Prodrug Derivatives of Carboxylic Acid Drugs

Patentamt JEuropaischesEuropean Patent Office Office europeen des brevets © Publication number: 0 278 977 B1 © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification : © Int. CI.5 : C07C 233/01, A61 K 31/21 06.05.92 Bulletin 92/19 © Application number : 87905946.7 @ Date of filing : 25.08.87 © International application number : PCT/DK87/00104 @ International publication number : WO 88/01615 10.03.88 Gazette 88/06 (54) PRODRUG DERIVATIVES OF CARBOXYLIC ACID DRUGS. The file contains technical information (56) References cited : submitted after the application was filed and US-A- 4 588 525 not included in this specification US-A- 4 678 806 CHEMICAL ABSTRACTS, vol. 106, 1987, ab- stract no. 781 87t, 16 March 1987; H. © 26.08.86 DK 4066/86 Priority : BUNDGAARD et al, Esters of N,N-disub- stituted2-hydroxyacetamides as a novel high- © Date of publication of application : ly biolabile prodrug type for carboxylic acid 24.08.88 Bulletin 88/34 agents'' © Publication of the grant of the patent : © Proprietor : Bundgaard, Hans 06.05.92 Bulletin 92/19 36, Tjornevej DK-2970 Horsholm (DK) Niels Mork States Proprietor : NIELSEN, © Designated Contracting : st.th. AT BE CH DE FR GB IT LI LU NL SE Cumberlandsgade 15, DK-2300 Kobenhavn S (DK) References cited 56 : Inventor Hans EP-A- 0 073 397 © : Bundgaard, EP-A- 077 720 36, Tjornevej DK-2970 Horsholm EP-A- 106 541 (DK) Inventor : NIELSEN, Niels Mork EP-A- 201 829 st.th. EP-A- 224 178 Cumberlandsgade 15, DK-2300 Kobenhavn S EP-A- 227 355 (DK) EP-A- 237 051 WO-A-86/00066 © Representative : Andersen, Henrik Rastrup et CH-A- 513 815 al US-A- 4 206 220 c/o Plougmann & Vingtoft Sankt Annae Plads US-A- 4 235 887 11 P.O. Box 3007 CO DK-1021 Copenhagen K (DK) h- h- 00 h- CM Note : Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been LU filed until the opposition fee has been paid (Art. 99(1) European patent convention). Jouve, 18, rue Saint-Denis, 75001 PARIS EP 0 278 977 B1 Description The present invention relates to novel highly biolabile prodrug forms of drugs containing one or more carboxylic acid functions, to methods for preparing the prodrug forms, to pharmaceutical compositions containing 5 such prodrug forms, and to methods for using the prodrug forms. For purposes of this specification, the term "prodrug" denotes a derivative of a known and proven carboxylic acid functional drug (e.g. naproxen, L-dopa, salicylic acid, etc.) which derivative, when administered to warm- blooded animals, e.g. humans, is converted into the proven drug. The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent w carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. These novel prodrug forms are esters of certain hydroxy-amides. These esters combine a high susceptibility to undergo enzymatic hydrolysis in vivo with a high stability in aqueous solution. The new ester prodrug type is further characterized by providing ample possibilities for varying the aqueous solubility as well as the 15 lipophilicity of the prodrug derivatives with retainment of a favourable enzymatic/-non-enzymatic hydrolysis index. Description of the prior art 20 It is well-known that a wide variety of compounds containing carboxylic acid functions are biologically active. For example, such structure is characteristic of non-steroidal anti-inflammatory agents such as naproxen, ibuprofen, indomethacin and the like; penicillin and cephalosporin antibiotics such as ampicillin, cef- metazole and the like; as well as other compounds having diverse biological properties and structures. It is also well-known that such prior art compounds are characterized by certain inherent disadvantages, 25 notably bioavailability problems upon administration via oral, rectal or topical routes. The unionized form of a drug is usually absorbed more efficiently than its ionic species and as the carboxylic acid functional group is significantly ionized at physiological pH, the result is that carboxylic acid agents are poorly absorbed through lipid-water membrane barriers. In addition, by suffering from reduced bioavailability, some acidic drugs, notably non-steroidal anti-inflammatory agents (ibuprofen, tolmetin, naproxen, indomethacin, etc.), are irritating to the 30 mucous membrane of the gastro-intestinal tract. A promising approach to solve such problems may be esterification of the carboxylic acid function to pro- duce lipophilic and non-irritating prodrug forms, provided that the biologically active parent drug can be released from the prodrug form at its sites of activity. However, several aliphatic or aromatic esters of carboxylic acid drugs are not sufficiently labile in vivo to ensure a sufficiently high rate and extent of prodrug conversion. For 35 example, simple alkyl and aryl esters of penicillins are not hydrolyzed to active free penicillin acid in