CA2295807A1 - Use of selective rxr agonists to prevent surgical adhesions - Google Patents
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Abstract
Certain retinoid derivatives, most or all of which are selective RXR retinoid agonists, have been found to be useful in the prevention or minimization of surgical adhesion formation.
Description
WO 99/06036 PCT/US98/15b25 .:
USE OF SELECTIVE RaCR AGONI TD'S _ 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.
U.S. 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 particular retinoid derivatives of the present invention.
Selective agonists of RXR retinoid receptors are known in the literature along with suitable assays for determining if a given retinoid-like 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 *rB
WO 99/06036 PCT/US98/15625 _ angonists 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 hyperproliferaHve diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer arid 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 {e.g. 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 agorust 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 *rB
WO 99/06036 PCT/US98/15625 =
USE OF SELECTIVE RaCR AGONI TD'S _ 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.
U.S. 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 particular retinoid derivatives of the present invention.
Selective agonists of RXR retinoid receptors are known in the literature along with suitable assays for determining if a given retinoid-like 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 *rB
WO 99/06036 PCT/US98/15625 _ angonists 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 hyperproliferaHve diseases such as epithelial cancer, breast cancer, prostatic cancer, head and neck cancer arid 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 {e.g. 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 agorust 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 *rB
WO 99/06036 PCT/US98/15625 =
is 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 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.
SUMMARY OF THE ~~~VENTION
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 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.
The retinoid derivatives which are the subject of the present invention have the general formula Z
i C R~ COOH
I
A
Q X~ 'Y -wherein Z is -c- or X in which Q, X and Y are each independently O, S or CH2;
A is -(CRZ)" wherein n is an integer of from 1 to 3; -B and C are each independently O, S, CHZ or C{CH3)Z; and Rl is hydrogen or (C,-C6) 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 this patent is defined in several ways, no mention is made of selective _ RXR agorusts 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 agorusts 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(CH3)2, i.e.
WO 99/06036 PCTNS98l15625 R~ COOH
IA
in which Z and R1 are as defined above for the formula I compounds..
The most preferred compounds of formula I and IA are those in which R, 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 (e.g. 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 99/05036 PCT/US98115625 .
COMPOUND STRUCTURE
I
I ~ I ~ CooH
II o y y CooH
III cH2 w I ~ cooH
IV
s i i W
COOH
V
S O
~ COOH
V I ~ H3 I~
~ COOH
VII
s s ~ COOH
VIII
w I ~ CooH
IX o CH31 ~ COOH
WO 99/06036 PCT/US98/15625 _ _g_ X /
S S _ CH3 ~ COOH
- XI
s s w w cH3~ cooH
Compounds I-V, VII, and IX have been reported in MI Dawson et al;
Medicinal Chemistry 1995, ~$, 3368-3383, where they are described as selective RXR agonists. Compounds VI, VIII, X, and XI may be prepared using the following scheme:
A A, X~ ~Y X~ Y
HX-A~YH
~ R I ~ COOCH3 eCld I ~ R I ~ COOCH3 I R I / COOH
R=H,CH3 R=H,CH3 R=H,CHg A diaryl ketone-ester, 1, is condensed with a diol, dithiol, or mixed alcohol/thiol under acidic conditions to generate a cyclic ketal-ester, 2, whose ester group is then hydrolyzed to yield the final compound, 3.
x 1: -2- tra t 7 -t tra al 2-~l)-(13ldioxolan-2-~,1-benzoic acid Compound VI
750 mg (2.1 mmol) keto-ester 1 (R = H, from MI Dawson et al; J Medicinal Chemistry 1995, ~$, 3368-3383) and 1.6 ml (1.66 g; 21.9 mmol) 1,2-propanediol were dissolved in 40 ml benzene and then 50 mg WO 99/06036 PCT/US98/15625 .
p-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.
NaHC03, water (2x), and brine. The organic layer was dried over MgS04, 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-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxolan-2-ylJ-benzoic acid methyl ester. Each isomer exists as a pair of enantiomers.
1H NMR (300 MHz, CDC13): 1.24 (d,12H), 1.37 (dd, 3H), 1.65 (d, 4H), 3.55-3.65 (m,1H), 3.9 (d, 3H) 4.05-4.35 (m, 2H), 7.15-7.25 (m, 2H), 7.42 (dd, IH), 7.65 (m, 2H), 8.05 (m, 2H); IR: 2959, 1727, 1277, 1110 cm-1; MS (ESI): 409 (M+H)'.
