RETINOID ANTAGONISTS FOR PREVENTION OF SURGICAL ADHESIONS FIELD OF THE INVENTION The present invention is directed to methods for the minimization or prevention of post-surgical adhesion formation using retinoid antagonist compounds, particularly the retinoid antagonist compounds disclosed in published applications WO 97/09297, WO 97/48672, and U.S.

Patent No. 5,648,514.

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 promising drugs for the treatment of several cancers.

Published patent application WO 97/09297 discloses retinoid antagonist compounds of the general formula

wherein X is S, O or NR1 where R1 is H or alkyl of 1-6 carbons, or X is [C(R,)2)n where R, is independently H or alkyl of 1 to 6 carbons, and n is 0, 1 or 2; R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons or F; m is 0, 1, 2 or 3; o is 0, 1, 2 or 3; Z is -C#C-, <BR> <BR> <BR> <BR> <BR> <BR> -N#N-,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> -N#CR1-,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> -CR,=N, -(CR1=CR1)N ) where nl is O or an integer of 1-5, -CO-NR1-, -CS-NR,-, -NR,-CO, -NR,-CS, -COO-,

-OCO-, -CSO-, or -OCS-; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or when Z is -(CR1=CR1)n, and n' is 3, 4 or 5, then Y represents a direct valence bond between said (CR1=CR1)n group and B; A is (CH2)q where q is O or an integer of 1-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, or alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, -CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -C OR7, CR7(0R,2)2 CR70Rl30 or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group having 1-5 carbons, R8 is an alkyl group of 1 to 10 carbons, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to

10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R,2 is lower alkyl, and R,3 is a divalent alkyl radical of 2-5 carbons; and Rl4 is (R15)r-phenyl, (R<5)r-naphthyl or (R,5)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of 0, S and N, r is O or an integer of 1-5; and R,5 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8(CON(R8)2, OH, OCOR8, OR8, C N, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 2 to 10 carbons and 1 to 3 double bonds, alkynyl group having 2-10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons.

Also disclosed as retinoid antagonist compounds are compounds of the general formula wherein X is S, O or NR' where R' is H or alkyl of 1-6 carbons, or

X is [C(Rl)2]n, where Rl is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2; R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer having the value of O - 3; o is an integer having the value of O - 3; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyrid azinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR,2)2, CHORl30, -COR7, CR7 (OR12)2, CR70Rl30, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rlo in dependently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R" is lower alkyl, phenyl or lower alkylphenyl, R,2 is lower alkyl, and R,3 is divalent alkyl radical of 2-5 carbons, and R,4 is (R,5)r-phenyl, (R,5)r-naphthyl, or (R,5)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of 0, S and N, r is an integer having the values of 0-5, and R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, C N, an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a trialkylsilyl or trialkylsilyloxy group where the alkyl groups independently have 1 to 6 carbons;

R,6 is H, lower alkyl of 1 to 6 carbons; R,7 is H, lower alkyl of 1 to 6 carbons, OH or OCOR11, and p is zero or 1, with the proviso that when p is 1 then there is no R,7 substituent group, and m is an integer between 0 and 2.

Published patent application WO 97/48672 discloses retinoid antagonists of the formula wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 to 2; Z is -N=N-, -N(O=N-, -N=N(O)-, -N=CR1-, -CR1=N, -(CR1=CR1)n'- where n' is an integer having the value 0-5,

-CO-NR,-. <BR> <BR> <BR> <BR> <BR> <BR> <P> -CS-NR,-.

-NR,-CO, -NR,-CS-, -COO-, -OCO-, -CSO-, -OCS-, -CO-CR,= CR,-; R2 is hydrogen, lower alkyl or 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3is hydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer having the value of 0-3; o is an integer having the value of 0-3; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or

when Z is -(CR1=CR1)n'- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR2=CR2) group and B; A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, -CH2OR11, -CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(0R2)2, CR70Rl30, or Si(C,6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rlo independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, Rl1 is lower alkyl, phenyl or lower alkylphenyl, R,2 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; X2 is 0, S, SO or SO2, and R20 is Si(C, 6alkyl)3, Rl4, COR14, SO2R21, where R<4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond,

alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10-alkyl, naphthyl- C,-C,O-alkyl, or R20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons, and R2, is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl and phenyl-C1-C10-alkyl, and retinoids of the formula wherein X, is [C(R,)2]n where R, is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2; Z is -N=N-, -N(O)=N-, -N=N(O)-, -N=CR1-, -CR,=N, -(CR1=CR1)n'- where n' is an integer having the value 0-5, <BR> <BR> <BR> <BR> <BR> -CO-NR,-. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> -CS-NR,-.

