AU733236B2 - Use of selective RXR agonists to prevent surgical adhesions - Google Patents

Description

USE OF SELECTIVE RXR AGONISTS TO PREVENT SURGICAL

ADHESIONS

FIELD OF THE INVENTION The present invention is directed to methods for the minimization or prevention of post-surgical adhesion formation using agonists of the RXR retinoid receptors.

BACKGROUND OF THE INVENTION Retinoic acid and its natural and synthetic analogs exert a wide array of biological effects. They have been shown to affect cellular growth and differentiation and are useful in a variety of dermatological and malignant conditions.

Patent 5,534,261 discloses that retinoids, particularly all-trans retinoic acid, can be used to minimize or prevent adhesion formation following surgery. There is no disclosure, however, that selective RXR agonists would have this same utility and there is no disclosure of the 25 particular retinoid derivatives of the present invention.

Selective agonists of RXR retinoid receptors are disclosed in the literature along with suitable assays for determining if a given retinoidlike compound is considered to be a selective RXR agonist. For example, U.S. Patents 5,455,265 and 5,399,586 disclose a wide variety of such compounds and their utility in the same diseases or conditions against which retinoids are useful. U.S. Patent 5,455,265 states that RXR selective WO 99/06036 PCTIUS98/1 5625 -2angonists are useful as regulators of cell proliferation and differentiation, and are particularly useful as agents for treating dermatoses such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopic dermatitis, and for treating and preventing malignant hyperproliferative diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer and myeloid leukemias, for reversing and preventing atherosclerosis and restenosis resulting from neointimal hyperproliferation, for treating and preventing other non-malignant hyperproliferative diseases such as endometrial hyperplasia, benign prostatic hypertrophy, proliferative vitreal retinopathy and dysplasias, for treating autoimmune diseases and immunological disorders lupus erythematoses), for treating chronic inflammatory diseases such as pulmonary fibrosis, for treating and preventing diseases associated with lipid metabolism and transport such as dyslipidemias, for promoting wound healing, for treating dry eye syndrome and for reversing and preventing the effects of sun damage to skin. U.S. Patent 5,399,586 discloses that RXR agonists, particularly selective RXR agonists, induce apoptosis of tumor cells.

The prior art also indicates that selective RXR agonists surprisingly lack substantial teratogenic activity and have substantially reduced skin toxicity, properties which have been serious disadvantages with other classes of retinoid compounds.

U.S. Patent 5,455,265 discloses a suitable assay for determining the potency of a retinoid or retinoid-like compound as an agonist at the RXR receptor sites and RAR receptor sites. For purposes of defining the term "selective" RXR agonist in this application, applicant adopts the definition of this term as used in U.S. Patent 5,455,265, i.e. a "selective" RXR agonist -3is one which is at least approximately ten times as potent as an agonist at the RXR receptor sites then at the RAR receptor sites.

The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

The present invention involves the finding that certain retinoid derivatives, most or all of which are selective RXR agonist compounds, have utility in preventing or minimizing post-surgical adhesion formation.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

SUMMARY OF THE INVENTION The present invention provides a method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering an effective amount of a retinoid derivative of general o formula I below, most or all of which are selective RXR agonists, to a site of surgical activity on an organ surface for a period of time sufficient to permit tissue repair.

:i 30 The retinoid derivatives which are the subject of the present invention have the general formula aZ 3 COOH W:SPECM\86670-8 SPE JunOO.doc WO 99/06036 PCTIUS98/15625 -4-

A

Q x

II

wherein Z is or in which Q, X and Y are each independently O, S or CH 2 A is -(CR 2 n wherein n is an integer of from 1 to 3; B and C are each independently O, S, CH 2 or C(CH 3 2 and RI is hydrogen or (C 1

-C

6 alkyl; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Adhesion formation, particularly following peritoneal surgery, is a major source of postoperative morbidity and mortality. Appendectomy and gynecologic surgery are the most frequent surgical procedures implicated in clinically significant adhesion formation. The most serious complication of intraperitoneal adhesions is intestinal obstruction. In addition, adhesions are associated with chronic or recurrent pelvic pain and infertility in females.

