EP1005340A1 - Retinoid antagonists for prevention of surgical adhesions - Google Patents

Retinoid antagonists for prevention of surgical adhesions

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Publication number
EP1005340A1
EP1005340A1 EP98918060A EP98918060A EP1005340A1 EP 1005340 A1 EP1005340 A1 EP 1005340A1 EP 98918060 A EP98918060 A EP 98918060A EP 98918060 A EP98918060 A EP 98918060A EP 1005340 A1 EP1005340 A1 EP 1005340A1
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EP
European Patent Office
Prior art keywords
carbons
alkyl
group
phenyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98918060A
Other languages
German (de)
French (fr)
Other versions
EP1005340A4 (en
Inventor
Kenneth M. Tramposch
Xina Nair
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of EP1005340A1 publication Critical patent/EP1005340A1/en
Publication of EP1005340A4 publication Critical patent/EP1005340A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • 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.
  • X is S, O or NR 1 where R 1 is H or alkyl of 1-6 carbons, or X is
  • R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
  • R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
  • n 0, 1, 2 or 3;
  • o 0, 1, 2 or 3;
  • n 1 is O or an integer of 1-5
  • Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,
  • A is (CH 2 ) q where q is 0 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, COOR 8 , CONR 9 R 10 , -CH 2 OH, -CH 2 OR n , CH 2 OCOR u , CHO, CH(OR 12 ) 2 , CHOR 13 0,
  • R 8 is phenyl or lower
  • alkylphenyl Rg and R 10 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 12 is lower alkyl, and R 13 is a divalent alkyl radical of 2-5 carbons; and
  • R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl or (R 15 ) r -heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is 0 or an integer of 1-5; and R 15 is independently H, F, Cl, Br, I, N0 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 (CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, 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.
  • retinoid antagonist compounds are compounds of the general formula
  • X is S, O or NR 1 where R 1 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 an integer between 0 and 2;
  • R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro
  • substituted alkyl of 1 to 6 carbons OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
  • R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
  • n 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,
  • A is (CH 2 ) q where q is 0-5, lower branched chain alkyl having 3-6
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof
  • R 14 is (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) 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
  • R 15 is independently H, F, Cl, Br, I, N0 2 , N(R 8 ) 2 , N(R 8 )COR 8 ,
  • alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a
  • R 16 independently have 1 to 6 carbons;
  • R 16 is H, lower alkyl of 1 to 6 carbons;
  • R 17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR u , and
  • p is zero or 1, with the proviso that when p is 1 then there is no R 17 substituent group, and m is an integer between 0 and 2.
  • X ⁇ is [C(R 1 ) 2 ] n where R 2 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 to 2;
  • -CR 1 N, -(CR ⁇ CR j - where n' is an integer having the value 0-5, -CO-NR,-.
  • R 2 is hydrogen, lower alkyl or 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
  • R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
  • n 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
  • pyridyl consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,
  • A is (CH 2 ) 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, COOR 8 , CONRgR 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR n , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or Si(C 1.6 alkyl) 3 , where
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 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 R 8 is phenyl or lower alkylphenyl
  • Rg and R 10 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 n is lower alkyl, phenyl or lower
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • X 2 is O, S, SO or S0 2 , and
  • R 20 is Si(C 1 _ 6 alkyl) 3 , R 14 , COR 14 , S0 2 R 21 , where R 14 is hydrogen, alkyl of 1 to
  • R 20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons
  • R 21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, - o-alkylphenyl and phenyl-C j -C ⁇ -alkyl, and retinoids of the formula
  • X ⁇ is [C(R 1 ) 2 ] n where R ⁇ is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
  • n' is an integer having the value 0-5
  • R 2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3 , fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
  • R 3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
  • n 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
  • A is (CH 2 ) 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, COOR 8 , CONRgR 10 , -CH 2 OH, -CH 2 OR n , -CH 2 OCOR n , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or Si(C 1.6 alkyl) 3 , where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 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 R 8 is phenyl or lower alkylphenyl, R g and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower al
  • R 14 is (R 15 ) r -substituted alkyl of 1-6 carbons, (R 15 ) r -substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R 15 ) r -substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R 15 ) r -phenyl, (R 15 ) r -naphthyl, or (R 15 ) r -heteroaryl
  • heteroaryl group has 1 to 3 heteroatoms selected from the
  • R 15 is independently H, F, Cl, Br, I, N0 2 , N(R 8 ) 2 , N(R 8 )COR 8 , NR 8 CON(R 8 ) 2 , OH, OCOR 8 , OR 8 , CN, COOH, COOR 8 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.
