DE1910986A1 - Analgesics - Google Patents

Description

PATENT LAWYERS

Dr ₁ LMAAS

DRW. PFEIFFER
DR. F. VOITHENLEITNER

8 MUNICH 23
ÜNGERERSTR. 25 - TEL 39 02 36

79 425

Eli Lilly and Company "Indianapolis, Indiana ₉ YoSt" A,

Analgetics

The invention relates to improved Aßalgetiea, their Her = » position and its use.

There have already been proposed in some cases, combinations of a Malgeticum and a tranquilizer, hit such a combination, but was generally keiaa stronger Schmerserleiühterungj but due to tranquilizing effects a change in the response to the Schmers "sum as a reduction of fear ₉ with pain This goal was only achieved in a few cases. Sometimes the combination even led to the opposite of the desired «therapeutic effect. In addition, increased side effects were often noted ο

ffi ~ d ™ Propö2qrphen did a known analgesic and would already on a large scale sur treatment of various States used "associated with loaches.

9/1441

1910988

In spite of its extensive use, occasional side effects have been observed, and in some therapeutic cases it is not sufficiently effective »For these and other reasons there is a constant need for improved dosage form ^! for this remedy.

Surprisingly, it has now been found that the addition of one of the tranquilizers known by the names of ohlordiazepoxide and diazepam, or of both or their pharmaceutically acceptable salts, to the analgetleum a ~ d ~ propoxyphene itself in amounts below those 1ia = genes in which the first two substances mentioned show tranquilizer effects, an improved analgesic® effect, above all a higher pain threshold, is achieved.

The invention relates to a process for the preparation of an improved anaigetic, which is characterized in that (1) a first substance consisting of (a) oc-d-propoxyphene or (b) a thermally acceptable salt of cc-d-propoxyphene consists, in an amount which is analgesically effective in the presence of the second substance, with (2) a second substance ₉ which au3 (a) ^r : hlurdlazepo3Cd - od-ar a pharmaceutically acceptable salt; davoa «nd / or (b) diazepam or a pharmaceutically acceptable salt thereof, in an amount which strengthens the first substance, brings together«

The invention also relates to an analgesic which (1) a first substance consisting of (a) a-d-propoxyphene or (b) a pharmaceutically acceptable salt of α-d-propoxy = phen, in an amount effective analgesic in the presence of the second substance, and (2) a second

909839/1441

BAP

Substance «which consists of (a) chlordiasepoxide or a pharmaceutically acceptable salt thereof and / or (b) diazepam or a pharmaceutically acceptable salt thereof, in an amount that enhances the substance».

The chemical name for the compound, which is referred to herein as a = d ~ propoxyphene, is ad-4-dimethylamino = 3-methyl-1 ^ -diphenyl - ^ - butanolpropionato Chlordia & epoxide is the abbreviation for 7-chloro ^ -methylamino-S -phenyl ^ H-1,4 ~ benzodiazepine-4-oxide,> Diazepam is 7-chloro-1 ₉ 3- = dihydro-1-methyl-5- = phenyl-2H-1 β 4 ~ benzodiazepin-2-one ₀

For the purposes of the invention, each of the compounds ad 1 -propoxyphen _s Chlordia ze posid and diazepam can be used as the free base or in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt as those of dor it derives a Saiz ₉ whose toxicity is not significantly greater than the free base. Such salts are easily prepared by reacting the free amine with an acid, preferably a pharmaceutically acceptable acid. Organic or inorganic acids can be used. It is not important which pharmaceutically acceptable salt is used in the individual case, but certain salts can be preferred because they are, for example, more easily crystallized, dissolve more easily and do not have an undesirable taste. Suitable salts are for example the hydrochloride, hydrobromide, sulfate, bisulfate, acetates, salicylates, Valerate, 01eate _P, "mote, laurates, borates _£ benzoates, lactates, phosphates,

itej, citrates, moleates, fumarates, succinates, tertrates • md r? Tapayla - »: e (salts of 2-naphthalenesulfonic acid). At the the most common were a-d-Proposyphen sis hydrochloride, Diasepam • 3ΛΠ .frsiß Basse and Chlordiasegoxid used as hydrochloride

