DE1941584A1 - Analgesics - Google Patents

Description

BIi Iillly and Company, Indianapolis, Indiana,?. St _Λ Α ..

Analgeiiica

The invention relates to an anaigetic which contains an ester of 1,2-diphenyl-2-hydroxy-3-inethy1-4- (substituted) aminobutane or a pharmaceutically acceptable salt thereof and a 3- or 4-phenoxyphenylalkanoic acid
formula

GH-GOOH

wherein (a) R is a Methylreat or an ethyl radical and R means hydrogen when the phenoxy radical is in position 3, or (b) R is a hydrogen atom

009838/1834

■ - 2 -

or a methyl radical and, when R represents a hydrogen atom,.,. ,, ..., R a Wasserst off atom, a fluorine atom, a ■ .... _r methyl radical, an ethyl radical or a methoxy group or, if R represents a methyl group , R- denotes a hydrogen atom when the phenoxy radical is in position 4, or a pharmaceutically acceptable salt of the acid. Contains. .

The analgesics according to the invention are distinguished by improved effectiveness. It is known that some esters of 1,2-diphenyl-2-hydroxy-3-methyl-4- (substituted) aminobutane and their pharmaceutically acceptable salts are effective analgesics. These esters include, for example, 1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane; 1 ^ -Diphenyl ^ - acetoxy-J-methyl ^ -dimethylaminobutane and 1,2-diphenyl-2-propionoxy-4-pyr: s ⁱ olidinobutane »especially ad-1,2-Mphenyl-2-propiono-3-methyl -4-dimethylaminobutane, commonly known as ad-propoxyphene, and also so called herein, has been used extensively for pain relief. It is also known that ad-propoxyphene is a non-addictive analgesic. It is therefore used as other narcotics. ζ.Β. Morphine, strongly preferred. Ad-propoxyphene, however, is not as strong an analgesic as morphine, which is why morphine or other narcotics had to be administered in order to effectively relieve very severe pain.

According to the invention, the anaigetic effect associated with certain Esters of 1,2-diphenyl-2-hydroxy-3-methyl-4- (substituted) aminobutalene is achieved until the effect of the stronger but narcotic analgesics is increased, thus reducing the need for narcotics for relief

009835/1834

having to use severe pain, "eliminated or strong is restricted. The "esters and theirs accordingly pharmaceutically acceptable salts have the formula.

O-C-R

CH-CH ₂ -Il ₂

CH,

in which B. is a methyl or ethyl radical and R is a diniethylamino- or pyrrolidino group "means.

The phenoxy compounds used for the purposes of the invention are anti-inflammatory agents and show only mild aspirin-like analgesic activity. The reinforced anaigetic effect obtained with: an ester compound of formula I or a pharmaceutically acceptable salt of which obtained in connection with the phenoxyphenyl compound, is · therefore very surprising and completely unexpected.

Pharmaceutically acceptable salts of the phenoxyphenyl compound are for example the sodium, potassium, calcium, Magnesium, ammonium and benzylammonium salts. Examples for phenoxypheny! compounds used as potentiating agents are advantageous in the analgesics according to the invention

009835/1834

2- (4-phenoxyphenyl.acetic acid e.

2- (4 - Phe noxy phenyl Jptropl ons aur e - c al c iums alz.

2- (3-Me; thy ■ l.-4-pl·le.noχyphenyl) acetic acid-:

2- (5-Meth.OX3F-4-ph.enOxyp] ienyl) acetic acid:: ■ ■

2- (2-Mei; iiyl-4-plienö ^> xyphenyl) acetic acid · - ·

2- (4-Pheno3type renyl) propionic acid · " ¹ ^ 2- (3-Methyl-4-pkenoocyphenyl) es

2- (5-Piien; oxypiie; Hiy / l) prepionic acid - '■

2 ■ - (5-egg enoxyphen ^ l ·} proplQ'nsäurei ■ r ■ ealciumaal2 ■ .- · "; ■ · ■ -

They have prominent statements. are nac-ϊι general. loading

Known modes of production of phenylacetic acids: and ^: Phenylpropionic acids, eriiältlioh. ... "- ■

The preferred. Compound of formula I for the purposes of the invention is a-d-Pro.poxyph.en, its chemical: ■■ ..- name a-d-1,2-Diphenyl-2-propionoxy-3-methyl-4-di? -. ffiethylaminobutane is. The following explanation refers to - ■. mainly based on AHalgetica, the a-d-propoxyphene contained as an analgesic agent, of course .- .., can.aber also any other compound of the formula I than -. "..-, ■" ·. '. analgesic agent can be used.

a-d-propoxyphene can be used as a free base or in the form of a ■ its pharmaceutically acceptable acid addition salts. ■■■■■ -. be turned. -Such salts are by reaction of the free Amine readily available with an organic or inorganic acid. Examples of such salts are the hydrochloride, Hydrobramide, sulfate, bisulfate, acetate, valerate, oleate, phenate, l ^ aurate, borate, benzoate, lactate, phosphate,

0 983 5/1834

- 5 - ■ * ■

Tosylate, qitrate, maleate., J? Uraarat, succinate, -Iairtrat and Napsylate ^ -aphthalenesulfonic acid salt) ;.

