Prodrugs of non-steroid anti-inflammatory agents (NSAIDS)

Abstract

The present invention relates to novel depot formulations (prodrugs) comprising an immobility promoting unit linked via an ester to an active pharmaceutical ingredient, i.a. common NSAIDs. The novel depot formulations are suitable for intra-articular injections and are soluble at slightly acidic pH to facilitate ease of injection, and sparingly soluble at physiological pH thereby precipitating at the site of administration. The precipitate will slowly dissolve and the active drug is released from dissolved depot formulation following esterase mediated cleavage of the ester link between the immobility promoting unit and the active pharmaceutical agent.

Claims

1. A compound of formula (I): ##STR00017## wherein: R.sub.1 represents an immobility promoting unit (IPU) with a molecular weight lower than 1000 g/mol and a pK.sub.a of between 4 and 7.6 at 37° C., wherein the IPU is selected from the group consisting of: ##STR00018## wherein R.sub.3 is attached on any ring carbon or any nitrogen of the IPU and R.sub.3 is straight or branched C.sub.1-8 alkyl or alkoxyalkyl, with the proviso that when R.sub.3 is attached on a nitrogen atom R.sub.3 is not —CH.sub.2— R.sub.4 and R.sub.5 are each independently hydrogen, straight or branched C.sub.1-8 alkyl, alkoxyalkyl or phenyl, or when R.sub.1 is a phenylamino or benzimidazolyl moiety as set forth above, R.sub.4 may be R.sub.3, or when R.sub.1 is an imidazolyl moiety as set forth above, R.sub.5 may be R.sub.3; —O—(C═O)—R.sub.2 represents an acyloxy residue of a carboxylic acid group of; and x is 1; salts, solvates or hydrates thereof, wherein the aqueous solubility of the compound is pH dependent, such that the aqueous solubility at a pH between 2 to 6 pH units lower than a pH of a physiological fluid having a pH of from 6 to 8 is at least 100 times higher than its aqueous solubility at the pH of the physiological fluid.

2. A compound according to claim 1, wherein R.sub.1 is selected from the group consisting of the R.sub.1 moieties of the following R.sub.1—OH compounds: ##STR00019## ##STR00020##

3. A compound according to claim 1, selected from the group consisting of: ##STR00021## ##STR00022## ##STR00023##

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, and at least one pharmaceutically acceptable carrier, vehicle and/or adjuvant.

5. A pharmaceutical composition according to claim 4, wherein the composition is suitable for intra-articular injection.

6. A method of treating postoperative pain and/or inflammation in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 to the patient.

7. A method of treating postoperative pain following arthroscopic surgery in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 to the patient.

8. A composition for intra-articular injection comprising a compound according to claim 1, wherein the composition is in the form of an aqueous solution having a pH of from 1.5 to 5, from which the compound of formula I precipitates in the joint of a patient, at least partly, after administration.

9. A composition according to claim 8, wherein R.sub.1 is selected from the group consisting of the R.sub.1 moieties of the following R.sub.1—OH compounds: ##STR00024## ##STR00025##

10. A composition according to claim 8, wherein the compound is selected from the group consisting of: ##STR00026## ##STR00027## ##STR00028##

11. A method of treating postoperative pain and/or inflammation in a patient in need thereof, comprising administering a therapeutically effective amount of a composition according to claim 8 to the patient.

12. A method of treating postoperative pain and/or inflammation following arthroscopic surgery in a patient in need thereof, comprising administering a therapeutically effective amount of a composition according to claim 8 to the patient.

13. A compound of formula: ##STR00029## wherein: R.sub.1 represents an immobility promoting unit (IPU) with a molecular weight lower than 1000 g/mol and a pK.sub.a of between 4 and 7.6 at 37° C., wherein the IPU is selected from the group consisting of: ##STR00030## wherein R.sub.3 is attached on any ring carbon or any nitrogen of the IPU and R.sub.3 is straight or branched C.sub.1-8 alkyl or alkoxyalkyl, with the proviso that when R.sub.3 is attached on a nitrogen atom R.sub.3 is not —CH.sub.2—, and R.sub.4 and R.sub.5 are each independently hydrogen, straight or branched C.sub.1-8 alkyl, alkoxyalkyl or phenyl, or when R.sub.1 is a phenylamino or benzimidazolyl moiety as set forth above, R.sub.4 may be R.sub.3, or when R.sub.1 is an imidazolyl moiety as set forth above, R.sub.5 may be R.sub.3; salts, solvates or hydrates thereof, wherein the aqueous solubility of the compound is pH dependent, such that the aqueous solubility at a pH between 2 to 6 pH units lower than a pH of a physiological fluid having a pH of from 6 to 8 is at least 100 times higher than its aqueous solubility at the pH of the physiological fluid.

14. A compound according to claim 13, wherein R.sub.1 is selected from the group consisting of the R.sub.1 moieties of the following R.sub.1—OH compounds: ##STR00031## ##STR00032##

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 13, and at least one pharmaceutically acceptable carrier, vehicle and/or adjuvant.

16. A pharmaceutical composition according to claim 15, wherein the composition is suitable for intra-articular injection.

17. A method of treating postoperative pain and/or inflammation in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 13 to the patient.

18. A method of treating postoperative pain following arthroscopic surgery in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 13 to the patient.

19. A composition for intra-articular injection comprising a compound according to claim 13, wherein the composition is in the form of an aqueous solution having a pH of from 1.5 to 5, from which the compound of formula I precipitates in the joint of a patient, at least partly, after administration.

20. A composition for intra-articular injection comprising a compound according to claim 14, wherein the composition is in the form of an aqueous solution having a pH of from 1.5 to 5, from which the compound of formula I precipitates in the joint of a patient, at least partly, after administration.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 shows the structures of the twenty five prodrugs with the NSAIDs ketorolac, diclofenac, ibuprofen, and naproxen attached to different immobility promoting units (IPUs) including different linker structures.

(2) FIG. 2. The time course for DPX-4-0001 (ALE 408) and ketorolac in solution after addition of solid DPX-4-0001 (ALE 408) to synovial fluid at 37° C. illustrating the cleavage of dissolved prodrug to the active substance.

(3) FIG. 3. Precipitation of DPX-4-0001 after addition of a concentrated aqueous acidic solution to buffer pH 7.4 solution followed by non-enzymatic hydrolysis of dissolved DPX-4-0001 to ketorolac.

(4) FIG. 4 shows factors influencing the pharmacokinetic fate of the prodrug/drug after administration of the prodrug into the joint. The prodrug dissolved is converted into the active drug by enzymatic cleavage of the prodrug bond.

(5) The invention is illustrated in, but not limited to, the following examples

EXAMPLES

(6) The inventors have tested twenty five compounds/prodrugs (all promoieties comprising aniline, pyridine, imidazole and benzimidazole structures). The prodrugs were tested according to the “method for testing solubility” below. As expected, all prodrugs exhibited a low although variable solubility at pH 7.4 (due to the very low solubility of the neutral form of the prodrugs).

(7) The structures of the twenty five prodrugs with the NSAIDs ketorolac, diclofenac, ibuprofen, and naproxen attached to different immobility promoting units (IPUs) are shown in FIG. 1.

(8) Standard procedures were used to synthesize the ester derivatives as apparent from the more detailed description of the synthesis of the NSAID ester prodrugs presented below. Purity of the synthesized derivatives exceeded 95% as assessed by .sup.1H-NMR and HPLC.

(9) Method for Testing Solubility

(10) The determination of the solubility of a prodrug at different pH values of interest according to the present invention is carried by adding excess solid prodrug to a container containing a buffer solution with well-defined pH. The mixture is rotated at constant temperature until an equilibrium between solid prodrug and prodrug in solution has established (that is until the prodrug concentration in the supernatant remains constant). At each measurement the pH of the supernatant is controlled and eventually adjusted to the desired pH. In a similar manner the solubility of a prodrug in a tissue fluid including the synovial fluid can be determined.

Example 1

DPX-1-0001 (ALE463)

(11) 4-(dimethylamino)phenethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate

(12) 2-(4-(dimethylamino)phenyl)ethanol (3.3 mmol, 0.55 g), and Dichlofenac (3.3 mmol, 0.99 g) was suspended in dichloromethane (30 mL) under N.sub.2 and Dicyclohexylcarbodiimid (6.6 mmol, 1.36 g), 4-Dimethylaminopyridine (0.33 mmol, 36 mg) was added. The mixture was stirred overnight before being poured into sat. NH.sub.4Cl (100 mL) and extracted with dichloromethane (4×50 mL). Drying, filtration and evaporation gave 2.4 g crude material which was purified by Flash Chromatography using EtOAc and Heptanes as eluent giving 0.65 g (43%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) 7.52 (d, J=8.03 Hz, 4H), 7.13-7.24 (m, 4H), 7.04-7.10 (m, 2H), 6.93-7.02 (m, 5H), 6.85 (dt, J=1.25, 7.40 Hz, 2H), 6.58-6.63 (m, 4H), 6.26 (d, J=7.53 Hz, 1H), 4.21 (t, J=7.03 Hz, 4H), 3.78 (s, 2H), 2.82 (s, 11H), 2.77 (t, J=7.03 Hz, 4H) 13C NMR (400 MHz, DMSO-d6) 171.40, 137.07, 130.90, 129.28, 125.86, 123.20, 112.53, 65.51, 37.11, 33.40.

