.
Found : I 56-09%;-H, 3.h9%, N,--16.28% -C16H12N405S-
requires : C, 56~46%; H, 3.55%,~ N, 16,46%.
/
/
AL
3~9t
Example 35
Activity in whole human blood in vitro
Human blood was collected from volunteer donors into CUD
anticoagulant medium in the ratio 100 ml blood: 15 ml medium; 1 ml allocates
were dispensed into 2 ml polycarbonate vials and then kept for three hours at
4C to allow the cells to settle out from the plasma. The samples were then
held at room temperature while the test compounds, one per vial, were added
according to the following procedure to provide a 6 my concentration in whole
blood volume:
A small volume of plasma was removed from each vial: sodium salts TV
were dissolved therein directly while acids TV were added to warm aqueous
sodium bicarbonate (3ûû my, 2 drops) which was then mixed with the plasma; in
either case the compound-laden plasma was then returned to the original vial,
the vial capped and the contents mixed thoroughly.
For each experimental series three control vials were also prepared
containing respectively:
a) blood alone
b) blood + hydrochloric acid Old 150 microlitre)
c) blood + aqueous sodium hydroxide (Alma, 150 microlitre).
After a total of two hours at room temperature all samples were left at
37C for 16 hours and the pi of each then measured at that temperature. The
vials were then stored on ice and the oxygen-dissociation curve determined for
each sample using a whole-blood spectrophotometer (Hem-O-Scan, Trade
Name). Finally, after rewarming to 37C, the pi of each sample was
remeasured.
MlCjJAH/21st April.
~2~93~
., so
The right-displacement of the Pi point (the oxygen tension at
which the hemoglobin is 50% saturated with oxygen) for the oxygen-
dissociation curve was ascertained for each sample relative to the
calculated Pus value for the appropriate sample phi The results are
given below.
* CUD anticoagulant is an aqueous solution containing the following
per 100 ml:
Sodium citrate 2~63 9
An hydrous dextrose 2.32 9
Citric acid MindWrite 0.327 9
Sodium acid phosphate 0.251 9
Compounder hut -displacement tam Hug
Eye 13.0-
Ex.2 16.2
Ex.3 13.0
Ex.4a 15.6
Excuse 9 7
Ex.6a 5.3
Ex.8a 25.8
Ex.9 6.9
Ex.11a 25.0
Ex.12 23.1
Ex.13 19.9
Ex.14a 18.8
Ex.15a 27.4
so
I !93(:1gt
Ex~16a 23.2
Ex.17 14~6
Ex.18a 12.6
Ex.19a 9,5
Ex~20a 23.5
Ex~21a 28.7
Ex.22 17.3
Ex.23 19.0
Ex.24 20.0
Ex.25a 32.6
Ex~26a 25.6
Ex.27a 25~5
Ex.28a 26.1
Ex.29a 22.2
Ex.30a 20.0
Ex.31a - 16.6
Ex.32a 16.2
Ex.34 17.7
to)* 7.6
tub)* -owe**
to)* 3.5
* Japanese patent Cook no. 16821/82:
to): 3-t1H-tetrazol -5-yl)thioxanthone-10,10-dioxide
(B): 7-methoxy-2-(1H-tetrazol-5-yl)xanthone
to): 2-(1H-tetrazol-5-yl)xanthone
** denotes a left-displacement
~2Z~3~
Example 36
Cardiovascular effects in the anesthetized rat
Male Wisteria rats (240-420 9) were used, anesthesia being induced
with halothane/oxygen and maintained by CC-chloralose and sodium
pentobarbitone ivy. Test compounds (Ens. aye and aye) were given
ivy. as a solution in 5% dextrose and at a dose volume of 1.0m~/kg
given over 5 sec. and flushed in with 5% dextrose solution Tao ml);
doses were given in ascending order at 10-30 mix intervals over the
range 0.001 - 30 mg/kg.
Both compounds induced a dose-related hypotension in the dose range
3-3U mgfkg.
No significant waveform abnormalities were apparent in the electrocardiogram
following either compound.
-
Example 37
Toxicity Data
The compounds indicated were administered ivy. to female CD1 mice Charles River US Ltd.).
For En. aye the LDsO was found to lie between 140 mg/kg and 200 mg/kg
(calculated as the free acid).
For En. aye the LDso was found to be greater than 600 mg/kg.
Jo
ISLES
Example 38
Pharmaceutical Formulations
(A) CAPSULE
Compound (Acadia my
Starch 1500 250 my
Magnesium Stewart my
883 my
Mix the ingredients using a suitable mixer and fill into
capsules on a capsule filling machine.
(B) TABLET
Compound (Acadia my
Lactose 200 my
Polyvinylpyrrolidone 50 my
Starch 100 my
Magnesium Stewart my
985 my
Dissolve the polyvinylpyrrolidone in a suitable volume of water.
yucca the compound, lactose and starch and add the polyvinylpyrrolidone
solution. Add a further quantity of water if required. Pass through
a suitable screen and dry. Add the magnesium Stewart, mix and
compress on a tabulating machine.
by
I 9 3
(C) SUPPOSITORY
Compound
sodium salt, equivalent to acid 1.25 9
Hard fat BY to 3 ml
Melt part of the hard fat at 500C maximum. Add the compound
to the molten base and disperse. Add the remaining hard
fat to the suspension. When a smooth homogeneous suspension
has been obtained pour the suspension into 3 ml mounds.
to) INJECTION
Compound
sodium salt, equivalent to acid 1.25 9
Minutely BY 125.0 my
Water for injections BP/Ph/Gm to 2.5 ml
.
Dissolve the compound and the minutely in 2/3 the final
quantity of water for injections. Make to volume with more
water for injections Sterilize the solution by passage
through a sterilizing grade filter Fill 2.5 ml portions
into suitable vials under aseptic conditions and freeze
dry When drying is complete seal the vials under an
atmosphere of oxygen free nitrogen and cap with aluminum
collars
go
(E) INJECTION
Compound acid) 2~50 9
Bouncily alcohol 90.0 my
TRIP solution (0.05 M) 5 ml
Hydrochloric acid (0.1 N) 3 my
Water for injections BP/Ph/Gm to 10 ml
Dissolve the compound in the TRIP and hydrochloric acid.
Add and dissolve the bouncily alcohol and make to volume with
water for injections. Strolls the solution by filtration
through a suitable sterilizing grade filter. Fill unto 10 ml
vials under aseptic conditions and seal with rubber closures.
In the foregoing, acid) indicates that the compound of formula to))
is present as the free carboxyl or 5-tetrazolyl acid, as appropriate.
Example 39
Blood Storage
A sterile, sealed bag (Phenol, Triennial Laboratories Lid Thetford,
Norfolk, England) suitable for collection of SUE ml blood and
containing 63 ml of CUD anticoagulant solution, was taken . Under
sterile conditions the anticoagulant was removed, admixed with an
effective non-toxic amount (vise swooper) of a compound of formula (I)
and returned to the bag and the bag then resealed and stored at
room temperature.
Blood from a volunteer human donor was subsequently collected into the
bag by conventional procedures and the lull bag then stored at 4~-6DC.
