This invention relates to new organic acid anhydrides and to a pharmaceutical composition on a prodrug base.

Prodrugs are compounds which do not exhibit a pharmacological activity by themselves, but which, when absorbed in the body, release the active compound in order to enable the latter to fulfil its therapeutical funtion. Such prodrugs especially are of importance, on the one hand, to prevent the free active compound from undergoing a chemical alteration before reaching its destination in the body, this alteration resulting in the loss of activity, and on the other hand to modify the physico-chemical properties of the medicine in such a way as to enable in the body an appropriate and timely absorption as well as an appropriate and timely release of the medicine :

Numerous existing medicines contain an organic acid function. This acid function generally causes problems with respect to the absorption of the medicine, which could be ascribed to the polarity and acidity of such medicines. There are known many propositions for solving these problems, mainly utilizing prodrugs in the form of an ester or amide of the pharmacologically active organic acid. In these cases the active organic acid must be liberated in the body by hydrolysis of the ester or amide group. A disadvantage of these known ester and amide prodrugs resides in the fact, that their hydrolysis to the active free acid in vivo only takes place slowly, resulting in the medicine not immediately being available after absorption of its prodrug. The reason for this slow hydrolysis is the fact, that for the hydrolysis of these ester and amide prodrugs the action of enzymes, the esterases, is required.

It is now an object of the present invention to provide new organic acid anhydrides which are able to function as prodrug and of which the hydrolysis to the free active organic acid is not dependent on the action of enzymes.

The present invention is directed to new organic acid anhydrides, characterized in that the organic acid

anhydride is a mixed acid anhydride of formula 1

wherein R^ is the residue of an organic acid having anti-inflammatory, anti-epileptic, ACE-inhibiting, biocidal, cytostatic , diuretic , antidiarrheal or cerebrotonical activity, or of a steroid acid; and

R2 _s different from R and represents: either a group of formula 2

wherein R-^ , R4 and B~> are the same or different and are hydrogen or a C-j-2_- lkyl or -alkenyl, cyσloalkyl or -alkenyl, aryl, alkaryl, aralkyl group, optionally substituted by alkyl, aryl, alkoxy, aryloxy, alkoxycarbonyl or aryloxycarbonyl and optionally containing one or more hetero- atoms; or a steroid fragment; or an amino acid or peptide moiety; and the pharmaceutically acceptable salts thereof.

These mixed acid anhydrides of formula 1 possess the for prodrugs particularly advantageous property that the hydrolysis of the mixed acid anhydride to the pharmacologically active compound is independent on the action of enzymes, thereby permitting the adjustment of the degree of hydrolyzability in. vivo by selecting for a given R1-group a suitable ^-group. Inherent to the anhydride form, into which the medicine is converted, is a decreased polarity and acidity and an increased lipophilicity. On the one hand, this reduces the irritation of the gastro-Intestinal system in case of oral intake, while on the other hand the ability to be absorbed by the skin Increases, such as with transdermal and transmucosal

absorption of the mixed acid anhydride.

As mentioned above, a prodrug can be obtained by proper selection of the mixed anhydrides, which prodrug, when absorbed in the body and hydrolysed to the pharmacologically active organic acid, exhibits the desired pharmacological activity, whereas the physico-chemical properties of the prodrug, such as the degree of hydrolyzability in water and body fluids, the lipophilicity, the taste, odour and colour, the mixability with additives and the processability, are systematically adjustable in dependence on the nature of the medicine, the administration route and the objective. In the pharmaceutical practice this leads to important advantages.

The degree of hydrolyzability can be adjusted by defining one or more of the 3, R^ and R ⁵ groups in formula 2 as hydrogen atoms. When R3, R4 and R^ all represent hydrogen, the hydrolysis proceeds quickly. The more hydrogen atoms are replaced, the more the hydrolysis speed decreases.

The degree of lipophilicity is adjustable by selecting the chain length of one or more of the groups R-^, ^ and R^ in a suitable manner. The lipophilicity increases with increasing chain length.