vivo (Holysz & Stavely, 1950) and therefore have no therapeutic potential (Ferres, 1983). Similarly, the much reduced anti- inflammatory activity observed for the methyl or ethyl esters of naproxen (Harrison et al., 1970) and fenbufen (Child et al., 1977) relative to the free acids may be ascribed to the resistance of the esters to be hydrolyzed in vivo. In the field of angiotensin-converting enzyme inhibitors ethyl esters have been developed as prodrugs 40 for the parent active carboxylic acid drugs in order to improve their oral bioavailability. Enalapril is such a clini- cally used ethyl ester prodrug of enalaprilic acid. Plasma enzymes do not hydrolyze the ester and the necessary conversion of the ester to the free acid predominantly takes place in the liver (Tocco et al., 1 982; Larmour et al., 1 985). As recently suggested (Larmour et al., 1 985), liver function may thus be a very important determinant for the bioactivation of enalapril and hence its therapeutic effect. The limited susceptibility of enalapril to 45 undergo enzymatic hydrolysis in vivo has been shown to result in incomplete availability of the active parent acid (Todd & Heel, 1986). Pentopril is another ethyl ester prodrug of an angiotensin-converting enzyme inhibitor which also is highly stable in human plasma. In this case less than 50% of an oral dose of the prodrug ester appears to be deesterified in vivo to the active parent acid (Rakhit & Tipnis, 1984; Tipnis & Rakhit, 1985). As has been demonstrated in the case of penicillins (Ferres, 1983) these shortcomings of some ester prod- 50 rugs may be overcome by preparing a double ester type, acyloxyalkyl or alkoxycarbonyloxyalkyl esters, which in general show a higher enzymatic lability than simple alkyl esters. The general utility of this double ester con- cept in prodrug design is, however, limited by the poor water solubility of the esters of several drugs and the limited stability of the esters in vitro. In addition, such esters are oils in many cases, thus creating pharmaceutical formulation problems. 55 In view of the foregoing, it is quite obvious that a clear need exists for new ester prodrug types possessing a high susceptibility to undergo enzymatic hydrolysis in plasma or blood and furthermore being characterized by providing ample possibilities for varying or controlling the water and lipid solubilities. In accordance with the present invention it has now been discovered that esters of the formula I below are 2 EP 0 278 977 B1 surprisingly rapidly cleaved enzymatically in vivo, e.g. by plasma enzymes, and fulfil the above-discussed desi- rable attributes. A few compounds related to certain compounds of formula I have been reported in the literature. Thus, Boltze et al. (1980) have described various N-unsubstituted and N-monosubstituted 2-[1-(p-chloro-benzoyl)-5- 5 methoxy-2-methylindole-3-acetyloxy]-acetamide derivatives having anti-inflammatory properties. Similarly, some acetamide derivatives of flufenamic acid have been reported by Boltze & Kreisfeld (1977). 2-[2-(Acety- loxy)benzoyloxy]-acetamide and other related ester derivatives of acetylsalicylic acid are disclosed in Ger. Offen. 2,320,945. However, there is no suggestion that the compounds described have any prodrug activity, and enzymatic w hydrolysis of the compounds into the parent carboxylic acid drugs is neither explicitly nor implicitly mentioned. CH-A-513 815 relates to halophenoxyisobutyric acid and hydroxy-aliphatic acid derivatives, especially to esters of clofibric acid. The compounds have an ester group as well as a further ester or amide group, the two groups being separated from each other by a propylene group, i.e. three methylene units. In contrast thereto, compounds according to the present invention (formula I) have only one methylene unit which separates the 15 ester and amide groups. EP-A-77 720 relates to biphenyl acetic acid derivatives which per se are described as possessing anti- inflammatory and analgetic properties, i.e. the compounds are not prodrug compounds. US-4 588 525 relates to prodrug compounds for dermal application of topical medicaments. Ester compounds of retinoic acid are described in which the ester group is separated from an amide group by means of 20 three methylene units. In contrast thereto the compounds according to the present invention only have one methylene unit between the ester and amide group. US-4 206 220 relates to hydroxyamine derivatives of non-steroidal anti-inflammatory drugs and the derivatives are said to be prodrug forms of the parent drug compounds. However, the structures of these compounds differ from the structures of the compounds according to the present invention in that the hydroxyamine 25 derivatives do not at the same time have an ester group as well as an amide group.

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