Example 2

DPX-1-0002 (ALE 482)

(13) 2-(methyl(phenyl)amino)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate

(14) Using an identical procedure as described for DPX-1-0001:

(15) 2-(methyl(phenyl)amino)ethanol (3.3 mmol, 0.50 g), Dichlofenac (3.3 mmol, 0.99 g), Dichclohexylcarbodiimid (6.6 mmol, 1.36 g), 4-Dimethylaminopyridine (0.3 mmol, 36 mg) and dichloromethane (30 mL). Crude yield: 1.4 g; yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 0.83 g (59%). .sup.1H NMR (400 MHz, DMSO-d6) d 7.52 (d, J=8.28 Hz, 3H), 7.20 (t, J=8.16 Hz, 2H), 7.10-7.15 (m, 4H), 7.05 (dt, J=1.51, 7.78 Hz, 2H), 6.97 (s, 1H), 6.83 (dt, J=1.25, 7.40 Hz, 2H), 6.66-6.72 (m, 3H), 6.56-6.63 (m, 2H), 6.25 (d, J=8.03 Hz, 1H), 4.24 (t, J=5.77 Hz, 3H), 3.74 (s, 3H), 3.58 (t, J=5.77 Hz, 3H), 2.83 (s, 5H). .sup.13C NMR (400 MHz, DMSO-d6) δ 171.43, 148.71, 142.81, 137.06, 129.13, 128.94, 127.71, 123.02, 115.89, 111.98, 61.90, 50.24, 38.15, 37.02, 31.23, 28.34, 22.07,

(16) Methanesulfonate salt of DPX-1-0002.

(17) Methanesulfonic acid (113 μl, 167 mg, mmol) in dry diethyl ether (10 mL) was added by syringe to a magnetically stirred solution of 2-(methyl(phenyl)amino)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (746 mg, 1.74 mmol) in dry diethyl ether (20 mL) under nitrogen cooled in an ice bath. The resulting precipitate in the form of a sticky gum was isolated by decanting off the solvent and washing the gum with dry ether (10 mL). The gum was dried under high vacuum and crystallized from ethanol to afford the title compound as a colourless solid (653 mg). Mp. 143.6-144.6° C. (dec.) (ethanol). .sup.1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8 Hz, 2H), 7.27-6.78 (m, 11H), 6.26 (dd, J=8.0, 1 Hz, 1H), 4.23 (t, J=5.5 Hz, 2H), 3.75 (s, 2H), 3.68 (t, J=5.5 Hz, 2H), 2.95 (s, 3H), 2.45 (s, 3H). .sup.13C NMR (101 MHz, DMSO) δ 171.31, 142.83, 137.04, 131.01, 130.73, 129.26, 129.15, 127.76, 125.95, 122.93, 120.59, 115.83, 114.22, 61.21, 51.76, 39.70 (CH3), 36.94. DEPT .sup.13C NMR (101 MHz, DMSO) δ 131.01, 129.27, 129.16, 127.77, 125.96, 120.60, 115.84, 61.22, 39.70, 36.94.

Example 3

DPX-1-0004 (sdnX-20)

(18) 2-(pyridin-2-yl)ethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

(19) Using an identical procedure as described for DPX-1-0001:

(20) 2-(pyridin-2-yl)ethanol (37.7 mmol, 4.65 g), Dichlofenac (9.43 mmol, 3.0 g), 4-Dimethylaminopyridin (0.3 mmol, 35 mg), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl (11.32 mmol, 2.17 g), Dichloromethane (15 mL) and Dimethylformamide (10 mL). Yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 1.67 g. The solid HCl-salt was prepared by passing a stream of HCl through an ethereal solution of the product. .sup.1H NMR (CDCl.sub.3) 3.3-3.7 (m, 4H), 4.58 (br s, 2H), 6.24-7.30 (m, 8H), 7.60 (br s, 1H), 7.97 (br s, 1H), 8.57 (br s, 1H). .sup.13C (CDCl.sub.3): 13.76, 22.29, 25.24, 28.61, 30.62, 31.47, 32.39, 38.03, 62.30, 67.58, 111.37, 121.53, 123.17, 124.30, 124.77, 127.39, 127.81, 128.51, 128.59, 129.42, 130.78, 136.85, 140.77, 142.26, 145.15, 153.05.

Example 4

DPX-1-0005 (ALE460-2)

(21) 2-(1H-imidazol-1-yl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate

(22) Using an identical procedure as described for DPX-1-0001;

(23) 2-(1H-imidazol-1-yl)ethanol (12 mmol, 1.3 g), Dichlofenac (6 mmol, 1.77 g), Dimethylaminopyridin (0.3 mmol, 22 mg), Dicyclohexylcarbodiimid (7.2 mmol, 1.5 g) and Dichloromethane (50 mL). Crude yield: 2.13 g; yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 0.80 g (34%). .sup.1H NMR (400 MHz, DMSO-d6) d 7.58 (t, J=1.00 Hz, 3H), 7.50-7.55 (m, 6H), 7.13-7.27 (m, 7H), 7.09 (t, J=1.25 Hz, 3H), 7.06 (dt, J=1.51, 7.65 Hz, 3H), 7.02 (s, 3H), 6.81-6.87 (m, 6H), 6.24 (d, J=7.53 Hz, 1H), 4.30-4.35 (m, 6H), 4.21-4.26 (m, 6H), 3.82 (s, 2H).sup.13C NMR (400 MHz, DMSO-d6) 171.14, 142.85, 137.46, 130.92, 129.13, 127.75, 122.80, 120.50, 119.58, 115.70, 63.98, 45.02, 36.74, 33.33.

Example 5

DPX-1-0006 (JBX022)

(24) 2-(1H-benzo[d]imidazol-1-yl)ethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

(25) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (1.10 g, 5.74 mmol) was added solid all at once to a magnetically stirred solution of diclofenac (1.48 g, 5.00 mmol), 2-(1H-benzo[d]imidazol-1-yl)ethanol (0.810 g, 10.0 mmol) and 4-Dimethylaminopyridine (31 mg, 0.25 mmol) in dry Tetrahydrofuran (30 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture was stirred in an ice bath for 1 hour and then at ambient temperature. After stirring for 24 hours at room temperature the mixture was concentrated and the residue partitioned between water (25 mL), saturated NH.sub.4Cl (25 mL) and EtOAc (100 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×40 mL), 50% saturated NaHCO.sub.3 (40 mL) and brine (50 mL). The organic layer was dried and concentrated. Flash Chromatography using ethyl acetate and heptanes as eluent afforded a colourless oil that crystallised from ether (1.53 g) and was recrystallised to afford the title compound as a colourless solid (1.25 g, 57%). Mp. 128.8-129.3° C. (EtOAc-heptane). .sup.1H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 7.65-7.60 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.29-7.15 (m, 3H), 7.09-7.01 (m, 2H), 6.94 (s, 1H), 6.80 (td, J=7.5, 1.0 Hz, 1H), 6.23 (d, J=8.0 Hz, 1H), 4.54 (t, J=5.0 Hz, 2H), 4.44 (t, J=5.0 Hz, 2H), 3.75 (s, 2H). .sup.13C NMR (101 MHz, DMSO) δ 171.13, 144.16, 143.31, 142.82, 137.02, 133.85, 130.90, 130.86, 129.08, 127.74, 125.95, 122.74, 122.31, 121.46, 120.50, 119.38, 115.74, 110.31, 63.21, 43.20, 36.75. .sup.13C-DEPT NMR (101 MHz, DMSO) δ 144.17, 130.90, 129.09, 127.74, 125.96, 122.32, 121.46, 120.50, 119.38, 115.74, 110.31, 63.21, 43.20, 36.75.

Example 6

DPX-1-0007 (sdnX-18)

(26) 2-(2-phenyl-1H-imidazol-1-yl)ethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

(27) The required IPU: 2-(2-phenyl-1H-imidazol-1-yl)ethanol was prepared in the following way: A magnetically stirred solid mixture 2-phenylimidazole (37.7 g, 0.261 mol) and ethylene carbonate (28.8 g, 0.327 mol) in a 250 mL three necked flask round bottomed flask equipped with a bubble tube and an internal thermometer was heated in a oil bath to 130-140° C. were evolution of CO.sub.2 started. The mixture was kept at this temperature until evolution of CO.sub.2 ceased. More ethylenecarbonate in portions of 2-3 g was added and the mixture reheated until evolution of CO.sub.2 ceased or full conversion of 2-phenylimidazole as indicated by TLC was achieved. The dark brown mixture was cooled to room temperature and dissolved in water (100 mL) and extracted with ethyl acetate (3-4×100 mL). The combined organic layers were washed with brine (100 mL) and dried over Na.sub.2SO.sub.4. Concentration gave a dark brown oily residue (37.7 g) which was crystallised from EtOAc-heptane to give 21.5 g of a brown solid. This material was recrystallised from EtOAc-EtOH to afford the title compound as a pale brown solid in sufficient purity to be used in subsequent steps without further purification (18.7 g, 38%).

