Note: Descriptions are shown in the official language in which they were submitted.
1077932
B~CKGROUND OF TH~ INVENTION:
This invention relates to substituted xathines which are useful
in the treatment of bronchial asthma and other bronchospastic
and allergic diseases.
Bronchial asthma is characterized by bronchospasm caused by
contraction of the bronchial smooth muscle, increased secretion
of mucus from the bronchi, and edema of the respiratory mucosa.
While the etiology of asthma is not completely known, it is
believed to involve an allergic reaction. Allergic reactions
occur in sensitized indivlduals who are exposed to the antigen
to which they are sensitized. ~he antigen provokes the release
in the body of certain chemicals (allergic mediators) which in
.,
turn produce the allergic symptoms. Allergic reactions can also
produce effects in organs other than the bronchi, particularly
the skin, eyes and nasal mucosa and include such diseases as
allergic rhinitis and urticaria.
Acute asthmatic bronchospasm has been treated with drugs which
relax bronchial smooth muscle. Sympathomimetic drugs such as
epinephrine, isoproterenol, and terbutaline and xanthine drugs
such as theophylline and its salts (aminophylline, etc~ ) have
been used for this purpose. Drugs such as cromolyn sodium which
inhibit the release of allergic mediators, have been used
prophylactically to treat bronchial asthma. Corticosteriod drugs
i ~
-: have also been used to treat bronchial asthma and other allergy
diseased.
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7793~
Many of the drugs used hitherto have shortcomings which
- make them less than ideal for treatment of asthma and
other bronchospastic and allergic diseases. For example,
epinephrine and isoproterenol relieve the symptoms of
asthma for only a relatively short period of time and are
ineffective orally. Theophylline has limited efficacy
; and produces cardiac and gastrointestinal side effects.
Cromolyn sodium is only effective by inhalation or
injection and is ineffective by oral administration.
The corticosteroid drugs have serious side effects which
limit their chronic use.
Substituted xanthines have been known for some time as
bronchodilators, and theophylline (1,3-dimethylxanthine)
has long been used in the treatment of bronchial asthma.
Prior attempts have been made to improve theophylline by
substituting the xanthine nucleus with different groups
in several positions in the molecule. A number of 1,3-
dialkylxanthines and 1,3,8-trialkylxanthines have been
shown to be bronchodilators in anLmal models. However,
none of the substituted xanthine compounds hitherto
synthesized have displaced theophylline and its salts
, .,
as clinically useful bronchodilator and antiallergy agents.
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1077932
There are several references in the prior art disclosing
the synthesis of compounds which may be considered
structurally similar to the compounds of the claimed
invention. However, in each case where such similarity
exists, either the degree and/or duration of activity
of the claimed compounds is far superior to those of
the prior art or a completely different utility is
disclosed in connection with the prior art compounds.
Stoll (Stoll, J.H., et al., U.S. P~tent 3,729,643,
issued January 3, 1956), for example, discloses a method
for forming substituted xanthines which are said to be
effective as diuretics. In the Stoll process, inter-
mediate compounds are formed which are illustrated by
Stoll in the form of generic structural formulas.
The only specific example of a compound having a
7-carboalkoxy group within the context of these general
formulas is 1,3-diethyl-7-carboethoxyxanthine.
Stoll's specific compounds of the 1,3,8-trialkylxanthine
type are limited to those which have the same alkyl
~ 20 groups in both 1- and 3-position. He does not dis-
; close any 1,3,8-trialkylxanthines having a 1-methyl
- group combined with a group in the 3-position having
4 to 5 carbon atoms. There is no specific disclosure
of a 1,3,8-trialkyl-7-carboalkoxyxanthine, nor is there
any disclosure in the patent of a 3-(2-methyl-1-
butyl) substituted xanthine. Certain compounds
disclosed by Vieth (Vieth, H., et al., Biochem. Z .,
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1~7793Z
163, 13-26 (1925).), Cacace, (Cacace, F., et. al., Ann. Ch~m.
(Rome) 45, 983-993 (1955).), Giani, (Giani, M., et. al.,
P~rmaco (Pavia), ~d. Sci. 12, 1016-1024 (1957).), ~eRoy
(LeRoy, et. al., J. PharmacoZ. E~ptZ. Therap. 69, 45-51
(1940).), Speer (Speer, et. al.~ J. Am. Chem. Soc. 75,
114-115 (1953).), and Stoll may be construed as being
structurally similar to the compounds of this invention,
but again none of these references suggests a bronchodilating
or antiallergen use. They all acknowledge the diuretic use
, 10 of theophylline derivatives although Cacace and Giani have
no disclosure of a utility for the 7-carboalkoxy compounds
discussed therein.
ii:
Armitage, (Armitage, A. K., et. al., Brit. J. PharmacoZ., 17,
196-207 (1961).), who deals with certain di- and tri-alkyl
xanthines, alleges uses relating to bronchodilation, but does
not show a 2-methyl-1-butyl grouping in the 3-position.
Goodsell, (Goodsell, E. B., et. al., J. Med. Chem. 1971, 14
(12) 1202-1205.~ who deals with tri-alkyl xanthines, discusses
the 3', 5'-cyclic adenosine monophosphate phosphodiesterase
inhibition (which is generally conceded to be correlated with
bronchodilator activity) by certain 1,3-dimethyl-8-alkylxanthines
and also reports some pharmacological data for these compounds.
However, Goodsell did not test these compounds for broncho-
; dilator or antiallergy properties either in vitro or in vivo.
Furthermore, no experiments were done to test the duration ofactivity of these compounds. Hence, Goodsell teaches nothing
. ; .
107793Z
regarding the long-acting bronchodilator and antiallergy
properties of 8-alkylxanthines.
Neither Armitage nor Goodsell shows a 7-carboalkoxy substituent
on a xanthine nucleus and substitution in the 3-position does
5 not include a 2-methyl-1-butyl grouping. Thus, whlle a similar
use is involved, the compounds of this invention are n~t
suggested by these prior art compounds. This is especially
so in light of Beavo's disclosure, (Beavo, J. A., et. al.,
Mo~. Pharmaco~. 1970, 6 (6) 597-603) that in studying the
; 10 adenosine 3', 5' monophosphate phosphodiesterase ~PDE)
inhibiting activity of substituted xanthines he noted that
; substitution in the 7-position either has no affect or
decreases the potency of the compounds tested.
; Beavo also discloses a few compounds having an 8-alkyl group.
15 His in vitro data do not teach anything about duration o'f
pharmacological activity in vivo.
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107793;~
A class of substituted xanthine compounds has no~ been
found which are very effective bronchodilator and anti-
allergy agents with rapid onset and prolonged duration
of action. These compounds are effective, rapid-acting
bronchodilators by all routes of administration and
accordingly can be used to abort an acute bronchospastic
attack. In addition, they are orally efective,
long-acting antiallergy compounds, by suppressing the
-~ release of allergic mediators. Henc~, these compounds
may be used prophylactically to treat bronchial asthma,
and other bronchospastic and allergic diseases.
Sl;M~.ARY OF THE INVENTION:
It is an object of this invention to provide a method
of treating bronchial asthma and other bronchospastic
and allergic diseases. A further object is to provide
a method for treating bronchial asthma and other broncho-
spastic and allergic conditions by administering drugs
comprising substituted xanthines. A further object is
to provide a method of treatment which may be used
prophylactically as well as in acute bronchospastic and
allergic attacks. A further object is to provide a
` method for producing long-lasting relief of bronchial
asthma and other bronchospastic and allergic diseases.
A further object is to provide novel compounds for the
treatment of bronchial asthma and other bronchospastic
a~d allergic diseases.
