TW399056B - Long analgesic acting nalbuphine polyester derivative and method of use - Google Patents

Abstract

The present invention, Nalbuphine polyester derivative is related to a novel long acting agent. The chemical structure of Nalbuphine polyester derivative is shown in Formula IV, in which the R is selected from a nonsaturated aliphatic fatty acid, or saturated aliphatic fatty acid; n represents the number of ester groups in Nalbuphine polyester derivative, is an integer in the range of 1 to 4. When R is described by R'CO, the R' denotes the aliphatic group consisting of alkyl or alkylene having 1 to 40 carbon atoms. The aliphatic group is selected from (a) a straight alkyl group, (b) a branched alkyl group, (c) a straight alkyl group where substituted with a benzene ring, (d) a branched alkyl group substituted with a benzene ring, (e) a benzenyl group where benzene ring contains a straight chain aliphatic group, (f) a benzenyl group where benzene ring contains a branch chain of aliphatic group. The present invention also provides the process of preparation method and the long acting preparations of pharmaceutical composition comprising the Nalbuphine polyester derivative. The Nalbuphine polyester derivatives are synthesized by the step; as chlorinated the Nalbuphine base, then carry out the esterification by reacting with nonsaturated fatty acid anhydrides, saturated fatty acid anhydrides, alkyl (C1-40) acids chlorides or alkylene (C1-40) acids chlorides to undergo. The analgesic effect produced by single dose of Nalbuphine polyester derivative was last for 4 to 5 days, such effect was adequate enough for the treatment of acute and chronic pain. The Nalbuphine polyester derivative can be formulated into various dosage forms, the present invention also provides the preparation method to produce a clear injection solution, which was in contrast to traditional suspensions. Besides it had better stability. The advantage of Nalbuphine polyester derivative was to reduce the amount of injection and its long acting analgesic effect.

Description

_Case No. 8510615ft

Five 'Invention Description CO Background of the Invention An opiate with a new form of addictive affinity-narcotic agonist-antagonists, such as the shown bupronorphine, muphine, butorin Butorphanol and other classes have appeared successively. In 1985, Schmidt, w. K. et al. In Drug Alcohol Depend. Vol. 14 p. 339 discussed the biggest feature of these drugs is that they also have quail receptors. Affinity and antagonism, such as Nalbuphine is an antagonist of Mu receptor and an affinity agent of Kappa sensory body. These drugs improve the serious shortcomings of the original addictive analgesics, such as greatly reducing their addictive and additive properties, and reducing their respiratory depression. i ο 1ogy The same as the analgesic need to be published by the original phlogistics, and the existing apparent system is safer and more severe. According to Shafer, SL, et al., published in 1991 ^ "" "Volume 74, page 53 Compare the pain relief of such drugs The effect is that the dose of the drug administered to achieve phase strength is 10 mg regardless of morphine and nerbuterin, but Butorphan is 2 and Buprenorphine is 0.3 mg. According to Schmidt, wK ^ described in 1 985, this kind of drug has been administered for a long time ^ For example, Nalbuphine has not been used continuously for 6 months = addictive and additive. The drug is only The call to the patient = slight inhibitory effect, so it is considered that this kind of drug is clinically second, and it does not need to be like a traditional addictive analgesic, and it must be used for respiratory depression.

Published in 1987 by Drugs. Scholars who study pain all agree that it is an ideal analgesic with no side effects such as painlessness, no additiveness, and effects. Because for surgery or burns and end-cancer bupivacaine intoxicants, although it can exert local pain, there is no improvement, so when injecting through the extrameningeal cavity, it should be necessary for the general needs of Volume 33. Cardioplegia, which is produced by the heart and chest, and has analgesic effect. And the diameter of the drug is maintained for a long time. According to the data on page 520 of Bovi l 1, j. G., etc., and many researches, fast, strong analgesia, long-acting, tube inhibitory effect, and no respiratory depression are used as clinically severe pain. Cavity, abdomen, obstetrics, orthopedics and other severe pain 'select local anesthesia such as, Xy locaine', but it has short analgesic effect on drugs such as widespread or deep disease, that is, no more than 6 small analgesia when prolonging the effect The effect of the disease is not applicable to use Acetamin phen, aspirin, non-addictive analgesics, even if it can relieve minor pain such as migraine, tooth pain, but it is not effective for severe pain. Therefore, Bov, u, G et al. Reported in hugs. Vol. 33, p. 52 that addictive analgesics (η "⑶ analgesics) have a strong analgesic effect, and can be applied to a wide range of deep pain, Such agents act on opioid receptors (such as Mu receptors) in the central nervous system to produce analgesic effects, according to Hayes, AG •, et al. = 983, Br.J. Pharmac.l. 79, p. 731 The data shows this! The class of drugs still retains some of the common shortcomings of opioids such as addiction, additivity and respiratory depression. Moreover, the efficacy of such drugs is too short, under normal circumstances: injections are required every 3-5 hours Even if the lumbar spinal cord injection is administered, the prolonged time of drug effect cannot exceed 4S hours.

Page 10

修 _ 5. Explanation of the Invention (4) (narcotic antagonists and analgesics)

Formulations, gelling agents (jelling agents), emulsifiers, hormone derivatives, Tween 80, etc. are made into preparations for nasal solutions, nasal softness, and nasal gels. 3-morphine compound (^ benzoate ester) is published in European Patent Gazette M, which is made of the ester into capsules, tablets, suspensions. And U.S. Patent Publication No. 4,722, 9 28 discloses a patented nitrogen-containing 3-hydroxymorphine compound, which is added to an excipient such as a vitamin derivative, lactose, starch and the like to make a tablet = solid preparation, or Liquid musculature compositions such as suspensions and syrups. In the above-mentioned narbuferin compounds, any teaching method for the preparation of narbufurin long-acting preparations has touched the purpose of narbufurin. Objective of the invention 'and adding pΗ humectants, fiber nasal suspensions, benzoic acid esters No. 0, 1 7 0, 0 9 0, suppositories, injections have been obtained stearic acid, fiber, powder or The patents for capsules for oral administration have no or even the slightest amount of white base ring length. In view of this, the compounds of the present invention, in which the saturated or unsaturated R-based chain can be a straight chain, with another The number of straight chain dazzling bases or branched chains can be 1 to 4. An effective injection, Buferin is prepared into a large number of esters, and it is not easy to cause respiratory depression. Nabubutyl is based on R 'C0, which is an alkyl branched chain with a substituted alkyl group and a large number of esters. But a simple number represents the number of chain carbons. It is 1 with a benzene ring; the value of n means that only one dose or several doses per day is needed to improve that cloth. Department 5 and other types of chain, linyl ester and other causes caused by long-acting agent system, although one is similar. non-

Page 12

Fatal side effects. Benfa Sun and Moon # 6 improvements in medical products. Although the main advantages have been stated such as ^, such as long-acting, safe, painkillers, cancers, patients do not need to ask a doctor for injections 3-5 hours after surgery. More importantly, the long-term use of such analgesics without the need for hospitalization is equivalent to the design and synthesis of g cloth, which has the so-called soft drug properties, that is, when nabufurin is more than dandan and fulindol, It must be considered that in vivo organisms, in vivo, will know that it will decompose to form buferin, and inactive decomposition will generate new metabolites .... Come, open as a new drug, Duo Dan = Cheng Zhong, Xin Salts, new stereoisomers, single esters are all drug competent units = more broken FI) A and one of the world's most popular medicines (including China) is a new drug. At present, every 7 000 new compounds are limited only by their pass; Ben / Ping 'is mainly encountered in toxicological and pharmacological tests that cannot be used in the pharmacology of various animals, and the soft drug design of a large amount of esters is enough to rule out the use and fail. The factors ignorance in the trial 'due to the toxicity and pharmacological action of the metabolites' clearly show that β has greatly increased the feasibility of the market of this new drug and can greatly increase the twilight 8Ϊ ^ Not only does Daxue Po effectively use medical resources 'Vocal commercial therapy products. Of course, the present invention is more suitable for administration, and a large amount of the ester compound of Nabufurin is made into various types. Based on the safety of Taikuoyanuo & preparations or oily injections and other different agents, the safety of Shibuyao Shaobuocong, and the single ~ ^ = cup Xi "ester with soft drugs (SOft drug) is sufficient for acute and chronic pain M ^ Can maintain long-lasting analgesic effect and clinical treatment for 4-5 days.