  • R j is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are 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;
  • n 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 R 2 groups;
  • A is (CH 2 ) 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, COOR 8 , CONRgR 10 , -CH 2 OH, -CH 2 OR ⁇ , -CH 2 OCOR ⁇ , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R g 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 R 8 is phenyl or lower alkylphenyl, Rg and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons and
  • R 22 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10
  • alkenyl of 2 to 10 carbons and having 1 to 3 double bonds alkynyl
  • carbocyclic aryl selected from the group consisting of phenyl, C j -C ⁇ -alkylphenyl, naphthyl, C ⁇ -C 10 -alkylnaphthyl, phenyl, - Q alkyl, naphthyl- - o alkyl, C j -C jQ -alkenylphenyl having 1 to 3 double bonds, C : -C 10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C j -C ⁇ alkenyl having 1 to 3 double bonds, phenyl-C C 10 alkynyl 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
  • phenyl - g-alkylphenyl, naphthyl, - o-alkylnaphthyl, phenyl- - o alkyl, or naphthyl- - g alkyl.
  • 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.
  • the present invention provides a method for the minimization or
  • the retinoid antagonist used in the above method is a compound having formulae I-V as described above.
  • Adhesion formation 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.
  • adhesions are associated with chronic or recurrent pelvic pain and infertility in females.
  • retinoids for prevention of adhesion formation
  • 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.
  • 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.
  • 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.
  • alkyl refers to and
  • alkenyl refers to and covers
  • 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
  • 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.
  • esters 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.
  • 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.
  • ester is derived from compounds where B is -CH 2 OH, this term covers compounds derived from organic acids
  • esters including phosphorous based and sulfur based
  • aliphatic aromatic group preferably with 1-6 carbons in the aliphatic
  • 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
  • R is lower alkyl.
  • K may be -OR 7 0- where R 7 is lower
  • 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.
  • salts may be derived from organic or inorganic bases.
  • the salt may be a mono or polyvalent ion.
  • the inorganic ions sodium, potassium, calcium, and
  • 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
  • Some of the compounds of the present invention may have trans
  • inventions may contain one or more chiral centers and therefore may exist
  • 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
  • the A-B group of the preferred compounds is (CH 2 ) n -COOH or
  • n is zero and R 8 is lower alkyl, or n is zero and B is COOH or a
  • n is zero (indene derivatives) and where X is S or O
  • R x preferably is alkyl of 1 to 6 carbons, even more preferably methyl.
  • R 2 group attached to the aromatic portion of the tetrahydronaphthalene, benzopyran, benzothiopyran or dihydroquinoline moiety is preferably H, F or CF 3 -.
  • R 3 is preferably hydrogen or methyl, even more preferably hydrogen.
  • Z in certain of the compounds of the invention, in a plurality of preferred examples Z represents an acetylenic
  • Tinker group' Z is also preferred as a
  • R 15 group is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl, and 2-thiazolyl.
  • R 14 group (substituent of the R 14 group) is preferably H, lower alkyl, trifluoromethyl, chlorine, lower alkoxy or hydroxy.
  • R 14 group is preferably H, lower alkyl, trifluoromethyl, chlorine, lower alkoxy or hydroxy.
  • Table 1 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.
  • 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
  • the A-B group of the preferred compounds is (CH 2 ) n -COOH or (CH 2 ) n -COOR 8 , where n and R 8 are defined as above. Even more preferably n is zero and R 8 is lower alkyl, or n is zero and B is COOH or a pharmaceutically acceptable salt thereof.
  • X is [C(R a ) 2 ] n , where n is 1. Nevertheless, compounds where X is S or O
  • R lr preferably is alkyl of 1 to 6 carbons, even
  • tetrahydronaphthalene, benzopyran, benzothiopyran or dihydroquinoline moiety of the compounds of Formula II is preferably H, F or CF 3 .
  • R 3 is preferably hydrogen or methyl, even more preferably hydrogen.
  • R 14 is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl and 2-thiazolyl.
  • the R 15 group (substituent of the R 14 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.
  • 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.
  • adhesion barrier devices One such model is the trauma-induced caecal
  • Intra-abdominal treatments were applied once post-trauma and just prior to wound closure.
  • the compounds of the present invention are useful in the prevention of post-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.
  • 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.
  • the retinoid antagonist may be
  • the retinoid can be administered in a suitable vehicle such as 5% dextrose in water adjusted to a pH to assure complete salt formation.
  • a suitable vehicle such as 5% dextrose in water adjusted to a pH to assure complete salt formation.
  • microcapsules in the art including microcapsules, microspheres, liposomes, viscous
  • instilates and polymeric delivery materials.

