WO2000059861A1 - Selective retinoic acid analogs - Google Patents
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- WO2000059861A1 WO2000059861A1 PCT/US2000/007751 US0007751W WO0059861A1 WO 2000059861 A1 WO2000059861 A1 WO 2000059861A1 US 0007751 W US0007751 W US 0007751W WO 0059861 A1 WO0059861 A1 WO 0059861A1
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- alkyl
- hydrogen
- naphthalenyl
- ethenyl
- trimethyl
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- 0 CC(c1ccc(*)cc1)(c1cc(C(*)=C(*)C(*2*)I)c2cc1*)N Chemical compound CC(c1ccc(*)cc1)(c1cc(C(*)=C(*)C(*2*)I)c2cc1*)N 0.000 description 5
- HQMNCQVAMBCHCO-DJRRULDNSA-N CCOC(/C=C(\C)/C=C/C=C(\C)/C=C/c(c(C)c1)c(C)c(C)c1OC)=O Chemical compound CCOC(/C=C(\C)/C=C/C=C(\C)/C=C/c(c(C)c1)c(C)c(C)c1OC)=O HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N CCOC(c1ccc(C#Cc(cc2)cc3c2SCCC3(C)C)nc1)=O Chemical compound CCOC(c1ccc(C#Cc(cc2)cc3c2SCCC3(C)C)nc1)=O OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/66—Polycyclic acids with unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to compounds having selective activity for specific retinoid acid receptors. More specifically, this invention provides a novel series of substituted (5,6)- dihydronaphthalenyl and substituted (5,6,7,8)-tetrahydronaphthalenyl compounds which selectively activate Retinoid X Receptors (RXRs) in comparison to Retinoic Acid Receptors (RARs). Also included in this invention are compounds from these series which activate both types of Retinoid Receptors (RARs and RXRs) and act as "bifunctional ligands" similarly to 9-ris-retinoic acid.
- RXRs Retinoid X Receptors
- RARs and RXRs Retinoic Acid Receptors
- These compounds are useful as antiinflammatory agents for chronic skin inflammatory diseases such as psoriasis and atopic dermatitis, as agents for the treatment of rheumatic diseases such as rheumatoid arthritis, as antitumor agents for the treatment of various tumors as well as non-malignant proliferative skin conditions and as agents for the minimization or prevention of post- surgical adhesion formation.
- 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.
- a few retinoids are already in clinical use in the treatment of dermatological diseases such as acne and psoriasis.
- isotretinoin is used clinically for oral therapy of severe acne, and etretinate and tazarotene are particularly useful in the treatment of psoriasis.
- Retinoid Receptors There are two subfamilies of Retinoid Receptors, the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs). Both subfamilies are divided into three isoforms, ⁇ , ⁇ and ⁇ .
- RARs Retinoic Acid Receptors
- RXRs Retinoid X Receptors
- Both subfamilies are divided into three isoforms, ⁇ , ⁇ and ⁇ .
- the structural differences between these receptors have been recently shown with the crystal structures of apo-RXR- ⁇ and RAR- ⁇ liganded with all-t r ⁇ ns-retinoic acid (Renaud J.-P. et ⁇ l, Nature vol. 378 p. 681 to 689 (1995) and Bourguet W. et ⁇ l, Nature vol. 375 p. 377 to 382 (1995)
- retinoids is associated with many side-effects such as teratogenicity and irritation. These side-effects may be related to the ability of the retinoids to activate multiple retinoid receptors in a wide variety of tissues. Therefore, current retinoid research targets the development of receptor-selective retinoids for improving their therapeutic profile.
- 9-cis-retinoic acid is a natural ligand which can interact with both the RARs and the RXRs. This compound was recently found to have good potential as an anti-proliferative agent which could be used in the treatment of various tumors as well as non-malignant proliferative skin conditions.
- RXR receptor selective ligands have been recently found to display synergistic activation of genes when they are used in combination with RAR-specific ligands (Chen, J.-Y. et al, Nature vol. 382, 819-822 (1996)).
- the development of synthetic retinoids combining both activities could therefore increase the therapeutic efficacy.
- the relative instability of 9-czs-retinoic acid dictates the development of more stable synthetic retinoids having a similar activity profile.
- WO Patent Applications 95/04036, 94/15901 and 93/21146 describe bicyclic benzyl, pyridinyl, thiophene, furanyl, pyrrole and polyenic acid derivatives which selectively or preferentially activate RXR receptors.
- WO patent 96/05165 discloses novel retinoic acid X-receptor ligands of this general formula:
- US patent No. 5,455,265 and WO patent 94/17796 describe a method of treatment with compounds having selective agonistlike activity on RXR receptors while WO patent 94/20093 is directed to a process for inducing apoptosis in tumor cells by administration of compounds having agonist-like activity at RXR retinoid sites.
- WO patent 97/12853 describes novel RXR modulators that selectively bind to RXR receptors in preference to RAR receptors and that, depending upon the receptor and /or cellular context, display activity as full agonists, partial agonists and/or full antagonists on RXR homodimers and/or heterodimers.
- the present invention provides a novel series of substituted (5,6)- dihydronaphthalenyl and substituted (5,6,7,8)-tetrahydronaphthalenyl compounds which selectively activate Retinoid X Receptors (RXRs) in comparison to Retinoic Acid Receptors (RARs). These compounds selectively modulate processes mediated by Retinoid X Receptors. Also provided in this invention are compounds included in these series which activate both types of Retinoid Receptors (RARs and RXRs). Finally, the present invention describes compounds included in these series which have been found to be particularly useful as agents for the minimization or prevention of post-surgical adhesion formation.
- the retinoid is defined by the generic formula:
- R' and R" are independently hydrogen, Ci- 6 alkyl, hydroxy,
- A is carbon, nitrogen, oxygen or sulfur
- R 2 and R 3 are independently hydrogen or Ci-6 alkyl when
- A is carbon or nitrogen; independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
- R 4 is hydrogen, Ci-io alkyl, C 3 - 10 cycloalkyl, alkyl
- R 5 is hydrogen, Ci- 6 alkyl, Ci- 6 alkoxy or alkythio, C 2 - 6 alkenyl or C 2 _ 6 alkynyl;
- R 6 is hydrogen or Ci- 6 alkyl
- R 7 are independently hydrogen, Ci- 6 alkyl, hydroxyl, fluoride, Ci- 6 alkyloxy or alkylthio; but when n is one, R 6 and R 7 together can form a radical of the formula
- R 8 and R 9 are independently hydrogen, halogen, Ci-6 alkyl, hydroxy, azide, cyanide, Ci- 6 alkoxy or nitro;
- R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or Ci- 6 alkyl
- R 15 is OH, Ci- 6 alkyl, aryl or heteroaryl
- n 0 to 2;
- n and q are independently 2 to 5;
- p 0 to 2;
- Z is Ci- 6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as
- the retinoid is defined by the generic formula:
- A is carbon, nitrogen, oxygen or sulfur
- R 2 and R 3 are independently hydrogen or C ⁇ _ 6 alkyl when A is carbon or nitrogen; each independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
- R 5 is hydrogen, Ci- 6 lower alkyl, Ci- 6 alkoxy or Ci- 6 alkythio, C 2 _ 6 alkenyl or C 2 - 6 alkynyl;
- R 6 is hydrogen or Ci- 6 alkyl
- R7 are independently hydrogen, - 6 alkyl, hydroxyl, fluoride, Ci- 6 alkyloxy, Ci-6 alkylthio or carbonyl; but when n is one, R 6 and R 7 together can form a radical of the formula
- R 8 and R 9 are independently hydrogen, halogen, Ci- 6 alkyl, hydroxy, azido, cyano, Ci-6 alkoxy or nitro;
- R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or C ⁇ - 6 alkyl
- R 15 is OH, Ci- 6 alkyl, aryl or heteroaryl
- R a is hydrogen, Ci- 6 alkyl, Ci- 6 alkoxy or Ci- 6 alkylthio
- R b is hydrogen, C ⁇ _ 6 alkyl, C 3 - 6 cycloalkyl or Ci- 6 alkyl-C3- 6 cycloalkyl;
- X is O, S or N
- n 0 to 2;
- IT p is 0 to 2;
- Z is Ci- 6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as
- the compounds of the present invention are useful for treating a host animal, preferably a mammal and most preferably a human, for chronic skin inflammatory diseases (e.g. psoriasis and atopic dermatitis), rheumatic diseases (e.g. rheumatoid arthritis), non-malignant skin conditions, and as antitumor agents for the treatment of tumors sensitive to the compounds.
- chronic skin inflammatory diseases e.g. psoriasis and atopic dermatitis
- rheumatic diseases e.g. rheumatoid arthritis
- non-malignant skin conditions e.g. rheumatoid arthritis
- an effective therapeutic amount of a compound of the present invention is administered to said host animal in the same manner as with other retinoid compounds.
- one aspect of the present invention is 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 compound of the present invention for a period of time sufficient to permit tissue repair.
- the compounds may be administered systemically or topically, depending on the condition to be treated, the need for site-specific treatment or the quantity of drug to be administered.
- the present invention relates to compounds of formula I
- R' and R" are independently hydrogen, Ci- 6 alkyl, hydroxy,
- A is carbon, nitrogen, oxygen or sulfur
- R 2 and R 3 are independently hydrogen or C ⁇ - 6 alkyl when
- A is carbon or nitrogen; independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
- R 4 is hydrogen, C ⁇ . ⁇ o alkyl, C 3 - 0 cycloalkyl, alkyl C ⁇ - 0 polyfluoroalkyl, C ⁇ . ⁇ o alkylthio, C 3 - 0 cycloalkylthio, C ⁇ . ⁇ o alkylsulfoxy, C3- 0 cycloalkylalkylsulfoxy, C ⁇ . ⁇ o alkylsulfone, C3-X0 cycloalkylsulfone, C ⁇ . ⁇ o alkoxy, C3- ⁇ o cycloalkoxy, C ⁇ - ⁇ o alkylamino, C 3 - X 0 cycloalkylamino, -COR 13 , -C(OR 14 ) 2 R 13 ,
- phenyl or heteroaryl wherein the phenyl or the heteroaryl radicals can be substituted by C ⁇ _ 6 alkyl, halogen, C ⁇ - 6 alkoxy, C ⁇ -6 alkylthio, -C0 2 R 13 , -COR 13 or -NR 13 R 14 ;
- R 5 is hydrogen, C ⁇ -6 alkyl, C ⁇ -6 alkoxy or C ⁇ - 6 alkythio, C 2 - 6 alkenyl or C 2 - 6 alkynyl;
- R 6 is hydrogen or C ⁇ - 6 alkyl
- R 7 are independently hydrogen, C ⁇ - 6 alkyl, hydroxyl, fluoride, C ⁇ - 6 alkyloxy or C ⁇ - 6 alkylthio; but when n is one, R 6 and R 7 together can form a radical of the formula
- R 8 and R 9 are independently hydrogen, halogen, C ⁇ -6 alkyl, hydroxy, azide, cyanide, C ⁇ - 6 alkoxy or nitro;
- R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or C ⁇ - 6 alkyl
- Rl5 is OH, C ⁇ - 6 alkyl, aryl or heteroaryl
- n 0 to 2;
- n and q are independently 2 to 5;
- p 0 to 2;
- Z is C ⁇ -6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as Li + , Na + or K + .
- the retinoid is defined by the generic formula:
- R' and R" are independently hydrogen, C - 6 alkyl, hydroxy
- A is carbon, nitrogen, oxygen or sulfur
- R 2 and R 3 are independently hydrogen or C ⁇ - 6 alkyl when
- A is carbon or nitrogen; each independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
- R 5 is hydrogen, C ⁇ - 6 lower alkyl, C - 6 alkoxy or
- R 6 is hydrogen or C ⁇ - 6 alkyl
- R 7 are independently hydrogen, C ⁇ - 6 alkyl, hydroxyl, fluoride, C ⁇ _ 6 alkyloxy, C ⁇ - 6 alkylthio or carbonyl; but when n is one, R 6 and R 7 together can form a radical of the formula
- R 8 and R 9 are independently hydrogen, halogen, C ⁇ - 6 alkyl, hydroxy, azido, cyano, C ⁇ - 6 alkoxy or nitro;
- R 10 , R 11 and R 12 are independently hydrogen or C ⁇ - 6 alkyl
- R 15 is OH, C ⁇ - 6 alkyl, aryl or heteroaryl
- R a is hydrogen, C ⁇ -6 alkyl, C ⁇ - 6 alkoxy or C ⁇ _ 6 alkylthio
- R b is hydrogen, C ⁇ - 6 alkyl, C 3 - 6 cycloalkyl or C ⁇ _ 6 alkyl-C 3 - 6 cycloalkyl;
- X is O, S or N;
- n 0 to 2;
- n and q are independently 2 to 5;
- p 0 to 2;
- Z is C ⁇ - 6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as Li + , Na + or K ⁇
- C ⁇ . ⁇ o alkyl refers to straight and branched chain alkyl groups with one to ten carbon atoms, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl etc.
- cycloalkyl is intended to include straight or branched cycloalkyl groups containing three to ten carbon atoms.
- polyfluoroalkyl means that at least one hydrogen atom in the alkyl side-chain is replaced by a fluorine atom.
- alkenyl defines a carbon chain having at least one double bond.