____ Case No. 8510615fi_ Year and month 倏 ___ V. Description of the invention (6) In addition, the present invention also provides a method for preparing a plough containing a lot of nabufurin ester compound injection solution plow, the resulting clear injection solution, and the conventional Nabufulin-containing monoester compounds are different from suspension injections and have more stable properties. SUMMARY OF THE INVENTION Description of narbufulin-based compounds with novel structures. The narbufulin-based compounds of the present invention are shown in formula ν The compound, is a schematic compound, whose η value represents the number of nabufurin ester groups may be 1 to 4, and formula Vb is another expression; R in the 苴 represents a saturated fatty acid of a different bond length, or an unsaturated state Fat: Acid. The structure of the ester, the United States and the United States is the dibasic ester of nabufurin, and the simplified form of the tribasic sum represents' its R, which is an optionally self-saturated or unsaturated alkyl group, and the alkyl chain has a carbon number of 1 to 40, chain alkyl groups, alkyl groups with branched alkyl groups; ^ straight alkyl groups, (d) branched alkyl groups with benzene rings, (e) linear alkyl groups, (f) stupid rings It is substituted by a branched alkyl group. There are straight-chain alkyl groups for taking Bufulin monoester, Nabufulin n vinegar refers to Nafulin four aliquots ... etc., n value 1 is Zhelin three vinegar, Nabu example It is 1: 1 as shown in the formula (the ratio of the structure of D to the base and acetic acid group 1 is 2 and the value of η is 2 as shown in formula (Π) t structure system :: series, when the ratio is 2: 3: 1: 1, the value of 11 is 3Such as the type (dish) of the She 槎 A forest two esters; analogy by analogy. ,,, ° constitute the three volume brewing of Nabu Fulin, according to this

Case No. 85106156 V. Description of the invention (7) The present invention "Nabufurin is a large amount of ester, and the combination is the dissolution of Nabufurin (Hbuphine) in the second gas field ' Nail with substituents, and then add acid anhydrides or the chlorinated gates of the fatty acids to long de-fatty acid fractions ^ The product is separated by hair gel chromatography :: chemical :: two (I) A single amount of ester of Fulin. The Nabufuhua & Nalbuphine can be obtained (add a portion of Li-Day once Sa, chaos tongue, the structure of the door 1 () is Nabufu Lin-Li S said, the same steps can be repeated to obtain the formula (jy), the ester. You can also make the bufolin two formula of the formula (Π) and then bufulin four set # 二: Γτν1 () Three volumes of Fulin; then repeat the same steps to obtain four volumes of Nabufulin vinegar of formula (IV). In Figure 丨 the artificial method of route A is to directly dissolve four portions of Nalbuphine in Di & formamidine 'and then add different chain lengths of substituents which have been dissolved in dichloromethane solution = water fatty acids (aCId anhydrides) or vapors of the fatty acids After the esterification is fully reacted, the product is separated and purified by silica gel chromatography to obtain a large amount of nabufurin ester of formula (VI). A reactant suitable for making a large amount of nabufurin ester is propionic acid (pr. pionic acid), n-vaieric acid, pivalic acid, benzoic acid, enanthic acid, decanoic acid, and including Some saturated fatty acids, such as stearic acid, 1 aur ic ac id, arachidic acid, cerotic acid, etc., or unsaturated Fatty acids such as linoleic acid (Π no 1 en ic ac id), undecylenic acid (undecylenic acid), cinnamic acid (cinnamic acid), etc.

Page 15 __ Case No. 85106156_ Year Month __ Amendment _ V. Description of the Invention (8) (V) In the structure, the 'R group is represented by R' C 0, and R, which is optional since Or unsaturated alkynyl group, the alkynyl chain has 1 to 40 carbon atoms, and (a) a linear alkyl group, (b) a branched alkyl group, and (c) a benzene ring (A) a branched alkyl group with a benzene ring, (e) a branched alkyl group on the benzene ring, and (f) a linear alkyl group on the benzene ring. According to the present invention, a large amount of nabufurin ester, and other synthetic methods are provided, as shown in route C of FIG. 1: a saturated or unsaturated state containing a large number of fatty acids and dimethylformamidine with different chain lengths and substituents. Amine ((1111161;) 171_ & 11] 11 ^), 2-pyridine carbonate, nitrogen, nitrogen hydrazone: :) N, N-dimethylaminopyridine and nabu The reaction of Fulin hydrochloride is to neutralize the acid with acid to control the pH value to be near neutral. The product is separated and purified by silica gel chromatography to obtain a large amount of nabufurin ester of formula (π ~ still). Comparing Nabufurin, saturated or unsaturated different chain-length fatty diacids, dicyclohexanebisimide (N, N, _dicycl〇_hexylcarb〇diimide), bismethylamino group τ »ratio By biting (4-dimethylaminopyridine), a large amount of nabufurin of formula (VI) can be obtained. Among them, aminopyridine can also be changed to H0BT and pyridine, but the addition of ^ ring ^ appearance and imine, bismethyl version of the bite or Hobt, howl. The amount of participation in the reaction is related to the number of ester groups of the product formula (VI) nabufulin ester, usually based on saturated or unsaturated states of different chain-length fatty diacids containing substituents. The amount of Fulin diester needs to be added to the amount of Nabuferin and dicyclohexylbiyl, but the amount of difluorenylamino group should be less than j% ^, and the amount of Fulin triester should be added to Nabufulin, Bicyclohexane bisimine port __ Case No. 85106156_I Month (Bei Zheng _____ V. Description of the invention (9) Nabufurin is adjusted by the S base of a large amount of vinegar. Preparation of the Nabufurin large amount ester of the present invention) The method, as shown in Figure 1, is to use Nalbuphine as a starting material, and react it with fatty acid dentin and aromatic fatty acid i to obtain a large amount of nabufulin of formula (VI). Ester. Although JACS Vol. 97, p. 3515 in 1975 discussed the use of Mg (OCOCF3) 2 and alkaline reagents to form esters, or to react with nabufurin to synthesize nabufurin esters directly by reacting halide with acid reagents. 1981 Volume π, page 21, discusses the use of fluoro_2,4,6_trinitrobenzene, and the synthesis of nitrogen, nitrogen-monomethylamine Buferin ester. BU1, 983 ". Chem. Soc. Jpn. Vol. 5 6 6 6 9 discusses the use of pyridine and chloro-2,4-nitropyridine reagents to stir aromatic fatty acids with that Buferin. Aromatic fatty esters of Nabuferin. In addition, Tetraheder L ^ tt. Vol. 25, p. 4943, 1984, talks about changing the reaction reagent to gas, nitrogen-dimethyl— = Γ 丄Bi-2-Hou Ding carbonic acid® is intended to synthesize narbuferin vinegar. However, the "mouth-to-mouth method of forming narbufurin esters" is limited to the synthesis of narbufurin 5 cost invention " nabufurin A large amount of vinegar & general synthesis: especially in order to achieve the stability of the product, it is necessary to base 2 on the reaction conditions; 8 of: Γ is in a biased weak state is appropriate ^ Temperature 2 :: rate = f is sufficient to affect the yield , Ί 芳; made between, ~ 1〇 " and lower two = Yi ί as a reactant 丄 its aroma * pick up ... :: 佳 选 ----- 诚 85] nm.RR_ 年月 日____ 5. Description of the invention (10) It can be 1 ~ 4, and its binding position is also ortho, meta, para or 'acid' depending on the number of fatty acids. Aromatic fatty acids are used as reactants and their reactions Temperature is usually 0 ~ 8 0 ° C is preferably lower than room temperature. Aromatic fatty acid hafnium halide is used as a reactant. Its reaction temperature is usually between _ 丨 ～ 5 00c, and the lower the temperature is better. Although the above reaction theory And the addition of bicyclohexyl bisimine, bisamidopyridine or HOBT, pyridine can also participate in the reaction, but the amount of it is related to the number of ester groups of the product formula (VI) nabufulin vinegar, usually with the product (VI ) The amount of the vinegar ester base is adjusted; it may be twice the amount or 2%, or even less than 1%. The ratio of Nabuferin to dehydrated fatty acids (aci (ianhydrides) or monthly fatty acid chlorides, fatty diacids influences the conversion rate. When Nabufulin and dehydrated fatty acids' or fatty acid chlorides, fatty diacids The ratio is 2: 1, the conversion rate of the synthesized diester is 80%; and the ratio of the nabufurin is 2.2%. The conversion rate of the synthesized diester is 85%, the nabufurin and the dehydrated fatty acid or fatty acid The ratio between chloride and fatty diacid is 2: 丨. 丨 5, and the conversion rate of the combined diester can be increased to 90%. Σ The above-mentioned synthetic extract rij is mixed with the second production in the low-grade water .... I 呷Xi Xidan ton one mile preparation method,

Page 5 of 5 is a solvent that needs to be considered in the purification step, due to the large amount of synthesis; solutions and methanol solutions are easy to decompose; and solvents in THF, hexane, and ethyl acetate ^ involving mass production and environmental protection are not suitable for use in this invention,. Intermediate solvents such as methyl chloride and digas ethane cause crystallization to be too slow and costly; therefore, suitable solvents used in the purification step are usually multiple = Erfa uses multiple solvents, and two-stage pure 3 W1MJ IkVLIlklV ^ IVriUri 地 ⑽ ... , "Second '" ------

Process' Precipitation of ethanol followed by ethanol / propanol precipitation of Nabu Fu Yao Xi θ Α 外 外 城城 名 名 思 ”(NMR), infrared spectroscopy (IR), purple ίϋ, analysis / mass spectrometry Instrument (GC / MaSS), and physical properties of the element knife / shellfish, and then make a suitable dosage form as required. The suitable dosage form of Buferin ester can be σ BE t, I d sanapine sacrifice 俨 田 m * nr is too much to take the dosage form 'can also be made into an injection dosage form for grasping muscle, subcutaneous, spinal cavity, annihilation π person > — Le 4 on the epidural space and other injections. In order to meet the needs of clinical administration +, the large amount of enabufulin ester can also be made into dental skin absorption, haze, buccal, non-pi, ^ Sheng A @ ϋ A 5 sublingual, external patch, ointment, Suppositories, such as nettles, are used to sculpt the drug. New drug design concept of Nabufulin vinegar soft medicine-The nabufulin ester of the present invention provides a large amount of ester to become a new drug design concept that complies with soft drug. The so-called soft drug is related to Prodrugs and hard drugs are different. The concept of new drugs is different; the design of early new drugs was biased towards the synthesis or isolation of active drugs. The active drug itself may have a tolerable degree of toxicity, so there is a saying that "medicine is poison". According to the current standard of drug design, this drug is a hard drug. Later, the metabolic state of drugs in the body can be analyzed and understood due to the development of pharmacodynamics and pharmacokinetics. Therefore, when designing new drugs, they tend to synthesize a prodrug of an active drug ( Pr〇drugs) 'The drug can only be metabolized into active drug structures