By defining R^ as a steroid fragment or a amino acid or peptide fragment, very specific properties can be obtained. For example, the R^ group can perform a carrier function in order to transport the active organic acid through the eel membranes.

As mentioned, R in formula 1 can be the residue of an organic acid having anti-inflammatory, anti-epileptical, ACE-inhibiting, biocidal, cytostatical, diuretical, anti- diarrhetic or cerebrotonical activity, or of a steroid acid.

Examples of residues R of free organic acids having anti-inflammatory activity include: residues of tolmetin, zomepirac, tiaprofenic acid, sulindac, niflumiσ acid, ibuprofen, mefenamic acid, ketoprofen, indometacin, flurbiprofen, fenoprofen, fenclofenac, naproxen, fenbufen, diclofenac, etodolac, cinmetacin, acetylsalicylic acid and penicillamine. However, this recitation is not restrictive, and also other non-steroidal anti-inflammatory organic acid residues may be used. As R the residues of ibuprofen, ketoprofen, flurbiprofen, diclofenac, naproxen, etodolac.

sulindac and indometacin are particularly preferred.

Examples of residues of anti-epileptic organic acids are defined by the general formula 3, wherein R*> and R? are the same or different and represent an aliphatic group. Preferably R^ is the residue of valproic acid, R^ and ^ in formula 3 both being n-propyl.

The term "ACE-inhibiting activity" used in the specification and claims stands for "angiotensin-converting enzyme-inhibiting activity". This activity resides in the inhibition of the renin-angiotensin system and more particularly of the enzym which converts angiotensin. Compounds exhibiting such ACE-inhibiting activity possess anti-hypertensive properties.

Examples of residues of organic acids having ACE-inhibiting activity are defined by general formula 4 or 5, wherein ⁸ is hydrogen, alkyl- or arylcarbonyl, ⁹ is hydrogen, alkyl or aminoalkyl, R^® is alkyl or a 5_s~ cycloalkyl optionally substituted by alkyl or aryl, is alkyl or aryl, or R10 and R together may form a C3_g-alkylene or -alkenylene optionally substituted by alkyl or aryl, the C3_ς-alkylene or -alkenylene optionally being part of a saturated or unsaturated quinoline or isoquinoline group, R is hydrogen or alkyl, R 3 is hydrogen, alkyl or R ² -C(0)- and R ⁴ is alkyl or aralkyl. A favourable representative hereof is the residue having formula 4, wherein R ⁸ is tert-butylcarbonyl, R^ is methyl, R10 and 1 together form a propylene group and R is hydrogen. This residue is the residue of captopril, in which the hydrogen atom of the thiol function is replaced by a tert-butylcarbonyl protecting group.

An other preferred residue R^ has formula 4, in which R ⁸ is tert-butylcarbonyl, R ⁹ is methyl, R ¹ ° is cyclopentyl and R ¹ 1 and ² both are hydrogen. This residue is the residue of pivopril in which the hydrogen atom of the thiol function Is replaced by a tert-butylcarbonyl protecting group.

Other especially advantageous residues R have formula 5 in which R ⁹ is methyl of 4-arainobutyl, R^0 and R ^* *^ together form a propylene group, R 2 is hydrogen, R 3 is R2-C(0)- and R ⁴ is phenylethyl. Such anhydrides in which R ¹³

has the meaning of R ² -C(0)- could be considered as the dianhydride of enalapril and lysinopril respectively. In the residues of enalapril and lysinopril, on the contrary, ' ^ is an ethyl group. In the latter case there exists an ester 5 function which should be hydrolysed in vivo, resulting in the disadvantages mentioned-above. These disadvantages could be avoided by replacing the ester function by an anhydride function, both anhydride functions of the mixed dianhydride being the same or different.

10 As examples of residues of organic acids having biocidal activity, the residues of pipemidinic acid, oxoliniσ acid, flu equin, nalidixic acid and cinoxacin can be mentioned, whereas the residues of oxolinic acid, flumequin and cinoxacin are preferred.

15 Examples of R residues of organic acids having cytostatic activity include the residues of chlorambucil and of the free acid of vinblastin, the former being preferred.

