KR20060131933A - Combination of deramciclane and opioids as analgesics - Google Patents

Abstract

The invention relates to a combined analgesic pharmaceutical composition which comprises as component: A) (1R,2S,4R)-(-)-2-[N,N- (dimethylaminoethoxy)]-2-phenyl-1,7-7-trimethylbicyclo[2.2.1]heptane or a pharmaceutically acceptable acid addition salt thereof and as component B) morphine, an opioide type analgesic and/or a non-opioide type analgesic in admixture with suitable pharmaceutical carriers and/or auxiliary agents. Deramciclane increases the analgesic effect of morphine.

Description

Combination of Deramcyclane and Opioids as Analgesics {COMBINATION OF DERAMCICLANE AND OPIOIDS AS ANALGESICS}

The present invention relates to a mixed pharmaceutical composition for analgesics.

(1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1 of formula (I) ] Heptane (international non-proprietary name: deramciclane) is an anti-anxiety pharmaceutically active ingredient under the general formula of HU 179,174:

Deramcyclane preparation is disclosed in HU 212,274.

Deramcyclane has shown significant effects in various depression and stress animal models. In a drinking test provided by Vogel, deramcyclane was active at 1 and 10 mg / kg after oral administration [ Gacsalyi et al., Receptor binding profile and anxiolytic activity of deramciclan (EGIS-3886) in animal models, Drug Dev . Res. 40: p. 338-348 (1997 ) In the social interaction model, the compound increased the time spent on social interaction after 0.7 mg / kg single oral treatment [ Crawley, JN Neuropharmacological specifity of a simple modl of anxiety for The behavioural actions of benzodiazepine, Pharmacol.Biochem.Behavior, 15: p. 695-699 (1981) , demonstrated that deramcyclane was active at a single oral dose of 3 mg / kg sc.marble burying model) [ Broekkamp, CL et al, Major Tranquillizers Can Be Distinguished from Minor Tranquillisers on the Basis of Effects on Marble Burying and Swim-Induced Grooming in Mice.Eur. J. Pharmacol. 126: p.2223-229 (1986) ] The molecule was active at 10 and 30 m / kg after oral treatment Deramcyclane had no analgesic activity at the doses mentioned above.

In addition to the potential analgesic effects, morphine unfortunately has many side effects that limit its therapeutic use. These side effects include tolerance, psychological and physiological dependence, and sometimes fatal respiratory depression.

An object of the present invention is to develop a drug that enhances the analgesic effect of morphine.

A further object of the present invention is to develop a drug product having an analgesic effect.

The above objects are solved by developing the mixed pharmaceutical product of the present invention.

The present invention provides (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2 of formula (I). .1] based on the recognition that heptane or its pharmaceutically acceptable acid addition salts increase the analgesic effect of morphine.

The present invention further provides (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo of formula (I). [2.2.1] Based on the recognition that a combination of heptane or a pharmaceutically acceptable acid addition salt thereof with morphine, opioide type analgesics and / or other types of analgesics has an excellent analgesic effect.

From a therapeutic point of view, the morphine-boosting effect of deramcyclane is very advantageous because such means reduce the effective dose of morphine, resulting in less unwanted side effects.

The combination of deramcyclane with low dose morphine is advantageous in the following ways:

1. Low dose morphine without any effect and thus no side effects can be used successfully (Table 1). When combined with deramcyclane, an analgesic effect occurs, increasing the effect without the potential for abuse (deramcyclane has no potential for abuse).

2. When using a dose of morphine for which an analgesic effect is expressed (eg, in the treatment of cancer), deramcyclane will further enhance the analgesic effect of morphine. This means that lower doses of morphine can be used to achieve the same analgesic effect, resulting in fewer side effects.

3. In patients who have already developed morphine resistance, the combination with deramcyclane may reduce and / or not further increase the dose of morphine.

The present invention relates to a mixed pharmaceutical composition for treating pain and preventing the symptoms of morphine withdrawal.

Summary of the Invention

According to the invention, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7, of formula (I) As 7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt and component B), morphine, opioid type analgesic and / or non-opioide type analgesic can be used as a suitable pharmaceutical carrier. And / or a mixed pharmaceutical composition for analgesic is provided comprising the adjuvant.

The mixed pharmaceutical composition for analgesics according to the present invention is component A), preferably (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1 , 7,7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1).

The mixed pharmaceutical composition for analgesics according to the present invention is component A), particularly preferably (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl) of formula (II) )]-1,7,7-trimethylbicyclo [2.2.1] heptan-2-one or a pharmaceutically acceptable acid addition salt thereof containing less than 0.2% (1R, 2S, 4R)-(-) -2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof:

The mixed pharmaceutical composition for analgesics according to the invention is component A), particularly preferably (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7 (1R, 2S, 4R)-(-)-containing 0.2% or less of, 7-trimethylbicyclo [2.2.1] heptan-2-one-2- (E) -butenedioate (1: 1) 2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1) Include.

