Note: Descriptions are shown in the official language in which they were submitted.
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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
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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
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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
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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
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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.
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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:
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COMPOUND STRUCTURE
I
0 0
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
0 0
I~
~ COOH
VII
s s
~ COOH
VIII
0
w
I ~ CooH
IX o
CH31 ~ COOH
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_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, ~$, 3368-3383, where they are described as
selective RXR agonists. Compounds VI, VIII, X, and XI may be prepared
using the following scheme:
A A,
X~ ~Y X~ Y
HX-A~YH
~ R I ~ COOCH3 eCld I ~ R I ~ COOCH3 I R I / COOH
R=H,CH3 R=H,CH3 R=H,CHg
3
A diaryl ketone-ester, 1, is condensed with a diol, dithiol, or mixed
alcohol/thiol under acidic conditions to generate a cyclic ketal-ester, 2,
whose ester group is then hydrolyzed to yield the final compound, 3.
x 1: -2- tra t 7 -t tra al
2-~l)-(13ldioxolan-2-~,1-benzoic acid Compound VI
750 mg (2.1 mmol) keto-ester 1 (R = H, from MI Dawson et al; J Medicinal
Chemistry 1995, ~$, 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
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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-
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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
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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
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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.
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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%)
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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
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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.
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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:
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_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:
30
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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
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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.
