DK167007B1 - Prodrug derivatives of carboxylic acid medicaments, a process for preparing them, and a preparation which comprises these derivatives - Google Patents

Description

in DK 167007 B1

The present invention relates to novel highly biolabile prodrug forms of the general formula I of drugs containing one or more carboxylic acid functions, methods of preparing the prodrug forms, pharmaceutical compositions containing such prodrug forms and methods of using the prodrug forms.

In this specification and claims, the term "prodrug" refers to a derivative of a known and used 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 to the 10 drugs already known. The enzymatic and / or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a way that the known drug form (the carboxylic acid drug itself) is released and the cleaved molecule (s) remain nontoxic or metabolized in such a way. that 15 non-toxic metabolic products are obtained.

These novel prodrug forms are esters of certain hydroxyamides.

In these esters, a strong tendency to undergo enzymatic hydrolysis in vivo is combined with high stability in aqueous solution. The novel type of ester prodrug is further characterized in that it provides ample opportunities to both vary the water solubility and lipophilicity of the prodrug derivatives while maintaining a favorable enzymatic / non-enzymatic hydrolysis index.

It is known that a wide variety of compounds containing carboxylic acid functions are biologically active. For example, such a structure is characteristic of non-steroidal anti-inflammatory agents such as naproxen, ibuprofen, indomethacin and the like; penicillin and cephalosporin antibiotics such as ampicillin, cefmetazole and the like; as well as other compounds with different biological properties and structures.

It is also known that such known compounds are characterized by having certain inherent disadvantages, especially problems with bioavailability after oral, rectal or topical administration. The non-ionized form of the drug is usually more efficiently absorbed than the ionic forms, and as the carboxylic acid functional group is significantly ionized at physiological pH, the result is that the carboxylic acid agents are poorly absorbed through lipid-water membrane barriers. In addition, certain acidic drugs, especially non-steroidal anti-inflammatory agents (ibuprofen, tolmetine, naproxen, indomethacin, etc.), are irritating to the gastrointestinal tract mucosa, in addition to their reduced bioavailability.

A promising way to solve such problems may be esterification of the carboxylic acid function to form lipophilic and non-irritating prodrug forms, provided that the biologically active original drug can be released from the prodrug form at the sites of action. However, several aliphatic or aromatic esters of carboxylic acid drugs are not sufficiently labile in vivo to ensure a sufficiently high rate and degree of prodrug conversion.

For example, simple alkyl and aryl esters of penicillins 15 are not hydrolyzed to active free penicillic acid in vivo (Holysz & Stavely, 1950) and therefore have no therapeutic potential (Ferres, 1983). Similarly, the greatly reduced anti-inflammatory effect observed for methyl or ethyl esters of naproxen (Harrison et al., 1970) and fenbufen (Child et al., 1977) relative to the 20 free acids can be attributed to the resistance of the esters. against being hydrolyzed in vivo. In the field of angiotensin-converting enzyme inhibitors, ethyl esters have been developed as prodrugs for the original active carboxylic acid drugs to improve their oral bioavailability. Enalapril is one such clinically 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 takes place mainly in the liver (Tocco et al., 1982; Larmour et al., 1985). Thus, as recently suggested (Larmour et al., 1985), liver function may be a very important determinant of the bioactivation of enalapril and thus the therapeutic effect. Enalapril's limited propensity to undergo enzymatic hydrolysis in vivo has been shown to result in incomplete availability of the active original acid (Todd &

Heel, 1986). Pentopril is another ethyl ester prodrug of an angiotensin-converting enzyme inhibitor, which is also very stable in human plasma. In this case, it is found that less than 50% of an oral dose of the prodrug ester is deesterified in vivo to the active native acid (Rakhit & Tipnis, 1984; Tipnis & Rakhit, 1985).

3 DK 167007 B1

As shown in the case of penicillins (Ferres, 1983), these deficiencies in some ester prodrugs can be remedied by producing a double ester type, namely acyloxyalkyl or alkoxycarboxyloxyalkyl esters, which generally exhibit greater enzymatic lability than simple alkyl esters. However, the general use of this double-star concept in prodrug design is 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 in many cases oils, thus creating pharmaceutical formulation problems.

In view of the foregoing, it is quite obvious that there is a clear need for new types of ester prodrugs which showed a strong tendency to undergo enzymatic hydrolysis in plasma or blood, and which are further peculiar in that they provide ample opportunities for 15 to vary or control the water and lipid solubilities.

In accordance with the present invention, it has now been found that esters of formula I below are surprisingly rapidly enzymatically cleaved in vivo, e.g. by plasma enzymes, and have the desired properties mentioned above.

A few compounds related to certain compounds of formula I have been discussed in the literature. Thus, Boltze et al. (1980) described various N-unsubstituted and N-monosubstituted 2- [1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyloxy] acetamide derivatives with anti-inflammatory properties. Similarly, some 25 acetamide derivatives of flufenamic acid have been discussed by Boltze & Kreisfeld (1977). 2- [2- (Acetyloxy) benzoyloxy] -acetamide and other related ester derivatives of acetylsalicylic acid are described in DE-0S 23 20 945.

However, it has not been suggested that the compounds described should have any prodrug effect, just as enzymatic hydrolysis of the compounds to the original carboxylic acid drugs has not been explicitly or implicitly mentioned.

4 DK 167007 B1

It is an object of the present invention to prepare a novel type of ester prodrugs, characterized in that they have a strong propensity to undergo enzymatic hydrolysis in vivo while providing ample opportunities to vary the water and lipid solubility of the derivatives.

It is a further object of the present invention to prepare novel bioreversible derivatives of drugs or biologically active agents having a carboxylic acid function, which derivatives, when administered to warm-blooded animals, e.g., humans, elicit the bio-responsive / pharmacological response. which are characteristic of the acids from which they are derived but which are characteristic of being less irritating to topical and gastric or in-testinal mucosa.

It is a further object of the invention to provide prodrugs of carboxylic acid drugs which are capable of providing enhanced biomembrane transport so that the original drugs are more bioavailable from the site of administration such as the gastrointestinal tract, rectum, skin or human eye.

It is a further object of the present invention to prepare such derivatives of conventional carboxylic acids which are prodrugs intended to be cleaved in such a way that the original drug form can be released at the treatment site or site of action, while leaving the remaining cleaved. molecular moiety is non-toxic and / or is metabolized in a non-toxic manner.

It is a further object of the invention to prepare prodrug compounds which use hydrolytic enzymes to form the original drug of the carboxylic acid type from the prodrug form.

It is a further object of the present invention to prepare derivatives of carboxylic acid agents which are "soft" in nature, i.e., which are peculiar in that they are degraded in vivo to substantially non-toxic moieties after have performed the desired therapeutic role (for example, the compounds derived from steroid acids of formula II below).

5 DK 167007 B1

Other objects, features and advantages of the invention will be apparent to those skilled in the art from the following description of the invention.

The above objects, features and advantages are achieved by the novel compounds of formula I

0 Ri H / 1

R - C00 - CH2 - C - I

X * r2 wherein R-C00- represents the acyloxy acid residue of a carboxylic acid drug or drug selected from: salicylic acid, indomethacin, naproxen, ibuprofen, 15-ketoprofen, tolmetine, flurbiprofen, tolfenamic acid, enalaprilic acid, 20-enalaprilic acid L-dopa, tranexamic acid, 25-furosemide and N-acetylcysteine ° g

R 1 and R 2 are the same or different and are selected from the class consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 cycloalkyl group, or an aryl group or an aralkyl group wherein aryl or an aryl part is phenyl or naphthyl optionally substituted with one or more substituents selected from C 1-6 alkylthio, C 1-6 alkyl, nitro or C 1-6 alkanoyl and wherein alkyl, alkenyl the aryl, aralkyl or cycloalkyl group is unsubstituted or substituted by one or more substituents selected from: 5 - a halogen atom, - a hydroxy group, - a straight or branched alkoxy group of formula R3-O- wherein R3 represents a C g -alkyl group, a phenyl group or a naphthyl group, which groups may be unsubstituted or substituted once or more by a halogen atom or a hydroxy group, - a carbamoyl group of the formula.