Various approaches for the prevention of adhesion formation have been explored, but an effective therapeutic approach has not been discovered to date.

The use of retinoids for prevention of adhesion formation is described in U.S. Patent 5,534,261. While the term "retinoid" as used in WO 99/06036 PCT/US98/1 5625 this patent is defined in several ways, no mention is made of selective RXR agonists and there is no indication that such agonists would possess this property.

Applicant has unexpectedly found that certain retinoid derivatives, most or all of which are selective RXR agonists, possess surprisingly potent activity in preventing or minimizing adhesion formation. The reduction or absence of teratogenicity and skin irritation described for selective RXR agonists in the prior art (See, for example, H Jiang et al, Biochemical Pharmacology Vol 50, 669-676 (1995); DM Kochhar et al, Chemico-Biological Interactions Vol 100, 1-12 (1996); C Willhite et al, Drug Metabolism Reviews Vol 28, 105-119 (1996); SM Thatcher et al, J Pharmacology and Experimental Theraputics Vol 282, 528-534 (1997); RL Beard et al, J Medicinal Chemistry Vol 39, 3556-63 (1996)) would also make such agonists more advantageous for this use than the retinoids described in U.S. Patent 5,534,261.

Thus, the present invention provides a method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering an effective amount of a retinoid derivative of general formula I above to a site of surgical activity for a period of time sufficient to permit tissue repair.

Preferred compounds of general formula I are those wherein B and C are both C(CH 3 2 i.e.

WO 99/06036 PCT/US98/15625 -6- R COOH

IA

in which Z and Ri are as defined above for the formula I compounds.

The most preferred compounds of formula I and IA are those in which RI is hydrogen.

The compounds of the present invention have a carboxylic acid functional group and can, therefore, form salts with suitable bases. It is intended that the present invention encompass pharmaceutically acceptable salts of the compounds of formula I formed with conventional bases, i.e. both inorganic and organic bases. Examples of suitable salts include ammonium, alkali metal salts, particularly sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris (hydroxymethyl) aminomethane, or with bases such as piperidine or morpholine.

Examples of the compounds of the present invention are given in the table below: WO 99/06036 WO 9906036PCT/US98/1 5625 COMPOUND STRUCTURE o 0

COOH

II 0

COOH

III CH 2

COOH

IV

S S

COOH

V

S 0

COOH

VI CH 3 o 0

COOH

VII

S S

COOH

Vill o o 4-COOH Ix 0

CH

3

COOH

WO 99/06036 WO 9906036PCT/US98/1 5625 x S

S~

CH

3

COOH

~XI r"h S S

CHQ

3

COOH

Compounds INV, VII, and IX have been reported in MI Dawson et al; Mediclinal Chemiistry 1995, 38, 3368-3383, where they are described as selective RXR agonists. Compounds VI, VIII, X, and XI may be prepared using the following scheme: N, N. HX-A-YH N a R COOCH 3 acdR R CH 3 R CH 3 1 2

A

R QCOOH R H, CH 3 3 A diaryi ketone-ester, 1, is condensed with a diol, dithiol, or mixed alcohol/thiol under acidic conditions to generate a cyclic ketal-ester, 2, whose ester group is then hydrolyzed to yield the final compound, 3.

Example 1: 4-[4-Methy1-2-(5,5,8,8-tetramethy1-5,6,7,8-tetrahydro-napthalen- 2-yl)-[1.3Idioxolan-2-y 1-benzoic acid, Compound VI 750 mg (2.1 mmol) keto-ester 1 (R fromn MI Dawson et al; j Medicinal Chemistry 1995, 368-3383) and 1.6 ml (1.66 g; 21.9 mmol) 1,2propanediol were dissolved in 40 ml benzene and then 50 mg WO 99/06036 PCT[US98/1 5625 -9p-toluenesulfonic acid monohydrate was added. The resulting mixture was heated at reflux under a Dean-Stark trap for 24 hours. The reaction mixture was then cooled to room temperature, washed with 5% aq.

