PHARMACEUTICAL COMPOSITION AND USE

Abstract: A biologically active preparation for human or veterinary use for the selective blockade of opioid binding sites of the brain responsible for respiratory depression containing in a biologically active quantity the codeinone derivative of general formula (I) or its salt; R<1> means amino-, hydroxyl-, -NH-phenyl or -NH-CO-NH2 groups, R<2> means a hydrogen atom or a hydroxyl group. The invention also covers a process for selective blocking the opioid binding sites of the brain responsible for respiratory depression by administering to a patient in need of an analgetic a preparation containing a codeinone derivative of general formula (I) or its salt preferably three times per day in doses of 2.5 - 5 mg. A preferred feature of the invention is an analgetic composition containing a codeinone derivative of general formula (I) and in a mass ratio of 1 : 2-3 morphine of formula (IV) or an other, biologically equipotent agonist type opiate or opioid compound and optionally inert, pharmaceutically acceptable accompanying materials.

Description: PHARMACEUTICAL COMPOSITION AND USE. The subject of the invention is a biologically active composition for selective blocking of the opiate-binding sites of the brain which are responsible for respiratory depression, which contains codeinone derivatives of the general formula (I) or its salts in a biologically acti ve quantity. In this specification the substituents of changing signi¬ fication are always the following: Rl means amino-, hydroxyl-, -NH-phenyl or -NH-CO-NH2- groups, R 2 means a hydrogen atom or a hydroxyl group, R 3 means amino-, hydroxyl-, -NH-phenyl- or -NHCONH2 groups or such which can be transformed into said groups. It is known that the morphine-like analgetics 1 opiates ■ act as respiratory-depressants, on tne course of acute toxicity investigations lethality of such compounds is attributed to this activity [Prog. Neurobiol.33(198411- 16; 22(1984) 345]. Interpretation of relations between respiratory-depreε sant activity and opiate receptors is rather difficult. » According to the present conceptions there are several I receptors which might participate in mediating this ef- 5 feet. However the relative contribution of various re¬ ceptor populations mediating this effect is not clear enough. Since evaluating the respiratory parameters is complicated, selectivity of the methods is questionable and because of the big differences amongst the species the difficulties are further increased. The difficulties and problems inherent in these methods partially explain the difference in receptor assignments in opioid-induced respiratory depression which have appeared in literature. Several biochemical and pharmacological data prove the heterogeneity of the opioid receptors both in the neu¬ rological system and in the periferies [Trends. Neuro. Sci.7.(l984) 31; Pharmac.Rev.3_9, 197-249 (1987).] The main receptors - marked μ, o , and σ receptors show different dispersit in the different tissues, have different ligand specifities and mediate different phy siological processes. In recent times it was clarified also that these main receptor types can be divided into sub-types. From these in the case of the μ type receptor it is possible to distinguish μi and μ 2 sub-ty¬ pes. It is suggested that the μi receptor mediates the analgesic effects of opiates while the μ 2 mediates opio¬ id induced respiratory depression. Identification of these two sub-types of opioid re¬ ceptors may be brought about by way of their binding ca¬ pacity to opioid receptors of so called high and low affinity. Ligands for μi receptors are bound to the high affinity (3H)naloxone binding sites. (Their affinity conεtantε are below nanomole concentrations. ) The μ 2 receptors (low affinity binding sites) mediate among others opioid induced respiratory depression. (Their af¬ finity constants are in the range of nanomole concentra¬ tion or above. ) Ligands are known which are capable to inhibit selectively the μi receptors. E.g. naloxonazine, oximor- phazone, several other C-6 morphinane derivatives and in¬ terestingly also some peptides (the chloro-methyl-ketoneε of enkephalines) are of this group. As far as we are aware no compounds capable to block the μ2 receptors were known hitherto. It is a new observation that codeinone, oxycodone and dihydrocodeinone derivatives substituted in position C-6 are bound in a partially irreversible manner to μ 2 receptors. It has to be mentioned however that the existence of μi and μ 2 receptors has not yet found general acceptance. There were several who could not repeat the experiment which serves as main proof namely that the respiratory depression caused by morphine is not inhi¬ bited by the selective μi antagonist naloxonazine. A further difficulty may be caused also by analysis cf the complex action of opiates on respiration. There are opiates known which are depressing ( μ-agonists: morphine etc.), others which are stimulating (receptor agonists: cyclazocine) and others which have dualistic (deprimating and stimulating) effects (partial antagoni¬ sts: nalorphine). The significance of identification of the μ2 receptor would be in theory and in practice that knowing the same there would be a possibility to synthesize such compounds which would not have respiratory depressing while having considerable analgesic properties. It is also known that there are certain dihydro-morphino- ne and dihydro-codeinone derivatives substituted in position 6 with hydrazone-, phenyl hydrazone, -dinitro-phenyl-hydrazone, semicaroazone and thiose i- carbazone groups as well as their 14-OH-derivatives pos¬ sess increased analgesic activity as compared with the analogues which are 6-unsubstituted (Hungarian patent application No. 56-85 or patent specification 199.901). The C-6 carbonyl group of the morphinane ketones is easily substituted and earlier publications suggest that changes of this type in general do not influence the opioid character of the ligand. It has been stated when investigating 6-substituted hydrazone derivatives of 14-hydroxy- dihydro-morphinone [J.Med.Chem. 23 (1980) 674-677, Pharm.Res. 3 (1986) 56- 60, Life Sci., 40(1987) 1579-1588] that both the μ and the δ high affinity binding sites are irreversibly blocked by these derivatives [J.Pharm. Exp. Ther. (1980) 214 and 455-462]. It has been shown by pharmacolo¬ gical tests that irreversible blocking of this receptor is manifested in the case of agonists in a long-lasting analgesic effect, while in the case of antagonists the analgetic activity of morphine is blocked for a long pe¬ riod of time while however the protection against lethal respiratory depression does not take place. [Life Sci. _1 (1983) 1389-1392, Science 208 (1989) 514-516]. It naε thus been stated that the opiate analgesia is mediated by the common receptor named μi- Thus it would be a most desirable task for pharmaceutical planning to separate the analgetic effect from other opiate effects. When εtarting work according to our invention we studied different C-6 substituted (hydrazone-, phenylhydrazone-, dinitro-phenylhydrazone-, oxime-, semicarbazone-) deri vatives of dihydro-morphinone and dihydro-codeinone on brain membranes of rats. The C-6 substitution did not change their affinities to (3H)naloxone-binding εites in the case of substituents of small size, while the af¬ finity decreased in case of substituents having a grea¬ ter volume. We stated that all tested C-6 substituted derivatives of oxymorphone and dihydromorphinone are blocking irreversibly, in a dose-dependent manner the specific bondage of ( 3 H)naloxone at isotope concentrations of InM and this concerns the μ^ receptor. We have found surprisingly that oxycodone and dihydro- codeinone derivatives of general formula (I) are irrever¬ sible inhibitors in a dose-dependent manner of specific binding of ( 3 H)naloxone at isotope concentrations of InM and they have a lower affinity to the ( 3 H)naloxone bin¬ ding siteε as compared with the corresponding morphine derivatives. We ascertained however that at isotope concentrationε of 10 nM preincubation with these dihydrocodeinone derivativeε blockε the εpecific binding of ( 3 H)naloxone irreversibly