- C 2 - 6 alkenyl refers to a straight or branched chain of two to six carbons bearing at least one double bond, such as ethenyl, 1- methyl-ethenyl, 1- or 2-propenyl, 1-methyl-l-propenyl, l-methyl-2- propenyl, l,l-dimethyl-2-propenyl, 2-methyl-2-propenyl, 1-, 2- or 3- butenyl, 1-methyl-l-butenyl, 2-methyl-l-butenyl, 3-methyl-l-butenyl, 3,3- dimethyl-1-butenyl, 2,3-dimethyl-l-butenyl, l-methyl-2-butenyl, 1,1- dimethyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1,3-butenyl, 1,3-butadienyl, l,3-d
- alkynyl define a carbon chain having at least one triple bond.
- C 2 - 6 alkynyl refers to a straight or branched chain of two to six carbons bearing at least one triple bond, such as ethynyl, 1- or 2- propynyl, l-methyl-2-propynyl, l,l-dimethyl-2-propynyl, 1-, 2- or 3- butynyl, 3-methyl-l-butynyl, 3,3-dimethyl-l-butynyl, l-methyl-2-butynyl, l,l-dimethyl-2-butynyl, 1-, 2-, 3, or 4-pentynyl etc.
- C 3 -6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals.
- C ⁇ - 6 alkoxy and C ⁇ - 6 alkylthio refers to an ether or a thioether bearing a straight or branched carbon chain, such as methoxy, methylthio, ethoxy, ethylthio, n-propoxy, n-propylthio, isopropoxy, isopropylthio, n-butoxy, n-butylthio, tert-butoxy, tert-butylthio, n-pentoxy, n-pentylthio etc.
- halogen refers to fluorine, chlorine, bromine or iodine.
- heteroaryl as used herein includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1 to 4 O, N or S atoms; preferred are 5- and 6-membered heterocyclic groups such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.
- Some compounds of formula I and II may also form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. Such cations are also referred to herein as "pharmaceutically acceptable cations.” These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred.
- Amines which are capable of forming stable salts include mono-, di-, and trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or the like pharmaceutically acceptable amines.
- physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I or formula II compounds per se. They are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester ⁇ er se is active, or in those instances where hydrolysis occurs in the blood.
- physiologically hydrolyzable esters of compounds of formula I and II include C ⁇ - 6 alkyl benzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C ⁇ - 6 alkanoyloxy-C ⁇ - 6 alkyl, e.g.
- esters used, for example, in the penicillin and cephalosporin arts. Such esters are prepared by conventional techniques known in the art.
- the compounds of the present invention may have trans and cis (E and Z) isomers.
- 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).
- a mixture of such isomers, or either one of the isomers is intended (where applicable).
- the preferred compounds are those where R 1 is limited to -C0 2 Z.
- R 2 and R 3 groups of the preferred compounds are preferably C ⁇ - 6 alkyl and even more preferably methyl.
- R 7 , R 8 and R 9 are also preferably hydrogens.
- Grignard type reaction is intended to include the addition of an organometallic compound to a carbonyl-containing compound. This includes addition of Grignard (organomagnesium) reagents, alkyl or aryllithiums, alkylzinc, alkylaluminum, organotitanium, organozirconium or organocerium compounds in an inert organic solvent such as ethyl ether, tetrahydrofuran, dichloromethane, benzene or toluene and the like.
- Grignard organomagnesium
- Grignard type reaction is also intended to include the addition of a Grignard reagent to an acid chloride that has been first reacted with tributylphosphine to form the corresponding phosphonium salt.
- the reaction is performed in an inert organic solvent such as ethyl ether, tetrahydrofuran, benzene and the like.
- Friedel- Crafts reaction is intended to include the acylation or alkylation of aromatic rings.
- the acylation includes the addition of an acyl halide, a carboxylic acid, an anhydride or a ketene to an aromatic ring under Lewis acid conditions such as aluminum, tin, antimony, zirconium, boron halides and the like or under proton acid conditions such as polyphosphoric acid, sufluric acid, methanesulfonic acid and the like.
- Lewis acid conditions such as aluminum, tin, antimony, zirconium, boron halides and the like
- proton acid conditions such as polyphosphoric acid, sufluric acid, methanesulfonic acid and the like.
- the alkylation includes the addition of alkyl halides, olefins or alcohols under Lewis or proton acid conditions such as the one listed above.
- aromatic halogenation is intended to include the addition of chlorine, bromine or iodine to an aromatic ring in the presence or absence of a catalyst, usually iron or a Lewis acid such as aluminum, tin, antimony halides and the like. It is also intended to include the reaction of N-chloro and N-bromoamides catalyzed by the addition of acids.
- iodine may be used in presence of an oxidizing agent such as nitric acid, iodic acid, sulfur trioxide or hydrogen peroxide or in the presence of copper salts, silver trifluoromethanesulfonate or thallium(I) acetate.
- Iodine monochloride can also be used.
- reaction is intended to include well-known reduction procedures of ketone groups by the use of aluminum or boron hydrides such as lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and the like in an organic solvent such as tetrahydrofuran, ethyl ether, ethanol, dichloromethane and the like.
- aluminum or boron hydrides such as lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and the like in an organic solvent such as tetrahydrofuran, ethyl ether, ethanol, dichloromethane and the like.
- reduction is also intended to include the reduction or desulfurization of dithioacetals by the use of Raney nickel with or without hydrogen, in organic solvents such as methanol, ethanol, ethanol /water, ethanol/ethyl ether, dioxane, acetone, tetrahydrofuran, benzene and the like.
- These methods include the use of aluminum, boron or trialkylsilyl hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or triethylsilylhydride with or without aluminum chloride, zinc iodide or an acid such as hydrochloric acid, trifluoroacetic acid or trifluoroboron etherate in an organic solvent such as tetrahydrofuran, ethyl ether or ethanol.
- Well-known hydrogenation procedures using hydrogen with a catalyst such as palladium on charcoal or Raney nickel in methanol or ethanol may also be used if appropriate.
- the term "reductive animation” is intended to include conventional imine formation procedures well-known to those skilled in the art. These procedures involve the reaction of an amine with a Lewis acid such as titanium(IV) chloride or isopropoxide. Subsequently, this imine is reduced with well- known reducing agents such as sodium borohydride or sodium cyanoborohydride.
- reducing agents such as sodium borohydride or sodium cyanoborohydride.
- hydrolysis is intended to include conventional hydrolytic procedures of esters well- known to those skilled in the art. For example, methyl or ethyl esters may be removed by the use of aqueous solutions of sodium or potassium hydroxides or alkoxides in tetrahydrofuran or ethanol.
- tert-butyl esters The hydrolysis of tert-butyl esters is carried out under acidic conditions such as 90% trifluoroacetic acid or 6N hydrochloric acid in solvents such as tetrahydrofuran or dichloromethane. Allyl esters may be removed by the use of Pd(0) catalyst with a base, such as sodium acetate, potassium or sodium 2-ethylhexanoate, pyrrolidine or morpholine and the like in an organic solvent such as acetonitrile, tetrahydrofuran, dichloromethane and the like.
- a base such as sodium acetate, potassium or sodium 2-ethylhexanoate, pyrrolidine or morpholine and the like
- organic solvent such as acetonitrile, tetrahydrofuran, dichloromethane and the like.
- silyl esters such as trimethylsilylethyl esters may be cleaved by the use of tetrabutylammonium fluoride in tetrahydrofuran.
- hydrolysis is also intended to include conventional hydrolytic procedures of carbonyl protecting groups.
- the hydrolysis of ketals and acetals may be carried out under acidic conditions such as IN hydrochloric acid, 80% acetic acid or p-toluenesulfonic acid in solvents such as tetrahydrofuran or acetone.
- the term "enol triflate or enol formation” is intended to include conventional and well-known enolate formation procedures and subsequent trapping of this enolate by the well-known triflating or silylating agents.
- a base such as 2,6-di-tert-butyl-4-methyl-pyridine, sodium hydride, potassium hydride, lithium diisopropylamide or lithium bis(trimethylsilyl)amide in an inert organic solvent such as tetrahydrofuran, dimethylformamide or dichloromethane and the like.
- cross- coupling is intended to include all the cross-coupling methods well- known by those skilled in the art that involve the reaction of a vinyl or aromatic triflate, bromide or iodide with a tin, zinc, magnesium or boronic derivative catalyzed by a palladium(O) or palladium(II) catalyst such as tetrakis(triphenyl-phosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate, tris(dibenzylidene-acetone)dipalladium(0), bis(diphenylphosphineferrocene)palladium(II) chloride and the like or a nickel(O) or nickel(II) catalyst such as tetrakis(triphenylphosphine) nickel(O), bis(triphenylphosphine)nickel(II)
- the term "Heck coupling” is intended to include all known vinylations of alkenes or alkynes.
- a vinyl or aromatic triflate, bromide or iodide reacts with various substituted or non-substituted alkenes or alkynes in the presence of a trialkylamine base or an inorganic base such as potassium carbonate, sodium acetate and the like and a catalytic amount of Pd(II) complex such as palladium(II) acetate, bis(triphenylphosphine) palladium(II) chloride or bis(acetonitrile)palladium(II) chloride.
- phosphine ligands such as triphenylphosphine, tritolylphosphine, diphenylphosphineferrocene or l,3-bis(diphenylphosphino) propane and the like may facilitate the reaction.
- alkylation is intended to include conventional and well-known alkylation procedures.
- an organic or inorganic base such as sodium hydride, potassium hydride, lithium diisopropylamine or lithium bis(trimethylsilyl)amide in an inert organic solvent such as tetrahydrofuran, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, N-methylpyrolidinone and the like.
- an alkylating agent such as an alkyl, allyl or benzyl halide, mesylate or tosylate is added to this generated enolate, phenolate or thiophenolate.
- an alkylating agent such as an alkyl, allyl or benzyl halide, mesylate or tosylate is added to this generated enolate, phenolate or thiophenolate.
- the term "reductive alkylation” is intended to include the methods used to convert a tertiary alcohol to an alkyl, aryl or allyl group.
- the alcohol that has to be transformed may be treated by an organosilicon compound in the presence of boron trifluoride in dichloromethane or by a trialkylboron in the presence of trifluoromethanesulfonic acid in 1,1,2-trichlorotrifluoroethane.
- Another method is to react the corresponding alkoxide with iron pentacarbonyl to perform a deoxygenation reaction which may be followed by treatment with various alkyl or aryl halides.
- the alkoxide may be generated by treatment with a metal such as potassium, sodium or lithium in toluene.
- oxidation is intended to include conventional allylic or benzylic oxidation methods such as selenium dioxide with or without the use of tert-butyl peroxide, sodium peroxide in ethanol and chromium(VI) reagents such as chromium(VI) trioxide in acetic acid and pyridinium dichromate and preferably potassium bromate in the presence of eerie ammonium nitrate in dioxane.
- aromatic substitution is intended to include nucleophilic substitutions of aromatic halides by water in the presence of sulfuric acid or trifluoroacetic acid, by alkoxides, aryloxides, thioalkoxides or thioaryloxides in an inert organic solvent such as hexamethylphosphoramide, dimethylsulfoxide, dimethylformamide and the like.
- alkoxides aryloxides, thioalkoxides or thioaryloxides in an inert organic solvent
- the reaction of aryl halides with alkoxides may be promoted by copper salts and the reaction with thioalkoxides may be catalyzed by Pd(0) salts such as tetrakis(triphenylphosphine) palladium(O).
- enone formation is intended to include the well-known dehydrogenation procedures of ketones.
- the ketone to be dehydrogenated is converted to a silyl enol ether as described above and then treated with an oxidizing agent such as dichlorodicyanoquinone, triphenylmethylcation or palladium(II) acetate in an inert organic solvent such as acetonitrile or dichloromethane.
- the term "Michael addition” is intended to include all conventional methods of conjugate addition of organometallic compounds or anions formed from malonates, cyanoacetates, acetoacetates, ⁇ -ketoesters, esters, ketones, aldehydes, nitriles, nitro compounds, sulfones and the like to an ⁇ , ⁇ -unsaturated carbonyl compound.
- the organometallic compounds include lithium dialkylcopper, organoaluminum, trialkylzinc lithium, arylpalladium, arylmercury, borane reagents and the like.
- the inert organic solvents used may be tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, benzene and the like.
- acid halide formation is intended to include the well-known methods of the conversion of a carboxylic acid to an acid halide such as the use of thionyl chloride, oxalyl chloride or bromide in the presence of dimethylformamide in dichloromethane and phosphorus trichloride or tribromide.
- an alkyl or aryl phosphonate is treated with a base such as sodium hydride, lithium diisopropylamide or lithium bis(trimethylsilyl)amide and the like in an inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde.
- a base such as sodium hydride, lithium diisopropylamide or lithium bis(trimethylsilyl)amide and the like
- an inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde.
- an alkyl or arylphosphonium salt is treated with a base such as butyllithium, lithium diisopropylamine or lithium bis(trimethylsilyl)amide and the like in an inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde.
- a base such as butyllithium, lithium diisopropylamine or lithium bis(trimethylsilyl)amide and the like
- an inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde.
- the ketone is treated with ⁇ cyclo-dibromodi- ⁇ -methylene[ ⁇ - (tetrahydrofuran)]trizinc ⁇ (Nysted reagent) in the presence of titanium chloride in an inert solvent such as tetrahydrofuran and dichloromethane.
