申请人：Schering Corporation
公开号：US04237051A1
公开（公告）日：1980-12-02
Reaction of 6- or 7-diazo-.beta.-lactams with allylic halides in the presence of a catalytic amount of metallic copper or a copper salt affords 6- or 7-carbon-substituted-.beta.-lactams with the desired stereochemical configuration at the 6- or 7-position. Subsequent reduction with a trialkyl stannane affords useful intermediates for further syntheses affording 6- or 7-carbon-substituted-.beta.-lactams. The present invention relates to a process for the production of 6- or 7-carbon-substituted-.beta.-lactams having the desired stereochemical configuration at the 6- or 7-position. More particularly, this invention provides a process for the preparation of a .beta.-lactam of the formula ##STR1## wherein R.sub.1 is cyano or COOR.sub.2 wherein R.sub.2 is a readily removable ester-forming moiety, hydrogen or an alkali-metal cation; R.sub.3 and R.sub.4 are independently hydrogen, lower alkyl, aryl or aralkyl; Z is a group of the formula ##STR2## wherein R.sub.5 is hydrogen, lower alkyl or aralkyl; and the dotted line indicates the optional presence of a double bond; which comprises (1) reacting a diazo-.beta.-lactam of the formula ##STR3## wherein Y is a sulfur or an oxygenated sulfur atom and Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinbefore defined; with an allyl halide of the formula ##STR4## wherein R.sub.3 and R.sub.4 are as hereinbefore defined and X is bromo or iodo; in the presence of a catalytic amount of metallic copper or a copper salt; and where Y is an oxygenated sulfur atom, followed by transformation of the resultant oxygenated sulfur intermediate to a compound wherein Y is a sulfur atom; and (2) subjecting the resultant intermediate of the formula ##STR5## wherein X, Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinabove defined, to reduction with a trialkyl stannane to afford the compound of formula I. The lower alkyl groups referred to contain 1 to 6 carbon atoms and are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched-chain isomers thereof. The lower alkoxy groups referred to above likewise contain 1 to 6 carbon atoms and are exemplified by methoxy, ethoxy, propoxy, and the like. The term "aryl" as used herein refers to phenyl substituted by one or more substituent groups selected from among chloro, bromo, fluoro, lower alkyl, hydroxy, nitro, amino, aminomethyl, lower monoalkylamino, lower dialkylamino, lower alkoxy and carboxy. Such aryl groups represented by R.sub.1 can be, for example, 4-hydroxyphenyl, 3,4-dichlorophenyl, 2,6-dimethoxyphenyl, 4-methylphenyl, 2-fluorophenyl, 4-carboxyphenyl, 3-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 4-dimethylaminophenyl, 4-aminomethylphenyl and 4-ethoxyphenyl. The term "aralkyl" encompasses aryl-substituted lower alkyl groups such as benzyl, phenethyl, p-fluorobenzyl, o-tolylethyl and m-hydroxy-phenethyl. The process of this invention initially involves the reaction of a diazo-.beta.-lactam of formula II and the allyl halide of formula III in the presence of a catalytic amount of metallic copper or a copper salt to induce the decomposition of the diazo-.beta.-lactam at temperatures of about 0.degree.-50.degree. C. to provide the intermediate of formula IV. The diazo-.beta.-lactam utilizable in this step of the invention may be any type of readily removable ester-blocked acid, i.e., the compound of formula II wherein R.sub.1 is COOR.sub.2 or a nitrile, i.e., the compound of formula II wherein R.sub.1 is cyano. Preferably, benzyl or benzhydryl esters are employed in the reaction wherein R.sub.1 is COOR.sub.2. The starting materials of formula II wherein Y is oxygenated sulfur are preferred due to the stability of the starting compound. However, the reaction using the equivalent sulfide also proceeds with good yields and avoids the need for a subsequent deoxygenation step. The allyl halides of formula III utilizable in the present invention are those wherein the halogen is iodine or bromine with iodine being most particularly preferred. The allyl halide of formula III may be substituted by lower alkyl, aryl or aralkyl groups. Those compounds wherein R.sub.3 and R.sub.4 are methyl or phenyl are preferred. The copper compound utilizable as a catalyst for this step of the instant invention may be almost any copper salt or finely divided elemental copper. Preferably, 1-10 mole percent of the copper or copper salt is utilized. The most preferred catalysts are cuprous chloride and copper (II)-2,4-pentanedioate. In order to maximize the yield for this step of the instant