NaHCO 3 water and brine. The organic layer was dried over MgSO 4 filtered, and then evaporated in vacuo directly onto silica. Flash chromatography through silica gel using 5% EtOAc/hexane afforded 870 mg 99 product as a colorless, viscous oil. NMR revealed the presence of the desired compound plus its isomer: 4-[5-methyl-2-(5,5,8,8tetramethyl-5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxolan-2-yl]-benzoic acid methyl ester. Each isomer exists as a pair of enantiomers.

1H NMR (300 MHz, CDC13): 1.24 12H), 1.37 (dd, 3H), 1.65 4H), 3.55- 3.65 1H), 3.9 3H) 4.05-4.35 2H), 7.15-7.25 2H), 7.42 (dd, 1H), 7.65 2H), 8.05 2H); IR: 2959, 1727, 1277, 1110 cm'; MS (ESI): 409 870 mg (2.1 mmol) 4-[5-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapthalen-2-yl)-[1,3]dioxolan-2-yl]-benzoic acid methyl ester was dissolved in 10 ml MeOH plus 10 ml THF. 8.0 ml 1.0 N NaOH (8.0 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was neutralized with 8.0 ml 1.0 N HC1 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water brine, dried over MgSO 4 filtered, and then evaporated in vacuo to give 775 mg (92%) dioxolane-acid as a white solid. The product was recrystallized from hexanes/CH 2 C2l to afford 570 mg of a white solid VI. NMR revealed the presence of the desired compound plus its isomer: 4-[5-methyl-2-(5,5,8,8- WO 99/06036 PCTIUS98/15625 tetramethyl-5,6,7,8-tetrahydro-napthalen-2-yl)- [1,31 dioxolan-2-yl] -benzoic acid (compound VI). Each isomer exists as a pair of enantiomers.

1H NMR (300 MHz, CDCl 3 1.24 12H, J 4.8 Hz), 1.36 (dd, 3H, J 14.7 Hz, 6.0 Hz), 1.65 4H, J 3.3 Hz), 3.55-3.65 (in, 1H), 4.05-4.35 (in, 2H), 7.15- 7.25 (in, 2H), 7.43 (dd, 1H, J 7.5 Hz, 2.1 Hz), 7.65 (in, 2H), 8.07 (in, 2H); IR: 2962, 1689, 1423, 1291, 1084, 1020 cm- 1 MS (ESI): 393 Anal. caic. for

C

25

H

30 0 4 C, 76.11; H, 7.66. Found: C, 76.01; H, 7.71.

Example 2: 4-[5 .5-Dimethyl-2-(5.5 .8 8-tetramethyl-5.6 .7,8-tetrahydronapthalen-2-yl)-[1 .31dioxan-2-yl]-benzoic acid, Compound VIII 750 mg (2.1 minol) keto-ester 1 (R H, from MI Dawson et al; J Medicinal Chemistry 1995, 38, 3368-3383) and 2.2 g (21.1 mmnol) 2,2-dimethyl-1,3propanediol were dissolved in 40 ml benzene and then 50 mg ptoluenesulfonic acid monohydrate was added. The resulting mixture was heated at reflux under a Dean-Stark trap for 24 hours. The reaction mixture was cooled to room temperature, washed with 50/ aq. NaHCO 3 water, and brine. The organic layer was dried over MgSO 4 filtered, and then evaporated in vactio directly onto silica. Flash chromatography through silica using a 3% to 5% EtOAc/hexane gradient afforded 890 mg 4-[5,5-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalen-2yl)-[1,3]dioxan-2-yl]-benzoic acid methyl ester as a colorless oil.