Abstract

Certain retinoid antagonists have been found to be useful in the prevention or minimization of surgical adhesion formation.

Description

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(Ra)2)n where R,^ is independently H or alkyl of 1 to 6 carbons, and n is O, l 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-,
-N=N-,
-N=CR ,
-CRα=N,
-(CR^CR n- where n1 is O or an integer of 1-5,
-CO-NR ,
-CS-NR ,
-NRrCO,
-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 -(CR^CRj)^ and n' is 3, 4 or 5, then Y represents a direct valence
bond between said (CR^CR ^ group and B;
A is (CH2)q where q is 0 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, -CH2ORn, CH2OCORu, CHO, CH(OR12)2, CHOR130,
-COR7, CR7(OR12)2, CR7OR130, 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 1.0
carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower
alkylphenyl, Rg 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, Rια is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is a divalent alkyl radical of 2-5 carbons; and
R14 is (R15)r-phenyl, (R15)r-naphthyl or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is 0 or an integer of 1-5; and R15 is independently H, F, Cl, Br, I, N02, N(R8)2, N(R8)COR8, NR8(CON(R8)2, OH, OCOR8, OR8, CN, 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 NR1 where R1 is H or alkyl of 1-6 carbons, or_ X is [C(R,)2]n, where Rα 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 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;
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, CONRgRjo, -CH2OH, CH2ORπ, CH2OCORαι, CHO, CH(OR12)2, CHOR130, -COR7, CR7 (OR12)2, CR7OR130, 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, Rg 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, Rn is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R14 is (R15)r-phenyl, (R15)r-naphthyl, or (R15)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, N02, N(R8)2, N(R8)COR8,
NR8CON(R8)2, OH, OCOR8, OR8, CN, 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; R16 is H, lower alkyl of 1 to 6 carbons;
R17 is H, lower alkyl of 1 to 6 carbons, OH or OCORu, and
p is zero or 1, with the proviso that when p is 1 then there is no R17 substituent group, and m is an integer between 0 and 2.
Published patent application WfO 97/48672 discloses retinoid antagonists of the formula
I
wherein Xλ is [C(R1)2]n where R2 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 to 2;
Z is -N=N-,
-N(0)=N-,
-N=N(0)-,
-N=CR ,
-CR1=N, -(CR^CR j - where n' is an integer having the value 0-5, -CO-NR,-.
-CS-NR . -NRΓCO,
-NR CS-,
-COO-, -OCO-,
-CSO-, -OCS-, -CO-CRα= 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;
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^ - 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, CONRgR10, -CH2OH, -CH2ORαι, -CH2OCORn, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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, Rg 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, Rn is lower alkyl, phenyl or lower
alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X2 is O, S, SO or S02, and
R20 is Si(C1_6alkyl)3, R14, COR14, S02R21, where R14 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, -CjQ-alkylphenyl, naphthyl, - g-alkylnaphthyl, phenyl-Cj-C^-alkyl, naphthyl- - o-alkyl, or R20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons, and R21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, - o-alkylphenyl and phenyl-Cj-C^-alkyl, and retinoids of the formula
V
wherein Xλ is [C(R1)2]n where Rα is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
Z is -N=N-,
-N(0)=N-,
-N=N(0)-,
-N=CRr,
-CR1=N,
where n' is an integer having the value 0-5,
-CO-NRr.
-CS-NR .
-NR CO,
-NRΓCS-, -COO-,
-OCO-, -CSO-, -OCS-,
-CO-CRα= CRα-;
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 -(CR1=CR1)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) 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, CONRgR10, -CH2OH, -CH2ORn, -CH2OCORn, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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, Rg 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, Rπ is lower alkyl, phenyl or lower alkylphenyl, R12 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, (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl
where the heteroaryl group has 1 to 3 heteroatoms selected from the
group consisting of O, S and N, r is an integer having the values of 0-5, and
R15 is independently H, F, Cl, Br, I, N02, N(R8)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
wherein