- epoxidation or thioepoxidation is intended to include the well-known methods of epoxide formation by reaction of an olefin with a peracid as well as the epoxide formation by reacting a gem-dihalide in the presence of a strong base such as butyllithium, t-butyllithium methyllithium or lithium with a ketone in inert organic solvents such as tetrahydrofuran or ether.
- organic base such as sodium hydride or potassium tert-butoxide
- organic solvents such as dimethylsulfoxide, tetrahydrofuran, t-butanol, dimethoxyethane and the like with a ketone.
- epoxidation or thioepoxidation is also intended to include the methods by which a diazoalkane reacts with a ketone in a solvent such as methanol or ethyl ether.
- acetal, ketal, thioacetal or thioketal formation are processes well-known in the art and they are well illustrated in "Protective Groups in Organic Synthesis", Second Ed., T. W. Green and P. G. W. Wuts, John Wiley & Sons, New York, 1991, Chapter 4 and references therein.
- the ketone or aldehyde to be protected is treated with the desired alcohol or diol, thiol or dithiol in the presence of an inorganic or organic acid such as p- toluenesulfonic acid, hydrochloric acid, trifluoroboron etherate, oxalic acid, adipic acid, pyridinium tosylate, acetic acid and the like, in inert organic solvents such as benzene, toluene, acetonitrile or dichloromethane.
- an inorganic or organic acid such as p- toluenesulfonic acid, hydrochloric acid, trifluoroboron etherate, oxalic acid, adipic acid, pyridinium tosylate, acetic acid and the like
- inert organic solvents such as benzene, toluene, acetonitrile or dichloromethane.
- cyclopropanation is intended to include the well-known Simmons- Smith procedure involving the reaction of a dihaloalkane and zinc- copper couple with an olefin in organic solvents such as ethyl ether, dimethoxyethane or tetrahydrofuran.
- the preparation of the zinc-copper couple is preferably carried out with zinc dust and cuprous chloride.
- Other variations of this procedure are the use of a dihaloalkane with samarium, mercuric chloride in tetrahydrofuran or with diethylzinc in dichloromethane or toluene.
- cyclopropanation is also intended to include the addition of carbenes to carbon-carbon double bonds such as the reaction of a diazoalkane with rhodium acetate or palladium(II) acetate in tetrahydrofuran or dichloromethane, the reaction of a dihaloalkane with a strong base such as n-butyllithium, methyllithium or t-butyllithium in inert organic solvents such as ethyl ether or tetrahydrofuran or the reaction of chloroform with sodium or potassium hydroxide under phase transfer conditions such as tetraalkylammonium halide in water or a mixture of water /ethanol.
- the term "imine formation” is intended to include the well- known procedures by which a ketone reacts with an amine in presence of an acid with or without a drying agent. These conditions include various inorganic and organic acids such as zinc chloride, titanium chloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, p- toluenesulfonic acid and the like in solvents such as dichloromethane, ethanol, benzene, toluene, tetrahydrofuran, dimethylformamide and the like.
- inorganic and organic acids such as zinc chloride, titanium chloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, p- toluenesulfonic acid and the like in solvents such as dichloromethane, ethanol, benzene, toluene, tetrahydrofuran, dimethylformamide and the like.
- the compounds of the present invention are useful for treating a host animal, preferably a mammal and most preferably a human, for chronic skin inflammatory diseases (e.g. psoriasis and atopic dermatitis), rheumatic diseases (e.g. rheumatoid arthritis), non-malignant skin conditions, and as antitumor agents for the treatment of tumors sensitive to the compounds.
- chronic skin inflammatory diseases e.g. psoriasis and atopic dermatitis
- rheumatic diseases e.g. rheumatoid arthritis
- non-malignant skin conditions e.g. rheumatoid arthritis
- an effective therapeutic amount of a compound of the present invention is administered to said host animal in the same manner as with other retinoid compounds.
- one aspect of the present invention is 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 compound of the present invention for a period of time sufficient to permit tissue repair.
- the compounds may be administered systemically or topically, depending on the condition to be treated, the need for site-specific treatment or the quantity of drug to be administered.
- Modes of Administration are particularly preferred
- a compound of the present invention may be administered by a variety of systemic and local methods.
- the compounds may be administered orally, by intravenous injection, by intramuscular injection or by intracavity instillation.
- the general range of doses will depend on the efficacy of 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 routes of adminstration are oral administration or direct administration (intracavity administration) to a site of surgical activity on an organ surface.
- administration of a compound 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 compound 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.
- the compound 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.
- many other single dose delivery systems could be contemplated by those skilled in the art including microcapsules, microspheres, liposomes, viscous instilates, and polymeric delivery materials.
- the compounds of formula I or II above may be used topically or systemically, as anticancer agents and in the treatment, amelioration or prevention of the skin disorders and rheumatic illnesses (including rheumatoid arthritis) described in U.S. Patent 5,618,839.
- they may be used for therapy in animals, including humans, of premalignant epithelial cell lesions, as a prophylaxis against tumor promotion in epithelial cells and treatment for dermatoses such as ichthyoses, follicular disorders, benign epithelial disorders and other proliferative skin diseases such as psoriasis, eczema, atopic dermatitis, non-specific dermatosis and the like. They may also be used in reversing and preventing the effects of irradiation damage to skin. When used for the above purposes, they will usually be formulated with a pharmaceutically acceptable liquid, semi-solid, or solid carrier.
- a pharmaceutically acceptable carrier is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely. Such materials are well known and include those materials sometimes referred to as diluents or vehicles (excipients) in the pharmaceutical formulation art.
- the carrier may be organic or inorganic in nature.
- Examples of pharmaceutically acceptable carriers that may be used to formulate a compound of formula I or II are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, orbital, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers.
- the formulation may contain minor amounts of additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
- additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
- the drug In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases oral administration may also be used. If the compounds according to the invention are used topically, it will be found that they exhibit a good activity over a very broad range of dilution; in particular, concentrations of the active compound or compounds ranging from 0.0005% to 2% by weight can generally be used. It is of course possible to use higher concentrations if this should become necessary for a particular application; however, the preferred concentration of active principle are from 0.002% to 1% by weight.
- the compounds of formula I or II are conveniently provided in the form of unguents, gels, creams, ointments, powders, dyeing compositions, solutions, suspensions, emulsions, lotions, sprays, adhesive plasters and impregnated pads.
- the compounds according to the invention can be mixed with inert nontoxic, generally liquid or pasty, bases suitable for topical treatment. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. Other medicaments can be added to such formulation for such secondary purposes as treating skin dryness, providing protection against light, treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
- the compounds according to the invention can also be used enterally.
- the compounds according to the invention are suitably administered at the rate of 100 ⁇ g to 100 mg per day per kg of body weight.
- the required dose can be administered in one or more portions.
- suitable forms are, for example, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using pills containing from 1 mg to about 1000 mg of active substance.
- Isotretinoin (Accutane ® ) and Etretinate (Tegison ® ) are used clinically to treat severe recalcitrant cystic acne and severe recalcitrant psoriasis, including the erythrodermica and generalized pustular types, respectively. Their mode of use is amply illustrated in the Physicians' Desk Reference, 47th Edition, 1993, published by Medical Economics Data.
- the compounds of formula I or II may also be used to treat severe recalcitrant psoriasis.
- the compounds of the present invention may be used in a similar fashion to isotretinoin and etretinate; thus, the relevant sections on isotretinoin and etretinate in the Physicians' Desk Reference will serve as a convenient guide which will obviate the need for any undue experimentation.
- the compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections.
- the compounds according to the invention are generally administered at the rate of about 10 ⁇ g to 10 mg per day per kg of body weight; a preferred method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml.
- retinoids have been found to possess anti-tumor properties. See, for example, Roberts, A.B. and Sporn, M.B. in "The Retinoids.” Sporn, M.B., Roberts, A.B., and Goodman, D.S., eds, 1984, 2_ pp. 209-286, Academic Press, New York; Lippman, S.M., Kessler, J.F., and Meyskens, F.L.. Cancer Treat. Rep.. 1987, _ p. 391; ibid., p. 493.
- anti-tumor includes both chemopreventive (prophylactic or tumor promotion inhibiting) and therapeutic (curative) use.
- all-trans retinoic acid can be used to treat acute promyelocytic leukemia (Huang, M. et al, Blood. 1988, 72, p. 567). Isotretinoin has been shown to be useful in the prevention of second primary tumors in squamous-cell carcinoma of the head and neck (Hong, W.K. et al., N. Engl. T. Med.. 1990, 223, p. 795).
- the compounds of formula I or II can be used in a substantially similar manner to other retinoids for treating (both chemopreventively and therapeutically) various tumors.
- the anti-tumor dose to be administered whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient, the type of tumor, and the nature of the patient's condition.
- the dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
- an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention, such as by referring to the earlier published studies on retinoids found to have anti-tumor properties.
- an oncologist may refer to the study by Hong, W.K et al. in N. Engl. J. Med., 1990, 323. p. 795.
- the oncologist may refer to the study by Huang, M. et al. in Blood. 1988, 72, p. 567.
- the retinoid-like activity and efficacy of these compounds has been confirmed by a retinoid transactivation assay described in Skin Pharmacology, vol. 8, p. 292-299 (1995).
- HeLa cells are co-transfected with DNA encoding RAR ⁇ , ⁇ or ⁇ , and an RAR-responsive CAT reporter gene.
- Retinoid efficacy is measured by the concentration of induced CAT gene product as determined by ELISA assay.
- the compounds of the present invention have shown activity as agonist or partial agonist in at least one of the three RXR receptor subtypes ( ⁇ , ⁇ , ⁇ ).
- the apparent Kds for binding of these compounds to the three RAR receptors have been also evaluated (Skin Pharmacology, vol. 8, p. 292-299 (1995) and Mode of Action of Drugs on Cells, Arnold publishers, London (1933)) and Table 1 shows the data of some representative examples.
- Adhesion formation is a severe problem following most surgical procedures. Factors that influence adhesion formation include mechanical trauma, infection, and foreign bodies and tissue ischemia. Common examples of postoperative surgical adhesions are pelvic adhesions of the fallopian tubes and or ovaries resulting in infertility, and intestinal adhesions leading to bowel obstruction. Initial insult to the serosa or mesentery leads to the formation of fibrous exudate. Trauma- induced adhesion formation in rat is similar in characteristics to post- surgical adhesion formation in human. The in vivo model offers a means for evaluating drug effect on adhesion formation under conditions that are similar to the clinical process.
- retinoids primarily RAR antagonists are effective inhibitors of fibrotic changes (see, for example, WO 98/46228 published October 22, 1998).
- the inhibition of fibrotic changes of the compounds of the present invention is shown here as exemplified by the activity of compound C.
- the inhibition or prevention of surgical adhesions does not seem to be necessarily related to the RXR retinoid activity per se since LGD1069, described in WO patents 95/04036, 94/15901 and 93/21146 and claimed as an RXR agonist was found to be inactive in this assay.
- the compounds of the present invention appear to demonstrate, in addition to a potent and specific RXR activity, this unexpected property of inhibiting trauma-induced post-surgical adhesions.
- the various desired tetralones having an R 5 substituent are advantageously prepared from alkyl 4-(p-alkylated or halogenated-phenyl)-butyrate X easily obtained from the known corresponding carboxylic acid.
- Grignard type reaction of this compound affords the corresponding carbinol XI, which may then react under Friedel-Crafts conditions to give the tetrahydronaphthalene XII.
- the resulting tetralone Vb wherein x is a halogen substituent may be substituted under traditional aromatic substitution, cross-coupling or Heck conditions.
- the tetralones of type Va or b may then be submitted to an aromatic halogenation to afford compounds XHIa or b as described in Scheme 2. Subsequent alkylation, if desired, affords the tetralones XI Va or b.
- the p-bromophenol, p-bromophenylthiol or p- bromoaniline of type XV may be alkylated with 3-bromopropionic acid to give the acid XVI which may then be cyclized under Friedel-Crafts acylation conditions.
- 6-bromochroman-4-one, 6- bromothiochroman-4-one or 6-bromo-l,2,3,4-tetrahydroquinolin-4-one of formula XIIIc may then be alkylated if desired to give the compounds of formula XIVc.
- A is sulfur
- the thiochroman-4-one may be oxidized if desired, and give the corresponding sulfoxide or sulfone of formula xmd.
- a Michael type reaction (1,4 addition) may also be carried out with enones XVIIa or b to afford the substituted tetralones, chromanones, thiochromanones or tetrahydroquinolinones of type XlVf.
- tertiary alcohols of formula XXa to f may also be alkylated, if desired, and lead to the ethers of formula XXa to f.
- the same compounds of type XlVa to f may be also advantageously converted to the corresponding enol triflates XVIIIa to f which under cross-coupling conditions, produce also the intermediates of type XlXa to f.
- the compound of formula XlVa to f may also be directly converted to the corresponding enol ethers, affording the intermediates of type XlXa to f wherein R 4 is a C ⁇ - 6 alkoxy group.