I NMR (300 MHz, CDCl 3 1.0 6H), 1.21 6H), 1.22 6H), 1.63 4H), 3.6 4H), 3.9 3H), 7.19 (dd, 1H), 7.21 1H), 7.4 1H), 7.6 2H), 8.0 (d, 2H); IR: 2956, 1727, 1277, 1101 cm- 1 MS (ESI): 437 890 mg (2.0 inmol) 4-[5,5-dimethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronap tha len-2-yl)- [1,31 dioxan-2-yl] -benzoic acid methyl ester was dissolved WO 99/06036 PCTIUS98/1 5625 -11in 25 ml MeOH plus 25 ml THF. 8.0 ml 1.0 N NaOH (8.0 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was neutralized with 8.0 ml 1.0 N HC1 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water brine, dried over MgSO 4 filtered, and then evaporated in vacuo to give 790 mg (92%) dioxane-acid as a white solid. The product was recrystallized from hexanes/CH 2 Cl 2 to afford 705 mg 4-[5,5-dimethyl-2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxan-2-yl]-benzoic acid, Compound VIII.

H NMR (300 MHz, d 6 -DMSO): 0.88 3H), 0.93 3H), 1.19 12H), 1.61 4H), 3.55 4H), 7.16 (dd, 2H, J 8.3 Hz, 1.8 Hz), 7.28 1H, J 8.3 Hz), 7.39 1H, J 1.8 Hz), 7.58 2H, J 8.5 Hz), 7.92 2H, J 8.5 Hz); IR: 2961, 2868, 1685, 1290, 1099 cm' 1 MS (ESI): 423 Anal. calc. for

C

27 H340 4 C, 76.75; H, 8.11. Found: C, 76.53; H, 8.22.

Example 3: 4-r2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-napthalen-2-yl)- [1.3ldithiolan-2-yl]-benzoic acid, Compound X 750 mg (2.05 mmol) keto ester 1 (R CH 3 from MI Dawson et al; J Medicinal Chemistry 1995, 38, 3368-3383) and 0.52 ml (0.58 g; 6.2 mmol) 1,2-ethanedithiol were dissolved in 3 ml CH 2 C12 under a dry nitrogen atmosphere. The mixture was cooled to 0-5 0 C in an ice bath and then ml (1.15 g; 8.1 mmol) BF 3 *Et 2 0 was added via syringe. The reaction mixture was warmed to room temperature and stirred for 2 days. The mixture was diluted with EtOAc and then washed with 5% aq. Na 2

CO

3 aq. NaHCO 3 water, and brine. The organic layer was dried over MgSO 4 WO 99/06036 PCT/US98/15625 -12filtered and evaporated in vacuo directly onto silica. Flash chromatography through silica using 5% EtOAc/hexane then afforded 855 mg white solid, 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronapthalen-2-yl)-[1,3]dithiolan-2-yl]-benzoic acid methyl ester.

'H NMR (300 MHz, CDCl 3 1.24 6H), 1.36 6H), 1.7 4H), 1.84 3H), 3.35-3.55 4H), 7.0 1H), 7.58 2H), 7.93 2H), 8.1 1H); IR: 2959, 1724, 1277 cm-l; MS (DCI): 441 855 mg (1.9 mmol) 4 2 3 ,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronapthalen-2-yl)-[1,3]dithiolan-2-yl]-benzoic acid methyl ester was dissolved in 10 ml MeOH plus 25 ml THF. 8.0 ml 1.0 N NaOH (8.0 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was neutralized with 8.0 ml 1.0 N HC1 mmol) and left to stir at room temperature. After about 5 minutes, white crystals came out of solution. The mixture was further cooled in the freezer for 1 hour, and the resulting crystals were filtered off, washed with copious amounts of water, and dried under high vaccuum 1mm Hg) to give 820 mg 4 2 3 ,5, 5 ,8, 8 -Pentamethyl-5,6,7,8-tetrahydro-napthalen- 2 -yl)-[1,3]dithiolan-2-yl]-benzoic acid, Compound X.