and completely, as well seen from saturati- on isotherms of ( 3 H)naloxone (preincubation of the mem¬ branes with these dihydrocodeinone derivativeε followed by waεhing) . It iε essential that this involves the bin¬ ding site of low affinity (μ2) which is responsible for respiratory depression. In our pharmacological tests based on the above we sear¬ ched the reply whether the derivatives of general for mula (I) would be exempt from respiratory depression actions which are presumably mediated by the μ 2 receptor. Starting from the fact that toxicity of morphine is attributed to respiratory paralysis, we conducted toxi¬ city tests of the above compounds and morphine on rats to get indirect information on the nature of the respirato¬ ry depressant activity. From the clasεical opiate spec¬ trum we investigated along with the analgetic effect the sedative action as well. We verified that the codeinone derivatives of general formula (I) significantly inhibit the lethal respiratory depression caused by morphine (e.g. on rats), when increaεing the LD5 0 value measured on morphine controls in the average to its twofold. On the basiε of the tableε shown in the experimental examples we also can state that a part of the co pounαs stimulated in small dose ranges the frequency of re¬ spiration and some even the amplitude, administered i.v. and s.c. For example the oxycodone-semicarbazone and -oxi e when used in small doses considerably increase the respiration number and in some tests they reduced the depressant effect of morphine. In all experimentε we reverεed reεpiration with naloxone to prove that the de- presεion waε mediated by an opiate receptor. When admi- niεtering together the morphine effect was slightly inhi¬ bited in a 100 μg/kg dose. Oxycodone hydrazone increaεes both the volume and the frequency of reεpiration in an 50 μg/kg dose. When administered after morphine a partial reversal takes place. While somewhat depressing respira¬ tion oxycodone-phenyl-hydrazone partially antagonizes the effect of morphine. It has to be mentioned that amongst the referred "mother compounds" dihydrocodeinone and oxycodone cause respiratory depression in 50-2500 μg/kg and 10-2500 μ/kg s.c. doses. Both compounds unambi¬ guously potentiate the respiratory depression effect of morphine. The above experiments suggeεt that the codeinone deri¬ vativeε of general formula (I) according to our invention block selectively the opioid binding sites of the brain which are mediating respiratory depression and thus they can be used both in human and in veterinary preparations in all caseε where such blocking is necessary. Thus the codeinone derivatives of general formula (I) can be used as active ingredients in analgetic preparations without the appearance of lethal respiratory depression after longer treatment or higher doses. The derivatives of general formula (I) also can be used preferably in combinations according to our invention. Thus it iε specifically important to our view that when administered together with morphine the respiratory depression can be decreased and the lethal effect can be avoided. Thus it is possible to administer morphine in prolonged and higher doseε in caεes where the patient needs it without the occurrence of lethal respiratory paralysiε. In preparationε where morphine and the codeinoneε of - s - general formula (I) are applied together the mass propor¬ tion of morphine : codeinone derivative amounts to l : 2—3. Instead of morphine biologically equipotent amounts of other opiates of the agonist type or opioid compounds can be used in these combination preparations. Such compounds are e.g. orphinanes, benzomorphanes, opioid peptides or other pentacyclic compounds with morphine activity. In addition to the above active ingredients the composi tionε according to our invention contain inert, phar a ceutically acceptable additive compounds. A further subject of our invention consists in a method to selectively block opioid binding sites of the brain which are responsible for depression of respiration by way of administering to the patient in need of such treatment a