invention, it is preferable to use a large excess of the allyl halide of formula III. Most preferably, allyl bromide or allyl iodide is used as the reaction medium. Substituted allyl halides of formula III are preferably diluted with a non-polar co-solvent such as methylene chloride. Polar solvents may also be used, e.g., dimethylformamide, dimethylsulfoxide or acetonitrile, but these provide poorer yields. The reaction is preferably carried out at room temperature; however, depending on the nature of the starting materials, the reaction temperatures may range from about 0.degree. to 50.degree. C. Occasionally, warming to about 40.degree. C. is utilized to initiate the reaction which is then continued without further heating. The stereochemistry at C-6 or C-7 of the intermediate of formula IV is generally a mixture of alpha and beta compounds. Generally, use of the bromides gives a higher ratio of beta to alpha compounds, i.e., 5 to 6:1. Use of the iodides gives more approximately equal amounts of the alpha and beta isomers. The reduction of step 2 to afford the cis product of formula I is accomplished using trialkyl stannane (trialkyl tin hydride). Preferably, tri-n-butyl stannane is utilized. The intermediate of formula IV is heated at about 60.degree.-100.degree. C. with 1-2 equivalents of the tin hydride in an inert solvent. Preferred solvents are tetrahydrofuran, benzene and toluene. Typically, the product is separated by chromatography in yields of greater than 80%. The compounds of formula II wherein Y is an oxygenated sulfur atom may be obtained from the corresponding compounds wherein Y is sulfur by any of the conventional oxidation procedures, e.g., ozone, iodobenzene dichloride in aqueous pyridine, etc. An oxygenated sulfur penicillin compound, i.e., wherein Z is ##STR6## may then be converted to the corresponding cephalosporin, i.e., wherein Y is S and Z is ##STR7## by various literature methods. See, for instance, Flynn, "Cephalosporins and Penicillins", Academic Press, pp. 193-199 and 670-673 (1972). By such methods benzyl 6.beta.-allyl-6.alpha.-bromopenicillanate-1.beta.-oxide may be converted to benzyl 7.beta.-allyl-6.alpha.-bromo-3-methyl-3-cephem-4-carboxylate. The sulfoxide compound is also particularly useful wherein it is desired to convert a mixture of 2- and 3-cephem compounds to a pure 3-cephem compound. The 6- or 7-diazo starting materials of formula II are preparable via a variety of literature methods or variations thereof. A preferred method involves degradation of the penicillin or cephalosporin side chain via the N-nitroso derivative as described by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967); and Sheehan, J. Org. Chem., 39, 1444 (1974). This process involves treatment of the penicillin or cephalosporin, e.g., benzylpenicillin benzyl ester or benzhydryl ester, to form the N-nitroso derivative, followed by decomposition of the nitroso amide side chain with methylene chloride-pyridine or methylene chloride at about 40.degree. C. to afford the diazo compound. An improvement of this process, omitting the pyridine and allowing the reaction to proceed at room temperature in a polar solvent, e.g., dimethylsulfoxide or dimethylformamide, affords a cleaner reaction and better conversion, i.e., >90%. This reaction sequence may be represented by the following scheme: ##STR8## wherein Y, Z and R.sub.1 are as hereinbefore defined. Preferable by this route are the following: benzyl 6-diazopenicillanate; benzhydryl 6-diazopenicillanate; 6-diazopenicillanonitrile; and benzyl 7-diazo-3-methylcephalosporanate. Another modification of the decomposition step in the preparation of the starting materials of formula II is to utilize triphenylphosphine and water in place of the methylene chloride and pyridine according to the method of Sheehan, J. Org. Chem., 42, 1012 ( 1977) to afford the hydrazone of the formula: ##STR9## Oxidation of this hydrazone by the method of U.S. Pat. No. 3,880,837 affords the desired diazo compound. This route is particularly preferred for the cephalosporin starting materials of this invention. Preparable by this route are the following: benzhydryl 7-diazo-3-methylcephalosporinate; benzhydryl 7-diazo-3-acetoxymethylcephalosporinate; and benzhydryl 6-diazopenicillanate. An additional method for preparing the 6- or 7-diazo compounds of formula II involves diazotisation of the corresponding amino compounds using nitrous acid according to the procedure originally carried out by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967) and further delineated in J. Amer. Chem. Soc., 94, 1408 (1972) and J. Org. Chem., 41, 1578 (1976). Once prepared, the compounds of formula I are utilizable to prepare various 6- or 7-substituted-.beta.