WO1998046223A1 - Retinoid antagonists for prevention of surgical adhesions - Google Patents
Retinoid antagonists for prevention of surgical adhesions Download PDFInfo
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- WO1998046223A1 WO1998046223A1 PCT/US1998/007060 US9807060W WO9846223A1 WO 1998046223 A1 WO1998046223 A1 WO 1998046223A1 US 9807060 W US9807060 W US 9807060W WO 9846223 A1 WO9846223 A1 WO 9846223A1
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- carbons
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- 0 CC(C)C1(C)c(ccc(-c(cc2)cc(cc3)c2cc3C(O)=O)c2)c2C(C*)=CC1 Chemical compound CC(C)C1(C)c(ccc(-c(cc2)cc(cc3)c2cc3C(O)=O)c2)c2C(C*)=CC1 0.000 description 1
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.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU71053/98A AU723146B2 (en) | 1997-04-11 | 1998-04-09 | Retinoid antagonists for prevention of surgical adhesions |
JP54403098A JP2001524082A (en) | 1997-04-11 | 1998-04-09 | Retinoid antagonist for preventing surgical adhesions |
CA002286261A CA2286261A1 (en) | 1997-04-11 | 1998-04-09 | Retinoid antagonists for prevention of surgical adhesions |
EP98918060A EP1005340A4 (en) | 1997-04-11 | 1998-04-09 | Retinoid antagonists for prevention of surgical adhesions |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4352897P | 1997-04-11 | 1997-04-11 | |
US60/043,528 | 1997-04-11 | ||
US5075197P | 1997-06-25 | 1997-06-25 | |
US60/050,751 | 1997-06-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998046223A1 true WO1998046223A1 (en) | 1998-10-22 |
Family
ID=26720518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/007060 WO1998046223A1 (en) | 1997-04-11 | 1998-04-09 | Retinoid antagonists for prevention of surgical adhesions |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1005340A4 (en) |
JP (1) | JP2001524082A (en) |
AU (1) | AU723146B2 (en) |
CA (1) | CA2286261A1 (en) |
WO (1) | WO1998046223A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6713515B2 (en) | 2000-09-13 | 2004-03-30 | 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 |
WO2004045595A1 (en) * | 2002-11-15 | 2004-06-03 | Galderma Research & Development, S.N.C. | USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFβ |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0732328A1 (en) * | 1995-03-14 | 1996-09-18 | Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) | Aromatic heterocyclic compounds, pharmaceutical and cosmetic compositions containing them and their uses |
US5618839A (en) * | 1994-01-03 | 1997-04-08 | Bristol-Myers Squibb Company | Retinoid-like compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5534261A (en) * | 1995-01-17 | 1996-07-09 | University Of Southern California | Retinoid-based compositions and method for preventing adhesion formation using the same |
-
1998
- 1998-04-09 WO PCT/US1998/007060 patent/WO1998046223A1/en not_active Application Discontinuation
- 1998-04-09 EP EP98918060A patent/EP1005340A4/en not_active Withdrawn
- 1998-04-09 JP JP54403098A patent/JP2001524082A/en active Pending
- 1998-04-09 AU AU71053/98A patent/AU723146B2/en not_active Ceased
- 1998-04-09 CA CA002286261A patent/CA2286261A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5618839A (en) * | 1994-01-03 | 1997-04-08 | Bristol-Myers Squibb Company | Retinoid-like compounds |
EP0732328A1 (en) * | 1995-03-14 | 1996-09-18 | Centre International De Recherches Dermatologiques Galderma (C.I.R.D. Galderma) | Aromatic heterocyclic compounds, pharmaceutical and cosmetic compositions containing them and their uses |
Non-Patent Citations (1)
Title |
---|
See also references of EP1005340A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6713515B2 (en) | 2000-09-13 | 2004-03-30 | 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 |
WO2004045595A1 (en) * | 2002-11-15 | 2004-06-03 | Galderma Research & Development, S.N.C. | USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFβ |
Also Published As
Publication number | Publication date |
---|---|
JP2001524082A (en) | 2001-11-27 |
AU723146B2 (en) | 2000-08-17 |
EP1005340A4 (en) | 2001-02-07 |
EP1005340A1 (en) | 2000-06-07 |
AU7105398A (en) | 1998-11-11 |
CA2286261A1 (en) | 1998-10-22 |
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