-NR,-CO, -NR,-CS-,

-COO-, -OCO-, -CSO-, -OCS-, -CO-CR,= CR,-; R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is hydrogen, lower alkyl of 1 to 6 carbons or F; m is an integer having the value of 0-3; o is an integer having the value of 0-3; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or when Z is -(CR,=CR,)n- and n' is 3, 4 or 5 then Y represents a direct valence bond between said (CR2=CR2) n' group and B;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR8, CONR9R10, -CH2OH, -CH2OR11, -CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, C R7(0 R12)2, CR70R130, or Si(C1-6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rlo independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R,2 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and R14 is (R15)r-substituted alkyl of 1-6 carbons, (R15)r-substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R15)r-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R,5)r-phenyl, (R,5)r-naphthyl, or (R,5)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of 0, S and N, r is an integer having the values of 0-5, and R15 is independently H, F, Cl, Br, I, NO2, N(R6)2, N(R8)COR8,

NR8CON(R8)2, OH, OCOR8, OR8, CN, COOH, COOR8 an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons.

U.S. Patent 5,648,514 discloses retinoid antagonists of the formula R1 R1 (R2)m (R3)o-#-Y(R2)-A-B R22 III wherein R1 is hydrogen or alkyl of 1 to 10 carbons; R2and R3are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0-3; o is an integer having the value 0-3;

Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R2 groups; A is (CH2)n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, -CH2OR11, -CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(0Rl2)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and Rlo independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R" is lower alkyl, phenyl or lower alkylphenyl, R,2 is lower alkyl, and R,3 is divalent alkyl radical of 2-5 carbons and R22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl

selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl, C1-C10 alkyl, naphthyl-C1-C10 alkyl, C1-C10-alkenylphenyl having 1 to 3 double bonds, Cl-ClO-alkynylphenyl having 1 to 3 triple bonds, phenyl-Cl-ClOalkenyl having 1 to 3 double bonds, phenyl-C,-C,0alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds, where the acyl group is represented by COR,4, CN, CON(Rl)2, (CH2)pCO2R8 where p is an integer between 0 to 10, or R22 is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a C, to C10 alkyl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of 0, S, and N, or R22 is represented by (CH2)pXR, or by (CH2)pNR,R2; where X is O or S, the R,4 group is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C,-C,O alkyl, or naphthyl-C -C10al alkyl.

The above-mentioned retinoid antagonist compounds are said to be useful for preventing certain undesired side effects of retinoids which are administered for the treatment or prevention of certain diseases or conditions. They are also said to be useful in the treatment of acute or chronic toxicity resulting from overdose or poisoning by retinoid drugs or Vitamin A.

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 illustration or suggestion, however, that a retinoid antagonist compound would have this same utility.

The present inventors have surprisingly found that the retinoid antagonist compounds of formulae I-V have utility in preventing or minimizing post-surgical adhesion formation and, in fact, are significantly more active for this use than the retinoid agonists described in U.S. Patent 5,534,261.

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 antagonist for a period of time sufficient to permit tissue repair.

In a preferred embodiment the retinoid antagonist used in the above method is a compound having formulae I-V as described above.

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, it appears that the inventors intended this term to refer to retinoid agonists, as the specific embodiments and preferred compounds are all of this class. No mention

is made of retinoid antagonists or whether such antagonists would have this desirable property.

The present inventors have unexpectedly found that retinoid antagonists possess utility to prevent or minimize adhesion formation and, in fact, appear to be significantly more effective for this use than retinoid agonists. Moreover, the retinoid antagonists are less toxic than retinoid agonists in that, unlike the agonists, they do not appear to induce hypervitaminois A, a syndrome which can result in death.