1H NMR (300 MHz, d 6 -DMSO): 1.23 6H), 1.31 6H), 1.67 4H), 1.76 (s, 3H), 3.35-3.55 4H), 7.06 1H), 7.49 2H, J 8.4 Hz), 7.88 2H, J 8.4 Hz), 8.05 1H); IR: 2956, 1718, 1682, 1604, 1259 cm 1 MS (ESI): 425 Anal. calc. for C 25

H

30

S

2 0 2 C, 70.38; H, 7.09; S, 15.03. Found: C, 69.65; H, 7.45; S, 12.83.

WO 99/06036 PCTfUS98/1 5625 -13- Example 4. 4-[2-(3,5,5,8.8-pentamethyl-5.6,7.8-tetrahydro-napthalen-2-yl)- [1.3]dithian-2-yll-benzoic acid, Compound XI 750 mg (2.05 mmol) keto ester 1 (R CH 3 from MI Dawson et al; J Medicinal Chemistry 1995, 38, 3368-3383) and 0.62 ml (0.67 g; 6.2 mmol) 1,3-propanedithiol were dissolved in 3 ml CH 2 C1 2 under a dry nitrogen atmosphere. The mixture was cooled to 0-5 0 C in an ice bath and then ml (1.15 g; 8.1 mmol) BF 3 'Et 2 0 was added via syringe. The reaction mixture was warmed to room temperature and stirred for 2 days. The mixture was diluted with EtOAc and then washed with 5% aq. Na 2

CO

3 aq. NaHCO 3 water, and brine. The organic layer was dried over MgSO 4 filtered and evaporated in vacuo directly onto silica. Isolation of the less polar fraction by flash chromatography through silica using EtOAc/hexane then afforded 490 mg 4-[2-(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dithian-2-yl]-benzoic acid methyl ester as a colorless, viscous oil.

1 H NMR (300 MHz, CDCI 3 1.20 6H), 1.25 6H), 1.64 4H), 2.0 (m, 2H), 2.9 (4H, 3.9 3H), 7.2 2H), 7.55 1H), 7.9 2H), 8.05 2H); IR: 2926, 1720, 1282, 1113 cm 1 MS (DCI): 441 490 mg (1.1 mmol) 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronapthalen-2-yl)-[1,3]dithian-2-yl]-benzoic acid methyl ester was dissolved in 10 ml MeOH plus 25 ml THF. 5.0 ml 1.0 N NaOH (5.0 mmol) was added and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was neutralized with 5.0 ml 1.0 N HC1 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water brine, dried over MgSO 4 filtered, and then evaporated in vacuo to give 465 mg (98%) WO 99/06036 PCTIUS98/15625 -14dithiane-acid as a white solid. The product was recrystallized from hexanes/CH 2 C1 2 to afford 300 mg white solid,4-[2-(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dithian-2-yl]-benzoic acid, Compound XI.

'H NMR (300 MHz, d 6 -DMSO): 1.22 12H), 1.61 4H), 1.95 (br s, 2.75-2.95 4H), 7.05 1H), 7.6 2H, J 8.4 Hz), 7.78 1 7.95 2H, J 8.4 Hz); IR: 2960, 2918, 1688, 1422, 1287 MS (ESI): 439 Anal. calc. for C 2 6

H

3 2S 2 0 2 C, 70.87; H, 7.32; S, 14.55. Found: C, 69.89; H, 7.29; S, 13.88.

Biological Activity For prevention of surgical adhesions, the retinoid derivative of the present invention may be administered by a variety of systemic and local methods. The compounds may be administered orally, by intravenous injection, by intramuscular injection or by intracavity instillation. The general range of doses will depend on the efficacy of the compound and the intended route but is expected to be from about 0.1 mg/kg to about 100 mg/kg with a preferred range of about 1 to about 25 mg/kg.

The term of administration may vary depending upon a number of factors which would be readily appreciated by those skilled in the art. In general, administration of a retinoid derivative of the present invention should be effected 12-48 hours prior to the time of surgery and for at least 24-48 hours post-surgery. In general the retinoid derivative may be WO 99/06036 PCT/US98/15625 administered from 72 hours prior to surgery and continue up to 2 weeks after surgery and preferably for a period 12 hours prior to surgery and continuing 48 hours after surgery.