Examples of residues of organic acids having diuretic activity include residues of tienilic acid,

20 _. ethacrynic acid and furosemid, whereas the latter residue is preferred.

As examples of residues of organic acids having antidiarrheal activity, the residues of the free acid of loperamide and of the free acid of diphenoxylate are

25 mentioned. The residue of the free acid of loperamide is particularly suitable in the present mixed acid anhydrides.

Representatives of residues of organic acids having cerebrotonical activity include the residues of the free acid of piracetam and of the free acid of vincamine, the former

30 residue being preferred.

Finally, examples of residues of steroid acids are the residues of chenodiol, ursodeoxycholic acid and canrenoiσ acid. The residue of ursodeoxycholic acid is especially preferred.

35 A special form of the mixed acid anhydrides results if both the R as well as R group represent a residue of a pharmacologically active organic acid. By hydrolysis in vivo of the mixed acid anhydride two active compounds are released, thereby permitting to combine the actions of two medicines. This offers various advantages

above the conventional combination preparations, which contain two separate active compounds, optionally each in the form of a prodrug.

The preparation of the mixed acid anhydrides according to the invention is performed out on a manner known per se for analogous compounds. However, problems could arise therein, when beside the anhydride function also free amine, alcohol Or thiol functions are present in the mixed anhydride. Such free amine, alcohol and thiol functions often don't go together with anhydride functions and should therefore be masked by means of protecting groups. Such protecting groups should be easily removable in vivo. Primary and secondary amines could be protected by means of salt formation, preferably hydrochloride salt formation, or by substitution of the or each hydrogen atom of the amine group by a suitable protecting group. The protection of alcohols may be performed by converting the alcohol function in a suitable protecting group. Also the thiol function can be protected by substitu¬ ting the hydrogen atom of the thiol group by an alkyl- or arylcarbonyl.

The mixed acid anhydrides of the invention may contain asymmetrical carbon atoms in both the R and group. Accordingly, the mixed acid anhydrides may exist in a certain diastereoisomeric form or as a mixture of various diastereoisomeric forms. As starting materials for the preparation of the compounds according to the invention racemates or diastereomeres can be used. The products having the desired diastereoisomeric form can be prepared by a specific asymmetrical synthesis. On the other hand, when obtaining a mixture of diastereomeriσ products, these can be separated by conventional methods, such as chromatography or fractional crystallisation. The amino acid moieties present in the mixed acid anhydrides are preferably in the S-configuration. According to a further aspect the present invention is directed to pharmaceutical compositions of the prodrug type, characterized in that these contain as prodrug a mixed anhydride or an pharmaceutically acceptable salt thereof according to the invention, in association with a pharmaceuti- cally acceptable carrier.

Such pharmaceutical compositions possess the advantages which were mentioned for the mixed acid anhydride of the invention. Furthermore, such compositions could be applied topically on the required places, because the degree and manner of absorption could be influenced by selecting a suitable R ² group for a certain R group. As the absorption of the prodrug and the release of the pharmacologically active organic acid take place in a more efficient way, a more efficient use of the medicine, which is present in the acid anhydride form as a prodrug, is possible so that the composition could contain a smaller amount of prodrug, decreasing the costs of such a composition and resulting in a reduction of the volume of the composition.

Apart from the prodrug or its pharmaceutically acceptable salt, the compositions of the invention can also comprise physiologically acceptable carriers, vehicles, excipients, binders, preservatives, stabilizers, flavoring agents, penetration promoting agents and such.

The pharmaceutically compositions can be administered orally, anally, sublingually, parenterally. ^' hey could be formulated in tablets, dragees, capsules, gelules, suppositoria, aerosol preparations with an inert carrier gas, ointments. Especially the forms suitable for transdermal, transbuccal and oral administration are preferred. In this respect, the compositions according to the invention may contain penetration promoting agents, such as isopropyl- myristate, lauracapram and such. Also technical assisting means, for example adhesive plasters and hypo- or hyperdermic pastilles are advisable. With the aid of such assisting means a time-controlable and more uniform release of the medicine in the blood stream may be obtained.