(1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7-trimethylbicyclo [2.2.1] heptan-2 of formula (II) (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl containing up to 0.2% of -one or a pharmaceutically acceptable acid addition salt thereof 1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof is disclosed in the Hungarian patent application HU 1559/99.

The mixed pharmaceutical composition for analgesics according to the present invention is an opioid type analgesic, preferably, tramadol, codeine, dihydrocodeine, nalbufine or buprenorfine, or Pharmaceutically acceptable salts thereof.

The mixed pharmaceutical composition for analgesics according to the present invention is a non-opioid type analgesic, preferably, acetyl salicylic acid, paracetamol, aminophenazone, diclofenac, naproxen, ibuprofene, ibuprofene, Pyroxicam or pharmaceutically acceptable salts thereof.

The mixed pharmaceutical composition for analgesics according to the present invention comprises component A) and a morphine or opioid type analgesic as component B) in a weight ratio of 500: 1, preferably 100: 1 and particularly preferably 30: 1.

The mixed pharmaceutical composition for analgesics according to the present invention comprises component A) and a bipioid type analgesic as component B) at 500: 1, preferably at 100: 1, particularly preferably at 30: 1.

The daily dose of the mixed pharmaceutical composition for analgesics according to the present invention is generally 0.1 to 150 mg / kg, preferably 1 to 150 mg / kg, particularly preferably 10 to 150 mg / kg.

The term "pharmaceutically acceptable acid addition salt" relates to salts formed with pharmaceutically acceptable inorganic or organic acids. For salt formation, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, fumaric acid, maleic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be used. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] of formula (I) Heptane is particularly advantageously in the form of fumarate, i.e. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7- Trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1).

Pharmaceutical compositions according to the present invention can be prepared in the form of herbals commonly used in the pharmaceutical industry. Such pharmaceutical compositions may be in solid or liquid form (eg, tablets, coated tablets, dragees, capsules, solutions, etc.). The pharmaceutical composition may be administered orally or parenterally, preferably orally. Mixed pharmaceutical compositions according to the invention can be prepared as is known in the pharmaceutical industry.

According to a further aspect of the invention, there is provided a process for preparing a mixed pharmaceutical composition for analgesics, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy) ] -2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), morphine, opioid type analgesic and / or non-opioid type analgesic Is mixed with an inert, pharmaceutically acceptable carrier and / or adjuvant, and the mixture is made into the herbal form.

According to a further aspect of the invention, as component A), to relieve pain, (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl- Use of a combination comprising 1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof and component B) as morphine, opioid type analgesic and / or non-opioid type analgesic Is provided.

According to a further aspect of the invention, as component A) for preparing an analgesic pharmaceutical composition, (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2 -Phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B) comprising morphine, opioid type analgesic and / or non-opioid type analgesic The use of the combination is provided.

According to a further aspect of the invention, as a method for alleviating pain, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2- Phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a medicament comprising morphine, opioid type analgesic and / or non opioid type analgesic Methods are provided that include administering a pharmaceutically active amount of a combination to a patient in need of such treatment.

According to a further aspect of the invention, (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1, for enhancing the effect of morphine, Use of 7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof is provided.

Increased analgesic effect of morphine by deramcyclane was demonstrated by hot plate testing in mice. Eddy et al. ( Eddy, NB, Leimback, D., Synthetic Analgasic II.Dithienylbutenyl and Dithienylbutylamines. J. Pharmacol.Exp. Ther. 107: p. 385-393, 1953 ). Male NMRI mice (20-25 g body weight) were placed on a hot plate (56 ± 0.5 ° C.) and the waiting time elapsed before licking the forefoot was measured. The reaction time was tested twice before treatment. Animals were discarded if the initial base waiting time exceeded 5 seconds or if the difference between measurements between the two controls exceeded 3 seconds. Mice were subcutaneously treated with saline or morphine HCl 1 mg / kg (sc.) And intraperitoneally treated with vehicle or deramcyclane or buspyron 30 mg / kg HCl, respectively (ip.). After the treatment (15 minutes, 30 minutes, 45 minutes, and 60 minutes), the reaction time was measured again. Animals were considered positive if they yielded a 2.5-fold response time that increased by at least 2 fold compared to the initial control value. Statistical analysis was performed using the chi-square method. This result is shown in Table 1.