Thus, in one aspect, 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 antagonist for a period of time sufficient to permit tissue repair.

The preferred retinoid antagonists for use in the method of the present invention are those described above as compounds of the general formulae I-V.

As used herein and in the claims, the term "alkyl" refers to and covers any and all groups which are known as normal alkyl, branched chain alkyl and cycloalkyl. The term "alkenyl" refers to and covers normal alkenyl, branched chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation. Similarly, the term "alkynyl" refers to

and covers normal alkynyl branched alkynyl groups having one or more triple bonds.

Lower alkyl unless otherwise indicated means the above-defined broad definition of alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups. Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.

The term "ester" as used here refers to and covers any compound failing within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B in formulae I-V above is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons. Where the ester is derived from compounds where B is -CH2OH, this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH2OCOR11 where Rll is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.

Unless stated otherwise in this application, preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms. Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols. Also preferred are the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono and di-substituted amides. Unless stated otherwise in this application, preferred amides are the mono- and di- substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the substituted and unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula -CK where K is (-OR)2. Here, R is lower alkyl. Also, K may be -OR7O- where R7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect an the subject to which it is administered and in the context in which R is administered.

Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide.

Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.

Some of the compounds of the present invention may have trans and cis (E and Z) isomers. In addition, the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present

invention is intended to cover all such isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. In the present application when no specific mention is made of the configuration (cis, trans or R or S) of a compound (or of an asymmetric carbon) then a mixture of such isomers, or either one of the isomers is intended.

With reference to the symbol Y in formulae I-V, the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl, and still more preferred where Y is phenyl. As far as substitutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para) substituted by the Z and A-B groups, and where the pyridine ring is 2,5 substituted by the Z and A- B groups. (Substitution in the 2,5 positions in the "pyridine" nomenclature corresponds to substitution in the 6-position in the "nicotinic acid" nomenclature.) In the preferred compounds of the invention either there is no optional R2 substituent on the Y group, or the optional R2 substituent is fluoro (F).

The A-B group of the preferred compounds is (CH2)n-COOH or (CH2)n-COOR8, where n and R8 are defined as above. Even more preferably n is zero and R8 is lower alkyl, or n is zero and B is COOH or a pharmaceutically acceptable salt thereof.

In the majority of the presently preferred examples of compounds of the invention X is [C(Rl)2]n, where n is 1. Nevertheless, compounds where n is zero (indene derivatives) and where X is S or O (benzothiopyran and benzopyran derivatives) are also preferred. When X is [C(Rl)2]n and n is 1, then Rl preferably is alkyl of 1 to 6 carbons, even more preferably methyl.

The R2 group attached to the aromatic portion of the tetrahydronaphthalene, benzopyran, benzothiopyran or dihydroquinoline moiety is preferably H, F or CF3-. R3 is preferably hydrogen or methyl, even more preferably hydrogen.

Referring now to the group Z in certain of the compounds of the invention, in a plurality of preferred examples Z represents an acetylenic linkage (Z = -C-C-). However, the 'linker group' Z is also preferred as a diazo group (Z = -N=N-), as an olefinic or polyolefinic group (Z = -(CRl= CRl)n,-), as an ester (Z = -COO-), amide (Z = -CO-NR2-) or thioamide (Z = -CS-NR2-) linkage.

Referring now to the Rl4 group, compounds are preferred where R14 is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl, and 2-thiazolyl. The R15 group (substituent of the Rl4 group) is preferably H, lower alkyl, trifluoromethyl, chlorine, lower alkoxy or hydroxy.

The presently most preferred compounds of the invention are shown in Table 1 with reference to Formula 2, Formula 3, Formula 4, Formula 5, and Formula 5a.