The following embodiments are provided for the purpose of illustrating the invention and should not be regarded as limiting it in any way.

EXAMPLE I

Anhydride of ibuprofen and propionic acid

20 g (97 mmol) of ibuprofen (2-(4-isobutylphenyl)- propionic acid) were dissolved in 160 ml tetrahydrofuran.

Hereto were added 13.5 ml of triethylamine drop by drop at 0°C. 8.44 ml of propionylchloride were dissolved in 100 ml of

ether and added to the ibuprofen solution in a time period of 60 minutes, at 0 ^β C. After complete dissolution the mixture was stirred during a further 30-60 minutes at ambient temperature. The reaction mixture thus obtained was poured into an ice cold 10% solution of sodiumcarbonate and the organic solution was washed herewith three times. After washing with cold distilled water until neutral, the solution was dried and evaporated under reduced pressure.

After column chromatography over Siθ2 using chloroform as eluent, 17.4 g of the mixed anhydride were obtained as a light yellow oil.

Thin layer chromotography, infrared and mass spectroscopy point to the title compound.

TLC (Si0 ₂ ) : Rf (CHC1 ₃ ) = 0,60; Rf (ether) = 0.69 Infrared spectrum : IR (NaCl): 3040, 3020, 3010, 2950,

2875, 1820, 1750, 1520, 1460, 1040 (broad), 850, 800 cm~1 Mass spectrum : (FAB, pos) : m/z = 264, 263, 262, 252,

219, 205, 202, 161, 145, 132, 131, 129, 105, 91 , 77.

EXAMPLE II Anhydride of ibuprofen and lauric acid

Analogous to the method described in example I 20 g of ibuprofen were reacted with lauroyl chloride, obtained from 19.5 g lauric acid and thionyl chloride, to form 30 g of anhydride of ibuprofen and lauric acid. This anhydride was purified by colomn chromatography over Si0 ₂ utilizing chloroform as eluent. Thin layer chromatography: TLC (Si0 ₂ ) ϊ Rf (CHCI3 ) = 0.60;

Rf (ether) = 0.76 Infrared spectrum : IR (NaCl) : 3100, 3050, 3020, 2950,

2925, 2850, 1820, 1750, 1460, 1040 cm" ¹ Mass spectrum MS (FAB, pos): m/z = 284, 256, 161, 145, 131, 119

118, 117, 105, 102, 91, 77, 71, 69

EXAMPLE III Anhydride of ibuprofen and cis-9-octadecenoic acid (oleic acid) Analogous to the method described in example I, 20 g

of ibuprofen were reacted with oleolyl chloride, obtained from 27.5 g of oleic acid and thionyl chloride, to form 38 g of the anhydride of ibuprofen and oleic acid. This anhydride was purified by colomn chromatography over Si0 ₂ using chloroform as eluent.

Thin layer chromatography: TLC (Si0 ₂ ) : Rf (CHCI3) = 0.69;

Rf (ether) = 0.76 Infra red spectrum : IR (NaCl) : 3050, 3000, _, 2920, 2850,

1820, 1750, 1460, 1040 cm" ¹ Mass spectrum: MS (FAB, pos) : m/z = 338, 321, 310, 280, 265,

263, 247, 233, 219, 206, 205, 161, 145, 128, 119, 118, 117, 105, 97, 91 , 78

EXAMPLE IV

Anhydride of ibuprofen and benzoic acid

Analogous to the method described in example I 20 g of ibuprofen were reacted with 11.3 ml benzoyl chloride, to obtain 19 g of the anhydride of ibuprofen and benzoic acid. This mixed anhydride was purified by column chromatography over Si0 ₂ using chloroform as eluent. Thin layer chromatography : TLC (Si0 ₂ ) : Rf (CHCI3) = 0.53;

Rf (ether) = 0.67 Infrared spectrum : IR (NaCl) : 3050, 3020, 2950, 2925,

2820, 1800, 1730, 1600, 1450, 1210, 1040, 1020, 1000, 700 cm ^~ 1 Mass spectrum : MS (FAB, pos) : m/z = 229, 217,