870 mg (2.1 mmol) 4-[5-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalen-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 HCl (8.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgSO.~, filtered, and then evaporated in vacuo to give 775 mg (92%) dioxolane-acid as a white solid. The product was recrystallized from hexanes/CH2C12 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-tetramethyl-5;6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxolan-2-yl]-benzoic _ acid {compound VI). Each isomer exists as a pair of enantiomers.
1H NMR (300 MHz, CDC13): 1.24 (d,12H, J = 4.8 Hz),1.36 (dd, 3H, J =14.7 Hz, 6.0 Hz),1.65 (d, 4H, J = 3.3 Hz), 3.55-3.65 (m,1H), 4.05-4.35 (m, 2H), 7:15-7.25 (m, 2H), 7.43 (dd,1H, J = 7.5 Hz, 2.1 Hz), 7.65 (m, 2H), 8.07 (m, 2H);
IR:
2962, 1689, 1423, 1291, 1084,1020 cm 1; MS (ESI): 393 (M-H)+; Anal. calc. for C~H~04: C, 76.11; H, 7.66. Found: C, 76.01; H, 7.71.
a th -t t 1- 7 - h napthalen-2-3r1)-[1.3]dioxan-2-yl]-benzoic acid. Compound VIII
750 mg (2.1 mmol) keto-ester 1 (R = H, from MI Dawson et al; j Medicinal Chemistry 1995, ~$, 3368-3383) and 2.2 g (21.1 mmol) 2,2-dimethyl-1,3-propanediol were dissolved in 40 ml benzene and then 50 mg p-toluenesulfonic 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 5% aq. NaHC03 (2x), water, and brine. The organic layer was dried over MgS04, filtered, and then evaporated in vacuo directly onto silica. Flash chromatography through silica using a 3% to 5% EtOAc/hexane gradient afforded 890 mg (95%) 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 methyl ester as a colorless oil.
1H NMR (300 MHz, CDCl3): 1.0 (d, 6H),1.21 (s, 6H),1.22 (s, 6H),1.63 (s, 4H), 3.6 (q, 4H), 3.9 (s, 3H), 7.19 (dd,1H), 7.21 (s,1H), 7.4 (d,1H), 7.6 (d, 2H), 8.0 (d, 2H); IR: 2956,1727, 1277,1101 cm 1; MS (ESI): 437 (M+H)+.
890 mg (2.0 mmol) 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 methyl ester was dissolved in 25 ml MeOH plus 25 ml THF. 8.0 ml 1.0 N NaO~I (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 HCl (8.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgS04, filtered, and then evaporated in vacuo to give 790 mg (92%) dioxane-acid as a white solid. The product was recrystallized from hexanes/CH2C12 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-ylJ-benzoic acid, Compound VIII.
1H NMR (300 MHz, d6-DMSO}: 0.88 (s, 3H), 0.93 (s, 3H),1.19 (s,12H), 1.61 (s, 4H), 3.55 (s, 4H), 7.16 (dd, 2H, J = 8.3 Hz,1.8 Hz), 7.28 (d,1H, J = 8.3 Hz), 7.39 (d,1H, J =1.8 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.92 (d, 2H, J = 8.5 Hz);
IR:
2961, 2868, 1685, 1290, 1099 cm 1; MS (ESI): 423 (M+H)+; Anal. calc. for C2~H~O4: C, 76.75; H, 8.11. Found: C, 76.53; H, 8.22.
Example 3: 4-[2-(3 5 5,,8,8-Pentamethyl-5,~ø,7,8-tetrahydro-naptha]en-2-~)_-j~.,_3]dithiolan-2-yl]-benzoic acid, Compound X
750 mg (2.05 mmol) keto ester 1 {R = CH3, from MI Dawson et al; j Medicinal Chemistry 1995, ,~$, 3368-3383) and 0.52 ml (0.58 g; 6.2 mmol) 1,2-ethanedithiol were dissolved in 3 ml CH2C12 under a dry nitrogen atmosphere. The mixture was cooled to 0-5°C in an ice bath and then 1.0 ml (1.15 g; 8.1 mmol) BF3 Et20 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. Na2C03, 5%
aq. NaHC03, water, and brine. The organic layer was dried over MgS04, *rB
WO 99/06036 PCT/US98/15625 .
filtered and evaporated in vacuo directly onto silica. Flash _ chromatography through silica using 5% EtOAc/hexane then afforded 855 mg (94%) white solid, 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dithiolan-2-yl]-benzoic acid methyl ester.