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~077932
According to this invention, bronchial asthma and other
bronchospastic and allergic diseases are treated by
administering an effective amount of a substituted
xanthine compound having the formula:
i'
wherein R1 = Cl-C2 alkyl
R3 = -CH2-(C3-C4) alkyl, -CH2-(C3-C4 cycloalkyl)
R7 = H, COOR
8 = H~ Cl-~4 alkyl
o R = Cl-C4 alkyl, 2-halo C2-C3 alkyl, or phenyl
The novel compounds of this invention which are preferred
as bronchodilator and antiallergy agents have the follow-
.~ ing formula:
: ;
R~ NC/~
;. R3
. .
wherein: Rl = Cl-C2 alkyl
. R~ = CH2(C3-C4 alkyl)
~ or -CH2-(C3-C4 cycloalkyl)
... R8 = Cl-C2 alkyl
R = Cl-C4 alkyl, 2-halo (C2-C3 alkyl), phenyl
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107793Z
According to another preferred embodiment of this
invention, prolonged bronch~dilation and prolonged
; inhibition of allergic mediator release in mammals are
produced by administerin~ an effective amount of a
substituted xanthine compound having the formula:
,:,
0 H
o~
: R3
:.
wherein: Rl = methyl
R3 = -CH2-(C3-C4 alkyl); -CH2-(C3-C4 cycloalkyl)
R8 = Cl-C2 alkyl
These compounds may be administered orally, parenterally,
or by inhalation in the form of tablets, capsules,
solutions, elixirs, emulsions, aerosols and the like.
Typical effective doses in man range from 0.01 to 50
milligrams per kilogram of body weight depending on route
of administration and potency of compound selected.
i
- OESCRIPTION OF PREFERRED EMBODIMENTS:
Suitable groups for Rl in the compounds used in the method
, of treatment of this invention include methyl, ethyl,
n-propyl and isopropyl. Suitable groups for R3 include
; 20 methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
:; ,.
l-methyl-l-propyl, n-pentyl, l-methyl-l-butyl, 2-methyl-1-
butyl, 3-methyl-1-butyl, 2,2-dimethyl-1-propyl, n-hexyl,
1-methyl-1-pentyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
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. .
., .
~077932
4-methyl-1-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-
butyl, 3,3-dimethyl-1-butyl, l-ethyl-l-butyl, 2-ethyl-1-
butyl, n-heptyl, l-methyl-1-hexyl, 2-methyl-1-hexyl,
3-methyl-1-hexyl, 4-methyl-1-hexyl, 5-methyl-1-hexyl,
1,2-~imethyl-1-pentyl, 2,2-dimethyl-1-pen~yl, 2,3-dimethyl-
l-pentyl, 1,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,
l-ethyl-l-pentyl, 2-ethyl-1-pentyl, 2-ethyl-3-methyl-1-
pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
allyl, methallyl, 2-methyl-2-buten-1-yl, 2-methyl-3-buten-
l-yl, 3-methyl-2-buten-1-yl, propargyl, 2-methyl-3-butyn-
l-yl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-
methyl, cyclohexylmethyl and 2-cyclopropylethyl and the like.
Suitable groups for R8 include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, l-methylpropyl, t-butyl,
cyclopropyl and cyclobutyl.
Suitable groups for R include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, 2-chloroethyl, 2-chloropropyl,
3-chloropropyl, 2-bromoethyl, 2-bromopropyl, 3-bromopropyl
and phenyl. In this application the term "halo" signifies
either chlorine or bromine.
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~077932
With respect to the xanthine compounds of the prior art,
the introduction of the carboalkoxy group in the 7-position
of the compounds of ~his invention has been found to give
an improvement in efficacy. For example, as shown below
in Example 5, 1,3-dimethyl-7-carbomethoxyxanthine, i.e.,
7-carbomethoxytheophylline OL theophylline-7-carboxylic
acid, methyl ester, is significantly more effective than
- theophylline itself. The data show that the xanthine
carboxylate ester is more potent, with both faster onset
and longer duration of action. These data indicate a
greater bioavailability of the xanthine carboxylate ester.
The 7-carboalkoxyxanthines are believed to act as latent
forms of the alkylxanthine bronchodilators and are bio-
transformed to the corresponding xanthine-7-carboxylic
acids, which then decarboxylate to yield the corresponding
alkylxanthine. Thus for the case of 1,8-dimethyl-3-(2-
methylbutyl)-xanthine-7-carboxylic acid, methyl ester,
the major reaction sequence is thought to proceed as
follows:
. .
O COOCH O COOH
CH 1I N 3 CE~3 N~ N
3 d~ J'~N~
CH2CIHCH2CH3 CH2CHCH2CH3
CH3 CH3
O
C 3~N/>--CH3
, CH2CHCH2CH3
CH3
,, _g_
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107793Z
It is preferred to have R8 = methyl. The introduction
of an alkyl group in the 8-position of the xanthine
nucleus has been discovered to produce a compound having
a long lasting activity. As shown below in Example 6,
all of the 8-alkylxanthine bronchodilatQrs have a longer
duration of activity than the corresponding ~-H xanthine.
It is believed that the 8-alkyl group prevents the normal
- enzymic oxidation at the 8-position of xanthines and
thereby prevents rapid bioinactivation of the xanthine.
It is preferred to have R3 selected from the sroup
consisting of methyl, ethyl, n-propyl, n-butyl, isobutyl,
n-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2,2-dimethyl-
l-propyl, n-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-1-hexyl, methallyl, cyclo-
propylmethyl, cyclobutylmethyl, and 2-cyclopropylethyl
groups. ~ore preferred R~ groups are isobutyl, 2-methyl-
l-butyl, 2-methyl-1-pentyl, 3-methyl-1-butyl, n-pentyl,
2,2-dimethyl l-propyl, methallyl, cyclopropylmethyl and
cyclobutylmethyl groups. Of these the isobutyl and
, 20 2-methyl-1-butyl are most preferred and 2-methyl-1-butyl
is uniquely preferred. This group has never been reported
~. ~
as a substituent in a xanthine compound and has a signifi-
, cant advantage over the prior art R3 groups~ In comparison
; ; with the known R3 groups, as shown below in Example 7,
; ,. .;
, 25 the 2-methyl-1-butyl group surprisingly confers on the
;: xanthine bronchodilators an effectiveness equal to the
best R3 group reported in the prior art, the isobutyl group.
This is surprising because the next higher homolog, the
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~0~793Z
2-methyl-1-pentyl group, confers much lower broncho-
dilation potency. Furthermore, the 2-methyl-1-butyl
group surprisingly combines this great potency with
a substantially lower toxicity. Thus the 2-methyl-1-
butyl group is uniquely suitable for the R3 groupof a xanthine bronchodilator, particularly in combina-
tion with a 7-carboalkoxy group which, as previously
indicated, increases the efficacy of the compound, and
therefore such compounds which contain the 2-methyl-1-
butyl group are greatly preferred.
Thus the preferred groups for Rl, R8 and R are methyl-
The most preferred group for R3 is 2-methyl-1-butyl.
The most preferred compound is that which combines
all four preferred groups, namely 1,8-dimethyl-3-
(2-methyl-1-butyl)-7-carbomethoxyxanthine.
,...
The 1,3,8-trialkyl-7-carboalkoxyxanthines of this
invention may be prepared by reacting the sodium salt
of the corresponding 1,3,8-trialkylxanthine with an
alkyl chloroformate ClCOOR according to the following
reaction:
` `
R1~N ~ NNa 1 ~ ~ N
J\N~N~R8 clcooR~ J~ ~ ~R
R3 R3
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~77g32
The sodium salt of the 1,3,8-trialkylxanthine can be
prepared by the action of a strong base such as sodium
hydride on the 1,3,8-trialkylxanthine. The reaction
can be carried out in a suitable inert solvent such as
tetrahydrofuran.
:'
The 1,3,8-trialkylxanthines can be prepared by the
well-known general procedure of Traube, Berichte 33,
1371 and 3055 (1900).
'`
A 1,3-dialkyl urea having the general formula
, O
. 10 R1_NH C_NH R3
" .
' is first prepared. This urea can be prepared by
reacting one mole of an alkyl isocyanate with one
: mole of an amine according to the reaction
, O
R1-NCO + H2N-R3~ R1_NH_C NH R3
:........ 15 It is evident from the symmetry of the product that
;~ either R1 or R3 may be in the isocyanate reagent and
`!~" either group may be in the amine reagent. The condi-
- tions under which this well-known reaction proceeds
.. are known to one skilled in the art.
. 20 The isocyanate required for the above reaction may be
prepared by reacting the corresponding amine with
phosgene acoording to the equation
R1-NH2 + COC12 3 R1-NCO + 2 HC1
;,
.....
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1077932
The conditions for this reaction are well-known to
those skilled in the art and are described in the
chemical literature, e.g., in British Patent 901,337.
