DE19802327A1 - Synergistic analgesic composition containing 1-phenyl-cyclohexene and aminobutyric acid derivatives - Google Patents

Abstract

Analgesic composition contains a 1-phenyl-2-amino-cyclohex- 3-ene-1-carboxylic acid derivative (I) and an aminobutyric acid derivative (II), or their acceptable salts. (I) and (II) have formulae R1 and R2 = 1-6C alkyl, or together form alkylene; R3 = 1-6C alkyl; R'1 = 1-6C linear or branched alkyl, phenyl or 3-6C cycloalkyl; R'2 = hydrogen or methyl, or R'1 and R'2 together complete 4-6C cycloalkyl; R'3 = hydrogen, methyl or carboxy; R'4 = hydrogen or 1-4C alkyl.

Description

The invention relates to synergistic pharmaceutical preparations with an analgesic effect, comprising an active ingredient combination consisting of

• a) a basic substituted cyclohexene of the general formula I.
  wherein
  R ₁ and R ₂ , which may be the same or different, are an alkyl radical having 1 to 6 carbon atoms or two alkylene radicals linked to one another and
  R _{3 is} an alkyl radical having 1 to 6 carbon atoms and
• b) a glutamic acid or gamma aminobutyric acid analog of the general formula II
  wherein
  R _{1 is} a straight-chain or branched alkyl radical with 1 to 6 C atoms, phenyl or cycloalkyl with 3 to 6 C atoms,
  R _{2 is} hydrogen or methyl, or
  R ₁ and R ₂ together with the carbon atom represent cycloalkyl having 4 to 6 carbon atoms,
  R _{3 is} hydrogen, methyl or carboxyl, and
  R _{4 is} hydrogen or an alkyl group with 1 to 6 carbon atoms and pharmacologically acceptable and pharmaceutically acceptable salts of the compounds of the general formula I and II.

Preferred compounds of the general formula I are those in which R ₁ and R _{2 are} identical or different and are hydrogen or a methyl group and R _{3 is} an ethyl group. (±) -Ethyl- (trans-2-dimethylamino-1-phenyl-3-cyclohexene-trans-1-carboxylate (tilidine) and (±) -ethyl-(trans-2- (methylamino) -1- phenyl-3-cyclohexene-trans-1-carboxylate (nortilidine) or their enantiomers and their salts, preferably the hydrochloride or the dihydrogen orthophosphate.

Preferred compounds of the general formula II are those in which R _{1 is} hydrogen, R _{2 is} an isobutyl group or R ₁ and R ₂ together with the carbon atom are a cyclohexyl group and R ₃ and R _{4 is} hydrogen. Aminomethyl-1-cyclohexanoacetic acid (gabapentin), 3-aminomethyl-5-methyl hexanecarboxylic acid and its enantiomer (S) -3-aminomethyl-5-hexanecarboxylic acid (pregabalin) are particularly preferred.

Compounds of the general formula I are known from DE 15 18 959, Compounds of the general formula II are for example in WO 93/23383 for the treatment of epileptic seizures described.

Because of the basic nature of the compounds of the general Formula I also directly salts with the acidic compounds of general formula II are formed.

The compounds of general formulas I and II and their Salts or addition salts of both can be used in conventional Preparations and in mixtures with usual pharmaceutical acceptable carriers or diluents.

The preparations according to the invention can be in liquid or solid form can be administered orally, topically or parenterally. Water is mainly used as the solution for injection, which are the usual additives for injection solutions such as Contains stabilizers, solubilizers or buffers.

The preparations can be used as conventional pharmaceutical formulations, such as B. tablets, capsules, coated tablets, plasters, emulsions or Ointments are present. They are made by using the Compounds or their salts in a manner known per se in a pharmacologically acceptable carrier and where appropriate, incorporates suitable additives.

Such additives are e.g. B. tartrate or citrate buffers, Ethanol, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Celebrations  Carriers are e.g. B. starch, lactose, mannitol, Methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids (such as stearic acid), gelatin, agar Agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as Polyethylene glycol); suitable for oral application Preparations can, if desired, additional Contain flavor and / or sweeteners.

Compounds of the general formula I, in particular tilidine, have a medium analgesic potency. The effect of Tilidine can be increased in a limited way increase the dose, but must be in severe pain higher potent active ingredients, such as B. morphine.

The structural analogues of glutamine or gamma aminobuteric acid according to general formula II, in particular Gabapentin and Pregabalin are known for their effectiveness for cerebral seizures. In the clinical application of Gabapentin turned out to be an additional one has analgesic efficacy, especially in neuropathic pain, the mechanism of action however, is still unclear.

Surprisingly, it was found that the combination of both Active ingredients have a significantly lower dosage than that Single use allowed, with an analgesic effect is unfolded, which is the maximum effect of each Components far outperformed and therefore superadditive. It was also found that an inventive Active ingredient combination can be applied intrathecally and in Contrary to the compounds of general formula I, the administered ineffective are unexpectedly high  develop analgesic effect compared to normal enteral or parenteral administration another considerable reduction in the amount of active ingredient used enables.

With the active ingredient combination according to the invention, extreme potent analgesic drug preparations with minimal Side effects provided, their analgesic Potency in the range of strong opioids such as morphine or Fentanyl lies. Due to the synergistic effect of Combination, mainly related to the compounds of the formula I affects, the dosage of this component can be very low being held. This has the additional advantage that Risk of abuse is significantly reduced and one Tolerance development and the possible euphoric effect strong analgesics is counteracted. Through the The combination according to the invention will therefore be one against all previously strong analgesics drug superior Provided because compounds of formula II do not have this show undesirable properties of usual strong analgesics.

Claims (5)

1. Pharmaceutical preparation with an analgesic effect, comprising an active ingredient combination consisting of

• a) a substituted cyclohexene of the general formula I.
  wherein
  R ₁ and R ₂ , which may be the same or different, are an alkyl radical having 1 to 6 carbon atoms or two alkylene radicals linked to one another and
  R _{3 is} an alkyl radical having 1 to 6 carbon atoms and
• b) a glutamic acid or gamma aminobutyric acid analog of the general formula II
  wherein
  R _{1 is} a straight-chain or branched alkyl radical with 1 to 6 C atoms, phenyl or cycloalkyl with 3 to 6 C atoms,
  R _{2 is} hydrogen or methyl, or
  R ₁ and R ₂ together with the carbon atom represent cycloalkyl having 4 to 6 carbon atoms,
  R _{3 is} hydrogen, methyl or carboxyl, and
  R _{4 is} hydrogen or an alkyl group with 1 to 6 carbon atoms
  as well as pharmacologically acceptable and pharmaceutically acceptable salts of the compounds of the general formula I and II.

2. Medicament according to claim 1, characterized in that for compounds of the general formula IR ₁ and R _{2 are the} same or different and are hydrogen or a methyl group and R _{3 is} an ethyl group and for compounds of the general formula II R _{1 is} hydrogen, R _{2 is} a Isobutyl group or R ₁ and R ₂ together with the carbon atom represent a cyclohexyl group and R ₃ and R _{4 are} hydrogen. 3. Medicament according to claims 1 or 2, containing

• a) tilidine and / or nortilidine and
• b) gabapentin and / or pregabalin.

4. Medicament according to claims 1 to 3, containing the most pharmacologically active enantiomers of the components. 5. Use of compounds of general formulas I and II according to claims 1 to 4 for the production of Medicines used to treat pain.