1H NMR (300 MHz, CDC13): 1.24 (s, 6H),1.36 (s, 6H),1.7 (s, 4H),1.84 (s, 3H), 3.35-3.55 (m, 4H), 7.0 (s,1H), 7.58 (d, 2H), 7.93 (d, 2H), 8.1 (s,1H); IR:
2959, 1724, 1277 cmi l; MS (DCI): 441 (M+H)+.
855 mg (1.9 mmol) 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-napthalen-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 HCl (8.0 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 (< lmm Hg) to give 820 mg (99%) 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, d6-DMSO): 1.23 (s, 6H),1.31 (s, 6H),1.67 (s, 4H),1.76 (s, 3H), 3.35-3.55 (m, 4H), 7.06 (s,1H), 7.49 (d, 2H, J = 8.4 Hz), 7.88 (d, 2H, J
= 8.4 Hz), 8.05 (s,1H); IR: 2956,1718,1682,1604,1259 cm 1; MS (ESI): 425 (M-H)+;
Anal. calc. for C25H~S2O2: C, 70.38; H, 7.09; S, 15.03. Found: C, 69.65; H, 7.45; S,12.83.
-13_ 750 mg (2.05 mmol) keto ester 1 (R = CH3, from MI Dawson et al; J
Medicinal Chemistry 2995, ~$, 3368-3383) and 0.62 ml (0.67 g; 6.2 mmol) 1,3-propanedithiol were dissolved in 3 ml CH2C12 under a dry nitrogen atmosphere. The mixture was cooled to 0-5°C in an ice bath and then 1.0 ml (1.15 g; 8.1 mmol) BF3 Et20 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. Na2C03, 5%
aq. NaHC03, water, and brine. The organic layer was dried over MgS04, filtered and evaporated in vacuo directly onto silica. Isolation of the less polar fraction by flash chromatography through silica using 5%
EtOAc/hexane then afforded 490 mg (52%) 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.
1H NMR (300 MHz, CDC13): 1.20 (s, 6H),1.25 (s, 6H),1.64 (s, 4H), 2.0 (m, 2H), 2.9 (4H, q), 3.9 (s, 3H), 7.2 (s, 2H), 7.55 (s,1H), 7.9 (d, 2H), 8.05 (d, 2H);
IR: 2926,1720,1282,1113 cxri 1; MS (DCI): 441 (M+H)+.
490 mg (1.1 mmol) 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 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 HCl (5.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgS04, filtered, and then evaporated in vacuo to give 465 mg {98%) WO 99/0603b PCT/US98/15625 ..
dithiane-acid as a white solid. The product was recrystallized from -hexanes/CH2C12 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.
1H NMR (300 MHz, d6-DMSO): 1.22 (d,12H), 1.61 (s, 4H),1.95 (br s, 5H), 2.75-2.95 (m, 4H), 7.05 (s,1H}, 7.6 (d, 2H, J = 8.4 Hz), 7.78 (s,1 H), 7.95 (d, 2H, J = 8.4 Hz); IR: 2960, 2918,1688,1422, 1287 cm-'; MS (ESI): 439 (M-H)+;
Anal. calc. for C26H32S2~2~ C, 70.87; H, 7.32; S, 14.55. Found: C, 69.89; H, 7.29; S,13.88.
Biological ActivitT
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 adrnirustration the retinoid derivative of the present invention can be administered in a suitable vehicle such as 5%
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 anti-adhesion 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 PCT/US98/15625 =
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 (10 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 PCT/US98/15625 .-_17_ Grade Description 0 - no adhesions;
1.0 - easily separable, filmy, non-vascularized adhesions covering 25% of the caecum;
2.0 - dense adhesions separated by blunt dissection and involving 50% of the caecum;
3.0 - dense, fibrous, vascularized adhesions requiring sharp dissection and covering 75% of the caecum;
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.
SUMMARY OF THE ~~~VENTION
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 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.