composition containing a codeinone derivative of general formula (I) or its salt preferably in a 3x2,5 - 5 mg daily dose. It is preferable to use the product in the form of i.m., i.v., or epidural injections it is however possible to use other doεage forms as well. A further subject of our invention is a process for the preparation of a biologically active composition con¬ taining codeinone derivatives of general formula fl: DV reacting a ketone of the general formula (II) with a hydrazine derivative of the formula (III) by admixing kodeinone derivatives of the general formula (I) -[alone or applied together with 1 : 2-3 maεε ratio of morphine or some other opiate or opioid compound of the agonist type]- with additive or auxiliary compounds usually ap¬ plied in pharmaceutical production for human or veterina¬ ry purposes so as to formulate compositions capable to block the opioid binding siteε responsible for respiratory depression, preferably analgesics. According to our invention the codeinone derivative of general formula (I) can be present in the form of its salt formed with mineral or organic acids preferably phosphoric acid, hydrochloric acid. According to our invention it is possible to use the compounds in the form of their cis and/or trans iso erε. We have thus stated - as compared with the molecules protected in our Hungarian Patent No. 199.901 - that ac¬ cording to our invention it is only possible to use a distinct, limited part of the 6-substituted derivatives protected there . It is not possible to use the big group of morphinane derivatives. Thus the selective binding exposed accor¬ ding to our invention represents a property, the recogni¬ tion of which constitutes the essential basiε of our in¬ vention and on the basiε of thiε new point of view the εelection of outstandingly useful compounds out of the bigger range of otherε. According to our knowledge the oximeε falling under general formula (I) have never been deεcribed aε pharma¬ ceuticals at all. The details of our invention are illustrated in the Examples. I. Examples for compositions Compositionε containing the following active ingredients are prepared with usual additive material and methods: Table Compound tablet or im. or iv. epidur. capsule sc. i j. inj. inj. 1.1. Oxycodone-oxime phosphate 5 2 1 0,5 1.2. Oxycodone-oxime 2 0,5 0,1 0,1 .HC1 + morphine.HC1 5,0 5,0 5,0 1,0 1.3. Oxycodone-semi- carbazone-bi- tartarate 2,5 l 0,5 G,l 1.4. Oxycodone-phenyl- hydrazone.HCl 2,5 1 0,5 0,1 1.5. Oxycodone- hydrazone.HBr 2,5 1 0,5 0,1 1.6. Oxycodone-semi- carbazone.HC1 2,5 1 0,5 0,1 + morphine.HC1 5,0 5,0 5,0 1,0 Oxycodone-phenyl The dose of the active ingredient is given in relation to the base, the size is mg/formulated unit (tablet, ampou le) . Example I.11. Tablets of the following composition are prepared with usual methodε: Salt of the active ingredient 5,0 mg (calculated as base; Lactose 60.0 mg Starch 30.0 mg Magnesium stearate 1,0 mg Talc 3,0 mg II. Binding tests Methods: Membrane preparation: A crude membrane fraction from rat brain (PVG/C strain) was prepared [Mol.Pharm.il (1975) 340-351] and the protein content was defined [Anal. Bio chem.72(1976) 248-254). Description of the binding essay: The membrane suspension (200-400 μg protein) was incuba¬ ted with the specific radioligand for 1 hour on ice. In¬ cubations were terminated by rapid filtration under vacuo followed DV washing with ice-cold tris-HCl buffer (50 M, pH 7,4). Radioactivity was measured in a toluene-oased scintillation mixture on a LKB Minibeta Liquid Scintillation Spectrophotometer. Nonspecific binding was defined in the presence of 10 μM unlabeled naloxone. All assays were performed in triplicate and repeated several times. Ki values were determined from equilibrium experi¬ ments and calculated with the Tshang-Prusov equation. The data were evaluated using the Ligand program [Anal.BioI. Chem. 107 (1980) 220 - 239] (Data shown on Table III/l ' j . Determination of wash-resistant binding: After preincubation a thorough washing was performed. [ Life Sci.32 (1983) 2777- 2784]. Control values are re¬ presented by the specific