(28) DPX-1-0007 was subsequently prepared using an identical procedure as described for DPX-1-0001: 2-(2-phenyl-1H-imidazol-1-yl)ethanol (12 mmol, 2.26 g), Dichlofenac (6 mmol, 1.77 g), 4-Dimethylaminopyridin (0.3 mmol, 22 mg), Dicyclohexylcarbodiimid (7.2 mmol, 1.5 g) and dichloromethane (50 mL). .sup.1H NMR (400 MHz, DMSO) δ 7.61-7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.48-7.36 (m, 3H), 7.29 (d, J=1.2 Hz, 1H), 7.23-7.17 (m, 1H), 7.10-7.02 (m, 2H), 6.96 (d, J=1.2 Hz, 1H), 6.91 (s, 1H), 6.83 (td, J=7.4, 1.1 Hz, 1H), 6.23 (d, J=7.8 Hz, 1H), 4.38-4.27 (m, 4H), 3.69 (s, 2H).

Example 7

DPX-1-0008 (ALE459-3)

(29) 2-(2-propyl-1H-imidazol-1-yl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate.

(30) Using an identical procedure as described for DPX-1-0001:

(31) Dichlorfenac (6 mmol, 1.7 g), 6-(1H-imidazol-1-yl)ethan-1-ol (12 mmol, 1.8 g), Dicyclohexylcarbidiimide (7.2 mmol, 1.4 g), 4-Dimethylaminopyridine (0.6 mmol, 72 mg) and dichloromethane (50 mL) Crude yield: 3.6 g; yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 1.2 g (46%). .sup.1H NMR (400 MHz, DMSO-d6) d 7.52 (d, J=8.03 Hz, 5H), 7.20 (t, J =8.03 Hz, 2H), 7.14 (dd, J=1.51, 7.53 Hz, 2H), 7.06 (dt, J=1.51, 7.78 Hz, 2H), 6.95-7.01 (m, 4H), 6.84 (dt, J=1.13, 7.47 Hz, 2H), 6.70 (d, J=1.25 Hz, 2H), 6.25 (d, J=7.78 Hz, 1H), 4.26-4.35 (m, 2H), 4.10-4.17 (m, 2H), 3.80 (s, 2H), 1.63 (dquin, J=7.28, 7.47 Hz, 2H), 0.90 (t, J=7.40 Hz, 3H). .sup.13C NMR (400 MHz, DMSO-d6) 171.15, 147.40, 142.85. 130.92, 130.82, 129.13, 127.77,126.48, 125.98, 122.82, 119.44, 115.81, 63.95, 43.69, 27.65, 20.85, 13.75.

Example 8

DPX-1-0009 (ALE480-1)

(32) 6-(1H-imidazol-1-yl)hexyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate

(33) Using an identical procedure as described for DPX-1-0001:

(34) Dichlorfenac (6 mmol, 1.7 g), 6-(1H-imidazol-1-yl)hexan-1-ol (6 mmol, 1.0 g) Dicyclohexylcarbidiimide (12 mmol), 4-Dimethylaminopyridine (0.6 mmol, 72 mg) dichloromethane (50 mL). Crude yield: 2.1 g; yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 0.5 g (20%). .sup.1H NMR (400 MHz, DMSO-d6) 7.46-7.66 (m, 5H), 7.16-7.25 (m, 3H), 7.12 (s, 2H), 7.02-7.08 (m, 3H), 6.81-6.88 (m, 3H), 6.26 (d, J=7.78 Hz, 1H), 4.03-4.08 (m, 4H), 3.89 (t, J=7.03 Hz, 3H), 3.79 (s, 2H), 1.64 (quin, J=7.28 Hz, 3H), 1.56 (ddt, J=6.78, 7.03, 7.15 Hz, 3H), 1.22-1.33 (m, 4H), 1.14-1.22 (m, 4H). .sup.13C NMR (400 MHz, DMSO-d6) 171.53, 142.73, 137.06, 129.15, 128.28, 127.67, 125.85, 123.30, 119.15, 115.89, 64.38, 45.75, 37.10, 30.40, 27.92, 25.49, 24.74.

Example 9

DPX-1-0010 (ALE481-2)

(35) 6-(2-propyl-1H-imidazol-1-yl)hexyl 2-(2-(2, 6-dichiorophenylamino) phenyl)acetate

(36) Using an identical procedure as described for DPX-1-0001:

(37) Dichlorfenac (6 mmol, 1.4 g), 6-(2-propyl-1H-imidazol-1-yl)hexan-1-ol (6 mmol, 1.25 g), Dicyclohexylcarbidiimide (12 mmol, 2.4 g), 4-Dimethylaminopyridin (0.6 mmol, 72 mg) and dichloromethane (60 mL). Crude yield: 1.9 g; yield after Flash Chromatography using ethyl acetate and heptanes as eluent: 0.21 g (10%). .sup.1H NMR (400 MHz, DMSO-d6) d 7.52 (d, J=8.03 Hz, 1H), 7.13-7.27 (m, 1H), 6.94-7.09 (m, 2H), 6.81-6.88 (m, 1H), 6.72 (d, J=1.00 Hz, 1H), 6.27 (s, 1H), 4.06 (t, J=6.53 Hz, 2H), 3.72-3.83 (m, 3H), 1.50-1.73 (m, 4H), 1.15-1.36 (m, 3H), 0.91 (t, J=7.40 Hz, 2H). .sup.13C NMR (400 MHz, DMSO-d6) d 171.52, 146.91, 142.2, 137.06, 130.84, 130.52, 129.15, 127.66, 123.31, 119.10, 115.89, 64.38, 44.64, 30.35, 27.94, 27.79, 20.92, 13.75.

Example 10

DPX-1-0011

(38) 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2((2,6-dichlorophenyl)amino)phenyl)acetate

(39) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (0.661 g, 3.45 mmol) was added solid all at once to a magnetically stirred solution of diclofenac (0.888 g, 3.00 mmol), 2-(1-methyl-1H-imidazol-2-yl)ethanol (0.379 g, 3.00 mmol) and 4-Dimethylaminopyridine (19 mg, 0.15 mmol) in dry tetrahydrofuran (20 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture was stirred in an ice-bath for 30 min and then at ambient. After stirring for 12 hrs at room temperature more EDC-HCl (115 mg, 0.6 mmol) was added and stirring was continued at room temperature for 72 hrs. The mixture was concentrated and the residue partitioned between 50% saturated NH.sub.4Cl (25 mL) and EtOAc (60 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×25 mL), 50% saturated NaHCO.sub.3 (25 mL) and brine (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. Flash Chromatography using ethyl acetate and heptanes as eluent provided the title compound which crystallised from heptane as a colorless solid (196 mg). Mp. 114.5-115.2° C. (EtOAc-Heptane). .sup.1H NMR (400 MHz, DMSO) δ 7.53 (d, J=8.1 Hz, 2H), 7.24-7.18 (m, 1H), 7.17 (dd, J=7.5, 1.4 Hz, 1H), 7.10 (s, 1H), 7.06 (td, J=7.8, 1.5 Hz, 1H), 6.99 (d, J=1.2 Hz, 1H), 6.83 (td, J=7.4, 1.1 Hz, 1H), 6.71 (d, J=1.2 Hz, 1H), 6.24 (d, J=7.4 Hz, 1H), 4.39 (t, J=7.0 Hz, 2H), 3.79 (s, 2H), 3.52 (s, 3H), 2.98 (t, J=7.0 Hz, 2H). .sup.13C NMR (101 MHz, DMSO) δ 171.37, 144.11, 142.93, 137.08, 130.98, 130.94, 129.12, 127.72, 126.27, 126.03, 122.91, 121.13, 120.45, 115.63, 62.61 (CH2), 37.08 (CH2), 32.07, 25.48 (CH2). DEPT-.sup.13C NMR (101 MHz, DMSO) δ 130.95, 129.12, 127.73, 126.27, 126.03, 121.13, 120.44, 115.62, 62.61, 37.07, 32.07, 25.48.