X

wherein R4 and R5 are the same or different and are hydrogen, a C1-6 alkyl group or selected from a group of the formula -CH2NR7R5, wherein Rg and R7 are the same or different and are hydrogen, a C1-6 alkyl group or together with the adjacent nitrogen atom forms a 4-, 5-, 6- or 7-membered heterocyclic ring which, in addition to the nitrogen, may contain one or two additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, - an amino group of the formula -NRgRg wherein Rg and Rg are the same or different and are hydrogen, a C1-6 alkyl group or together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring which, in addition to the nitrogen, can - holding one or two additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, - an acyloxy group of the formula -COOR 2 q wherein R 2 is a C 1-6 alkyl, aryl or aralkyl group, wherein the aryl or aryl moiety is phenyl or naphthyl, an oxyacyl group of the formula R ^ is hydrogen, a

C 1-6 alkyl group, an aryl group, an aralkyl group, a cycloalkyl group wherein the aryl or aryl moiety is phenyl or naphthyl and wherein the alkyl, aryl, aralkyl or cycloalkyl group is unsubstituted or substituted one or more times by a halo 7 DK 167007 B1 genome, a hydroxy group, an alkoxy group of formula R3-O- as defined above, a carbamoyl group of formula -CONR4R5 as defined above or an amino group of formula -NRgR9 as defined above; 5 or R 2 and R 2 are combined so that -NR 2 forms a 4-, 5-, 6- or 7-membered heterocyclic ring which may contain, in addition to the nitrogen atom, one or two additional hetero atoms selected from the class consisting of nitrogen, oxygen and sulfur, which heterocyclic ring may be substituted by a hydroxy group, a carbonyl group, a C1-6 alkyl group or an oxyacyl group of the formula Rj ^COO- wherein R ^ j j has the meaning given above, or an acyloxy group of the formula -COOR ^ q wherein R ^ q is as defined above; and non-toxic pharmaceutically acceptable acid addition salts thereof.

In this specification and claim, the term "C 1-6 alkyl" means an alkyl group which may be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl . The term "C2-6 alkenyl" refers to a C2-6 monounsaturated aliphatic carbohydride hydride group which may be straight or branched, such as propenyl, butenyl or pentenyl. The term "aryl" includes, as stated, phenyl and naphthyl and also the corresponding aryl radicals containing one or more substituents which may be the same or different, such as alkylthio, alkyl, halogen, alkoxy, nitro, alkanoyl, carbalkoxy, dialkylamino, alkanoyloxy or hydroxy -25 groups. The term "C 1-6 cycloalkyl" denotes a radical containing from 4 to 7 carbon atoms, for example cyclohexyl. The term "aralkyl" means a radical of the type -alkylene-aryl wherein aryl has the meaning given above and the alkylene moiety contains from 1 to 6 carbon atoms and may be straight-chain or branched, for example methylene, 1,2-butylene and the like.

When R 2 and R 2 in formula I, R 4 and R 5 in the formula -CONR 4 R 5 and R g and R 9 in the formula -NR g R g together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring which, in addition to the nitrogen atom may contain 1 or 2 additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, it may be, for example, 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, hexamine B1 thylenimino, morpholinyl, thiomorpholinyl, 1-pyrazolyl and 1-imidazolyl.

When one or more asymmetric carbon atoms are present in the or R2 groups as defined above, it will be understood that the present invention also encompasses all diastereomers or enantiomers or mixtures thereof. Examples of isomers are D, L and DL forms.

The term "non-toxic pharmaceutically acceptable acid addition salts" in this specification and claims generally encompasses the non-toxic acid addition salts of compounds of formula I formed with non-toxic inorganic or organic acids. For example, they include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric and the like; and salts with organic acids such as acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, glycolic acid, lactic acid, stearic acid, malic acid, pamoic acid, ascorbic acid, phenylacetic acid, benzoic acid, glutamic acid, sulfuric acid, sulfuric acid, sulfuric acid, sulfuric acid and sulfuric acid.

In preferred compounds of formula I, 20 Rx - CH3 or C2H5,

and R 2 = -CH 2 CH 2 OH

-CH2CH2CH2NO2 -CH2CH2N (CH3) 2 -CH2CH2N (C 2 -ch2conhch2nh2.

-ch2conh-ch3 or -NR} _R2 is -N_p, 0 OH 'j' j '* N ^ 5 CONH2 C00CH3 / -Λ Λ- \ A.

-n ^ n-ch3, -n_ ^ n-ch2ch2oh, -N ^ /

It will be appreciated that in the particularly preferred compounds immediately defined above, any possible combination of the given examples of R 1 and R 2 in the derivative group -CH 2 CONR 2 R 2 can, of course, be combined with each group R-C00 derived from the compounds A listed above, and that the definition given above corresponds to specifying every possible combination of the given examples of R-C00, R 2 and R 2.

Particularly preferred compounds of the general formula I are those in which R 1 and R 2 are both C 1-6 alkyl or both are -CH 2 CH 2 OH.

When R 1 and R 2 are both O 1-8 alkyl, they may be the same or different and are preferably 3-alkyl such as methyl, ethyl, n-propyl or isopropyl. Obviously, in such preferred compounds, every possible combination of R 2 and R 2 (i.e., both of them are -CH 2 CH 2 OH, 20 or R 2 and R 2 are each selected from methyl, ethyl, propyl and isopropyl) of the derivative group -CH2CONR ^ R2 is, of course, combined with each group R-C00 derived from the compounds listed above and that the above definition corresponds to the indication of every possible combination of the given examples of R-C00, R 1 and R 2.

The prodrug compounds of formula I of the present invention can be used to treat any condition to which the original carboxylic acid-containing drug, drug or pharmaceutical can be used. For example, if naproxen is the original drug of choice, the ester prodrug can be used for any condition or treatment in which naproxen would be administered.

Thus, the prodrug compounds of formula I can be administered orally, topically, parenterally, rectally or with inhalation spray in dosage forms 5 or formulations containing conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and carriers. The formulation and preparation of this entire spectrum of dosage forms into which the prodrugs in question may be incorporated are known in the art of pharmaceutical formulation. However, 10 specific information can be found in "Remington's Pharmaceutical Sciences", 16th Edition, 1980.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. . Compositions for oral use can be prepared by any method known in the art of preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from the class consisting of sweeteners, flavorings, dyes and preservatives so as to obtain a pharmaceutically elegant and tasty preparation.

Formulations for oral use include tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example potato starch or alginic acid; binders, for example starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques for delaying degradation and absorption in the gastrointestinal tract, thereby providing prolonged efficacy over a prolonged period. For example, a retarding material such as glyceryl monostearate or glyceryl distearate may be used.

11 DK 167007 B1

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient 5 is mixed with water or an oil medium. for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions usually contain the active materials in admixture with relevant excipients. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents which may be a naturally occurring phosphatide, for example lecithin; a condensation product of an alkylene oxide with a fatty acid, for example polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example heptadecaethylene oxycetanol; a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example methyl, ethyl or n-propyl p-hydroxybenzoate; one or more dyes; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those listed above and flavorings may be added to provide a tasty oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional excipients, such as sweeteners, flavorings and dyes, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifiers may be naturally occurring gums, for example, acacia gum or tragacanth gurami; naturally occurring phosphatides, for example, soybean lycithin; and esters, including partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring substances.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a soothing agent (demulcent), a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated in the prior art using the appropriate dispersing or wetting agents and suspending agents listed above. The sterile injectable composition may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable carriers and solvents that may be used are water, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, conventionally sterile fixed oils are used as solvent or suspending medium. For this purpose, any inert oil, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid can also be used to make injectable preparations.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These preparations DK 167007 B1 13.

can be prepared by mixing the drug with an appropriate non-irritating excipient which is solid at normal temperatures but liquid at rectal temperature and therefore will melt in the rectum to release the drug, for example cocoa butter or adeps solidus-5 polyethylene glycols.

