KR100704085B1 - Novel ester derivatives of buprenorphine and their preparation processes, and long acting analgestic pharmaceutical compositions - Google Patents

Abstract

The present invention relates to novel buprenophine monocarboxyl ester derivatives and dibuprenophine dicarboxyl ester derivatives which exhibit long-term analgesic effects compared to buprenopine hydrochloride. The present invention also relates to a method for synthesizing a novel buprenopine ester derivative and a sustained analgesic pharmaceutical composition containing a compound selected from the novel buprenopine ester derivative and a buprenopine base.

Description

NOVEL ESTER DERIVATIVES OF BUPRENORPHINE AND THEIR PREPARATION PROCESSES, AND LONG ACTING ANALGESTIC PHARMACEUTICAL COMPOSITIONS             

1 shows a ¹ H-NMR spectral plot of buprenopine enanthate.

2 shows a mass spectral plot of buprenopine enanthate.

3 shows the UV plot of buprenopine enanthate.

4 shows an IR spectral plot of buprenopine enanthate.

FIG. 5 shows a ¹ H-NMR spectral plot of buprenopine decanoate. FIG.

6 shows a mass spectral plot of buprenopine decanoate.

FIG. 7 shows the UV plot of buprenopine decanoate.

8 shows an IR spectral plot of buprenopine decanoate.

9 shows a mass spectral plot of buprenopine pivalate.

10 shows the UV plot of buprenopine pivalate.

FIG. 11 shows an IR spectral plot of buprenopine pivalate.

12 shows the UV plot of buprenopine pivalate.

FIG. 13 shows an IR spectral plot of buprenopine palmitate. FIG.

FIG. 14 shows an IR spectral plot of dibuprenopine pimelate. FIG.

FIG. 15 shows the UV plot of dibuprenopine pimelate.

FIG. 16 shows a ¹ H-NMR spectral plot of dibuprenopine sebacoyl ester. FIG.

FIG. 17 shows the UV plot of dibuprenopine sebacoyl ester.

FIG. 18 shows an IR spectral plot of dibuprenopine sebacoyl ester.

19 depicts the dosing response of buprenopine hydrochloride administered intramuscularly in rats.

20A and 20B show dosing responses of buprenopine base administered intramuscularly and subcutaneously in rats, respectively.

21A-21E illustrate the analgesic effect of the five buprenopine monocarboxyl ester derivatives of the present invention administered intramuscularly in rats, respectively.

FIG. 22 depicts the dosing response of buprenopine propionate administered intramuscularly in rats.

Figures 23a and 23b show the analgesic effect of two dibuprenopine dicarboxyl ester derivatives of the present invention administered intramuscularly in rats, respectively.

The present invention relates to novel buprenopine ester derivatives, in particular buprenopine monocarboxyl ester derivatives and dibuprenopine dicarboxyl ester derivatives, which exhibit a long-term analgesic effect compared to buprenopine hydrochloride. The present invention also relates to a process for the preparation of the novel buprenopine ester derivatives and to persistent analgesic pharmaceutical compositions containing a compound selected from the novel buprenopine ester derivatives and the buprenopine base.

Persistent analgesia is especially required in patients suffering from moderate to severe pain, such as postoperative pain and cancer pain. Currently, local anesthetics, mild analgesics and strong analgesics are used in this field, but they are all fast-acting drugs.

Local anesthetics such as xylocaine or bupivacaine alleviate some types of pain, but they can only be applied to limited areas. In addition, topical anesthetics are fast-acting and usually show an action time of 6 hours or less upon intradural infusion. Thus, local anesthetics are not satisfactory to relieve cardiac surgery, lung surgery, abdominal surgery, orthopedic surgery, obstetric surgery, severe burn injury and severe acute pain caused by terminal cancer.

Mild analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) only relieve pain caused by low-intensity pain, such as headache or toothache, but are not helpful in severe pain.

For high-intensity pain that is widespread in the causative site, strong analgesics such as morphine, meperidine and fentanyl are used. They interact with specific opioid receptors (ie μ receptors) in the central nervous system (CNS) and exhibit strong analgesic action. However, all opioid analgesics present a common disadvantage (Hayes A. G. et al., Br. J. Pharmcol., Vol 79, 731, 1983). The most unfavorable problem associated with the long term use of these strong analgesics is their addiction. In addition, these strong analgesics can cause severe respiratory depression in patients with poor respiratory function. In addition, these strong analgesics exhibit relatively short durations of action, namely 3 to 5 hours of action. Even when administered intraluminally, they do not provide a duration of action that lasts longer than 24 hours. In addition, administration of higher doses of these agents, ie 0.5 to 1.0 mg / dose of morphine, intraluminally to provide a sustained analgesic effect can result in fatal respiratory depression (Baxter, AD, et al. Can. J. Anesth., Vol 36, 503, 1989).

(5α, 7α (S) -17-cyclopropyl-methyl) -α- (1,1-dimethylethyl) -4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy- Buprenopine with the chemical name α-methyl-6,14-ethenomorphin-7-methanol is known as an opioid partial agonist with a strong analgesic effect. Buprenopine (in free base form) having a molecular weight of 467.7 is represented by Formula A:

(A)

(A)

Buprenopine shares many of the opioid agonists such as analgesic. Buprenopine does not exhibit the psychoanxiety and psychopathic effects often seen in agonistic / antagonistic drugs because there is no κ agonism. Other studies suggest that the opioid antagonistic effects of buprenophine can be mediated through interaction with δ opioid receptors.