-lactams having useful antimicrobial activity, many of which are known in the art. For instance, ozonolysis of 6.beta.-(allyl)penicillanonitrile, benzyl 6.beta.-(allyl)penicillanate or benzhydryl 6.beta.-allylpenicillanate affords 6.beta.-(formylmethyl)-penicillanonitrile, benzyl 6.beta.-(formylmethyl)penicillanate and benzhydryl 6.beta.-(formylmethyl)penicillanate, respectively. This ozonolysis is carried out according to standard methodology. The aldehyde obtained by the ozonolysis described in the preceding paragraph may then be subjected to reduction utilizing a mild reducing agent such as sodium borohydride to afford the corresponding alcohol. For instance, obtainable by this reaction is 6.beta.-(2-hydroxyethyl)penicillanonitrile, benzyl 6.beta.-(2-hydroxyethyl)penicillanate and benzhydryl 6.beta.-(2-hydroxyethyl)penicillanate. The ester group of the preceding two compounds may, of course, be removed utilizing standard hydrogenolysis typically with a palladium catalyst to afford the resulting free acids. Workup with a weak base, e.g., potassium carbonate or sodium carbonate, will afford the potassium or sodium salts, e.g., potassium 6.beta.-(2-hydroxyethyl)penicillanate or sodium 6.beta.-(2-hydroxyethyl)penicillanate. Oxidation of the aldehydes obtainable by the ozonolysis procedure affords the corresponding carboxylic acids. For instance, benzhydryl 6.beta.-(formylmethyl)penicillanate treated with chromic acid in acetone and water affords benzhydryl 6.beta.-(carboxymethyl)penicillanate. Reaction of the foregoing carboxylic acids with suitable azides provides various homo-penicillanates. For instance, benzhydryl 6.beta.-(carboxymethyl)penicillanate treated with diphenylphosphoryl azide and triethylamine at a reaction temperature of about 80.degree. C. according to the method of Ninomiya, et. al., Chem. Pharm. Bull. Japan, 22, 1398 (1974), affords benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate which is typically not isolated. Treatment of this intermediate with the desired acid or alcohol provides homopenicillanates which then may be optionally deblocked. Obtainable in this method are potassium 6.beta.-(phenylacetamidomethyl)penicillanate and potassium 6.beta.-(ethoxycarbonylaminomethyl)penicillanate. Treatment of benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate with trichloroethanol followed by a zinc/acetic acid reduction affords benzhydryl 6.beta.-(aminomethyl)penicillanate. Conventional deblocking of this compound then affords 6.beta.-(aminomethyl)penicillanic acid. Several of the foregoing compounds are described by Sheehan, et. al. as having useful and interesting antimicrobial activity in German Pat. Nos. 2,416,492 and 2,643,085. However, 6.beta.-(aminomethyl)penicillanic acid has not heretofore been described in any publication and is therefore a novel compound. The 6.beta.-(aminomethyl)penicillanic acid produced by the process of this invention possesses antibacterial activity. Additionally, it is a penicillinase inhibitor which may be used concomitantly with other penicillin-type antibiotics in infection therapy. Thus, when tested in standardized microbiological assays, this compound exhibits activity vis-a-vis such organisms as Staphylococcus aureus, Klebsiella, Bacillus subtilis, and Pseudomonas aeruginosa at test levels of 0.1 to 100 .mu.cg/ml. Thus, as antibacterial agents this compound is conventionally formulated for oral, intramuscular, intravenous or topical therapy. Thus, the present invention includes within its scope pharmaceutical compositions comprising an antibacterially effective amount of the novel 6.beta.-(aminomethyl)penicillanic acid with a compatible pharmaceutical carrier therefor, and a method of using such compositions for the treatment of microbial infections. The dosage administered of this compound is dependent upon the age and weight of the animal species being treated, the mode of administration, and the type and severity of bacterial infection being prevented or reduced. Typically, the dosage administered per day will be in the range of 100-5000 mg with 500-1000 mg being preferred. For oral administration, this compound may be formulated in the form of tablets, capsules, elixirs or the like. For parenteral administration it may be formulated into solutions or suspensions for intramuscular injection. Topical formulations include creams, ointments, gels and the like.