------ Case No. 85106156__Year Month and Day _____ V. Description of the Invention (12) # 金 明 车 人 乐 (soft drug) is to first understand that drugs in vivo can produce part of the municipal structure. The drug is combined with a compound that is inactive but not toxic to become active prodrugs. Mysterious / tongue prodrug is synthesized into a soft drug. As shown in Figure 2: Nabuferin (VI) is a soft drug, which is decomposed into nabufurin monoester (I) when it enters the body. This is an active prodrug. The compound of formula (丨) will It is decomposed into nabufurin and inactive decomposition products. Nabufurin is effective in the body and these ester groups will never be metabolized into toxic metabolites. Therefore, soft drugs have the greatest safety. . Soft drug properties of narbuferin (1) In rats: (A) SDN'sebacoyl dinalbuphine ester in acetonitrile (acetoni trile) ) Concentration of 7.75 mg / ml (B) 250 ml Collected from the whole blood of rats fed with sinabufulin sebacate (SDN), and then added anticoagulant (2) to rabbit experimental material: (A) Acetonitrile (acetonitriU) dinabuferin sebacate (SDN) concentration was 5.2 mg / ml (B) 150 ml. Blood's additional anticoagulant (3) In dog experimental materials ... (A) Binabuferin sebacate (SDN) dissolved in acetonitriU (acetonitriU) at a concentration of 12. 5 mg / ml

_ 皇 号 85〗 nfi15fi_ Year, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, month, week (4) In human experimental materials: (A) acetonitrile (SDN'sebacoyldinalbuphine ester) dissolved in acetonitrile (SDN'sebacoyldinalbuphine ester) at a concentration of 10mg / ml (B) 250m 1 collected from Administration of sinabufulin sebacate (sdn) human whole blood, and addition of anticoagulant, the blood of various animals was analyzed by high-speed liquid chromatography. As a result, sinabufulin sebacate ( The half-life of SDN) into active nabufurin is shown in Tables 2 and 3. Various animals are 2.8 minutes for rats, 7.0 minutes for rabbits, 27.8 minutes for dogs, and 9.0 minutes for humans. Significance during this time ‘90% of the time for the conversion of sinabufulin adipic acid ester (SDN) to nabufulin. The various animals are 10 minutes for rats, 25 minutes for rabbits, 95 minutes for dogs, and 30 minutes for humans. Long-acting pharmaceutical composition of a large amount of buferin ester compound published in 1986 by Gelders YG in Int. Clin. Psychophacol Vol. 1 page 1 Haloperidol is made into Haloperidol decanoate ) It is made into a long-acting prodrug, and the administration interval by intramuscular injection is extended from the original 2-4 times per day to 1-2 times per month. In 1987, Norman T.R. int. Clin. Psychopharmacol. Vol. 2 pp. 299-305 reported that Fluphenazin was made into Fluphenazin decanoate. Hinko C.N. in 1988

Page 21 Case No. 85106156 Amendment V. Description of Invention (14)

Neuropharmacology, Vol. 27, p. 475-8, 3 reports that nipectic acid is made into esters. Broekkamp CL, 1988, reported in J. Pharm. Pharmacol., Vol. 40, pp. 434-37. Morphine is made into nicotinoyl morphine esters. Joshi, J.V. et al., Published in Steroids Vol. 53, pp. 751-61, 1989, reported that the prodrug of Northisterone enanthate can be prolonged to 2 months. In terms of formulation, in order to prolong the drug effect, the original drug is esterified to form a drug containing an ester structure, which is then dispersed in oil to make an injectable suspension. When administered to the drug in the body The release state is controlled by factors such as drug dissolution, increased fat solubility, or less blood flow ', thus achieving a long-lasting effect. According to Gelders in 1986

Int · Clin · Psychophacol Magazine Vol. 1 p. 1 and 1988 Hinko, C.N_ et al. Reported in Neuropharmacology Vol. 27 p. 475 'precursor of Haipoperidate decanoate' The drug is added to the main injection oil such as sesame oil (same oil, soybean 〇11) to make a controlled release dosage form. However, the dosage form prepared by simply dispersing the drug in the oil may also become a short-acting preparation, such as In 1 974, "⑽, et al., In Chem. Pharm. Bull., Vol. 22, pages 1275-84, reported that testosterone suspended in oil for injection could exert rapid release through intramuscular administration. Appearance of the phenomenon, and in 1990 it was reported by Ti tulaer, HA c. Et al. ^ 1 ^ 1'111, ^ > 1 ^]: 11 ^ 〇: 〇1. Vol. 42 pp. 81〇-13 The formulations prepared by artemisinin for injection oil can exhibit fast-acting release effects regardless of muscle, oral, and rectal. So different drugs are

Amendment on page 22, V. Description of the invention (15) Quick-acting effect of a dosage form prepared by suspending in the same oil for injection, Zuidema, ζ, 994, 994, 7 Long-acting or J. Of Pharmaceutics No. Volume 105 189_2〇7 erna = = al drug can be dispersed in oil for injection to achieve long-term effect ;, drugs with a structure of the same class are dispersed in oil to make a suspension preparation in order to prolong drug two, must Consider the stability of the drug in terms of solubility and release ^. Obviously, the above is dispersed in the injection 性 ==. The preparation method of the preparation is still in an inconclusive stage. The physical properties of all kinds of fun animals can be achieved through various attempts and developments. G: = Most of the effective preparations are antipsychotics. 2. Hormone a: 〇Lt t new type of 31-type sexual affinity-antagonistic analgesics /, Lin Bing ..., related to the silk house, so there is no teaching for the development of Nabufulin long-acting | y agent, especially For that :: Effective formulation is the long-acting pharmaceutical composition of the ester which is the first successful amount of esters accumulated by the inventors' accumulated years of R & D experience to add injection oil or phosphorous agent to make a controlled release dosage form. (sesame oil), peanut oil, soybean oil (soybean oi, such as hydroxy paraben, propyl paraben), cumin ff * rPmrKr \ V > av > T? T, compound salt in this ethyl ester 1) Ester Pituben or Pulprin The present invention also provides narbuferin, which is a large amount of narbuferin esterified buffer solution and is added with the conventionally used invention oil for injection, which refers to the ethylester of peanut oil. Oils for injection; and the conventionally used ingredients (methylparaben, hydroxyphenylpropryl (BHA), piphexidine (BHT),

Case No. 85106156

V. Description of the invention (17) (1) Drugs: sesame oil (Slgma, Mo, United States), soybean oil (Sigma, Mo, United States), chemical oil ethyl ester (Zhong Zuo Pu A ,,, _ group, And take potassium linate (KΗ: ρ; '子 " North: t Republic of China) as experiment

u gram and chloride group h * cm · " dina (ν ~ ηρ〇4) Α was added to 1 liter of water to prepare isotonic and isotonic and pH (^ • 4 square of the acid salt buffer was used as a control group, each group There are 6 samples each. Take Nabufurin hydrochloride 50 Cang coupon, η 197 gupamine + 45 mg free base, 0.127 no more than = or Nabufurin buffer, and ,,, The main input is 4. The liters of the above oil or phosphate (Union Γ h 'Η' ητ large permeation molecular weight of 12,000-14,000 millimeters in the United States) are used in a dialysis membrane. Milliliters of phosphate buffer solution, Θ set with-magnet stir

Far (Farg〇, Taipei, Republic of China), placed on a magnetic stirrer 1 Zhuren ^ Taipei), stir at 500 rpm. Then put the 3 dialysis membrane (made in different oils or slow 豳 忐 豳 忐 豳 忐 ϋ ϋ 4J · · 丄 κ team J I Shao Bufulin == medium rr salt buffer to = detect =-two Contains the amount of Nabufurin, (3) Results: Nabuphine hydrochloride (nalbuphine ΗΓη ¥ dissolved in different injection oils (sesame oil, soybean H 2), or that, Fulin free test; salt buffer In the release of Nabu Fulin, the situation is shown in Figure 3. "^^^

Page 25-In the hydrochloride salt, that :: --- 85106156 Rev. V. Invention Description (18) '' " '-~ The slowest amount released from the dosage form is sesame oil (ρ < 〇. 〇5), and there is no difference between the other three groups. In Fig. 3 Nabufurin free base test, the amount of 7 'Nabufurin released in the sesame oil group was significantly slower than that in the arachid oil and phosphate buffer group (ρ < 0.05 ). If you compare (A) Nabufurin hydrochloride in sesame oil or (B) Nabufurin hydrochloride in phosphate buffer and (c) Nabufurin free test in sesame oil, compare them with the three groups. As shown in Figure 4, 'the release rate of benabufulin at 3 I Shou is B> a> c, and between 3 hours and 28 hours it is A > C. Long-acting dosage form efficacy test of Nabuferin monoester: (1) Animals: Male SpragUe-Dawley rats (Rat 1 75-225 g) were tested in groups of six. 'Each rat received thighs Intramuscular injection of drug once 0 (2) Drugs: A. Dose-response diagram of analgesics: (a) Nalbuphine hydrochloride (Nalbuphine HC1) at a dose of 100 rag / kg '10 mg / kg' 1 mg / kg, 0.5mg / kg, 0.1mg / kg, 0.05mg / kg, 0.00mg / kg. (b) Morphine hydrochloride (Morphine HC1) at a dosage of 10 mg / kg, 5 mg / kg > i mg / kg > 0.5 mg / kg 5 0.lmg / kg 5 0.05 mg / kg s 0 · 01 mg / kg. (c) Butyl. Non-causal hydrochloride (BUpren〇rphine HC1), use agent