Formula 2 Formula 3 Formula 4 Formula 5 Formula 5a

TABLE I<BR> Compound &num Formula R19 Z R2 R8<BR> 1 2 4-methylphenyl -C#C- H Et<BR> 1a 2 phenyl -C#C- H Et<BR> 2 2 3-methylphenyl -C#C- H Et<BR> 3 2 2-methylphenyl -C#C- H Et<BR> 4 2 3,5-dimethylphenyl -C#C- H Et<BR> 5 2 4-ethylphenyl -C#C- H Et<BR> 6 2 4-t-butylphenyl -C#C- H Et<BR> 7 2 4-chlorophenyl -C#C- H Et<BR> 8 2 4-methoxyphenyl -C#C- H Et<BR> 9 2 4-trifluoromethylphenyl -C#C- H Et<BR> 10 2 2-pyridyl -C#C- H Et<BR> 11 2 3-pyridyl -C#C- H Et<BR> 12 2 2-methyl-5-pyridyl -C#C- H Et<BR> 13 2 3-hydroxyphenyl -C#C- H Et<BR> 14 2 4-hydroxy phenyl -C#C- H Et<BR> 15 2 5-methyl-2-thiazolyl -C#C- H Et<BR> 15a 2 2-thiazolyl -C#C- H Et<BR> 16 2 4-methyl-2-thiazolyl -C#C- H Et

TABLE I<BR> Compound &num Formula R14 Z R2 R8<BR> 17 2 4,5-dimethyl-2-thiazolyl -C#C- H Et<BR> 18 2 2-methyl-5-pyridyl -C#C- H H<BR> 19 2 2-pyridyl -C#C- H H<BR> 20 2 3-methylphenyl -C#C- H H<BR> 21 2 4-ethylphenyl -C#C- H H<BR> 22 2 4-methoxyphenyl -C#C- H H<BR> 23 2 4-trifluoromethylphenyl -C#C- H H<BR> 24 2 3,5-dimethylphenyl -C#C- H H<BR> 25 2 4-chlorophenyl -C#C- H H<BR> 26 2 3-pyridyl -C#C- H H<BR> 27 2 2-methylphenyl -C#C- H H<BR> 28 2 3-hydroxyphenyl -C#C- H H<BR> 29 2 4-hydroxyphenyl -C#C- H H<BR> 30 2 5-methyl-2-thiazolyl -C#C- H H<BR> 30a 2 2-thiazolyl -C#C- H H<BR> 31 2 4-methyl-2-thiazolyl -C#C- H H<BR> 32 2 4,5-dimethyl-2-thiazoyl -C#C- H H<BR> 33 2 5-methyl-2-thienyl -C#C- H Et

TABLE I<BR> Compound &num Formula 14 Z R2 R8<BR> 33a 2 2-thienyl -C#C- H Et<BR> 34 2 5-methyl-2-thienyl -C#C- H H<BR> 34a 2 2-thienyl -C#C- H H<BR> 35 2 4-methylphenyl -CONH- H Et<BR> 36 2 4-methylphenyl -CONH- H H<BR> 37 2 4-methylphenyl -COO- H Et<BR> 38 2 4-methylphenyl -COO- H (CH2)2Si(CH3)<BR> 39 2 4-methylphenyl -COO- H H<BR> 40 2 4-methylphenyl -CONH- F Et<BR> 41 2 4-methylphenyl -CONH F H<BR> 42 2 4-methylphenyl -CSNH- H Et<BR> 43 2 4-methylphenyl -CSNH- H H<BR> 44 2 4-methylphenyl -CSNH- H Et<BR> 45 2 4-methylphenyl -CH-CH- H Et<BR> 46a 2 4-methylphenyl -N-N- H Et<BR> 46b 2 4-methylphenyl -N-N- H H<BR> 47 3 4-methylphenyl -C#C- H Et<BR> 48 3 4-methylphenyl -C#C- H H<BR> 49 4 4-methylphenyl -C#C- H Et<BR> 50 4 4-methylphenyl -C#C- H H 5 TABLE I<BR> Compound &num Formula R14 Z R2 r8<BR> 51 5 4-methylphenyl - - Et<BR> 52 5 4-methylphenyl - - H<BR> 60 2 4-methylphenyl -C#C- H H<BR> 60a 2 phenyl -C#C- H H<BR> 61 2 4-t-butylphenyl -C#C- H H<BR> 62 2 4-methylphenyl -CSNH F Et<BR> 63 2 4-methylphenyl -CSNH F H<BR> 64 5a 4-methylphenyl - - Et<BR> 65 5a 4-methylphenyl - - H<BR> 66 2 2-furyl -C#C- H Et<BR> 67 2 2-furyl -C#C- H H