在微量金属铜或铜盐的催化下，6-或7-重氮-.beta.-内酰胺与烯丙基卤化物的反应，可得到在6-或7位具有所需立体化学配置的6-或7-碳取代-.beta.-内酰胺。随后使用三烷基锡烷进行还原，可得到适用于进一步合成6-或7-碳取代-.beta.-内酰胺的有用中间体。本发明涉及一种生产在6-或7位具有所需立体化学配置的6-或7-碳取代-.beta.-内酰胺的方法。更具体地，本发明提供了一种制备具有以下公式的.beta.-内酰胺的方法：
##STR1##
其中R1是氰基或COOR2，其中R2是易于移除的酯形成基团、氢或碱金属阳离子；R3和R4独立地为氢、低级烷基、芳基或芳烷基；Z是具有以下公式的基团：
##STR2##
其中R5是氢、低级烷基或芳烷基；虚线表示双键的可选存在；该方法包括：(1)将具有以下公式的重氮-.beta.-内酰胺：
##STR3##
其中Y是硫或氧化的硫原子，Z、R1、R3和R4如前所述；与具有以下公式的烯丙基卤化物反应：
##STR4##
其中R3和R4如前所述，X是溴或碘；在微量金属铜或铜盐的存在下；当Y是氧化的硫原子时，随后将所得的氧化的硫中间体转化为Y为硫原子的化合物；以及(2)将具有以下公式的所得中间体：
##STR5##
其中X、Z、R1、R3和R4如前所述，进行还原，使用三烷基锡烷得到公式I的化合物。所提及的低级烷基含有1至6个碳原子，例如甲基、乙基、丙基、丁基、戊基、己基及其相应的支链异构体。所提及的低级烷氧基同样含有1至6个碳原子，例如甲氧基、乙氧基、丙氧基等。术语“芳基”如本文所用，指的是被一个或多个选自氯、溴、氟、低级烷基、羟基、硝基、氨基、氨基甲基、低级单烷基氨基、低级二烷基氨基、低级烷氧基和羧基的取代基团取代的苯基。代表R1的此类芳基可以是例如4-羟基苯基、3,4-二氯苯基、2,6-二甲氧基苯基、4-甲基苯基、2-氟苯基、4-羧基苯基、3-硝基苯基、4-氨基苯基、3-氨基苯基、4-二甲基氨基苯基、4-氨基甲基苯基和4-乙氧基苯基。术语“芳烷基”包括被芳基取代的低级烷基基团，如苄基、苯乙基、对氟苄基、邻甲苯乙基和间羟基苯乙基。本发明的过程首先涉及在微量金属铜或铜盐的存在下，将公式II的重氮-.beta.-内酰胺与公式III的烯丙基卤化物反应，以在约0°至50°C的温度下诱导重氮-.beta.-内酰胺的分解，提供公式IV的中间体。在本发明这一步骤中可用的重氮-.beta.-内酰胺可以是任何类型的易于移除的酯阻断酸，即公式II的化合物，其中R1是COOR2或腈，即公式II的化合物，其中R1是氰基。优选地，在R1是COOR2的反应中使用苄基或二苄基酯。由于起始化合物的稳定性，公式II的起始材料，其中Y是氧化的硫，是优选的。然而，使用等效硫化物的反应也以良好的产率进行，并避免了随后的脱氧步骤的需要。在本发明中可用的公式III的烯丙基卤化物是那些卤素为碘或溴的，其中碘是最特别优选的。公式III的烯丙基卤化物可以被低级烷基、芳基或芳烷基基团取代。那些R3和R4为甲基或苯基的化合物是优选的。在本发明这一步骤中可用的铜化合物可以是几乎任何铜盐或细分的金属铜。优选地，使用1-10摩尔百分比的铜或铜盐。最优选的催化剂是氯化亚铜和铜(II)-2,4-戊二酸酯。为了最大化本发明这一步骤的产率，优选使用大量过量的公式III的烯丙基卤化物。最优选地，作为反应介质使用烯丙基溴或烯丙基碘。