Note: Descriptions are shown in the official language in which they were submitted.
iO~5604
Background o. the Invention
1. Field of the Invention
The .invention relates to pha:rmaceutical compositions
and more particularly relates to pharmaceutical compositions
~ 5 useful as antispasmodics.
: 2. Brief.Description of the Prior Art
A number of antispasmodic compositions ha~e been
, known ~eretofore. However, they have not been satisfactory
; for all purposes. For example, atropine is a well known
.antispasmodic but it has associated with its use a number
of side efects such as the inducement of sleepiness,
mental confusion and a state of inattentiveness. In many
cases, especially with long term treatment, drug dependence
: can occur. Papaverine is anothe~ well known antispasmodic
but its nse in the treatment of severe spasms requires very
high dosages,,.near the'lethal dose, that is to say the
, dose at which a particular death rate is to be expected in
animal experiments. Also, w,hile papaverine .is very active
in animal experiments, when used on humans its activity -
, ~. . ~ .
,20 is insu~ficient and papa~erine there~ore.has.no signi~icance
in human therapy. .
:The compositions o the invention are therapeutically
~ ~ active and~ are useful as antispasmodics in the treatment o~
:., muscle spasms in animals including humans. They axe
antispa~odics having a specific cramp-releasing action on
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muscles which are in a state of cramp. The~ are efective
in a small dosage, even in the case of se~ere spasms.
Summary of the Invention .
_ .
The invention com~rises an antispasmodic pharmaceutical
pxeparation, which comprises; an effective amount of a compound
.of the formula:`-
~ ~ O - R
: : . . C3 Hs
(I)
...
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: ~ wherein R lS selected from the group consistin~ of the acyl
i~ radical of a carboxylic acid and hyd.rocarbyl' ând a
. 10 pharmaceutically acce~tablè ca.rrier.
. The term "acyl radical of a carboxylic acid" is used
: herein in its conventionally accepted sense. Representative
. of carboxylic acid acyl radicals are the acyl radicals of
; . the following acids:
:.~ lS (a~ saturated or unsaturated, straight or hranched
. chain aliphatic carboxylic acids, for example ace~ic, pxopionic,
: butyric, isobutyric, tert-butylacetic, ~aleric, isovalexic,
caproic, capryllc, succinic, decanoic, dodecanoic, lauric,
. . txidecanoic, myxistic, pentadecanoic, palmitic, marga~ic,
steariC, acrylic, crotonic, undecylenic, ~leic, hexynoic,
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107560~
.~ heptynoic, octynoic acidsr and the like;
~b) saturated or unsaturated, alicyclic carboxylic
acids, for example,-cyclobutanecarboxylic acid, cyclopenta-
necarboxylic acid, methylcyclopentenecarboxylic acid~
cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid,
; dipropylcyclohexanecarboxylic acia, and the like;
(c) saturated or unsaturated, alicyclic aliphatic
carboxylic acids, for example cyclopentanepropionic acid
: cyclohexanebutyric acid,.methylcyclohexaneacetic acid, ~nd
the like; .
(d) aromatic carboxylic acids, fox example, benzoic .
acid, toluic acid, n~phthoic acid, ethylbenzoic acid,
isobutylbenzoic acid, methylbut~lbenzoic acid, and the l.ike; and
(e) aromatic-aliphatic carbox~lic acids, ~or example,
phenylacetic ~cid, phenylpropionic acid, phenylvaleric acid,
cinnamic acid, phenylpropionic acid and naphthylacetic acidr
and the like.
. The term "hydrocarb~l" as used herein means the
. ~ . monovalent moiety obtained upon removal of a h~drogen atom
20 ~rom a parent.hydrocarbon having, for example, 1 to 20 carbon
: : atoms, inclusive.
~ Illustrative.of such hydrocarbyl groups are alkyl
: of from 1 to 20 carbon atomsr inclusive, such as methylr ethyl,
. propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,~: :
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the
isomeric forms thereof; cycloalkyl of from 3 to 20 carbon atom~
: : such as cyclopropyl, cyclobu~yl, cyclopentyl, cyclohexyl, cyclo-
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~ 1~75604
hexylmethyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl~
2,3-dimethylcyclobutyl, 4-methylcyclobutyl, 3-cyclopentylpropyl,
and the like; polycycloalkyl such as adamantyl and the like;
aralkyl such as henzyl, phenethyl, ~-phenylpropyl, phenylhexyl,
phenyldodecyl, ~-naphthylmethyl, and the like; alkenyl such
as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,
octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl,
tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl,
octadecenyl, nonadecenyl, eicosodecenyl and isomeric orms
thereof; cycloalkenyl such as cyclobutenyl, cyclopentenyl,
cyclohexenyl and the like; aryl of 6 to 20 carbon atoms,
inclusive, such as phenyl, o-, m- and p-tolyl, ethylphenyl,
xylyl, naphthyl, diphenylyl/ anthracyl, dipropylphenylyl
and the like.