Rj is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are 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, CONRgR10, -CH2OH, -CH2ORπ, -CH2OCORπ, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, or tri-lower alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, Rg 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, Rg 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, Rπ is lower alkyl, phenyl or lower alkylphenyl, R12 is lower
alkyl, and R13 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, Cj-C^-alkylphenyl, naphthyl, Cα-C10-alkylnaphthyl, phenyl, - Q alkyl, naphthyl- - o alkyl, Cj-CjQ-alkenylphenyl having 1 to 3 double bonds, C:-C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-Cj-C^alkenyl having 1 to 3 double bonds, phenyl-C C10alkynyl 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 COR14, CN, CON(Rα)2, (CH2)pC02R8 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 to C10 alkyl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R^ is represented by (CH2)pXRj or by (CH2)pNR1R2; where X is O or S, the R14 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, - g-alkylphenyl, naphthyl, - o-alkylnaphthyl, phenyl- - o alkyl, or naphthyl- - g 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 -CH2OCORn where Rπ 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 -OR70- 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(R 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(Rα)2]n and n is 1, then Rx 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 Tinker group' Z is also preferred as a
diazo group (Z = -N=N-), as an olefinic or polyolefinic group
(Z = -(CR1= CR,)n,-), as an ester (Z = -COO-), amide (Z = -CO-NR2-) or thioamide (Z = -CS-NR2-) linkage.
Referring now to the R14 group, compounds are preferred where R14
is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl, and 2-thiazolyl. The R15 group
(substituent of the R14 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 5a cπ
TABLE I
Compound # Formula Rl4 Z R B.β
1 2 4-methylphenyl -C≡C H Et la 2 phenyl -C≡C H Et
2 2 3-methylphenyl -C≡C H Et
3 2 2-methylphenyl -C≡C H Et
4 2 3,5-dimethylphenyl -C≡C H Et
5 2 4-ethylphenyl -C≡C H Et
6 2 4-t-butylphenyl -C≡C H Et
7 2 4-chlorophenyl -C≡C- H Et
8 2 4-methoxyphenyl -C≡C H Et
9 2 4-trifluoromethylphenyl -C≡C- H Et
10 2 2-pyridyl -C≡C- H Et
11 2 3-pyridyl -C≡C- H Et
12 2 2-methyl-5-pyridyl -C≡C- H Et
13 2 3-hydroxyphenyl -C≡C- H Et
14 2 4-hydroxy phenyl -C≡C- H Et
15 2 5-methyl-2-thiazolyl -C≡C- H Et
15a 2 2-thiazolyl -C≡C- H Et
16 2 4-methyl-2-thiazolyl -C≡C- H Et
Or
TABLE I
Compound # Formula Kl4 Z R2 Kβ
17 2 4,5-dimethyl-2-thiazolyl -C≡C H Et
18 2 2-methyl-5-pyridyl -C≡C H H
19 2 2-pyridyl -C≡C H H
20 2 3-methylphenyl -C≡C H H
21 2 4-ethylphenyl -C≡C H H
22 2 4-methoxyphenyl -C≡C H H
23 2 4-trifluoromethylphenyl -C≡C H H
24 2 3,5-dimethylphenyl -C≡C- H H
25 2 4-chlorophenyl -C≡C- H H
26 2 3-pyridyl -C≡C- H H
27 2 2-methylphenyl -C≡C- H H
28 2 3-hydroxyphenyl -C≡C- H H
29 2 4-hydroxyphenyl -C≡C- H H
30 2 5-methyl-2-thiazolyl -C≡C- H H
30a 2 2-thiazolyl -C≡C- H H
31 2 4-methyl-2-thiazolyl -C≡C- H H
32 2 4,5-dimethyl-2-thiazolyl -C≡C- H H
33 2 5-methyl-2-thienyl -C≡C- H Et
ϋi
TABLE I
Compound # Formula Rl4 Z 2 Ks
33a 2 2-thienyl -C≡C- H Et
34 2 5-methyl-2-thienyl -C≡C- H H
34a 2 2-thienyl -C≡C- H H
35 2 4-methylphenyl -CONH- H Et
36 2 4-methylphenyl -CONH- H H
37 2 4-methylphenyl -COO- H Et
38 2 4-methylphenyl -COO- H (CH2)2Si(CH3)
39 2 4-methylphenyl -COO- H H
40 2 4-methylphenyl -CONH- F Et
41 2 4-methylphenyl -CONH F H
42 2 4-methylphenyl -CSNH- H Et
43 2 4-methylphenyl -CSNH- H H
44 2 4-methylphenyl -CH-CH- H Et
45 2 4-methylphenyl -CH-CH- H H
46a 2 4-methylphenyl -N-N- H Et
46b 2 4-methylphenyl -N-N- H H
47 3 4-methylphenyl -C≡C- H Et
48 3 4-methylphenyl -C≡C- H H
49 4 4-methylphenyl -C≡C- H Et
50 4 4-methylphenyl -C≡C- H H
cπ
TABLE I
Compound # Formula R-14 K2 Rs
51 5 4-methylphenyl - Et
52 5 4-methylphenyl - H
60 2 4-methylphenyl -C≡C- H H
60a 2 phenyl -C≡C- H H
61 2 4-t-butylphenyl -C≡C- H H 62 2 4-methylphenyl -CSNH F Et 63 2 4-methylphenyl -CSNH F H 64 5a 4-methylphenyl - Et
65 5a 4-methylphenyl - H
66 2 2-furyl -C≡C- H Et
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
-CR16-CR17- and A-B groups, and where the pyridine ring is 2,5 substituted by the -CR16-CR17- 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(Ra)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(Rj)2]n and n is 1, then Rlr 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 R14 group, compounds are preferred where R14 is phenyl, 2-pyridyl, 3-pyridyl, 2- thienyl and 2-thiazolyl. The R15 group (substituent of the R14 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.
TABLE 2
Compound Bos R*
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)
*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.