- the triflates XVIIIa to f may successively undergo two cross-coupling reactions to produce first the vinyl trialkyltin compounds XXI which may then give the corresponding alkyl ketones XlXa to f. From these compounds, one may prepare various thioketal, thioacetal, acetal or ketal analogs of type XlXa to f using conditions well-known by those skilled-in-the-art.
- the same intermediates XlVa to f may also be converted, if desired, to the amines XXa to f by reductive amination.
- retinoids of type I bearing the different linker substituents R',R" may be carried out by coupling the intermediate of type XIX or XIV with the desired p-substituted benzoate entity as shown in Schemes 6, 7 and 8. It should be understood by those skilled in the art that the illustration in the schemes is not intended to be limiting, since slight modifications are often deemed desirable or necessary to achieve a particular result. Thus, many retinoids of type I may be prepared from ketone XXVIIIa (Scheme 6) which is produced by a Grignard type reaction between halides XlXa to f and the desired acid chlorides.
- a Friedel-Crafts acylation with the acid chloride may also be employed.
- Subsequent Wittig-type reaction under conditions known by those skilled in the art affords the protected retinoid XXVIIIb bearing a double bond as linker.
- Epoxide formation from ketone XXVIIIa leads to the protected retinoid XXVIIIc.
- This same ketone XXVIIIa may also undergo a Grignard type reaction to give the carbinol XXVIIId which, if desired, may be alkylated using conditions known by those skilled in the art and produce the protected retinoid of type XXVIIIe.
- the ketone XXVIIIa is directly converted to compound XXVIIIh.
- the same compound XXVIIIa may also be transformed to the imine XXVIIIi.
- the ketone XXVIIIa may be converted to the corresponding thioketone XXVIIIf by treatment with P 2 Ss or Lawesson's reagent and, if desired, this compound may lead to the protected retinoid XXVIIIg bearing a thioepoxide group as linker.
- the protected retinoid of type XXVIIIh prepared in Scheme 6 and bearing a dithiolane or dithiane linker (Scheme 7) may be reduced under conditions known by those skilled in the art if it is desired to have a retinoid bearing a methylene linker (XXVIIIk).
- the carbinol XXVIIId prepared also in Scheme 6 may be reduced, if desired, to the protected retinoid of formula XXVIIIm or, under reductive alkylation conditions as described above, may give the dialkylated protected retinoid of formula XXVIIIn.
- a second approach to the preparation of retinoid of type I is the coupling of the different ketones XlVa to f with the p-substituted benzoate entity XXV under cross-coupling conditions known in the art (Scheme 8).
- the resulting protected ketone XXIX is desilylated to give the ketone XXXa which then serves as a common intermediate for the preparation of many retinoids of type I and II bearing various linker substituents R',R".
- the silylated ketone XXIX may also be submitted to a Grignard type reaction followed by dehydration to give the protected retinoid of type XXVIIIb bearing a silylated double bond as linker.
- the tetralone intermediate XXXa may be reacted under Grignard conditions to give, after elimination the intermediate of type XXVIIIb.
- the same intermediate may be obtained by first converting the ketone XXXa to the corresponding enol triflate XXXIIa, which is then submitted to a cross- coupling or Heck type reaction under conditions known by those skilled in the art.
- the intermediate ketone XXXa is first protected as ketal XXXIa.
- the cyclopropanation reaction may then be carried out under conditions known in the art to give intermediate XXXIb, which is hydrolized to recover the ketone XXXb.
- This compound may then be submitted to a Grignard type reaction followed by the dehydration of the resulting carbinol to give the protected retinoid of formula XXVIIIo.
- the same compound may be obtained by first converting the tetralone XXXb to the corresponding enol triflate XXXIIb, which is then submitted to a cross-coupling or Heck type reaction under conditions known by those skilled in the art.
- retinoids of type II bearing the different linker substituents R', R" may be carried out by coupling the tetrahydronaphthalene, tetrahydroquinoline, chroman or thiochroman moieties of formula XX with the desired p-substituted benzoate entity as shown in Schemes 9 and 10. It should be understood by those skilled in the art that the illustration in the schemes is not intended to be limiting, since slight modifications are often deemed desirable or necessary to achieve a particular result.
- retinoids of type II may be prepared from ketone XXXIc (Scheme 9) which is produced by Grignard type reactions between halides XXa to f and the desired acid chloride XXVII. Subsequent Wittig-type reaction under conditions known by those skilled in the art affords the protected retinoid XXXIa bearing a double bond as linker. Epoxide formation from ketone XXXIc leads to the protected retinoid XXXIf bearing an epoxide as linker.
- This same ketone XXXIc may also undergo a Grignard type reaction to give the carbinol XXXId which, if desired, may be alkylated using conditions known by those skilled in the art and produce the protected retinoid of type XXXIe.
- the ketone XXXIc is directly converted to compound XXXIi.
- the same compound XXXIc may also be transformed to the imine XXXIj.
- the ketone XXXIc may be converted to the corresponding thioketone XXXIg by treatment with P 2 Ss or the Lawesson's reagent and, if desired, this compound may lead to the protected retinoid XXXIh bearing a thioepoxide group as linker.
- the protected retinoid of type XXXIi prepared in Scheme 9 and bearing a dithiolane or dithiane linker (Scheme 10) may be reduced under conditions known by those skilled in the art if it is desired to have a retinoid bearing a methylene linker (XXXIm).
- the carbinol XXXId prepared also in Scheme 9 may be reduced, if desired, to the protected retinoid of formula XXXIn or, under reductive alkylation conditions as described above, may give the dialkylated protected retinoid of formula XXXIo.
- retinoid of formula II bearing a cyclopropyl groups as linker
- the protected retinoid of formula XXXIa prepared in Scheme 9 is submitted to cyclopropanation conditions to give the compound of type XXXIb.
- the preparation of retinoid of formula II wherein X is a nitrogen may be prepared by reductive amination of the ketones of type XXXa or b to lead to the amines XXXIa or b.
- the compounds of type XXVIIIa to o may be oxidized to afford the ketones XXVIIIa to o (Scheme 11). Subsequently, this ketone may be converted to the ketal XXVIIIa to o under conditions known in the art. Alternatively, a Wittig type reaction affords the dienes of formula XXVIIIa to o.
- A O, S, NR 2
- R 4 C-i-g alkyl, C ⁇ polyfluoroalkyl, substituted phenyl or heteroaryl, Q-g alkylthio, C, ⁇ alkoxy
- R 4 -COR 13 , -C(OR 14 ) 2 R 13 , -C(SR 1 ) 2 R 13 , -CfSCH j CH j SJR 13 or -C(OCH 2 CH2 ⁇ )R 13
- R 17 -(CH--CHp-C ⁇ 2R 16 , -(C-CJp-COjR 16 , -(CH ⁇ p ⁇ R 16 , C ⁇ alkyl and halogen
- R 17 -(CH--CH p -C ⁇ 2R 16 , -(C-C) p -C ⁇ 2R 16 , -(CHipCO ⁇ R 16 , Ci-e alkyl and halogen
- R", R' contain O or S
- R 17 -(CH--CH)p-C0 2 R 16 , -(C--C)p-C0 2 R 16 , -(CH 2 ) p C ⁇ 2R 6 and C . 6 alkyl
- A C, N, O, S
- TMS tetramethylsilane
- the relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule.
- the nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet (q), quintet (qi), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quarter (dq).
- the solvents employed for taking NMR spectra are DMSO-d 6 (perdeuterodimethylsulfoxide), D 2 0 (deuterated water), CDC1 3 (deuterochloroform) and other conventional deuterated solvents.
- the infrared (IR) spectral description include only absorption wave numbers (cm "1 ) having functional group identification value. All melting points were not corrected.
- Patent 5,618,839 and EP 661,259) (3.0 g, 11.0 mmol) in tetrahydrofuran (15 mL) was then added dropwise to this mixture and the resulting mixture was stirred for 45 minutes at 0-5°C.
- Methyl 4-[(8-phenyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate (0.200 g, 0.487 mmol) was saponified as described in Example 1 for the preparation of 4-[(8-methoxy-5,5,8- trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoic acid.
- the title material (0.177 g, 96%) was obtained as a white solid.
- IR (KBr) ⁇ max (cm "1 ): 3300-2300 (br), 1690 (C 0), 1605.
- Methyl 4-[(8-isopropyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate (0.050 g, 0.139 mmol) was saponified as described in Example 2 and afforded the title material (0.041 g, 85%) as a white solid.
- Methyl 4-[(5,5,8-trimethyl-5,6-dihydro-2-naphthalenyl)ethenyl]benzoate (0.160 g, 0.481 mmol) was saponified as described in Example 2 and afforded the title material (0.139 g, 90%) as a white solid.
- the organic phase was separated and the aqueous phase was extracted with ethyl ether.
- the combined organic phases were washed with water, saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
- the residue was purified by silica gel chromatography (4.5 x 15 cm, 30 to 100% hexane /toluene) and triturated in hexane (3.9 g, 73%) as a white solid.
- the organic phase was separated and washed with IN hydrochloric acid, saturated sodium bicarbonate, aqueous sodium thiosulfate and brine.
- the aqueous phases were extracted with ethyl ether and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated.
- the title material was obtained (6.1 g, 63%) as a white solid along with the starting material (1.0 g, 11%) and ethyl 4-[(3,5,5-trimethyl-5,6-dihydro-8-hydroxy-2- naphthalenyl)ethenyl]benzoate (1.0 g, 11%).
- Ethyl 4-fl-.5.6.7.8-tetrahydro-3.5.5-trimethyl-8-.cyclopropylaminoV2- naphthalenyl.ethenyl]benzoate A powdered form of ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2- naphthalenyl)-ethenyl]benzoate (110 mg, 0.3035 mmol) was placed into a 7 mL vial equipped with a stirrer.
- the compounds prepared are the following:
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Abstract
Certain novel substituted (5,6)-dihydronaphthalenyl and substituted (5,6,7,8)-tetrahydronaphthalenyl compounds selectively activate Retinoid X Receptors (RXRs) and are useful in various dermatological diseases, in the treatment of malignant tumors and as agents for the minimization or prevention of post-surgical adhesion formation.
Description
SELECTIVE RETINOIC ACID ANALOGS
FIELD OF THE INVENTION
The present invention relates to compounds having selective activity for specific retinoid acid receptors. More specifically, this invention provides a novel series of substituted (5,6)- dihydronaphthalenyl and substituted (5,6,7,8)-tetrahydronaphthalenyl compounds which selectively activate Retinoid X Receptors (RXRs) in comparison to Retinoic Acid Receptors (RARs). Also included in this invention are compounds from these series which activate both types of Retinoid Receptors (RARs and RXRs) and act as "bifunctional ligands" similarly to 9-ris-retinoic acid. These compounds are useful as antiinflammatory agents for chronic skin inflammatory diseases such as psoriasis and atopic dermatitis, as agents for the treatment of rheumatic diseases such as rheumatoid arthritis, as antitumor agents for the treatment of various tumors as well as non-malignant proliferative skin conditions and as agents for the minimization or prevention of post- surgical adhesion formation.
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. A few retinoids are already in clinical use in the treatment of dermatological diseases such as acne and psoriasis. For example, isotretinoin is used clinically for oral therapy of severe acne, and
etretinate and tazarotene are particularly useful in the treatment of psoriasis.
Isotretinoin Etretinate
There are two subfamilies of Retinoid Receptors, the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs). Both subfamilies are divided into three isoforms, α, β and γ. The structural differences between these receptors have been recently shown with the crystal structures of apo-RXR-α and RAR-γ liganded with all-t rαns-retinoic acid (Renaud J.-P. et αl, Nature vol. 378 p. 681 to 689 (1995) and Bourguet W. et αl, Nature vol. 375 p. 377 to 382 (1995)). These differences had also been previously demonstrated by the responsiveness of RARs and RXRs to various vitamin A metabolites and synthetic retinoids and by their different patterns of tissue distribution.
The use of retinoids is associated with many side-effects such as teratogenicity and irritation. These side-effects may be related to the ability of the retinoids to activate multiple retinoid receptors in a wide variety of tissues. Therefore, current retinoid research targets the development of receptor-selective retinoids for improving their therapeutic profile.
On the other hand, 9-cis-retinoic acid is a natural ligand which can interact with both the RARs and the RXRs. This compound was recently found to have good potential as an anti-proliferative agent which could be used in the treatment of various tumors as well as non-malignant proliferative skin conditions. Furthermore, synthetic RXR receptor selective ligands have been recently found to display synergistic activation of genes when they are used in combination with RAR-specific ligands (Chen, J.-Y. et al, Nature vol. 382, 819-822 (1996)). The development of synthetic retinoids combining both activities could therefore increase the therapeutic efficacy. Also, the relative instability of 9-czs-retinoic acid dictates the development of more stable synthetic retinoids having a similar activity profile.
With respect to compounds or classes of compounds acting selectively or specifically as agonists of the RXR receptor sites in preference over the RAR receptor sites, the following examples are noted.
WO Patent Applications 95/04036, 94/15901 and 93/21146 describe bicyclic benzyl, pyridinyl, thiophene, furanyl, pyrrole and polyenic acid derivatives which selectively or preferentially activate RXR receptors. Specific examples of these disclosures are 4-[l-(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydro-2-naρhthalenyl)ethenyl]benzoic acid, 2-[l-(3,5,5,8,8- pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]pyridine-5- carboxylic acid, 3-methyl-5-{2-[2-(2,6,6-trimethylcyclohexen-l- yl)ethenyl]phenyl}-2E,4E-pentadienoic acid and (2E,4E,6Z)-7- [5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-3,8-dimethyl-nona-2,4,6- trienoic acid.