For topical application, creams, ointments, gels, solutions, suspensions or the like containing the prodrug compounds are used in accordance with recognized methods in the art.

Of course, the therapeutic dose range of the compounds 10 of the present invention will vary with the size and needs of the patient and the particular pain or disease symptom being treated. However, the following dosage guidelines will generally suffice. On the oral basis, the required therapeutic dose of a compound of the present invention will generally, on a molecular basis, be similar to the dose of the original carboxylic acid drug. On a topical basis, application of a 0.01-5% concentration of a compound of the present invention (in a suitable topical carrier material) to the affected site should be sufficient.

From the above description, the person skilled in the art can readily ascertain the essential features of the present invention and, without departing from the spirit and scope thereof, make various changes and / or modifications of the invention to adapt it to different uses and conditions. These changes and / or modifications fall within the full equivalence range of the requirements below.

The amount of active ingredient that can be combined with the carrier materials to obtain a single-dose form will vary depending on the host organism treated and the mode of administration concerned. For example, a formulation intended for oral administration to 30 people may contain from 5 mg to 5 g of the active agent, together with a relevant and appropriate amount of carrier material, which may range from approx. 5 to approx. 95% of the total composition. Other dosage forms such as ophthalmic dosage forms contain less active ingredient such as for example DK 167007 B1 14 from 0.1 mg to 5 mg. Unit dosage forms will generally contain between approx. 0.1 mg and approx. 500 mg of active ingredient.

However, it will be understood that the dosage level in question for any particular patient will depend on a variety of 5 factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, the rate of excretion, the drug combination and the severity of the disease being treated.

The compounds of the present invention can be prepared by a variety of synthetic methods. A generally applicable process (process a) is characterized in that the carboxylic acid agent of formula A or a salt (e.g., a metal salt) thereof R - G00H (A)

Wherein R-C00- has the meaning set forth above for formula I, is reacted with a compound of formula B

[X - CH 2 - c - NC "(B) wherein R 1 and R 2 are as defined above and X is an appropriate leaving group (e.g., halogen such as Cl, I or Br, or a methanesulfonyloxy or toluene sulfonyloxy group) The reaction is preferably carried out in a solvent (e.g., N, N-dimethylformamide, water, acetonitrile, a lower alcohol, ethyl acetate, toluene or the like).

Typically, one equivalent of an organic base such as triethylamine, tetramethylguanidine or the like is added, or crown ethers are used as phase transition catalysts. If X of formula B is chlorine, catalytic amounts of an iodide salt can be added to the reaction mixture. The reaction is carried out at a temperature of from room temperature to the boiling point of the solvent and for a period of from 0.5 to 48 hours.

DK 167007 B1

A further process (process b) for the preparation of compounds of the invention is characterized in that a compound of formula B wherein X is hydroxy is reacted with an acid of formula A or with the corresponding acid chloride of formula C

R-COC1 (C) When an acid starting material is used, i.e. a compound of formula A, the reaction is carried out in the presence of a suitable dehydrating agent, for example N, N-dicyclohexylcarbodiimide. The reaction using an acid starting material is conveniently carried out in an inert solvent such as dichloromethane, dioxane, pyridine or the like at a temperature of from 0 ° to 60 ° C for from 1 to 48 hours. A catalyst such as p-toluenesulfonic acid or 4- (N, N-dimethylamino) pyridine can be added. When an acid chloride starting material is used in the reaction, the process can conveniently be carried out by reacting the compound of formula B wherein X is hydroxy, with the desired acid chloride in an inert solvent such as benzene, dichloromethane, dimethylformamide, acetone, dioxane, acetonitrile or the like. reflux temperature for from 1 to 24 hours in the presence of an acid-absorbing agent such as an alkali metal carbonate or an organic base such as triethylamine or pyridine.

The acid chlorides of formula C, which can be used in the process above, are prepared from the corresponding acids in known manner, for example by treating the acid with thionyl chloride or oxalyl chloride. Instead of acid chlorides, acid anhydrides or mixed anhydrides can be used.

The starting materials of formula B wherein X is halogen are also prepared in known manner, for example, by treating the relevant amine with an appropriately halogen-substituted acid chloride, acid anhydride or ester as shown by the following chemical equation for an acid chloride: R1R2NH + X -CH2C0C1 -) x-ch2conr1r2 16 DK 167007 B1

Several compounds of formula B wherein X is halogen and processes for their preparation are described in the literature, cf. e.g., Hankins (1965), Weaver and Whaley (1947), Ronwin (1953), Berkel-hammer et al. (1961) and Speziale and Hamm (1956).

The starting materials of formula B wherein X is hydroxy are also prepared in known manner, for example, by hydrolysis of 2- (acetoxymethyl) acetamides or 2- (benzoyloxymethyl) acetamides. Specific examples are given below.

Several compounds of formula B wherein X is hydroxy and processes for their preparation are described in the literature, cf. eg DE-OS 29 04 490, DE 22 01 432 and DE 22 19 923.

A third process (process c) for the preparation of compounds of the present invention is characterized in that a compound of formula D

H1% R2 (D)

wherein R 1 and R 2 are as defined in formula I are reacted with an acid of formula E

R-C00CH2C00H (E) wherein R-C00- has the meaning given in formula I,

20 or with the corresponding acid chloride (or acid anhydrides) of formula F

R-C00CH2 COC1 (F) When a compound of formula E is used, the reaction is carried out in the presence of a suitable dehydrating agent, for example N, N-di-cyclohexylcarbodiimide. The reaction is conveniently carried out in an inert solvent such as dichloromethane, dioxane, pyridine or the like at a temperature of from 0 ° to 60 ° C for from 1 to 48 hours. When an acid chloride starting material of formula F is used in the reaction, the process can conveniently be carried out by reacting the compound of formula F with the desired amine or amine salt in a solvent such as benzene, dichloromethane, dimethylformamide, acetone, dioxane, acetonitrile, water or the like at 0 ° C to reflux temperature for from 1/2 to 24 hours in the presence of an acid-absorbing agent such as alkali metal carbonate or an organic base such as triethylamine or an excess of the amine.

The acid chlorides of formula F, which can be used in the process above, are prepared from the corresponding acids in known manner, for example by treating the acid with thionyl chloride or oxalyl chloride.

The acids of formula E, which can be used in the process above, are prepared from the original acids (i.e., R-C00H) in known manner, for example, by reacting the acid or a salt of the acid (e.g., a metal or trimethylammonium salt) with compounds of formula G

X-CH2COOCH2C6H5 (G)

Wherein X and n are as defined above or with compounds of formula H

X-CH 2 CONH 2 (H) where X and n are as defined above. The intermediates obtained therefrom, viz. R-COO-CH2 COOCH2CgH5 and R-COO-CH2-CONH2 are then converted to the compounds of formula E by, for example, hydrogenation or acid hydrolysis. Several compounds of formula E and processes for their preparation are known from the literature, cf. e.g., Boltze et al. (1980) and Concilio & Bongini (1966).