9 0 9 8 3 9/1441

BATHROOM OBlGINAL

1910388

In the following, the terms ®- = d ~ Pr © poxyphen _e diagepoxicä naä Dia ^ epam oov / ohl 'refer to the free © base as a pharmaceutically acceptable solution of the relevant

The amount of s = -o "proposyphQn _i, according to the invention, is analgotically effective, can be within wide limits and in saaacheri cases below the dosage limits, which are already known for the use of ss-d ^ proposals alone · = bräuöhlich sinäo For the purposes of this invention will ever = · öooh bekamst generally the forthcoming @ n · Doaieriasigsmengen. BUgto These depend on factors such as beispsslsweiss zn treated Tieriapeeies, the particular condition being treated nnä dsm Verabrsichuagswsg from "in allgemeinen.- It is an effective oral Einsseldoeie to c ^ d-propoxyphene in the range of. 0.5 l'is 30 mg compound per Ig of body weight of Si ere "in a sensitive species typically range ₉ O 5 to 5 rag 'per kg body weight. For The human medical application is also based on the information on the dosage in Physicians' De3k Reference to Pharmaceutical Specialties and Biologicals (see "Bo 22" Aufl » _r 1967» published by Medical Economies _?! ώ ο <· _ρ Soehtesrgosr. von Chapman-Reinhold _t lae », Oradellj NoJ = _c So 777) hinge \ * issen _o - For parenteral administration, the dosage levels are modified accordingly. For example, subcutaneous injection in rats is the dosage amounts lower and are 1/5 to 1/5 the amount of oral dosage »

The amount of Chlordiaseposiid © de ?, "Diar.spam _s die veretärkendl v / irkt,. Depends © benfallo, for example, on the animal species ₉ -dem v © t <5riKärmedi..Tiis" ilseh öder hueisES5edisiniseh to state uaä do? A "srabK -aioiiucga ^ eg abc In general, Vgr-otärkmig becomes through the turn of Chlfes-'diaa © pöxia Ode in den M © Bg © H _P in-dirnen ßie alone ice SranquiXiser

909839 / U4

1910985

However, since the tranquiliser effect is not important for the purpose according to the invention and this can even be undesirable, smaller amounts are generally preferred within this dosage range, for example amounts in the lower half of the range *, For dosage for human medical applications, see Physicians Desk R @ ferene @ ₃ loo. oit «., S ₀ 989 and 1004

If a tranquilizer effect is unnecessary or un ~

is, even smaller amounts can be used ₉ for example half of the lowest recommended dose for a certain animal or a certain route of administration or Diagepam arford @ rlich ₈ and correspondingly less chlorine = diasepoxide or Diaaepam for reinforcement are required with higher amounts of <x ~ d-propoxyphene. As is explained in the examples, a ° d ~ propoxyphene is given subcutaneously to rats in a dosage of 7.5 mg per kg reinforced by doses of 1 to 4 mg per kg of diazepam and 2 to 8 mg per kg of ohlordiasepoxide «

In all different cases of application in which edosyphen and therefore also the agent according to the invention can be used, the administration can be repeated, intermittent or recurring at regular intervals, in which case the state of exposure lasts for a longer period of time

The advantages of the invention are most easily achieved if the two necessary s ^ bstanaen are about the same Time to be administered. However, this is not necessarily the case © rföKlerlic & u Di © application of one of the substances in one Form in which delayed release takes place is made possible by explaining the duration of their phyeiological effectiveness through administration of the other substance