P.26 The description of the invention (19) is 1: 0 mg / kg ′ 10mg / kg, 5mg / kg, one ~. · 5㈣ ~, 0 · 1 m g / k g '〇 〇 1 m g / k g. B. Efficacy test of Nabufulin monoester: Guil) The Λ photo group is Nabufulin hydrochloride (dissolved in physiological saline) and Nabufurin free base (dissolved in sesame oil) are 2 ^ And ^ The dosage is 25 micromolar to catty per rat, shoot 8 ... give () nabufurin soap ester (propionate, second brew, benzoate vinegar, capric vinegar, etc.) each 25 days Made from 1 ml of acetic acid in sesame oil ... Controlled; 25 μmol / kg intramuscularly. π Le4 is the mother (3) experimental device: This device is a refrigerated low-temperature circulating water tank, and the re-water tank is cooled down to -20 ° C. 〇. In the experiment, after muscle a [, Neal and alcohol (Sprague Dawl ey Rat), the big white /, skillful in the ice-cold alcohol bath of rats, flash away from the ice-bath of the rat's tail *, 1/3 behind the head The immersion fruit proves that 'this test can be used extensively in the case' as an analgesic effect for various types of sepal preparations. The formula for calculating the analgesic effect: "The analgesic effect after administration" 20) Description of the 5 'invention (male Sprague 1 5 minutes test: Basically, 40 seconds is used for the rat tail to be frostbite or more than 10 minutes is measured for male big white gas Daw ley rat weighing 175-225 g) , 35, 25, reaction time before administration, in order to prevent the experimental animal from being injured by the tail of the animal, the time when we stopped the test 'During this time, we have not found any signs. 5 minutes after the administration of various drugs every 10 minutes 6 Formula 10 (0 Results: A. Dose-response curve: When intramuscular injection of morphine hydrochloride 0.05 to 10 mg / kg (mg / kg), 2 effects have reached the measurable It has the strongest analgesic effect. Nabufurin is .UU00 mg / kg (mg / kg), but butylogen is due to the hydrochloride; / to 100 micrograms / kg (/ Zg / kg). The painkillers drawn ^ The picture is shown in Figure 5. Um β. Detection of Nalbuphine and its single-ester analgesic drugs! Rats' thigh muscles are injected with molars (25 micromoles / kg) of nafurin salts Acid salt, nabufurin free base and five kinds of nabufurin monoesters = ice alcohol (-20. 0 flash tail test to detect the analgesic effect period, but in this experiment, bobuline hydrochloride was made Due to the increase in fat solubility of nabufurin free base, the release time of music has been significantly extended as shown in Figure 6. Long-acting dosage form efficacy test of nabufurin multi-esters: (1) Animals: soil male Sprague-Dawley rats (Rat 1 75-225 cm)

Page 28 __Case No. 8mnRiM_Year Month and Day_____ V. Description of the Invention (21 g), male guinea pigs (guinea pig 200-250 kg) will be taken as a group and 6 will be tested. (2) Drugs: (a) Nalbuphine hydrochloride (Nalbuphine HC1), the dosage for rats is 15.625uM / kg, 62.5uM / kg, 250,000uM / kg, and the dosage for guinea pigs is 500uM / kg, 250 uM / kg. (b) Nalbuphine hydrochloride (Nalbuphine HC1) injection, dissolving Nabufulin hydrochloride in 0.9% physiological saline. (c) The dosage of sebacoyldinal buphine ester (SDN) is 7.8125 uM / kg, 31.25 uM / kg, 125 uM / kg. (d) Long-acting injection of bisnabuferin sebacate (s D N). Dissolve bisnabuferin sebacate (SDN) in sesame oil to give a 50 mg / ml injection. (3) Results As shown in Figures 7 and 8, intramuscular injections of 15.625, 62.5, and 250 uM / kg of nalbufurine hydrochloride (Nalbuphine HC1) were performed in rats and 50 μM / kg and 250 uM / kg of nerbufurin. The hydrochloride salt showed a significant analgesic effect in guinea pigs' as shown in Figure 9. Intramuscular injection of 7. 8125, 31. 25, 125 uM / kg sinacoyl dinalbuphine (SDN) rats I1, The increase of the dosage showed a significant analgesic effect, while the dinabuferin sebacate (SDN) at a dose lower than 25 uM / kg could prolong the analgesic effect to 4-5 days. Clinically, Schmidt WK et al. Proposed intramuscular injection of nabufurin hydrochloride 20 mg / 65 kg (0.308 mg / kg) in Drug Alc0h01 Depend Vol. 14 No. 2 pages 338-362 in 1985. ) Can maintain analgesic effect

The dose of Nabufurin hydrochloride needs 1 U mg / kg) to achieve the same case number 85106156 V. Description of the invention (22) Animal experiments in rats are performed by intramuscular injection of 20 and 1 5. 625 uM / kg (6. Analgesic effect. As shown in Fig. 10, intramuscular injection of .125 uM / kg Sinabactam occluded decoction (SDN) produces analgesic effect that can be extended to 88 hours, which is 8.8 times as much as Bufu stick hydrochloride. Therefore, it is estimated that the analgesic effect can be maintained in humans at a dose of 125 uM / 23 kg; diacid § g.) 4_t Linmu Shanghanyangli intramuscular injection 20 ni g / d ο κ g QU 3 0 8 Nabufurin Taco miscellaneous hydrochloric acid: + / ζ_ emr, · m ^ mr 丄, according to this estimate · ^ Even the fork with 8 8 m 1 Nabu Fu 钬:-文 息,! The analgesic effect cannot be maintained at all due to metabolic results. The large dose is no longer part of the single dose method, and 5 雔 = single-dose death day. In other words, only 7 ml b days, such as ϊΠΐ! Sebacic acid vinegar (SDN) can maintain the analgesic effect. Nabufurin is more effective for the treatment of acute pain. And the analgesic effect is maintained by the sakiri 4 for 4-5 days, and the bufolin system is known to be released in multiple ways, and the helmet is suspected of being early-the dose can be maintained. Radiopharmacokinetic test

Case No. 85106156 Description of the Five 'Invention (23) Method: 5 Beagle, 30 intramuscularly injected

Dog 'intramuscular injection of 100 mg / kg degraves_u_LL, .1 ng of bisnabuferin sebacate (SDN) oil M',, 6, 24, 30, 48, 54, 72 , 78, 96, 102, T, J8, 192 * Hours' blood was drawn from the veins of the forelimbs, and the blood was analyzed in double :: Fulin sebacic acid vinegar and Nabu Fupu Lbuphine) l; agricultural degree: The relationship between time can be calculated by the computer software program PC_IN, the dual-chamber model of physics dynamics and the formula of pharmacokinetics. The absorption and distribution in the dog's body can be calculated and eliminated. As shown in Fig. 11 and Fig. 12, taking bufolin sebacate (SDN) oil = dry-dried angle wood to see the double that is bigger, i \ this agent meets zero absorption, and the dose of sebacic acid coffee N) in The body is longer. The Shuangnabu Fulin Shengshan No. 1 ^ inner knife cloth roughly matches the distribution of the two-chamber model. From the time around = the elimination half-life of Gufulin Sebacate (SDN) is about 30, which is more than the traditional Nabufurin hydrochloride. Shi Xi, Lu Gu—He # Bonabufulin Sebacate (SDN) oily agent Zhitian ^ J J is longer than the traditional Nabufulin Hydrochloride Nabufulin Sebacate (SDN) Two due to another double thirteen or so. From the comparison in Table 7, the value of m reaches the six-percent division rate. The values are quite close to Λ. This shows that the cumulative dose is reduced.) And Clt (the drug of the overall clearance rate). The increase in the dose makes K (zero absorption rate half ) Growth during the period of large and zero absorption.