Table 1: Effect of Deramcyclane and Buspyron on Morphine Analgesics in Hot Plate Testing of Mice

process Positive / treated animals effect % Brine sc. + 0.4% methyl cellulose ip. Brine sc. + Deramcyclane-30 mg / kg ip. Morphine HCl-1 mg / kg sc. + 0.4% methyl cellulose ip. Morphine HCl-1 mg / kg sc. + Deramcyclane-30 mg / kg ip. 0/10 0/10 0/10 6/10 * 0 0 0 60 Brine sc. + Brine ip. Brine sc. + Buspirone HCl-30 mg / kg ip. Morphine HCl-1 mg / kg sc. + Brine ip. Morphine HCl-1 mg / kg sc. + Buspyron HCl-30 mg / kg ip. 0/10 0/10 0/10 1/10 0 0 0 10

* p <0.05

Morphine HCl 1 mg / kg sc., Deramcyclane 30 mg / kg ip., And buspyrone HCl 30 mg / kg ip. All showed no analgesic effect alone. Surprisingly, when an ineffective amount of morphine HCl (1 mg / kg sc.) And deramcyclane (30 mg / kg ip.) Were administered simultaneously, the analgesic effect of this combination was statistically significant. Antianxiety buspirone did not affect the analgesic effect of morphine.

These results demonstrate that the increase in the analgesic effect of morphine by deramcyclane does not come from the anti-anxiety effect. This is also emphasized by the evaluations demonstrated by the experiments that Deramcyclane and Buspyrone do not have analgesic effects on their own.

Claims (13)

 As component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] Heptane or a pharmaceutically acceptable acid addition salt thereof and component B) comprising morphine, opioide type analgesics and / or non-opioide type analgesics together with suitable pharmaceutical carriers and / or adjuvants. Mixed pharmaceutical composition for analgesics. A compound according to claim 1, wherein as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethyl ratio A mixed pharmaceutical composition comprising cyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1). A compound according to claim 1, wherein as component A), (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7 of formula (II) (1R, 2S, 4R)-(-)-2 of formula (I) containing up to 0.2% of -trimethylbicyclo [2.2.1] heptan-2-one or a pharmaceutically acceptable acid addition salt thereof A mixed pharmaceutical composition comprising [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof:

A compound according to claim 3, wherein as component A) (1R, 3S, 4R)-(-)-3- [2-N, N- (dimethylaminoethyl)]-1,7,7-trimethylbicyclo [2.2 .1] (1R, 2S, 4R)-(-)-2- [N, N- () containing 0.2% or less of heptane-2-one-2- (E) -butenedioate (1: 1) Dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2.1] heptan-2- (E) -butenedioate (1: 1). The opioid type analgesic (component B) according to any one of claims 1 to 4, wherein tramadol, codeine, dihydrocodeine, nalbufine or buprenorphine mixed pharmaceutical composition comprising buprenorfine or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 4, wherein as the non-opioid type analgesic [component B), acetyl salicylic acid, paraacetamol, aminophenazone, diclofenac, naproxen, A mixed pharmaceutical composition comprising ibuprofene, piroxicam or a pharmaceutically acceptable salt thereof. 7. The morphine or opioid analgesic as component A) and component B) is included in a weight ratio of 500: 1, preferably 100: 1, particularly preferably 30: 1. Mixed pharmaceutical composition. The non-opioid analgesic as component A) and B) in a weight ratio of 500: 1, preferably 100: 1, particularly preferably 30: 1. Mixed Pharmaceutical Compositions. A method for producing a mixed pharmaceutical composition for analgesic, comprising component A) as (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7 , 7-trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), wherein morphine, opioid-type analgesic and / or non-opioid-type analgesic are inert, pharmaceutically acceptable carriers And / or mixing with an adjuvant and making the mixture in herbal form. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethyl ratio as component A) to alleviate pain Use of a combination comprising cyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), including morphine, opioid type analgesics and / or nonopioid type analgesics.  As component A), for the preparation of a pharmaceutical composition for analgesics, (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7 -Trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), the use of a combination comprising morphine, opioid type analgesic and / or non-opioid type analgesic.  As a method for alleviating pain, as component A), (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7- As trimethylbicyclo [2.2.1] heptane or a pharmaceutically acceptable acid addition salt thereof, and component B), a combination of a pharmaceutically active amount comprising morphine, opioid type analgesics and / or non opioid type analgesics is provided for such treatment. A method comprising administering to a patient in need thereof. (1R, 2S, 4R)-(-)-2- [N, N- (dimethylaminoethoxy)]-2-phenyl-1,7,7-trimethylbicyclo [2.2 to enhance the effect of morphine .1] the use of heptane or a pharmaceutically acceptable acid addition salt thereof.