205, 188, 162, 161, 145, 131, 128, 119, 118, 117, 105, 91, 78, 77, 63

EXAMPLE V Anhydride of diclofenac and propionic acid

50 mg (0.18 mmol) of diclofenac ( 2-(2,6-dichloro- anilino)phenyl]acetic acid) were dissolved in 2 ml of dry tetrahydrofuran. Thereto were added 25 μl of triethylaraine drop by drop at -15°C. After approximately 5 minutes 60 yl of propionyl chloride were dropped in thereby forming immediately a white precipitate. Then the reaction flask was brought at ambient temperature and stirred for another 30 minutes. The solution was filtrated and evaporated. Thus were obtained 60 mg of the anhydride of diclofenac and propionic acid in the form of a light yellow liquid which became solid rapidly.

IR spectrum : IR (NaCl) : 3330, 3050, 3020, 2970, 2930, 1805,

1730, 1450, 1040, 780, 750 cm ^"1 Mass spectrum: MS (FAB, pos) j 280, 278, 244, 214, 180, 102,

91, 77, 57 NMR spectrum : ^1' ' ^" HH..NNMMRR ((CCDDCC1-) : 7.7-6.3 (7H, ) , 5.30 (2H, s) ,

3.80 (1H) , 2.40 (2H, m) , 1.16 (3H, t) dpm

EXAMPLE VI Anhydride of valproic acid and 4-acetamidobenzoic acid. In an anologous manner as described in Example I

1.34 g of acetamidobenzoic acid were reacted with 1-95 g of valproic acid chloride, resulting in 1.60 g (54%) of the anhydride of valproic acid and 4-acetamodobenzoic acid, after purificatio . IR spectrum : IR(NaCl) : 3370, 3280, 3190, 3110, 2960, 2940,

2870, 1810, 1735, 1600, 1530, 1470, 1260, 1160, Mass spectrum: MS (FAB, pos) m/z = 306, 305, 304, 288, 246,

235, 221, 200, 162, 127, 99, 84, 74 NMR spectrum ¹ H-NMR (CDC1-.) : 7.97 (2H,d) , 7,67 (2H,d); 4.37 (lH,s), 2.65(lH,m), 2.21(3H,s), 1.80(8H,m), 0.92(6H,t) dpm

EXAMPLE VII

Anhydride of diclofenac and benzoic acid.

In an analogous manner as described in Example I 0.59 g of diclofenac were reacted with 0.35 g of benzoic acid chloride, giving 0.66 g (83%) anhydride of diclofenac and benzoic acid.

Melting point: 90 - 98°C.

IR spectrum : IR (NaCl) : 3350, 3060, 2950, 2910, 1785, 1730,

1610, 1490, 1460, 1450, 1240, 1210, 1170, 1040, 1015, 995, 790, 780, 750, 705, 670 cm ^"1 Mass spectrum: MS (FAB,pos) m/z = 279, 277, 244, 216, 214,

179, 151, 122, 105, 89, 78, 77 NMR spectrum : ^" ^-NMR (CDC1-) : 8.18 (2H,m) , 7.70-7.10 (10H,m) ,

6.41 (lH,d), 3.79(2H,s) dpm

EXAMPLE VIII Anhydride of diclofenac and 3-me hoxybenzoic acid.

In an analogous manner as described in Example I 1.20 g of diclofenac were reacted with 0.77 g of 3-methoxy¬ benzoic acid, giving 1.08 g (62%) of the title compound. Melting point: 104 - 110°C.

IR spectrum : IR (NaCl) : 3440, 3320, 3060, 3020, 2940, 2910,

1780, 1730, 1605, 1480, 1450, 1430, 1315, 1300, 1260, 1235, 1190, 1175, 1150, 1020, 780, 750,

10 665 cm ^"

Mass spectrum: MS (FAB,pos) : m/z = 280, 278, 214, 180, 179, 178, 177, 165, 152, 135, 105, 91, 89, 77, 74, 73 NMR spectrum : ¹ H-NMR (CDC1 ₃ ) : 7.76 - 7.00 (HH,m) 6.40 (lH,d) ,

3.87 (2H,d), 3.79 (3H, s) dpm

15 EXAMPLE IX

Anhydride of diclofenac and 1-naphtoic acid.