The 1,3-dialkyl urea is next converted into a 1,3-dialkyl-
l-cyanoacetylurea by reaction with cyanoacetic acid
according to the following reaction:
o
0 N R1_C -~ H 2CN
R1 NH C NH R3 + NCCH2COOH > CO
NH--R3
; The reaction is conveniently carried out in acetic
anhydride at 60 to 70. The reaction gives preferen-
tially although not ~xclusively the product containing
the smaller alkyl group as R1. The isomers may be
separated by fractional crystallization. The 1,3-
dialkyl-l-cyanoacetylurea is next cyclized to form a
4-amino-1,3-dialkyluracil according to the following
reaction:
~NRl-C C~2
CO NaOH
\ NH-R3 R
. 3
The reaction is carried out by treating the 1,3-dialkyl-
l-cyanoacetylurea with a strong base such as sodium
hydroxide in an aqueous medium.
The 4-amino-1,3-dialkyl uracil is then converted into
4-amino-5-nitroso-1,3-dialkyluracil by treating with
sodium nitrite in glacial acetic acid at room tempera-
ture, according to the following reaction:
~-13-
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~77932
o o
R1~ N ~ Rl~ N ~ No
Na 2' 3 ~ ~ 1
The 4-amino-5-nitroso-1,3-dialkyl-uracil is then reduced
. to a 4,5-diamino-1,3-dialkyluracil by reaction with
sodium dithionite in ammonium hydroxide solution according
to the following reaction:
'- O O
N ~ ~ OH Rl~ ~ NH2
~ ~ Na2S2o4~ NH4 ~ ~ ~
O N NH N NH2
: R3 R3
~,
The 4,5-diamino-1,3-dialkyluracil is next converted
to a 4-amino-5-alkylamino-1,3-dialkyluracil by reacting
with a lower aliphatic acid according to the following
equation:
Rl ~N /~ NH;~ CRl~ ~NH-CI- R~
R8
: ~ 2
` R3 R3
,...
, . .
. wherein R8 is a lower group.
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1(~77932
The 4-amino-5-alkanoylamino-1,3-dialkyluracil is then
cyclized to form the 1,3,8-trialkylxanthine by heating
in 10% aque~us sodium hydroxide solution to reflux
temperature according to the following equation:
R1~ N J~ NH~ R8 R~ N
~ ~ NaOH > ~ R8
R3 2 R3
The compounds of this invention wherein R3 contains an
asymmetric carbon atom can exist in optically active
enantiomeric forms. These forms may exist separately
or mixed in any proportions. The racemic, or equimolar
mixture of enantiomeric forms is obtained in the synthesis
using reagents devoid of optical activity. The optically
active forms of the substituted xanthines can be
prepared by using the corresponding optically active
amines R3NH2 in the synthesis. For exampler the optically
active dextro- or levo- form of the substituted xanthines
having R3 = CH2CH(CH3)CH2CH3 can be obtained by startins
with the corresponding optically active form of 2-methyl-
` butylamine. Dextro- and levo-2-methylbutylamines can be
prepared from the corresponding commercially available
dextro- and levo-2-methylbutanols by the procedure
described by Vasi, I.G., and De~ai, R.K., J. InBt. Chemists
` CaZ¢~tta, 45, 66 (1973).
R3-OI~ > R3-B~ > R3-N~1 > R3-N~2
, .
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~ L077932
The compounds of this invention may be administered
; in the customary ways such as orally, sublingually,
inhalation, rectally and parenterally. Tablets, cap-
sules, solutions, suspensions and aerosol mist may be
used as forms for administration.
The compounds of this invention can be formulated into
compressed tablets incorporating the customary inert
excipients including diluents, binders, lubricants,
disintegrants, colors, flavors, and sweetening agents.
Commonly used pharmaceutical diluents such as calcium
sulfate, lactose, kaolin, mannitol, sodium chloride,
dry starch, and powdered sugar may be used.
Suitable binders for tablets include starch, gelatin,
sugars, such as sucrose, glucose, lactose, molasses,
natural and synthetic gums such as acacia, sodium alginate,
extract of Irish moss, panwar gum, ghatti gum, carboxy-
methyl cellulose, polyvinylpyrrolidone and the like.
Commonly used lubricants which are suitable for tablets
include talc, hydrogenated vegetable oils and the like.
- 20 A suitable disintegrant may be incorporated into the
tablets. Suitable disintegrants such as starches,
, ~,
clays, cellulose, algins, and gums may be used as is
well-known to those skilled in the art.
,',:"
Conventional coloring agents such as phaxmaceutically
~: 25 acceptable dyes and lakes and flavoring agents such as
'~ mannitol, lactose, or artificial sweetenersmay also be
added to the tablet composition.
-15-
1~77g3Z
The compounds of this invention may also be administered
orally contained in hard or soft capsules of gelatin or
other suitable material~ The compounds of this invention
may be present in the capsule alone or mixed with a suit-
able diluent such as lactose or starch.
The compounds of this invention may also be administeredsublingually as rapidly disintegrating tablets or as
troches or sublingual lozenges or pastilles. These
dosage forms are prepared by mixing the active ingredient
with flavored, rapidly dissolving or rapidly disinte-
grating excipients. For example, a suitable base would
comprise starch, lactose, sodium saccharin and talc.
Parenteral means can also be used for administering
the compounds of this invention. They may be incorporated
into implantable, slow-dissolving pellets or into
;. a~ueous injectable suspensions or solutions, or oily
injectable media such as fixed oils. In general, the
parenteral forms should be prepared just prior to use.
The compounds of this invention may also be administered
by inhalation of a mist. The active compound may be
dissolved or suspended in an aerosol propellant or
suitable carrier liquid and loaded into a standard aero-
sol container with sufficient propellant to provide the
proper pressure for dispensing the compound. These
propellants are usually fluorinated or fluorochlorinated
lower saturated aliphatic hydrocarbons. The active
ingredient is then dispensed through a special valve in
the form of a fine mist which is inhaled.
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107793Z
The great potency of 1,8-dimethyl-3-(2-methyl-1-butyl)-
7-carbomethoxyxanthine and 1,8-dimethyl-3-~2-methyl-1-
butyl)xanthine makes them preferred compounds for
aerosol administration, like epinephrine and isoprotere-
nol, to abort acute attacks. Aerosols of theophyllineand its saIts have been tried in the art, but the high
doses required for these drugs to be efficacious and the
resulting toxic reactions make this mode of administra-
tion impractical.
As is well-known in the pharmaceutical art, it is necessary
in compounding dosage forms to avoid incompatibilities
between ingredients. In formulating dosage forms
containing the compounds of this invention, it is
necessary to avoid combinations of ingredients which
will result in the instability of the active compound
if the dosage forms are to be stored for long periods
of time. The particular incompatibilities to be avoided
to attain this goal will be evident to one skilled in
the art for each par~icular dosage form. Thus, for
example, aqueous dosage forms of some of these com-
pounds cannot be stored for long periods of time; however,
.~.
they are perfectly satisfactory dosage forms if prepared
immediately before administration. It i8 preferred to
administer the bronchodilator and antiallergy compounds
of this invention orally in the form of tablets or
capsules. Preferred dosage ranges in humans are from
2 to 50 mg. The following examples illustrate the
practice of this invention but are not intended to
limit its scope.
-17-
, v
:'
1~77932
Example 1
Synthesis of 1,8-dLmethyl-3-(2-methyl-1-butyl)xanthine
Step 1
l-meth~Z-3-(2-methyZ-l-buty~urea (1)
3 2NCH21CHC2H5 ~ CH3NHcoNHcH2cHc2H5
(1)
1.03 kg (11.8 mole) of 2-methyl-1-butylamine was added
to 4.5 L of chloroform and the solution cooled to 0-5C.
Then 674.0 g (11.8 mole) of methylisocyar.ate was added
slowly while maintaining the temperature at 0.5C.
After the addition was complete the reaction was allowed
to reach room temperature. Stirring was continued
for 18 hrs.
The chloxoform was removed under vacuum to yield ~ 1.7 kg
of l-methyl-3-(2-methyl-1-butyl)urea. (1) - an oil.
Yield 100%.
Step 2
1-meth~-1-c~eno~oetyZ-3-(2-methr~-1-but~Z)urea (2)
:~ C2E~5CHCH2NHCONHCH3 + NCCH2COOH ~ ~NMeCOCH2CN
, CH3 NHCH2CHMeEt
(2)
To ~ 1 7 kg (11.8 mole) of 1-methyl-3-(2-methyl-1-butyl)-
20 urea (i~ were added 4.3 L of acetic anhydride and 1.18 kg
(13.9 mole) of cyanoacetic acid. This was heated for
2 hrs. @ 60-70C.