The retinoid derivatives which are the subject of the present invention have the general formula Z
i C R~ COOH
I
A
Q X~ 'Y -wherein Z is -c- or X in which Q, X and Y are each independently O, S or CH2;
A is -(CRZ)" wherein n is an integer of from 1 to 3; -B and C are each independently O, S, CHZ or C{CH3)Z; and Rl is hydrogen or (C,-C6) 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 this patent is defined in several ways, no mention is made of selective _ RXR agorusts 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 agorusts 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(CH3)2, i.e.
WO 99/06036 PCTNS98l15625 R~ COOH
IA
in which Z and R1 are as defined above for the formula I compounds..
The most preferred compounds of formula I and IA are those in which R, 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 (e.g. 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 99/05036 PCT/US98115625 .
COMPOUND STRUCTURE
I
I ~ I ~ CooH
II o y y CooH
III cH2 w I ~ cooH
IV
s i i W
COOH
V
S O
~ COOH
V I ~ H3 I~
~ COOH
VII
s s ~ COOH
VIII
w I ~ CooH
IX o CH31 ~ COOH
WO 99/06036 PCT/US98/15625 _ _g_ X /
S S _ CH3 ~ COOH
- XI
s s w w cH3~ cooH
Compounds I-V, VII, and IX have been reported in MI Dawson et al;
Medicinal Chemistry 1995, ~$, 3368-3383, where they are described as selective RXR agonists. Compounds VI, VIII, X, and XI may be prepared using the following scheme:
A A, X~ ~Y X~ Y
HX-A~YH
~ R I ~ COOCH3 eCld I ~ R I ~ COOCH3 I R I / COOH
R=H,CH3 R=H,CH3 R=H,CHg A diaryl 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.
x 1: -2- tra t 7 -t tra al 2-~l)-(13ldioxolan-2-~,1-benzoic acid Compound VI
750 mg (2.1 mmol) keto-ester 1 (R = H, from MI Dawson et al; J Medicinal Chemistry 1995, ~$, 3368-3383) and 1.6 ml (1.66 g; 21.9 mmol) 1,2-propanediol were dissolved in 40 ml benzene and then 50 mg WO 99/06036 PCT/US98/15625 .
p-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.
NaHC03, water (2x), and brine. The organic layer was dried over MgS04, 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-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxolan-2-ylJ-benzoic acid methyl ester. Each isomer exists as a pair of enantiomers.
1H NMR (300 MHz, CDC13): 1.24 (d,12H), 1.37 (dd, 3H), 1.65 (d, 4H), 3.55-3.65 (m,1H), 3.9 (d, 3H) 4.05-4.35 (m, 2H), 7.15-7.25 (m, 2H), 7.42 (dd, IH), 7.65 (m, 2H), 8.05 (m, 2H); IR: 2959, 1727, 1277, 1110 cm-1; MS (ESI): 409 (M+H)'.
870 mg (2.1 mmol) 4-[5-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-napthalen-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 HCl (8.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgSO.~, filtered, and then evaporated in vacuo to give 775 mg (92%) dioxolane-acid as a white solid. The product was recrystallized from hexanes/CH2C12 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-tetramethyl-5;6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dioxolan-2-yl]-benzoic _ acid {compound VI). Each isomer exists as a pair of enantiomers.
1H NMR (300 MHz, CDC13): 1.24 (d,12H, J = 4.8 Hz),1.36 (dd, 3H, J =14.7 Hz, 6.0 Hz),1.65 (d, 4H, J = 3.3 Hz), 3.55-3.65 (m,1H), 4.05-4.35 (m, 2H), 7:15-7.25 (m, 2H), 7.43 (dd,1H, J = 7.5 Hz, 2.1 Hz), 7.65 (m, 2H), 8.07 (m, 2H);
IR:
2962, 1689, 1423, 1291, 1084,1020 cm 1; MS (ESI): 393 (M-H)+; Anal. calc. for C~H~04: C, 76.11; H, 7.66. Found: C, 76.01; H, 7.71.
a th -t t 1- 7 - h napthalen-2-3r1)-[1.3]dioxan-2-yl]-benzoic acid. Compound VIII
750 mg (2.1 mmol) keto-ester 1 (R = H, from MI Dawson et al; j Medicinal Chemistry 1995, ~$, 3368-3383) and 2.2 g (21.1 mmol) 2,2-dimethyl-1,3-propanediol were dissolved in 40 ml benzene and then 50 mg p-toluenesulfonic 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 5% aq. NaHC03 (2x), water, and brine. The organic layer was dried over MgS04, filtered, and then evaporated in vacuo directly onto silica. Flash chromatography through silica using a 3% to 5% EtOAc/hexane gradient afforded 890 mg (95%) 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 methyl ester as a colorless oil.