In the following, the term / ^ a-dauf is used the free base or a pharmaceutically acceptable one Salt of the compound as defined above. di © loading »Calibration" Phenoxypheny! Connection "on the through (the ö; ben

gsb.en3 formula defined Verbiadungolclasse ± u -fxeian acids or as salts.

, the a-e "anal ^ etiseh 1 (/ irisaine Henge iur die Inventiongeinäien * 2wecli: e representib »- icann innexnalb "weiter Gr e na en sohwäiiksiii * through reinforcement analgetise & sn effect a-d-propoxypliene with a wier above defined iiüenöxypiienylverbindungen are therapeutiaelie Effects achieved with dosages that are significant are less than the quantities required for the application of «-D- ^ EropQxyp & en alone 'are already known and customary. In general, the single effective oral dose is for a-d-propoxyphene (X,: 5 *> is 30 mg / kg body weight. Da- ' against is the effective single oral dose for oc-d-propoxyphene in the range iron Q.05 to 30 mg / kg body weight and the effective subcutaneous dose in the range of 0.2 to 20 mgAs * .if it is, according to the invention, with a phenoxyphenyl compound is united *

The usual practice in Bessug on the administration of ad-propoxyphene is in. Physicians ¹ D <33k Reference to Pharmaceutical Specialties and Biologicals (aB

22 ed., 1967, Medical Economics, Inc., subsidiary by Qhapman-Reinhold, Inc., Oradell, N.J. P. 777)

described.

009 * 35/1834

The phenoxyphenyl compounds are proven in doses of 0.20 to 50 mg / kg in combination with the usual therapeutic Dosages for d-propoxyphene administered to achieve a stronger analgesic effect. In general, the compounds can be in the ratio of 1 part by weight of a phenoxyphenyl compound at 0.005 to -20 Parts by weight of cc-d-propoxyphene are administered. Preference is given a ratio of 1 part by weight of one of the above potentiating compounds to 5 parts by weight a-d-propoxyphene. For example, if 30 mg a-d-propoxyphene hydrochloride administered for pain relief are to be, they are combined, for example, with 6 mg of 2- (4-phenoxyphenyl) propionic acid sodium salt.

The agents according to the invention can be used in any of the customary therapeutic dosage forms. Solid dosage forms for oral administration are, for example, tablets, pills »Powder and Granules !. In such solid dosage forms, the active ingredients are mixed with at least one inert diluent, for example sucrose, lactose or starch. In addition to inert diluents, the agents can also contain other substances, for example lubricants such as magnesium stearate, in accordance with customary practice. Liquid dosage forms for oral use. Examples of administration are pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as are used for this. Conventional purposes are, for example water. In addition to inert diluents, such preparations can also contain auxiliaries, for example wetting agents, emulsifiers and suspension aids and sweeteners, aromatics and fragrances. The agents according to the invention for oral administration also include capsules made of absorbable material, for example gelatin, which contain the active ingredients with or without the addition of diluents or carrier monkeys.

00383571 * 34

The preparations according to the invention for parenteral Administration includes sterile aqueous or non-aqueous Solutions, suspensions or emulsions. At- . ...... games for non-aqueous solvents or carriers Propylene glycol, polyethylene glycol, vegetable oils, e.g. olive oil, and in; organic esters, e.g. B. Ethyl * - oleat. Such preparations can also contain aids contain, e.g. preservatives, wetting agents, emulsifiers and,! dispersants. For example, you can: by filtration through a bacteria-retaining filter, by adding "sterilizing agents" to the preparations, by irradiation or by heating. They can also be sterilized in the form of sterile solid preparations are prepared immediately before use in sterile water or in another sterile injectable medium.

Preparations for rectal administration are suppositories, which, in addition to the active substances, are carriers such as cocoa butter or a. May contain suppository wax.

Because of their ease of administration, filled capsules are the preferred therapeutic dosage form. Such filled Capsules can easily be manufactured using conventional carriers and diluents known for this purpose * the new agents according to the invention may also contain other active therapeutic ingredients be.