The acetic anhydride was removed under vacuum to yield
2.9 kg of an oil. This material is a mixture of cyano
25 acetic acid and 1-methyl-1-cyanoacetyl-3-(2-methyl-1-
butyl)urea (2). No attempt was made at purification;
(2) was used immediately in the next step.
:'.
'
~: .
;
!
''''~
.'.
.'
-18-
.
','' "'~ '
;, . . . .
:. :
. .
107793Z
~3
~-amino~ eth.~Z-3-(2-meth~-l^but~)uraciZ (3)
o
NMeCOCH2CN CH ~ ~
NHCH2CHMeEt N NH2
' CH2CHMeEt
(2) (3)
:'
i 10.3 L of 10% NaO~ solution was slowly added to 2.9 kg
(11.8 mole) of crude 1-methyl-1-cyanoacetyl-3-(2-methyl-
butyl)urea (2) with stirring.
The oil dissolved and shortly another oil precipitated.
The temperature rose to ~ 60C and then dropped.
After stirring for awhile at room temperature the oil
crystallized.
After cooling the praduct was filtered. The crude
product was slurried in water and dried @ 50C in vacuo
to yield ~ 2.1 kg of 4-amino-1-methyl-3-(2-methyl-1-
butyl)uracil r3) (m.p. 121-124C). Yield 85% from (lJ.
Step 4
~ 4-amino-S-n*troso-l-meth.~Z-3-(2-meth.~-1-but.~Juraci~ (~J
: O O
CH ~ CH ~ NO
" ~ O I NH2 I NH2
." CH2CHMeEt CH2CHMeEt
~ r3J r~J
j
; 21. kg (9.9 mole) of 4-amino-1-methyl-3-(2-methyl-1-
~, butyl)uracil r3J was suspended in 22.0 L of water. A
solution of 745.5 g (10.8 mole) of sodium nitrite in 5.7 L
of water was added to the suspension. Then 1.2 L of
; glacial acetic acid was added dropwise and the suspension
;~ was stirred for 18 hrs. at room temperature.
;~ After cooling the precipitate was filtered. The crude
product uas slurried in water and dried @ 80C *n vacuo
to yield ~ 1.9 kg of 4-amino-5-nitroso-1-methyl-3-(2-methyl-
~ butyl)uracil r~J (m.p. 202-204C). Yield 80%.
.':'
-19-
:
'',.,' ~
.' .
. . . . .
107793Z
Step 5
., _
~,.5-d?,amino-l~meth.~Z-3-(?-met~Z-?-butz~ZJ ur~aci,Z (5)
o CH~ 2
NH2 ~ NH~
H2CHMeEt CH2~E~leEt
f~ L (5)
,
8.65 L of conc. ammonium hydroxide (58%) was added to
; 5 1.9 kg (7.9 mole) of 4-amino-5-nitroso-1-methyl-3-(2-methyl-
1-butyl)uracil f~). An orange salt formed.
The suspension was placed in an oil bath at 80-90C and a
' solution resulted.
5.6 kg (32~3 mole) of sodium dithionite was added in portions
. 10 over about 30 min. When the addition was complete stirring
was continued for 30 min.
"~ The reaction was allowed to cool to room temperature and
stirred overnight.
~' After cooling the precipitate was filtered, slurried with
;, 15 water and dried @ 80C ~n vacuo to yield ~ 1.25 kg of
4,5-diamino-1-methyl-3-(2-methyl~ utylJuracil (5) (m.p.
}61-163C). Yield 70%.
;, .
~,~ Step 6
4-amino-s-acet~Zamino-l-methz~-3-(~-mety~-?-butz~) uraci~ (6)
CH3 ~ ~ ,NH2 ~ CH3~ ~ ~NHCOCH3
i~ ~ N ~NH2 ~ N ~ NH2
j~ ~5~ CH2 I HC2H5 CH2~HC2H5
.. `';. .
1.25 kg (5.5 mole) of 4,5-diamino-1-methyl-3-(2-methyl-1-
~1' butyl) uracil (5) was added to 4.5 L of glacial acetic acid
and heated to reflux for 2 hrs.
:~ The acetic acid was evaporated and the residue triturated with
ether. The solid was filtered and dried @ 60C in vac~o to
yield ~ 1.26 k~ of 4-amino-5-acetylamino-1-methyl-3-(2-methyl-
l-butyl)uracil ~6J (m.p. 178 182C). Yield 8S~.
.. . .
. , .
- ~
t ~ ~
~07793Z
Step 7
1,8-dimeth.~Z-3-(2-meth~Z-l-butyI) xanthine ~)
~UCOC~ C~ C113
~ H2 N
CH27HC2H5 CH2CHC2H5
~6J CH3 f7~ H3
. . .
1.26 kg (4.7 mole) of 4-amino-5-acetylamino-1-methyl-3-
~ 5 (2-methyl-1-butyl)uracil (6J was added to 3.9 L of 10~
; sodium hydroxide solution and heated at reflux for 30 min.
The solution was filtered and the filtrate cooled to room
temperature.
`~ The pH of the filtrate was adjusted to 5.0 with glacial
acetic acid.
After cooling the precipitate was filtered. The crude pro-
duct was slurried twice with water and dried @ 80C in vacuo
to yield about 1.0 kg of 1,8-dimethyl-3-(2-methyl-1-butyl)_`
xanthine (7) (m.p. 189-191C). Yield 85%~
. ,
:
" .
.,,.,, '
,~
~,
... .
.
.
s
:
:.`'
... .
.
'
~ . . .
. . ~ .
.: . , .
1077932
Example 2
1,3-dialkylxanthines and 1,3,8-trial~ylxanthines.
By the procedure of Example 1, a number of 1,3-dialkyl-
: xanthines and 1,3,8-trialkylxanthines are synthesized.
By proper choice of the reagents containing the precursors
: of the Rl, R3 and R8 groups the particular compounds are
synthesized- Rl and R3 are determined by the reagents
reacted in Step 1. R8 is determined by the carboxylic
: acid reagent used in Step 5. Table 1 shows the reagents
10 used in Steps 1 and 5 to introduce Rl, R~ and R~ and
produce the listed compounds.
_ TABLE 1 .
STEP 1 STEP 5
i~ No. Compound isocyanate amine acid
:. 156825 1-methyl-3-ethyl- methyl methylamine formic acid
;:, xanthine isocyanate
;- 6826 1-methyl-3-n-propyl- methyl n-propylamine formic acid
. xanthine isocyanate
6762 1-methyl-3-isopropyl- methyl isopropylamine formic acid
'. 20 xanthine isocyanate
~:~............... 4315 1-methyl-3-(n-butyl)- methyl n-butylamine formic acid
. xanthine isocyanate
4258 1-methyl-3-(isobutyl~- methyl isobutylamine formic acid
xanthine isocyanate
~; 25 6806 1-methyl-3-(n-pentyl)- methyl pentylamine formic acid
~,, xanthine i~ocyanate
,,~ 4280 DL-l-methyl-3-(2- methyl 2-methylbutyl- formic acid
: methyl-l-butyl)- isocyanate amine
. ~ xanthine
~- 30 4340 1-methyl-3-(2,2- methyl 2,2-dimethyl-formic acid
dimethyl-l-propyl)- isocyanate propylamine
xanthine
.. 4372 DL-l-methyl-3-(2- methyl 2-methylpentyl- formic acid
. methyl-l-pentyl)- isocyanate amine
35 _ xanthine _
;~'
-22-
.,
.'''''`'''' ~ .
' '
~ . .
. .