Example 11

DPX-1-0012

(40) 2-(2-(2-phenyl-1H-imidazol-1-yl)ethoxy)ethyl 2-(2-((2,6-dichlorophenyl)-amino)phenyl)acetate

(41) The required IPU: 2-(2-(2-phenyl-1H-imidazol-1-yl)ethoxy)ethanol was obtained as a byproduct in the synthesis of another IPU: 2-(2-phenyl-1H-imidazol-1-yl)ethanol (see under DPX-1-0007) in the following way: The filtrate from the initial crystallisation was purified by Flash Chromatography using EtOAc:heptane.fwdarw.EtOAc:MeOH as eluent and fractions containing the title compound was combined (˜7 g) and recrystallised from EtOAc:heptane to give 4.56 g of pale yellow solid. This material was purified again by Flash Chromatography using EtOAc.fwdarw.EtOAc:MeOH (90:10) as eluent. Relevant fractions were combined and recrystallised from toluene to afford the title compound as a colourless solid (1.39 g, 2.3%). Mp. 94.4-95.1° C. (toluene). .sup.1H NMR (400 MHz, DMSO) δ 7.66-7.62 (m, 2H), 7.51-7.41 (m, 3H), 7.38 (d, J=1.0 Hz, 1H), 7.00 (d, J=1.0 Hz, 1H), 4.59 (t, J=5.5 Hz, 1H), 4.17 (t, J=5.5 Hz, 2H), 3.72 (t, J=5.5 Hz, 2H), 3.49-3.42 (m, 2H), 3.40-3.35 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 148.19, 130.91, 129.23, 128.91, 128.72, 128.70, 121.06, 72.68, 70.58, 61.71, 46.73.

(42) Subsequently, DPX-1-0012 was prepared in the following way: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (551 mg, 2.87 mmol) was added solid all at once to a magnetically stirred solution of Diclofenac (741 mg, 2.50 mmol), 2-(2-(2-phenyl-1H-imidazol-1-yl)ethoxy)ethanol (581 mg, 2.50 mmol) and 4-Dimethylaminopyridine (16 mg, 0.13 mmol) in dry tetrahydrofuran (15 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture was stirred in an ice bath for 30 min and then at ambient temperature. After stirring for 12 hours more EDC-HCl (96 mg, 0.5 mmol) was added and stirring was continued at room temperature for 72 hours. The mixture was concentrated and the residue partitioned between 50% saturated NH.sub.4Cl (25 mL) and EtOAc (50 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×25 mL), 50% saturated NaHCO.sub.3 (25 mL) and brine (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by Flash Chromatography using ethyl acetate and heptanes as eluent to afford the title compound (274 mg) as thick pale yellow oil. .sup.1H NMR (400 MHz, DMSO) δ 7.64-7.59 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.48-7.37 (m, 3H), 7.30 (d, J=1.2 Hz, 1H), 7.23-7.18 (m, 1H), 7.16 (dd, J=7.6, 1.4 Hz, 1H), 7.07-7.01 (m, 2H), 6.98 (d, J=1.2 Hz, 1H), 6.82 (td, J=7.4, 1.1 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H), 4.17-4.09 (m, 4H), 3.78 (s, 2H), 3.69 (t, J=5.3 Hz, 2H), 3.59-3.54 (m, 2H). .sup.13C NMR (101 MHz, DMSO) δ 171.45, 146.93, 142.81, 137.08, 130.92, 130.85, 130.63, 129.14, 128.78, 128.38, 128.30, 127.86, 127.71, 125.88, 123.12, 121.44, 120.62, 115.89, 69.61, 68.18, 63.75, 46.00, 36.94. DEPT .sup.13C NMR (101 MHz, DMSO) δ 130.85, 129.13, 128.78, 128.38, 128.30, 127.86, 127.71, 125.88, 121.44, 120.62, 115.89, 69.60 (CH2), 68.18 (CH2), 63.75 (CH2), 46.00 (CH2), 36.94 (CH2).

Example 12

DPX-2-0001 (ALE 406)

(43) 4-(dimethylamino)phenethyl 2-(6-methoxynaphthalen-2-yl)propanoate

(44) 2-(6-methoxynaphthalen-2-yl)propanoyl chloride (acid chloride of Naproxen) (1 g, 4 mmol) was dissolved in dichloromethane (20 mL) and pyridine (30 mL) was added, and finally a solution of the 2-(4-(dimethylamino)phenyl) ethanol (0.64 g, 4 mmol) in dichloromethane (10 mL) was added. The mixture was left over night under stirring at room temperature. After addition of dichloromethane the reaction mixture was washed with first a saturated bicarbonate solution (100 mL) and second water (100 mL). The organic phase was dried and concentrated to yield an oily residue. The crude product was purified by vacuum liquid chromatography on silica (20-45 μm) using heptane (60 mL) followed by heptane-ethyl acetate (4:1 v/v) as eluent. Yield 0.52 g (35%). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.70-7.64 (3H, m); 7.37 (1H, dd, J=6.60; 1.5 Hz); 7.15-7.11 (2H, m); 6.9 (2H, d, J=8.8 Hz); 6.52 (2H, d, J=8.56); 4.27 (2H, t, J=6, 88 Hz); 3.92 (3H, s); 3.84 (1H, q, J=7.15 Hz); 2.88 (6H, s); 2.76 (2H, t, J=7.15 Hz); 1.57 (3H, d, J=7.15 Hz). 13C NMR (400 MHz, DMSO-d6) δ 173.76, 157.18, 135.60, 135.60, 129.24, 126.96, 126.23, 125.73, 118.66, 105.69, 65.29, 55.15, 44.51, 33.30, 18.17.

Example 13

DPX-2-0002 (ALE 412)

(45) 2-(methyl(phenyl)amino)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate.

(46) Using an identical procedure as described for DPX-2-0001 using 2-(6-methoxynaphthalen-2-yl)propanoyl chloride (1.7 g, 7.2 mmol) and 2-(methyl(phenyl)amino)ethanol (1.10 g, 7.2 mmol). Yield 0.9 g (36%). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.7 (3H, d, J=8.53 Hz); 7.62 (1H, d, J=1.38 Hz); 7.35 (1H, dd, J=8; 1.65 Hz); 7.22-7.10 (2H, m), 6.69 (3H, m); 4.23 (2H, t, J=5.78); 3.92 (3H, s); 3.80 (1H, q, J=7.15 Hz); 3.53 (2H, t, J=5.78 Hz); 2.83 (3H, s); 1.54 (3H, d, J=6.88 Hz). .sup.13C NMR (400 MHz, DMSO-d6) δ 173.87, 157.17, 135.53, 133.31, 128.92, 126.94, 126.64, 118.71, 115.88, 111.91, 105.70, 61.80, 55.14, 50.18, 44.50, 38.06, 18.22.

Example 14

DPX-2-0003 (ALE 416)

(47) 3-(methyl(phenyl)amino)propyl 2-(6-methoxynaphthalen-2-yl)propanoate

(48) Using an identical procedure as described for DPX-2-0001 using 2-(6-methoxynaphthalen-2-yl)propanoyl chloride (1.7 g, 7.14 mmol) and 3-(methyl(phenyl)amino)propan-1-ol (1.19 g; 7.14 mmol). Yield 1.75 g (64%). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.72-7.68 (3H, m); 7.41 (1H, dd, J=6.60 Hz; 1.93 Hz); 7.17-7.10 (3H, m); 7.71-7.53 (2H, m); 4.14 (2H, t, J=6.60 Hz); 3.92 (3H, s); 3.86 (2H, t, J=7.15 Hz); 3.28-3.19 (2H, m); 3.75 (3H, s); 1.84-1.78 (2H, m) 1.605 (3H, d, J=7.15 Hz). .sup.13C NMR (400 MHz, DMSO-d6) δ 173.84, 157.19, 148.73, 135.71, 133.34, 128.88, 126.99, 125.64, 118.75, 115.56, 111.79, 105.75, 62.10, 55.15, 48.14, 44.48, 37.55, 25.17, 18.13.

Example 15

DPX-2-0004 (sdnX9)

(49) 2-(pyridin-2-yl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate

(50) Using an identical procedure as described for DPX-1-0001:

(51) 2-(pyridin-2-yl)ethanol (8.12 mmol, 1.00 g), Naproxen (8.93 mmol, 2.06 g), Dimethylaminopyridin (0.4 mmol, 50 mg), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl (EDC-HCl) (12.18 mmol, 2.33 g), Acetonitrile (5 mL) and Dimethylformamide (3 mL). Crude yield: 4.3 g. The oil was purified by flash chromatography using ethyl acetate and heptanes as eluent to give a colorless oil. The pure oil was dissolved in diethyl ether (50 mL) and 2M HCl in diethyl ether (500 uL) was added. After drying under oil pump vacuum, white crystals precipitated. .sup.1H (CDCl.sub.3) 1.52 (d, 2H), 3.02 (t, 2H), 3.91-3.95 (m, 1H), 3.98 (s, 3H), 4.36-4.41 (m, 2H), 6.60 (d, 1H), 7.00-7.04 (m, 1H), 7.12-7.19 (m, 2H), 7.24-7.29 (m, 1H), 7.45 (dd, 1H), 7.60 (s, 1H), 7.16-7.20 (m, 2H), 8.46-8.49 (m, 1H). .sup.13C (CDCl.sub.3) 105.53, 118.86, 121.35, 123.32, 125.95, 126.19, 127.02, 128.88, 129.25, 133.63, 135.62, 136.03, 149.26, 157.60, 157.84, 174.39.