The first compound listed above and related analogs are also disclosed in the French patent 86 10423 as medicines or cosmetics. In addition, the US patent No. 5,466, 861 describes the two first above- mentioned examples and related series. These compounds are claimed to be useful in modulating genetic expression by a receptor selected from the group consisting of retinoic acid receptors, retinoid X receptors, vitamin D receptors and thyroid receptors.
WO patent 96/05165 discloses novel retinoic acid X-receptor ligands of this general formula:
Specific examples encompassed by this generic structure are (2E,4E)- 3-methyl-5-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)- phenyl]-penta-2,4-dienoic acid and (2E,4E)-3-methyl-5[(lRS,2RS)-2-(5,5,8,8-
tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4- dienoic acid.
In another aspect, US patent No. 5,455,265 and WO patent 94/17796 describe a method of treatment with compounds having selective agonistlike activity on RXR receptors while WO patent 94/20093 is directed to a process for inducing apoptosis in tumor cells by administration of compounds having agonist-like activity at RXR retinoid sites. Finally,
WO patent 97/12853 describes novel RXR modulators that selectively bind to RXR receptors in preference to RAR receptors and that, depending upon the receptor and /or cellular context, display activity as full agonists, partial agonists and/or full antagonists on RXR homodimers and/or heterodimers.
SUMMARY OF THE INVENTION
The present invention provides a novel series of substituted (5,6)- dihydronaphthalenyl and substituted (5,6,7,8)-tetrahydronaphthalenyl compounds which selectively activate Retinoid X Receptors (RXRs) in comparison to Retinoic Acid Receptors (RARs). These compounds selectively modulate processes mediated by Retinoid X Receptors. Also provided in this invention are compounds included in these series which activate both types of Retinoid Receptors (RARs and RXRs). Finally, the
present invention describes compounds included in these series which have been found to be particularly useful as agents for the minimization or prevention of post-surgical adhesion formation.
In a preferred embodiment, the retinoid is defined by the generic formula:
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which,
R' and R" are independently hydrogen, Ci-6 alkyl, hydroxy,
Cι-6 alkoxy or Ci-6 alkylthio; or when taken together are =0, =S, =NR15,
=CR10R11, C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -S(CH2)mS- or -0(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Cχ-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur;
R1 is -(CH=CH)p-C02Z, -(C---C)p-C02Z, -(CH2)p -C02Z, Ci-6 alkyl, -CH2OH, -CONHR12,
-CHO, -COC02Z or C=N(OR12)-C02Z;
R2 and R3 are independently hydrogen or Ci-6 alkyl when
A is carbon or nitrogen; independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
R4 is hydrogen, Ci-io alkyl, C3-10 cycloalkyl, alkyl
Ci-10 polyfluoroalkyl, Cι-10 alkylthio, C3.10 cycloalkylthio, Ci-io alkylsulfoxy, C3-10 cycloalkylalkylsulfoxy, Ci-io alkylsulfone, C3-10 cycloalkylsulfone, Cχ-ιo alkoxy, C3-10 cycloalkoxy, Ci-io alkylamino, C3-10 cycloalkylamino, -COR13, -C(OR1 )2R13, -C(SR14)2R13, phenyl or heteroaryl, wherein the phenyl or the heteroaryl radicals can be substituted by Ci-6 alkyl, halogen, Ci-6 alkoxy, Ci-6 alkylthio, -C02R13, -COR13 or -NR1 R14 ;
R5 is hydrogen, Ci-6 alkyl, Ci-6 alkoxy or
alkythio, C2-6 alkenyl or C2_6 alkynyl;
R6 is hydrogen or Ci-6 alkyl;
R7 are independently hydrogen, Ci-6 alkyl, hydroxyl, fluoride, Ci-6 alkyloxy or
alkylthio; but when n is one, R6 and R7 together can form a radical of the formula
R8 and R9 are independently hydrogen, halogen, Ci-6 alkyl, hydroxy, azide, cyanide, Ci-6 alkoxy or nitro;
R10, R11, R12, R13 and R14 are independently hydrogen or Ci-6 alkyl;
R15 is OH, Ci-6 alkyl, aryl or heteroaryl;
n is 0 to 2;
m and q are independently 2 to 5;
p is 0 to 2;
Z is Ci-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as
Li+, Na+ or K+.
In another preferred embodiment, the retinoid is defined by the generic formula:
R' and R" are independently hydrogen, Ci-6 alkyl, hydroxy, Ci-6 alkoxy or Ci-6 alkylthio; or when taken together are =0, =S, =NR15, =CR10R11 / C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -S(CH2)mS- or -0(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Cχ-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur;
R1 is -(CH=CH)p-C02Z, -(C≡C)p-C02Z, -(CH2)p
-C02Z, Ci-6 alkyl, -CH2OH, -CONHR12, -CHO, -COC02Z or -C=N(OR12)-C02Z;
R2 and R3 are independently hydrogen or Cι_6 alkyl when A is carbon or nitrogen; each independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
R5 is hydrogen, Ci-6 lower alkyl, Ci-6 alkoxy or Ci-6 alkythio, C2_6 alkenyl or C2-6 alkynyl;
R6 is hydrogen or Ci-6 alkyl;
R7 are independently hydrogen, -6 alkyl, hydroxyl, fluoride, Ci-6 alkyloxy, Ci-6 alkylthio or carbonyl; but when n is one, R6 and R7 together can form a radical of the formula
7 and when n is two, both R taken together can be =0, =S, =CH2, =C(CH3)2, =CH(CH3), -0(CH2)20-, -S(CH2)20- or -S(CH2)20-;
R8 and R9 are independently hydrogen, halogen, Ci-6 alkyl, hydroxy, azido, cyano, Ci-6 alkoxy or nitro;
R10, R11, R12, R13 and R14 are independently hydrogen or Cχ-6 alkyl;
R15 is OH, Ci-6 alkyl, aryl or heteroaryl;
Ra is hydrogen, Ci-6 alkyl, Ci-6 alkoxy or Ci-6 alkylthio;
Rb is hydrogen, Cι_6 alkyl, C3-6 cycloalkyl or Ci-6 alkyl-C3-6 cycloalkyl;
X is O, S or N;
n is 0 to 2;
m and q are independently 2 to 5;
IT p is 0 to 2;
Z is Ci-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as
Li+, Na+ or K+.
The compounds of the present invention are useful for treating a host animal, preferably a mammal and most preferably a human, for chronic skin inflammatory diseases (e.g. psoriasis and atopic dermatitis), rheumatic diseases (e.g. rheumatoid arthritis), non-malignant skin conditions, and as antitumor agents for the treatment of tumors sensitive to the compounds. In such cases an effective therapeutic amount of a compound of the present invention is administered to said host animal in the same manner as with other retinoid compounds.
The compounds of the present invention are also useful as agents for the minimization or prevention of post-surgical adhesion formation in animals, preferably mammals and most preferably, humans. Thus, one aspect of the present invention is 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 compound of the present invention for a period of time sufficient to permit tissue repair.
The compounds may be administered systemically or topically, depending on the condition to be treated, the need for site-specific treatment or the quantity of drug to be administered.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula I
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which,
R' and R" are independently hydrogen, Ci-6 alkyl, hydroxy,
Ci-6 alkoxy or Ci-6 alkylthio; or when taken together are =0, =S, =NR15, =CR10R1:l, C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -S(CH2)mS- or -0(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Ci-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur;
R1 is -(CH=CH)p-C02Z, -(C-EC)P-C02Z, -(CH2)p
-C02Z, Ci-6 alkyl, -CH2OH, -CONHR12, -CHO, -COC02Z or C=N(OR12)-C02Z;
R2 and R3 are independently hydrogen or Cχ-6 alkyl when
A is carbon or nitrogen; independently
oxygen or nothing when A is sulfur and nothing when A is oxygen;
R4 is hydrogen, Cχ.χo alkyl, C3- 0 cycloalkyl, alkyl Cχ- 0 polyfluoroalkyl, Cχ.χo alkylthio, C3- 0 cycloalkylthio, Cχ.χo alkylsulfoxy, C3- 0 cycloalkylalkylsulfoxy, Cχ.χo alkylsulfone, C3-X0 cycloalkylsulfone, Cχ.χo alkoxy, C3-χo cycloalkoxy, Cχ-χo alkylamino, C3-X0 cycloalkylamino, -COR13, -C(OR14)2R13,
-C(SR1 )2R13, phenyl or heteroaryl, wherein the phenyl or the heteroaryl radicals can be substituted by Cχ_6 alkyl, halogen, Cχ-6 alkoxy, Cχ-6 alkylthio, -C02R13, -COR13 or -NR13R14;
R5 is hydrogen, Cχ-6 alkyl, Cχ-6 alkoxy or Cχ-6 alkythio, C2-6 alkenyl or C2-6 alkynyl;
R6 is hydrogen or Cχ-6 alkyl;
R7 are independently hydrogen, Cχ-6 alkyl, hydroxyl, fluoride, Cχ-6 alkyloxy or Cχ-6 alkylthio; but when n is one, R6 and R7 together can form a radical of the formula
R8 and R9 are independently hydrogen, halogen, Cχ-6 alkyl, hydroxy, azide, cyanide, Cχ-6 alkoxy or nitro;
R10, R11, R12, R13 and R14 are independently hydrogen or Cχ-6 alkyl;
Rl5 is OH, Cχ-6 alkyl, aryl or heteroaryl;
n is 0 to 2;
m and q are independently 2 to 5;
p is 0 to 2;
Z is Cχ-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as Li+, Na+ or K+.
These compounds are distinguished from those of the prior art by the presence of the carbon-carbon double bond in the 7,8 position of the dihydronaphthalene ring; consequently only one 8-substituent can exist.
In another preferred embodiment, the retinoid is defined by the generic formula:
or nontoxic pharmaceutically acceptable salts, physiologically hydrolyzable esters or solvates thereof, in which,
R' and R" are independently hydrogen, C -6 alkyl, hydroxy,
Cχ-6 alkoxy or Cχ-6 alkylthio; or when taken together are =0, =S, =NR15, =CR10R11, C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -S(CH2)mS- or -0(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Cχ-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur;
R1 is -(CH=CH)p-C02Z, -(C≡C)p-C02Z, -(CH2)p
-C02Z, Cχ-6 alkyl, -CH2OH, -CONHR12, -CHO, -COC02Z or -C=N(OR12)-C02Z;
R2 and R3 are independently hydrogen or Cχ-6 alkyl when
A is carbon or nitrogen; each independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
R5 is hydrogen, Cχ-6 lower alkyl, C -6 alkoxy or
Cχ-6 alkythio, C2-6 alkenyl or C2-6 alkynyl;
R6 is hydrogen or Cχ-6 alkyl;
R7 are independently hydrogen, Cχ-6 alkyl, hydroxyl, fluoride, Cχ_6 alkyloxy, Cχ-6 alkylthio or carbonyl; but when n is one, R6 and R7 together can form a radical of the formula
7 and when n is two, both R taken together can be =0, =S, =CH2, =C(CH3)2, =CH(CH3), -0(CH2)20-, -S(CH2)20- or -S(CH2)20-;
R8 and R9 are independently hydrogen, halogen, Cχ-6 alkyl, hydroxy, azido, cyano, Cχ-6 alkoxy or nitro;
R10, R11 and R12 are independently hydrogen or Cχ-6 alkyl;
R15 is OH, Cχ-6 alkyl, aryl or heteroaryl;
Ra is hydrogen, Cχ-6 alkyl, Cχ-6 alkoxy or Cχ_6 alkylthio;
Rb is hydrogen, Cχ-6 alkyl, C3-6 cycloalkyl or Cχ_6 alkyl-C3-6 cycloalkyl;
X is O, S or N;
n is 0 to 2;
m and q are independently 2 to 5;
p is 0 to 2;
Z is Cχ-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation such as Li+, Na+ or K\
These compounds are distinguished from those of the prior art by the presence of only a single carbon atom linker between the tetrahydronaphthalene and benzoate rings.
Definitions
In the present application, the numbers in subscript after the symbol "C" define the number of carbon atoms that a particular group can contain. For example, Cχ.χo alkyl refers to straight and branched chain alkyl groups with one to ten carbon atoms, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl etc.
The term cycloalkyl is intended to include straight or branched cycloalkyl groups containing three to ten carbon atoms.
The term polyfluoroalkyl means that at least one hydrogen atom in the alkyl side-chain is replaced by a fluorine atom.
The term alkenyl defines a carbon chain having at least one double bond. For example, C2-6 alkenyl refers to a straight or branched chain of two to six carbons bearing at least one double bond, such as ethenyl, 1- methyl-ethenyl, 1- or 2-propenyl, 1-methyl-l-propenyl, l-methyl-2- propenyl, l,l-dimethyl-2-propenyl, 2-methyl-2-propenyl, 1-, 2- or 3- butenyl, 1-methyl-l-butenyl, 2-methyl-l-butenyl, 3-methyl-l-butenyl, 3,3- dimethyl-1-butenyl, 2,3-dimethyl-l-butenyl, l-methyl-2-butenyl, 1,1- dimethyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1,3- butadienyl, l,3-dimethyl-l,3-butadienyl, 1-, 2-, 3- or 4-pentenyl etc.