09 8 39/1441

Since achieving the reinforcement according to the invention "If the two substances are administered practically at the same time, it is not necessary to" mix the substances before administration " te manganese by means supplied di @ 1 weight part or Chlordiaeepoxid Diaaepam and about 1 to 10 Gewiehtsteil® .ad-propoxyphene contain "Zwar'kommt it mar thereon to ₉ that sine of the compounds chlordiazepoxide. or Diassepam in -w®r ~ fortifying amount present ₉ but they can also simultaneously aur reinforcement used by ad-propoxyphene advertising ü®n "the amounts of Ghlordia ^ eposld and Siaae ^ ia be so reduced that both ₉ In this Ausfähruagsform ^ collecting dl © © required reinforcing effect on cs = -d = propoxyph @ o

ad-propoxyphene and Chlordia ^ eposid odar Diasepaia can be separated © preferably together in the iiblichsn therapeutic forms _s for example as tablets "elixirs ₉ suspensions and the like <3ieh @ n prepared weräea. For reasons of ease of administration and stability, filled capsules and compressed tablets are the preferred pharmaceutical forms. These forms can easily be subsided with the usual carriers and diluents »

Other therapeutic active ingredients can be used together with a ^ d-propoxyphane and asepoxide or diasepam. Such other active ingredients are, for example, acetylsaliöylsäurgs acetophanetidin ₉ acetaminophen and harcotia such as codeine. In such preparations, the concentrations of the various constituents can be adjusted that aie balance the therapeutic effect of every further component.,

9098 39 / U4

The following examples will make your experience closer

BQ ^ L _a, P ie 1 __1

cs-d "Pj'opoxyphenhyaroehloriä and Ghlordiozepoxidhydroehle-rid are separately traded together on rats after a T © st ~ methcde goprlift, in which the reaction time of treated miö untreated rats to a heat crack applied to the rat tail serves as an indicator of analgesia« Bias © test method has been described by Robbins Journal of the American Pharmaceutical Aaso8ietion _e Vol, 44, S «497 (1955) * The administration is by subcutaneous route, and the reaction to the warmth is kestiraat 30 minutes and 1 hour after the flor injection» The The reaction time is defined as the duration of the application of the heat stimulus and the point in time at which the swan is moved away from the rice. Bio-average reaction time of control groups is around 4 seconds. The analgesic effect is shown by a longer reaction time is: Cür, 1 <acle (IrupiJ © of rats ₀ that receive the same treatment, rattled «After the end of a study After 6 injections, the rats are examined for signs of weakness. Di «? Prlifsrgataisae aiad in the iebells? asigegebsn «.

909 839/144

Administered®

s (© η)

OhlordlazepoxicU

hydrochloric

pyp hydrochloride

ct-d-propoi & yphan = hdlid

p hydrochloride

4.0

16.0

7.5

2.0

ReaktioasaeitJLn, 5®C or similar

MiR _n after-- 1 SMe = after prior agreement - appointment »

55 number of

"55

_8c 50

4 ρ 22

7 _ß 62

8 _P 50 (a)

4p5O_ 4 ρ 25 4th 4 "37 4pO6 (a) 4th 4.43 4 _β 18 (ο) 4th 4 "43 4 25 (b) 4th

hydroo

α ^ d --- Prop oxjrpheahydro chlorine id -t-

, 5

4.0

7.5)

) 8.0) 8 _B 93 (b).

(a) ^ slight microscopic weakness p 1 tone 4 ^ fieren

(b) - slight muscle weakness ρ? ■ ^ on 4 animals ίο] ■ - slight muscle weakness 5 ¹ ^ n 4 animals id} - 'slight muscle weakness _r 4 of 4 animals

909839/144 1

BATH ORIGINAL

B e i gj TP ί a i -2

and Bias®pasa

nnä together according to the example 1 1b @ sehri @ b @ nen M © thoä @ gep ?. ^s lift ₃ Di © results aind in ά @ τ following @ ώ Tafeei3, @ on- = · listed?

90 9 839 / 144Λ

Y @ rahreichte

A, exam I.