Example 16

DPX-2-0005 (JBX019)

(52) 2-(1H-benzo[d]imidazol-1-yl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate

(53) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (2.20 g, 11.5 mmol) was added solid all at once to a magnetically stirred solution of naproxen (2.30 g, 10.0 mmol), 1-(2-hydroxyethyl)imidazole (1.12 g, 10.0 mmol) and 4-Dimethylaminopyridine (61 mg, 0.5 mmol) in dry tetrahydrofuran (50 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture was stirred in an ice bath for 30 min and at ambient temperature. More EDC-HCl (400 mg, 2 mmol) was added after 13 hrs, 17 hrs. After stirring for 22 hrs at room temperature the mixture was concentrated and the residue partitioned between water (50 mL), saturated NH.sub.4Cl (20 mL) and EtOAc (120 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×50 mL), 50% saturated NaHCO.sub.3 (50 mL) and brine (50 mL). The organic layer was dried and concentrated. The oily residue was purified by Flash Chromatography using ethyl acetate and heptanes as eluent afforded a colourless oil (2.74 g, 84%) after drying in high vacuum. The oil was crystallised from ether and recrystallised from Tert-butylmethylether (˜20 mL, seeded) to afford the title compound as a colourless solid (2.21 g, 68.3%). Mp. 60.6-61.3° C. .sup.1H NMR (400 MHz, DMSO) δ 7.80 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (d, J=1 Hz, 1H), 7.51 (s, 1H), 7.33 (dt, J=5.5, 3 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.17 (dd, J=9, 2.5 Hz, 1H), 6.98 (t, J=1 Hz, 1H), 6.78 (t, J=1 Hz, 1H), 4.34-4.12 (m, 4H), 3.92 (q, J=7 Hz, 1H), 3.88 (s, 3H), 1.45 (d, J=7 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) δ 173.52, 157.19, 137.40, 135.30, 133.33, 129.15, 128.37, 128.25, 126.99, 126.20, 125.63, 119.46, 118.73, 105.69, 63.74, 55.15, 44.94, 44.35, 18.19.

Example 17

DPX-2-0006 (JBX017)

(54) 2-(1H-benzo[d]imidazol-1-yl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate

(55) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (2.20 g, 11.5 mmol) was added solid all at once to a magnetically stirred solution of naproxen (2.30 g, 10.0 mmol), 2-(1H-benzo[d]imidazol-1-yl)ethanol (1.62 g, 10.0 mmol) and 4-Dimethylaminopyridine (68 mg, 0.5 mmol) in dry tetrahydronfuran (50 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture (slurry-EDC-HCl failed to dissolve) was stirred in an ice bath for 30 min and at ambient temperature. More EDC-HCl (400 mg, 2 mmol) was added after 3, 5 and 6 hours. After stirring for 48 hours the mixture was concentrated and the residue partitioned between water (50 mL), saturated NH.sub.4Cl (20 mL) and EtOAc (120 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×50 mL), 50% saturated NaHCO.sub.3 (50 mL) and brine (50 mL). The organic layer was dried and concentrated. Flash Chromatography using ethyl acetate and heptanes as eluent afforded the title compound as a colourless solid (3.33 g, 88.8% yield). Mp. 125.0-125.7° C. .sup.1H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.69-7.63 (m, 1H), 7.61-7.54 (m, 2H), 7.28 (d, J=2.5 Hz, 1H), 7.26-7.18 (m, 3H), 7.16 (dd, J=9, 2.5 Hz, 1H), 4.58-4.32 (m, 4H), 3.87 (s, 3H), 3.83 (q, J=7 Hz, 1H), 1.37 (d, J=7 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) δ 173.52, 157.18, 144.13, 143.29, 135.19, 133.83, 133.29, 129.13, 128.32, 126.93, 126.09, 125.58, 122.25, 121.46, 119.38, 118.69, 110.37, 105.67, 63.03, 55.15, 44.36, 43.10, 18.12. DEPT .sup.13C NMR (101 MHz, DMSO) b 144.12, 129.13, 126.93, 126.09, 125.58, 122.25, 121.45, 119.37, 118.69, 110.36, 105.67, 63.03 (CH2), 55.14, 44.36, 43.10 (CH2), 18.12.

Example 18

DPX-2-0007 (JBX018)

(56) 2-(2-phenyl-1H-imidazol-1-yl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate

(57) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (2.20 g, 11.5 mmol) was added solid all at once to a magnetically stirred solution of naproxen (2.30 g, 10.0 mmol), (1.88 g, 10.0 mmol) and 4-Dimethylaminopyridine (61 mg, 0.5 mmol) in dry tetrahydrofuran (50 mL) cooled in an ice bath and kept under nitrogen. The reaction mixture (slurry-EDC-HCl failed to dissolve) was stirred in an ice bath for 30 min and at ambient temperature. More EDC-HCl (400 mg, 2 mmol) was added after 13 hrs and 17 hrs. After stirring for 22 hours at room temperature full conversion of naproxen was obtained. The mixture was concentrated and the residue partitioned between water (50 mL), saturated NH.sub.4Cl (20 mL) and EtOAc (120 mL). The organic layer was washed with 50% saturated NH.sub.4Cl (2×50 mL), 50% saturated NaHCO.sub.3 (50 mL) and brine (50 mL). The organic layer was dried and concentrated. Flash Chromatography using ethyl acetate and heptanes as eluent afforded the title compound as a pale yellow oil. .sup.1H NMR (400 MHz, DMSO) δ 7.77 (d, J=9.0 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.58-7.51 (m, 2H), 7.45-7.38 (m, 3H), 7.29 (d, J=2.5 Hz, 1H), 7.24 (dd, J=8.5, 1.8 Hz, 1H), 7.19-7.13 (m, 2H), 6.90 (d, J=1.2 Hz, 1H), 4.37-4.20 (m, 4H), 3.86 (s, 3H), 3.77 (q, J=7.1 Hz, 1H), 1.36 (d, J=7.1 Hz, 3H).

(58) HCl-salt of DPX-2-0007: 571 mg of this oil was dissolved in a mixture of dry ether (20 mL) and dry tetrahydrofuran (10 mL) under nitrogen at 0° C. 2M HCl in ether (4 mL, 8 mmol) was added drop wise by syringe resulting in the formation a sticky gum. The solvent was decanted off and the gum was washed with dry ether (20 mL). The gum was dried in high vacuum and then crystallised by dissolving it in ethanol (2 mL) and slowly adding dry diethyl ether until no more solid formed. The free flowing solid was dried in vacuum to afford the title compound (452 mg) as an off white solid. Mp. 188.5-189.6° C. (ethanol/ether). .sup.1H NMR (400 MHz, DMSO) δ 15.29 (br s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.80-7.71 (m, 3H), 7.69-7.64 (m, 1H), 7.63-7.53 (m, 5H), 7.30 (d, J=2.5 Hz, 1H), 7.21-7.15 (m, 2H), 4.46-4.35 (m, 4H), 3.88 (s, 3H), 3.81 (q, J=7.0 Hz, 1H), 1.37 (d, J=7.0 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) δ 173.46, 157.20, 144.42, 135.15, 133.30, 131.88, 129.71, 129.15, 129.06, 128.32, 127.06, 125.81, 125.55, 122.90, 122.34, 119.58, 118.82, 105.77, 62.28, 55.18, 46.50, 44.11, 18.15. DEPT .sup.13C NMR (101 MHz, DMSO) δ 131.88, 129.71, 129.15, 129.06, 127.06, 125.82, 125.56, 122.90, 119.59, 118.82, 105.77, 62.28 (CH2), 55.18, 46.50 (CH2), 44.11, 18.15.

Example 19

DPX-3-0001 (ALE405)

(59) 4-(dimethylamino)phenethyl 2-(4-isopropylphenyl)propanoate

(60) Using an identical procedure as described for DPX-1-0001 using 2-(4-isobutylphenyl)propanoyl chloride (7.14 mmol, 1.5 g), 2-(4-(dimethylamino)phenyl) ethanol (7.0 mmol, 1.1 g), pyridine (50 mL) and dichloromethane (50 mL). Yield: 2.6 g. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.05-7.23 (m, 5H), 6.93 (d, J=8.53 Hz, 2H), 6.60 (d, J=8.78 Hz, 2H), 4.02-4.24 (m, 2H), 3.70 (q, J=7.03 Hz, 1H), 3.30 (s, 1H), 2.62-2.73 (m, 2H), 1.74-1.88 (m, 1H), 1.27-1.43 (m, 3H), 0.77-0.93 (m, 6H). .sup.13C NMR (400 MHz, DMSO-d6) δ 173.78, 149.10, 139.67, 137.78, 129.27, 127.07, 126.22, 112.48, 65.19, 44.20, 33.35, 29.57, 22.16, 18.43.