Page 31, No. 85106156 V. Physical description of the invention (24) Beagle dog pharmacokinetic parameters of esters (SDN) Table 1 Nabufulin Ester Compounds Table 2 Properties of soft drugs Table 3 Properties of soft drugs Table 4: Compatible excipients in the formulations Table 5. Stability experiments of the formulations Table 6: Shuangnabufulin decane Table Pharmacokinetic parameters of different doses of sinanabufulin sebacate (SDN) Fulin ester compounds product diagrammatic illustration Figure 1 Synthesis method of Nabufulin Ester " A, B, 0 ... Route Figure 2 Soft metabolism metabolism state of Nabufulin Ester (π, 羾) Figure 3 Buferin hydrochloride (nalbuphine HC1) in vitro release test (mean soil standard deviation, N = 6) 1 .... sesame oil 2 .... soy oil 3 ... peanut oil ethyl ester 4 ... .. Phosphate buffer Figure 4 Naibuphine free base in vitro release test (mean soil standard deviation, N = &) 1 · ... sesame oil 2 .... Dalley oil 3 .. ·. Peanut oil ethyl ester 4 ..... phosphate buffer solution

Page 32_SS_85106156 V. Description of the invention (25) 1 · · · · Butylorphine hydrochloride date correction ♦ · · · Morphine hydrochloride Nabuferin hydrochloride 圊 6 5 kinds of esterification Du Guang ^ Naibuphine and 庵 (mean n = 6) Response time diagram Decanoate, Methyl Formate Dimethyl Acetate 4 · · · · Enanthate 5 · · .. Propionate, 6 ... Nabufurin Figure 7 Intramuscular injection of Nabufurine hydrochloride (Nalbuphine HC1: > Analgesic effect in rats) 1.... 25 μM / kg 2. 3____ 1 5.6 2 5 uM / kg · Figure 8 Analgesic effect of nabufurin hydrochloride (Nalbuphine HC1) on guinea pigs 1 ... 500 uM / kg 2 ... _ 250 uM / kg 3 .. .Baseline Figure 9 Analgesic effect of intramuscular injection of sinabufulin sebacate (SDN) long-acting dosage form in rats. 1 ---- 125 uM / kg 3 .... 7.8125 uM / kg 2 .. ..31.25 uM / kg 4 · .. Baseline Figure 10 Intramuscular injection of sinabufulin sebacate (SDN) long-acting dosage form, nabufulin hydrochloride. 62.5 uM / kg 1 .... that Buferin hydrochloride 2 ... Sinabuferin sebacate (SDN) Figure 11 Intramuscular injection 30 mg / kg That cloth Fu Lam sebacate (SDN) long-acting dosage form in dogs, its plasma concentration that cloth Fu Lin

Page 33 ^^ 85106156 said. Revised V. Description of the invention (26) 1 .. Observed value 2. Calculated value Figure 12 Intramuscular injection of 1000 mg / kg sinabuterin sebacate (SDN) Long-acting dosage form in dog's "concentration of narbuferin in plasma" 1 .... S ten different values 2 .... observed value Example 1. Nalbuphine propi 〇nate) 's production of ml of digas methane (mol)) narbuferin and slowly add 0.16 ml of dichloromethane solution 011 mol of propionic anhydride ml. Remove the ice bath and wash with 20 ml of nanometer to remove sodium sulfate and purify it by subtractive column chromatography. Add 75 (methylene chloride) and 3,57 g (0.005) to a 250 ml round neck flask. 1 (hlbUphine), and place the flask in an ice bath to stir one of the ethyl amines (tr ie thy 1 am i ne), and in 2 0, dropwise add Propionic anhydride while dipping. Chloromethane was stirred for 1 hour at room temperature, then 10% carbonic acid, residual acid solution, and water-soluble impurities were removed. The solid product was obtained by drying, and this product was used to obtain purified nabufurin propionate. Examples 2 to 8 Preparation method of categorized example 1 'Synthesis of nabufurin vinegar as shown in Table 8 Example 9

Page 34 V. Description of the invention (27) Case No. 85106156 month a_ dinabuferin adipate (ad i poy 1 di rm 1 buph i ne es t er) Add 5 grams of nabu hydrochloride to the round bottom bottle Fulin, and 20 ml of anhydrous dichloromethane, ice-bath for 5 minutes, drip 4.4 ml of triethylamine, and stir for 5 minutes; then add hexamethylene chloride dissolved in 5 ml of dichloromethane ( adip〇yi chloride) reaction under ice bath for 30 minutes. Stir for another 30 minutes at room temperature, pass through the oven, add 10 ml of dichloromethane to the salt and filtrate, wash 3 times with 10 ml of saturated brine, and then wash with 10 ml of 5% Citric acid solution 2 Then, water was removed with anhydrous magnesium sulfate, and the organic layer was concentrated to obtain a white solid, which was then crystallized with ethyl acetate and isopropanol to obtain 4.2 g of bisnabuferin adipate ChUA. , Melting point: 78 ~ 79 ° C. Example 1 0 ~ 1 4. According to the preparation method of Example 9, as shown in Table 8, a large number of nabufurin ester compounds were synthesized. Example 15: Sebacoyl dinalbuphine ester (Method 1) In a round-bottomed bottle, 20.2 g of sebacic acid 'and 200 ml of dimethyamine (dimethy 1) were added. amine), ice bath for 5 minutes, 32.4 g of 2-pyridine carbonate (2-pyridine carbonate) was added and stirred for 30 minutes, and 78.7 g of narbuferin hydrochloride and N, N-dimethylamidamine ( Ν, Ν-dimethyl

Page 35-Plug No. 85ΐ〇β15β__Year Month Day_Amendment ___ V. Description of the Invention (28) -aminopyridine) 5g, stir for 30 minutes, move to room temperature for 18 hours and add 'acetic acid to neutralize the pH value Equal to 7, dimethylformamide is distilled off, 500 ml of dichloromethane is added, washed 3 times with 20 ml of saturated brine, and then washed 2 times with 20 ml of 5% Citric acid solution, and sulfuric acid is used. The water was concentrated, and the organic layer was concentrated to give a yellowish solid, which was crystallized from ethyl acetate and n-hexane to obtain 50.2 g of bisnabuferin sebacate. Example 16: Sebacoyl dinalbuphine ester (method two) In a round-bottomed flask, 1.84 g of sebacic acid and 5 ml of dichloromethane were added, and 3.93 g of hydrochloric acid was added at room temperature. Nabufurin and triethylamine react for 30 minutes, ice bath for 5 minutes, filter the salts, concentrate the dioxane solution, add 5 ml of 10% sodium bicarbonate solution to dissolve the oil, and adjust the pH with 5N hydrochloric acid To 2.0, narbuferin sebacate was precipitated, the above narbuferin sebacate was dissolved in 5 ml of dimethylformamide, and bis-2 _pyridine carbonate 2.16 g was added under ice bath. 3.39 g of narbuferin hydrochloride and 1 g of N, N-dimethylamine hydrochloride bite and mix for 30 minutes, and react at room temperature for 18 hours. Dichloromethane was washed three times with 10 ml of saturated saline, and then twice with 10 ml of a 5% citric acid solution. The magnesium sulfate was used to remove the water, and the organic layer was concentrated, and crystallized with ethyl acetate and isopropanol. To obtain sinabufulin sebacate. Example 17:

Page 36 --- Case No. 85106156__Year Month__g__Amendment_ V. Description of the Invention (29) Sinabufulin 1,3-cyclohexane dicarboxylic acid vinegar (1, 3-eye 1 ohexane dicarboxylic acid) acid dinalbuphin.e ester) In a round-bottomed bottle, add 2 g of narbuferin hydrochloride and 10 ml of dichlorohydrazone, and heat on ice for 5 minutes. Drop 1.76 ml of triethylamine and drop 5 ml. Dichloromethane-soluble 0.53 g of 1,3-cyclohexane-dicarboxylic acid chloride (l, 3-cycl0-hexane dicarboxylic acid chloride) was reacted for 30 minutes. "Transfer to room temperature and react for 30 minutes." Ice bath for 5 minutes, filtered Salts and filtrates were added to 20 ml of monogas, washed 3 times with 20 ml of saturated brine, and then washed 2 times with 20 ml of 5% citricacid solution. The magnesium sulfate was removed from the water, and the organic layer was concentrated to obtain a white solid. The product was separated by chromatography to obtain bisnabuferin, CsoHOu, 1,3-cyclo-hexane dicarboxylic acid dinalbuphine ester. Example 18: Sinabufulin + Docosanodioic acid dinalbuphine ester In a round-bottomed bottle, add 2 g of narbuferin hydrochloride and 10 mmol 1 m of dichloromethane, ice bath for 5 minutes, 1.76 ml of triethylamine was added dropwise, 1.03 g of docosanodic di acid chloride dissolved in 5 ml of dichloromethane was added dropwise for 30 minutes, Transfer to room temperature for another 30 minutes' React in ice bath for 5 minutes, filter the salts and filtrate, add 20 ml of dioxane, wash 3 times with 20 ml of saturated brine, and then use 20 ml of 5% lemon

Page 37_Case No. 85106156__ 年月 日 __ V. Description of the Invention (30) The citric acid solution was washed twice, the magnesium sulfate was used to remove the water, and the organic layer was concentrated to obtain a white solid, which was then separated by chromatography. Product with molecular formula 匸 6411921 ^ 2001. Docosanodioic. Acid dinalbuphine ester with a molecular weight of 104.92. Example 19: 3,3-Dimethyl glutaric acid dinalbuphine ester of dinabufurin. 2 g of nabufurin hydrochloride was added to a round-bottomed bottle, and i. 1 ml of dichloromethane, 5 minutes in an ice bath, 1 76 ml of triethylamine was added dropwise, and 0.5 g of 3,3-bismethylpentanefluorene (3,3- (dimethyl-glutaryl chloride) reaction for 30 minutes, transfer to room temperature for another 30 minutes, ice bath for 5 minutes, filter the salts, and add 20 ml of dichloromethane to the filtrate, wash 3 times with 20 ml of saturated saline, and then use 20 04 was washed twice with 5 ml of a solution containing 5% Citric acid, anhydrous magnesium sulfate was removed, the organic layer was concentrated to obtain a white solid, and the product was separated by chromatography to obtain a molecular formula of C49H62N201 () with a molecular weight of 839.04. Buferin 3, 3-dimethylglutar ic acid dinalbuphine ester ° Example 20: trinalbuphine trimesoyl ester (Method 1)