Although the basic methods described above can be used to prepare all the compounds of the invention, certain conditions and / or modifications thereof may be made in specific cases. Thus, for example, the basic processes can be modified in cases where the desired product of formula I contains free aliphatic amino, thiol or hydroxyl groups which, if present in the acid starting material, would be involved in undesirable side reactions and / or would interfere with the desired '18 DK 167007 B1

course of the ester formation described above. In such cases, the compounds of formula B or D are reacted with an acid of formula J

bA-COOH (J) 5 wherein bA-COO- is the amino, thiol or hydroxyl protected acyloxy residue of a carboxylic acid agent (R-C00H) containing amino, thiol or hydroxyl groups. The amino, hydroxy or thiol function of the original acids of formula RC00H is converted to their protected counterparts of formula J by known methods, for example the methods known in the peptide synthesis technique. For example, amino groups are suitably protected by the carbobenzoxycarbonyl or t-butyloxycarbonyl group. The compound of formula J, its corresponding acid chloride or protected counterpart of formula E is then reacted with a compound of formula B or D as described above to give the compound of formula I, but containing a protected acyloxy residue, i. R --COO- as defined above, instead of R-C--in Formula I. This protected compound is then deprotected by known methods, for example, by hydrogenation or hydrolysis.

The process variants described above involving the addition and, ultimately, removal of protecting groups are used only when the free amino, hydroxy and / or thiol functions need protection.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. Figure 1 shows time course of naproxen-N, N-dimethylglycolamide ester (·) 25 and naproxen (o) during hydrolysis of the ester in 80% human plasma at 37 ° C. The initial ester concentration was 10 µM; Fig. 2 shows the first-order kinetics of hydrolysis of various esters (initial concentration 10 µM) in 80% human plasma at 37 ° C.

Signature explanation: o o, Ν-diethylglycolamide ester of L-phenylalanine; • Ν, Ν-diethylglycolamide ester of naproxen; 19 DK 167007 B1 Δ N-methyl, N-carbamoylmethylglycolamide ester of ketoprofen; FIG. 3 shows the rate of hydrolysis of the Ν, Ν-dimethylglycolamide ester of salicylic acid in 80% human plasma at 37 ° C.

In the following examples, Examples 1-34 illustrate the preparation of model prodrug compounds having benzoic acid as a model for a carboxylic acid drug, and Examples 35-61 illustrate the preparation of compounds of the invention.

The derivatives described all had spectroscopic data (IR and 1 H-NMR) 10 and elemental analysis (C, H and N) that were consistent with their structure.

Example 1 2- (Benzoyloxy) -N, N-dimethylacetamide

Benzoic acid (2.44 g, 0.02 mol) and 2-chloro-N, N-dimethylacetamide (2.43 g, 0.02 mol) were dissolved in 10 ml of N, N-dimethylformamide. Sodium iodide (150, 2 mmol) and triethylamine (2.02 g, 0.02 mol) were added and the mixture was stirred at room temperature (20-25 ° C) overnight.

After the addition of 50 ml of water, the reaction mixture was extracted twice with ethyl acetate. The combined extracts were washed with a 20-dilute solution of sodium thiosulfate, a 2% aqueous solution of sodium bicarbonate and with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol-water to give 3.5 g (85%) of the title compound, mp 81-82 ° C.

EXAMPLE 2 DK 167007 B1

The compound of Example 1 was also prepared by the following procedure: 2-Chloro-N, N-dimethylacetamide (12.16 g, 0.1 mole) was added to a solution of sodium benzoate (14.4 g, 0.1 mole). and sodium iodide (3.75 g, 0.025 mol) in 75 ml of water. The reaction solution was refluxed for 2 hours. On standing overnight at 4 ° C, the title compound precipitated. It was filtered off, washed with water and recrystallized from aqueous ethanol (15.7 g; 76%), mp 81-82 ° C.

EXAMPLE 3 (Benzoyloxy) acetyl chloride 2-Chloroacetamide (18.7 g, 0.2 mole) was added to a solution of sodium benzoate (28.8 g, 0.2 mole) and sodium iodide (7.5 g, 0.05 mol) in 150 ml of water. The mixture was stirred at 90 ° C for 14 hours. After cooling to 4 ° C, 2- (benzoyloxy) acetamide precipitated and was isolated by filtration. Recrystallization from ethanol-water gave 32.2 g (90%), mp 120.5-121 ° C.

2- (Benzoyloxy) acetamide (19.7 g, 0.11 mol) was added to 200 ml of 7.8 M hydrochloric acid. The mixture was stirred at 75 ° C for 10 minutes. After cooling, 2- (benzoyloxy) acetic acid precipitated. It was isolated by filtration, dried and recrystallized from benzene (15.8 g, 80%), mp 111-112 ° C.

A mixture of 2- (benzoyloxy) acetic acid (12.6 g) and thionyl chloride (15 ml) was refluxed for 3 hours. Excess thionyl chloride was removed in vacuo and the crude (benzoyloxy) acetyl chloride obtained was purified by distillation in vacuo. The yield was 88%, m.p. 25-26 ° C.

Example 4 21 1- (Benzoyloxy) - (N-methyl-N-ethoxycarbonylmethyl) acetamide

A solution of (benzoyloxy) acetyl chloride (0.8 g, 4 mmol) in 4 ml of benzene was added to a cooled (about 5 ° C) solution of sarcosinethyl-5 ester hydrochloride (0.84 g, 12 mmol) in 6 ml 2 M sodium hydroxide.

The mixture was stirred vigorously at room temperature for 2 hours. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (20 mL). The combined organic extracts were washed with 2 M hydrochloric acid (10 ml) and dried. Evaporation in vacuo gave an oily residue which crystallized by trituration with petroleum ether at -20 ° C.

Recrystallization from ether-petroleum ether gave the title compound (0.68 g, 61%), mp 39-40 ° C.

EXAMPLE 5 1- Methyl 4- (benzoyloxyacetyl) piperazine hydrochloride A solution of 1-methylpiperazine (0.40 g, 4 mmol) in 5 ml of benzene was added dropwise with stirring to a solution of (benzoyloxy) acetyl chloride (0 80 g, 4 mmol) in 10 ml of benzene. After the addition was complete (about 10 minutes), the reaction mixture was stirred at room temperature for 1 hour. Ether (10 ml) was added and the mixture was filtered. The white crystalline compound on the filter was washed with ether and finally recrystallized from ethanol to give 0.70 g (59%) of the title compound, mp 227-228 ° C.

EXAMPLE 6 2- (Benzoyloxy) - (N-methyl-N-β-hydroxyethyl) acetamide A solution of (benzoyloxy) acetyl chloride (1.5 g, 8 mmol) in 8 ml of benzene was mixed with N-methylethanolamine (1, 8 g, 24 mmol). The solution was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and water (10 ml). The phases were separated and the organic phase was washed with 2 M hydrochloric acid (5 ml) and water (5 ml), dried and evaporated in vacuo. The residue crystallized by trituration with ether and left to stand overnight at -20 ° C. The compound was filtered off and recrystallized from ethyl acetate-petroleum ether to give 1.1 g (50%) of the title compound, mp 78-80 ° C.

EXAMPLE 7 2- (Benzoyloxy) -N, N- (dicarbamoylmethyl) acetamide A solution of (benzoyloxy) acetyl chloride (0.8g, 4mmol) in benzene (4ml) was added to a mixture of iminodiacetamide with stirring at room temperature. hydrochloride (1.06 g, 6 mmol) and sodium bicarbonate (2.52 g, 30 mmol) in water (5 ml). The mixture was stirred for 3 hours. The resulting precipitate was filtered off, washed with a small amount of water and recrystallized from water to give 0.70 g (60%) of the title compound, mp 195-196 ° C.

Example 8 N- (Benzoyloxymethylcarbonyl) pyrrolidone

A mixture of (benzoyloxy) acetyl chloride (1.98 g, 0.01 mole), pyrrolidone (0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) in acetone ( 10 ml) was refluxed for 3 hours. The cooled mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with a 2% aqueous solution of sodium bicarbonate, 2 M hydrochloric acid and water. After drying over 25 anhydrous sulfate, the organic phase was evaporated under reduced pressure to give a residue which crystallized by the addition of ether. Recrystallization from ether-petroleum ether afforded 1.6 g (65%) of the title compound, mp 83-84 ° C.