Those skilled in the art will appreciate that there
are two isomers of each compound of the formula (I) given
above. They may be schematically xepresented as
O - CH3 ~Ro ~ - CH3
CH2 - CH C 2 CH = CEI ~ CH3
~.: . ~ - .
Isomer A Isomer B
wherein R is as be~ore defined. Both isomers are active,
effective ingreaients of the compositions of the invention and
the formula (I) given above is intended to include both isomeric
, formL., ~ ~ . . .'
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107564
Detailed Description of the Preferred E~odiments
of the Invention _ _ _
The essential active ingredient for the compositions of
the invention are provided by compounds of the formula ~I) given
above. Compounds of the formula (I) are generally well known as
is their preparation. In general, the compounds of formula (I)
may be prepared by processes which are customary in the preparat-
ion of organic compounds, from the corresponding 4-hydroxy
compounds. More specifically, in the case o esterification,
the preparation of a compound (I) wherein R is an acyl radical
may be carried out, for example, by the action of an appropriate
acid halide or acid anhydride on 4-hydroxy-3-methoxy-l-allyl- (or
-l-propenyl-) benzene in the presence of a base, for example
potassium carbonate or pyridine. The ~rocedure may be according
to the well known SCHOTTEN-BAUM~NN method.
i In the case of etherification -the preparation of compounds
(I) wherein R is hydrocarbyl may be carried out, for example, by
the action of an appropriate hydrocaxbyl halide in alcoholic (e.g.
ethanolic) solution on 4-hydroxy-3-methoxy-l-propenyl-(or -l-
~/ 20 allyl-) benzene according to the well known WILLIAMSON synthesis.
~ ~ Representative of the compounds (I) where R is the acyl
; radical of an aliphatic carboxylic acid are the preferred
;~ compounds 4-allyl-2-methoxyphenyl acetate, 2-methoxy-4-
propenylphenyl acetate, 4-allyl-2-methoxyphenyl valerate and
2 methoxy-4-propenylphenyl valerate. Also preferred as
active ingredients in the compositions of the invention and
representative of those wherein R is the acyl radical of an
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aromatic carboxylic acid are 4-allyl-2-methoxyphenyl benzoate
and 2-methoxy-4-propenylphenyl benzoate.
Of those ethers of the formula (I) wherein R is hydxo-
carbyl, preferred are -those wherein R is lower alkyl such as
1-allyl-3,4-dimethoxybenzene and 3,4~dimethoxy-1-propenyl-
benzene which are preferred examples of such compounds. In the
case where R is aralkyl, 2-methoxy-4-propenylphenyl-1 benzyl
ether is a preferred example o~ such a compound.
The composition of the present invention are preferably
presented for administration to humans and animals in unit dosage
forms, such as tablets, capsules, powders, granules, and oral
solutions or suspensions, containing effective amounts of the
principal active ingredient, i.e.; a compound of the formula (I),
supra.
For~oral administration either solid or fluld unit
dosage forms can be prepared. For preparing soli~ compositions
such as tablets, the principal active ingredient is mixed
with conventional ingredients such as talc, magnesium stearate,
dicalcium phosphate, magnesium aluminum silicate, starch, lactose,
acacia, methylcellulose, and functionally similar materials as
~ pharmaceutical diluents or carriers. In their simplest embodimen
; capsules, like tablets, are prepared by mixing the principal
active ingredient with an inert pharmaceutical diluent and
, filling the mixture into a hard gelatin capsule of appropriate
size. Soft gelatin capsules are prepared by machine encapsulation
of a slurry of the principal active ingredient with corn oil,
light liquid petrolatum F other inert oil.
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107~604
Fluid unit dosage forms for oral administration such as
syrups~ elixirs, and suspensions can be prepared. The water-
soluble forms can be dissolvea i.n an aqueous vehicle to~ether
with sugar, aromatic ~lavoring agents and preservatives to
form a syrup. An elixir is pre~ared by using a hydro-alcoholic
(ethanol) vehicle with suitable sweeteners such ~s sugar, .