公式III的取代烯丙基卤化物优选地用非极性共溶剂如二氯甲烷稀释。也可以使用极性溶剂，例如二甲基甲酰胺、二甲基亚砜或乙腈，但这些提供较差的产率。反应优选在室温下进行；然而，根据起始材料的性质，反应温度可以从约0°到50°C。偶尔，加热到约40°C以启动反应，然后在没有进一步加热的情况下继续进行。公式IV的中间体在C-6或C-7的立体化学通常是α和β化合物的混合物。一般来说，使用溴化物给出β到α化合物的更高比例，即5到6:1。使用碘化物给出α和β异构体更接近相等的量。步骤2的还原以得到公式I的顺式产物是通过使用三烷基锡烷（三烷基锡烷氢化物）完成的。优选地，使用三正丁基锡烷。将公式IV的中间体在约60°至100°C下与1-2当量的锡烷在惰性溶剂中加热。优选的溶剂是四氢呋喃、苯和甲苯。通常，产品通过色谱法分离，产率超过80%。公式II的化合物，其中Y是氧化的硫原子，可以通过任何常规氧化程序从相应的Y为硫的化合物获得，例如臭氧、碘苯二氯化物在水性吡啶中等。氧化的硫青霉素化合物，即Z为：
##STR6##
可以然后通过各种文献方法转换为相应的头孢菌素，即Y为S且Z为：
##STR7##
例如，参见Flynn，“头孢菌素和青霉素”，学术出版社，第193-199页和670-673页（1972）。通过这些方法，苄基6.β.-烯丙基-6.α.-溴青霉烷酸-1.β.-氧化物可以转换为苄基7.β.-烯丙基-6.α.-溴-3-甲基-3-头孢-4-羧酸酯。当希望将2-和3-头孢化合物混合物转换为纯3-头孢化合物时，亚砜化合物也特别有用。公式II的6-或7-重氮起始材料可以通过各种文献方法或其变体制备。优选的方法涉及通过N-亚硝基衍生物描述的青霉素或头孢菌素侧链的降解，如Hausler和Sigg，Helv. Chim. Acta.,1327（1967）；以及Sheehan，J. Org. Chem.,39,1444（1974）。该过程涉及处理青霉素或头孢菌素，例如苄基青霉素苄基酯或二苄基酯，形成N-亚硝基衍生物，然后在大约40°C的甲基氯仿-吡啶或甲基氯仿中分解亚硝基酰胺侧链，得到重氮化合物。对该过程的改进，省略了吡啶并允许反应在极性溶剂如二甲基亚砜或二甲基甲酰胺中在室温下进行，提供了更清洁的反应和更好的转换，即>90%。该反应序列可以由以下方案表示：
##STR8##
其中Y、Z和R1如前所述。通过这条路线优选的是以下：苄基6-重氮青霉烷酸酯；二苄基6-重氮青霉烷酸酯；6-重氮青霉烷腈；和苄基7-重氮-3-甲基头孢菌酸酯。在制备公式II的起始材料的分解步骤的另一种修改是使用三苯基膦和水代替甲基氯仿和吡啶，根据Sheehan的方法，J. Org. Chem.,42,1012（1977），得到具有以下公式的肼：
##STR9##
根据美国专利第3,880,837号方法氧化此踪可得到所需的重氮化合物。此路线特别适用于本发明中的头孢菌素起始原料。通过此路线可制备以下物质：苯并二氢吡喃-7-重氮-3-甲基头孢菌酸酯；苯并二氢吡喃-7-重氮-3-乙酰氧甲基头孢菌酸酯；以及苯并二氢吡喃-6-重氮青霉烷酸酯。制备公式II中6-或7-重氮化合物的另一种方法涉及使用亚硝酸对相应氨基化合物进行重氮化，该方法最初由Hausler和Sigg在Helv. Chim. Acta.,1327 (1967)中描述，并在J. Amer. Chem. Soc.,94,1408 (1972)和J. Org. Chem.,41,1578 (1976)中进一步详细说明。