EXAMPLE 9-33 23 DK 167007 B1

Following the procedures of the foregoing examples, a number of additional esters of benzoic acid according to the invention were prepared. The structure of these esters and their melting points is shown in Table 1.

TABLE 1

Compounds of formula I wherein R =, i.e.

0 R; L

^ Q ^ -COO (CH2) n-C-N-R 2

Example No. n R 2 R2 Melting point (eC) 10 ___ '9 1 CH3 C2H5 -20 10 1 C2H5 C2H5 62.5-63.5 11 1 C3H7 C3H7 -20 12 1 1C3H7 1C3H7 104.5-105.5 15 13 1 CH2CH = CH2 CH2CH = CH2 42-43 14 1 nC4H9 nC4H9 -25 15 1 iC4H9 iC4H9 44-45 16 1 CH3 CH2CH2OH 78-80 17 1 CH2CH20H CH2CH20H 80-82 20 18 1 CH3 CH2CONH2 101-102 19 1 CH3 CgHii 100 -101 20 1 C6HU 162-163 21 2 CH3 CH3 <20 22 3 CH3 CH3 40-41 25 23 1 C2H5 CH2CH2OH 79-80 23a 1 CH3 CH2CH2N- 158-159 - (CH3) 2, HC1 23b 1 CH2CH2OCH3 CH2CH2OCH3 57- 58 24 1 -N ^> 74'75 24 DK 167007 B1 25 1 - / jj 57.5-58 26 1 - / ^ 87-88 27 1 107-108 / - \ 28 1 -NO 103-104 \ _ / 5 'CH3 7 "Λ 29 1 -N) 118-118.5 -CH3-- 30 1 -Έ 194-195 CONH2 (L-) 10 31 1 -) / 72-73 COOCH3 (L-) 32 1 - / H -OH 121-122 33 1 -N ^ N-CH 2 CH 2 OH, HCl 228-229 33a 1 -N \ 54-55

V

CH2CH3 EXAMPLE 34 DK 167007 B1 2- (Benzoyloxy) - (N-methyl-N- (N, N-dimethylglycyloxyethyl) acetamide (monofumarate)

A mixture of 2- (benzoyloxy) - (N-methyl-N-γS-hydroxyethyl) -acetamide 5 (0.95 g, 4 mmol), N, N-dimethylglycine (0.41 g, 4 mmol), N, N'-dicyclohexylcarbodiimide (0.82 g, 4 mmol) and 4-toluenesulfonic acid (50 mg) in pyridine (10 ml) were stirred at room temperature for 24 hours. Methylene chloride (20 ml) was added. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was extracted with 20 ml of boiling ethyl acetate and the extract was evaporated. The obtained oily residue was dissolved in ether (20 ml) and a solution of fumaric acid in 2-propanol was added. After standing overnight at 4DC, the title compound was isolated by filtration in a yield of 59%. Recrystallization from methanol-ether gave an analytically pure product, mp 127-127.5 ° C.

EXAMPLE 35 2- [1- (p-Chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyloxy] -N, N-diethylacetamide

Indomethacin (1.43 g, 4 mmol) and 2-chloro-N ', N-diethylacetamide (0.61 g, 4.1 mmol) were dissolved in 5 ml of N, N-dimethylformamide, and triethylamine (0.56 ml, 4 mmol) and sodium iodide (60 mg) were added. The mixture was stirred at room temperature for 20 hours and poured into 50 ml of water. The mixture was extracted with ethyl acetate (2 x 50 ml). The extract was washed with 2% aqueous solution of hydrogen carbonate and water.

After drying over anhydrous sodium sulfate, the organic phase was evaporated in vacuo. The residue was recrystallized from ethyl acetate-petroleum ether to give 1.6 g (90%) of the title compound, mp 148-149 ° C.

EXAMPLE 36 26 2- 16 (00) -6-Methoxy-α-methyl-2-naphthalenacetyloxy] -N, N-dimethylacetmide

Naproxen (1.07 g, 5 mmol) and 2-chloro-N, N-diethylacetamide (0.90 g, 6 mmol) were dissolved in 7 ml of N, N-dimethylformamide and 5 triethylamine (1.4 ml, 10 mmol) and sodium iodide (76 mg). The mixture was refluxed for 2 hours, cooled and poured into 35 ml of water. The precipitate formed overnight at 4 ° C was collected by filtration, washed with water and recrystallized from 95% ethanol to give 1.5 g (92%) of the title compound, mp 89-89.5 ° C.

EXAMPLE 37 2- [2-Hydroxybenzoyloxy] - (N-methyl-N-carbamoylmethyl) -acetamide

The ester was prepared from salicylic acid and N-chloroacetylsarcosine amide (prepared as described below by the procedure described in Example 1. The crude product was recrystallized from ethyl acetate ether, mp 142-143 ° C.

Preparation of α-chloroacetylsarcosinamide

Sarcosinamide hydrochloride was prepared by reaction of methylamine with 2-chloroacetamide as described by Marvel et al. (1946). The compound was recrystallized from ethanol, mp 160-161 ° C.

A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40 ml) was added over 30 minutes to a mixture of sarcosinamide hydrochloride (0.1 mole, 12.45 g) and sodium bicarbonate (0, 25 moles, 20.0 g) in 40 ml of water. The mixture was stirred vigorously for 3 hours at room temperature. The aqueous phase was acidified to pH 5 with 5 M hydrochloric acid and extracted with ethyl acetate (3 x 400 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo. The obtained solid residue was recrystallized from ethanol ether to give 8.5 g (52%) of the title compound, m.p.

EXAMPLE 38 27 2-6 1- [1- (p-Chlorobenzoyl) -5-methoxy-2-methylindole-3-aethyloxy] -N, N-dimethylacetamide a. To a stirred suspension of indomethacin (3.58 g, 0 (1 mol) in benzene (10 ml) at 60 ° C thionyl chloride (1.12 ml, 0.015 mol) was added dropwise. The mixture was stirred for 1 hour at 65-70 ° C and concentrated to ca. In vacuo. Hot petroleum ether (25 ml) was added and the mixture was filtered to give 3.2 g (85%) of 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetyl chloride 10 (acid chloride of indomethacin), mp 126-127 ° C.

b. 2-Hydroxy-Ν, Ν-dimethylacetamide was prepared by basic hydrolysis of 2- (benzoyloxy) -N, N-dime thylacetamide obtained as described in Example 1. 2- (Benzoyloxy) -N, N-dimethylacetamide (20, 7 g, 0.1 mol) was dissolved in 50 ml of ethanol by heating to 40-50 ° C. Potassium hydroxide (2 M, 70 ml) was added and the mixture was allowed to stand at room temperature for 1 hour. The pH of the solution was adjusted to 8-9 by the addition of 4 M hydrochloric acid and the ethanol removed in vacuo. The pH of the mixture was adjusted to 3.5-4 with hydrochloric acid. Precipitated benzoic acid was filtered off and the filtrate was basified (pH 8-9) with potassium hydroxide. The solution was evaporated in vacuo. The resulting semi-solid residue was slurried in ethyl acetate (100 ml) and the mixture heated to ca. 60 ° C. It was filtered, dried over sodium sulfate and evaporated in vacuo to give crude 2-hydroxy-Ν, Ν-dimethylacetamide. This extraction process was repeated two 25 times. Recrystallization from ether-petroleum ether gave 7.1 g (69%) of the compound, mp 49-50 ° C.

c. Indomethacinic acid chloride (1.14 g, 3 mmol) was added in portions to a solution of 2-hydroxy-N, N-dimethylacetamide (340 mg, 3.3 mmol) in acetonitrile (3 ml) and pyridine (320 g, 4 mmol) cooled to 0-4 ° C.

The mixture was stirred at room temperature for 4 hours and evaporated in vacuo. The residue was taken up in a mixture of water and ethyl acetate.