Like other strong opioid agonists, buprenopine exhibits strong dose-related analgesia. The exact mechanism is not yet fully understood, but the analgesic effect of buprenopine appears to be due to the high affinity for μ opioid receptors in the central nervous system. Buprenophine can also change pain thresholds (thresholds of afferent nerve endings to harmful stimuli). By weight, the analgesic effect of parenteral buprenopine is about 25-50 times that of morphine, about 200 times that of pentazocine, and about 600 times that of meperidine.

Buprenopine provides several patients with several therapeutic advantages when compared to opioid agonists (eg morphine) and mixed action-antagonists (eg pentazosin, butopanol, nalbuphine). For example, unlike mixed action-antagonists, buprenophine has less psychotic-causing effects. When compared to agonists such as morphine and fentanyl, buprenopine has a relatively low risk of respiratory depression.

Buprenopine is less prone to abuse compared to opioid complete agonists. However, buprenophine, although rare, can cause limited physical dependence, and withdrawal of prolonged treatment with buprenopine alone may result in mild withdrawal signals and symptoms. Since dissociation of buprenophine from the μ receptor occurs slowly, the removal of buprenophine from the CNS is delayed after abrupt use ceases. As a result, the signals and symptoms attributable to acute withdrawal of buprenophine are less intense than those caused by morphine and develop later.

Buprenopine, disclosed in U.S. Patent No. 3,433,791 (1968), is under the trade names Buprenex (Morton-Norwich) and Tempesic (Reckitt and Colman). It is commercially available for the treatment of pain caused by trauma due to surgery, cancer, accidents and myocardial infarction. Buprenophine has also been used in the detoxification treatment of heroin poisoning due to the nature of its opioid partial agonists (Bickel, WK et al., Chem. Pharmacol. Ther. (1988), 43 (1): 72-78, and Fudala, PJ et al. Clin. Pharmacol, Ther. (1990), 47 (4): 525-534). Buprenopine has typically been administered by intramuscular injection or intravenous injection, but its action time is only 6-8 hours.

Persistent analgesic effects are particularly desirable for patients suffering from acute or chronic pain. These pains can last from days to months. For example, acute pain, such as post-operative pain, traumatic pain and pain due to burns, can last 4 to 6 days; Chronic pain, such as non-malignant and cancer pain, can last from weeks to months.

In order to control or prolong the time of action of the target drug during clinical use, special pharmaceutical preparation methods have been developed. With respect to buprenopine, buprenopine by itself is not a good example for transdermal delivery of drugs because of its high crystallinity at 218 ° C., its melting point of free base. Hydrochloride salts have been used as a solution with penetration enhancers to achieve sufficient skin penetration of buprenopine for analgesic purposes. For example, US Pat. No. 6,004,969 discloses a method for transdermal delivery of buprenopine, which is a pure ingredient from Chinese herb for buprenopine or its hydrochloride salt, transdermal penetration enhancer, and transdermal. Other excipients required for the preparation.

The prodrug strategy is another possibility. Stinchcomb et al., Pharm. Res. (1995), 12 (10): 1526-1529, wherein 6 buprenopine alkyl ester precursors; And a reaction comprising the reaction of buprenopine free base, acid anhydride and 4-dimethylamino pyridine in the presence of dimethylformamide (DMF) as solvent starting from buprenopine hydrochloride. Its physicochemical properties, including the hexane solubility of the six buprenopine alkyl ester precursors, were compared with the physicochemical properties of buprenopine HCl and buprenopine free base. Stinzcom et al. Also investigated the permeability of buprenopine and its C ₂ -C ₄ alkyl ester precursors through hairless mouse skin and human skin, wherein light mineral oil was used as the vehicle in the test formulation for the permeation experiment. (Hirofumi Imoto et al., Biol. Pharm. Bull. (1996), 19 (2): 236-267); and Stinzcom et al., Pharm. Res. (1996), 13 (10 ): 1519-1523]).

However, no injectable sustained dosage form of buprenopine suitable for treatment has been described so far. In addition, there is still a need for the development of novel buprenopine derivatives that effectively extend the action time of buprenopine in vivo.

Accordingly, an object of the present invention is to provide a novel buprenopine ester derivative having the same activity as buprenophine HCl and having a longer duration of action so that it can be used in the treatment of living subjects, including humans suffering from severe pain. To provide.

In a first aspect, the present invention provides novel buprenopine monocarboxyl ester derivatives of the general formula

Where

R is selected from the group consisting of straight or branched saturated or unsaturated aliphatic groups optionally substituted with aryl groups, and aryl groups optionally substituted with straight or branched saturated or unsaturated aliphatic groups, with R being methyl, ethyl , Propyl, n-butyl, n-pentyl, n-hexyl and isopropyl.

In a second aspect, the present invention provides novel dibuprenopine dicarboxyl ester derivatives of the formula

Where

R ₁ is a divalent residue of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group.

In a third aspect, the present invention provides a process for preparing the novel buprenopine ester derivative described above.

The process for the preparation of the buprenopine monocarboxyl ester derivative of formula 1 comprises the following steps:

(Iii) treating buprenopine HCl or base with trimethylamine in the presence of methylene chloride; And

(Ii) in the mixture from step (iii) in the presence of methylene chloride, the formula RCOOH, wherein R is a straight or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, and a straight or branched saturated Or an aryl group optionally substituted with an unsaturated aliphatic group), or an acid anhydride or acid chloride thereof.

The process for preparing the dibuprenopine dicarboxyl ester derivative of formula (II) comprises the following steps:

(Iii ′) treating buprenopine HCl or base with trimethylamine in the presence of methylene chloride; And

(Ii ') to the mixture from step (iii') in the presence of methylene chloride, of the formula R ₁ (COOH) ₂ , wherein R ₁ is a divalent moiety of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group; Adding the compound, or acid anhydride or acid chloride thereof.

In a fourth aspect, the present invention provides an analgesic pharmaceutical composition comprising a buprenopine monocarboxyl ester derivative of Formula 1 or a dibuprenopine dicarboxyl ester derivative of Formula 2 as described above.

In a fifth aspect, the invention provides a buprenopine base, a buprenopine monocarboxyl ester derivative of formula (1), and a dibuprenopine dicarboxyl ester of formula (2), which exhibit a longer duration of action upon intramuscular or subcutaneous administration. Injectable oil suspending agents containing a compound selected from the derivatives are provided.

These and other features and advantages of the present invention will become apparent from the following detailed description of preferred embodiments with reference to the accompanying drawings.

Parenteral solutions of buprenophine hydrochloride (0.3 mg buprenopine / ml) for intramuscular and intravenous administration are commercially available as Buprenex RTM. (Recket and Coleman). For adults 13 years of age and older, the typical intramuscular or intravenous dose required to relieve pain from normal to severe pain is 0.3 mg every 6 to 8 hours. Pediatric dosages of 2-12 years old are 2-6 μg / kg body weight every 4-6 hours. The average analgesic time after intramuscular or intravenous dosing at 2-4 μg or 0.2-0.3 mg / kg body weight is generally 6 hours.

The pharmacokinetics of buprenophine administered parenterally and sublingually is known. Intravenous administration of a single dosage of about 0.3 mg of buprenophine has been shown to provide an average peak plasma drug concentration of 18 ng / ml within about 2 minutes. After about 5 minutes and 3 hours plasma reduced to about 9 and about 0.4 ng / ml respectively. Three hours after the initial intravenous dose, after a second 0.3 mg dose intramuscularly, an average peak plasma buprenopine concentration of about 3.6 ng / ml within about 2 to 5 minutes and 0.4 ng after about 3 hours Reduced to / ml. After about 10 minutes of administration, the plasma concentration of buprenopine was similar to that after intravenous or intramuscular injection. Conventional sublingual analgesic dosages of buprenopine have been previously reported to be 0.2 to 0.4 mg every 8 hours (see, eg, Kuhlman JJ et al., J. Analyt. Toxicol. (1996), 20 (10). ): 369-378). For a sublingual dose of 0.4 mg, C _max is 0.5 ± 0.06 ng / ml; T _max is 210 ± 40 min; Systemic availability was reported to be 57.7 ± 6%.

Buprenopine is metabolized almost completely by the N-dealkylation reaction mainly in the liver to form norbuprenorphine (N-dealkylbuprenophine). Buprenopine and norbuprenopine are also conjugated to glucuronic acid. Like metabolites of other opioid agonists, norbuprenopine may have mild analgesic activity. However, no attempt has been made to determine the analgesic activity of buprenopine metabolites. Buprenopine and its metabolites are excreted mainly through the removal of bile from the feces and also into the urine. Buprenophine is excreted in the most unchanging drug state in feces. Small amounts of norbuprenopine are also excreted in feces. Drugs and their metabolites are known to undergo the enterohepatic circulation. Norbuprenopine is shown to be excreted in the urine at a slower rate than the parent drug. The total plasma clearance of buprenopine is reported to be about 0.28 L / min in conscious patients after surgery. Limited data indicate that in children, the pharmacokinetics of buprenophine vary considerably among individuals. However, children (eg children 5-7 years old) appear to have a faster drug removal than adults. The optimal dosing interval for buprenopine should be narrowed in pediatric patients.

In view of the foregoing, Applicants have endeavored to prolong the action time of buprenopine and have synthesized novel buprenopine ester derivatives which have proven to have the same analgesic action as buprenopine HCl. A pharmaceutical composition comprising a compound selected from the buprenopine base and the novel buprenopine ester derivatives according to the invention has been developed for consistent release. These compositions have been demonstrated to have a sustained analgesic effect of several days with relatively rapid onset of action (within 2 hours).

The esterification of the phenol group on carbon number 3 of the morphine ring (basic structure of morphine, buprenopine, nalbuphine, etc.) allows the esterified derivative to have the following characteristics: (1) lipophilicity is increased; (2) has a low affinity for morphine receptors; (3) side effects are reduced, but the released parent drug retains the same pharmacokinetic activity; And (4) the effects and safety of esterified derivatives and parent compound remain the same (Broekkamp CL et al., J. Pharm. Pharmacol, 1988, 40: 434-7).

The present invention provides novel buprenopine monocarboxyl ester derivatives of Formula 1:

Formula 1

Where

R is selected from the group consisting of straight or branched saturated or unsaturated aliphatic groups optionally substituted with aryl groups, and aryl groups optionally substituted with straight or branched saturated or unsaturated aliphatic groups, with R being methyl, ethyl , Propyl, n-butyl, n-pentyl, n-hexyl and isopropyl.

Preferably, R is an alkyl group optionally substituted with a phenyl group.

Preferably, R is an alkyl group having 2 to 40 carbon atoms, more preferably an alkyl group having 5 to 20 carbon atoms.

Preferably, R is selected from the group consisting of a straight alkyl group optionally substituted with a phenyl group, a branched alkyl group optionally substituted with a phenyl group, a phenyl group optionally substituted with a straight aliphatic group, and a phenyl group optionally substituted with a branched aliphatic group do.

In a preferred embodiment of the invention, R is an alkyl moiety derived from a fatty acid of the formula RCOOH. More preferably, R is an alkyl group optionally substituted with a phenyl group having 2 to 40 carbon atoms (preferably 5 to 20).

Preferred buprenopine monocarboxylic esters according to the invention are prepared from carboxylic acids selected from the group consisting of: and buprenopine: propionic acid, benzoic acid, enanthic acid, n-valeric acid, pivalic acid, decanoic acid; Saturated fatty acids such as lauric acid, palmitoyl acid, stearic acid, arachidic acid and seric acid; And unsaturated fatty acids such as oleic acid, linolenic acid, undecylenic acid and cinnamic acid.

Preferably, the buprenopine monocarboxyl ester derivative according to the invention is selected from buprenopine pivalate, buprenopine benzoate, buprenopine decanoate and buprenopine palmitate.

The present invention also provides novel dibuprenopine dicarboxyl ester derivatives of Formula 2:

Formula 2

Where

R ₁ is a divalent residue of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group.

Preferably, the aliphatic group is selected from straight chain alkyl groups, branched alkyl groups, straight chain alkyl groups substituted with phenyl groups, and branched alkyl groups substituted with phenyl groups. Preferably, the aliphatic group has 1 to 40 carbon atoms, more preferably 1 to 20 carbon atoms.

Preferably, R ₁ is an alkylene group having 1 to 40 carbon atoms (more preferably 3 to 20).

Preferably, the dibuprenopine dicarboxylic ester according to the invention is prepared from buprenopine and aliphatic dicarboxylic acids of C ₅ -C ₂₀ .

Preferably, the dibuprenopine dicarboxyl ester derivative according to the invention is selected from dibuprenopine pimelate and dibuprenopine sebacoyl ester.

Buprenopine base was prepared from its HCl salt. After dissolving a predetermined amount of commercial buprenophine HCl in water and then adding a saturated solution of Na ₂ CO ₃ , the buprenopine base precipitated. The precipitate was then filtered and washed several times with cold deionized water to remove excess Na ₂ CO ₃ . The white residue was then dried overnight in the atmosphere. The dried residue was added to a mixture of water: ethanol (80:20), heated to 60 ° C. to dissolve the free base, and immediately filtered. As cooled, the buprenopine base crystallized. The crystalline product was then filtered and dried with gentle flowing of nitrogen. The purity of the base was checked by melting point and HPLC assay. The melting point of the base was 209 ° C., which was in fact the same as reported in the literature. The purity of the base measured by HPLC assay was 99%.

The buprenopine monocarboxylic ester derivative of formula 1 can be prepared by a process comprising the following steps:

(Iii) treating buprenopine HCl or base with trimethylamine in the presence of methylene chloride; And

(Ii) in the mixture from step (iii) in the presence of methylene chloride, the formula RCOOH, wherein R is a straight or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, and a straight or branched saturated Or an aryl group optionally substituted with an unsaturated aliphatic group), or an acid anhydride or acid chloride thereof.

Preferably, aliphatic carboxylic acids having 1 to 40 carbon atoms (more preferably 5 to 20), or acid anhydrides or acid chlorides thereof, are used in step (ii) above. More preferably, saturated C ₅ -C ₂₀ aliphatic carboxylic acid is used in step (ii) above.

In a preferred embodiment of the invention, heptanoyl chloride is used in step (ii).

In another preferred embodiment of the invention, decanoyl chloride is used in step (ii).

In a further preferred embodiment of the invention, pivaloyl chloride is used in step (ii).

In another further preferred embodiment of the invention, hexadecanoyl chloride is used in step (ii).

In another preferred embodiment of the invention, benzoyl chloride is used in step (ii).

The buprenopine polyester derivative of Formula 2 according to the present invention may be prepared by a process comprising the following steps:

(Iii ′) treating buprenopine HCl or base with trimethylamine in the presence of methylene chloride; And

(Ii ') to the mixture from step (iii') in the presence of methylene chloride, of the formula R ₁ (COOH) ₂ , wherein R ₁ is a divalent moiety of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group; Adding the compound, or acid anhydride or acid chloride thereof.

Preferably, aliphatic dicarboxylic acids having 3 to 40 carbon atoms (more preferably 5 to 20), or acid anhydrides or acid chlorides thereof, are used in step (ii ') above. More preferably, saturated C ₅ -C ₂₀ aliphatic dicarboxylic acid is used in step (ii ′) above.

In a preferred embodiment of the invention, heptanedioatyl chloride is used in step (ii ') above.

In another preferred embodiment of the invention, sebacoylic acid is used in step (ii ').

In order to synthesize the buprenopine ester derivatives represented by the formulas (1) and (2), respectively, buprenopine HCl or a base was dissolved in methylene chloride, and then a solution of trimethylamine in methylene chloride was added. To the mixture was added dropwise a solution of the compound of formula R (COOH) ₂ or R ₁ (COOH) ₂ in methylene chloride.

At the same time as the esterification reaction was completed, the product was purified by passing through a silica gel column to obtain a buprenopine ester derivative represented by the formula (1) or (2).

Alternatively, the buprenopine ester derivatives of the present invention may be prepared by the general process for preparing esters from alcohols or phenols, such as the hydroxy groups of buprenopine with the acid of the compound of formula R (COOH) ₂ or formula R ₁ (COOH) ₂ . It can be obtained by reacting with chlorides, acid anhydrides, esters or sulfonyl chlorides.

Buprenopine ester derivatives synthesized by the methods described above have been characterized by nuclear magnetic resonance (NMR), infrared (IR) and ultraviolet (UV) spectroscopy, gas chromatography / mass spectrometry (GC / MS) and elemental analysis.

Buprenopine ester derivatives can be formulated in different dosage forms as described.

In general, to achieve sustained therapeutic efficacy of a target, a variety of dosage forms can be prepared in which the target drug is esterified or dissolved in an oil vehicle to form a parenteral formulation, and as administered to the body of a human or animal, The release rate of the drug may be reduced due to the effects of several factors, such as the increased solubility of the target drug in the oil. In these cases, the dosing interval of the target drug may be set longer by its duration of action.

Gelders is described in Int. Clin. In Phychophacol (1986), volume 1, page 1, Hinko CN et al., In Neuropharmacology (1998), volume 27, page 475, describe the incorporation of haloperidol decanoate in injectable oils such as sesame oil or soybean oil. The sustained analgesic effect has been reported due to the formulation in a release-controlled dosage form, and to prolong the dosing interval from 1 to 2 times / month to 2 to 4 times / day.

Norman T. R., Int. Clin. Phychopharmacol. (1987), volume 2, pp. 229-305 reported the production of flufenazine decanoate from flufenazine. Hinco et al., Neuropharmacology (1988), volume 27, pp. 475-483 reported the preparation of nipectic acid esters. Broekkamp is described in J. Pharm. Pharmacol. (1998), volume 40, pp. 434-437 reported the preparation of nicotinoyl morphine esters from morphine. Josh, J. V. et al., Steroids (1989), volume 53, pp. 751-761 reported the preparation of precursors of nortisterone enenthate, which can be established by extending the dosing interval up to two months.

However, due to unknown factors present in nature, rapid release of the target drug from the oil vehicle can sometimes result. For example, when testosterone suspensions are administered intramuscularly, testosterone is known to release rapidly (Cak. Pharm. Bull. (1974), vol. 22, pp. 1275 by Takana, T.). -1284]). Titulaer (H.A.C.) reported the addition of atemisinin to parenteral oils for preparation in various dosage forms for intramuscular, intravenous, oral or rectal administration. However, the drug was rapidly released from this dosage form (J. Pharm. Pharmacol. (1990), vol. 42, pp. 810-813). Zuidema, Z. et al., International J. of Pharmaceutics (1994), Vol. 105, pp. 189-207] reported very irregular and varied release rates and dosages for dosage forms for parenteral administration.

According to the above-mentioned studies, dosage forms containing a pharmaceutical composition suspended or dissolved in an oil vehicle do not appear to significantly prolong the duration of the therapeutic effect. In general, in attempts to add a target drug into an oil vehicle for the purpose of obtaining a sustained dosage form, it is necessary to take into account the physical solubility, stability, and release rate of the target drug from the vehicle.

As mentioned above, in order to achieve the purpose of prolonging the action time of buprenopine, the present applicant, as described above in the present application, uses the buprenopine base, the buprenopine monocarboxylic ester derivative of formula (1) and the formula An analgesic pharmaceutical preparation is provided which contains an injectable oil containing a compound selected from the dibuprenopine dicarboxyl ester derivative of 2 in admixture with an injectable oil and optionally a pharmaceutically acceptable excipient. In this preparation, the compounds contained therein have longer action times to alleviate pain.

Examples of injectable oils suitable for use in the present invention that serve as vehicles of injectable preparations include sesame oil, soybean oil, castor oil, cottonseed oil, peanut oil or ethyl esters of peanut oil, or combinations thereof. Injectable oil preparations may be administered intramuscularly or subcutaneously.

The present invention also provides a process for the preparation of the novel buprenopine ester derivatives and the sustained dosage forms of the buprenopine base according to the present invention, wherein the buprenopine base, or the buprenopine ester of Formula 1 or Formula 2 described above Derivatives may be mixed with injectable oil vehicles and optionally formed into controlled release dosage forms with the addition of pharmaceutically acceptable excipients conventionally used in the manufacture of pharmaceuticals.

According to the invention, pharmaceutically acceptable excipients are selected from benzyl alcohol or chlorobutanol, or combinations thereof, if present.

Sustained parenteral dosage forms of the invention may be administered only once every few days. Even when the sustained parenteral dosage forms of the present invention are administered in higher amounts, the occurrence of undesirable effects is minimized.

As mentioned above, the advantages of the pharmaceutical compositions of the present invention are in the prolongation of the action time, the rapid onset of action (within 2 hours), and the safety of achieving a qualitative improvement of the treatment. The pharmaceutical composition of the present invention may be set at intervals of several days instead of 6 to 8 hours for patients suffering from pain.

Example

The following examples are presented for illustrative purposes only and are not intended to limit the scope of the invention.

Table 1 below shows the chemical structures of the preferred buprenopine ester derivatives according to the invention:

Bup: Buprenopine

The buprenopine ester derivatives listed in Table 1 may be synthesized by known suitable methods, such as those disclosed in US Pat. Nos. 5,750,534 and 6,225,321.

Synthesis Example 1 Preparation of Buprenopine Enanthate

75 ml of methylene chloride (Mallinckrodt, Baker, USA) and 0.01 mole of buprenopine HCl or base were added to a 250 ml round bottom flask placed in an ice bath for cooling. The mixture was stirred and gradually added 20 ml of methylene chloride containing 0.03 mole of trimethylamine (Sigma, Missouri, USA). Simultaneously with rapid stirring, 20 ml of methylene chloride containing 0.011 mole of heptanoyl chloride (Aldrich, Milkyway, USA) was added dropwise. The mixture was then stirred at rt for 1 h. 20 ml of 10% sodium carbonate solution was then added to neutralize the residual acid and remove water soluble impurities. Sodium sulfate was used to remove water from the solution. After drying in vacuo, the title compound, ie buprenopine enanthate, was obtained. The product was purified by column chromatography.

The resulting title compound was identified by FIGS. 1, 2, 3 and 4 showing the ¹ H-NMR spectral plot, mass spectrometry plot, UV plot, and IR plot, respectively, of the title compound.

Detected characteristics of the title compound:

Representative ¹ H-NMR (400 MHz, CDCl ₃ ): 6.71 (d, 1H, J = 8.1 Hz), 6.52 (d, 1H, J = 8.0 Hz), 5.83 (s, 1H), 4.35 (s, 1H), 3.40 (s, 3H), 2.99-2.80 (m, 3H), 2.59-2.43 (m, 3H), 2.28-1.59 (m, 11H), 1.35-0.41 (m, 33H).

Representative mass segments (amu): 580, 564, 523, 490, 478, 464, 378, 113, 84, 55 (detected using a GC-MS spectrometer (spectrum RXI, Perkin Elmer, UK)) .

Representative IR absorption (cm ⁻¹ ): 3441.2, 3076.6, 2929.9, 1763.2, 1610.8 (detected using FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Synthesis Example 2 Preparation of Buprenopine Decanoate

The title compound was prepared according to the procedure described in Synthesis Example 1 above, except that 0.011 mole of decanoyl chloride (Fluka, Buch, Switzerland) was used instead of heptanoyl chloride. Pure buprenophine decanoate was obtained (see FIGS. 5, 6, 7 and 8 showing ¹ H-NMR spectral plot, mass spectrometry plot, UV plot, and IR plot, respectively, of the title compound).

Detected characteristics of the title compound:

Representative ¹ H-NMR (400 MHz, CDCl ₃ ): 6.76 (d, 1H, J = 8.0 Hz), 6.58 (d, 1H, J = 8.1 Hz), 5.91 (s, 1H), 4.41 (s, 1H), 3.45 (s, 3H), 3.00 (m, 2H), 2.87 (m, 1H), 2.50 (t, 2H, J = 7.4 Hz), 2.33-2.10 (m, 5H), 2.00-1.78 (m, 4H) , 1.72-1.66 (m, 4H), 1.37-1.25 (m, 18H), 1.04 (m, 11H), 0.87 (t, 3H, J = 6.6 Hz), 0.80 (m, 1H), 0.69 (m, 1H ), 0.48 (m, 2H), 0.11 (m, 2H).

Representative mass segments (amu): 622, 607, 565, 533, 521, 507, 380, 55 (detected using a GC-MS spectrometer (spectrum RXI, Perkin Elmer, UK)).

Representative IR absorption (cm ⁻¹ ): 3448.0, 3076.4, 2927.1, 1763.8, 1610.7 (detected using an FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Synthesis Example 3 Preparation of Buprenopine Pivalate

75 ml of methylene chloride and 0.01 mol of buprenopine HCl or base were injected into a 250 ml round bottom flask in an ice bath. 0.011 mole of pivaloyl chloride (Acros, NJ) dissolved in 20 ml of methylene chloride was gradually added to the flask under stirring. According to the procedure described in Synthesis Example 1 above, pure buprenopine pivalate was obtained (see FIGS. 9, 10 and 11 showing the mass spectrometry plot, UV plot, and IR plot of the title compound, respectively).

Detected characteristics of the title compound:

Representative mass segments (amu): 552, 537, 519, 495, 463, 451, 436, 84, 57 (detected using a GC-MS spectrometer (spectrum RXI, Perkin Elmer, UK)).

Representative IR absorption (cm ⁻¹ ): 3439.2, 3077.1, 2976.6, 1753.0, 1610.2 (detected using FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Synthesis Example 4 Preparation of Buprenopine Palmitate

The title compound was prepared according to the procedure described in Synthesis Example 1 above, except that 0.011 mole of hexadecanoyl chloride (Aldrich, Milkyway, USA) was used instead of heptanoyl chloride. Pure buprenophine palmitate was obtained (see FIGS. 12 and 13 showing the UV and IR diagrams of the title compound, respectively).

Detected characteristics of the title compound:

Representative IR absorption (cm ⁻¹ ): 3447.0, 3076.9, 2924.0, 1763.3, 1610.9 (detected using an FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Synthesis Example 5 Preparation of Dibuprenopine Pimelate

The title compound was prepared according to the procedure described in Synthesis Example 1 above, except that 0.006 mole of heptanedioatyl chloride (Aldrich, Milkyway, USA) was used instead of heptanoyl chloride. Pure dibuprenopine pimelate was obtained (see FIGS. 14 and 15, showing the UV and IR diagrams of the title compound, respectively).

Detected characteristics of the title compound:

Representative IR absorption (cm ⁻¹ ): 3435.0, 3077.0, 2953.0, 1760.8, 1611.0 (detected using FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Synthesis Example 6 Preparation of Dibuprenopine Sebacoyl Ester

The title compound was prepared according to the procedure described in Synthesis Example 1 above, except that 0.006 mole of sebacoyl chloride (Fluka, Buchs, Switzerland) was used instead of heptanoyl chloride. Pure dibuprenopine sebacoyl ester was obtained (see Figures 16, 17 and 18 showing the ¹ H-NMR spectral plot, UV plot and IR plot, respectively, of the title compound).

Detected characteristics of the title compound:

Representative ¹ H-NMR (400 MHz, CDCl ₃ ): 6.75 (d, 2H, J = 8.0 Hz), 6.57 (d, 2H, J = 8.0 Hz), 5.90 (s, 2H), 4.40 (s, 2H), 3.44 (s, 6H), 2.99 (m, 4H), 2.87 (m, 2H), 2.59 (m, 2H), 2.50 (t, 4H, J = 7.6 Hz), 2.32-2.23 (m, 8H), 2.10 (m, 2H), 2.00-1.66 (m, 16H), 1.36-1.26 (m, 18H), 1.05-1.01 (m, 22H), 0.80 (m, 2H), 0.69 (m, 2H), 0.47 (m , 4H), 0.10 (m, 4H).

Representative IR absorption (cm ⁻¹ ): 3453.3, 3077.2, 2931.9, 1760.0, 1611.3 (detected using an FT-IR spectrometer (spectrum RXI, Perkin Elmer, UK)).

In addition, the physical properties of the title compounds are shown in Table 2 below.

Physical Properties of Buprenopine HCl, Bases, and Ester Derivatives thereof compound Molecular Weight Molecular formula Melting point (℃) Ester Bond IR (cm ^-1 ) Buprenopine HCl 504.11 C ₂₉ H ₄₁ NO ₄ · HCl 279 to 281 - Buprenopine Base 467.65 C ₂₉ H ₄₁ NO ₄ 208 to 210 - Buprenopine Propionate 523.72 C ₃₂ H ₄₅ NO ₅ 133 to 135 1765.6 Buprenopine Pivalate 551.77 C ₃₄ H ₄₉ NO ₅ 141 to 143 1753.0 Buprenopine Benzoate 571.76 C ₃₆ H ₄₅ NO ₅ 168 to 170 1742.1 Buprenopine Enanthate 579.83 C ₃₆ H ₅₃ NO ₅ 84 to 86 1763.2 Buprenopine Decanoate 621.91 C ₃₉ H ₅₉ NO ₅ 87 to 89 1763.8 Buprenopine Palmitate 706.07 C ₄₅ H ₇₁ NO ₅ <0 1763.3 Dibuprenopine pimelate 1059.45 C ₆₅ H ₉₀ N ₂ O ₁₀ 103 to 105 1760.8 Dibuprenopine sebacoyl ester 1101.53 C ₆₈ H ₉₆ N ₂ O ₁₀ 89 to 90 1760.0

Ultraviolet spectra of each compound were detected using FT-IR spectroscopy (spectrum RXI, Perkin Elmer, UK).

Preparation Example 1 Preparation of Injectable Oil Formulations Containing Buprenopine Base or Buprenopine Ester Derivatives of the Invention

(1) 10 micromoles of buprenopine base was added to 1 ml of sesame oil. The mixture was shaken gently to dissolve completely.

(2) 20 micromoles of buprenopine propionate was added to 1 ml of sesame oil. The mixture was shaken gently to dissolve completely.

(3) 20 micromoles of buprenopine decanoate was added to 1 ml of sesame oil. The mixture was shaken gently to dissolve completely.

(4) 20 micromoles of buprenopine pimelate was added to 1 ml of sesame oil. The mixture was shaken gently to dissolve completely.

(5) 20 micromoles of buprenopine ester or polyester was added to 1 ml of peanut oil or soybean oil ethyl ester. The mixture was shaken gently to dissolve completely.

Pharmacological Example 1

In vivo analgesic efficacy of buprenopine hydrochloride via intramuscular injection (dose-result study)

(1) Animals: Male Sprague-Dawley rats (175-225 g, 6 weeks old), n = 6 in each group.

(2) Drug: 0.9% buprenopine hydrochloride solution in saline, 0.02 micromol / kg (= 0.01 mg / kg), 0.06 micromol / kg (= 0.03 mg / kg), 0.18 micromol / kg (= 0.09 Mg / kg), 0.6 micromol / kg (= 0.3 mg / kg), intramuscularly injected into the right hind leg of the test rat.

(3) Test: Plantar test using apparatus (7370, UGO, Basile, Italy).

Sole testing allows the investigator to identify peripheral mediated responses to thermal stimuli caused by drugs in untreated rats. It basically consists of a movable I.R (ultraviolet) generator placed under the glass plate on which the operator places the rat. Perspex enclosures define the maximum space in which an animal is not restrained. It is divided into three compartments, which help the operator to quickly perform the "screening" task: up to three rats can be tested without delay.

The operator is an I.R. Place the generator just under the rear foot of the rat and press the I.R. Turn on both the source and response time counters. If the rat feels pain and shrugs, I.R. The generator automatically switches off, the timer stops, and the withdrawal latency is determined.

For detailed foot tests, see Hargreaves et al., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia", Pain 32: 77-88, 1988, and Hargreaves et al., "Peripheral Action". of Opiates in the Blockade of Carrageenan-Induced Inflammation ", Pain Research and Clinical Management , Vol. 3. Elsevier Science Publishers, Amsterdam: 55-60, 1988.

The incubation period from the time of stimulation (radiation fever) to the movement of the foot (left hind leg) was designated as the response incubation time. Radiant heat was set to provide a predrug latency of 7-9 seconds. In order to prevent tissue damage, a blocking time of 25 seconds was set.

(4) Statistics: Data are presented as averages. "*" Means P <0.05 when compared to preliminary test values using ANOVA and Dunnett tests. Anova is often a variance analysis (abbreviated as ANOVA) and is a very strong statistical technique that can be used to isolate and measure the different causes of variance. The Dunnett test is a comparison of the averages of the follow-up to Anova. This test allows all possible comparisons between groups. P means probability, where P <0.05 means very different in statistics.

(5) Results: Different dosages of buprenophine HCl showed analgesic action time of 3 to 5 hours (see Table 3 and FIG. 19).

Pharmacological Example 2

In vivo dosing-result study of buprenopine base via intramuscular injection or subcutaneous injection

(1) Animals: Male Sprague-Dully Rat (175-225 g) (n = 6)

(2) drug: buprenopine base in sesame oil, 0.6 micromol / kg, 6 micromol / kg, 60 micromol / kg; Intramuscular injection into the right hind leg of the test rat.

(3) Test: Sole test (see pharmacological example 1 described above).

(4) Statistics: Two and four tests following the Anova test. Data is shown as "average value".

(5) Results: Different doses of buprenophine base showed analgesic action time of 48-50 hours (see Table 3 and FIG. 20A).

Likewise, different dosages of buprenopine base via subcutaneous injection showed a time of action of 48-50 hours (see Table 3 and FIG. 20B).

Pharmacological Example 3

In vivo analgesic efficacy of the 5 buprenopine monocarboxyl ester derivatives of Formula 1 via intramuscular injection.

(1) Animals: Male Sprague-Dullley rats (175-225 g), n = 6 in each group.

(2) Drug: Buprenopine propionate 0.6 micromole / kg, buprenopine pivalate 0.6 micromole / kg, buprenopine enanthate 0.6 micromole / kg, buprenopine decanoate 0.6 micromole / kg And buprenopine palmitate 0.6 micromol / kg. All these ester derivatives are dissolved in sesame oil as an oil solution and injected intramuscularly in the right hind leg.

(3) Test: Sole test (see pharmacological example 1 described above).

(4) Statistic: The dunova test followed by the Anova test (see pharmacological example 1 described above).

(5) Results: Intramuscular injection of the five buprenopine monocarboxyl ester derivatives of the present invention tested at a dosage of 0.6 micromol / kg showed an action time of 48 to 96 hours and a rapid onset of action. In particular both buprenopine decanoate and palmitate provided 96 hours of action (see Table 3 and FIGS. 21A-21E).

Pharmacological Example 4

In Vivo Dose-result Study of Buprenopine Propionate Via Intramuscular Injection

(1) Animals: Male Sprague-Dullley rats (175-225 g), n = 6 in each group.

(2) drug: buprenopine propionate (oil solution), dosage: 0.6 micromol / kg, 6 micromol / kg, 60 micromol / kg; Inject intramuscularly into the right hind limb of the rat.

(3) Test: Sole test (see pharmacological example 1 described above).

(4) Statistic: The dunova test followed by the Anova test (see pharmacological example 1 described above).

(5) Results: Different dosages of buprenopine propionate via intramuscular injection showed an action time of 48 to 60 hours (see Table 3 and FIG. 22).

Pharmacological Example 5

In vivo analgesic efficacy of two dibuprenopine dacarboxyl ester derivatives of formula 2 via intramuscular injection

(1) Animals: Male Sprague-Dullley rats (175-225 g), n = 6 in each group.

(2) drug: dibuprenopine pimelate, dibuprenopine sebacoyl ester, dosage; Inject intramuscularly to the right hind leg of 0.3 micromol / kg (oil solution in sesame oil).

(3) Test: Sole test (see pharmacological example 1 described above).

(4) Statistic: The dunova test followed by the Anova test (see pharmacological example 1 described above).

(5) Results: Intramuscular injection of both dibuprenopine pimelate and sebacoyl ester at a dosage of 0.3 micromol / kg resulted in an action time of 72 to 96 hours and a rapid onset of action (2 hours). (See Table 3 and Figures 23A and 23B).

Table 3 below summarizes the analgesic action times of buprenopine and its derivatives in the rats used in the plantar test.

Analgesic Action Time of Buprenopine and Its Derivatives in Rats Used in Sole Testing compound Dosage (micromoles / kg) Route of administration Pain Relief Period (hours) Buprenopine HCl 0.6 IM 5 Buprenopine Base 0.6; 6; 60 IM 48; 48; 50 Buprenopine Base 0.6; 6; 60 SC 48; 50; 48 Buprenopine Propionate 0.6; 6; 60 IM 48; 54; 54 Buprenopine Pivalate 0.6 IM 48 Buprenopine Benzoate 0.6 IM 72 Buprenopine Enanthate 0.6 IM 72 Buprenopine Decanoate 0.6 IM 96 Buprenopine Palmitate 0.6 IM 96 Dibuprenopine pimelate 0.3 IM 72 Dibuprenopine sebacoyl ester 0.3 IM 96

IM: intramuscular, SC: subcutaneous

Although the present invention has been described in connection with what is considered to be the most practical and preferred embodiment, it is not intended to limit the invention to the disclosed embodiments, but to cover various changes that are included within the spirit and scope of the broad interpretation of the disclosed embodiments. It is understood that all such changes and equivalent changes are included.

Buprenopine or dibuprenopine and derivatives thereof according to the present invention exhibit fast onset of action and long analgesic action time in vivo.

Claims (51)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete Dibuprenopine dicarboxyl ester derivative of formula Formula 2

Where R ₁ is an alkylene group having 1 to 40 carbon atoms, optionally substituted with a phenyl group. delete 36. The method of claim 35 wherein Dibuprenopine dicarboxyl ester derivative whose R <_1> is a C1-C20 alkylene group. 36. The method of claim 35 wherein Dibuprenopine dicarboxyl ester derivatives which are dibuprenopine pimelate or dibuprenopine sebacoyl ester. (a) a therapeutically effective amount of the dibuprenopine dicarboxyl ester derivative according to any one of claims 35, 37 and 38; And (b) comprising a pharmaceutically acceptable oil carrier, Analgesic pharmaceutical composition. The method of claim 39, An analgesic pharmaceutical composition wherein the carrier is sesame oil, castor oil, cottonseed oil, soybean oil, peanut oil, or an ethyl ester of peanut oil, or a combination thereof. delete delete delete delete delete delete delete delete A method for preparing a dibuprenopine dicarboxyl ester derivative of formula 35 according to claim 35, (Iii ′) treating buprenopine HCl or base with trimethylamine in the presence of methylene chloride; And (Ii ') A compound of the formula R ₁ (COOH) ₂ in the mixture from step (iii') in the presence of methylene chloride, wherein R ₁ is an alkylene group having 1 to 40 carbon atoms, optionally substituted with a phenyl group. ), Or an acid anhydride or acid chloride thereof. The method of claim 49, The compound of formula R ₁ (COOH) ₂ used in step (ii ′) is an aliphatic dicarboxylic acid having 3 to 40 carbon atoms, or an acid anhydride or acid chloride thereof. The method of claim 49, Process using heptanedioatyl chloride or sebacoylic acid in step (ii ').

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