Example 20

DPX-3-0002 (ALE411)

(61) 2-(methyl(phenyl)amino)ethyl 2-(4-isobutylphenyl)propanoate

(62) Using an identical procedure as described for DPX-1-0001 using 2-(4-isobutylphenyl)propanoyl chloride (7.14 mmol, 1.6 g), 2-((4-(dimethylamino)phenyl) (methyl)amino)ethanol (7.14 mmol, 1.0 g), pyridine (50 mL) and dichloromethane (50 mL). Yield 0.62 g (25%). .sup.1H NMR (400 MHz, DMSO-d6) δ 7.05-7.27 (m, 13H), 6.50-6.75 (m, 6H), 3.98-4.27 (m, 4H), 3.66 (q, J=7.28 Hz, 2H), 3.52 (t, J=5.65 Hz, 4H), 2.73 (s, 6H), 2.41 (d, J=7.28 Hz, 5H), 1.80 (td, J=6.78, 13.55 Hz, 3H), 1.27-1.36 (m, 6H), 0.74-0.92 (m, 6H). .sup.13C NMR (400 MHz, DMSO-d6) δ 173.87, 148.63, 139.75, 137.72, 129.03, 128.92, 127.08, 111.87, 61.79, 50.14, 44.17, 38.14, 29.57, 22.11, 18.28.

Example 21

DPX-3-0003 (ALE415)

(63) 3-(methyl(phenyl)amino)propyl 2-(4-isobutylphenyl)propanoate

(64) Using an identical procedure as described for DPX-1-0001 using 2-(4-isobutylphenyl)propanoyl chloride (7.14 mmol, 1.6 g), 3-((4-(dimethylamino)phenyl)-(methyl)amino)propan-1-ol (7.14 mmol, 1.01 g), pyridine (50 mL) and dichloromethane (50 mL). Yield 1.55 g (68%). .sup.1H NMR (400 MHz, DMSO-d6) δ 7.19-7.29 (m, 4H), 7.05-7.14 (m, 9H), 6.42-6.71 (m, 6H), 3.96-4.10 (m, 4H), 3.77 (q, J=7.19 Hz, 2H), 3.18-3.23 (m, 4H), 2.73 (s, 6H), 2.41 (d, J=7.03 Hz, 5H), 1.79 (td, J=6.74, 13.36 Hz, 2H), 1.68-1.75 (m, 4H), 1.37-1.42 (m, 6H), 0.81-0.85 (m, 6H). .sup.13C NMR (400 MHz, DMSO-d6) δ 173.84, 148.77, 139.80, 137.92, 129.09, 128.92, 127.06, 115.58, 111.83, 62.00, 48.15, 44.18, 37.66, 29.55, 25.19, 22.11, 18.20.

Example 22

DPX-3-0004 (sdnX-8)

(65) 2-(pyridin-2-yl)ethyl 2-(4-isobutylphenyl)propanoate

(66) Using an identical procedure as described for DPX-1-0001:

(67) Ibuprofen (1.84 g, 8.93 mmol), 2-(pyridin-2-yl)ethanol (1.00 g, 8.12 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (2.33 g, 12.18 mmol), 4-dimethylaminopyridine (50 mg, 0.4 mmol) in Acetonitrile (4 mL). The oil was purified by flash chromatography using ethyl acetate and heptanes as eluent to give a colorless oil. The oil was dissolved in dioxane (5 mL) and 2M HCl in diethyl ether (3 mL) was added. The mixture was evaporated and placed under oil pump vacuum. After three hours the highly viscous substance began to crystallize. .sup.1H (CDCl.sub.3) 0.87 (d, 6H), 1.41 (d, 3H), 1.83 (m, 1H), 2.43 (d, 1H), 3.41-3.60 (m, 3H), 4.47-4.68 (m, 2H), 6.99-7.03 (m, 5H), 7.74 (m, 1H), 7.96 (m, 1H), 8.69 (m, 1H). .sup.13C (CDCl.sub.3) 17.84, 22.27, 30.11, 32.41, 44.78, 44.88, 61.80, 124.45, 127.20, 127.33, 129.29, 137.38, 140.63, 140.72, 144.63, 153.90, 173.88.

Example 23

DPX-3-0006 (sdnX-11)

(68) 2-(1H-benzo[d]imidazol-1-yl)ethyl 2-(4-isobutylphenyl)propanoate

(69) Using an identical procedure as described for DPX-1-0001:

(70) Ibuprofen (2.44 g, 11.84 mmol), 2-(1H-benzo[d]imidazol-1-yl)ethanol (1.60 g, 9.87 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (2.27 g, 11.5 mmol), 4-Dimethylaminopyridine (36 mg, 0.3 mmol) in Acetonitrile (4 mL). The crude oil was purified by flash chromatograph to give 1.55 g of a white solid. .sup.1H (CDCl.sub.3) 0.80 (d, 6H), 1.37 (d, 3H), 1.84 (m, 1H), 2.41 (d, 2H), 3.57 (m, 1H), 4.05-4.38 (m, 4H), 6.99-7.03 (m, 4H), 7.01-7.16 (m, 3H), 7.59 (s, 1H), 7.77 (m, 1H). .sup.13C (CDCl.sub.3) 18.13, 22.34, 30.10, 43.65, 44.92, 44.97, 62.38, 109.29, 120.42, 122.28, 123.09, 127.05, 129.45, 133.54, 137.02, 140.87, 143.02, 143.57, 174.22.

Example 24

DPX-3-0007 (sdnX-14)

(71) 2-(2-phenyl-1H-imidazol-1-yl)ethyl 2-(4-isobutylphenyl)propanoate

(72) Using an identical procedure as described for DPX-1-0001:

(73) Ibuprofen (2.01 g, 9.75 mmol), 2-(2-phenyl-1H-imidazol-1-yl)ethanol (1.54 g, 8.12 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (1.87 g, 9.75 mmol), 4-Dimethylaminopyridine (50 mg, 0.4 mmol) in dichloromethane (10 mL). The crude oil was purified by flash chromatography to give 2.74 g of a yellow oil. The HCl-salt was formed by dissolving the oil in diethyl ether and adding 2M HCl in diethyl ether. .sup.1H (CDCl.sub.3) 0.70 (d, 6H), 1.37 (d, 3H), 1.56 (m, 1H), 2.21 (d, 2H), 3.27 (m, 1H), 3.95-4.22 (m, 2H), 6.80 (br s, 1H), 6.86-6.97 (m, 4H), 7.20-7-38 (m, 6H). .sup.13C (CDCl.sub.3) 17.99, 22.27, 25.26, 30.08, 44.75, 44.82, 47.00, 62.01, 119.61, 121.55, 121.79, 126.95, 127.01, 129.57, 129.62, 129.64, 132.36, 136.74, 141.16, 144.79, 173.69.

Example 25

DPX-40001 (ALE408)

(74) 4-(dimethylamino)phenethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate

(75) 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carbonyl chloride (acid chloride of Ketorolac) (0.40 mmol) was dissolved in dichloromethane (4 mL) and pyridine (4 mL). 2(4-dimethylaminophenyl)ethanol (66 mg, 0.4 mmol) was added and the mixture was stirred overnight at room temperature. Standard aqueous work-up followed by Flash Chromatography gave the desired material. .sup.1H NMR (400 MHz, DMSO-d6) δ 7.72-7.82 (m, 6H), 7.41-7.66 (m, 9H), 7.02 (d, J=8.78 Hz, 6H), 6.57-6.86 (m, 8H), 5.99 (d, J=4.02 Hz, 1H), 4.32-4.41 (m, 1H), 4.24 (t, J=6.78 Hz, 2H), 4.16 (dd, J=6.27, 8.53 Hz, 1H), 2.83 (s, 6H), 2.76-2.81 (m, 2H), 2.64-2.75 (m, 2H). .sup.13C NMR (400 MHz, DMSO-d6) δ 183.55, 170.85, 149.23, 142.86, 138.78, 131.78, 129.29, 128.41, 128.33, 126.24, 125.05, 124.29, 112.57, 103.06, 65.78, 47.31, 33.33, 30.60

Example 26

Further characterization of DPX-4-0001 (ALE 408)

(76) We have coupled 4-(hydroxyethyl)-N,N-dimethylaniline (IPU I) to ketorolac in the form of an ester prodrug (DPX-4-0001) (FIG. 3). The pK.sub.a value of IPU 1 (and thus DPX-4-0001) is about 5.2. At pH 2.02, the solubility of the hydrochloride salt of DPX-4-0001 is 65 μg/ml. At pH 7.4, the solubility decreases 1300-fold to about 0.05 μg/ml (neutral form). This should be noted that, according to Eq. 1, a similar relative solubility enhancement can be obtained at pH 4 in case an IPU with a pK.sub.a value of 7.2 was selected.
S.sub.t=S.sub.0*(1+10.sup.pKa-pH)  (Eq. 1)

(77) In the following HPLC method used, the retention time of DPX-4-0001 and ketorolac were 4.5 and 6.5 min, respectively: Merck-Hitachi L-6200 pump connected to a Merck-Hitachi L-4000 UV detector and a Merck-Hitachi L-7200 autosampler (VWR International, Tokyo, Japan). Reversed phase chromatography was performed using a C18 Gemini® RP column (150×4.6 mm, 5 μm particles) (Phenomenex, Torrance, Calif., USA) equipped with a SecurityGuard precolumn (Phenomenex, Torrance, Calif., USA) with the column oven set at 30° C. The flow rate was set at 1 mL/min and the column effluent was monitored at 320 nm. The mobile phase consisted of 57.5% (v/v) methanol and 43.5% (v/v) of 0.1% (v/v) phosphoric acid.