Page 38 Case No. 85106156 V. Description of the invention (31)

In a round-bottomed bottle, add 5 g of narbuferin hydrochloride, and 20 ml of dichloro 2 'in an ice bath for 5 minutes, drip 4.4.4 ml of triethylamine, and then drip into 5 liters of dichloroarsine. The dissolved trimesoyi chloride was reacted in an ice bath for 30 minutes, stirred at room temperature for 30 minutes, and then ice-baked for 5 minutes. The salts were filtered, and the filtrate was added to 2Q 1. Wash 3 times with ml of saturated brine, and then wash twice with a solution of 10.4: formic acid (CUric acid), remove the water with anhydrous magnesium sulfate, add dichloromethane-n-hexane to crystallize, and obtain 4.5 § molecular formula C72H8iN3. 15ter Nabufurin trimellitate. Example 2 1: Trinalbuphine trimes〇yl ester (Method 2) In a four-necked round-bottomed bottle, 18.6 g of this isomeric acid and ml of dichloromethane were placed in an ice bath for 5 minutes. Add 20.3 g of 1-gas 2, 4 nitro glutamate and 9.9 g of pyridine, stir for 30 minutes, add 丨 5. 0 g of narbuferin hydrochloride under ice bath, and at 30 ° C Reaction 18 hours 'Add 2000 ml of dichloromethane' and wash 4 times with 20 ml of saturated brine, and then wash 3 times with 20 ml of 5% Citric acid solution, remove water with magnesium sulfate, and add dichloride Hyun-hyun and n-hexanol crystals' obtained 9 · 1 g of trinabuferin trimellitate. Example 2 2: 1,3,5-Cyclo hexane tricarboxylic acid trinalbuphine

Case No. 85106156 on page 39 V. Description of the invention (32) ester In a round-bottomed bottle, add 2 g of narbuferin hydrochloride and ιmL ml of dichloromethane: ice-bath for 5 minutes, and drop L76 ml of triethylamine s dropwise with 5 ml. 0.46 g of 1,3,5-cyclohexanetristrimium chloride (1, 3, 5 — cyci〇_ hexane tricarboxylic aC1d chl0ride) in diazepam for 5 minutes to 5 React for another 30 minutes at room temperature, ice bath for 5 minutes, filter the salts, add 20 ml of dichloromethane to the filtrate, wash 3 times with 20 ml of saturated saline, and then use 20 ml of a 5% Citricacid solution After washing twice, the magnesium sulfate was used to remove water, and the organic layer was concentrated to obtain a white solid. The product was separated by chromatography to obtain the molecular formula C72H87N3015, Nabufurin with a molecular weight of 1 234, 49, and 3, 5 -cyclohexane. Phosphonic acid ester (1,3,5-Cyclo-hexane tricarboxylic acid trinalbuphine ester) ° Example 23: Pyrome melamine tetraylbuphine ester Add 2 to round bottom bottle G of narbuferin hydrochloride and 10 ml of dichloromethane, ice bath for 5 minutes, drip 1. 76 ml of triethylamine 'drop into 5 0.42 grams of phenylene tetrachloride (Py "⑽eni toy], chloride) dissolved in 1 liter of dichloromethane, reacted for 30 minutes," moved to room temperature and reacted for another 30 minutes, "and ice-bathed for 5 minutes. L2 gas simmered with '0 also: wash 3 times with a liter of saturated brine, and then wash 2 times with a solution containing 0 / () ipanic acid (eight i 11 ΐ c acid), remove the water with anhydrous magnesium sulfate , The organic layer was concentrated to give a white solid

Case No. 85106156 V. Description of Invention (33)

The molecular formula of benzene stilbene is C94H1 () 6N401Q and the molecular weight is ester (P yr omme 1 1 it 〇y 1 body, and then used. Chromatographic separation of the product 1611.88 tetranabuferin tetrana1buphine ester) Example 24 Injection Preparation of dosage form: Take 50.mg of Sebacoyl di-nalbuphine ester, add 50ml of sesame oil, add 1,8mg of methyl paraben, 0.2mg of propyl paraben, 10mg of Pluronic F68. Shake to make a saturated injection solution. Example 25 ~ 36 Preparation of injection solution dosage form 50 mg of Sinabacillin-Second medicine (Sebac 0y I di-nalbuphine ester) is prepared according to the preparation method of Example 24, and a suitable excipient is added as shown in Table 4 2.8 ml of sesame oil can be made into a saturated injection solution by slight shaking.

_ Case No. 85106156_Amended on the date of the month __ Five 'Description of the invention (34) Table 1 adipoyl dinalbuphine ester FAB MS (MH +): 825 (Int, 30¾),] H- NMR (200MHz, DMSO-d ^ δ 6.80 (d, J = 12Hz S1H), 6.62 (d, J = 12Hz, 1H), 4.80 (s, 1H), 4_50 (d, J = 22Hz,: IH), 4.28 (d, J = 22Hz, 1H), 4.00 (br, 1H), 3.0 ~ 1.0 (m, 24H) I3C ~ NMR (δΟΜΗτ ^, ΟΌΟΙ ^ δ 171.7 149.5 132.2 131.5 130.4 122.2 118.2 91.4 69.9, 85.2 61.9, 59.9, 46, 42.9, 40.7, 40.3, 33.1, 32.8, 27.9, 26.5, 26.2, 23.7, 22.9, 18.3 IR (KBr): vcm13600-3100 OH stretch, 2900 CH stretch, 1745 C = 0 stretch. Suseroyl dinalbuphine ester MP.Ί04-105 ° C FABMS (MH +): 853 (Int, 100%) 'H-NMR (50MH2 .CDCyd 6.76 (d, J = 9Hz, 1H), 6.62 (d, J = 9Hz, 1H), 5.05 (br, lH), 4.64 (d, J = 9Hz, 1H), 4.20 (br, lH), 3.2-3.0 (m, 3H), 2.9-1.0 (m, 24H) l3C -NMR (50MHz.CDCls) δ 171.5 (22), 148.4 (3), 133.0 (4), 131.3 (12), 130.7 (11), 121.5 (1), 118.7 (2), 91.5 (5), 70.0 ( 14), 66.5 (6), 62.9 (9), 60.5 (17), 46.1 (13), 43.6 (16), 33.7, 33.6 (23,18), 32.0 (15), 28.4 (25), 26.7, 26.8 (19,21), 26.2 (8), 24.6 (24), 23.9 (7), 23.3 (10), 18.6 ( 20) IR (KBr): vcm 13700-3100 OH stretch, 2900 CH stretch, 1760 C = 0 stretch sebacoyl dinalbuphine ester MP.-130-131 ° C FAB MS (MET) : 881 (Int, 85%), 'H-NMR (200MHZ, DMSO) δ 6.77 (d, J = 8Hz, lH), 6.60 (d, J = 12Hz, lH), 4.78 (s51H), 4.49 (d, J = 16Hz, 1H), 4_24 (d, J = 4Hz, 1H), 4.0 (m, 1H), 3,1 to 1.0 (m, 28H) I3C-NMR (50MHz .CDCl ^) δ 171.7 (22), 148.5 (3), 133.0 (4), 131.1 (12), 130.8 (11), 121.5 (1), 118.8 (2), 9ί. 6 (5), 70.0 (14), 66.6⑹, 62.9 (9), 60.6 (17), 46,1 (13), 43.7 (16), 33.9 (23), 33.6 (18), 32.0 (15), 28,8, 28.9 (25,26), 26.9, 26.7 (19,21 ), 26.2 (8), 24.8 (24), 23.9⑺, 23.3 (10), 18.7 (20), / and 3700 ~ 3100 OH stretch, 3000-2800 CH stretch, 1760 OO stretch.

Page 42__Case No. 85106156_Revision of the Year and Month_ V. Description of the Invention (35) Shuangfang P dobucanedioyl dinalbuphine ester MP: 103-104 ° C FAB MS (MH ^) : 909 (Int, 100%), 'H-NMR (200MHZ .DMSO-d ^ δ 6.76 (d, J = 4Hz, 1H), 6.62 (d, J = 8Hz, 1H), 4.63 (m, lH), 4.17 (br, lH), 3.7 ~ 1.0 (m, 32H), l3C-NMR (50MHZ.CDCls), δ 171.7 (22), 148.5 (3), 133.0 (4), 131.4 (12), 130.7 (11) , 121.5 (1), 118. (2), 91.6 (5), 70.0 (14), 66.6⑹, 63.0 (9), 60.6 (17), 46.1 (13), 43.7 (16), 33.9 (23), 33.6 (18), 32.0 (15), 28.8, 28.9 (25,26), 26.9, 26.7 (19,21), 26.3 (8), 24.9 (24), 24.0 (7), 23.4 (10), 18.7 ( 20), IR (KBr): vcm'13700-3100 OH stretch, 3000-2800 CH stretch, 1760 C = 0 stretch. Isophthaloyl dinalbuphine ester