With reference to the symbol Y in Formula II, the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl, and still more preferred where Y is phenyl. As far as substitutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para) substituted by the -CRl6-CRl7- and A-B groups, and where the pyridine ring is 2,5 substituted by the -CRl6-CRl7- and A-B groups. (Substitution in the 2,5 positions in the "pyridine" nomenclature corresponds to substitution in the 6- position in the "nicotinic acid" nomenclature.) In the preferred compounds of the invention there is no optional R2 substituent on the Y group.

The A-B group of the preferred compounds is (CH2)n-COOH or (CH2)n-COOR8, where n and R8 are defined as above. Even more preferably n is zero and R8 is lower alkyl, or n is zero and B is COOH or a pharmaceutically acceptable salt thereof.

In the presently preferred examples of compounds of the invention X is [C(Rl)2]n, where n is 1. Nevertheless, compounds where X is S or O (benzothiopyran and benzopyran derivatives) are also preferred. When X is [C(Rl)2]n and n is 1, then Rl, preferably is alkyl of 1 to 6 carbons, even more preferably methyl.

The R2 group attached to the aromatic portion of the tetrahydronaphthalene, benzopyran, benzothiopyran or dihydroquinoline

moiety of the compounds of Formula II is preferably H, F or CF3. R3 is preferably hydrogen or methyl, even more preferably hydrogen.

Referring now to the Rl4 group, compounds are preferred where Rl4 is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl and 2-thiazolyl. The Rl5 group (substituent of the Rl4 group) is preferably H, lower alkyl, trifluoromethyl, chlorine, lower alkoxy or hydroxy.

Preferred compounds of the invention are shown in Table 2 with reference to Formula 6.

Formula 6

TABLE 2 Compound R15 Re 101 CH3 H 102 CH3 Et 103 H H 104 H Et The retinoid antagonists useful in the process of the present invention may be prepared by the procedures described in WO 97/099297 (see, in particular, pages 30-96), U.S. Patent 5,648,518 and WO 97/48672.

Biological Activity Prevention of Surgical Adhesions 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. A representative retinoid antagonist compound of the present invention,

[referred to below as compound A] was used with this model to demonstrate efficacy.

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 intra-abdominally by direct instillation into the peritoneal cavity. 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: 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.

A single dose of the test compound in 3 ml volume was instilled over the traumatized caecum and abdominal cavity prior to closing the incision. Seven days later the animals were sacrificed and the abdominal cavity was examined for adhesions to the caecum. Compared to the vehicle control, a single intra-abdominal application of compound A at 5 mg significantly reduced the number of adhesions formed. At this dose

compound A also effectively reduced the severity of caecal adhesions as illustrated by the results in the following table.

Table (Effect of Retinoid Antagonist Test Compound Following a Single Intra- Abdominal Treatment in the Trauma-Induced Caecal Adhesion in Rats) Treatment Dose Mean # of Mean Adhesion Adhesions Severity Grade (mg/kg) per Rat per Rat +/- SEM +/- SEM Vehicle Control 8.0+/-1.9 18.8+/-1.9 Compound A 0.3 6.5+/-0.6 20.3+/-1.3 Compound A 1.0 7.5 +/- 0.3 20 +/- 1.1* Compound A 3.0 4.40 +/-1.1* 9.6 +/- 2.4* *p = 0.01 As shown above the compounds of the present invention are useful in the prevention of post-surgical adhesions.

For prevention of surgical adhesions, the retinoid antagonist 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 each compound and the intended

route but is expected to be from 0.1 mg/kg to 100 mg/kg with a preferred range of 1 to 25 mg/kg. Preferred methods of administration are oral administration or direct administration (intracavity instillation) to a site of surgical activity on an organ surface.

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 antagonist 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 antagonist may be 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 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.