一旦制备完成，公式I中的化合物可用于制备各种6-或7-取代的β-内酰胺，这些化合物具有有用的抗微生物活性，其中许多已为业界所知。例如，6.β.-(烯丙基)青霉烷腈、苄基6.β.-(烯丙基)青霉烷酸酯或苯并二氢吡喃-6.β.-烯丙基青霉烷酸酯的臭氧化反应分别产生6.β.-(甲酰甲基)青霉烷腈、苄基6.β.-(甲酰甲基)青霉烷酸酯和苯并二氢吡喃-6.β.-(甲酰甲基)青霉烷酸酯。此臭氧化反应按照标准方法进行。前述段落中描述的臭氧化反应得到的醛可以通过使用如硼氢化钠等温和还原剂还原，得到相应的醇。例如，通过此反应可得到6.β.-(2-羟乙基)青霉烷腈、苄基6.β.-(2-羟乙基)青霉烷酸酯和苯并二氢吡喃-6.β.-(2-羟乙基)青霉烷酸酯。前述两种化合物中的酯基当然可以通过标准氢解（通常使用钯催化剂）去除，得到相应的自由酸。使用弱碱（如碳酸钾或碳酸钠）处理，将得到钾盐或钠盐，例如钾6.β.-(2-羟乙基)青霉烷酸酯或钠6.β.-(2-羟乙基)青霉烷酸酯。通过臭氧化反应得到的醛的氧化可以得到相应的羧酸。例如，苯并二氢吡喃-6.β.-(甲酰甲基)青霉烷酸酯在丙酮和水中用铬酸处理，得到苯并二氢吡喃-6.β.-(羧甲基)青霉烷酸酯。上述羧酸与适当的叠氮化物反应可以提供各种同型青霉烷酸酯。例如，苯并二氢吡喃-6.β.-(羧甲基)青霉烷酸酯在约80°C的反应温度下，按照Ninomiya等人（Chem. Pharm. Bull. Japan,22,1398 (1974)）的方法，与二苯基磷酰叠氮和三乙胺反应，得到苯并二氢吡喃-6.β.-(羰基氨基甲基)青霉烷酸酯，该中间体通常不进行分离。将此中间体与所需的酸或醇反应，得到同型青霉烷酸酯，然后可以进行选择性脱保护。通过此方法可得到钾6.β.-(苯乙酰氨基甲基)青霉烷酸酯和钾6.β.-(乙氧羰基氨基甲基)青霉烷酸酯。苯并二氢吡喃-6.β.-(羰基氨基甲基)青霉烷酸酯与三氯乙醇反应后，通过锌/乙酸还原，得到苯并二氢吡喃-6.β.-(氨基甲基)青霉烷酸酯。对此化合物进行常规脱保护，得到6.β.-(氨基甲基)青霉烷酸。Sheehan等人描述了上述几种化合物在德国专利第2,416,492号和第2,643,085号中具有有用和有趣的抗微生物活性。然而，6.β.-(氨基甲基)青霉烷酸在此前未在任何出版物中描述过，因此是一种新化合物。本发明过程中产生的6.β.-(氨基甲基)青霉烷酸具有抗菌活性。此外，它是一种青霉素酶抑制剂，可与其他青霉素类抗生素联合用于感染治疗。因此，在标准微生物学测定中测试时，该化合物对金黄色葡萄球菌、克雷伯菌、枯草杆菌和铜绿假单胞菌等微生物在0.1至100微克/毫升的测试水平上显示出活性。因此，作为抗菌剂，该化合物通常被配制成口服、肌肉注射、静脉注射或局部治疗的形式。因此，本发明包括其范围内的药物组合物，该组合物包含有效量的新6.β.-(氨基甲基)青霉烷酸和兼容的药物载体，以及使用这些组合物治疗微生物感染的方法。该化合物的给药剂量取决于被治疗动物的年龄和体重、给药方式以及预防或减少的细菌感染的类型和严重程度。通常，每日给药剂量将在100-5000毫克范围内，其中500-1000毫克为首选。对于口服给药，该化合物可以制备成片剂、胶囊、糖浆等形式。对于肠胃外给药，它可以制备成用于肌肉注射的溶液或悬浮液。局部制剂包括乳膏、软膏、凝胶等。