. saccharin, and cyclamate together with an aromatic flavoring
agent .Suspensions can be prepared of the i.nsoluble ~orms
~ with a syrup vehicle with the aid.o~ a suspendiny agent such: 10 as acacia/ tragacanth,.methylcellulose and -~he like.
: The term "unit.dosage ~orm" as used in the
specification and claims refers.to physically discrete units
suitable as unitar~ dosages for human subjects and animals,
each unit containing a predetexmined ~uantity of active
lS mate~ial calculated to pxoduce the desi.red therapeutic efect
' ~ ~ in association with the re~uired ~harmaceutical diluent
: carrier or vehicle. The specilcations for the novel unit
: . dosa~e ~orms o~ this invention are dictated by and di.rectly
. ~dependent on-(a) the unique characterictics of the active in~ien
material and the particular ~herapeutic e~fect to be achieved,
and (b) the limitations inherent in the art o~ compounding
. ~ such an.active material for therapeutic use in human: and animals
as disclosed in detail in this specification, these being
J, ~:features of the pre:ent invention. Examples o suitable unit
,~ ~ 25 : dosa~e ~orms in ~cc~rd with this invention are tablets~ capsules,
.~ troche:, suppos.itories,~powder packets, granules,-wa~ers,
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cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls,
vials, segregated multiples of any of the foregoin~, and
other forms as herein described.
The dosage of active ingred:ient, i.e.; a compound
of the formula tI) above depends on route o administration;
the age, weight and condition of the patient. For adults,
a dosage schedule o~ from about 5 mg.to 500 mg., as
required, usually embraces the effective range for the
treatment of most conditions.
The effective amount of a compound (I) re~uired for
administration to a mammal suffering from spasm~ is within
the range of from about l mg. per kilogram of body weight
to about 50 mg. per kilogram of body weight, of recipient,
as required.
The following examples describe the manner and
process of making and using the invention and set forth
the best mode contemplated by the inventor o~ carrying
out the invention but are not to be construed as limiting.
The antispasmodic effect of the compounds ~Il could
not be expected from a study of their structure alone.
Their effectiveness has been measured in a pharmaco1Ogical
standard test as follows:
; ~Several 3 cm-long pieces of an isolated guinea pig
; intestine were stretched under a load of 0.5 g in separate
baths. I~ all baths, the bath li~uid was Tyrode's solu~ion,
warmed to 32C. A first contraction of the pieces of
: ~ ~ iAtestine wa produoed in each case by adding 0.5 mg
; ~` : ' _ 9 _ :
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~0756~
(milligram) of histamine chloride per litre of bath li~uid.
~he reduction in length caused by the ~irst contraction was
measured 2 min (minutes) a~ter adding -the histamine chloride.
The ba-th liquids were then renewed and, after
rela~ation of the first contraction, the agent under test,
dissolvea in pro~ylene glycol, was added to the bath li~uids
and-2 min later 0.5 mg. of histamine chloride per litre of
bath liquid was again added. ~ second contraction was thereby
produced and the reduction in len~th caused by this was .
; 10 measured 2 min after the addition of the histamine chloride.
: . It was found that the second contractions, as compared with
the ~irst cOntxaCtiQn, were inhibited by the agent added~
The concent.rations (ED50) o~ a~ent per litre o~ b~th liquid,
which inhibit the contraction o~ the intestine by 50~ ~per-
: 15 . cent) were determined (ED50 = effective dose ts inhibit ~or
5.0~). The ~alues ~ound are given in-Table 1
TABLE 1
. Agent
.Compound of Formula .(I) ED tmg/litre)
', . . '' . ~tL, ,
4-Allyl-2-methoxyphenyl acetate 2S.0
204-Allyl-2-methoxyphenyl butanoate 14.5
. . 4-Allyl-2-methoxyphenyl valerate 44.6
I ~ 4-Allyl-2-methox~phenyl ben20ate 160.0
~ l-Al}yl-3~4-dimetho~ybenzene 11.8
i 3,4-Dimethoxy-propenylbenzol 27.0
2-Methoxl-4- open~lphenyl acetate 52.0
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In accordance w,ith the spasmolytic ef~ectiveness
proved by the pharmacologic test ~e have found that the
named compounds also have a speci~.ic cramp-releas.in~'
action on the human organism and display a significant
antispasmodic action in a small dosage even in the case
of a very severe attack of cramp. Unpleasant si~e effects,
. , at any rate to the extent to be expected in the case o~
known an-tispasmodic,,,agents, were not obsexved. The antispa~ic
. action occurred both after o.ral administration and after .