For intracavity administration the retinoid derivative of the present invention can be administered in a suitable vehicle such as dextrose in water adjusted to a pH to assure complete salt formation.

However it is understood that many other single dose delivery systems could be contemplated by those skilled in the art including microcapsules, microspheres, liposomes, viscous instilates, and polymeric delivery materials.

The method of the present invention may be used in the prevention of surgical adhesions in any animal (mammalian) host, but is particularly preferred for use in human hosts.

Models of peritoneal adhesions induced by surgical trauma have been used to predict the clinical activity of a number of marketed antiadhesion barrier devices. One such model is the trauma-induced caecal adhesion model in rats. Representative retinoid derivatives of the present invention as disclosed in the table above were used in this model to demonstrate efficacy.

WO 99/06036 PCTIUS98/1 5625 -16- Adult female Wistar rats were used in our studies. The trauma induction was carried out using aseptic conditions in animals anesthetized with a mixture of Ketamine (100 mg/kg) and Rompun mg/kg) given IP. A 2 cm midline abdominal incision was made and the caecum was exteriorized. Both sides of the caecum were abraded with a dry gauze until there was evidence of punctate bleeding. After replacing the organ in the abdominal cavity, the incision was closed. Trauma to the caecum produces fibrous scar tissue or adhesions to adjacent organs, peritoneal wall, or the omentum. Animals were treated with test compound orally or by intravenous injection or intra-abdominally by direct instillation into the peritoneal cavity. Oral treatments were administered once daily for up to 7 days. Intra-abdominal treatments were applied once post-trauma and just prior to wound closure.

On the seventh postoperative day, the animals were sacrificed and the peritoneal cavity was exposed and examined for adhesions.

Three criteria that were used to evaluate the adhesions are: severity of the adhesions, extent or area of the ceacum involved with adhesions and the number of adhesions formed in each animal. Statistical analysis of the data was performed using students' T test. The following scoring system was used: WO 99/06036 Grade PCT/US98/15625 -17- Description no adhesions; easily separable, filmy, non-vascularized adhesions covering 25% of the caecum; 3.0 dense adhesions separated by blunt dissection and involving 50% of the caecum; dense, fibrous, vascularized adhesions requiring sharp dissection and covering 75% of the caecum; severe, dense, vascularized adhesions unable to separate without tearing the adjacent membranes and covering greater than 75% of the caecum.

Data on the test compounds are given in the following tables: WO 99/06036 PCT/US98/15625 Dose Dependent Effect of Orally Dosed Test Compound I on Surgical Adhesions in Rat Ceacum Mean number of Mean Adhesion adhesions/rat Severity/Rat Compound Dose SD Vehicle 13 3.1 33 10.3 Compound I 15mg/kg 6.8 1.3 14.2 4.14* Compound I 30 mg/kg 5.4 2.3 12.2 4.32 *p 0.04 at Dose Dependent Effect of Orally Dosed Test Compound II on Surgical Adhesions in Rat Ceacum Compound Dose Mean Number of Mean Adhesion mg/kg Adhesions/rat Severity/Rat (orally) S.D. Inhibition) S.D. Inhibition) Vehicle 14.3 3.6 29 9.8 Compound II 1 8.4 1.7 18.3 Compound II 3 5.9 2.7* 12.2 5.6* Compound II 10 3.9 1.1* 8.0 2.1* *p 0.05 WO 99/06036 PCT/US98/15625 -19- Effect of Orally Dosed Test Compounds n S1uriala Adhesions in Rat Ccum Adhesio s in Rat (feacum Compound Dose Mean Number of Mean Adhesion mg/kg Adhesions/rat Severity/Rat (orally) S.D. Inhibition) S.D. Inhibition) Vehicle 7.5 ±2 15.3 4.9 Compound VI 10 Not active Not active Compound VII 10 3.1 1.2 6.7 2.4 (56)* Compound VIII 10 4.1 1.7 (37) 8.7 4.2 (43) Compound V 10 4.7 1.4 (37) 9.9 3.4 (36) *p 0.05 Effect of Orally Dosed Test Compounds on Surgical Adhesions in Rat Ceacum Compound Dose Mean Number of Mean Adhesion mg/kg Adhesions/rat Severity/Rat (orally) S.D. Inhibition) S.D. Inhibition) Vehicle 8.9 3.2 17.7 6.2 Compound IV 10 2.9 0.7 5.7 2.3 (68)* Compound X 10 6.7 2.9 (24) 13.1 5.0 (26) Compound III 10 4.3 1.5 8.7 3.6 (51)* Compound XI 10 4.3 2.1 8.6 4.0 (52)* *p 0.05 As demonstrated above, the retinoid derivatives of formula I are useful in the prevention of surgical adhesions.