11~)7793~:
_ _ _
TABLE 1 tcontinued)
. _ ~
~ ~ STEP 5
No Compound isocyanate ~mine acid
. __ . _ _ _
4276 DL-l-methyl-3-(2- methyl 2-ethylhexyl- formic acid
5ethyl-l-hexyl)- isocyanate amine
xanthine
4306 1-methyl-3-methallyl- methyl methallylamine formic acid
xanthine isocyanate
6788 1-methyl-3-cyclo- methyl cyclohexylamine formic acid
10hexylxanthine isocyanate
4362 1-methyl-3-cyclo- methyl cyciohexane- formic acid
hexylmethylxanthine isocyanate methylamine
4296 1,3,8-trimethyl- methyl methylamine acetic acid
xanthine isocyanate
156832 1,8-dimethyl-3- methyl ethylamine acetic acid
; ethylxanthine isocyanate
.~. 6834 1,8-dimethyl-3-n- methyl n-propylamine acetic acid
. propylxanthine isocyanate
. 6818 1,8-dimethyl-3- methyl isopropylamine acetic acid
. 20isopropylxanthine isocyanate
. 6840 1,8'dimethyl-3- methyl n-butylamine acetic acid
. (n-butyl)xanthine isocyanate
4506 1,8-dimethyl-3-n- methyl pentylamine acetic acid
. pentylxanthine isocyanate
254500 1,8-dimethyl-3- methyl isopentylamine acetic acid
isopentylxanthine isocyanate
6738 1,8-dimethyl-3- methyl neopentylamine acetic acid
(2,2-dimethylpropyl)- isocyanate
.` xanthine
6842 1,8-dimethyl-3-(n- methyl n-hexylamine acetic acid
hexyl)xanthine isocyanate
4515 1,B-dimethyl-3- methyl 2-methyl-1-pentyl acetic acid
(2-methyl-1-pentyl)- isocyanate amine
.. xanthine
: 356786 1,8-dimethyl-3-(2- methyl 2-methyl-1-hexyl- acetic acid
. methyl-l-hexyl)- isocyanate amine
xanthine
6794 1,8-dimethyl-3- methyl methallylamine acetic acid
. methallyl-l-xanthine isocyanate
406787 1,8-dimethyl-3-cyclo- methyl cyclohexylamine acetic acid
.. hexylxanthine isocyanate
_ _ _ _ _
-23-
...
.,
".,. ' '
1~7793Z
__
._ TABnP 1 (continued) _ _ _
. STEP 1 STEP 5
:- . _
No. Compoundisocyanate amine acid
_ _
6778 1,8-dimethyl-3-cyclo- methyl cyclohexanemethyl- acetic acid
5hexylmethylxanthine isocyanate amine
6822 1,8-dimethyl-3-cyclo- methyl 2-cyclopropyl- acetic acid
. propylethylxanthine isocyanate ethylamine
. 4325 1,3-dimethyl-8-ethyl- methyl methylamine propionic
xanthine isocyanate acid
104328 1,3-dimethyl-8-(n- methyl methylamine butyric
propyl)xanthine isocyanate acid
~ 4331 1,3-dimethyl-8- methyl methylamine isobutyric
(isopropyl)xanthine isocyanate acid
.,
4355 1,3-dimethyl-8- methyl methylamine cyclopropane
(cyclopropyl)xanthine isocyanate carboxylic
acid
:4339 1,3-dimethyl-8- methyl methylamine valeric
tn-butyl)xanthine isocyanate acid
4344 1,3-dimethyl-8- methyl methylamine 3-methyl-
..(isobutyl)xanthine isocyanate butyric
,~ acld
204345 1,3-dimethyl-8- methyl methylamine 2,2-dimethyl
~ (t-butyl)xanthine isocyanate prDpionic
,. acid
r' ' 4355 1,3-dimethyl-8- methyl methylamir.e cyclobutyl-
; (cyclobutyl)xanthine isocyanate carboxylic
'. ' . , acid
6828 DL-l-methyl-3-(2- methyl 2-methyl-1- 3-butenoic
25methyl-1-butyl)-8- isocyanate butylamine acid
allylxanthine
6783 DL-l-methyl-3-(2- methyl 2-methyl-1- 3-butynoic
methyl-l-butyl)-8- isocyanate butylamine acid
propargylxanthine
306796 D-1,8-di~ethyl-3-(2- methyl D-2-methyl-1- acetic acid
tnhyl-l-butyl)xan- isocyanate butylamine
6807 L-1,8-dimethyl-3-(2- methyl L-2-methyl-1- acetic acid
. methyl-l-butyl)- isocyanate butylamine
xanthine
~:; 354490 DL-l-methyl-3-(2- methyl 2-methyl-1- propionic
.;. ~ . methyl-l-butyl)-8- isocyanate butylamine acid
~ ethylxanthine .
.
.
:','' ~
: . -24-
;.''
,': .
~`
:
'"",",' ' :
.-"'
" 107793Z
--
TABLE 1 (continued)
_.................. _
rEp 1 STEP 5
No. Compound isocyanate amine acid
4489 DL-l-ethyl-3-(2- ethyl 2-methyl-1- acetic acid
5methylbutyl)-8- isocyanate butylamine
methylxanthine
4495 DL-1,8-diethyl-3- ethyl 2-methyl-1- propionic
t2-methyl-1-butyl)- isocyanate butylamine acid
xanthine
104388 1,8-dimethyl-3- methyl isobutylamine acetic acid
_ isobutylxanthine isocyanate .
-24a-
.'' '
",~
lC~7793~
Example 3
:
?~8-dimeth~Z-3-(2-meth~ butyIJ ~anthine-7-carbo~2ic ~cid,
meth~Z ester
CH ~ N
CH2~CHC2H5 CH2~HC2H5
.
,
1.0 kg (4.0 mole) of 1,8-dimethyl-3-(2-methyl-1-butyl)-
xanthine was suspended in 19.0 L of dry tetrahydrofuran.
288.0 g of sodium hydride (50~ in oil) (6.0 mole) waswashed with anhydrous ether and was then carefully added to
the suspension.
~ The suspension was stirred for 1 hr (a solution resulted).
- 10 5~7.0 g (4.0 mole) of methyl chloroformate was slowly added.
After addition was complete the reaction was heated to reflux
for 18 hrs.
Then the reaction was filtered hot. The filtrate was
evaporated and the residue triturated with hexane. The
resultant solid was washed with a little ether, filtered and
dried @ 40C ~n vacuo to yield ~ 1.0 kg of 1,8-dimethyl-3-
(2-methyl-1-butyl)xanthine-7-carboxylic acid, methyl ester
(m.p. 110-112C). Yield 82%.
, .
.... .
''''"
:.
. ,'
, ..
. .,
,.
,: .
., ' .
-25-
~77932
- Example 4
1,3,8-trialkylxanthine-7-carboxylic acid esters.
. By the procedure of Example 3 using the corresponding
1,3,8-trialkylxanthine and ester of chloroformic acid
listed in Table 2, the 1,3,8-trialkylxanthine-7-carboxy-
lic acid esters listed in Table 2 are prepared.
. TABLE 2
REAGENTS
No. Product xanthine chloroformic ester
4260 1,3-dimethylxanthine- 1,3-dimethylxanthine methylchloroformate
7-carboxylic acid, (theo~hylline)
: methyl ester
6862 1-methyl-3-ethyl- 1-methyl-3-ethyl- methylchloroformate
xanthine-7-carboxylic xanthine
acid, methyl ester
6853 1-methyl-3-n-propyl- 1-methyl-3-n-propyl- methylchloroformate
xanthine-7-carboxylic xanthine
: acid, methyl ester
. 6884 1-methyl-3-isopropyl- 1-methyl-3-isopropyl- methylchloroformate xanthine-7-carboxylic xanthine
: acid, methyl ester
. 6896 1-methyl-3-(n-butyl)- 1-methyl-3-(n-butyl)- methylchloroformate
: xanthine-7-carboxylic xanthine
` acid, methyl ester
:. 25 4274 1-methyl-3-(isobutyl)- 1-methyl-3-~isobutyl)- methylchloroformate
xanthine-7-carboxylic xanthine
acid, methyl ester
-~. 6865 1-methyl-3-(n-pentyl)- 1-methyl-3-(n-pentyl)- methylchloroformate
: xanthine-7-carboxylic xanthine
acid, methyl ester
... 4380 1-methyl-3-(2-methyl- 1-methyl-3-~2-~ethyl- methylchloroformate
l-butyl)xanthine-7-- l-butyl)xanthine
carboxylic acid,
methyl ester
:. 35 6854 1-methyl-3-(2,2-di- 1-methyl-3-(2,2-di- methylchloroformate
;:. methyl-l-propyl)xan- methyl-l-propyl)
thine-7-carboxylic xanthine
:-. . acid, methyl ester _ .
';' ,'
-26-
. '
.~ .
'. C~1
~ .' ' ' '' , . ~ ' '
. ~ . ' ' -
:.. . . ' : .
