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Патент USA US3089822

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?atenteti May id, 1953
2
and
3,089,812
THERAPEUTIQ CGMPOSH'E'EGN?» FQR THE PUTEN
gIAéI‘lQN ()F BAREETURATES AND ANALGE
ROOC~<
>~NHCOCHzGHOHr
1C
Arthur Ernest Wilder Smith, 18 Chemin ties Lilas Blames,
Geneva, Switzerland
No Drawing. Filed Jan. 29, 1962, Ser. No. 169,590
(Ilaims priority, application "Great Britain Feb. 7, 1961
11 Claims. (Ci. 167-52)
(IV)
(in which R, R1 and R2 represent alkyl groups having
from 1 to 5 carbon ‘atoms, X represents a group ROO¥C-—,
a hydrogen atom or a halogen atom and Y is a halogen
atom or a hydrogen atom) and/ or non-toxic salts thereof.
This invention is concerned with improvements in or
relating to therapeutic compositions more particularly
compositions containing one or more pharmacologically
active barbituratesv or- morphinic analgesics.
This application is a eontinuation-in-part of my appli
cation Serial No. 764,756, ?led October 2, 1958, now
Suitable non-toxic salts of both morphinic analgesics
and the potentiating compound include particularly addi
tion salts with acids which are physiologically compatible
at the dosages employed, examples of such acids being
abandoned.
As is known, pharmacologically active barbiturates and
hydrochloric, hydrobromic, sulphuric, citric, tartaric,
manifests'itself by- increasing the sopori?c and/or anti
N-(?-pyrrolidino)butyryl-p-amino benzoic acid ethyl
acetic, fumaric, and maleic acids.
morphinic analgesics suffer from a number of disadvan
, In the above general Formulae I and IV R is preferably
tages which limit their use in therapeutics. Thus, there 20 a methyl, ethyl, n-propyl or n-butyl group. In general
may be an inconveniently long latent period ‘after admin
Formula I R1 and R2 are preferably both ethyl groups.
istration of a barbiturate before it takes e?ect and the
The substituted butyric acid anilides of Formulae l to
sedation produced may not be of the required depth or
IV can be readily prepared by reacting the appropriately
length. The toxicity of some barbiturates is marked and
substituted crotonic acid anilide with an amine R1R2NH,
seriously limits the dose which can be administered. 25 such method being described, for example, in my US.
Morphinic analgesics alsoin-general possess marked toxic
Patent 2,801,247 and in my British Patent No. 801,405.
properties, which limits the dose which can be used.
As speci?c preferred examples of compounds of general
I have now found, however, that compounds of the
Formulae I—IV which we have found to be particularly
, general formulae set out below markedly potentiate the
suitable for potentiation of the action of barbiturates may
pharmacological activity of barbiturates and of morphinio 30 be mentioned the following:
analgesics. In the case of barbiturates this potentiation
epileptic etfect of barbiturates and also in some cases by
ester
shortening the latent period ‘which elapses after the ad
N—(l3-pyrrolidin0)-butyryl-p-amino benzoic acid methyl
ministration of the barbiturate before it takes effect. The
compounds mentioned also in general lower the acute
toxicity of barbiturates and render the therapeutic indices
more favourable. In the case of morphinic analgesics
N-(?-piperidino)-butyryl-p-arnino benzoic acid ethyl ester
N-(?-piperidino)-butyryl-p-amino benzoic acid n-butyl
the ratio of analgesic action to toxicity and respiratory
depression is increased thereby enabling more powerful
ester
ester
40
B-Pyrrolidino-butyric acid anihde
?-Pyrrolidino-butyric acid (2 : 4-d-ichloro ) —anilide
analgesic action to be safely achieved.
It is thus possible to formulate barbiturate and mor
,B-Pyrrolidino-butyric acid (4-chloro)-am'lide
phinic analgesic compositions containing compounds of
the general Formulae I-IV which compositions have a
far lower rate of toxicity to pharmacological action than
The barbiturate or barbiturates to be included in the
compositions according to the invention may be any de
sired barbiturate such as phenobarbitone, hexobarbitone,
the barbiturates and morphinic analgesics themselves, thus
enabling the barbiturates and morphinic analgesics to be
secobarbitone, pentobarbitone and butobarbitone. By the
peutic compositions comprising at least one pharmaco
logically-active compound chosen from the group com
By the expression “morphinic analgesic” as used herein
I mean morphine itself and analgesics structurally and/or
prising barbiturates and morphinic analgesics together
pharmacologically related thereto including particularly
with one or more compounds of the ‘following (general
but not exclusively naturally occurring substances.