. rectal administration, which is a further advanta~e. Non-
: specific actions, such as are observed in the case o~
: papaverine, do not occur.
~he efecti~eness o~ the compositions of the invention
is illustrated in the following examples.
Example l
lO0 g of 4-allyl-2-methoxyphenyl acetate are put în a
: tray of corrosion-proof steel and warmed within a water bath
to a temperature o~ 45C. The acetate melts. The molten
. mass is tempered'to 40C. and under stirring and further
, . 20 warming .2: 300.0 g of physiologic neutral suppository mass: : is added. A triglyceride mixture of saturated straight chain
., vegetable fatty acid of a chain length of Cl2 - Cl~ and a
: melting.point of 32 - 33.5C. is used as the suppository mass.
. After melting thoroughly and homogenizing~ the mass
., 25 is cooled to 36 - 38~C. and poured into molds for suppositories.
The mas~ is solidified by cooling to room-temperature. The
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1075604
o~tained sUppos~tories having a welc~ht o~ 2.4 g are loosened
.rom the ~olds and kept .ready for the examination of the
antispasmodic.e~fec~i~eness of 4-allyl-2-methoxyphenyl
~; acetate on humans.
The efEectiveness test is perfo~med by cystometric
: . measuring of the damping of the increase.of the bladder tonus
~ caused b~ the antispasmodic agent after intravesical
: . a*ministration of a spasmogenic agent as follows:
. The bladder capacity (BC) of several human
subjects with indwelling permanent cathetèrs is measured
b~ ~illing the bladdexs with water warmed to 37C. The maximum .
. micturition.pressure ~M)in the case o the filled bladder is; ~easured. The bladde.r is then emptied and filled again withwarm, clean water to half the capacity measured p.reviously
~5 (1/2 BC) and the p.ressure Pl in the case of the half-filled .
.~ . bladder is measured~ The bladder is again emptied and ~ d
again to h~l~ its capacity with a solution 1. The solution 1
consist~ o~ clea~ water, warmed to 37C., in which 1.76 g
:; : o~ carbachol, a spasmogenic agentt is dissol~ed per liter o~
w~ter. The ~ressure P2 for hal.f its capacity is measured~
The bladder is then again emptied and 100 mg of~4-allyl-2-meth-
. oxyphenyl acetate administered rectally into the rectum of the
, :
e.xperimental subjects in the form of one o the suppositories.
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1075604
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Thirty minutes thereafter the emptied bladder is
illed with water, warmed to 37C. to half its
capacity and the pressure P3 is measured. The bladder
is subsequently emptied and filled to half its ,
capacity with the solution 1 and the pressure P4 is
, measured. Fifteen minutes later, the bladder is
emptied again and filled to hal~ its capacity with
water, warmed to 37C. and the pressure P5 is measured.
Directly thereafter, the bladder is emptied and ~illed
to half its capaci-ty with solution 1 and the pressure
I Y6 is measured. The measured values are ~iven in
Table 2, below. , '
The micturition pressure is the intern21
I ~ bladder pressure re~uired to cause em~tying of the,, 15 bladder. All pressures Pl to P6~iven are micturition
'~ ~ pressures.
~ .
~ ~ TABLE 2 ~
': ' ''~'', ' i , ' .
MeRsured values on rectal administratio~ of
lOO mg o 4-allyl,-2-methox~phenyl acetate.
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1075604
Experimen tal BC M~l . Pl P2 P3 P4 p5 P6
Subject No.
200 59 0 19 0 6 0 9
l 2 300 60 2 16 0 0 0 0
5. ~ 3 300 56 0 5 0 2 0 5
. 1 4 400 80 6 10 0 2 0
400 ~5 0 40 0 6 0 2
. ~ 6 300 7Z 3 32 1 9 2 10
7 400 57 0 6 0 1 0 2
1 8 200 40 1 5 0 0 0 0
9 200 45 2 1~ 0 0 0 0
200 70 2 31 0 0 0 0
11 200 32 2 6
12 200 50 0 7 0 1 0
. 15 13 300 37 0 6 0 1 0
~ .