In an analogous manner as described in Example I 1.20 g of diclofenac were reacted with 0.86 g 1-naphtoic acid 2.0 chloride, giving 1.11 g (62%) of the title compound. Melting point: 98 - 104°C. IR spectrum : IR (NaCl) : 3310, 1780, 1730, 1600, 1450, 1360,

1300, 1240, 1020, 930, 770, 740 cm ^"1 Mass spectrum: MS (FAB, pos) : m/z = 280, 278, 263, 242, 214, 25 180, 165, 155, 127, 115, 102, 93, 75, 74, 73

NMR spectrum : ¹ H-NMR (CDC1-) : 8.0 - 6.9 (14H,m), 6.41 (lH,d),

3.79 (2H,s)

EXAMPLE X 0 Anhydride of ibuprofen and 4-chlorobenzoic acid.

In an analogous manner as described in Exampl I 2.00 g of ibuprofen were reacted with 2.10 g of 4-chlorobenzoic acid chloride, giving 3.18 g (95%) of the title compound. IR spectrum : IR (NaCl) : 3095, 3070, 3050, 3020, 2950, 2930, 5 2870, 1805, 1735, 1590, 1250, 1090, 1030, 1005,

840 cm ^"1 Mass spectrum: MS (EI,pos) : m/z = 345, 343, 296, 294, 268, 266,

189, 188, 162, 161, 141, 139, 119, 118, 117, 116, 111, 105, 91, 75

NMR spectrum : ¹ H-NMR (CDC1-) : 8.0 - 7.0 (8H,m) 3.93 (lH,q),

2.44 (3H,d), 1.85 (lH,m) , 1.61 (2H,d), 0.90 (6H,d) dpm

EXAMPLE XI

Anhydride of ibuprofen and 2, 6-dimethoxybenzoic acid.

In an analogous manner as described in Example I 2.00 g of ibuprofen were reacted with 2.41 g of 2,6-dimethoxy-_ benzoic acid chloride, giving 2.95 g (83%) of the title compound. IR spectrum : IR (NaCl) : 3100, 3050, 3005, 2950, 2850, 2840,

1800, 1740, 1600, 1475, 1460, 1295, 1255, 1110, 1030, 1010, 995, 780 cm ^"1 Mass spectrum: MS (El,pos) : m/z = 346, 258, 206, 188, 165, 161,

150, 145, 119, 118, 117, 107, 92, 91, 77 NMR spectrum: -" ^" H-NMR (CDC1-) : 7.30 - 7.00 (5H,m) , 6.5 (2H,m) ,

3.82 (6H,s and lH,m) , 2.44 (3H,d), 1.87 (lH,m) , 1.61 (2H,d), 0.89 (6H,d) dpm

EXAMPLE XII Anhydride of ibuprofen ^' and 4-toluic acid.

In an analogous manner as described in Example I 2.00 g of ibuprofen were reacted with 1.90 g of 4-toluiα acid, chloride, giving 2.94 g (94%) of the title compound. IR spectrum : IR (NaCl) : 3030, 3010, 2960, 2930, 2880, 1805, 1735, 1610, 1510, 1470, 1455, 1260, 1225, 1210,

1175, 1030, 1010, 875, 830, 780, 750 cm -1

Mass spectrum: MS (EI,pos) : m/z = 188, 161, 119, 105, 91, 77, 65 NMR spectrum: -"-H-NMR (CDCl ₃ ) : 8.05 - 7.0 (8H,m) 3.93 (lH,q),

2.45 (3H, s), 2.43 (3H,d), 1.85(lH,m) 1.60 (2H,d),

0.90 (6H,d) dpm

EXAMPLE XIII Anhydride of ibuprofen and 4-nitrobenzoic acid.