binding of ( 3 H)naloxone to membranes preincubated with a buffer and treated in the same way. Heterologouε diεplacement experiments were used tc eva¬ luate tne affinity of the investigated compounds for ( H naloxone binding sites. Resultε are εhown in Table II/2. II.1. Binding test Table Il/i. Affinity constantε (KinM) of different opioid ligandε ii competition aεsays hydrazone phenyl- semi oxime salt hydrazone carbazone oxymorphone 20 sulfate dihydro- morphinone sulfate oxycodone 800 1150 588 32 HC1 dihydro¬ codeinone 323 52 HC1 membranes were incubated with ( 3 H)naloxone (InM) and with increa¬ sing concentrations of the ligandε. Evaluation: The oxime derivatives exhibit the highest affinity for ( 3 H)naloxone binding sites. The codeinone and dihydroco¬ deinone derivatives have εubεtantially higher Ki values. II.2. Essay on wash-resistant binding Table II/2. Affinity constantε of oxycodone and dihydrocodeinone derivativeε Example Compound.HC1 Ki(nM) IV.2. Oxycodone 127 IV.3. Oxycodone-oxime 32 IV.5. Oxycodone-εemicarbazone 588 IV.8. Oxycodone-phenylhydrazone 1150 Dihydrocodeinone 476 IV.1. Dihydrocodeinone-oxime 53 Dihydrocodeinone-phen 1- hvdrazone 323 The membraneε were preincubated with ( H)naloxone (1 nM) and with increasing concentrations of tested compounds and the specific binding of the remaining ( 3 H)naloxone was measured after several washings. The data given repreεent the average of 2-4 data obεerved. The codeinone derivatives were measured in 10 μM preincu¬ bation concentrations. Evaluation: Table V. shows that the compounds of general formula (I) are week, irreversible inhibitors of specific binding of ( 3 H)naloxone at I nM concentration, especially on high activity receptors. At higher concentrations the situation is reverεed and they inhibit mainly the low affinity receptorε. As it is seen in Figure VI. the remaining ( H)naloxone specific binding is significantly decreased at 10 nM iso¬ tope concentration as a result of preincubation with dihy- drocodeinone-derivatives, while this decrease is rather small if preincubation takes place with dihydro-morphinone derivatives. It was already shown previously [Life Sci.40 (1980) 1579- 1588, J.Pharm.Exp. Ther.214 (1980) 455-462] that preincu- ba-tion with hydrazone derivatives of oxymorphone and na- loxone irreverεibly inhibitε the high affinity ( 3 H)naloxo- ne component, whereby the low affinity component remainε unchanged. Aε εeen on Table II/l., the oxycodone and di- hydro-oxycodone derivatives show a lower affinity to the ( 3 H)naloxone pinding εiteε aε compared with the corre¬ spondent morphine derivatives, if the isotope concentrati¬ on is low. These ligands however strongly inhibit at higher ( 10 nM) concentrations the ( 3 H)naloxone specific binding. This is why we studied the effect of preincubation with these de¬ rivativeε on saturation isotherms of ( 3 H)naloxone. Figure VII. shows the Scatchard transformations of the sa¬ turation binding isotherms of ( 3 H)naloxone specific bin¬ ding after pretreatment with dihydrocodeinone derivatives and with buffer only aε a control. From the Scatchard ana¬ lysis the result is clearly seen, that after preincubati¬ on and intensive washings the low affinity receptor-effect almost completely disappears. III. Pharmacological tests It is characteristic for the compounds that their greater part shows a substantial and some a light agonist (anal¬ getic or sedative) effect (Tables No. 1,2,3 ). III.l. Analgetic effects Comparison on the basis of data obtained in 4 tests on rats and mice (ED50 mg/kg): Table III/l. compound hot plate tail flick writhing algolyt. (rat) (rat) test test (rat) (mice) 100% acti¬ vity Oxycodone-oxime .phosphate 1,8 1,0 0,11 ιo,c"- Oxycodone-semi- carbazone.bi- tartarate 0,58 0,35 0,15 5,0' Oxycodone-pheny1- hydrazone.HCl 0,S 1,2 10,' Oxycodon- hydrazone.HBr 0,46 0,65 0,35 10,0' Oxycodone-thio- semicarbazone .HCl ,5 4,5 100,0 Dihydrocodei- none-semicar- bazone.HCl 0,38 0,35 10,0' Dihydrocodei- none phenyl- hydrazone.HCl 2,4 2,3 ιo,ι* χ Dihydrocodei- none-oxime .phosphate 4,2 3,7 0,38 25,0' Dihydrocodeinone thio-se icar- bazone.HCl 