MP: 155 ~ 156 ° C FAB MS (MH +): 845 (Int, 100%), 'H-NMR (200MHZ, DMSO-d6) (5 8.78 (s, lH), 8.46 (m, lH), 7.86 (m, lH), 7.01 (m, 1H), 6.69 (d, J-8Hz, 1H), 4.81 (s, lH), 4.52 (d, J = 4Hz, 1H), 4.43 (d, J = 6Hz, lH), 3.2-1.0 (m, 20H) l3C-NMR (50 MHZ, DMS0-ds) 5 162.9 (22), 149.4 (3), 135 ~ 129 (23; 26, 4, 12, 11), 122.2 ( 1), 118.3 (2), 91.7 (5), 69.3 (14), human 3700-3200 OH stretch, 3000 ~ 2750 CH stretch, 1728 C = 0 stretch. Phthaloyl dinalbuphine ester) 137 ~ 138 〇C FAB MS (MH +): 845 (Int, 31%), 'H-NMR (200 MHZ, CDCl ^ δ 8.3 (s, 2H), 6.93 (d, J = 8Hz, 1H ), 6.71 (d, J = 8Hz, 1H), 5, l (s; lH), 4.68 (d, J = 4Hz, 1H), I3C-NMR (δΟλίΗζ, ΟΌα ^ 6 163.3 (22), 148.4 (3 ), 133.3 (4), 131.2 (12), 130.4 (11), 121.5 (1), 118.9 (2), 91.8 (5), 70.0 (14), 66.5 (6), 62.9 (9), 60.5 (17 ), 46,1 (13), 43.7 (16), 33.5 (18), 32.0 (15), 26.9, 26.7 (19,21), 26.2 (8), 23.9 (7), 23.3 (10), 18.6 ( 20), / vcm "3700 ~ 3200 OH stretch, 3000 ~ 2750 CH stretch, 1728 C = 0 stretch

Page 43__Case No. 85106156_Amendment of the Year of the Year_ V. Description of the Invention (36) Binabufurin U-cyclohexanedicarboxylic acid vinegar (13-cyc ^ rthp.xane dicarboxylic acid dinalhuphine ester) FAB MSCMIf) : 850 (Int, 100%), lH-NMR (200 MHz, CDCl ^ δ 6.76, (d, J = 4Hz, 1H), 6.64 (d, J = 8Hz, 1H) S 5.10 (br, lH), 4.64 (br, lH), 4.17 (br, lH), 3.15 ~ 1.0 (m, 26H) l3C-NMR (δΟΜΗζ, ΟΏα ^ δ 171.6 (22), 148.4 (3), 133.1 (4), 131.2 (12), 131.0 (11), 121.4 (1), 118.8 (2), 91.7 (5), 70.0 (14), 66.5 (6), 63.0 (9), 60.6 (17) 46.1 (13), 43.7 (16), 41.7 (23), 33.6 (18), 32.0 (15), 30.2 (24), 26.9, 26.7, 26.3 (19, 21, 25), 25.3 (8), 23.9, 23.4 (7, 10), 18.7 (20) 3700 ~ 3100 0-H stretch, 1750 C = 0 Stretch. Docosanodioic acid dinalbuphine ester FAB MS (MFT): 1049 (Int, 30%) FAB high resolution MS = C64H92N2O10 Binabufurin 3,3-Dimethylglutaric acid dinalbuphine ester FAB MS (MH ^): 839 (Int, 89 ° / 〇)! H- NMR (200MHz, COCl ^) δ 6.79 (d, J = 4Hz, 2H), 6.65 (d, J = 8HZ, 2H), 5.10 (br, lH), 4.62 (d, J-4Hz, lH), 4.10 (br, lH), 3.29 (d, J = 4HZ, 1H), 3.10 (sJH), 3.05 (s, lH), 3.0- 1.0 (m, 38H), 3C-NMR (SOMHz.CDCls) δ 169.7 (22), 148.7 (3), 132.9 (4), 130.9 (12,11), 121.7 (1), 118.8 (2), 91.9 ( 5), 70.0 (14), 66.6 (6), 62.9 (9), 60.6 (17), 46.2 (13), 44.5 (23), 43.6 (16), 33.9 (18), 33.2 (15), 32.2 ( 24), 27.9, 26.9, 26.7, 26.5 (19, 21, 25, 8), 23.9, 23.4 (7, 10), 18.7 (20) vcm " 3700 ~ 3100 OH stretch, 3000 ~ 2800 CH stretch, 1750 C = 0 stretch.

Page 44_Case No. 85106156_Year_Day__ V. Description of the Invention (37) Trimesoy trinalbuphine ester MP / 232-233 ° C FAB MS (MIT): 1228 (Int, 50%), Ή-NMR (200MHz, CDCl3) δ 9.24 (s, 1H), 6.93 (d, J = 8HZ, 1H), 6.71 (d, J = 10HZ, 1H), 4.66 (d, J = 1HZ, 1H), 4.20 (br, 1H), 3.20 (m, 2H), 3.1 (m, 2H), 3.0 ~ 1.0 (m, 18H) l3C-NMR (50 MHz. CDCls) δ 162.4 (22) , 148.3 (3), 136.7-130.5 (23,24, 4, 11,12), 121.4 (1), 119.0 (2), 91.9 (5), 70.0 (14), 66.6 (6), 62.9 (9) , 60.5 (17), 46.2 (13), 43.7 (16), 33.6 (18), 32.1 (15), 26.9, 26.7 (19, 21), 26.3 (8), 23.9 (7), 23.4 (10), 18.7 (20), 3700 ~ 3200 OH stretch, 3000 ~ 2800 CH stretch, 1740 OO Stretch. Three men 1 ^ Bufulin 1,3,5-cyclohexyl tricarboxylic acid (1,3,5,-€ yah 〇1〇116 乂 3116 1 ^ 0 化 & (1 Shi ^^ 11311 port 1 ^ 116 65161 ·) FAB MS (MH +): 1234 (Int, 47%), Ή-NMR (200MHz, CDC13) 6 = 6.79 (d, J = 8HZ, 1H), 6.65 (d, J = 8HZ, 1H), 5.10 (br, 1H), 4.65 (d, J-5HZ, 1H), 4.20-4.00 (m, 1H), 3.2 -1.0 (m, 24H) l3C-NMR (50MH2 > CDCl ^ δ 171.6 (22), 148.4 (3), 133.1 (4), 131.1, 131.0 (12,11), 121.3 (1), 118.8 (2), 91.7 (5), 70.0 (14), 66.5 (6), 62.9 (9), 60.5 (17), 46.1 (13), 43.6 (16), 41.6 (23), 33.6 (18), 32.0 (15), 30.1 (24), 26.9, 26.7, 26.3 ( 19, 21, 25), 25.3 (8), 23.9. , 23.3 (10), 18,7 (20). Vcw " 3700 ~ 3100 OH stretch, 3000 ~ 2800 CH stretch, 1750 C = 0 stretch. Pyromellitoyl tetranalbuphine ester FAB MS (MH +): 1611 (Int, 48%), 'H-NMR (200MHZ, CDCl ^ δ 8.57 (s, 2H), 6.79 (d5 J = 8Hz, 4H), 6.65 (d, J = 8HZ, 4H), 5.10 (br, 4H), 4.65 (d, J = 5HZ, 1H), 4.15-4.01 (m, 4H), 3.15-3.06 (m, 8H), 2.91-1.19 (m, 76H) I3C-NMR (50 MHz .CDCls) δ 163.0 (22), 148.5 (3), 134.1 (24), 133.2 (4), 131.4 (12), 131.0 (11), 121.7 (1), 118.8 (2), 91.8 (5), 70.0 (14), 66.5 (6), 64.4 (23), 62.9 (9), 60.6 (17), 46.2 (13), 43.6 (16), 33_6 (18), 32.2 (15), 27.0, 26.8 (19, 21), 25.3 (8), 23.8, 23.5 (7, 10), 18.7 (20). / And vcm- / 3700 ~ 3100 OH stretch, 3000 ~ 2800 CH stretch, 1750 C = 0 stretch.

Page 45 Case No. 85106156 Rev. V. Description of the invention (38) Table II Samples of analysis (Elimination half-life) CCorrelation coefficient (min) of regression line Rat healthy enterprise fluid 2.2 ± 0.5 -0.98 ± 0.03 Plasma 2.8 ±--0.994 ±-Red blood cells hug 2.3 ± 0.6 -0.95 ± 0.05 Rabbit healthy blood and fluid 14.9 ± 1.3 -0.985 ± 0.003 Plasma 6.98 ± 0.03 -0.992 ± 0.002 Red blood cell 26.2 ± 4.8 -0.953 ± 0.03

Page 46 Case No. 85106156 Amendment V. Description of Invention (39) Table 3

Samples of analysis (.Elimination half-life) (.Correlation coefficient (min) of regression line; Dog's healthy blood and fluid 30.5 ± 0.8 -0.9943 ± 0.0008 Enterprise pulp 27.8 ± 0.5 -0 995 ± 0.003 Jiangqi Bed Cells 33.4 ± 1.4 -0.966 ± 0.007 Human healthy enterprise fluid 8.8 persons 0.4 -0.952 ± 0.003 Enterprise pulp 9 0 ± 0.4 -0.93 ± 0 02 Red enterprise ball fine 7.7 ± 0.4 -0.94 ± 0.03 page 47 _ Case No. 85106156_ Amendment 5 、 Explanation of invention (40) 'Table 4 Quantity of injection solution dosage unit / dose popularization example 24 25 26 27 28 29 Sebaooyi Dinalbuphine Ester 〇.7g 30mg / 3.〇g 25mg /2.5g 25mg /2.5g 30mg / 3g 50mg /5.0g Methyl paraben Hydroxybenzyl methyl alcohol: 1.8mg / 0. 8g Propyl paraben Hydroxybenzyl propyl 0.2mg /0.02 g Pluronic F68 Pluronic F68 Pluronic HS 15 Prol & HS15 Span 85 Poems 85 0.2mg / 0.02g 0.2 mg / 0.02g 0.2mg / 0.02g Β 笨 Α Pibentai Cremophor EL Seimae Sesame oil Chito Base Oil 1 ml / 20m! 1ml / 100ml 1ml / 100ml 1ml / 100ml 1 ml / iOOml Imi / 100ml Peanut, oil