1H NMR (300 MHz, CDCl3): 1.0 (d, 6H),1.21 (s, 6H),1.22 (s, 6H),1.63 (s, 4H), 3.6 (q, 4H), 3.9 (s, 3H), 7.19 (dd,1H), 7.21 (s,1H), 7.4 (d,1H), 7.6 (d, 2H), 8.0 (d, 2H); IR: 2956,1727, 1277,1101 cm 1; MS (ESI): 437 (M+H)+.
890 mg (2.0 mmol) 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 methyl ester was dissolved in 25 ml MeOH plus 25 ml THF. 8.0 ml 1.0 N NaO~I (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 HCl (8.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgS04, filtered, and then evaporated in vacuo to give 790 mg (92%) dioxane-acid as a white solid. The product was recrystallized from hexanes/CH2C12 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-ylJ-benzoic acid, Compound VIII.
1H NMR (300 MHz, d6-DMSO}: 0.88 (s, 3H), 0.93 (s, 3H),1.19 (s,12H), 1.61 (s, 4H), 3.55 (s, 4H), 7.16 (dd, 2H, J = 8.3 Hz,1.8 Hz), 7.28 (d,1H, J = 8.3 Hz), 7.39 (d,1H, J =1.8 Hz), 7.58 (d, 2H, J = 8.5 Hz), 7.92 (d, 2H, J = 8.5 Hz);
IR:
2961, 2868, 1685, 1290, 1099 cm 1; MS (ESI): 423 (M+H)+; Anal. calc. for C2~H~O4: C, 76.75; H, 8.11. Found: C, 76.53; H, 8.22.
Example 3: 4-[2-(3 5 5,,8,8-Pentamethyl-5,~ø,7,8-tetrahydro-naptha]en-2-~)_-j~.,_3]dithiolan-2-yl]-benzoic acid, Compound X
750 mg (2.05 mmol) keto ester 1 {R = CH3, from MI Dawson et al; j Medicinal Chemistry 1995, ,~$, 3368-3383) and 0.52 ml (0.58 g; 6.2 mmol) 1,2-ethanedithiol were dissolved in 3 ml CH2C12 under a dry nitrogen atmosphere. The mixture was cooled to 0-5°C in an ice bath and then 1.0 ml (1.15 g; 8.1 mmol) BF3 Et20 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. Na2C03, 5%
aq. NaHC03, water, and brine. The organic layer was dried over MgS04, *rB
WO 99/06036 PCT/US98/15625 .
filtered and evaporated in vacuo directly onto silica. Flash _ chromatography through silica using 5% EtOAc/hexane then afforded 855 mg (94%) white solid, 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-napthalen-2-yl)-[1,3]dithiolan-2-yl]-benzoic acid methyl ester.
1H NMR (300 MHz, CDC13): 1.24 (s, 6H),1.36 (s, 6H),1.7 (s, 4H),1.84 (s, 3H), 3.35-3.55 (m, 4H), 7.0 (s,1H), 7.58 (d, 2H), 7.93 (d, 2H), 8.1 (s,1H); IR:
2959, 1724, 1277 cmi l; MS (DCI): 441 (M+H)+.
855 mg (1.9 mmol) 4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-napthalen-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 HCl (8.0 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 (< lmm Hg) to give 820 mg (99%) 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, d6-DMSO): 1.23 (s, 6H),1.31 (s, 6H),1.67 (s, 4H),1.76 (s, 3H), 3.35-3.55 (m, 4H), 7.06 (s,1H), 7.49 (d, 2H, J = 8.4 Hz), 7.88 (d, 2H, J
= 8.4 Hz), 8.05 (s,1H); IR: 2956,1718,1682,1604,1259 cm 1; MS (ESI): 425 (M-H)+;
Anal. calc. for C25H~S2O2: C, 70.38; H, 7.09; S, 15.03. Found: C, 69.65; H, 7.45; S,12.83.