1,7 0,6 5,0 Dihydrocodei¬ none 2,2 0,98 0,9 4,9 *catalepsy ** convulsion Methods: Eur.J.of Pharm. (1982)239-241; Arzn.Forεchung 3_8 (1938j 552. The strongest analgetic on the hot plate test is the dihydrocodeinone-semicarbazone (EDso:0,38 mg/kg hot pla¬ te, tail flick). On the algolytic test the oxycodone-oxi¬ me, -se-micarbazone, -phenylhydrazone and -hydrazone are capable to total assuage of pain - though amidst the symptoms of slight cathatony - practically in the order of magnitude of morphine or the mother compounds (oxyco¬ done, dihydrocodeinone). III.2. Testing on sedative activity Inactine (35 mg/kg) was used as a base narcotic. Table III/2. Sedative (narcosis potentiating effect (EDsoo% mg/kg * . s.c. on rats oxycodone-hydrazone.HBr 0,45 oxycodone oxime.phosphate 0,5 oxycodone-semicarbazone.HCl 1,5 oxycodone-phenylhydrazone.HCl 1,5 dihydrocodeinone-phenyIhydrazone.HCl 3,5 dihydrocodeinone-semicarbazone . itartarate l,0 morphine 1,75 dihydrocodeinone 1,9 oxycodone l,2 ~ ED5oo%= dose increasing narcosis to five times the contrc The doses of the active ingredients are always given in relation to the base. Evaluation: All investigated compoundε potentiate the activity of In¬ actine strongly. The duration of narcosis is moεt effec¬ tively prolongated by oxycodone-hydrazone and -oxime re¬ spectively. III.3. Investigation of physical dependency Table III/3. "jumping test" on mice name treatment naloxone number %relation 7xmg/kg 50mg/kg of jumps of ip. ip. /mouse jumping (average) animals The dose of the active ingredient is given related to the base. Table III/3. shows the results of an informative physical dependency study on tne jumping test on mice. The mice were treated for three days with a total of 7 times i.p. with a high dose of the compounds to be tested and after the final injection the symptoms of withdrawal are gene¬ rated by administration of a morphine antagonist, i.e. a constraint for jumping is provoked. Morphine-equivalent quantities were administered from the test compounds. In the case of morphine the dose which effects dependence with certainty amounts to 7x100 mg/kg. Within this group on administration of 50 mg/kg of naloxone the average jumping rate amounted to 34,5 (total jumping number/jum¬ ping animals) and 100% of the investigated animals did jump. Oxycodone-semicarbazone-oxime and -hydrazone re¬ spectively when administered in equi-analgetic doses did not result but in a very low, almost negligible number of jumping reactions while 50-70% were participating. ϊie capacity of dependence of these compoundε iε thuε unusu¬ ally low. III.4. Morphine toxicity teεtε Morphine and the test εubstanceε were adminiεtered toge¬ ther, ε.c, to ratε. Aε seen from Table III/4. almoεt twi¬ ce as much is needed from morphine to develop the same mortality meaning that toxicity of morphine iε decreased to almoεt itε half aε a reεult of the activity of effec¬ tive test substances (oxycodone-oxime, - semicarbazone, -phenylhydra-zone, -hydrazone and dihydrocodeinone- oxime) . Dihydrocodeinone-semicarbazone and -phenylhyd- razone are less active. Oxycodone and dihydrocodeinone potentiate toxicity of morphine ( ! ) . Table III/4. Change of morphine toxicity in the presence of test substances i on ratε) Name Oxycodone-oxime.phos- 15 620 phate Oxycodone-semicarba- zone.bitartarate 50 580 2,0 2 , 3 1 , 7 2 , 6 0 , 57 0 , 53 1 , 0 The doses of the active substances are given in relation to the base. III.5. Effect on respiration test on rabbits Method: Investigation was carried out on conscious rabbits of both sexes and of 3-4 kg weight by way of a Marey-drum. Frequency and amplitude of respiration were quantitative¬ ly evaluated. Morphine decreased both freguency and volume of respira¬ tion in 2,5 - 5 mg/kg doses. Some results are shown in Table III/5. Table III/5. Effects on respiration on consciouε rabbits Compound dose μg/kg respiration respira- ε.c. volume tion frequency/ in. effect Morphine.HCl 2500-5000 i I deoreεsion i.v. , ε.c, Dihydrocodeinone .HCl 10 - 5500 depression l .v. , ε . c. * Morphine dose in combinations amounts to 5 mg/kg. III.6. Effect