The organic phase was separated and washed with 1 M hydrochloric acid, 5% sodium bicarbonate and water. Evaporation of the dried solution 28 gave a solid residue which after recrystallization of ethyl acetate gave the title compound, mp 149-150 ° C.

EXAMPLE 39 2- [α-Methyl-4- (2-methylpropyl) benzeneacetyloxy] - (N-methyl-N-5 carbamoylmethyl) acetamide

A mixture of ibuprofen (1.03 g, 5 mmol), 2-chloroacetylsarcosinamide (0.82 g, 5 mmol), triethylamine (0.8 ml, 5.7 mmol) and sodium iodide (100 mg) in N, N- dimethylformamide (10 ml) was stirred at room temperature for 20 hours. Water (50 ml) was added and the mixture was allowed to stand at 4 ° C for 5 hours. The precipitated title compound was isolated by filtration, washed with water and recrystallized from ethanol-water to give 1.35 g (81%), mp 100-100.5 ° C.

EXAMPLE 40 2- [1-Methyl-5- (a-methylbenzoyl) -1H-pyrrole-2-acetyloxy] -N, N-dimethylacetamide

A mixture of tolmetine (1.29 g, 5 mmol), 2-chloro-N, N-dimethylacetamide (0.74 g, 6 mmol), triethylamine (0.84 ml, 6 mmol) and sodium iodide (50 mg ) in N, N-dimethylformamide (10 ml) was stirred at 90 ° C for 3 hours. Water (50 ml) was added and the mixture was extracted with 20 ethyl acetate (75 ml). After washing with an aqueous hydrogen carbonate solution and water, the extract was dried and evaporated in vacuo. The residue obtained crystallized on standing at -20 ° C and was recrystallized from ethanol-ether to give 1.3 g (76%) of the title compound, mp 108-109 ° C.

Example 41 29 DK 167007 B1 2- [(+) -6-Methoxy-α-methyl-2-naphthalenacetyloxy] -N, N- (di-β-hydroxyethyl) acetamide

The compound was prepared from naproxen and 2-chloro-N, N- (di- / 3-5 hydroxyethyl) acetamide by the procedure described in Example 1.

The yield was 60%. Recrystallization of ethyl acetate gave an analytically pure product, mp 113-114 ° C.

EXAMPLE 42 2- [(+) -6-Methoxy-α-methyl-2-naphthalenacetyloxy] - (N-methyl-N- [hydroxyethyl) acetamide

The compound was prepared from naproxen and 2-chloro (N-methyl-N-γ-hydroxyethyl) acetamide by the procedure described in Example 1. The yield was 65%. Recrystallization of ethyl acetate gave an analytically pure product, mp 109-111 °.

Example 43 2- (trans-4- (Aminomethyl) cyclohexanoyloxy) -N, N-dimethylacetamide hydrochloride

Tranexamic acid (3.0 g, 0.019 mol) was dissolved in 12 ml of thionyl chloride. The solution was kept at room temperature for 30 minutes. After addition of ether, the acid chloride of tranexamic acid precipitated as hydrochloride salt. It was filtered off and dried over P2O5 in vacuo, mp 138-139 ° C.

The acid chloride (2.10 g, 0.01 mol) was added portionwise and with stirring to a solution of 2-hydroxy-N, N-dimethylacetamide (1.24 g, 0.012 mol) in 10 ml of dioxane. The solution was stirred at 60 ° C for 1 hour and then cooled to 0-4 ° C. The resulting precipitate was filtered off and recrystallized from ethanol to give 1.5 g of the title compound, mp 183-184 ° C.

EXAMPLES 44-61

Following the procedures of the foregoing examples, a number of additional novel esters of the present invention were prepared. The structure of these esters and their melting points is shown in Table 2.

TABLE 2

Compounds of Formula I, wherein n = 1 10 -

Example R-C00- is acyl-R2 Melting point number the oxy residue of: (eC) 44 Naproxen CH3 CH3 150-151 a 15 45 Naproxen CH3 CH2CONH2 179-180 46 Ibuprofen CH3 CH3 oil 47 Ketoprofen CH3 CH3 oil 48 Ketoprofen ^ 2 ^ 5 ^ 2¾ oil 49 Flurbiprofen CH3 CH3 74-75 20 50 Flurbiprofen c2 ^ 5 60-61 51 Indomethacin ^ 2 ^ 5 C2H5 104-105 52 Indomethacin CH3 CH2CH20H 138-139 53 Indomethacin CH2CH2OH CH2CH20H 144-146 54 Tolfenamic acid CH3 CH3 106-107 25 55 Tolfenamic acid ^ 2¾ ^ 2 ^ 5 114-115 56 Tolfenamic acid C2H5 CH2CH2OH 85-86 57 Tolfenamic acid CH2CH20H CH2CH2OH 176-180 58 L-methyldopa C2H5 C2H5 122-124 59 Furosemide CH3 CH3 193-194 30 60 Salicylic acid CH3 CH3 68 61 Salicylic acid ^ 2 ^ 5 c2% 73-74.5 31 DK 167007 B1

In vitro cleavage of ester prodrugs

Reaction Conditions. Solutions of various derivatives of the invention in aqueous buffer solutions or 50-80% human plasma solutions (pH 7.4) were maintained at 37 ° C. Initial concentration 5 of the derivatives ranged from 3 x 10 10 to 10 10 - * M. At different times, a sample was taken from the solutions and analyzed by HPLC for both residual derivative and for native acid. For the plasma solutions, the sample taken was protein. -seed with methanol, ethanol or acetonitrile, and after centrifugation, the clear supernatant was injected onto HPLC.

Analysis method. An HPLC method was used to determine the ester derivatives and their original acids. In this method, a reverse-phase LiChrosorb RP-8 column (250 x 4 mm) at ambient temperature was eluted with mixtures of methanol and 0.01 M acetate buffer pH 5.0, methanol and 0.01 M phosphate buffer pH 4.5 or methanol and 0.02 M phosphate buffer pH 3.5. The composition of the eluent was adjusted for each compound to obtain an appropriate retention time and separation of ester and the corresponding acid. The flow rate was 0.6 - 1.6 ml / minute and the column effluent was monitored spectrophotometrically at a suitable wavelength. Quantification of the compounds was done by measuring the peak heights relative to the peak heights of standards chromatographed under the same conditions.

The various prodrug esters were found to be quantitatively cleaved into the original acids in human plasma solutions. An example is shown in FIG. 1. The esters of the present invention were surprisingly rapidly hydrolyzed in human plasma, although the rate of hydrolysis largely depends on the substituents Rp and R2 of formula I. The half-lives of hydrolysis of various derivatives in 50% human plasma solutions (pH 7.4; 37 ° C ) are listed in Table 3. As can be seen from the 30 data, the Ν, Ν-disubstituted 2- (acyloxy) acetamide sterees are hydrolyzed particularly rapidly. Thus, the half-life of hydrolysis of 2- (benzoyloxy) -Ν, Ν-diethylacetamide is less than 3 seconds. In pure buffer solution of the same pH (7.4) and at 37 ° C, the half-life of hydrolysis of this compound and the related esters listed in Table 35 3 was found to be over 1,000 hours, which shows how easily it is used. 167007 B1 zymatic hydrolysis proceeds under conditions similar to those prevalent in vivo.

At initial concentrations of approx. 10 µM followed the course of hydrolysis of some esters strictly first-order kinetics (examples are shown in Figure 2), while in other cases mixed kinetics were observed. An example of the latter is shown in FIG. 3. In FIG. 3 it appears that the rate of hydrolysis initially followed zero-order kinetics and that as the substrate was consumed, it changed and followed first-order kinetics. This behavior is typical of 10 enzyme-catalyzed reactions in which the initial concentration of the substrate is higher than the Michaelis constant Km. At low substrate concentrations, i. corresponding to the concentrations of in vivo prodrug hydrolysis, the enzymatic reaction is of first order with the half-lives indicated in Table 3.