` ` 1(37793Z
_ _ _
TAsLE 2 (continued)
REAGENTS
NoO Product xanthine chloroformic ester
6857 DL-l-methyl-3-(2- DL-l-methyl-3-(2- methylchloroformate
methyl-l~pentyl)xan- methyl-l-pentyl)-
thine-7-carboxylic xanthine
: acid, methyl ester
6861 DL-l-methyl-3-(2- DL-l-methyl-3-~2- methylchloroformate
methyl-l-hexyl)xan- methyl-l-hexyl)-
thine-7-carboxylic xanthine
acid, methyl ester
6882 1-methyl-3-methallyl- 1-methyl-3-~ethallyl- methylchloroformate
xanthine-7-carboxylic xanthine
acid, methyl ester
6871 1-methyl-3-cyclohexyl- 1-methyl-3-cyclohexyl- methylchloroformate
:. xanthine-7-carboxylic xanthine
. acid, methyl ester
6877 1-methyl-3-cyclohexyl- 1-methyl-3-cyclohexyl- methylchloroformate
methylxanthine-7- methylxanthine
carboxylic acid,
methyl ester
4378 1,3,8-trimethylxan- 1,3,8-trimethyl- methylchloroformate
thine-7-carboxylic xanthine
.. acid, methyl ester
'
: 25 6866 1,8-dimethyl-3-ethyl- 1,8-dimethyl-3-ethyl- methylchloroformate
~',''! xanthine-7-carboxylic xanthine
. acid, methyl ester
. 6869 1,8-dimethyl-3-n- 1,8-dimethyl-3-n- methylchlorofor~ate. propylxanthine-7- propylxanthine
.~ 30 carboxylic acid,
-: methyl ester
6880 1~8-dimethyl-3-iso- 1,8-dimethyl-3-iso- methylchloroformate
: propylxanthine-7- propylxanthine
.. carboxyllc acid,
methyl ester
6892 1,8-dimethyl-3-(n- 1,8-dimethyl-3-(n- methylchloroformate
.. butyl)xanthine-7- butyl)xanthine
.`. carboxylic acid,
. methyl ester
:- 40 4507 1,8-dimethyl-3-n- 1,8-dimethyl-3-n- methylchloroformate
. pentylxanthine-7- pentylxanthine
~...................... carboxylic acid,
. methyl ester _
., .
'
. ,
.~ -2~-
. .
1~37793Z
_
TAsLE 2 (continued)
REAGENTS
No. Product xanthine chloroformic ester
_ . _
4505 1,8-dimethyl-3-iso- 1,8-dimethyl-3-iso- methylchloroformate
pentylxanthine-7- pentylxanthine
carboxylic acid,
methyl es~er
6897 1,8-dimethyl-3-(2,2- 1,B-dimethyl-3-(2,2- methylchloroformate
dimethylpropyl)xan- dimethylpropyl)-
thine-7-carboxylic xanthine
acid, methyl ester
6850 1,8-dimethyl-3-(n- 1,8-dimethyl-3-(n- methylchloroformate
hexyl)xanthine-7- hexyl)xanthine
carboxylic acid,
methyl estPr
4515 DL~1,8-dimethyl-3-(2- DL-1,8-dimethyl-3-(2- methylchloroformate
methyl-l-pentyl)xan- methyl-l-pentyl)-
thine-7-carboxylic xanthine
acid, methyl ester
20 4390 1,8-dimethyl-3-iso- 1,B-dimethyl-3-iso- methylchloroformate
. butylxanthine-7- butylxanthine
carboxylic acid,
methyl ester
. 68B8 DL,1,8-dimethyl-3-(2- DL-1,8-d~methyl-3-(2- methylchloroformate
: 25 methyl-l-hexyl)xan- methyl-l-hexyl)
thine-7-carboxylic xanthine
:. acid, methyl ester
~ 6906 1,8-dimethyl-3-~eth- 1,8-dimetbyl-3-meth- methylchloroformate
. allylxanthlne-7- allylxanthine
carboxylic acid,
.. methyl ester
6878 1,8-dimethyl-3-cyclo- 1,8-dimethyl-3-cyclo- methylchloroformate
. hexylxanthine-7- hexylxanthine
. carboxylic acid,
~ethyl e~ter
6898 1,8-dimethyl-3-cyclo- 1,8-dimethyl-3-cyclo- methylchloroformate
.~ hexylmethylxanthine-7- hexylmethylxanthine
carboxylic acid,
. ~ethyl ester
6911 1,8-dimethyl-3-cyclo- 1,8-dimethyl-3-cyclo- methylchloroformate
propylethylxanthine-7- propylethy}xanthine
- carboxylic acid,
~. methyl ester
'~'
.~
~<
-28-
. ~
.' ` ''.~'
1~77~32
_ . . .
TABLE 2 (continued)
REAGENTS
_ _ _ _ _ __ _
NoO Product xanthine chloroformic ester
_ _ _
6940 1,3-dimethyl-8-ethyl- 1,3-dimethyl-8-ethyl- methylrhloroformate
xanthine-7-carboxylic xanthine
acid, methyl ester
6957 1,3-dimethyl8-(n- 1,3-dimethyl-8-(n- methylchloroformate. propyl)xanthine-7- propyl)xanthine
carboxylic acid,
methyl ester
6932 1,3-dimethyl-8-(iso- 1,3-dimethyl-8-(iso- methylchloroformate propyl)xanthine-7- propyl)xanthine
carboxylic acid,
methyl ester
6947 1,3-dimethyl-8-(cyclo- 1,3-dimethyl-8-(cyclo- methylchloroformate
... propyl)xanthine-7- propyl)xanthine
: carboxylic acid,
: methyl ester .
... 6922 1,3-dimethyl-8-(n- 1,3-dimethyl-8-(n- methylchloroformate
. 20 butyl)xanthine-7- butyl)xanthine
: carboxylic acid,
: methyl ester
:. 6951 1,3-dimethyl-8-(iso- 1,3-dimethyl-8-(iso- methylchloroformate
. butyl)xanthine-7- butyl)xanthine
25 carboxylic acid,
methyl ester
6917 1,3-dimethyl-8-(t- 1,3-dimethyl-8-(t- methylchloroformate butyl)xanthine-7- butyl)xanthine
carboxylic ac~d,
: methyl ester
6914 1,3-dimethyl-8-(cyclo- 1,3-dimethyl-8-(cyclo- methylchloroformate
butyl)xanthine-7- butyl)xanthine
carboxylic acid,
methyl ester
: 35 6928 DL-l-methyl-3-(2- DL-l-methyl-3-(2- methylchloroformate
methyl-l-butyl)-8- methyl-1-butyl)-8-
allylxanthine-7- allylxanthine
carboxylic acid,
: methyl ester
6933 DL-l-methyl-3-(2- DL-l-~ethyl-3-(2- methylchloroformate
methyl-l-butyl)-8- methyl-1-butyl)-8-
propargylxanthine-7- propargylxanthine
:.~ carboxylic acid,
_ methyl ester _ _ .
'''
-28a-
, ,
. .
.~
, .
^~i
. .
7793Z
TABLE 2 (continued)
: REAGENTS
. _
NoO Product xanthine chloroformic ester
_
6919 D-1,8-dimethyl-3-t2- D-1,8-dimethyl-3-(2- methylchloroformate
methyl-1-butyl)xan- methyl-l-butyl)-
thine-7-carboxylic xanthine
acid, methyl ester
6938 ~-1,8-dimethyl-3-(2- L-1,8-dimethyl-3-(2- methylchloroformate
methyl-l-butyl)xan- methyl-l-butyl)-
thine-7-carboxylic xanthine
acid, methyl ester
4491 DL-l-methyl-3-(2- DL-l-methyl-3-(2- methylchloroformate
. methyl-l-butyl)-8- methyl-1-butyl)-8-
.~ ethylxanthine-7- ethylxanthine
~:- 15 carboxylic acid,
: methyl ester
. 4494 DL-l-ethyl-3-(2- DL-l-ethyl-3-(2- methylchloroformate
: methyl-l-butyl)-8- methyl-1-butyl)-8-
methylxanthine-7- methylxanthine
;..........20 carboxylic acid,
- methyl ester
4498 DL-1,8-diethyl-3-(2- DL-1,8-diethyl-3-(2- methylchloroformate
.~ methyl-l-butyl)xan- methyl-l-butyl)-
thine-7-carboxylic xanthine
25 acid, methyl ester
.. 4246 1,3-dimethylxanthine-7 1,3-dimethylxanthine ethylchloroformate
carboxylic acid,
ethyl ester
. 4356 1,3-dimethylxanthine-7 1,3-dimethylxanthine n~propyl
carboxylic acid, (theophylline) chloroformate
. n-propyl ester
:: 4361 1,3-dimethylxanthine-7 1,3-dimethylxanthine isopropyl: carboxylic acid, (theophylline) chloroformate
. isopropyl ester
4275 1,3-dLmethylxanthine-7 1,3-dimethylxanthine n-butyl
carboxylic acid, ttheophylline) chloroformate
n-butyl ester
. 4273 1,3-dimethylxanthine-7 1,3-dimethylxanthine isobutyl
; carboxylic acid, (theophylline) chloroformate
isobutyl ester
:: 4477 DL-1,8-dimethyl-3-~2- DL-1,8-dimethyl~3-(2- ethylchloroformate
.:. methyl-l-butyl)xan- methyl-l-butyl)-
. thine, ethyl ester xanthine
'.'~ _ _ .