■ ^ he agents according to the invention can as well as a-d-propoxyphene intermittently with individual attacks of pain, or, if the pain "persists for a long time, regularly (i.e. all 4 to 6 hours).

For reasons of simplicity, the inventive method is

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BATH ORIGINAL

Strengthening the anaetic activity a-d- - -preferably achieved by .. Preparation: © «given be that both a-a-propoxyphen and ei, n @ Ihenoxyphenylverbindungen contain. The analgesic effect, dit : is achieved with a-d-propoxyphene, leaves egg traps out reinforce by the fact that at the same time, but separately, © in © Phenoxyphenyl compound is administered «Ig is also apparent that the desired effects iiamer then achieved when the two substances are present in the body at the same time; '

* The invention will be further illustrated by the following examples explained. . . . ■ -. .

- At S ₁ ρ ie 1 1

A typical preparation that is suitable for filling into Gelatin © * capsules is made by thoroughly mixing 5 parts by weight of ad-propoxyphene hydrochloride, 1 part by weight of 2- (4-phenoxyphenyl) propionic acid and 1.3 parts by weight of starch. The mixture is filled into gilatine capsules No. T in such an ^iv % quantity that the finished capsule contains about 32 mg of ad-prupoxyphene hydrochloride and about 6.4 mg of 2- (4-phenoxyphenyl) propionic acid.

If desired, about 10 parts by weight of acetylsalioic acid can also be used for the production of this preparation. In this case the Kapsil also contains about 320 mg ^; Aoetylsalicylic acid @.

B ai a -, P;, ',!., "Β ,,,, Λ,!" "Β--

α-d-propoxyphene hydrochloride and 2- (4 «l ^} henoxyphenyl) propionic acid are separated and shared with morphine

ÖQi83f / 1834

BAD ORlQlHAL

is tested for sick alone on hats according to a test method in which the reaction time of treated and untreated rats to the action of a heat stimulus on the rat's tail serves as a measure of the analgesic effect. This test method was described by Robbins (Journal of the American Pharmaceutical Association, Vol. 44, S * 479 / ~ 1955_7). The compounds are administered subcutaneously. The reaction to the warmth is determined 30 minutes after the injection. The reaction time is the time that elapses under the action of the heat stimulus until the tail is moved away from the heat source. The reaction time is averaged for each group of rats receiving the same treatment. The test results are shown in Table I below.

Table I. link dose
n «/ k £ (sc) - reaction time
(Seconds) control .._ , 0 4.6 2- (4-phenoxyphenyl) propion
acid 100 , 5 3.8 a-d-propoxyphene hydrochloride 7th • 5 7.4 a-d-propoxyphene hydrochloride + 7 11.3

2- (4-phenoxyphenyl) propionic acid 2.5 · α-d-propoxyphene hydrochloride +7.5

12.6

2- (4-phenoxyphenyl) propionic acid 5.0

Morphine, 0.5 5.6

1.0 7.1

2.0 8.2

3.0 13.1

009835/1834

- ίο -

Example 3

A typical preparation suitable for filling into gelatin capsules is made by thoroughly mixing 5 parts by weight of a-d-propoxyphene hydrochloride, 1 part by weight of 2- (3-phenoxyphenyl) propionic acid and 1.3 parts by weight of starch * The mixture is produced in gelatin capsules No. 1 bottled in such a quantity that each finished capsule about 3 ^ mg a-d-propoxyphene hydrochloride and about 6.4 mg. ' Contains 2- (3-phenoxyphenyl) propionic acid.

If desired, about 10 parts by weight of acetylsalicylic acid can also be used in the production of this preparation be used. In each case, each capsule also contains about 320 mg acetylsalicylic acid. .

Example 4

a-d-propoxyphene hydrochloride and the sodium salt of 2- (3-Phenoxyphenyl) propionic acid are separately and tested together on rats according to a test method in which had the reaction time of treated and untreated on the action of a heat stimulus on the rat tail serves as a measure of the analgesic effect. This test method was developed by Robbins (Journal of the American Pharmaceutical Association, Vol. 44, p. 479 ΖΓ1955_7).

Female albino rats (Harlan strain) weighing between 70 and 80 g are fasted overnight prior to testing. Doses of 2 to 24 mg / kg of ad-propoxyphene hydrochloride are administered subcutaneously to groups of 8 rats. 4 rats in each dose group are also given 2- (3-phenoxyphenyl) propionic acid sodium salt subcutaneously at a dose of 2, 10 or 50 mg / kg or a saline solution.