-13_ 750 mg (2.05 mmol) keto ester 1 (R = CH3, from MI Dawson et al; J
Medicinal Chemistry 2995, ~$, 3368-3383) and 0.62 ml (0.67 g; 6.2 mmol) 1,3-propanedithiol were dissolved in 3 ml CH2C12 under a dry nitrogen atmosphere. The mixture was cooled to 0-5°C in an ice bath and then 1.0 ml (1.15 g; 8.1 mmol) BF3 Et20 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. Na2C03, 5%
aq. NaHC03, water, and brine. The organic layer was dried over MgS04, filtered and evaporated in vacuo directly onto silica. Isolation of the less polar fraction by flash chromatography through silica using 5%
EtOAc/hexane then afforded 490 mg (52%) 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.
1H NMR (300 MHz, CDC13): 1.20 (s, 6H),1.25 (s, 6H),1.64 (s, 4H), 2.0 (m, 2H), 2.9 (4H, q), 3.9 (s, 3H), 7.2 (s, 2H), 7.55 (s,1H), 7.9 (d, 2H), 8.05 (d, 2H);
IR: 2926,1720,1282,1113 cxri 1; MS (DCI): 441 (M+H)+.
490 mg (1.1 mmol) 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 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 HCl (5.0 mmol), diluted with water, and extracted several times with EtOAc. The combined organic extracts were washed with water (2x), brine, dried over MgS04, filtered, and then evaporated in vacuo to give 465 mg {98%) WO 99/0603b PCT/US98/15625 ..
dithiane-acid as a white solid. The product was recrystallized from -hexanes/CH2C12 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.
1H NMR (300 MHz, d6-DMSO): 1.22 (d,12H), 1.61 (s, 4H),1.95 (br s, 5H), 2.75-2.95 (m, 4H), 7.05 (s,1H}, 7.6 (d, 2H, J = 8.4 Hz), 7.78 (s,1 H), 7.95 (d, 2H, J = 8.4 Hz); IR: 2960, 2918,1688,1422, 1287 cm-'; MS (ESI): 439 (M-H)+;
Anal. calc. for C26H32S2~2~ C, 70.87; H, 7.32; S, 14.55. Found: C, 69.89; H, 7.29; S,13.88.
Biological ActivitT
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 adrnirustration the retinoid derivative of the present invention can be administered in a suitable vehicle such as 5%
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 anti-adhesion 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 PCT/US98/15625 =
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 (10 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 PCT/US98/15625 .-_17_ Grade Description 0 - no adhesions;
1.0 - easily separable, filmy, non-vascularized adhesions covering 25% of the caecum;
2.0 - dense adhesions separated by blunt dissection and involving 50% of the caecum;
3.0 - dense, fibrous, vascularized adhesions requiring sharp dissection and covering 75% of the caecum;
4.0 - 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 .
Mean number Mean Adhesion Campoimd Dose of Severity/Rat adhesions/rat+/- SD
+/-SD
Vehicle 13 3.1 33 t 10.3 Compound I 15 mg/kg 6.8 t 1.3 14.2 t 4.14*
Compound I 30 mg/kg 5.4 t 2.3 12.2 t 4.32 *p = 0.04 at N=5 / group Dose Dependent Effect of Orally Dosed Test Compound II
on Surlrical Adhesions in I~at Ceacum Compound Dose Mean Number Mean Adhesion mg/kg of Severity/Rat (orally)Adhesions/rat t S.D. (% Inhibition) S,D, (% Inhibition) Vehicle 14.3 3.6 29 9.8 Compound 1 g,4 1_7 18.3 4.5 II
Compound 3 5.9 2.7* 12.2 t 5.6*
II
Compound 10 3.9 t 1.1* 8.0 t 2.1*
II
*p < 0.05 Compound Dose Mean Number Mean Adhesion mg/kg of Severity/Itat (orally)Adhesions/rat t S.D. (% Inhibition) S,D. (% Inhibition) Vehicle 7.5 t 2 15.3 t 4.9 Com ound VI 10 Not active - Not active Compound VII 10 3.1 t 1.2 (58)*6.7 t 2.4 (56)*
Compound VIII 10 4.1 t 1.7 (37) 8.7 f 4.2 (43) Compound V 10 4.7 1.4 (37) 9.9 t 3.4 (36) *p < 0.05 Effect of Orall;v Dosed Test Compounds on Surgical Adhesions in Rat Ceacu~
Compound Dose Mean Number of Mean Adhesion mg/kg Adhesions/rat Severity/Rat (orally) S.D. (% Inhibition) S,D. (% Inhibition) Vehicle 8.9 t 3.2 17.7 t 6.2 Compound IV 10 2.9 0.7 (68)* 5.7 2.3 (68)*
Compound X 10 6.7 2.9 (24) 13.1 t 5.0 (26) Compound III 10 4.3 t 1.5 (52)* 8.7 3.6 (51)*
Compound XI 10 4.3 t 2.1 (52)* 8.6 t 4.0 (52)*
*p < 0.05 As demonstrated above, the retinoid derivatives of formula I are useful in the prevention of surgical adhesions.