Exam II

pyp hydroehlorid

pyp hydroehlorid

Tue & Sepam

Meng® in

f ρ

in seconds

Hinο n & Gh 1 hour © _o after 4 ₉ 43

8 "62

3 ₀ 43

7ο "6β

liytooehlojfd + 7.5) Diassepam 2 "0) hydroehlorid * Dia ^ epam 4pO) Exam III ■ -— ■ = --- = (control ©) ^ ==== α-d-Propoxyplieii · =
hydroehlorid 7 5

: C3)

4.25

9.43

909839/1 * 44

BAD ORlGINAi;

be '"= ;. . -. . Hung in Sale since m sefunaen SubataaSJgy .ä 4 · 7.5
I ₉ O 30 cinema near
Administer « Administered ad-PxOpoxj
hydrooliloif:
Blazepara 12.75 8pO

pyp hydrochlorldi +

7 ₈ 5

2.0}

12.18

:O)

pyp hydrochloride +

7.5 4.0

U ₈ 50

'1) c moderate muscular weakness _e 2 -of 4 animals a

(2) β moderate Huekclschwäohe «. 3 out of 4 animals

[3) Lassige Kuakelsliwache 4 by 4 fi

9 8 3 9/1441

Claims (1)

P a % e η ta η a ρ r Ü eh β. . Ι «Process for the preparation of an analgesic _v dadureh characterized ,, that one (1) a first substance ,, the
consists of (a) & = d-propoxyphene or (b) a pharmaceutically acceptable salt τοω e- = d = pr © posyph © ia, la one. Amount a which is anaigstiseh effective in the presence of the second substance _s with (2) © in a second substance which consists of
(a) Chloröiageposid or a pharmaceutically acceptable salt thereof and / or (b) or a Biagepam phayma ~ ssßutissh saig acceptable thereof, in an amount _s DI® the erate substance reinforced ₉ zueaiamgnbringt. Method according to claim 1, characterized in that measured as the first substance ß-d = Propoxyphenhydroehlorid or a «d-Propoxyphennapylat used. 3 «The method according to claim 1 or 2 _P, characterized ₉ that the second substance
used. 4 «Method according to claim 1, 2 or 5, characterized netp that the first and second substances are one commodity blood administered o. 3 π method according to claim 4, characterized in that the substances are administered separately or at the same time 6. The method according to claim 4 »geiseanzsiohnet characterized in that a mixture of the required amounts of each of the SufestanzeiJ versfereicht * 909 8 39 / U * 1 ■ ", .. ^ DOR ₁ GlNAL Method me claim 4, 5 or 6, dadureh marked = that administration is carried out by the oral route. S ₉ analgesic agent characterized in that <as (1) a first substance "which consists of (a) cE" = d = propoxyphene or (b) a pharmaceutically acceptable SaIs of es ~ d- ^ propoxy = phess ρ in an amount of ₉ th in the presence ύ & τ two = substance is an analgesic action _s, and (2) ein® second substance ₉ di © of (a) Chl @ rdiaz <ep @ xid ~ © of a ptiarmaseutiseh acceptable Saia thereof and / or ( b) Diasstpam "or a pharmaceutically acceptable sala dawn" consists in an amount that strengthens the first substance 9c, means according to spoke 10, characterized in that it contains ad-PropoxyphenhydSOehlorid or cj «= d-Pr®posyphennapsylat» as the first substance 10 «iiittel according to claim 8 or 9p characterized in that that there is ghlordiazep'oxidhydrochlcirid as an additional substance contains? 11. Composition according to claim B _9, characterized in that it contains a = d ° propoxyphene hydrochloride as the first substance and diaaepaa as the second substance 12g means according to one of the Aiasprliche 8 to 11, thereby g = indicates, that it is the substances in the ratio of i part by weight of the second substance to about 1 to 10 Ge = contains weight parts of the first substance BATH 9 O 9 8 3 9 / U 4 1: