TWI226830B - Novel ester derivatives of buprenorphine and their preparation processes, and long acting analgesic pharmaceutical compositions - Google Patents

Abstract

Disclosed herein are novel buprenorphine monocarboxylic ester derivatives and dibuprenorphine dicarboxylic ester derivatives which exert a longer analgesic effect as compared to buprenorphine hydrochloride. Also disclosed are the processes for synthesizing the novel ester derivatives of buprenorphine, and long-acting analgesic pharmaceutical compositions containing a compound selected from buprenorphine base and the novel ester derivatives of buprenorphine.

Description

1226830 发明 Description of the invention (The description of the invention should be stated. [Technical field, prior art, content, implementation, and drawings of the invention field month] Brief description of the technical field] & The month is related to the novel Bupino Buprenorphine ester derivatives are particularly concerned about bupinophene monocarboxylic acid ester derivatives and dibubinofen dioxobinate. Compared to bupinofen hydrochloride, these derivatives show more Long analgesic effect. The present invention also relates to a method for preparing the novel bupinofen ester derivatives, and a long-acting analgesic medicament containing a compound selected from the group of bupinofen test and a novel bupinofen g derivative.组合 物。 Composition. y L · mT ^ Description of related techniques, prolonged analgesia (pr0nged analgesia) is especially necessary for patients suffering from moderate to severe pain (such as postoperative pain and cancer pain). Currently, a 'local anesthetic, weak analgesic, and potent analgesic are used in this technical field, but they are all short-acting drugs. Local anesthetics, such as Xylocaine or bupivacaine, can relieve some forms of pain, but they can only be applied to restricted areas. In addition, local anesthetics are short-acting, and even when introduced by intrathecally, they exhibit a period of action that typically does not exceed 6 hours. Therefore, for acute and severe pain caused by heart, lung, abdomen, orthopedic and obstetric surgery, as well as severe burn injury and end-stage cancer, local anesthetics are not satisfactory for 1,268,30, and the description of the invention is satisfactory. · ~ Weak analgesics' such as acetaminophen and non-steroidal anti-inflammatory agents (NSAID) can only relieve low-level pain (such as pain due to headache or toothache), but they are effective for severe pain Words are useless. 10 15 For pain that is of high intensity and wide range in origin, such as morphine, mepiprene, meperidine, and fentanyl (Luzhou's powerful analgesics) are used. Specific opioid receptors (also known as #receptors) in the central nervous system (cns) interact and exhibit potent analgesic activity. However, all opioid analgesics exhibit common shortcomings {Hayes} AG et al.} Br. J. Pharmacol, Vol 79, 731, 1983) 〇The most undesired problem associated with the long-term use of these powerful analgesics is the occurrence of medicinal tincture. In addition, these powerful analgesics can cause severe respiratory depression in patients with poor beer suction. Furthermore, these potent analgesics exhibit a rather short period of action (i.e. 3 i 5 hours). Even when administered by intravertebral injection, they cannot provide a long-acting period that lasts for more than ^ small ^. In addition, if a higher dose of this agent = for example: morphine in a mother dose of 0.5 [0] 0 mg) is injected into the spinal canal with prolonged analgesic effect of morphine and levitation, fatal breathing It may happen (fine "— j · such as yell% milk 1989) 〇,, buprenorphine [chemical name is" Μ⑻ · ^ 7-cyclopropyl earth methyl] a- (l, i- : f-ethylethylM, 5 • epoxy ..., ⑼dichloro ^ meryl-6-methoxymethoxide-, vinyl bridge morphinane-7-rolol (5a, 7a (6 > l7-20 1226830 发明, Description of invention WK, et al., Chem. Pharmacol. Ther. (1988), 43 '(0-72-78; and Fudala, PJ ^ et al ^ CHn pharmac〇l Ther People 47 «) · 525- 5W). Buprenorphine is usually administered by intramuscular injection 5 or intravenous injection, but the period of action is only 6 to 8 hours. 5-long-acting analgesic effect is especially for patients suffering from acute or chronic pain ^ Necessary. These pains can last from several days to several months. For example, "heart pain, such as post-operative pain, trauma pain and burn pain," may last 4 to 6 days; chronic pain, such as non- Sexual pain and cancer pain may last from several weeks to several months. 10 Controlled or prolonged-target drugs have been used in clinical use during the period of 'specific pharmaceutical products have been developed. Regarding bupinofen, ^ The high degree of crystallinity reflected by its freely-dissolved melting point (218.00), bupinofin itself is unlikely to be a good candidate for transdermal drug delivery. Hydrochloride salts plus-penetration promotion The use of the agent has been provided as a 15 solution to obtain sufficient skin penetration of bupinophene to achieve pain in the bell "U.S.A., 004,969 discloses bupinophene-a transdermal delivery product ' Consisting of: Bupinofen or its hydrochloride, a pure component derived from Chinese herbal medicines as a percutaneous penetration enhancer, and other excipients required for leather products', ^ WJ1I1 〇 and other human corpses — "Lujusuke reports that six picoester prodrugs of bupicoxine 'have been synthesized starting from bupinofen hydrochloride, which involves the free test of bupinofen,-Zuanxuan and 4 -Dimethylamino 20 1226830 玖, description of the invention

° The reaction of 4-dimethylamino pyridine in the presence of dimethyl formamide (DMF) as a solvent. The physico-chemical properties of the six burner ester precursors of bupinofen, including the solubility of hexane, are compared with those of bupinofen HC1 and bupinofen free base. Stinchcomb et al. Further studied the penetrability of bupinofen and its C2-C4 alkyl ester precursors through hairless mouse skin and human skin, in which light mineral oil was used as a test for penetration experiments Formulated at noon (Hirofumi Imoto et al., Biol. Pharm. Bull. (1996), 19 (2): 263-267; and Stinchcomb et al., Pharm. 10 Res. (1996), 13 (10 ): 1519-1523. However, to date, no injectable long-acting dosage form of bupinofin suitable for therapeutic use has been described. In addition, it is still hoped that new derivatives of bupinofen will be developed It can effectively extend the period of action of bupinofen in vivo.

15 t Summary of the invention U Summary of the invention Therefore, it is an object of the present invention to provide a novel derivative of bupinofin having the same activity as that of bupinofen HC1 and a function longer than that of bupinofen HC1 In the meantime, the derivatives can be used to treat 20 living individuals, including humans, suffering from severe pain. In a first aspect, the present invention provides a novel bupprenorphine monobranched acid ester derivative having the following chemical formula (I): 10 1226830 玖, description of the invention

Where R is selected from the group consisting of a linear or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, and a linear or branched Branched saturated or unsaturated aliphatic groups substituted with aryl groups; provided that: R is not selected from methyl, ethyl, propyl, η-butyl, η-pentyl, η -Hexyl and isopropyl. 10

In a second aspect, the present invention provides a novel dibuprenorphine dicarboxylic acid derivative having the following chemical formula (Π):

11 1226830 发明, description of the invention where Ri is a divalent moiety composed of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group. In a third aspect, the present invention provides a method for preparing the novel bupinofen ester derivative described above. 5 The method for preparing the bupinofen monocarboxylic acid ester derivative having the formula (I) includes the following steps: (1) treating the bupinofen HC1 with trimethylamine in the presence of digas methane or Base; and (11) in the presence of dichloromethane, to the mixture 10 obtained from step XI, a compound of the formula RCOOH or its acid anhydride or acid chloride is added, wherein R in the chemical formula RC00H is selected from the group consisting of a linear or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, and an optional 15 An aryl group that is sexually substituted with a straight or branched saturated or unsaturated aliphatic group. · The method for preparing the dibupinenol dicarboxylic acid derivative having the chemical formula (Π) comprises the following steps: (Γ) treating bupinofen 20 with triamidine in the presence of dichloromethane HC1 or a base; and (ii ') in the presence of dichloromethane, the mixture obtained from step XI is added with a compound of the formula + Ri (C00H) 2 or its acid anhydride or hydrazone Acid chloride, of which the chemical formula Ri (C00H) 2 is a hydrazone substituted by a 12-1226830 玖, invention description is substituted by a phenyl group, and a saturated aliphatic group. The bivalent part of the composition. In a fourth aspect, the present invention provides a pharmaceutical composition for analgesics, which comprises the above-mentioned bupinofen monophosphate acid compound of the formula ⑴ or-dibupino compound of the formula 如上所述Fennic acid vinegar derivative. In a fifth aspect, the present invention provides an injectable oil suspension containing-a compound selected from the group consisting of a bupinofen test, a chemical formula (I) Bupinofen monoacetic acid derivative and a 10-Bupinophene disulfide derivative having the chemical formula ⑻, and the composition exhibits a longer period of action when administered intramuscularly 4 subcutaneously. The drawings briefly explain the other features and advantages of this month. From the details of the following preferred embodiments, the drawings attached to the Asian tea photos will become obvious after inspection. In the drawings: 15 1H-NMR spectrum of buprenorphine enanthate; Ludi 2 shows the mass spectrum of 7F bupinofen enanthate; Figure 3 shows the UV spectrum of bupinofen enanthate; Figure 4 shows the IR spectrum of bupinofen enanthate; 2 Figure 5 shows the 1H-NMR spectrum of bupnorphine decanoate; Figure 6 shows bupinofen decanoate The mass spectrum of the ester; Figure 7 shows the UV spectrum of the bupinofen caprate; Figure 8 shows the IR spectrum of the bupinofen caprate; 13 1226830 5 The people of Shangmu worked to extend the period of bupinofen, and made a new bupinofen vinegar derivative, which has been proven to be similar to the bupinofen hydrochloride. Has analgesic activity. Sustained-release pharmaceutical compositions comprising a compound far from the bupinofen assay and the new raisin bupinofen vinegar derivative according to the present invention have been further developed. These compositions have been shown to exhibit long-lasting analgesic effects over a period of several days and have a fairly rapid onset of effect (within 2 hours). · The vinegarization of the age group (_η〇ι gr〇up) on the carbon atom 3 of the morphine test ring (the basic structure of morphine test, bupkin, nalbufin and the like) will cause vinegar The derivatized derivatives have the following characteristics: (1) increased vinegar affinity (nP0Philicity) '· (7) low affinity for morphine receptors; (2) side effects are reduced, but the released parent drug maintains the same pharmacological activity; And ⑷ The effect and safety of the vinegarized derivative and the parent compound are the same as those of the parent compound b iBroekkamp CL et al., J. Pharm, Pharm ^ 1988, Valence 屮. The present invention provides novel bupinofen monochimic acid «S purpose derivatives having the following chemical formula:

(I) 17 1226830 发明, description of the invention wherein R is selected from the group Θ consisting of: a linear or branched saturated or unsaturated aliphatic group optionally substituted with an aryl group, And an aryl group optionally substituted with a straight or branched saturated or unsaturated aliphatic group; 5 provided that: R is not selected from methyl, ethyl, propyl, η · Butyl, η-pentyl, η-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, and more preferably, R is an alkyl group having 5 to 20 carbon atoms. Preferably, R is selected from the group consisting of a linear alkyl group optionally substituted with a phenyl group, and a branch optionally substituted with a phenyl group Alkyl group, a phenyl group optionally substituted with a linear aliphatic group, and a phenyl group optionally substituted with a 15 branched aliphatic group.

In a preferred embodiment of the present invention, R is an alkyl moiety derived from a fatty acid having a chemical formula RCOOH. More preferably, R represents an alkyl group optionally substituted with a phenyl group and having 2 to 40 (preferably 5 to 20) carbon atoms. 20 The preferred bupinofen monocarboxylate derivative according to the present invention is prepared from bupinofen and a carboxylic acid selected from the group consisting of: propionic acid, benzene Formic acid (benzoic acid), enanthic acid, n-valeric acid, pivalic acid, decanoic acid; saturated fatty acids such as lauric acid 18 1226830 发明, invention Lauric acid, palmitoyl acid, stericic acid, arachidic acid, and cerotic acid; and unsaturated fatty acids such as oleic acid ), Linolenic acid, linolenic acid—undecylenic acid and cinnamic acid 5. Preferably, the bupinofen monocarboxylic acid derivative according to the present invention is selected From the following: Bupinofen pivalate, Bupinofen benzoate, Bupinofen decanoate, and Bupinofen palmitate. The present invention also provides a dibupinenol dicarboxylic acid 10 ester derivative having the following chemical formula (Π):

Where I is a divalent moiety composed of a saturated or unsaturated aliphatic group optionally substituted with a phenyl group. Preferably, the aliphatic group is selected from the group consisting of a linear alkyl group 15, a branched alkyl group, a linear alkyl group substituted with a phenyl group 19 1226830 发明, invention Explanation (ii) In the presence of dichloromethane, a compound of the formula RCOOH or an acid anhydride or an acid chloride thereof is added to the mixed poplar obtained from step ⑴ in the presence of dichloromethane, wherein the chemical formula RCOOH Where R is selected from the group consisting of 5: a directly substituted by an aryl group

Chained or branched saturated or unsaturated aliphatic groups, and an aryl group optionally substituted with a straight or branched saturated or unsaturated aliphatic group. Preferably, an aliphatic carboxylic acid having 1 to 40 (preferably 5 to 20) carbon atoms 10 or its anhydride or monomethyl chloride is used in the above step (ii). More preferably, a saturated C5-C2G aliphatic carboxylic acid is used in the above step (ii). In a preferred embodiment of the present invention, heptanoyl chloride is used in the above step (ii). in.

15 In another preferred embodiment of the present invention, decanoyl chloride is used in the step (ii). In another preferred embodiment of the present invention, pivaloyl chloride is used in step (ii). In yet another preferred embodiment of the present invention, hexadecanoyl chloride 20 is used in the step (ii). In yet another preferred embodiment of the present invention, benzoyl chloride is used in the step (ii). The buprenorphine dicarboxylic acid ester derivative having the chemical formula (Π) according to the present invention can be extended from 2 to 4 times a day to 1 month by 21 2126830 玖, the description of the invention Stretched to 2 times. ΝοΐπίΜϊ T.R. reported in Int. Clin. Psychopharmacol. (1987), Fo / wm 299-305, that fluphenazin decanoate was prepared from fluphenazin. 5 Hinko, C.N. 27,

475-4S3 reports the preparation of an ester of 3-σ | σ niperctic acid. Broekkamp CL. Reported in J. Corpse / zarm. P / zarmaco / (1988), Vol. 40, β each 437, Preparation of nicotinoyl morphine ester from morphine base. Joshi, JV et α / • A precursor product of northisterone enanthate reported in Steroids 10, 53, 75 / -7 (57), which can be set to have a longer dose interval of up to 2 months. However Due to unknown factors existing in nature, rapid release of a target drug from an oil carrier may sometimes occur. For example, testosterone derived from intramuscular administration of 15 teosterone suspension was found

(Tanaka, T., Chem. Pharm. Bull. (1974), Vol. 22, Titulaer, HAC reported that artemisinin was added to parenteral oil to form various dosage forms for intramuscular "Intravenous' oral or rectal administration. However, the drug is released from the dosage form at a rapid rate of 20 (J. Pharm. Pharmacol. (1990), Vol. 42, pp. 810-. Zuidema, Z ··· ^ 乂 ρΥκχγjyicicctitics " 994 into F < 9 / · / 05, household / λ reported that the release rate and extent of dosage forms for parenteral administration are very irregular and variable. According to the aforementioned study 'a Dosage forms containing a pharmaceutical composition that is suspended or dissolved in an oil vehicle 24 1226830 kan, as described in the invention, do not necessarily exhibit _ brother out-a longer period of therapeutic utility, in general, 'any kind of add-target drug Attempts to achieve a long-acting dosage form in an oil carrier require consideration of the physical solubility, stability, and release rate of the drug from the carrier's far standard. 10 15 Based on the above, in order to achieve an extended cloth skin The applicant during the period of Noven's role provided in this case- An analgesic pharmaceutical product containing-an injectable oil, which contains-selected from the group consisting of bupinofen test, _ bupicofen single-derived derivative with the chemical formula 以及, and-having a chemical formula (taken dibuprofen The compound of tartaric acid is mixed with injectable oil, and optionally a pharmaceutically acceptable excipient. This preparation allows the contained compound to have a longer period of action in relieving pain. Injectable oils suitable as a carrier for injection products for use in the present invention include, for example, sesame oil, soybean oil, sesame oil, cottonseed oil, peanut oil or ethyl ester of peanut oil, or a combination thereof. The injectable oil product can be administered via intramuscular and subcutaneous routes. The present invention also provides a long-acting effect for preparing a novel bupinofen ester derivative for use in the bupinofen test and according to the present invention. Method of dosage form in which bupinofen base or a bupinofen ester derivative having the chemical formula ⑴ or (π) as described above is mixed with an oil carrier, optionally added often in the manufacture of pharmaceuticals Be made The pharmaceutically acceptable excipients are used to form a controlled release dosage form (3). According to the present invention, if a pharmaceutically acceptable excipient is present, , Can be selected from benzyl alcohol or chlorobutanol (chlororbutan) 25 20 1226830 玖, description of the invention or a combination of these. The long-acting effect of the present invention is parenteral The dosage form can be administered once for several days. That is, when the long-acting parenteral dosage form of the present invention is administered in a large amount, the occurrence of unwanted effects is minimized. As mentioned above, the advantages of the pharmaceutical composition of this case include an extended period of action, rapid onset of action (within 2 hours), and safety that should improve the quality of treatment. For patients suffering from pain, the pharmaceutical composition of the present case can be set at a dose interval of one day instead of 6.8 hours. Examples: The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. Table 1 below shows the chemical structure of a preferred bupinofen ester derivative according to the present invention. 26 1226830 发明, Description of the invention Table. Bupifen HC1, Bupinowine base and g-derivatives according to the present invention Molecular structure / of Bupi ^ Buprofen propionate

Bup · HC1

Bup molecular structure

BuP ^ Bupi Bupi δ right-separated stearic acid ester 0 --- BuP, cA | ^ | W owe β- Right split enanthate 0-Bupi δ-separated decanoate purpose BUP, 〇bubuyou Separate palmitate-/----- Pinolol pimemelate--right from ------ BuP ^ 〇Av ^ N ^^ A〇 / Bup 1min 5 Ester

Gaipu direct brake flutes, such as those disclosed in Wu a patent No. 75,534 and No. 6,225,321. Synthesis Example 1: Preparation of Bupinofen Enanthate Ester 75 ml of digas methane (Mallinckrodt, Baker, USA) and Bupinofen Hci of mol. Place in a 250 liter round bottom flask in an ice bath in the cold section. The mixture was stirred, and 20 ml of dichloromethane containing 0.03 mole of triethylamine (Sigma: MO, ILS.A ·) was slowly added to the mixture. With rapid stirring, another 20 ml of dichloropyrene, each containing 0.00111 mole of heptanoyl chloride (Aldrich Milwaukee, u.S.A.) was added dropwise. After that, 27 10 1226830 玖 was mixed, and the description of the invention was stirred at room temperature for 1 hour. 20 liters of 100 / ❹ sodium carbonate was then added to neutralize residual acid and remove water-soluble impurities. Sodium sulfate was used to dehydrate the solution. After drying under vacuum, the title compound (ie, bupinofen enanthate) was obtained. The product was purified by column chromatography. 5 The generation of the title compound was confirmed by the graphs 1, 2, 3, and 4, which respectively show the W-NMR spectrum, mass spectrum, UV spectrum, and iR spectrum of the title compound.

Measured properties of standard compounds: Representative 1H-NMR (400MHz, CDC13): 6.71 (d, 1H, 10 J = 8.1Hz), 6.52 (d, 1H, J = 8.0Hz), 5.83 (s, lH), 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 spectra (amu): 580, 564, 523, 490, 478, 464, 378, 113, 84, 55 [GC-MS spectroscopy (Spectrum RXI, 15 Perkin Elmer, UK) Come on].

Representative infrared absorption (cm · 1): 3441.2, 3076.6, 2929.9, 1763.2, 1610.8 [The measurement was performed using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. Furthermore, the physical properties of the title compound are shown in Tables 2 to 20 below. Synthesis Example 2: Preparation of Buprenorphin Decanoate The title compound was prepared according to the method described in Synthesis Example 1 above, except that 0.011 mole of decanoyl chloride (Fluka, Buchs, Switzerland) was used. Replaces heptyl chloride. Pure Bupijinfen 28 1226830 发明, description of the invention

~ Decanoate was obtained (see Figures 5, 6, 7, and 8 which show the W-NMR spectrum, mass spectrum, UV spectrum, and IR spectrum of the title compound, respectively). Measured properties of the title compound: 5 Representative W-NMR (400 MHz, CDC13) · 6.76 (d, lH, J = 8.0 Hz), 6.58 (d, lH, J = 8.1 Hz), 5.91 (s, lH), 4.41 (s, lH), 3.45 (s, 3H), 3.00 (m.2H), 2.87 (m, lH), 2.50 (t, 2H, J = 7.4Hz), 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 = 6.6Hz), 0.80 (m, lH), 10 0.69 (m, lH), 0.48 (m, 2H), 0.11 (m, 2H) · Representative mass spectrum fragment (amu): 622, 607, 565, 533, 521, 507, 380, 55 [The measurement was performed using GC-MS spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. Representative infrared absorption (cm · 1): 3448.0, 3076.4, 2927.1, 15 1763.8, 1610.7 [The measurement system uses FT-IR spectroscopy (Spectrum RXI,

Perkin Elmer, UK). In addition, the physical properties of the title compound are shown in Table 2 below. Synthesis Example 3: Preparation of Buprofen valproate 20 75 ml of dichloromethane and 0.01 mole of Buprofen HC1 or The base was placed in a 250 ml round bottom flask that was ice-bathed. 0.011 pivaloyl chloride (Acros, New Jersey, U.S.A.) dissolved in 20 ml of dichloromethane was slowly added to the flask while stirring. With reference to the method described in Synthesis Example 1 above, pure Bupi 29 1226830 玖, invention description Nofenvalerate was obtained (see Figures 9, Ί〇, and 11, which are shown separately) Mass spectrum, UV spectrum, and IR spectrum of the title compound). Measured properties of the title compound: Representative mass spectrum fragments (amu): 552, 537, 519, 495, 463, 451, 5 436, 84, 57 [The measurement system uses FT-IR spectroscopy (Spectrum RXI,

Perkin Elmer, UK). Typical infrared absorption (cm · 1): 3439.2, 3077.1, 2976.6, 1753.0, 1610.2 [The measurement was performed using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. 10 Furthermore, the physical properties of the title compound are shown in Table 2 below. Synthesis Example 4: Preparation of Buprenorphin Palmitate The title compound was prepared according to the method described in Synthesis Example 1 above, except that 0.011 mole of hexadecanoyl 15 chloride (Aldrich, Milwaukee, USA). Pure bupinofen palmitate was obtained (see Figures 12 and 13 which show the UV and IR spectra of the title compound, respectively). Measured properties of the title compound: Representative infrared absorption (cm · 1): 3447.0, 3076.9, 2924.0, 20 1763.3, 1610.9 [The measurement system uses FT-IR spectroscopy (Spectrum RXI,

Perkin Elmer, UK). Furthermore, the physical properties of the title compound are shown in Table 2 below. Synthesis Example 5: Preparation of Dibupinenofen pimelate 30 1226830 玖, Description of the Invention The title compound is based on that described in Synthesis Example 1 above. This method was prepared 'only using 0.006 mole of heptanedioatyl chloride (Aldrich, Milwaukee, USA ·) instead of heptyl chloride. Pure bupinofen pimelate was obtained (see Figures 14 and 15 which respectively show the IR and UV spectra of the title compound). Measured properties of the title compound:

Typical infrared absorption (cm_1): 3435.0, 3077.0, 2953.0, 1760.8, 16Π.0 [The measurement was performed using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. 10 Furthermore, the physical properties of the title compound are shown in Table 2 below. Synthesis Example 6: Preparation of dibupinenfen sebacate

The title compound was prepared according to the method described in Synthetic Example 1 above, except that instead of heptyl chloride, 0.06 mol of sebacoyl chloride (15 Eluka, Buchs, Switzerland) was used. Pure bupinofen sebacate was obtained (see Figures 16, 17, and 18, which show the W-NMR spectrum, UV spectrum, and IR spectrum of the title compound, respectively). Measured properties of the title compound: 20 Representative h-NlvlR (400MHz, CDC13): 6.75 (d, 2H, J = 8.0Hz), 6.57 (d, 2H, J = 8.0Hz), 5.90 (s, 2H ), 4.40 (s, 2H), 3.44 (S, 6H), 2.99 (m, 4H) 5 2.87 (m, 2H), 2.59 (m, 2H), 2.50 (t, 4H, J = 7.6Hz) , 2.32-2.23 (m, 8H), 2.10 (m, 2H), 2.0-1.66 (m? 16H) 5 1.36-1.26 (m, 18H), 1.05-1.01 (m, 22H), 0.80 31 1226830 玖, invention Explanation (m, 2H), 0.69 (m, 2H), 0.47 (m, 4H), 0.10 (m, 4H) · Representative infrared absorption (cm · 1): 3435.3, 3077.2, 2931.9, 1760.0, 1611.3 [Measurement It was performed using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. 5 In addition, the physical properties of the title compound are shown in Table 2 below. Table 2. Bupinofin HC1, Bupinofen test and its derivative physical properties Compound molecular weight General melting point (° c) Ester Bonding IRCcm4) Buprenorphine hydrochloride 504.11 C29H41N04 · HC1 279 ~ 281 — Buprenorphine base 467.65 C29H41NO5 208-210 — Bupifenfen propionate purpose 523.72 c32h45no5 133-135 1765.6 Buprenorfen Acid ester 551.77 C34H49N05 141-143 1753.0 Buprenorphin benzoate 571.76 c36h45no5 168 ~ 170 1742.1 Buprenorphin enanthate 579.83 c36h53no5 84 ～ 86 1763.2 Buprenorphin decanoate 621.91 C39H59N05 87 ～ 89 1763.8 cloth Pinofen palmitate 706.07 c45h71no5 < 0 1763.3 Dibupinofenil pimelate 1059.45 C65H90NO10 103 ~ 105 1760.8 Dibupinofenine sebacate 1101.53 〇68Η96N〇10989 ~ 90 1760 The infrared spectrum was detected using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK) Preparation Example 1: Injectable oil formulation containing bupinofen base and bupinofen ester derivative of the present invention Preparation 10 (1) 10 // Bupinuofen mole of base is added to 1 ml of sesame oil. The mixture was shaken slightly until complete dissolution was completed. (2) 20 # mole bupinofen propionate was added to 1 liter of sesame oil. The mixture was shaken slightly until complete dissolution was completed. (3) 20 / mole of bupinofen decanoate is added to 1 ml of sesame 15 oil. The mixture was shaken slightly until complete dissolution was completed. (4) 20 / mole of bupinofen pimelate is added to 1 ml of Zhiba 32 1226830 玖, description of invention sesame oil. The mixture was shaken slightly until complete dissolution was completed. (5) 20 / mole of bupinofen ester or polyester was added to 1 ml of ethyl ester of flower oil. The mixture is shaken slightly until complete dissolution is complete. Pharmacological Example 1 In vivo analgesic effect of bupinofen hydrochloride via intramuscular injection (dose-determining test) (1) Test animal · Male Sprague-Dawley rats (175-225 g 10 weight, 6 weeks old) ), N = 6 for each group. (2) Drugs: Buprenorphin hydrochloride solutions' in 0.9% physiological saline are each 0.02 / ζ mole / kg (= 〇 · 〇ΐ mg / kg), 0 06 # mole / kg (= 0.3 mg / kg), 0.18 / z mole / kg (= 0.09 mg / kg), 0.6 V mole / kg (= 0.3 mg / kg)), intramuscular injection To the right hind foot of 15 rats tested. (3) Test: piantar test, using the device (70, ug, BASILE, Italy). The test can enable researchers to identify one of the thermal stimuli caused by the drug in an unrestricted rat. Peripheral regulatory response. It basically consists of a movable infrared (IR) generator placed under a glass frame, and the operator places the rat on the glass frame. The transparent plastic (perspex) shell defines the space within which the animal will not be restrained. It is divided into 3 compartments. These compartments help the operator to perform a quick "screening" (sc-), work: to? 3 rats were tested and described in 33 1226830. The invention explains it There is no appreciable delay between bamboos. The operator places the infrared generator directly under the hind paw of the rat 'and passes a "start (8, 8, 11, 11)) button to activate the infrared light source and a reaction timer . When the rat felt pain and retracted its feet, the infrared generator was automatically turned off and the timer stopped to determine the retraction delay period. For a detailed description of the sparse test, see, for example, KM Hargreaves et al., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia,", P ^ jn 32: 77-88, 1988, and KM Hargreaves et al. ., 10 "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 delay period from the time of stimulus (radiant heat) to the retraction of the sole of the foot (left rear foot) is designated as "Reaction Delay Time" by 15. Radiant heat is set to provide a pre-dose delay of 7-9 seconds. To avoid tissue damage, a 25-second cutoff time was set. (4) Statistics: Data are displayed as "average". When compared to the pretest value using ANOVA and Dunnett's test, 20 represents P < 0.05. ANOVA refers to analysis of variance, often referred to as ANOVA, and it is a very useful statistical technique that can be used to distinguish and estimate different causes of “variation”. Dunnett's test is an after-the-fact comparison between the averages after an ANOVA (posterior 34 1226830

(Ii) Description of the invention (Cornpariosn). This test allows the tester to perform all possible comparisons between groups. "P, represents the possibility, where # p < 〇 05 means that there is a statistically significant difference. (5) Results 4 levels of bupinofen Ηα confirmed that there is an analgesic effect period of 3-5 hours (see Table 3 and Figure 19). Pharmacological Example 2 In vivo dose of Buprenorphine via intramuscular or subcutaneous injection-decision

Study 10: Test secret: Mixed Sprague_Dawley rats (75-225 weight) (n = 6). Medication (2) Drug: Bupinofine base solution in sesame oil, each of which is private mole / kg, 6 / z mole / k§, and mole / kg, injected intramuscularly to the test rat Right rear foot. (3) Test: 跛 test (see the pharmacological examples above). 15 (4) Statistics

Dunnett test. Data are expressed as' 'average 20'. (5) Results: Different doses of bupinofen verified by intramuscular injection have an analgesic effect of 48-50 hours. Similarly, the difference by subcutaneous injection: the amount of bupinofen verified that there is- Analgesic effect at 48.5 G hours (see Table 3 and Figure 20-B). Pharmacological Example 3