Page 48 _Case No. 85106156_ Year Month Day 'Amendment V. Description of Invention (41) Table 5

Test item a on page 49. The effect of the spray wave dosage form is confirmed by analysis. 24 Pale yellow oily solution pass 99.5% 2/8 vials with crystalline ppt 25 Pale yellow oily solution pass 105.2% 2/8 vials with crystalline ppt. 26 Pale yellow oily solution pass 97.0% 97.3% .27 Pale yellow oily solution With white granulate ppt pass 101.2% 101.9% 45 ° C test with crystalline ppt 28 Pale yellow oily'solution With crystalline ppt pass 103.0% 103.6% 45 ° C, 丨 M, 1/2 vial crv-sialline ppt 29 Pale yellow oily solution pass 96.8% 95.7% RT. \ M turbid solution Example 30 Pale yellow oily solution With crystalline ppt pass 107.0% 106.7% 31 Pale yellow oily solution With crystalline ppt pass 102.2% Temp T crystalline ppt T 32 Pale yellow oily solution pass 101.4% 101.3% 33 Pale yellow oily solution pass 101 5% 34 Pale yellow oily solution pass 106 1% 35 Pale yellow oily solution pass 109.6% SPAN 85 0.02% Case No. 85106156 Description of the invention (42) Table 6

Pharmacokinetic parameters Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 Mean 値 standard deviation A (μ ^ ιηΙ) 1 20.9 14.1 9.5 14.1 16.5 15.0 4.2 Β (μ ^ ιηΙ) 1 0.46 0.22 0.32 0.36 0.21 0.32 0.10 a (lZh) 1 8.54 6.85 23.02 4.76 6.74 9.98 7.41 13 (1 / ¾) 1 0.063 0.023 0.024 0.022 0.019 0.030 0.019 MPg / kg / h) 1 129.9 149.9 199.1 249.5 174.9 180.6 46.4 Half-life t1 / 2, a (h) 0.08 0.10 0.03 0.15 0.10 0.09 0.04 Half-life t1 / 2, p (h) 10.94 30.61 28.64 30.99 37.26 27.69 9.91 Zero absorption period (h) 164.5 95.6 49.3 58.0 95.6 92.6 45.4 Main distribution volume Vc 13.88 10.21 14.95 10.65 24.50 14.84 5.77 (I / kg) Stable distribution Volume Vss 360.9 450.1 428.1 303.6 1325 573.5 424 (I / kg) k21 (l / h) 0.25 0.13 0.78 0.14 0.11 0.28 0.29 klOCl / h) 1 2.20 1.21 0.71 0.75 1.23 1.22 0.60 kl2 (l / h) 6.16 5.53 21.55 3.89 5.43 8.51 7.34 Maximum concentration (ng / ml) 59 112 197 255 123 149 77 Area under the concentration curve 9.73 11.88 13.75 19.23 13.64 13.65 3.52 AUC (h ^ g / ml) Bioavailability F (%) 87.9 59.0 40.4 59.6 68.8 63.1 17.3 Concentration times curve 834.4 915.0 8 86.2 1217.4 1063.0 983.2 156.1 Area under AUMC (hVg / ml) Average retention time 84.3 78.8 61.1 62.7 79.1 73.2 10.6 MRT (h) Overall clearance CLt 2.195 1.207 0.714 0.753 1.225 1.219 0.597 (ml / h / kg) Page 50 No. 85106156_ year, month, day, date, five. Description of the invention (43) Table 7 Pharmacokinetic parameters Dog 2 Dog 2 Conversion of Nabufurin dose (mg / kg) 24.3 81.0 A ^ g / ml) 1 14.11 59.00 0.22 0.51 ¢ 1 (1/11) 1 6.85 10.73 βίΐ / h) 1 0.023 0.017 kobg / kg / h) 1 149.9 354.2 half-hearted period tu ^ a (h) 0.10 0.07 half-hearted period ti, 2, p (h) 30.61 41.92 zero times Absorption period (h) 95.63 168.0 Main distribution volume Vc (I / kg) 10.21 10.21 Stable fractional product Vss (i / kg) 450.1 860.6 k21 (l / h) 0.13 0.11 kliKl / h) 1 1.21 1.64 kl2 (l / h) 5.53 8.99 Maximum concentration (ng / ml) 112 204.3 Area under concentration curve AUC (h # g / ml) 11.88 36.23 Area under concentration curve divided by dose AUC / D (h.kg/ml) 0.478 0.488 Bioavailability F (%) 59.0 73.4 Area under the concentration-time curve AUMC (h \ g / mD 915.0 5025.9 Mean residence time MRT (h) 78.8 127.2 Overall clearance CLt (mlVkg) 1.207 1.641 _ No correction five 85106156_ date, description of the invention (44) Table VIII

Page 52 Example Raw Material Product 2 Gasified pivaloyl chloride Nalbuphine pivalate 3 benzoyl chloride benzoyl benzoate Nalbuphine benzoate 4 heptanoyl chloride Nalbuphine enanthate 5 decanoyl chloride Nalbuphine decanoate 6 Behenic anhydride Nalbuphine behenate 7 erucic anhydride nalbuphine erucicate 8 arachidic anhydride arabudic arachidate Nalbuphine arachidate 10 Suseroyl chloride Suseroyl dinalbuphine ester 11 Sebacoyl chloride Sebacoyl dinalbuphine ester

Claims (1)

6. Scope of patent application 1. A type containing a large amount of nabufurin ester and its commonly used salts as shown in the following formula, wherein the R group may optionally be a saturated or unsaturated alkyl group, and the alkyl chain carbon The number is 1 to 30, and the alkyl chain can be selected from (a) a straight-chain alkyl group, (b) a branched alkyl group, (c) a linear alkyl group with a benzene ring, and (d) a benzene ring Cyclic branched alkyl; η value represents that the number of narbuferin ester groups may be 1 to 4 2. A benzene ring containing a large amount of narbuferin vinegar and its commonly used salts as shown in the following formula, in which the R group may optionally have an alkyl substituent on the benzene ring, and the alkyl chain has a carbon number of 1 to 6 '( a) a branched base, (b) a straight-chain alkyl group; the value of η represents the number of nabufurin ester groups' may be 1 to 4. COO I II111 11 C: \ WINDOWS \ Desktop \ Temporary \ 4017.ptc p.53 6. Scope of patent application 1. A type containing a large amount of nabufurin ester and its commonly used salts as shown in the following formula, wherein the R group may optionally be a saturated or unsaturated alkyl group, and the alkyl chain carbon The number is 1 to 30, and the alkyl chain can be selected from (a) a straight-chain alkyl group, (b) a branched alkyl group, (c) a linear alkyl group with a benzene ring, and (d) a benzene ring Cyclic branched alkyl; η value represents that the number of narbuferin ester groups may be 1 to 4 2. A benzene ring containing a large amount of narbuferin vinegar and its commonly used salts as shown in the following formula, in which the R group may optionally have an alkyl substituent on the benzene ring, and the alkyl chain has a carbon number of 1 to 6 '( a) a branched base, (b) a straight-chain alkyl group; the value of η represents the number of nabufurin ester groups' may be 1 to 4. COO I II111 11 C: \ WINDOWS \ Desktop \ Temporary \ 4017. Ptc Page 53 Case No. 85106156 Amendment Month, Day 6, Patent Application _, J 3. If the compound and its salts in item 1 of the patent application, the f / Structure selected from one of the following categories: (a) linear alkyl lb) branched alkyl. 4. For example, apply for a patent, which is also # 1 is 20-30 5. For application for a patent | Special I. Draw the compound of item 1 or 2 and its compound of salts and its salts, where The number can be from 1 to 3. 6. A method for manufacturing a large amount of nabufurin as shown in item 1 of the scope of the patent application, which is made of nabufurin. It is halogenated with fatty acids containing different chain lengths, dehydrated fatty acids (acid anhydrides) or the fatty acid. Esterification of different chain length fatty acids with substituents in the unsaturated, saturated or non-significant state. 7. A method for manufacturing a large amount of nabufurin as shown in item 2 of the scope of the patent application, which consists of nabufurin and a fatty acid containing different chain length fatty acids, dehydrated fatty acids (acid anhydrides) or the fatty acid halides Esterification of different chain length fatty acids containing substituents in saturated, unsaturated or unsaturated states. 8. A pharmaceutical composition having analgesic activity, which contains a suitable pharmaceutical carrier, and an effective amount of a large amount of narbufurin ester as shown in item 1 of the scope of patent application. 9. A pharmaceutical composition having analgesic activity, which contains an appropriate pharmaceutical carrier, and an effective amount of a large amount of nabufurin ester as shown in item 2 of the patent application scope. 10. If the long-acting pharmaceutical combination of item 8 or item 9 of the scope of patent application C: \ WINDOWS \ Desktop \ Temporary \ 4017.ptc Page 54