Table 4 shows hydrolysis data for esters of various carboxylic acids of the present invention. The structure of the acyl moiety influences the enzymatic reactivity, but in all cases quite rapid rates of plasma hydrolysis were observed. By comparing the hydrolysis rates of the esters of the present invention with the rates of the corresponding simple methyl or ethyl esters (Table 5), the much easier enzymatic hydrolysis of the esters of the present invention is readily seen.

The esters of the present invention were found to be extremely stable in acidic media. For example, no hydrolysis took place (i.e. <1%) of 2- (benzoyloxy) -Ν, Ν-diethylacetamide in 0.01 M HCl solutions kept at 37 ° C for 3 hours.

These results show that the esters of the present invention combine a pronounced tendency to undergo enzymatic hydrolysis in plasma with a high stability in aqueous solution, for example in acidic medium 30 such as gastric fluids. Therefore, for example, the esters will remain intact in the gastrointestinal tract after oral administration, with the release of the free carboxylic acid compound occurring during the absorption process or in the blood after absorption.

DK 167007 Pg 33

Water solubility and lipophilicity of the ester prodrug compounds

The distribution coefficients (P) of some esters of the present invention were measured at 22 ° C using the commonly used octanol-water system. Similarly, the solubility of the derivatives in water or aqueous buffer solutions was determined. The values found for log P and the water solubilities are shown in Table 3.

The results obtained show that by changing the sub tenants R 1 and R 2 and nine of Formula I, it is easy to obtain ester prodrug derivatives of varying and any desired lipophilicity or water solubility while maintaining the strong lability of enzymatic hydrolysis. preserved. Thus, as shown in Table 3, the derivative 2- (benzoylloxy) -NN- (di- / J-hydroxyethyl) acetamide is soluble in water to a degree of more than 70% (w / v) a neutral compound with a positive log P value. As a further example, the corresponding ester derivative of naproxen (Example 44) was found to be more than 20 times more soluble in 0.01 M HCl than naproxen itself.

bioavailability

The naproxen prodrug derivative described in Example 44 was administered orally to rabbits. Similarly, naproxen itself was orally administered to rabbits in an equivalent dose (4.8 mg / kg naproxen). After drug administration, blood samples were taken at various times and the plasma fraction was examined for naproxen and prodrug using an HPLC method under the following conditions: Column: LiChrosorb RP-8; eluent: methanol-0.02 Μ KH 2 PO 4 (pH 3.5) 65:35; detection: UV at 230 run.

As shown in Table 6, the naproxen prodrug derivative is effectively absorbed after oral administration. No measurable concentrations (<0.1 pg / ml) of intact naproxen prodrug were observed, showing that the prodrug compound is rapidly converted back to naproxen 30 in vivo according to the "prodrug" definition of the present disclosure.

TABLE 3 34 DK 167007 B1

Rates of Enzymatic Hydrolysis, Water Solubility and Partition Coefficients for Various Compounds of Formula _ 0 Rj_ 5 / (^ yCOO (CH2) nCN-R2 When n * = 1, the formula corresponds to Formula I with benzoic acid as the drug-model compound E1 R2 n Sa log tjy2c 10 (mg / ml) (min) CH3 CH3 1 8.8 1.07 0.15 CH3 C2H5 1 - 1.27 0.10 C2H5 C2H5 1 2.0 2.06 0.04 nC3H7 nC3H7 1 1.1 2 65 0.14 iC3H7 iC3H7 1 0.12 2.56 0.08 CH2CH = CH2 CH2CH = CH2 1 0.71 2.34 0.08 nC4H9 nC4H9 1 0.080 3.91 3.1 iC4H9 iC4H9 1 0.081 3.80 <1.5 20 CH 3 C 6 H 1; L 1 0.14 2.99 0.54 C 6 H 11 1 0.0034 - 407 CH 3 CH 2 CH 2 OH 1 19.3 0.58 0.20 C 2 H 5 CH 2 CH 2 OH 1 10.8 0.93 0.16 CH2CH20H CH2CH20H 1,720 0.17 0.42 CH3 CH2CH2OOC- -CH2N (CH3) 2d 1> 200 - 0.08 CH3 CH2C0NH2 1 30.2 0.08 0.13 CH3 CH2COOC2H5 1 6.0 1.56 0, 22 CH3 CH3 2 17.6 1.28 5.6 CH3 CH3 3 13.9 1.86 14.1 CH3 CH2CH2N (CH3) 2d 1> 100 - 0.12 CH2CH2OCH3 CH2CH2OCH3 1 - 0.25 DK 167007 B1 'N \ r2 5 -N')> 1 5.4 1.20 0.83 -N 2 J 1 6.3 1.44 5.7, Q 1 0.78 1.95 2.5 -N ) 1 0.75 2.30 1.0 -t / ^ 1 1 4, 2 0.90 4.9 10 - / - OH 1 - - 5.8

H3C

K

-N) 1 0.15 2.90 0.40 y - / 1 1.5 0.20 2.3

V

CONH2 - / 1 2.4 1.42 1.9 '/ 3OOCH3 ΓΛ -N 1 0.49 1.83 18 yo /' λ d 20 -N ^ _ ^ N-CH3d 1> 100 - 12.7 36 DK 167007 B1 a Solubility in water at 22 ° C.

^ P is the coefficient of distribution between octanol and water at 22 ° C. c The half-life of hydrolysis in 50% human plasma (pH 7.4) at 37 ° C.

Hydrochloride Salt TABLE 4

The half-lives (t1 2) for hydrolysis of various compounds of formula 0 R 11/10 R-C00-CH 2 -C-N in 80% human plasma (pH 7.4) at 37 ° C.

\ r2 R-C00- is the acyloxy residue of R ^ r2 t ^ 2 (min) 15 ________

Naproxen CH3 CH3 1.5 C2H5 C2H5 0.6 CH2CH20H CH2CH20H 1.3 CH3 CH2COHH2 2.5 Ibuprofen CH3 CH3 8.6 CH3 CH2C0NH2 9.6 / CH3 CH2COHHCH2N

Ketoprofen CH3 CH3 1.1 G2H5 C2H5 0.5 CH3 CH2CONH2 2.3

Flurbiprofen CH3 CH3 10.8 C2H5 C2H5 4.7

Indomethacin CH3 CH3 130 37 DK 167007 B1 C2H5 C2H5 25 CH3 CH2CH20H 140 .CH2CH2OH CH2CH2OH 88

Tolmetin CH3 CH3 14.6 C2H5 C2H5 13.4

Tolfenamic acid CH3 CH3 2.8 C2H5 C2H5 5.0 C2H5 CH2CH2OH 3.0

Tranexamic acid CH3 CH3 1.2 Salicylic acid CH3 CH3 0.08 C2H5 C2H5 0.08 CH3 CH2CONH2 0.33 / “λ -N N-CHo 22

w J

TABLE 5 38 DK 167007 B1

The half-lives (/ 2) for hydrolysis of esters of various drugs containing a carboxylic acid function in 80% human plasma 5 Acid t1 / 2

Methyl N, N-diethylglycol ester amide ester Benzoic acid 2.0 hours 0.04 min

Salicylic acid 17.6 hours 0.08 min

Naproxen 20.1 hours ^ 0.6 min

Ketoprofen> 20 hours 0.5 min

Tolmetin 19 hours 13.4 minutes 15 Tolfenamic acid 100 hours 5.0 minutes

Indomethacin 150 hours 25 min

Tranexamic acid> 3 hours 1.2 minc a At pH 7.4 and 37 ° C.

Value of ethyl ester c Value of N, N-dimethylglycolamide ester TABLE 6 39 DK 167007 B1

Plasma concentrations of naproxen following oral administration of naproxen (4.8 mg / kg) or the equivalent amount of N, N - (/ 9-hydroxyethyl) glycolamide ester of naproxen to rabbits 5

Naproxenplasmakonc.