. .
`::
-29-
.
. ~i j
'
: ''',
107793Z
TABLE 2 (continued)
REA OE N~S
_
. No. Product xanthine chloroformic ester
_
4488 DL-1,8-dimethyl-3-(2- DL-1,8-dimethyl-3-(2- n-propyl
methyl-l-butyl)xan- methyl-l-butyl)- chloroformate
thine-7-carboxylic xanthine
.. acid, n-propyl ester
4278 1,3-dimethylxanthine-7- 1,3-dimethylxanthine 2-chloroethyl-
carboxylic acid, chloroformate
2-chloroethyl ester
4262 1,3-dimethylxanthine-7- 1,3-dimethylxanthine phenyl
. carboxylic acid, phenyl chloroformate
ester
~. 6852 DL-1,8-dimethyl-3-(2- DL-1,8-dimethyl-3-(2- 2-chloroethyl-
; 15 methyl-l-butyl)xan- methyl-l-butyl)- chloroformate
thine-7-carboxylic xanthine
. acid, 2-chloroethyl
ester
6860 DL-1,8-dimethyl-3-(2- DL-1,8-dimethyl-3-(2- phenyl
methyl-l-butyl)xan- methyl-l-butyl)- chloroformate
thine-7-carboxylic xanthine
acid, phenyl ester
. .
:,
, ,:
' '
~ -30-
. "
.:
C~7
~'
1~77~32
In the following comparative examples results of
pharmacological tests with a number of the compounds of
this invention and of the prior art are presented. The
pharmacological properties were evaluated by standard
tests ~7hich are defined, together with the symbols used as
follows:
BD Bronchodilator activity evaluated against histamine-
induced bronchoconstriction in the guinea pig, and
expressed as % protection at the stated time interval
- 10 (in minutes and hours) post-drug against histamine
agonist. -~oses are expressed in milligrams per kilo-
gram of body weight tmpk) per os (~)or intraperitoneally
(ip) ~
A modification of the method of Siegmund. O.H., et.al.,
J. Pharmacol. and Exp. Therap. 90:254-9, 1947~ is used.
Healthy guinea pigs weighing from 250 to 300 grams are placed
- four at a time and separated by wiring screening in anll liter
plastic chamber, at the time of peak activity following drug
administration. The challenge consists of histamine diphosphate
(1% solution) aerosolized in a de Vilbiss ~40 nebulizer at
200 mm Hg. Times for prostration are recorded. All animals
exposed to the aerosols for 10 minutes or longer without pros
tration, are arbitrarily considered fully protected.
: Per cent protection is calculated as follows:
% Protection =
lOO(Test prostration time-control prostration time)
600 ~ control prostration time
, wherein the times are measured in seconds.
: .
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~77~32
~p Cardiopulmonary activity evaluated against histamine-
induced bronchoconstriction in the dog and e~pressed
as % increase (~) or decrease (~) in the following parameters: -
BP blood pressure
HR heart rate
PR pulmonary resistance
; PC pulmonary compliance
RM~ respiratory minute volume
The method used is that of Giles, R. E., Finkel, N. P., and
1~ Mazurowski, J., Arch. Int Pharmacodyn. Therap. 194, 213 (1971).
A simulated asthmatic state is induced in anesthetized spontaneously
breathing dogs by graded intravenous doses of histamine. The
degree of induced bronchoconstriction is reflected by proportionate
increases in pulmonary resistance. Pretreatment with broncho-
1~ dilator drugs aims to ~lock the bronchospastic response to histamine.
Each dog serves as its o~m control. Mean values 2 hours post drug
.. . . . . . . . ........................ . ..
are given.
; SP Spasmolytic activity evaluated in vitro using guinea pig
tracheal chain preparation, and expressed as the molar (M)
concentration required to produce maximum relaxation.
; The method used in that of Castillo and de Beer, J. Pharmac. Expt~
Therap. 90, 104, 1947.
AA Antiallerg~ (anti-anaphylactic) activity evaluated against
antigen-induced bronchconstriction in rats sensitized with
; 25 N. brasliensis, and expressed as % protection (R).
The method used in that of Church, N. K., Collier, H. O. J., and
James, G. W. L., Brit. J. Pharmacol. 46, 56-65 (1972).
Rats sensitized with antigen from Nippostrongylus brasiliensis
exhibit anaphylactic shock when re-exposed to this antigen 28 days
later. The animals are subdivided into control and test groups.
`;`
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-32-
.
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107793Z
Test animals receive a drug either orally, intraperitoneally
or intravenously and are challenged with intravenous antigen
at fixed time interva]s after dosing. Antigen-induced increases
in tracheal pressure are monitored and reflect the extent of
bronchoconstriction.
PCA Antianaphylactic activity against passive cutaneous
anaphylaxis in the rat, expressed ag % protection against
antigen-induced wheal formation.
The method used is that of Ogilvie, B.M., Immunology 12, 113-131
(1367). Reaginic AgE antibodies develope in the rat following
subcutaneous injection of Nippostrongylus brasiliensis larvae.
Antisera, collected 28 days later are injected subcutaneously
into new rats. These new rats when challenged with antigen 24 hours
later exhibit an immediate type I reaction characterized by local
swelling and edema (wheal) at the si~e o antisera injection.
. . .
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LD50 ~ose required to ca~se death of 50~i of test animals.
The LD50 was determined in three species, the mouse (male,
18-25 g), the albino rat (female, 150-200 g) and the albino
guinea pig (male 180-280 g) by oral administration and in
the albino rat by intraperitoneal administration. The animals
are fasted overnight prior to testing. Six groups of ten
animals are used; five groups are dosed with the test substance,
the sixth group serves as a control ana receives the drug
vehicle at the highest test concentration. The compounds
were administered in a 0.5% gum tragacanth solution in distilled
water using a constant logarithmic increment in dose. Dose
volume ranged from 5 to 40 mg/kg.
The animals were housed five per cage (rat and guinea pig) or
ten per cage (mouse) with free access to food and water. The
number of dead anImals was recorded daily for five consecutive
days. The total mortality per group of ten for each dose level
was recorded and and LD50 with Confidence Limits calculated
according ~o the method described by Weil, C. S., Biometrics
8(3): 249-263, 1952.
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1(37793Z
Example 5
This example illustrates the superiority of 7-carboalkoxy-
xanthines over the corresponding 7-H xanthines. Several
pairs, of compounds were tested in a number of assays as
S described above.
The results may be seen in Table 4 wherein corresponding
xanthines ~ith and without the 7-carbomethoxy group are com-
pared. The effect can be seen most clearly by comparing the
potency of the compounds in the bronchodilation assay in the
guinea pig (BD[guinea pig]).
In-interpreting:the BD data it should be noted that a dose ' -'
; giving less than 40-50% protection is not considered useful.
Differences in percent protection of less than 10% are probably
not significant. ~378 gives 96% protection at 1 hour at a dose
of 60 mpK while the corresponding compound devoid of the 7-
'; carbomethoxy groups, 4296, gives only 53% protection at the
, larger dose of 100 mpK. Clearly, the 7-carbomethoxy derivative
is'superior. 4274 gives greater protection than 4258 at
", equal doses. In comparing 4387 and 4383 at equal
doses (10 mp~) it can be seen that the 7-carbomethoxy compound
4387 shows greater activity. Although both of these compounds
are already very potent, the benefit of the 7-carbome~hoxy'g'roup
" is particularly evident in the dog at 1 mpK. Another
comparison shows that 4260 is clearly superior to theophylline
. 25 at the same dose (80 mpK).