Analgesics related to morphine include, for example
term “pharmacologically active” when used herein in rela
tion to barbiturates is meant barbituric acid and related
administered in a lower dose toobtain the same pharma
compounds which have a sopori?c and/ or antiepileptic
cological e?ect.
‘According to the invention, therefore, I provide thera 50 effect.
"formulae:
pethidine, codeine, dihydrocodeine, oxymorphone, oxy
codone, dipipanone, dextromoramide, leverphanol, hydro
morphone, hydrocodone, methadone, phenazocine, pro
R0 0 o-Qnno o emotions
N
(19
Y
(II)
X-QNHCOCHMFICH;
Y
f \i
1
poxyphene, piminodine and anileridine.
60
The compositions according to the invention may be
formulated together with a pharmaceutical carrier or ex
cipient in any convenient form suitable for administration
orally, parenterally or in the form of a suppository.
Thus, the compositions may be formulated in a form
suitable for oral administration either in a solid or liquid
form. A particularly suitable solid formulation is as
tablets containing the desired barbiturate or morphinic
analgesic together with the potentiation compound in
an inert tablet base.
N
In liquid ‘form the compositions
may be made up as a syrup or like preparation, which
(III)
may if desired contain surface active and/ or ?avouring
3,089,812
3
4
agents, the latter serving to mask any undesirable taste
of the active components.
For parenteral administration the compositions can,
the following representative formulations are given by
way of illustration only:
Tablets
for example, be made up in liquid form in pyrogen-free
water, the active components preferably in such cases
being presented in a water soluble form. Surface active
agents may be added if desired.
In such formulations, the potentiating compounds can
be present as their Water soluble salts for example as hy
drochlorides, citrates or tartrates, whilst the barbiturates
may for example be present as their alkali-metal salts
if these are soluble; the morphinic analgesics may be
present as their acid addition salts.
Mgs.
(l) Phenobarbitone ________________________ __
45
IS-Pyrrolidino butyric acid anilide _________ __
75
Tablet base to 200 mgs.
(2) Butobarbitone _________________________ __
30
?-Pyrrolidino butyric acid anilide _________ __
50
Tablet base to 150 mgs.
(3) Butobarbitone _________________________ __.
40
N-(B-pyrrolidino)-butyryl-p-amino benzoic acid
ethyl ester ____________________________ _-
The proportion of the potentiating compounds to the
barbiturates or morphinic analgesics present in compo 15
sitions according to the invention can vary Within wide
limits.
In the case of barbiturates, in general, the ratio of po
tentiating compound to barbiturate should be at least
0.75 and preferably at least 1.5, advantageously 1.5-3.0 20
parts by weight, of potentiating compound to 1 part by
Weight of barbiturate.
In the case of morphinic analgesics, the proportion of
the potentiating compounds to the morphinic analgesic
is generally in the ratio of 10 to 50 parts by weight of 25
60
Tablet base to 200 mgs.
(4) 'Phenobarbitone ________________________ __
30
N- (,B-pyrrolidino ) -butyryl-p-amino-benzoic acid
ethyl ester ____________________________ __
50
Tablet base to 150 mgs.
In the above tablet formulations the mentioned bar
biturate can be replaced by hexobarbitone, secobarbitone
or pentobarbitone and the potentiating compound by N
(?-piperidino)-butyryl-p-amino benzoic acid ethyl ester.
(5) Dihydrocodeine acid tar
trate _______________ __ 10-15 mg., e.g. 10 mg.
potentiating compound to 1 part by Weight of morphinic
analgesic. Preferably the ratio is about 15-3021.
Where the compositions according to the invention
?-Pyrrolidino-butyric acid
anilide hydrochloride 1 __ 200-300 mg., e.g. 200 mg.