In an analogous manner as described in Example I 2.00 g-ibuprofen were reacted with 2.23 g 4-nitrobenzoic acid chloride, giving 3.03 g (88%) of the title compound. IR spectrum : IR (NaCl) : 3110, 3080, 3050, 3020, 2950, 2930,

2845, 1810, 1730, 1605, 1530, 1350, ^" 1240, 1030, 1010, 850, 710 cm ^"1

Mass spectrum: MS (EI,pos) : 282, 272, 239, 188, 161, 150, 145,

119, 118, 117, 104, 91, 76 NMR spectrum : -" ^" H-NMR (CDC1-) : 8.40 - 7.9 (4H,m) 7.25 - 7.0

(4H,m) , 3.96 (lH,q) , 2.43 (3H,d) , 1.89 (lH,m) 5 1.61 (2H,d), 0.89 (6H,d) dpm

EXAMPLE XIV Anhydride of flurbiprofen and benzoic acid.

In an analogous manner as described in Example I 10 0.49 g of flurbiprofen were reacted with 0.35 g benzoic acid chloride, giving 0.67 g (96%) of the totle compound. IR spectrum : IR (NaCl) : 3060, 3030, 2980, 2930, 2870, 1800,

1725, 1600, 1580, 1560, 1480, 1450, 1430, 1260, 1210, 1030, 1020, 995, 770, 700 cm ^"1 15 Mass spectrum: MS (El, os) : m/z = 348, 226, 199, 198, 197, 196,

178, 170, 152, 133, 105, 77 NMR spectrum : ^" 4. - NMR (CDC1-) : 8.3-7.2 (13H,m) 4.01 (lH,q),

1.67 (3H,d) dpm

20 EXAMPLE XV

Anhydride of flumequine and benzoic acid.

In an analogous manner as described in Example I 0.52 g of flumequine were reacted with 0.35 g of benzoic acid chloride, giving 0.57 g of the title compound. 25 IR spectrum : IR (NaCl) : 3050, 2990, 2950, 1800, 1730, 1620,

1470, 1260, 1030, 1010 cm ^"1 Mass spectrum: MS (EI,pos) : m/z = 365, 320, 293, 261, 244, 226,

217, 1981 122, 105, 77, 51 NMR spectrum : H-NMR (CDC1-) : 8.68 (lH,d) . 8.26-7.23 (6H,m) , 30 4.59 (lH,m) 3.31-3.03 (2H,m) 2.37-2.12 (2H,m) ,

1.54 (3H,d) dpm

EXAMPLE XVI Anhydride of valproic acid and benzoic acid.

35 In an analogous manner as described in Example I

2.41 g of valproic acid were reacted with 1.69 g of benzoic acid chloride, giving 2.61 g (63%) of the title compound.

I IR spectrum : IR (NaCl) : 3060, 3030, 2980, 2930, 2870, 1805,

1735, 1460, 1450, 1230, 1210, 1030, 1010, 995, 700 cm ^"1 Mass spectrum: MS (FAB,pos) m/z = 127, 99, 84, 77, 78, 69, 57,

57, 55 NMR spectrum : H-NMR (CDC1-) : 8.05-7.46 (5H,m) , 2.60 (lH,m) ,

1.80-1.25 (8H,m), 0.92 (6H,t) dpm

EXAMPLE XVII Anhydride of valproic acid and nicotinic acid. In an analogous manner as described in Example I

1.19 g of nicotinic acid were reacted with- 1.95 g of valproic acid chloride, giving 2.22 g (92%) of the title compound. IR spectrum : IR) NaCl) : 3060, 3040, 2960, 2940, 2880, 1810,

1740, 1590, 1470, 1425, 1380, 1270, 1235, 1170, 1030, 1010, 920, 730, 700 cm ^"1

Mass spectrum: MS (FAB,pos) : m/z = 250, 127, 124, 99, 84, 69,

57, 55,43, 41. NMR spectrum : ^" ^f-NMR (CDC1-) : 9.23 (lH,hump) 8.87 (lH,hump) ,

8.33 _, (lH,d) , 7.50 (lH,m) , 2.64 (lH,m) 1.84-1.22 (8H,m) 0.92 (6H,t) ^' dpm