; ~.
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1~77932
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107793Z
Exam~le 6
This example illustrates the prolonged activity of the
8-alkylxanthines over that of the corresponding 8-H
compounds. The increased and prolonged activity of the
1,3,8-trialkyl-7-carboalkoxyxanthines relative to that
of the 1,3-dialkyl-7-carboalkoxyxanthines may be seen
in Table 4 which compares the activity of corresponding
pairs of substituted xanthines with and without 8-alkyl
groups.
The data on bronchodilator activity in the guinea pig
(BD[guinea pig]) show the prolonged activity of the
compounds having an 8-alkyl group. In each pair the
protection at 4 hours or 6 hours produced by the
. 8-methyl compound is greater than the protection by
the corresponding compound devoid of the 8-methyl group.
For pairs 4387 vs. 4380, 4390 vs. 4274, 4378 vs. 4260,
pairs 4383 vs. 4280, 4388 vs. 4258 and 4296 vs. theophyl-
~s line the 8-methyl derivatives are shown to be effective
.':,
at lower doses and for longer duration than the 8-H
~r~ 20 compounds. This phenomenon is attributed to the 8-alkyl
substituent interfering with the normal bioinactivation
- of 1,3-dialkylxanthines by enzymatic oxidation at the
8-position, and was not anticipated by the teachings
of the prior art on xanthine compounds.
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~07793Z
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1~77932
Example 7
This example illustrates the decreased toxicity of
substituted xanthines having R3 = 2-methyl-1-butyl over
those having R3 = isobutyl while the potency of the compounds
remains approximately equal.
The unexpected improvement in activity of l-alkyl-3-(2-methyl-
l-butyl)-7-carbomethoxy xanthines, without a corresponding
increase in toxicity with reference to the corresponding 3-
, .
isobutyl homologs can be seen in Table 5 where the data for
corresponding pairs of compounds is presented. This effectis seen most clearly in the pair 4387 vs. 4390. The
effectiveness of the 7-carbomethoxy compounds can be compared
in the bronchodilation assay in the guinea pig and the
~I antiallergy assay in the rat. The effectiveness data show
that the 1-methyl-3-(2-methyl-1-butyl~-8-methyl-7-carbomethoxy-
xanthines (4387) is about as effective as the corresponding
~; 3-isobutyl compound (4390) in the guinea pig, rat and dog
. .
assays. Yet 4387 is only about one-half as lethal as 4390 in
.,
the rat and mouse. Likewise, in the guinea pig toxic effects
` 20 can be seen in the case of the xanthines having the 3-isobutyl
,~ group, while at the same dose the corresponding compound having
the 3-(2-methyl-1-butyl) group is effective and non-toxic.
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Among the 1,3,8-trialkylxanthines, 4383 has about the
same bronchodilation potency as 4388 in the BD (guinea
pig) assay at a dose of 10 mpK per os; yet at a dose of
20 mpK po 4383 shows no toxic effects while 4388 shows
pronounced toxicity and was even lethal to one animal.
4280 and 4258 show about equal potency as shown by the
results for doses of 20 mpK po and 15 mpK po, respectively;
however, 4258 shows lethal effects at only 25 mpK po, while
4280 must be given at a dose of 80 mpK po to show
similar lethal effects.
Clearly, the xanthines having a 2-methyl-1-butyl group
in the 3-position are less toxic than those having a
3-isobutyl group.
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~07793Z
Example 8
This example illustrates the activity of substituted
xanthines according to this invention and the variation
in pharmacological effects produced by introducing
different R3 substituents.
Table 6 shows the results of the bronchodilation assay
described above in the guinea pig for a series of
1,3-dialkyl and 1,3,8-trialkylxanthine-7-carboxylates
; in which the R~ group was v~ried. The most effective
compounds are those in which the lowest dose produces
an acceptable bronchodilation (~40%). Data is also
included showing effectiveness in the antiallergy assay
in the rat, and the in vitro bronchodilation activity.
The data for the effectiveness of the compounds shown
in the Table 6 teaches that the activity of xanthine
bronchodilators depends not only upon the total number
of carbon atoms comprising Rl, R3, R8 and R, but also
upon the distribution of these carbon atoms among
. Rl, R~, R8 and R, and especially upon the branching
within the structure of the R3 group-
':.?-~ Maximum activity i8 obtained when R1=R~=R=methyl and
R3 iS a C4 or C5 alkyl group. Peak activity is obtained
when the alkyl group of R3 is branched at the number
2 carbon -CH2CHR as in 2-methyl-1-butyl.
CH3
.
Optimal activity, i.e., maximum activity with relatively
lowest toxicity is obtained when R3 is a 2-methyl-1-butyl
group. Of all the possible C4 and C5 alkyl groups, only
the 2-methyl-1-butyl group is both primary and asymmetric,
i.e., capable of existing as dextro and levo forms.
;
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107793Z
Example 9
This example illustrates the antiallergy properties of the
compounds of this invention.
1,8-Dimethyl-3-(2-methyl-1-~utyl)-7-carbomethoxyxanthine
1,8-dime~hyl-3-isobutyl-7-carbomethoxyxanthine and 1,8-
- dimethyl-3-(2-methyl-1-butyl)xanthine were testea in the
rat passive cutaneous anaphylaxis screen described above.
The data in Table 6 shows that these compounds are efective
'"J'' antiallergy agents.
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1~i7793Z
Example 10
This example illustrates the effectiveness of the
compounds of this invention in the dog.
The results of studies of cardiopulmonary activity in
the dog by the above-described procedures are shown
in Table 8. The data show that compounds 4390, 4387,
and 4383 significantly reduce the decrease in pulmonary
compliance and increase in pulmonary resistance due to
histamine administration. The corresponding values
for theophylline, a clinically used xanthine broncho-
dilator, ar~ shown for comparison. It can be ~een that
the compounds of this invention are more potent broncho-
dilators than theophylline in the dog.
TABLE 8. CARDIOPULMONARY ACTIVITY IN THE DOG
CP (dog) (mean value at 2h)
m~K BP HR PC PR RMV
. _.
4387 lpo ~17 t40 t40 ~61 t39
2po ~03 tl6 t60 ~85 tlO
3po ~08 t08 t74~1~0 t68
4po ~25 tl7 t42 ~77 t76
4390 3po ~07 ~13 t70 ~85 t41
Theophylline 40po ~08 t06 t25 ~36 t38
4383 lpo ~12 t21 tl8 ~36 t33
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Example 11 107793Z
Tablets
19.5 grams of starch are dried to a moisture content of 10%.
0.5 grams of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxy-
S xantbine in finely powdered form are thoroughly mixed with
the starch. The mixture is compressed into slugs. The slugs
are reground into powder of 14-16 mesh size. This powder is
recompressed into tablets weighing 200 mg. each. Each tablet
thus has the composition:
1,8-dimethyl-3~(2-methyl-1-butyl)-
7-carbomethoxyxanthine S mg
; S~arch 195 mg
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Example 12
Capsules
A dry mixuture os 19.5 grams of starch and O.5 grams of
1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxyxanthine
B 5 is prepared as described in Example ~. The powder is
loaded into hard gelatin capsules so that each capsule
contains 200 mg of the powder.
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~ Example 13
Sublingual Tablets
.
Tablets for sublingual administration were prepared by
standard procedure, each tablet containing 5 mg of 1,8-
dimethyl-3-(2 methyl-1-butyl)-7-carbomethoxyxanthine in a
rapidly disintegrating base comprising starch, lactose,
sodium saccharin and talcum.
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107793Z
Example 14
Aerosol
Five grams of 1,8-dimethyl-3-(2-methyl-1-butyl)-7-carbomethoxy-
xanthine were dissolved in 1000 grams of a mixture of 20 parts by
weight of dichlorodifluoromethane and 80 parts by weight of 1,2-
dichloro-1,1,2,2-tetrafluoroethane and loaded into a conventional
aerosol medication dispenser to provide a means of administering
the active ingredient by inhalation.
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