on respiration teεt on conεcious rabbits Method: The method as described above in Example III.5 was used on consciouε rabbitε of 2,5-3 kg weight. Registration was continued for 3-4 hours. The sampleε were injected under the skin of the neck and the respiration parameters were registered at intervals of 10 minutes. Type A test: Determination of the dose-effect diagram of the substances ("low dose region" and "high dose region") between 0.01 to 2.5 mg/kg alone and after selection of particular dose values investigation of morphine preven¬ tion. Type B test: Sequence of application was the following: 5 mg/kg morphine were administered (causing with certainty respiratory depression) and after 10 -20 minutes it was investigated whether the depression could be reverεed. Type C test: Administration of 5 mg/kg of morphine and the investigated substance together to clarify whether the substance is capable to reduce the effect of morphi¬ ne. Some of the results are shown in the following tables. Table III/6. Oxycodone oxime (OX) OX dose pretr. morphine pretr. resp.change mg/kg period mg/kg period fr/min ampl, s.c, mm. s.c. mm. A. 0 . 1 10 +57 + 5 30 +71 40 -29 -40 pret= duration of pretreatment Table III/7 Oxycodone semicarbazone (OS) resp.cnange fr/min a j 0.01 10 +48 0 30 +51 +20 0.025 30 +51 +20 10 +50 +75 0.025 10 +48 +20 20 20 +24 3 30 +13 0.50 10 +36 0 30 20 20 +10 0 Table III/8 Oxycodone phenylhydrazone (OP) OP dose pretr. morphine pretr. resp.change mg/kg period mg/kg period fr/min ampl s.c. min. ε.c. mm. A. 0.1 10 0.5 10 10 60 B. 1.0 C. 0.25 20 +44 +20 30 +92 +30 Table III/9 Oxycodone hydrazone (OH) s.c. mm. s.c, mm. A. 0.25 20 30 10 C. 0.25 20 + 30 +10 Table 111/10. Dihydrocodeinone-phenylhydrazone (DP) DP dose pretr. morphine pretr. resp.change mg/kg period mg/kg period fr/min ampl, s.c. mm. s.c. mm. The Table shows, that doses of 0.01 to 0.05 mg/kg consi¬ derably increase the frequency without influence on the amplitude of respiration. Doses of 0.25 mg/kg when admi¬ nistered together with morphine retard depression to some degree. IV. Chemical process examples (Method: Hungarian patent specification No. 199.901) IV.1. Dihydrocodeinon-oxime 1,5 g of hydroxyla ine-chlorohydrate are reacted in 70 ml of water with 3,0 g of dihydrocodeinone base for 3 hours and then adjuεted to pH=9-10. The oxime precipitates as crystals, which are filtered, washed with water and cry¬ stallized from propanol. The product amounts to 2,5 g. M.p. : 265 - 266°C. IV.2. 14-Hydroxy-dihydrocodeinone-oxime The product of Example IV.1. is crystallized from aqueous ethanol. M.p.: 194°C. IV. . 14-OH-dihydrocodeinone-hydrazone (trans) 5 ml of 100% hydrazone hydrate are heated with 2,0 g of 14-OH-dihydrocodeinone in 10 ml of dimethyl-forma ide for two hours and then poured into water. The crystalline product which precipitates iε isolated and chromathogra- phized on εilicagel (chlorofor -methanol 9:1,v/v). The pure fractions obtained by TLC eluating with the eluent chloroform: methanol: cc. ammonium hydroxide mixture 90:10:5 are crystallized from methanol. M.p.:192- 194 ° C. IV.4. 14-OH-Codeinone-hydrazone Using the method of Example IV.3. l,8g 14-OH-codeinone- hydrazone are obtained from 2,0g of 14-OH-codeinone. The crude product contains two componentε aε εhown by TLC using the eluant chloroform: methanol: cc.ammonium hydro¬ xide 90:10:5. The main component can be obtained in pure state by way of preparative thin-layer chromatography. Crystallized from ethanol m.p.: 212- 215°C. IV.5. 14-OH-dihydrocodeinone-semicarbazone (tranε . ) According to the method described in Example IV.4. 3,2g of the crude product are obtained from 3,0g of 14-OH-di- hydrocodeinone, which is the mixture of syn and anti isc- merε (ciε:trans= 1:1). By way of crystallization (chloro¬ form - ethanol) the pure trans semicarbazone is obtained. M.p.: 236- 238°C. IV.6. 14-OH-dihydrocodeinone-phenylhydrazone (ciε) Starting from l,55g of 14-OH-dihydrocodeinone l,7g of 14-OH-dihydrocodeinone-phenylhydrazone are obtained with the process given in Example IV.3. M.p. after recrystal- lization: 174 - 176°C. Pure ciε iεomer.