In vivo analgesic effect of five kinds of bupinofen monoquinic acid with an ester derivative of formula (I) via intramuscular injection 35 1226830 玖, description of the invention ο) Test animals · Male Sprague_Dawiey rats (175-225 g in weight), each A group of n = 6. (2) Drug: Bupinofen propionate 0.6 [M / kg, Bupinofen pivalate 0.6 VM / kg, Bupinofen enanthate 0.6 // M / kg, cloth 5 skin Norfin Decanoate 0.6 and Buprenorphin Palmitate 0.6 / M / kg. All these ester derivatives were dissolved in sesame oil as an oil solution and injected intramuscularly into the tested Right hind foot of rat. (3) Test: 蹏 test (see the above pharmacological example 丨). () Statistics · ANOVA followed by Dunnett test (see above pharmacological example 1). (5) Results · Intramuscular injection of 5 bupinofen ester derivatives of the present invention at a dose of 0.6 // Moore / kg confirmed a rapid onset of action and a period of 48-96 hours, and in particular, Both bupinofen caprate and palmitate are available

The first is a 96-hour effect period (see Table 3 and Figures 21-A to 21_E). Music Theory Example 4 Intramuscular> Intramuscular Dosage of Buprenorphin Propionate-Determined in 20 studies, styli, male SPrague-Dawley rats (175-225 g), each group n = 6. (2) Drug: Bupifenfen propionate (oil solution), quantity: 0.6 # M / kg 6 "M / kg, 60 # M / kg, injected intramuscularly to 36 1226830 tested, Description of the invention The right hind foot of the rat. (3) Test: 跛 test (see above pharmacological example 1) (4) Statistics · ANOVA followed by Dunnett example 1). Test (see above pharmacological fact (5) Results: via muscle Intravenous injections of different doses of Pinofen propionate have been shown to have an analgesic effect period of 48-60 hours (see Table 3 for springs)

With Figure 22). Pharmacological Example 5 In vivo analgesic effect of two dibupinenven di-10 carboxylate derivatives having the general formula (n) by intramuscular injection (1) Test animal: Male Sprague-Dawley rats (175_225 eight Gram weight) 'n = 6 for each group. (2) Drug: Dibupinenofen pimelic acid vinegar and dibupinenofen sebacin vinegar, dosage: 0.3 / zM / kg (in oil solution in sesame oil), in 15 flesh / main shot to Right hind foot of rat being tested.

(3) Test: 跛 test (see the pharmacological examples above). (4) Statistics: ANOVA followed by Dunnett test (see Pharmacological Example 1 above). (6) Results. Z. dibupinenofen pimelic acid and dibupinenofen sebacate at a dose of 0.3 were confirmed to have a rapid onset of action ( 2 hours) and 72 hours and 96 hours each (see Table 3 and Figures 23_a to 23-B). Table 3 below summarizes the test of bupinofen and its derivatives in rats using rhenium 37

Claims (1)