Claims

We claim: 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 acid antagonist for a
period of time sufficient to permit tissue repair, said retinoid acid antagonist having the formula
wherein X is S, O or NR1 where R1 is H or alkyl of 1-6 carbons, or X is [C(R2)2)n where Rr is independently H or alkyl of 1 to 6 carbons, and n is O, 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 -CΓëíC-,
-N=N-,
-N=CRr,
-CR^N,
where n' is O or an integer of 1-5,
-CO-NR , -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 -(CR^CRj)^ and n is 3, 4 or 5, then Y represents a direct valence
bond between said (CR^CR^, group and B; A is (CH2) where q is 0 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, -CH2ORn, CH2OCOR , CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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, Rg 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, R╬▒╬╣ is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is a divalent alkyl radical of 2-5 carbons; and
R14 is (R15)r-phenyl, (R15)r-naphthyl or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group
consisting of O, S and N, r is 0 or an integer of 1-5; and R15 is
independently H, F, Cl, Br, I, N02, N(R8)2, N(R8)COR8, NR8(CON(R8)2, OH,
OCORg, ORg, CN, 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.
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 acid antagonist for a period of time sufficient to permit tissue repair, said retinoid acid antagonist having the 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 Rx 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, 1, 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;
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, CONRgR10, -CH2OH, CH2ORu, CH20CORn, CHO, CH(OR12)2, CHOR130, -COR7, CR7 (OR12)2, CR7OR130, 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, Rg 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, Rπ is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and
R13 is divalent alkyl radical of 2-5 carbons, and
R14 is (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R15 is independently H, F, Cl, Br, I, N02, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCORg, OR8, CN, 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;
R16 is H, lower alkyl of 1 to 6 carbons;
R17 is H, lower alkyl of 1 to 6 carbons, OH or OCOR╬▒╬╣, and
p is zero or 1, with the proviso that when p is 1 then there is no R17
substituent group, and m is an integer between 0 and 2.
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 antagonist for a period of time sufficient to permit tissue repair, said retinoic acid antagonist having the formula
IV
wherein X╬╗ is [C(R1)2]n where Rx is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 to 2;
Z is -N=N-,
-N(0)=N-, -N=N(0)-,
-N=CR ,
-CR1=N,
where n' is an integer having the value 0-5, -CO-NR .
-CS-NR .
-NRΓCO,
-NR CS-,
-coo-, -OCO-, -CSO-,
-OCS-,
-CO-CR1= 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;
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^- 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, CONRgR10, -CH2OH, -CH )^, -CH2OCOR╬▒╬╣, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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, Rg 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, R╬▒╬╣ is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X2 is O, S, SO or S02, and
R20 is Si(C1.6alkyl)3, R14, COR14, S02R21, where R14 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, -C^-alkylphenyl,
naphthyl, Cj-C^-alkylnaphthyl, phenyl- - g-alkyl, naphthyl- -CjQ-alkyl, or R20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10
carbons, and R21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C╬╣-C10-alkylphenyl and phenyl- - g-alkyl, and retinoids of the formula