Example 27

Dissolution of Prodrug in Synovial Fluid Followed by Formation of the Active Agent

(78) The stability of a suspension of DPX-4-0001 in 80% human synovial fluid pH 7.4 (SF) from arthritis patients was investigated at 37° C. The reaction was initiated by adding 5 ml preheated SF to 2 mg DPX-4-0001. At appropriate time intervals, 400 μl samples were taken and centrifuged for 5 min at 13.000 rpm and 200 μl of the supernatant was deproteinised with 400 μl acetonitrile. After centrifugation for 4 min at 13000 rpm, the supernatant was analysed by HPLC for DPX-4-0001 as well as formed ketorolac. The HPLC method described in Example 26 was applied.

(79) As appears from FIG. 2, the concentration of dissolved DPX-4-0001 in SF increased during the first 3 hours of the experiment however remained low (about 2.2×10.sup.−5 M) after 21 hours. The concentration of formed ketorolac in SF increased over time and after 21 hours 0.28 mM was found corresponding to conversion of 28% of the added amount of DPX-4-0001. The increased solubility of QPX-4-0001 in the synovial fluid (compared to buffer pH 7.4) can most likely be ascribed to binding of the prodrug to proteins residing in the synovial fluid. By extrapolation of the presented data, the total drug dose will be release over approximately 4 days.

(80) For comparison, the stability of a suspension of DPX-4-0001 in 67 mM phosphate buffer pH 7.4 was investigated by the same procedure at 37° C. In this experiment, no significant degradation of DPX-4-0001 (to ketorolac) was observed and the final DPX-4-0001 concentration amounted to about 8×10.sup.−7 M. The performed experiments strongly indicate that an esterase (currently not identified) present in the synovial fluid is responsible for the generation of ketorolac. Since the synovial disappearance half-lives of small-molecule drugs are in the range 2-5 h, the concentration of the active agent in the joint space is determined by the prodrug properties (i) solubility, (ii) degree of protein binding, and (iii) rate of cleavage of the prodrug bond, as well as (iv) the administered dose.

(81) The obtained data for DPX-4-0001 gives indication that the prodrug ketorolac-IPU provides the expected prolongation of NSAID release (up to about 4 days) and prodrug cleavage requires and is effectively accomplished by the action of esterases (or other hydrolases) residing in the synovial fluid.

Example 28

Preliminary Precipitation Experiment No Esterases Present

(82) A concentrated solution of DPX-4-0001 in 0.01 M HCl was prepared by adding 0.2 ml of 1×10.sup.−5 M methanol solution of DPX-4-0001 to 1.0 ml 0.01 M HCl resulting in a final concentration of 1.7×10.sup.−4 M. After addition of 300 μl of this solution (0.02 mg) to 5 ml 67 mM phosphate buffer pH 7.4, a precipitation process was observed. At appropriate time intervals, samples were withdrawn and centrifuged for 5 min at 13,000 rpm and the supernatant was analysed by HPLC for DPX-4-0001 and formed ketorolac. The HPLC method described in Example 26 was applied. After the initial precipitation phase, a low and fairly constant concentration of dissolved QPX-4-0001 over 25 h is observed. A slight increase in the ketorolac concentration is the result of pH dependent hydrolysis of the prodrug bond (FIG. 3).

Example 29

Solubility of DPX-2-0007 (JBX018) at pH 3.4 and Precipitation in Buffer pH 7.4

(83) A suspension of DPX-2-0007 (as hydrochloride salt) was formed by adding 30 mg to 4 mL demineralized water. After rotation of the suspension at 37° C. for 3 days, 1.0 mL sample was taken and after filtration (disposable syringe filters), the solution was diluted in methanol:water 1:1 and analyzed immediately by HPLC for prodrug. Quantitation of DPX-2-0007 was done from peak area measurements in relations to those of standards analysed by HPLC at the same conditions. The pH in the solution was measured to 3.40. The following HPLC method was used: Merck Hitachi L 6200 pump connected to Merck Hitachi 4250 UV detector. Reversed phase chromatography was performed using a RP 18 Symmetry Shields® column (150×4.6 mm, 5 μm particles) equipped with a SecurityGuard precolumn (Phenomenex, Torrance, Calif., USA). The flow rate was set at 1 mL/min and the column effluent was monitored at 230 nm. The mobile phase consisted of 35% (v/v) acetonitrile and 65% (v/v) of 0.1% (v/v) phosphoric acid pH 3.2. The retention time of naproxen and DPX-2-0007 were 19 and 5.8 min, respectively.

(84) The solubility of DPX-2-0007 at pH 3.4 was determined to 6.8+0.6 mg/mL. Thus, a 1000-fold increase in the solubility compared to the solubility of DPX-2-0007 in buffer pH 7.4 (PBS—see Table 1).

(85) TABLE-US-00001 TABLE 1 Solubilities of the prodrugs (S.sub.prodrug) in PBS (67 mM phosphate buffer pH 7.4), the apparent pseudo-zero-order rate constant (k.sub.0) and the estimated pseudo first-order rate constant (k.sub.hyd) for cleavage of the prodrugs in PBS and half-lives (t.sub.1/2) for hydrolysis of the prodrugs in 80% human plasma at 37° C. S.sub.prodrug ± SD k.sub.0 k.sub.hyd t.sub.1/2 in PBS t.sub.1/2 in plasma Prodrug μg/mL mM M/day day.sup.−1 day min DPX-1-0001 0.01 2 × 10.sup.−5 DPX-1-0002 <0.1 <0.0002 DPX-1-0004 3 ± 1 0.007 ± 0.001 1.1 × 10.sup.−6 1.5 × 10.sup.−1 5 25 DPX-1-0005 1 0.003 DPX-1-0006 7 ± 2 0.015 ± 0.004 2.4 × 10.sup.−6 1.7 × 10.sup.−1 4 3 DPX-1-0007 43 ± 2  0.086 ± 0.003 2.5 × 10.sup.−7 2.9 × 10.sup.−3 242 49 DPX-1-0008 0.3  0.0007 DPX-1-0009 <0.3 <0.0007 DPX-1-0010 <0.4 <0.0008 DPX-1-0011 0.1  0.0002 DPX-1-0012 <0.3 <0.0006 DPX-2-0001 <0.3 <0.0008 DPX-2-0002 <0.2 <0.0006 DPX-2-0003 <1 <0.003  DPX-2-0004 19 ± 1  0.052 ± 0.002 1.7 × 10.sup.−6 3.3 × 10.sup.−2 21 287 DPX-2-0005 146 ± 5  0.45 ± 0.02 64 DPX-2-0006 5 ± 1 0.015 ± 0.002 1.0 × 10.sup.−6 6.6 × 10.sup.−2 11 511 DPX-2-0007 7 ± 1 0.016 ± 0.001 1.0 × 10.sup.−6 6.5 × 10.sup.−2 11 62 DPX-3-0004 15 ± 2  0.044 ± 0.004 1.0 × 10.sup.−6 2.2 × 10.sup.−2 32 755 DPX-3-0006   4 ± 0.2 0.012 ± 0.001 5.7 × 10.sup.−7 4.8 × 10.sup.−2 15 stable DPX-3-0007 1 0.002 DPX-4-0001 0.05 ± 0.03 0.0001 ± 0.0001 Stable for 25 h

(86) Upon addition of 1.0 mL of the concentrated aqueous solution of DPX-2-0007 at pH 3.4 to 1.0 mL 67 mM phosphate buffer pH 7.4, a precipitation was immediately observed. The pH in the suspension was measured to 7.0.