Time after (µg / ml) administration _ (min) After naproxen- After ester administration administration 2.8 2.7 25 5.1 5.7 50 6.4 8.3 15 75 7.1 8, 2 100 7.4 7.7 125 7.1 6.7 200 5.4 4.0 300 3.6 3.6 20 400 2.7 3.3 450 2.4 3.2 DK 167007 Bl 40

REFERENCES

Boltze, K.-H. & H. Kreisfeld (1977): Arzneim.-Forsch. 27, 1300-1312.

Todd, P.A. & R.C. Whole (1986): Drugs 31, 198-248.

Concilio, C. & A. Bongini (1966): Ann. Chim. (Rome) 56, 417-426.

Hankins, E.M. (1965): U.S. Patent 3, 173, 900.

Speziale, A.J. & P.C. Hamm (1956): J. Am. Chem. Soc. 78, 2556-2559.

Berkelhammer, G., S. DuBreuil & R.W. Young (1961): J. Org. Chem. 26, 2281-2288.

Weaver, W.E. & W.M. Whaley (1947): J. Am. Chem. Soc. 69, 515-516.

Ronwin, E. (1953): J. Org. Chem. 18, 127-132.

Holysz, R.P. & H.E. Stavely (1950): J. Am. Chem. Soc. 72, 4760-4763.

Ferres, H. (1983): Drugs of Today 19, 499-538.

Harrison, I. T., B. Lewis, P. Nelson, W. Rooks, A. Roszkowski, A. Tomolonis & J. Fried (1970): J. Med. Chem. 13, 203-205.

Child, R.G., A.C. Osterberg, A.E. Sloboda & A.S. Tomcufcik (1977): J. Pharm. Sci., 66, 466-476.

Tocco, D.J., F.A. de Luna, A.E.W. Duncan, T.C. Vassil & E.H. Ulm (1982): Drug Metab. Disp. 10, 15-19.

Larmour, I., B. Jackson, R. Cubela & C.I. Johnston (1985): 20 Br. J. Clin. Pharmacol. 19, 701-704.

Rakhit, A. & V. Tipnis (1984): Clin. Chem 30, 1237-1239.

Tipnis, V. & A. Rakhit (1985): J. Chromatogr. 345, 396-401.

41 DK 167007 B1

Boltze, K.-H., 0. Brendler, H. Jacobi, W. Opitz, S. Raddatz, P.-R. Seidel & D. Vollbrecht (1980): Arzneim.-Forsch. 30, 1314-1325.

"Remington's Pharmaceutical Sciences," Sixteenth Edition (1980), Mack 5 Publishing Company, Easton, U.S.A.

Marvel, C.S., J.R. Elliott, F.E. Boeltner & H. Yaska (1946): J. Am. Chem. Soc. 68, 1681-1686.

Claims (6)

42 DK 167007 B1 1. Carboxylic Acid Drug Prodrug Derivatives of the General Formula I 0.Ri II / 1 R - C00 - CH2 - C - I Compounds according to claim 1, characterized in that R 1 is methyl or ethyl and R 2 is selected from -ch 2 -CH2CONH2 -ch2ch2conh2 -CH2CH2OOCCH2N (CH3) 2 -CH2CH200CCH2N (C2H5) 2 -ch2ch2oocch2nh2 -CH2CONHCH2 / \ -CH2CONHCH2N (CH3) 2 -CH2CONHCH2N (C2H5) 2 / ~ \ -CH2CONHCH2N> -CH2CH2N (CH3) 2 C) a compound of formula D HNRjF.2 (D) wherein RjL and R2 have the meaning given in formula I are reacted with an acid of formula E Compounds according to claims 1, 5, characterized in that R 1 and R 2 are both C 1-6 alkyl or both are -CH 2 CH 2 OH. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable excipient and a pharmaceutically effective amount of a compound 10 according to any one of claims 1-3. R ~ C00CH2C00H (E) wherein R-C00- has the meaning given in formula I, or with the corresponding acid chloride (or acid anhydride) of formula F R-COOCH2COC1 (F) Process for the preparation of compounds of formula I as defined in claim 1, characterized in that a) the carboxylic acid compound of formula A or a salt thereof R - C00H (A) wherein R-C00- has the meaning set forth above in connection with Formula I is reacted with a compound of Formula B 0 R 1 II X - CH 2 - C - N <"(B) 20 where R and R 2 is as defined above and X is a convenient leaving group; or b) a compound of formula B wherein X is hydroxy is reacted with an acid of formula A or with the corresponding acid chloride of formula Or R 2 is combined such that -NR 2 R 2 forms a 4-, 5-, 6-or 7-membered heterocyclic ring which, in addition to the nitrogen atom, may contain one or two additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, which heterocyclic ring may be substituted by a hydroxy group, a carbonyl group, a C 1-6 alkyl group or an oxyacyl group of the formula R the meaning given above, or an acyloxy group of the formula -COOR 2 q, wherein R 2 is as defined above; 10 and non-toxic pharmaceutically acceptable acid addition salts thereof. Wherein R-C00- represents the acyloxy acid residue of a carboxylic acid drug or drug selected from: salicylic acid, indomethacin, 10. naproxen, ibuprofen, ketoprofen, tolmetine, flurbiprofen, 15. tolfenamic acid, enalaprilic acid, captopril acid, captopril 20. L-dopa, tranexamic acid, furosemide and N-acetylcysteine ° g R 2 and R 2 are the same or different and are selected from the class consisting of a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 cycloalkyl group, or an aryl group or an aralkyl group wherein aryl or an aryl moiety is phenyl or naphthyl optionally substituted with one or more substituents selected from C 1-6 alkylthio, C 1-6 alkyl, nitro or C 1-6 alkanoyl, and wherein alkyl, alkenyl, aryl, aralkyl - or the cycloalkyl group is unsubstituted or substituted by one or more substituents selected from: DK 167007 B1 43 - a halogen atom, - a hydroxy group, - a straight or branched alkoxy group of formula R3-O- wherein R3 represents a C1-6 alkyl group, a phenyl group or a naphthyl group which may be unsubstituted or substituted one or more times by a halogen atom or a hydroxy group, - a carbamoyl group of the formula -CON 2 S> \ 10 wherein R 4 and R 5 are the same or different and are hydrogen, a C1-6 alkyl group or is v algae from a group of the formula -C1 NRyRg wherein Rg and R7 are the same or different and are hydrogen, a C1-6 alkyl group or together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic ring which may contain, in addition to the nitrogen, one or two additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, - an amino group of the formula -NRgRg wherein Rg and Rg are the same or different and are hydrogen, a C -alkyl group or together with the adjacent nitrogen atom forms a 4-, 5-, 6- or 20-membered heterocyclic ring which, in addition to the nitrogen, may contain one or two additional heteroatoms selected from the class consisting of nitrogen, oxygen and sulfur, - an acyloxy group of the formula -COOR ^ q wherein R R q is a C Cjgalkyl, aryl or aralkyl group wherein aryl or aryl moiety is phenyl or naphthyl, - an oxyacyl group of formula R R is hydrogen, a C 1-6 alkyl group, an aryl group, an aralkyl group, a cycloa 1-alkyl group wherein the aryl or aryl moiety is phenyl or naphthyl and wherein the alkyl, aryl, aralkyl or cycloalkyl group is unsubstituted or substituted once or more by a halogen atom, a hydroxy group, an alkoxy group of formula R O- as defined above, a carbamoyl group of the formula -CONR4R5 as defined above or an amino group of the formula -NRgRg as defined above; DK-167007 B1 or -NR ^ R ^ is -N ^ O, -M ^ ~ OH, -N, -1 ^ • O 'conh2' cooch3 Γ \ ΓΛ / \ -Ii ^ N-CH3, -N_N-CH2CH2OH, -N ^> Use of a compound according to any one of claims 1-3 for the preparation of a pharmaceutical composition for use in therapy.