The term alkynyl define a carbon chain having at least one triple bond. For example, C2-6 alkynyl refers to a straight or branched chain of two to six carbons bearing at least one triple bond, such as ethynyl, 1- or 2- propynyl, l-methyl-2-propynyl, l,l-dimethyl-2-propynyl, 1-, 2- or 3- butynyl, 3-methyl-l-butynyl, 3,3-dimethyl-l-butynyl, l-methyl-2-butynyl, l,l-dimethyl-2-butynyl, 1-, 2-, 3, or 4-pentynyl etc.
The term C3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals.
The term Cχ-6 alkoxy and Cχ-6 alkylthio refers to an ether or a thioether bearing a straight or branched carbon chain, such as methoxy, methylthio, ethoxy, ethylthio, n-propoxy, n-propylthio, isopropoxy, isopropylthio, n-butoxy, n-butylthio, tert-butoxy, tert-butylthio, n-pentoxy, n-pentylthio etc.
The term halogen refers to fluorine, chlorine, bromine or iodine.
The term "heteroaryl" as used herein includes mono-, bi- and polycyclic aromatic heterocyclic groups containing 1 to 4 O, N or S atoms; preferred are 5- and 6-membered heterocyclic groups such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc. and fused 5,6-membered and 6,6- membered heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indazolyl, indolizinyl, isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, quinazolinyl, pteridinyl etc.
Some compounds of formula I and II may also form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. Such cations are also referred to herein as "pharmaceutically acceptable cations." These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred. Amines which are capable of forming stable salts include mono-, di-, and trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or the like pharmaceutically acceptable amines.
When a compound of formula I and II contains a carboxy group, it can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I or formula II compounds
per se. They are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester γer se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I and II include Cχ-6 alkyl benzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Cχ-6 alkanoyloxy-Cχ-6 alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, Cχ_6 alkoxycarbonyloxy-Cχ-6 alkyl, e.g. methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4- yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters are prepared by conventional techniques known in the art.
The structural formulae as drawn in the instant application are believed to best represent the structures of compounds of the present invention. However, some compounds within the scope of the invention may exist as other tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the structural formulae represent all tautomeric forms, insofar as they may exist.
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). 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 (where applicable).
With reference to the substituent R1 in formula I and II, the preferred compounds are those where R1 is limited to -C02Z. When A is a carbon, the R2 and R3 groups of the preferred compounds are preferably Cχ-6 alkyl and even more preferably methyl. In the preferred compounds of the invention, R7, R8 and R9 are also preferably hydrogens.
As used herein and in the reaction schemes, the term "Grignard type reaction" is intended to include the addition of an organometallic compound to a carbonyl-containing compound. This includes addition of Grignard (organomagnesium) reagents, alkyl or aryllithiums, alkylzinc, alkylaluminum, organotitanium, organozirconium or organocerium compounds in an inert organic solvent such as ethyl ether, tetrahydrofuran, dichloromethane, benzene or toluene and the like. Sometimes, the complexation of the ketone or the Grignard reagent with cerium halides, perchlorate salts or tetraalkylammonium halides is necessary to improve the addition reaction. The term "Grignard type reaction" is also intended to include the addition of a Grignard reagent to an acid chloride that has been first reacted with tributylphosphine to form the corresponding phosphonium salt. The reaction is performed in an inert organic solvent such as ethyl ether, tetrahydrofuran, benzene and the like.
As used herein and in the reaction schemes, the term "Friedel- Crafts reaction" is intended to include the acylation or alkylation of aromatic rings. The acylation includes the addition of an acyl halide, a carboxylic acid, an anhydride or a ketene to an aromatic ring under Lewis acid conditions such as aluminum, tin, antimony, zirconium, boron halides and the like or under proton acid conditions such as polyphosphoric acid, sufluric acid, methanesulfonic acid and the like. The alkylation includes the addition of alkyl halides, olefins or alcohols under Lewis or proton acid conditions such as the one listed above.
The term "aromatic halogenation" is intended to include the addition of chlorine, bromine or iodine to an aromatic ring in the presence or absence of a catalyst, usually iron or a Lewis acid such as aluminum, tin, antimony halides and the like. It is also intended to include the reaction of N-chloro and N-bromoamides catalyzed by the addition of acids. For iodination, iodine may be used in presence of an oxidizing agent such as nitric acid, iodic acid, sulfur trioxide or hydrogen peroxide or in the presence of copper salts, silver trifluoromethanesulfonate or thallium(I) acetate. Iodine monochloride can also be used.
As used herein and in the reaction schemes the term "reduction" is intended to include well-known reduction procedures of ketone groups by the use of aluminum or boron hydrides such as lithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and the like in an organic solvent such as tetrahydrofuran, ethyl ether, ethanol, dichloromethane and the like. The term "reduction" is also intended to include the reduction or
desulfurization of dithioacetals by the use of Raney nickel with or without hydrogen, in organic solvents such as methanol, ethanol, ethanol /water, ethanol/ethyl ether, dioxane, acetone, tetrahydrofuran, benzene and the like. Other conditions to perform reduction are the use of trialkyltin hydrides in the presence of AIBN in an inert organic solvent such as benzene or toluene, or the use of aluminum or boron hydrides such as lithium aluminum hydride or sodium borohydride in the presence of titanium(IV) chloride or nickel(II) chloride in tetrahydrofuran, ethanol or dimethylformamide. The term "reduction" is also intended to include well-known reduction procedures of benzylic alcohols. These methods include the use of aluminum, boron or trialkylsilyl hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or triethylsilylhydride with or without aluminum chloride, zinc iodide or an acid such as hydrochloric acid, trifluoroacetic acid or trifluoroboron etherate in an organic solvent such as tetrahydrofuran, ethyl ether or ethanol. Well-known hydrogenation procedures using hydrogen with a catalyst such as palladium on charcoal or Raney nickel in methanol or ethanol may also be used if appropriate.
As used herein and in the reaction schemes, the term "reductive animation" is intended to include conventional imine formation procedures well-known to those skilled in the art. These procedures involve the reaction of an amine with a Lewis acid such as titanium(IV) chloride or isopropoxide. Subsequently, this imine is reduced with well- known reducing agents such as sodium borohydride or sodium cyanoborohydride.
As used herein and in the reaction schemes, the term "hydrolysis" is intended to include conventional hydrolytic procedures of esters well- known to those skilled in the art. For example, methyl or ethyl esters may be removed by the use of aqueous solutions of sodium or potassium hydroxides or alkoxides in tetrahydrofuran or ethanol. The hydrolysis of tert-butyl esters is carried out under acidic conditions such as 90% trifluoroacetic acid or 6N hydrochloric acid in solvents such as tetrahydrofuran or dichloromethane. Allyl esters may be removed by the use of Pd(0) catalyst with a base, such as sodium acetate, potassium or sodium 2-ethylhexanoate, pyrrolidine or morpholine and the like in an organic solvent such as acetonitrile, tetrahydrofuran, dichloromethane and the like. Finally, silyl esters such as trimethylsilylethyl esters may be cleaved by the use of tetrabutylammonium fluoride in tetrahydrofuran. The term "hydrolysis" is also intended to include conventional hydrolytic procedures of carbonyl protecting groups. For example, the hydrolysis of ketals and acetals may be carried out under acidic conditions such as IN hydrochloric acid, 80% acetic acid or p-toluenesulfonic acid in solvents such as tetrahydrofuran or acetone.
As used herein and in the reaction schemes, the term "enol triflate or enol formation" is intended to include conventional and well-known enolate formation procedures and subsequent trapping of this enolate by the well-known triflating or silylating agents. Thus the ketones are treated with a base such as 2,6-di-tert-butyl-4-methyl-pyridine, sodium hydride, potassium hydride, lithium diisopropylamide or lithium bis(trimethylsilyl)amide in an inert organic solvent such as tetrahydrofuran, dimethylformamide or dichloromethane and the like. The resulting enolates are then reacted with triflic anhydride or 2-[N,N-
bis(trifluoromethylsulfonyl)amino]pyridine and the like or alkylsilyl halides or triflates.
As used herein and in the reaction schemes, the term "cross- coupling" is intended to include all the cross-coupling methods well- known by those skilled in the art that involve the reaction of a vinyl or aromatic triflate, bromide or iodide with a tin, zinc, magnesium or boronic derivative catalyzed by a palladium(O) or palladium(II) catalyst such as tetrakis(triphenyl-phosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate, tris(dibenzylidene-acetone)dipalladium(0), bis(diphenylphosphineferrocene)palladium(II) chloride and the like or a nickel(O) or nickel(II) catalyst such as tetrakis(triphenylphosphine) nickel(O), bis(triphenylphosphine)nickel(II) chloride and the like. Very often, as known by those skilled in the art, copper iodide, lithium chloride, zinc chloride or triphenylarsine, tris(2-furyl)phosphine or tris(2,4,6-trimethoxyphenyl)phosphine must be added. When a boronic acid derivative is used, the reaction proceeds only in the presence of an inorganic base such as potassium phosphate or carbonate or sodium carbonate. These reactions may be performed in an inert organic solvent such as dioxane, N-methylpyrrolidone, dimethylformamide, dimethoxyethane, tetrahydrofuran, toluene, benzene and the like.
As used herein and in the reaction schemes, the term "Heck coupling" is intended to include all known vinylations of alkenes or alkynes. Thus, a vinyl or aromatic triflate, bromide or iodide reacts with various substituted or non-substituted alkenes or alkynes in the presence of a trialkylamine base or an inorganic base such as potassium carbonate,
sodium acetate and the like and a catalytic amount of Pd(II) complex such as palladium(II) acetate, bis(triphenylphosphine) palladium(II) chloride or bis(acetonitrile)palladium(II) chloride. Sometimes phosphine ligands such as triphenylphosphine, tritolylphosphine, diphenylphosphineferrocene or l,3-bis(diphenylphosphino) propane and the like may facilitate the reaction.
As used herein and in the reaction schemes the term "alkylation" is intended to include conventional and well-known alkylation procedures. Thus, the desired alcohol or ketone groups which are to be alkylated are treated in the presence of an organic or inorganic base such as sodium hydride, potassium hydride, lithium diisopropylamine or lithium bis(trimethylsilyl)amide in an inert organic solvent such as tetrahydrofuran, dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, N-methylpyrolidinone and the like. Then an alkylating agent such as an alkyl, allyl or benzyl halide, mesylate or tosylate is added to this generated enolate, phenolate or thiophenolate. As used herein and in the reaction schemes the term "reductive alkylation" is intended to include the methods used to convert a tertiary alcohol to an alkyl, aryl or allyl group. Thus, the alcohol that has to be transformed may be treated by an organosilicon compound in the presence of boron trifluoride in dichloromethane or by a trialkylboron in the presence of trifluoromethanesulfonic acid in 1,1,2-trichlorotrifluoroethane. Another method is to react the corresponding alkoxide with iron pentacarbonyl to perform a deoxygenation reaction which may be followed by treatment with various alkyl or aryl halides. The alkoxide may be generated by treatment with a metal such as potassium, sodium or lithium in toluene.
As used herein and in the reaction schemes the term "oxidation" is intended to include conventional allylic or benzylic oxidation methods such as selenium dioxide with or without the use of tert-butyl peroxide, sodium peroxide in ethanol and chromium(VI) reagents such as chromium(VI) trioxide in acetic acid and pyridinium dichromate and preferably potassium bromate in the presence of eerie ammonium nitrate in dioxane.
As used herein and in the reaction schemes the term "aromatic substitution" is intended to include nucleophilic substitutions of aromatic halides by water in the presence of sulfuric acid or trifluoroacetic acid, by alkoxides, aryloxides, thioalkoxides or thioaryloxides in an inert organic solvent such as hexamethylphosphoramide, dimethylsulfoxide, dimethylformamide and the like. The reaction of aryl halides with alkoxides may be promoted by copper salts and the reaction with thioalkoxides may be catalyzed by Pd(0) salts such as tetrakis(triphenylphosphine) palladium(O).
As used herein and in the reaction schemes the term "enone formation" is intended to include the well-known dehydrogenation procedures of ketones. Preferably, the ketone to be dehydrogenated is converted to a silyl enol ether as described above and then treated with an oxidizing agent such as dichlorodicyanoquinone, triphenylmethylcation or palladium(II) acetate in an inert organic solvent such as acetonitrile or dichloromethane.
As used herein and in the reaction schemes, the term "Michael addition" is intended to include all conventional methods of conjugate addition of organometallic compounds or anions formed from malonates, cyanoacetates, acetoacetates, β-ketoesters, esters, ketones, aldehydes, nitriles, nitro compounds, sulfones and the like to an α,β-unsaturated carbonyl compound. The organometallic compounds include lithium dialkylcopper, organoaluminum, trialkylzinc lithium, arylpalladium, arylmercury, borane reagents and the like. The inert organic solvents used may be tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, benzene and the like.
As used herein and in the reaction schemes, the term "acid halide formation" is intended to include the well-known methods of the conversion of a carboxylic acid to an acid halide such as the use of thionyl chloride, oxalyl chloride or bromide in the presence of dimethylformamide in dichloromethane and phosphorus trichloride or tribromide.