Data on the test compounds are given in the following tables:
WO 99/06036 PCT/US98/15625 .
Mean number Mean Adhesion Campoimd Dose of Severity/Rat adhesions/rat+/- SD
+/-SD
Vehicle 13 3.1 33 t 10.3 Compound I 15 mg/kg 6.8 t 1.3 14.2 t 4.14*
Compound I 30 mg/kg 5.4 t 2.3 12.2 t 4.32 *p = 0.04 at N=5 / group Dose Dependent Effect of Orally Dosed Test Compound II
on Surlrical Adhesions in I~at Ceacum Compound Dose Mean Number Mean Adhesion mg/kg of Severity/Rat (orally)Adhesions/rat t S.D. (% Inhibition) S,D, (% Inhibition) Vehicle 14.3 3.6 29 9.8 Compound 1 g,4 1_7 18.3 4.5 II
Compound 3 5.9 2.7* 12.2 t 5.6*
II
Compound 10 3.9 t 1.1* 8.0 t 2.1*
II
*p < 0.05 Compound Dose Mean Number Mean Adhesion mg/kg of Severity/Itat (orally)Adhesions/rat t S.D. (% Inhibition) S,D. (% Inhibition) Vehicle 7.5 t 2 15.3 t 4.9 Com ound VI 10 Not active - Not active Compound VII 10 3.1 t 1.2 (58)*6.7 t 2.4 (56)*
Compound VIII 10 4.1 t 1.7 (37) 8.7 f 4.2 (43) Compound V 10 4.7 1.4 (37) 9.9 t 3.4 (36) *p < 0.05 Effect of Orall;v Dosed Test Compounds on Surgical Adhesions in Rat Ceacu~
Compound Dose Mean Number of Mean Adhesion mg/kg Adhesions/rat Severity/Rat (orally) S.D. (% Inhibition) S,D. (% Inhibition) Vehicle 8.9 t 3.2 17.7 t 6.2 Compound IV 10 2.9 0.7 (68)* 5.7 2.3 (68)*
Compound X 10 6.7 2.9 (24) 13.1 t 5.0 (26) Compound III 10 4.3 t 1.5 (52)* 8.7 3.6 (51)*
Compound XI 10 4.3 t 2.1 (52)* 8.6 t 4.0 (52)*
*p < 0.05 As demonstrated above, the retinoid derivatives of formula I are useful in the prevention of surgical adhesions.
Claims (3)
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 wherein Z is or in which Q, X and Y are each independently O, S or CH2;
A is -(CR2)n- wherein n is 1-3;
B and C are each independently O, S, CH2 or C(CH3)2; and R1 is hydrogen or (C1-C6) alkyl; or a pharmaceutically acceptable salt thereof.
A is -(CR2)n- wherein n is 1-3;
B and C are each independently O, S, CH2 or C(CH3)2; and R1 is hydrogen or (C1-C6) alkyl; or a pharmaceutically acceptable salt thereof.
2. 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 wherein Z is or in which Q, X and Y are each independently O, S or CH2;
A is -(CR2)n- wherein n is 1-3; and R1 is hydrogen or (C1-C6) alkyl; or a pharmaceutically acceptable salt thereof.
A is -(CR2)n- wherein n is 1-3; and R1 is hydrogen or (C1-C6) alkyl; or a pharmaceutically acceptable salt thereof.