Tablet base to 500 mg.
contain more than one barbiturate the action of the bar
biturates may well be synergistic. In this case the total 30 (6) Levorphenol tartrate _______________ __mg__ 1.5
?-Pyrrolidino-butyric acid anilide acid male
dose of barbiturates given may Well be less, than if only
ate ______________________________ __mg__ 300
one barbiturate is given, and in such cases the concen
Tablet base to 500 mg.
tration of potentiating compound can be reduced accord
(7) Pethidine hydrochloride ____________ __mg__
ingly.
ate ______________________________ __mg.... 300
morphinic analgesic together with ?~pyrrolidino butyric
acid anilide or a non-toxic salt thereof.
25
?-Pyrrolidino-butyric acid anilide acid male
Preferred analgesic compositions include at least one 35
Tablet base to 500 mg.
Preferred salts
1This constituent may be replaced by the acid malcate
include the acid fumarate (M.P. 168° C.) and, in par
ticular, the hydrochloride (M.P. 141-2“ C.) and the
acid maleate (M.P. 125—7° C.).
The following table gives by way of example only fac
(300-325 mg).
Capsules
M gs_
(l) Pentobarbitone sodium __________________ __
tors by which ?-pyrroldino butyric acid anilide potentiates
25
N-(B-piperidino)-butyryl-p-amino-benzoic ethyl
the action of various morphinic analgesics as determined
ester hydrochloride _____________________ __
experimentally in rats.
50
Orally acceptable liquid base to 150 mgs.
In each case the ?-pyrrolidinoebutyric acid anilide was
(2) Butobarbitone sodium __________________ __
given in a ?xed dose of 50 mg./kg. body weight intra
peritoneally. The values given for potentiation are those
by which the original dose of the drug may be reduced to
obtain equi-analgesia when the drug is given in com
bination with ?-pyrrolidino-butyric acid anilide.
N-(?-pyrrolidino)-butyryl-p-amino benzoic acid
ethyl ester ____________________________ __
Morphine hydrochlorlde__
Codeine phosphate ______ ._
Dihydrocodeine acid tartr
Pethidine hydrochloride- .. _
(+)-Propoxyphene hydrochlor1de__-._
Sodium aspirin ________________________________________ __
60
Liquid ‘base to 200 mgs.
lnjectable Preparations
50
TABLE
Drug
40
Potentiation
55
Factor
(1)
Morphine hydrochloride ____________ "mg..-
5
,8-pyrrolidino-butyric acid
anilide acid maleate1 .. 200-300 mg., e.ig. 200mg.
Water for injection _________________ __ml__
5
(2) Methadone hydrochloride __________ __mg__
5
,B-Pyrrolidino-butyric acid anilide acid male
eate _____________________________ __mg__ 300
race-vimosuca
Water for injection _________________ __ml__
(3) 'Pethidine hydrochloride ____________ __mg.._.
60
5
25
?-Pyrrolidino-butyric ‘acid anilide acid male
ate
mg
300
Water for injection _________________ .._ml__
5
1This constituent may be replaced by the hydrochloride
(230 mg.).
Norm-These ?gures were obtained by using the rat
tail pressure method of assessing analgesia (modi?ed 65
(4) A preparation suitable for intravenous injection
from the method of Green and Young, Brit. J. Pharma
can be made by dissolving 50 mgs. of phenobarbitone
sodium and 70 mgs. of N-(?-pyrrolidino)-butyryl~p
col. (1951), 6, 572).
amino benzoic acid ethyl ester hydrochloride in pyrogen
30 groups (approx) of rats were used, each group con
free water. The phenobarbitone sodium may be replaced
taining 10 animals. A mean value was found for each
rat by recording the response to ?ve rapid and consecu 70 by any other suitable water-soluble barbiturate and any
tive pressures on the tail. The ten means thus obtained
were used to calculate the group mean response for both
untreated animals and those which receive an injection
other suitable water-soluble potentiating compound may
be used.
Suppositories
of the analgesic.
200_ mg. suppositories can be made by mixing suitable
In order that the invention may be well understood 75 quantities of barbiturate and potentiating compound in a
3,089,812
the group consisting of phenobarbitone, hexobarbitone,
suitable suppository base. A single 200 mg. suppository
could have the following constitution:
secobarbitone, pentobarbitone and butobarbitone and an
e?ective amount of at least one compound potentiating
Mgs.
Butobarbitone
_____________________________ __
45
,B-Pyrrolidino butyric acid anilide _____________ __
70
the activity of the pharmacologically active compound,
said potentiating compound being selected ‘from/the group
consisting of:
Suppository base to 200 mgs.