As used herein and in the reaction schemes, the term "Wittig type reaction" is intended to include conventional methods of Horner-
Emmons, Nysted or Wittig olefination reactions of aldehydes or ketones. Thus, in a Horner-Emmons olefination, an alkyl or aryl phosphonate is treated with a base such as sodium hydride, lithium diisopropylamide or lithium bis(trimethylsilyl)amide and the like in an inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde. In a Wittig reaction, an alkyl or arylphosphonium salt is treated with a base such as butyllithium, lithium diisopropylamine or lithium bis(trimethylsilyl)amide and the like in an
inert organic solvent such as tetrahydrofuran, dichloromethane, benzene and the like and reacted with a ketone or an aldehyde. In a Nysted olefination, the ketone is treated with {cyclo-dibromodi-μ-methylene[μ- (tetrahydrofuran)]trizinc} (Nysted reagent) in the presence of titanium chloride in an inert solvent such as tetrahydrofuran and dichloromethane.
As used herein and in the reaction schemes, the term "epoxidation or thioepoxidation" is intended to include the well-known methods of epoxide formation by reaction of an olefin with a peracid as well as the epoxide formation by reacting a gem-dihalide in the presence of a strong base such as butyllithium, t-butyllithium methyllithium or lithium with a ketone in inert organic solvents such as tetrahydrofuran or ether. It is also intended to include methods of methylenation using the reaction of sulfur ylides such as dimethyloxosulfonium methylide and dimethylsulfonium methylide which are generated by treatement of the corresponding sulfonium salt with an organic base such as sodium hydride or potassium tert-butoxide in organic solvents such as dimethylsulfoxide, tetrahydrofuran, t-butanol, dimethoxyethane and the like with a ketone. The term "epoxidation or thioepoxidation" is also intended to include the methods by which a diazoalkane reacts with a ketone in a solvent such as methanol or ethyl ether.
As used herein and in the reaction schemes, the term "acetal, ketal, thioacetal or thioketal formation" are processes well-known in the art and they are well illustrated in "Protective Groups in Organic Synthesis", Second Ed., T. W. Green and P. G. W. Wuts, John Wiley & Sons, New York, 1991, Chapter 4 and references therein. Thus, the ketone or
aldehyde to be protected is treated with the desired alcohol or diol, thiol or dithiol in the presence of an inorganic or organic acid such as p- toluenesulfonic acid, hydrochloric acid, trifluoroboron etherate, oxalic acid, adipic acid, pyridinium tosylate, acetic acid and the like, in inert organic solvents such as benzene, toluene, acetonitrile or dichloromethane.
As used herein and in the reaction schemes, the term "cyclopropanation" is intended to include the well-known Simmons- Smith procedure involving the reaction of a dihaloalkane and zinc- copper couple with an olefin in organic solvents such as ethyl ether, dimethoxyethane or tetrahydrofuran. The preparation of the zinc-copper couple is preferably carried out with zinc dust and cuprous chloride. Other variations of this procedure are the use of a dihaloalkane with samarium, mercuric chloride in tetrahydrofuran or with diethylzinc in dichloromethane or toluene. The term "cyclopropanation" is also intended to include the addition of carbenes to carbon-carbon double bonds such as the reaction of a diazoalkane with rhodium acetate or palladium(II) acetate in tetrahydrofuran or dichloromethane, the reaction of a dihaloalkane with a strong base such as n-butyllithium, methyllithium or t-butyllithium in inert organic solvents such as ethyl ether or tetrahydrofuran or the reaction of chloroform with sodium or potassium hydroxide under phase transfer conditions such as tetraalkylammonium halide in water or a mixture of water /ethanol.
The term "imine formation" is intended to include the well- known procedures by which a ketone reacts with an amine in presence of an acid with or without a drying agent. These conditions include various
inorganic and organic acids such as zinc chloride, titanium chloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, p- toluenesulfonic acid and the like in solvents such as dichloromethane, ethanol, benzene, toluene, tetrahydrofuran, dimethylformamide and the like.
The compounds of the present invention are useful for treating a host animal, preferably a mammal and most preferably a human, for chronic skin inflammatory diseases (e.g. psoriasis and atopic dermatitis), rheumatic diseases (e.g. rheumatoid arthritis), non-malignant skin conditions, and as antitumor agents for the treatment of tumors sensitive to the compounds. In such cases an effective therapeutic amount of a compound of the present invention is administered to said host animal in the same manner as with other retinoid compounds.
The compounds of the present invention are also useful as agents for the minimization or prevention of post-surgical adhesion formation in animals, preferably mammals and most preferably, humans. Thus, one aspect of the present invention is 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 compound of the present invention for a period of time sufficient to permit tissue repair.
The compounds may be administered systemically or topically, depending on the condition to be treated, the need for site-specific treatment or the quantity of drug to be administered.
Modes of Administration
For prevention of surgical adhesions, a compound of the present invention may be administered by a variety of systemic and local methods. The compounds may be administered orally, by intravenous injection, by intramuscular injection or by intracavity instillation. The general range of doses will depend on the efficacy of 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 routes of adminstration are oral administration or direct administration (intracavity administration) 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 compound 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 compound 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 compound can be administered in a suitable vehicle such as 5% dextrose in water adjusted to a pH to assure complete salt formation. However, it is understood that many other single dose delivery systems could be contemplated by those skilled in the art including microcapsules, microspheres, liposomes, viscous instilates, and polymeric delivery materials.
The compounds of formula I or II above may be used topically or systemically, as anticancer agents and in the treatment, amelioration or prevention of the skin disorders and rheumatic illnesses (including rheumatoid arthritis) described in U.S. Patent 5,618,839. In this regard they may be used for therapy in animals, including humans, of premalignant epithelial cell lesions, as a prophylaxis against tumor promotion in epithelial cells and treatment for dermatoses such as ichthyoses, follicular disorders, benign epithelial disorders and other proliferative skin diseases such as psoriasis, eczema, atopic dermatitis, non-specific dermatosis and the like. They may also be used in reversing and preventing the effects of irradiation damage to skin. When used for the above purposes, they will usually be formulated with a pharmaceutically acceptable liquid, semi-solid, or solid carrier. A pharmaceutically acceptable carrier is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely. Such materials are well known and include those materials sometimes referred to as diluents or vehicles (excipients) in the pharmaceutical formulation art. The carrier may be organic or inorganic in nature. Examples of pharmaceutically acceptable carriers that may be used to formulate a compound of formula I or II are water, gelatin, lactose, starch, mineral oil, cocoa butter, dextrose, sucrose, orbital, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, and other commonly used pharmaceutical carriers. In addition to a compound of formula I or II and carrier, the formulation may contain minor amounts of additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
The dosages and dosage regimen in which the compounds of formula I or II are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases oral administration may also be used. If the compounds according to the invention are used topically, it will be found that they exhibit a good activity over a very broad range of dilution; in particular, concentrations of the active compound or compounds ranging from 0.0005% to 2% by weight can generally be used. It is of course possible to use higher concentrations if this should become necessary for a particular application; however, the preferred concentration of active principle are from 0.002% to 1% by weight.
For topical administration the compounds of formula I or II are conveniently provided in the form of unguents, gels, creams, ointments, powders, dyeing compositions, solutions, suspensions, emulsions, lotions, sprays, adhesive plasters and impregnated pads. The compounds according to the invention can be mixed with inert nontoxic, generally liquid or pasty, bases suitable for topical treatment. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. Other medicaments can be added to such formulation for such secondary
purposes as treating skin dryness, providing protection against light, treating dermatoses, preventing infection, reducing irritation, inflammation and the like.
The compounds according to the invention can also be used enterally. Orally, the compounds according to the invention are suitably administered at the rate of 100 μg to 100 mg per day per kg of body weight. The required dose can be administered in one or more portions. For oral administration, suitable forms are, for example, tablets, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using pills containing from 1 mg to about 1000 mg of active substance.
U.S. Patent No. 4,876,381 issued on October 24, 1989 to Lang et al. provides examples of formulations constituting gel, unguent, powder, cream, etc. The aforesaid U.S. patent can be used as a guide to formulate a compound of formula I or II and is herein incorporated by reference in its entirety.
Isotretinoin (Accutane®) and Etretinate (Tegison®) are used clinically to treat severe recalcitrant cystic acne and severe recalcitrant psoriasis, including the erythrodermica and generalized pustular types, respectively. Their mode of use is amply illustrated in the Physicians' Desk Reference, 47th Edition, 1993, published by Medical Economics Data. The compounds of formula I or II may also be used to treat severe recalcitrant psoriasis. In so doing, the compounds of the present invention may be used in a similar fashion to isotretinoin and etretinate; thus, the relevant sections on isotretinoin and etretinate in the
Physicians' Desk Reference will serve as a convenient guide which will obviate the need for any undue experimentation.
The compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections. In that case, the compounds according to the invention are generally administered at the rate of about 10 μg to 10 mg per day per kg of body weight; a preferred method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml.
Several retinoids have been found to possess anti-tumor properties. See, for example, Roberts, A.B. and Sporn, M.B. in "The Retinoids." Sporn, M.B., Roberts, A.B., and Goodman, D.S., eds, 1984, 2_ pp. 209-286, Academic Press, New York; Lippman, S.M., Kessler, J.F., and Meyskens, F.L.. Cancer Treat. Rep.. 1987, _ p. 391; ibid., p. 493. As used herein, the term "anti-tumor" includes both chemopreventive (prophylactic or tumor promotion inhibiting) and therapeutic (curative) use. For example, all-trans retinoic acid can be used to treat acute promyelocytic leukemia (Huang, M. et al, Blood. 1988, 72, p. 567). Isotretinoin has been shown to be useful in the prevention of second primary tumors in squamous-cell carcinoma of the head and neck (Hong, W.K. et al., N. Engl. T. Med.. 1990, 223, p. 795).
The compounds of formula I or II can be used in a substantially similar manner to other retinoids for treating (both chemopreventively and therapeutically) various tumors. For the compounds of this invention, the anti-tumor dose to be administered, whether a single dose,
multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient, the type of tumor, and the nature of the patient's condition. The dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects. An oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention, such as by referring to the earlier published studies on retinoids found to have anti-tumor properties. For example, for the prevention of second primary tumors with a compound of formula I or II in squamous-cell carcinoma of the head and neck, an oncologist may refer to the study by Hong, W.K et al. in N. Engl. J. Med., 1990, 323. p. 795. For treating acute promyelocytic leukemia, the oncologist may refer to the study by Huang, M. et al. in Blood. 1988, 72, p. 567.
Biological Activity
1) In vitro retinoid activity:
The retinoid-like activity and efficacy of these compounds has been confirmed by a retinoid transactivation assay described in Skin Pharmacology, vol. 8, p. 292-299 (1995). HeLa cells are co-transfected with DNA encoding RARα, β or γ, and an RAR-responsive CAT reporter gene.
Retinoid efficacy is measured by the concentration of induced CAT gene product as determined by ELISA assay. The compounds of the present invention have shown activity as agonist or partial agonist in at least one of the three RXR receptor subtypes (α, β, γ). The apparent Kds for binding of these compounds to the three RAR receptors have been also evaluated (Skin Pharmacology, vol. 8, p. 292-299 (1995) and Mode of Action of Drugs on Cells, Arnold publishers, London (1933)) and Table 1 shows the data of some representative examples.
Table 1
2) Trauma-induced post surgical adhesion inhibition:
Adhesion formation is a severe problem following most surgical procedures. Factors that influence adhesion formation include
mechanical trauma, infection, and foreign bodies and tissue ischemia. Common examples of postoperative surgical adhesions are pelvic adhesions of the fallopian tubes and or ovaries resulting in infertility, and intestinal adhesions leading to bowel obstruction. Initial insult to the serosa or mesentery leads to the formation of fibrous exudate. Trauma- induced adhesion formation in rat is similar in characteristics to post- surgical adhesion formation in human. The in vivo model offers a means for evaluating drug effect on adhesion formation under conditions that are similar to the clinical process. It has been shown that several retinoids, primarily RAR antagonists are effective inhibitors of fibrotic changes (see, for example, WO 98/46228 published October 22, 1998). The inhibition of fibrotic changes of the compounds of the present invention is shown here as exemplified by the activity of compound C.
Adult male Wistar rats were obtained from Charles River Labs and acclimated for at least one week according to NIH guidelines. Animals were housed individually in stainless steel cages. The trauma induction was carried out using aseptic conditions in animals anesthetized with a mixture of Ketamine (lOOmg/Kg) and Rompun (lOmg/kg) given IP. A 2- cm midline abdominal incision was made and the ceacum was exteriorized. Both sides of the ceacum were abraded with a dry gauze until there was evidence of punctuate bleeding. After replacing the organ in the abdominal cavity, the incision was closed with sterile autoclips. Trauma to the ceacum produces fibrous scar tissue or adhesions to adjacent organs or the omentum.
Compound C was prepared daily as a solution in peanut oil. Animals were dosed orally with approximately 1 ml of the test materials beginning 2 hours before surgery and once daily for 5 days.
On the seventh post-operative day, the animals were sacrificed by
C02 asphyxiation. The peritoneal cavity was exposed and examined for adhesions. Three criteria that were used to evaluate the adhesions are involved with adhesions and the number of adhesions formed in each animal.