Claims: CLAIMS 1. Biologically active preparation for human or veterinary- use for the selective blockade of opioid binding sites of the brain responsible for respiratory depresεion c h a r a c t e r i z e d by its containing in a biolo¬ gically active quantity the codeinone derivative of gene¬ ral formula (I) or its salt - R 1 means amino-, hydroxyl-, -NH-phenyl or -NH-CO-NH2 groups, R2 means a hydrogen atom or a hydroxyl group. 2. Process for selective blocking the opioid binding sites of the brain responsible for respiratory depression c a¬ r a c t e r i z e d by administering to a patient in need of an analgetic a preparation containing a codeinone derivative of general formula (I) or its salt - the meaning of Rl and R2 iε the above - preferably three timeε per day in doεeε of 2,5 - 5 mg. 3. An analgetic composition containing several components c h a r a c t e r i z e d by containing a codeinone deri¬ vative of general formula (I) - the meaning of Rl and R2 iε the above - and in a mass ratio of 1 : 2-3 morphine of the formula (IV) or an other, biologically equipotent agoniεt type opiate or opioid compound and optionally inert, pharma¬ ceutically acceptable accompanying materials. 4. A composition according to any of claims 1-3 c h a - r a c t e r i z e d in that the codeinone derivative of general formula (I) - the meaning of R 1 and R 2 is the above - is in the form of its salt formed with a mineral or an organic acid preferably with phosphoric acid, hydrochlo¬ ric acid. 5. A preparation or a process according to any of claimε 1 -4 c h a r a c t e r i z e d in that the codeinone deri¬ vative is in its cis or trans isomeric form. 6. A process for the preparation of a biologically active composition containing the codeinone derivative of gene¬ ral formula (I) or its salt - the meaning of Rl and R2 is the above - by reacting a ketone of the general formula (II) - the meaning of R 2 is the above - with a hydrazine derivative of the general formula (III , - the meaning of R 3 is an amino-, hydroxyl-, -NH-phenyl or -NHCONH2 group or a group capable to be transformed into these groups, c h a r a c t e r i z e d by admixing the codeinone de¬ rivative of general formula (I) or its salt - the meaning of Rl and 2 is the above - with additional and auxiliary products which are generally used in pharmaceutical production for human or veterinary purposes so as to prepare a composition capable of the selective blockade of opioid binding sites of the brain responsible for respiratory depression.

Inventors: BENYHE SANDOR, BORSODI ANNA, BUZAS BEATA, FRIEDMANN TAMAS, FUERST ZSUZSA, HOSZTAFI SANDOR, SCHAEFFERNE VARGA EVA, SZUECS MARIA, BENYHE, SANDOR, BORSODI, ANNA, BUZAS, BEATA, FRIEDMANN, TAMAS, FUERST, ZSUZSA, HOSZTAFI, SANDOR, SCHAEFFERNE VARGA, EVA, SZUECS, MARIA
Applicants: ALKALOIDA VEGYESZETI GYAR, ALKALOIDA CHEMICAL COMPANY LTD.
Application year: 1992
Main classification: C07D489
IPC codes: A61K31, A61P25, C07D489