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 surface for a period of time sufficient to permit tissue repair, said retinoid derivative being a compound of the formula or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5401797P | 1997-07-29 | 1997-07-29 | |
| US60/054,017 | 1997-07-29 | ||
| PCT/US1998/015625 WO1999006036A1 (en) | 1997-07-29 | 1998-07-28 | Use of selective rxr agonists to prevent surgical adhesions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2295807A1 true CA2295807A1 (en) | 1999-02-11 |
Family
ID=21988221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002295807A Abandoned CA2295807A1 (en) | 1997-07-29 | 1998-07-28 | Use of selective rxr agonists to prevent surgical adhesions |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1003493A4 (en) |
| JP (1) | JP2001511445A (en) |
| AU (1) | AU733236B2 (en) |
| CA (1) | CA2295807A1 (en) |
| WO (1) | WO1999006036A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6624154B1 (en) * | 1999-04-23 | 2003-09-23 | Bristol-Myers Squibb Company | Compositions and methods for treatment of hyperproliferative diseases |
| EP2286807A3 (en) * | 2005-09-09 | 2012-08-29 | Kemphys Ltd. | Medicament for preventive and/or therapeutic treatment of adhesion of bowel |
| JP5055971B2 (en) | 2006-11-16 | 2012-10-24 | 株式会社ニコン | Surface treatment method, surface treatment apparatus, exposure method, exposure apparatus, and device manufacturing method |
| JP2008179570A (en) * | 2007-01-25 | 2008-08-07 | R&R Inc | Medicine for preventing and/or treating internal organ adhesion |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2133587C (en) * | 1992-04-22 | 2008-11-18 | Marcus F. Boehm | Compounds having selectivity for retinoid x receptors |
| BR9307528A (en) * | 1992-11-25 | 1999-08-31 | Jolla Cancer Research Foudatio | Process for inspecting substance for ability to affect the formation of homodimer at retinoid x receptor, process for inspecting substance for ability to selectively induce heterodimer formation at retinoid receptor X, process for inspecting substance for the ability to affect the ability of a homodimer, in a retinoid receptor x, to bind to dna, process to inspect a response element for the ability to bind to a homodimer in retinoid receptor x, homodimer in retinoid receptor x , bicyclic aromatic compound, process to inhibit heterodimer activity at retinoid receptor x, process to promote transcription of a homodimer-activated gene at retinoid receptor in a cell, process to inhibit homodimer activity at retinoid receptor x, process to determine increased likelihood of pathology, process for treating pathology, process for active selectively formation of homodimer at retinoid receptor x in a cell, process to promote formation of homodimer at retinoid receptor x in a cell, pharmaceutical composition, process for modulating gene expression, and process for treating patient |
| US5455265A (en) * | 1993-02-11 | 1995-10-03 | Allergan, Inc. | Method of treatment with compounds having selective agonist-like activity on RXR retinoid receptors |
| US5399586A (en) * | 1993-03-11 | 1995-03-21 | Allergan, Inc. | Treatment of mammals afflicted with tumors with compounds having RXR retinoid receptor agonist activity |
| FR2722985B1 (en) * | 1994-07-27 | 1996-09-13 | Cird Galderma | NOVEL COMPOSITIONS BASED ON A SYNERGETIC MIXTURE BETWEEN AT LEAST ONE LIGAND SPECIFIC FOR RXRS AND AT LEAST ONE LIGAND SPECIFIC FOR RAR-X OR VDR, AND USES THEREOF |
| US5534261A (en) * | 1995-01-17 | 1996-07-09 | University Of Southern California | Retinoid-based compositions and method for preventing adhesion formation using the same |
-
1998
- 1998-07-28 CA CA002295807A patent/CA2295807A1/en not_active Abandoned
- 1998-07-28 JP JP2000504850A patent/JP2001511445A/en active Pending
- 1998-07-28 WO PCT/US1998/015625 patent/WO1999006036A1/en not_active Application Discontinuation
- 1998-07-28 AU AU86670/98A patent/AU733236B2/en not_active Ceased
- 1998-07-28 EP EP98938064A patent/EP1003493A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU733236B2 (en) | 2001-05-10 |
| JP2001511445A (en) | 2001-08-14 |
| EP1003493A1 (en) | 2000-05-31 |
| WO1999006036A1 (en) | 1999-02-11 |
| EP1003493A4 (en) | 2002-03-27 |
| AU8667098A (en) | 1999-02-22 |
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