Example 30

Solubility of DPX-2-0006 at pH 3 in the Presence of N,N-Dimethyl Acetamide (DMA)

(87) A suspension of DPX-2-0006 was formed by adding 10 mg to 3 mL demineralized water, 0.05 mL 0.100 M HCl was added to obtain a pH of 3. After rotation of the suspension at 37° C. for 1 days, 0.5 mL sample was taken and after filtration (disposable syringe filters), the solution was diluted in methanol:water 1:1 and analyzed immediately by HPLC for prodrug. Quantitation of DPX-2-0006 was done from peak area measurements in relations to those of standards analysed by HPLC at the same conditions. The HPLC method described in Example 29 was applied and the retention time of DPX-2-0006 was 14 min, respectively. N,N-dimethylacetamide (DMA) was added stepwise to the acidic suspension of DPX-2-0006 and the amount of DPX-2-000 dissolved in the presence of various volumes of DMA was determined after 1-3 days rotation at 37° C. as described above.

(88) The solubility of DPX-2-0006 at pH 2.9 was 0.18 mg/ml. In the presence of 5%, 15%, 30% and 50% (v/v) DMA, the solubility was increased to 0.25, 0.35, 0.57 and 2.25 mg/ml, respectively.

Example 31

Determination of Solublities and Stabilities of the Prodrugs in Buffer pH 7.4

(89) Suspensions of the prodrugs in 67 mM phosphate buffer pH 7.4 (PBS) were prepared by adding 10 mL PBS to approximately 5 mg prodrug. The suspensions were kept unstirred at 37° C. in an incubator hood. At appropriate time intervals over 23 days, about 500 μL samples were taken and after filtration (disposable syringe filters), the solutions were analyzed immediately by HPLC for parent drug and remaining prodrug. Quantitation of parent drug and prodrug was done from peak area measurements in relations to those of standards analysed by HPLC at the same conditions. For the naproxen prodrug, the HPLC method described in example 29 were applied. For the diclofenac and ibuprofen prodrugs, the following method was used: Merck Hitachi L 6000 pump connected to Merck Hitachi 4250 UV detector. Reversed phase chromatography was performed using a C18 Gemini® RP column (150×4.6 mm, 5 μm particles) (Phenomenex, Torrance, Calif., USA) equipped with a SecurityGuard precolumn (Phenomenex, Torrance, Calif., USA). The flow rate was set at 1 mL/min and the column effluent was monitored at 230 nm. The mobile phase consisted of 35% (v/v) acetonitrile and 65% (v/v) of 0.1% (v/v) phosphoric acid pH 3.2. The retention times varied in the range of 3 to 30 min.

(90) From the observed relatively stable concentration of dissolved prodrugs measured in the suspensions after 8-9 day up to 23 days, the solubilities of the prodrugs (S.sub.prodrug) were determined. In this time interval, the rate of appearance of parent drug was determined and an apparent pseudo-zero-order rate constant (k.sub.0) was obtained. By assuming that the dissolution rates were much faster than the conversion of the prodrugs to the parent drug, pseudo first-order rate constants (k.sub.hyd) for cleavage of the prodrugs were calculated according to:

(91) $-\frac{d\left[\mathrm{Prodrug}\right]}{dt}=\frac{d\left[\mathrm{Drug}\right]}{dt}=k_{\mathrm{hyd}}=S_{\mathrm{prodrug}}=k_0$

(92) All data are summarized in Table 1.

Example 32

Hydrolysis of the Prodrugs in 80% Human Plasma

(93) At 37±0.5° C., the hydrolysis rate of the prodrugs was measured in 80% human plasma. An appropriate aliquot (20-100 μL) of 1 mg/ml prodrug solution in methanol was transferred to 5.0 ml of preheated plasma. At appropriate time intervals, 300 μl sample aliquots were withdrawn and transferred to 600 μl acetonitrile and mixed thoroughly. After centrifugation at 13500 rpm for 5 min, the supernatant was analyzed by HPLC for parent drug and remaining prodrug. The HPLC methods described in Example 29 and 31 were applied.

(94) The half-lives for cleavage of the prodrugs in 80% human plasma were in the range 3-755 min (DPX-3-0006 remained intact after incubation in plasma for 10 h).

REFERENCES

(95) Ref. 1: Reuben et al.

(96) Reuben S. S., Connelly N. R. (1995) Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular bupivacaine and ketorolac. Anesth Analg 80: 1154-1157

(97) Ref. 2: Rasmussen et al.

(98) Rasmussen S., Larsen A. S., Thomsen S. T., Kehlet H. (1998) Intra-articular glucocorticoid, bupivacaine and morphine reduces pain, inflammatory response and convalescence after arthroscopic meniscectomy. Pain 78: 131-134

(99) Ref. 3: R. Williams

(100) pKa Data Compiled by R. Williams (downloadable from http://research.chem.opu.edu/brpgroup/pKa_compilation.pdf)

(101) Ref. 4: Caballero et al.

(102) Caballero et al. (2006) “Theoretical prediction of relative and absolute pKa values of aminopyridines”, Biophysical Chemistry 124(2), p 155-160 (Ref. 3).

(103) Ref. 5: Drustrup et al.

(104) Drustrup et al. (1991) “Utilization of prodrugs to enhance the transdermal absorption of morphine”, International Journal of Pharmaceutics 71, 105-116

(105) Specific embodiments include the following items 1. A compound of formula (I):

(106) ##STR00014##
wherein:

(107) R.sup.1 represents an immobility promoting unit selected from an organic moiety with a molecular weight lower than 1000 g/mol comprising one or more nitrogen containing moieties each with a pK.sub.a of between 4 and 7.4 at 37° C.; —O—(C═O)—R.sup.2 represents a acyloxy residue of a carboxylic acid group containing active pharmaceutical ingredient, preferably a non-steroidal anti-inflammatory agent or immunosuppressant; —O—R.sup.3 represents a hydroxyl residue of a hydroxyl group containing active pharmaceutical agent, preferably an opiate or a corticosteroid; x is an integer selected from 0, 1, 2, 3 or 4; y is an integer selected from 0, 1, 2, 3 or 4; where the sum x+y is at least 1; and pharmaceutically acceptable salts, solvates and hydrates thereof. 2. Compound according to item 1, wherein x is 1, 2, 3, or 4, and y is 0 or wherein x is 0, and y is 1, 2, 3, or 4. 3. Compound according to item 1, wherein x is 0, and y is 1, or wherein x is 1, and y is 0. 4. Compound according to item 1, having a solubility of between 0.01 μM and 1 μM in 10 mM PBS at 37° C. and pH 7.4, and a solubility of more than 100 μM at pH 3. 5. Compound according to item 1, wherein the one or more nitrogen containing moeities are selected from substituted or unsubstituted phenylamino, imidazolyl, isoquinolinyl, quinolinyl, benzimidazolyl, acridinyl. 6. Compound according to item 1, wherein the carboxylic acid group containing active pharmaceutical ingredient is selected from the list consisting of: naproxen, ibuprofen, ketorolac, ketoprofen, fenoprofen, flurbiprofen, oxaprofen, diclofenac, tolmetin, tolfenamic acid, mefenamic acid, sulindac, indomethacin, salicylic acid, acetylsalicylic acid, deflunisal, loxoprofen, indoprofen, priprofen, clidanac, fenclorac, meclofenamate, benoxaprofen, carprofen, isofezolac, acedofenac, fenbufen, etodolic acid, fleclozic acid, amfenac, efenamic adic, bromfenac, flenclofenac, alcofenac, orpanoxin, zomopirac, flufenamic acid, niflumic acid, pranoprofen, zaltoprofen, and suprofen. 7. Compound according to item 1, wherein the hydroxyl group containing active pharmaceutical ingredient is selected from the list consisting of: prednisolone, methylprednisolone, triamcinolone and dexamethasone. 8. Compound according to item 1, wherein the hydroxyl group containing active pharmaceutical agent is selected from the list consisting of: codeine, morphine, oripavine, dihydrocodeine, hydromorphone, oxycodone, oxymorphone, ohmefentanyl, ketobemidone, dezocine, pentazocine, phenazocine, buprenorphine, dihydroetorphine, etorphine, butorphanol, nalbuphine, levorphanol, meptazinol, tramadol, tapentadol. 9. Compound according to item 1, wherein R.sup.1 is selected from the list consisting of the R.sup.1 moieties of the R.sup.1—OH and R.sup.1—COOH compounds below:

(108) ##STR00015## 10. Compounds of formula I, selected from the list consisting of:

(109) ##STR00016## 11. Pharmaceutical composition, characterised in that it contains a therapeutically effective amount of a compound according to any one of claims 1 to 10, and at least one pharmaceutically acceptable carrier, vehicle and/or adjuvant. 12. Pharmaceutical composition according to item 11, wherein the composition is suitable for intra-articular injection. 13. Compound or pharmaceutical composition according to any one of items 1-12 for use as a medicament. 14. Compound or pharmaceutical composition according to any one of items 1-12 for use in treatment of inflammation in joints. 15. Compound or pharmaceutical composition according to any one of items 1-12 for use in treatment of postoperative pain control following arthroscopic surgery. 16. A method for the preparation of a medicament with anti-inflammatory activity, characterized in that it comprise a prodrug according to any one of items 1-12 as an active ingredient.