I claim:
1. A therapeutic composition comprising at least one
pharmacologically active compound selected from the 10
group consisting of barbiturates and morphinic analgesics
and an e?ective amount of at least one compound po
tentiating the activity of the pharmacologically active
compound, said potentiating compound being selected
from the group consisting of
ROOC-
15
--NHOOCH2CHOH3
2
X-Q-NHCQoHZcHCHt
Y
i1
(I)
|
20
XQ-NHOO onulnnons
Y
(Mi
_:
X—©—Nrto0om<|mom
Y
(W
|
N
and
(II)
25
|
N
-—-—
30
in which R, R1 and R2 are each alkyl radicals containing
(III)
from 1 to 5 carbon atoms, X is a member selected from
and
the group consisting of the group ROOC-, a hydrogen
no 0 o-<
35 atom and a halogen atom and Y is a member selected
>—NHC 0 omcaom
N1
from the group consisting of a hydrogen atom and a
halogen atom.
11. A therapeutic composition comprising at least one
(1V)
in which R, R1 and R2 are each alkyl radicals contain
pharmacologically active morphinic analgesic selected
40
from the group consisting of pethidine, codeine, dihydro
codeine, oxymorphone, oxycodone, dipipanone, dextro
ing from 1 to 5 carbon atoms, X is a member selected
from the group consisting of the group ROOC-—, a
moramide, levorphanol, hydromorphone, hydrocodone,
methadone, phenazocine, propoxyphene, piminodine and
hydrogen atom and a halogen atom and Y is a mem—
anileridine and an e?ective amount of at least one com
ber selected from the group consisting of a hydrogen
pound potentiating the activity of the pharmacologically
45 active compound, said potentiating compound being se
atom and a halogen atom.
2. A composition as claimed in claim 1 in which said
lected from the group consisting of
potentiatinig compound is present in the form of its water
soluble acid addition salt.
3. A composition as claimed in claim 1 in which the
/N\ at
pharmacologically active compound is a barbiturate and 50
from 0.75 to 3.0 parts by weight of said potentiating
compound are present for each part by weight of barbi
R1
X-—
turate present.
4. A composition as claimed in claim 3 in which said
potentiating compound is -/3~pyrrolidino butyric acid ani
|
55
Y
lide.
5. A composition as claimed in claim 3 in which said
(I)
NHOOOHQCHCH;
N
ii
Z
(11)
potentiating compound is N-(B-pyrrolidino)-butyryl-p
amino 'benzoic acid ethyl ester.
6. A composition as claimed in claim 1 in which the 60
pharmacologically active compound is a morphinic anal
gesic and 10 to 50 parts by weight of potentiating com
X-QNHQO ormlmom
Y
r1
N
pound are present for each part by weight of morphinic
__
(111)
analgesic.
7. A composition as claimed in claim ‘6 in which 15 65 and
to 30 parts ‘by weight of potentiating compound are pres
ent for each part by weight of morphinic analgesic.
8. A composition as claimed in claim 6 in which the
no 0 o-Qnnoomnonom
N\
potentiating compound is ?-pyrrolidinobutyric acid ani
70
lide.
9. A composition as claimed in claim 8 in which the
?-pyrrolidino-butyric acid anilide is present in the form
of its water-soluble acid addition salt.
(W)
in which R, R1 and R2 are each alkyl radicals containing
from 1 to 5 carbon atoms, X is a member selected from
the
group consisting of the group ROOC—-, a hydrogen
one pharmacologically active barbiturate selected from 75
‘10. A therapeutic composition comprising at least
3,089,812
atom and a halogen atom and Y is a member selected
from the group consisting of a hydrogen atom and a
halogen atom.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,657,210
Clinton _____________ __ Oct. 27, 1953
2,793,155
Smith _______________ __ May 21, 1957
2,801,247
Smith _______________ -_ July 30, 1957
8
FOREIGN PATENTS
83,130
Netherlands _________ _.. Oct. 15, 1956
89,384
Norway _____________ __ Apr. 13, 1957
OTHER REFERENCES
Beiler: Arch. Int. Pharmacodyn., November 1, 1956,
CVIII, No. 2, pp. 129-134.
A.M.A. Council on Drugs, New and Nonot?cial Drugs,
1958, pages 299-330.
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