Turn to If I I-Click ^ 1 to turn the application range: L I-No. 091133175 Patent Application Application Patent Range Amendment Date of this amendment: August 1993 1. A Bupino with the following chemical formula (II) Fendicarboxylic acid derivatives: Where R! Is a divalent moiety composed of a saturated or unsaturated aliphatic group having 1 to 40 carbon atoms and optionally substituted with a phenylfluorene. 2. For example, the derivation of bupinofin dicarboxylic acid ester 10 in the scope of the first patent application, wherein R! Is an alkylene group having 1 to 40 carbon atoms. 3. For example, the scope of application for patent No. 2 bis bupinofen dicarboxylic acid derivative, wherein Ri is an alkylene fluorene having 1 to 20 carbon atoms. 4. For example, the dibupinenol dicarboxylic acid derivative of the first patent application scope is selected from the group consisting of dibupinenol pimelate and dibupinenol dec 15 difluorenyl ester. 5.-An analgesic pharmaceutical composition for intramuscular or subcutaneous administration, which comprises 1226830, the scope of application ... There are: (a)-a therapeutically effective amount of at least one of the following compounds: (i)-having the following chemical formula (A Bupinofen test (A) (ii) A bupinofen monocarboxylic acid derivative having the following chemical formula (I): (I) wherein R is selected from the group consisting of: a group of 2 to 40 carbon atoms and optionally a group of 5 to 20 A rs 1226830 10. scope of patent application: aryl group of carbon atoms A straight or branched saturated or unsaturated aliphatic radical substituted by a radical, and a saturated one having 5 to 20 carbon atoms and optionally being saturated by a straight bond or branch having 2 to 40 carbon atoms Or an unsaturated aryl group substituted by an aliphatic aliphatic group 圑; provided that: R is not selected from methyl, ethyl, propyl, η-butyl, η-pentyl, η-hexyl and iso Propyl (iii) a bupinophene dicarboxylate derivative having the following chemical formula (II): Where R! Is a divalent moiety consisting of a saturated or unsaturated aliphatic group having 1 to 40 carbon atoms and optionally substituted with a phenyl hydrazone; and (b)-a pharmaceutically acceptable Oil carrier. 15 6. The analgesic pharmaceutical composition according to item 5 of the scope of patent application, wherein the oil load Λ ^ 1226830 X. Applying for Guanguanwei: The agent is selected from the group consisting of: sesame oil, ramie oil, cotton seed oil , Soybean oil, peanut oil or ethyl ester of peanut oil, and combinations of these +. 7. The analgesic pharmaceutical composition according to item 5 of the patent application scope, which comprises a bupinofen test having a chemical formula (A). 8. The analgesic pharmaceutical composition according to item 5 of the patent application scope, which comprises a bupinofin monocarboxylic acid ester derivative having the formula ⑴, wherein R is an alkane optionally substituted with a phenyl group Kiki. 9. The analgesic pharmaceutical composition according to item 5 of the scope of patent application, which comprises a bupinofin monocarboxylic acid ester derivative of formula (I), wherein R is an alkane having 2 to 40 carbon atoms. Group. 10. The analgesic pharmaceutical composition according to item 5 of the scope of patent application, which comprises a bupinofin monocarboxylic acid ester derivative having the formula ⑴, wherein R is an alkyl 圑 having 5 to 20 carbon atoms. 15 11. The analgesic pharmaceutical composition according to item 5 of the scope of patent application, which comprises a bupinofin monocarboxylic acid ester derivative having the formula (I), wherein R is selected from the group consisting of: A linear alkyl group optionally substituted with a phenyl group, a branched alkyl group selectively substituted with a phenyl group, a linear aliphatic group optionally Group 20 is a phenyl group 取代, and a phenyl group optionally substituted with a branched aliphatic group 圑. 12. The analgesic pharmaceutical composition according to item 5 of the patent application scope, which comprises a bupinofen monocarboxylic acid ester derivative having the chemical formula (I), the derivative being selected from the following: bupinofen pentaphene Acid esters, bupinofen benzoate, cloth 1226830 X. Application scope: Pinofin decanoate and bupinofen palmitate. 13. An analgesic pharmaceutical composition according to claim 5 in the scope of patent application, which comprises a dibuprofen dicarboxylic acid derivative having the formula (II), wherein fluorene is an alkylene having 1 to 40 carbon atoms Kiki. 5 14. The analgesic pharmaceutical composition according to item 5 of the scope of the patent application, which comprises a bupinophene dicarboxylic acid derivative of the formula (II), the center of which is an extension of 1 to 20 carbon atoms Alkyl fluorene. 15. The analgesic pharmaceutical composition according to item 5 of the scope of patent application, which comprises a dibupinofen dicarboxylate derivative having the chemical formula (II), the derivative ten and ten are selected from dibupinofen Pimelate and dibupineaufen sebacic acid. 16. —A method for preparing a dibupinen dicarboxylic acid derivative having the formula (II) as described in the scope of the patent application, comprising the following steps: 15 (i ') in dichloroform Treat bupinofen HC1 or alkali with triamidine in the presence of sintering; and (ii,) in the presence of dichloromethane, force the mixture obtained from step (i,) into a chemical formula of RKCOOHh Compound or an acid anhydride or an acid chloride thereof, wherein Ri in the 20 formula RKCOOHh is a compound having 1 to 40 carbon atoms and optionally substituted by a phenyl group A bivalent moiety consisting of a saturated or unsaturated aliphatic fluorene. 17. The method of claim 16 in the scope of patent application, wherein the compound having the chemical formula R / COOHh used in step (ii5) is a compound having 3-40 1226830 10. Application range of fj: aliphatic two carbon atoms Carboxylic acid or its mono anhydride or mono acid chloride. 18. The method according to item 16 of the patent application, in which heptyl chloride is used in step (ii '). 19. The method according to item 16 of the patent application, in which sebacin chloride is used in step (ii5). 1226830 BUPIC7 2275 (43 · 71e # Iridium «+ 1226830 BUP-PLAM. SP-2002 / 9 / 10—Every lingering milkman 恙 Miao Ji 铖 Lbs 1226830 25 Ο.όΛΐΜ / kg 6 juM / kg 60. «M / kg baseline 20 Time (hour) Figure 20-A 1226830 25 1 0.6 ^ iM / kg 6 juM / kg 60 juM / kg 20 Baseline * Time (hours) Figure 20-B 1226830 25 Bupinofen propionate 0.6 μM / kg baseline 20- (， #) 踩 ^ 礅 汝 0 缳 C4W 5 I | I 1 I 1 I 1 I I 0 10 20 30 40 50 60 Time (hours) Figure 21-A 1226830 25 η Bupinofenvalerate 0.6 jLiM / kg Baseline 20 (, #) 5Fi tree so 0 slow Yi 吆 0 10 20 30 40 50 60 Time (hour) Figure 21-B 1226830 25 0.6 juM / kg Bupinofen enanthate Baseline (, #) Step ^ neodymium 0 bismuth β Time (hours) Figure 21-C Figure 1226830 „丨 m 8. 13 correction 丨 month 25 0.6 μM / kg bupinofen capric acid target baseline 0 5 0 2 11 (, #) s £ f ^^ 0 Bismuth W 0 20 40 60 80 100 Time (hours) Figure 21-D 1226830 20 Tree 0 0 slow {4 吆 20 Buprofen palmitate 0.6; uM / kg baseline 40 60 80 100 Time (hours) Figure 21-E 1226830 0 5 0 2 11 (, #) s £ f Min field 0 bismuth W 8 8 ”Month and month Revision Supplement 25 5 1 Γ " " I · t I I I I 'I 0 10 20 30 40 50 60 70 80 Time (hours) Figure 22 1226830 Τττ'τ;:, lacquer year, month, dibupinofenil pimelate 0.3juM / kg baseline 20 30 40 50 60 70 80 Time (hours) Figure 23-A 1226830 25 Dibupinetafen sebacate 0.3 juM / kg Baseline 0 5 0 2 11 (, #) Step ^ Silver 涑 0 Slow C4W Time (hours) Figure 23-B