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: ~ ~ 15 ~00 51 0 10 0 4 0 4
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1075604
Example 2
The procedure of Example 1, supra, is ~ollowed with
the only difference that instead of 100 g o~ 4-all~l-2~metho~y-
phenyl acetate, 50 g of 1-allyl-3,4-dimethoxybenzene a:ee mixed
into 2 350.0 g of the suppository mass. The obtained
suppositories with a weight of 2.4 g contain 50.0 mg of
~ l-allyl-3,4~dimethoxybenzene. Ten experimental subjects are .
.~ treated as in Example l by usin~ the l~tter su~positories. The
measured values~are given in Table 3 below.
TAB~E 3
: ~
Measured values on rectal administration of 50 mg of
l-allyl-3,4-dimethoxybenzene.
. . ' .
; Experimental BC MM Pl P2 P3 P4 P5 P6
Subject No.
. . ___-_ ...... ... ... .
' 15 21 300 60 0 22 0 2 0 4
: 22 400 55 1 8 0 0 0 2
~3 ~ 300 85 0 15 1 0 0 0
~4 200 57 3 10 0 2 1 2
: 25 200 70 2 32 1 6 1 4
26 400 37 0 -12 0 2 0 0
27 500 52 0 10 0 0 0 0
28 350 45 1 14 0 ~
` 29 300~ 65 2 23 2 1 1 1
~ 300 48 2 12 0 1 0 2
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~756~4
Exam~le 3
10.0 ~ of 4-allyl-2-methoxyphenyl aceta-te is warmed
to 40C. in a tray of corrosion-proof steel, 10.0 g of disperse
silicic acid ~with 9~.8% of SiO2 and a density of 60 g/1) and
; 5 lQ~0 g of maize starch are then addecL under stirring. Thereafter
the powdery mixture is pressed five times through a lOO ~m
mesh sieve, to secure the equipartition of the acetate
within the powdery mixture. A 300 my portion of this homogeneous
mixture is filled into hard gelatine capsules~ E~ch o~ the
capsules contain 100 mg o~ 4-allyl-2-methoxyphenyl acetate and
serve fox oral administration to humans.
Five hu~an subjects ~re treated accordin~ to
the general procedure of Example 1, with the difference that
instead of rectal administration of the agent, one of the above
capsules are orally administered. The measured values are given
in Table 4, below.
TABLE 4
Measured values on oral administration of 100 m~ of
4-allyl-2-methoxyphenyl acetate.
Experimental
;Subject No. BC MM Pl P2 P3 P4 P5 P6
. . .
1 ~ 400 80 15 55 22 32 13 18
2 500 ~50 5 10 7 7 5 7
3 350 75~ 22 30 20 25 20 22
4 600 66 15 25 20 23 12 15
400 55 5 17 12 15 8 10
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~ 10756(~4
In all exam~les there has been set a cramp by the
. carbachol of the Solution 1. This is shown by the fact that
the values of P2 are greater than the values of Pl. This cramp
~ was released totally ~y the rectally administered composition
: of the invention and considerably reduced by the orally
administered composition o the invention, as it is shown by
the values of P3 and P5 within all examples. ~he compositions
: . of the invention even has an effect against the direct action
of the carbachol still present in the bladder. This is shown
by the fact that the values P4 and P6 are lower than the values
of P2. ~'he values o P3 and P5 show that 30 minutes
respectively 45 minutes after the administration of the
. composition of the invention, a considerable cramp-releasing
: : action was obtained. Especially these values show the
remarkable effectiveness of the compositions of
., the inventlon used according to these examples on humans.
~I . The examples specifically show the e~fectiveness of 4-allyl-2-
: methoxyphenyl acetate after rectal or oraL administra~ion and
. . of l-a.llyl-3,4-dimethoxybenzene after rectal administration
. : 20 on humans.
. The clinical correlativ~ of the test results according
to the above examples is in the therapeutic effectiveness on spasms -
! ~ of the smooth muscular system as arterial and venous circulatory
disturbance, Angina pectoris, asthma, spastic bronchiti~,
stomach spasms and intestinal spasms, unspecific 7 rrltation o~
~ , . ' .
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10756,04
bladder, renal and bilious colics, menstruation complaintsand abortion of gallstones, renal stones and bladder stones,
. obtained by administration to mammals afflicted with these
conditions, an effective amount of a composition of the
invention.
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