0 0 98 35/1834 bad original

Further groups of 8 rats receive either oc-d-propoxypiien hydrochloride or 2- (J-phenoxyphenyl) propionic acid alone. The seizure reaction times are with the help of the rat tail weighing test on groups of 20 rats 30 and Determined 60 minutes after the treatment. Be for comparison Control values determined for rats treated with saline solution. The duration of the thermal stimulus is a maximum of 15 seconds.

The results are shown in FIG. Subcutaneous doses of the phenoxyphenyl compound give from 2 to 50 mg / kg Pain reaction times ("A") which cannot be distinguished from the control values. The subcutaneous administration of a-d-propoxyphene hydrochloride leads to pain reaction times, which result in a dose-response curve, which in Pig. is labeled "B".

By adding 2, 10 and 50 mg / kg phenoxyphenyl compound (curve C, D or E in I ¹ Ig. 1), the oc-d-propoxyphene hydrochloride dose-effect curve is increasingly shifted to the left, and the effect of ad- Propoxyphene increased by 120, 150 and 175 #, respectively. »

Example 5

a-d-propoxyphene hydrochloride and 2- (3-phenoxyphenyl) acetic acid sodium salt are separated and shared on rats according to the. method described in Example 2 tested. Additional rats are given 0.5 to 4 mg / kg subcutaneously Administered morphine. The test results are shown in Table II. It can be seen that the analgesic Effect of a-d-propoxyphene is greatly increased when simultaneously a-d-propoxyphene and a phenoxyphenyl compound administered «. When 2- (3-phenoxyphenyl) acetic acid is administered alone, reaction times comparable to those of the control animals are obtained.

009835/1834

co 00 ω cn

co co

dose
ICgAg
S. C. link
A ¹ Compound A ¹
2 mg of compound 0 4.50 ^: , 0.50 : - 'V 1.00 2.00 4.38 . ■ '; -.5,1 «.'ν,;, ■ 3.00 5.12 6.00 4.00 5.19 6.06 6.00 7.00 8.12 Τ 8.00 8.56; 10.43 ' 1 ^, 00 10.38 12.12 16.00 12.25 13.38; 24.00 > 15, OO —— :: '■'

Connection A ' Connection A

mg compound _cn + "....

r.;. r,. - 50 rag connection

Jj 'TD

4.56

; 5.44

.. '·. 6.58

7.25

10.00

'12, 88

5;, 56
8.31

ir, 44
i4vi9

> 15.00

α-d-Propoxyphene hydrochloride is denoted by " A"

Morphine

7.10

ß, 20

13.10

■ 2- (3-Phenoxyphenyl) acetate, sodium salt is referred to by "Compound ¹ B".

Control

4.62 4.40 4.50 4.19 4.44 4.38 '4.56 ßO 4.62

4.56 ^: 4.50,

Claims (6)

1. Analgesieum geJseamz-ei ahnet dimeii a first 1 3 2-I) i ^ lienyl-2-jiydroxy-3-met] ayl-4-'C isüaibaxi "-ocLer a p3iarmazentiseii -aimeiaanlare salt daTroii and a 3 - Q && c 4 -! ^ «NoxyjOaenylallcaaasätiiie, the wherein (a) E is a methyl radical or an ethyl radical and H represents a hydrogen atom when the .Phenoxy radical is in position 3 "or (b) R a 3 V / hydrogen atom or a methyl radical and when R is a V / hydrogen atom, R a hydrogen atom, a fluoratoine, a methyl radical, an ethyl radical or 3
a methoxy group or, when R represents a methyl group, R represents a hydrogen atom when the phenoxy radical is in position 4, or a pharmaceutically acceptable salt of the acid. 2. Means according to claim Ί, characterized in that the '' Ester of 1,2-Mphenyl-2-hydroxy-3-methyl-4- (substituted) aminobutane the formula 009836/1834 OC-2 ¹ GH-CH ₉ -H ' 1 ·· has, wherein R is a methyl · or Ath.ylr.est and 2
R is a dimethylamine or pyrrolidino group. 3. smock according to claim 1 or 2, characterized in, that it is an ester of ct-d-propoxyphene napsylate or a-d-propoxyphene hydrochloride contains. 4.Means according to xln & pruch 1,2 or 3 »characterized by that it is as an acid compound 2- (3-phenoxyphenyl) propionic acid, 2- (4-phenoxyphenyl) propionic acid or a pharmaceutical contains acceptable salt thereof. 5. Agent according to one of claims 1 to 4, characterized in that that the compounds in a ratio of 1 part by weight of the phenoxyphenylalkanoic acid compound about 0.005 to 20 parts by weight of the ester are present. 6. Agent according to one of claims 1 to 5, characterized in that that it is the acid compound 2- (3-phenoxyphenyl) propionic acid sodium salt contains. 009835/1834 BATH ORIGINAL