V
wherein Xj is [C(Rj)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(0)=N-,
-N=N(0)-,
-N=CR ,
-CR1=N,
-(CR^CRj)^- where n' is an integer having the value 0-5, -CO-NR╬▒-.
-CS-NRr.
-NR CO,
-NRΓCS-,
-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 ,, - 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) 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, CONRgR10, -CH2OH, -CH2ORαι, -CH2OCORπ, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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, Rg 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, Rπ is lower alkyl, phenyl or lower alkylphenyl, R12 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, (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl
where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R15 is independently H, F, Cl, Br, I, N02, N(R8)2, N(R8)COR88'
NR8CON(Rg)2, OH, OCORg, 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.
4. 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 antagonist for a period of time sufficient to permit tissue repair, said retinoic acid antagonist having the formula
wherein
Rj is hydrogen or alkyl of 1 to 10 carbons;
R2 and R3 are 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, CONRgR10, -CH2OH, -CH2OR╬▒╬╣, -CH2OCOR╬▒╬╣, CHO, CH(OR12)2, CHOR130, -COR7, CR7(OR12)2, CR7OR130, 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 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, Rn is lower alkyl, phenyl or lower alkylphenyl, R12 is lower
alkyl, and R13 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, Cj-C^-alkylphenyl, naphthyl, - o-alkylnaphthyl, phenyl, - o alkyl, naphthyl- - g alkyl, Cj- o-alkenylphenyl having 1 to 3 double bonds, Cj-C^-alkynylphenyl
having 1 to 3 triple bonds, phenyl-C^C^alkenyl having 1 to 3 double bonds, phenyl-Cj-C^alkynyl 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 COR14, CN, CON(R1)2, (CH2)pC02R8 where p is an integer between 0 to 10, or R^ is aminoalkyl or thioalkyl of 1 to 10 carbons, or a 5 or 6 membered heteroaryl group optionally substituted with a to C10 alkyl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, or R^ is represented by (CH^XRj or by (CH2)pNR1R2; where X is O or S, the R14 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, C╬▒-C10-alkylphenyl, naphthyl, C C10-alkylnaphthyl, phenyl-
J-CJO alkyl, or naphthyl-C C10 alkyl.
5. The method of any of Claims 1, 2, 3 or 4 wherein the retinoid antagonist is administered orally.
6. The method of any of Claims 1, 2, 3 or 4 wherein the retinoid antagonist is administered directly to a site of surgical activity on an organ surface.
EP98918060A 1997-04-11 1998-04-09 Retinoid antagonists for prevention of surgical adhesions Withdrawn EP1005340A4 (en)

Applications Claiming Priority (5)

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US5075197P 1997-06-25 1997-06-25
US50751P 1997-06-25
PCT/US1998/007060 WO1998046223A1 (en) 1997-04-11 1998-04-09 Retinoid antagonists for prevention of surgical adhesions

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AU2001290816A1 (en) 2000-09-13 2002-03-26 Bristol-Myers Squibb Company Retinoic acid receptor antagonists as promoters of angiogenesis
FR2847167A1 (en) * 2002-11-15 2004-05-21 Galderma Res & Dev Method for treating disorders associated with TGF-beta signal deficiency, e.g. cicatrization disorders, ulcers, cancers or graft rejection, comprises administration of retinoic acid receptor-Gamma antagonists
AU2003302070A1 (en) * 2002-11-15 2004-06-15 Galderma Research And Development, S.N.C. USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFBeta

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