Claims (6)

1. A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a retinoid derivative to a site of surgical activity on an organ surface for a period of time sufficient to permit tissue repair, said retinoid derivative being a compound of the formula B Z C Ri COOH I A Q X Y 10 wherein Z is or in which Q, X and Y are each independently O, S or CH2; S: A is -(CR 2 wherein n is 1-3; B and C are each independently O, S, CH 2 or C(CH 3 2 R is hydrogen or (C1-C6) alkyl; and R 2 is hydrogen or CH 3 or a pharmaceutically acceptable salt thereof; CH 2 with the proviso that when Z is R 1 cannot be (Ci-C 6 )alkyl.

2. A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an S effective amount of a retinoid derivative to a site of surgical activity on an organ V:\SPECI86670doc -21 surface for a period of time sufficient to permit tissue repair, said retinoid derivative being a compound of the formula Z R, COOH IA A Q X Y wherein Z is or in which Q, X and Y are each independently O, S or CH 2 A is -(CR 2 wherein n is 1-3; R 1 is hydrogen or (C1-C6) alkyl; and R 2 is hydrogen or CH 3 or a pharmaceutically acceptable salt thereof; CH 2 10 with the proviso that when Z is "K R 1 cannot be (C 1 -C 6 )alkyl.

3. A method for the minimization or prevention of post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a retinoid derivative to a site of surgical activity on an organ 15 surface for a period of time sufficient to permit tissue repair, said retinoid derivative being a compound of the formula V:\SPECI86670.doc WO 99/06036 WO 9906036PCTIUS98/1 5625 -22- COMPOUND STRUCTURE 0I COOH II COOH COOH IV S S COOH V S 0 COOH VI CH 3 I 0 COOH VII S S COOH VIII 0 COOH Ix 0 CH 3 COOH -23 CH 3 COOH XI ss CH 3 COOH or a pharmaceutically acceptable salt thereof.

4. Use of a retinoid derivative being a compound of the formula I as defined in claim 1 in the manufacture of a medicament for use in minimizing or preventing post-surgical adhesion formation between organ surfaces by administering to an animal host an effective amount of the medicament to a site of surgical activity or an organ surface for a period of time sufficient to permit tissue repair. 20

5. Use of a retinoid derivative being a compound of the formula IA as 1defined in claim 2 in the manufacture of a medicament for use in minimizing or preventing post-surgical adhesion formation between organ surfaces by Sadministering to an animal host an effective amount of the medicament to a site of surgical activity or an organ surface for a period of time sufficient to permit tissue repair.

6. Use of a retinoid derivative as defined in claim 3 in the manufacture of a medicament for use in minimizing or preventing post-surgical adhesion formation between organ surfaces by administering to an animal host an 30 effective amount of the medicament to a site of surgical activity or an organ surface for a period of time sufficient to permit tissue repair. DATED: 15 June 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: 4e BRISTOL-MYERS SQUIBB COMPANY WASPECOAGGO-98 SPE JunOOdoc