The following scoring system was used:
0 = no adhesions;
1 = easily separable, filmy, non-vascularized adhesions covering 25% of the ceacum;
2 = dense adhesions separated by blunt dissection and involving 50% of the ceacum;
3 = dense, fibrous, vascularized adhesions requiring sharp dissection and covering 75% of the ceacum; 4 = severe, dense, vascularized adhesions unable to separate without tearing the adjacent membranes and covering greater than 75% of the ceacum.
Compound C administered orally had a significant effect on the number and severity of adhesions formed as compared to the vehicle control (Table 2). Compared to the vehicle control, Compound C significantly reduced the number of adhesions per animal at 10 mg/kg.
The results are summarized in table 2.
Table 2 Effect of Compound C dosed orally to trauma-induced rats
Compounds dosed orally lx daily 5 days/week for 1 week, beginning on the day of surgery. *p<0.05 (N=7 rats/ group)
Interestingly, the inhibition or prevention of surgical adhesions does not seem to be necessarily related to the RXR retinoid activity per se since LGD1069, described in WO patents 95/04036, 94/15901 and 93/21146 and claimed as an RXR agonist was found to be inactive in this assay. Thus, the compounds of the present invention appear to demonstrate, in addition to a potent and specific RXR activity, this unexpected property of inhibiting trauma-induced post-surgical adhesions.
DESCRIPTION OF THE SPECIFIC EMBODIEMENTS
The preparation of the various substituted tetralone intermediates is described in Schemes 1 and 2. Sometimes, it may be advantageous to introduce the substituent at position 8 (R4 ) before the coupling of the substituted benzoate moiety. The preparation of these substituted (5,6)- dihydronaphthalene and the (5,6,7,8)-tetrahydronaphthalene moieties is described in Schemes 3 and 4. Thus, when it is desired to have a retinoid
wherein R5 is a hydrogen, the tetralone of formula Va (Scheme 1) is advantageously prepared by Grignard reaction of ketoester III to give the lactone IV. Friedel-Crafts reaction of this lactone with benzene affords the tetralone of type Va. When it is desired to have a retinoid wherein R5 is not a hydrogen, two routes may be used. In the first one, the various desired tetralones are advantageously prepared from oc-tetralone VI as outlined in Scheme 1 (Route A). Thus, aromatic halogenation under conditions well-known by those skilled-in-the-art, affords the 7- halogenated tetralone VII [Cornelius L.A.M. and Combs D.W. Synth. Commun. 24, (19), 2777-2788, (1994)] which may be submitted to a Grignard-type reaction to give the dialkylated compound VIII. Subsequent benzylic oxidation using the known conditions in the art leads to the 6-halogenated-tetralone IX which may be substituted under traditional aromatic substitution, cross-coupling or Heck conditions to give the tetralone Vb.
In the second route (Scheme 1, Route B), the various desired tetralones having an R5 substituent are advantageously prepared from alkyl 4-(p-alkylated or halogenated-phenyl)-butyrate X easily obtained from the known corresponding carboxylic acid. Thus, Grignard type reaction of this compound affords the corresponding carbinol XI, which may then react under Friedel-Crafts conditions to give the tetrahydronaphthalene XII. After oxidation, the resulting tetralone Vb wherein x is a halogen substituent may be substituted under traditional aromatic substitution, cross-coupling or Heck conditions.
The tetralones of type Va or b may then be submitted to an aromatic halogenation to afford compounds XHIa or b as described in Scheme 2.
Subsequent alkylation, if desired, affords the tetralones XI Va or b. When it is desired to have a retinoid of formula I or II wherein A is an oxygen, a sulfur or a nitrogen atom, the p-bromophenol, p-bromophenylthiol or p- bromoaniline of type XV may be alkylated with 3-bromopropionic acid to give the acid XVI which may then be cyclized under Friedel-Crafts acylation conditions. The resulting 6-bromochroman-4-one, 6- bromothiochroman-4-one or 6-bromo-l,2,3,4-tetrahydroquinolin-4-one of formula XIIIc may then be alkylated if desired to give the compounds of formula XIVc. When A is sulfur, the thiochroman-4-one may be oxidized if desired, and give the corresponding sulfoxide or sulfone of formula xmd.
When it is desired to have a retinoid wherein R7 is not a hydrogen, the various tetralones, chromanones, thiochromanones or tetrahydroquinolinones of type XlVa to d prepared in Schemes 1 and 2 wherein Y is a halogen, may be converted to the corresponding enones XVIIa or b as described in Scheme 2. When R6 is hydrogen, the enone XVIIa may be submitted to a Diels- Alder reaction with butadiene to give the tricyclo compound XlVe. If it is desired, a Michael type reaction (1,4 addition) may also be carried out with enones XVIIa or b to afford the substituted tetralones, chromanones, thiochromanones or tetrahydroquinolinones of type XlVf.
Sometimes, it may be advantageous to incorporate the R4 substituent earlier in the synthetic sequence during the preparation of retinoids of type I or II. The preparation of the substituted dihydronaphthalene, tetrahydronaphthalene, dihydroquinoline, tetrahydroquinoline, chroman, thiochroman, benzopyran and
benzothiopyran intermediates is described in Schemes 3 and 4. Thus, the various compounds of formula XlVa to f prepared as described in Schemes 1 and 2 may be reacted under Grignard type reaction conditions to give the tertiary alcohols XXa to f, which upon dehydration, provide the intermediates of formula XlXa to f (Scheme 3). These tertiary alcohols of formula XXa to f may also be alkylated, if desired, and lead to the ethers of formula XXa to f. The same compounds of type XlVa to f may be also advantageously converted to the corresponding enol triflates XVIIIa to f which under cross-coupling conditions, produce also the intermediates of type XlXa to f. The compound of formula XlVa to f may also be directly converted to the corresponding enol ethers, affording the intermediates of type XlXa to f wherein R4 is a Cχ-6 alkoxy group. The triflates XVIIIa to f may successively undergo two cross-coupling reactions to produce first the vinyl trialkyltin compounds XXI which may then give the corresponding alkyl ketones XlXa to f. From these compounds, one may prepare various thioketal, thioacetal, acetal or ketal analogs of type XlXa to f using conditions well-known by those skilled-in-the-art.
The preparation of the various tetrahydronaphthalene, tetrahydroquinoline, chroman or thiochroman intermediates is illustrated in Scheme 4. Compounds of formula XlVa to f may be converted to the thioketones XXIIa to f by reaction with P2Ss or the Lawesson's reagent. Grignard type reaction of these resulting thioketones followed by an alkylation lead to the compounds of type XXa to f wherein X is a sulfur. It should be appreciated by those skilled in the art that the intermediates XlVa to f may be converted to ketals or thioketals, giving the compounds of formula XXa to f wherein Ra = XRb. The same
intermediates XlVa to f may also be converted, if desired, to the amines XXa to f by reductive amination.
The preparation of the non-commercially available benzoate entities that need to be coupled with the various ketones of formula XIV, dihydronaphthalenes, dihydroquinolines, benzopyrans or benzothiopyrans of type XIX and tetrahydronaphthalenes, tetrahydroquinolines, chromans or thiochromans of type XX, is described in Scheme 5. Thus, the alkyl p-halogenated benzoate XXIII is submitted to a cross-coupling reaction with trialkylsilylacetylene to give, after removal of the silyl group under conditions known in the art, the acetylene XXIV. Reaction of the triple bond with trimethylsilyltributyltin leads to the p- substituted benzoate intermediate XXV. When it is desired to have a retinoid of formula I or II wherein R1 is -(CH=CH)p-C02Z or -(CH=CH)p- C02Z, the same alkyl p-halogenated benzoate XXIII may be submitted to a Heck coupling and produce intermediate XXVI which, after a selective hydrolysis, may be convert to the corresponding acid halide XXVII.
The preparation of retinoids of type I bearing the different linker substituents R',R" may be carried out by coupling the intermediate of type XIX or XIV with the desired p-substituted benzoate entity as shown in Schemes 6, 7 and 8. It should be understood by those skilled in the art that the illustration in the schemes is not intended to be limiting, since slight modifications are often deemed desirable or necessary to achieve a particular result. Thus, many retinoids of type I may be prepared from ketone XXVIIIa (Scheme 6) which is produced by a Grignard type reaction between halides XlXa to f and the desired acid chlorides. Where Y=H, a Friedel-Crafts acylation with the acid chloride may also be employed.
Subsequent Wittig-type reaction under conditions known by those skilled in the art affords the protected retinoid XXVIIIb bearing a double bond as linker. Epoxide formation from ketone XXVIIIa leads to the protected retinoid XXVIIIc. This same ketone XXVIIIa may also undergo a Grignard type reaction to give the carbinol XXVIIId which, if desired, may be alkylated using conditions known by those skilled in the art and produce the protected retinoid of type XXVIIIe.
When it is desired to have a retinoid bearing a ketal or thioketal as linker, the ketone XXVIIIa is directly converted to compound XXVIIIh. The same compound XXVIIIa may also be transformed to the imine XXVIIIi. Furthermore, the ketone XXVIIIa may be converted to the corresponding thioketone XXVIIIf by treatment with P2Ss or Lawesson's reagent and, if desired, this compound may lead to the protected retinoid XXVIIIg bearing a thioepoxide group as linker.
The protected retinoid of type XXVIIIh prepared in Scheme 6 and bearing a dithiolane or dithiane linker (Scheme 7) may be reduced under conditions known by those skilled in the art if it is desired to have a retinoid bearing a methylene linker (XXVIIIk). On the other hand, the carbinol XXVIIId prepared also in Scheme 6 may be reduced, if desired, to the protected retinoid of formula XXVIIIm or, under reductive alkylation conditions as described above, may give the dialkylated protected retinoid of formula XXVIIIn.
A second approach to the preparation of retinoid of type I is the coupling of the different ketones XlVa to f with the p-substituted benzoate entity XXV under cross-coupling conditions known in the art (Scheme 8).
The resulting protected ketone XXIX is desilylated to give the ketone XXXa which then serves as a common intermediate for the preparation of many retinoids of type I and II bearing various linker substituents R',R". If desired, the silylated ketone XXIX may also be submitted to a Grignard type reaction followed by dehydration to give the protected retinoid of type XXVIIIb bearing a silylated double bond as linker. The tetralone intermediate XXXa may be reacted under Grignard conditions to give, after elimination the intermediate of type XXVIIIb. Alternatively the same intermediate may be obtained by first converting the ketone XXXa to the corresponding enol triflate XXXIIa, which is then submitted to a cross- coupling or Heck type reaction under conditions known by those skilled in the art.
When it is desired to have a retinoid bearing a cyclopropyl linker, the intermediate ketone XXXa is first protected as ketal XXXIa. The cyclopropanation reaction may then be carried out under conditions known in the art to give intermediate XXXIb, which is hydrolized to recover the ketone XXXb. This compound may then be submitted to a Grignard type reaction followed by the dehydration of the resulting carbinol to give the protected retinoid of formula XXVIIIo. Alternatively, the same compound may be obtained by first converting the tetralone XXXb to the corresponding enol triflate XXXIIb, which is then submitted to a cross-coupling or Heck type reaction under conditions known by those skilled in the art.
The preparation of retinoids of type II bearing the different linker substituents R', R" may be carried out by coupling the tetrahydronaphthalene, tetrahydroquinoline, chroman or thiochroman
moieties of formula XX with the desired p-substituted benzoate entity as shown in Schemes 9 and 10. It should be understood by those skilled in the art that the illustration in the schemes is not intended to be limiting, since slight modifications are often deemed desirable or necessary to achieve a particular result. Thus, many retinoids of type II may be prepared from ketone XXXIc (Scheme 9) which is produced by Grignard type reactions between halides XXa to f and the desired acid chloride XXVII. Subsequent Wittig-type reaction under conditions known by those skilled in the art affords the protected retinoid XXXIa bearing a double bond as linker. Epoxide formation from ketone XXXIc leads to the protected retinoid XXXIf bearing an epoxide as linker. This same ketone XXXIc may also undergo a Grignard type reaction to give the carbinol XXXId which, if desired, may be alkylated using conditions known by those skilled in the art and produce the protected retinoid of type XXXIe.
When it is desired to have a retinoid bearing a ketal or thioketal group as linker, the ketone XXXIc is directly converted to compound XXXIi. The same compound XXXIc may also be transformed to the imine XXXIj. Furthermore, the ketone XXXIc may be converted to the corresponding thioketone XXXIg by treatment with P2Ss or the Lawesson's reagent and, if desired, this compound may lead to the protected retinoid XXXIh bearing a thioepoxide group as linker.
The protected retinoid of type XXXIi prepared in Scheme 9 and bearing a dithiolane or dithiane linker (Scheme 10) may be reduced under conditions known by those skilled in the art if it is desired to have a retinoid bearing a methylene linker (XXXIm). On the other hand, the carbinol XXXId prepared also in Scheme 9 may be reduced, if desired, to
the protected retinoid of formula XXXIn or, under reductive alkylation conditions as described above, may give the dialkylated protected retinoid of formula XXXIo. When it is desired to have a retinoid of type II bearing a cyclopropyl groups as linker, the protected retinoid of formula XXXIa prepared in Scheme 9 is submitted to cyclopropanation conditions to give the compound of type XXXIb. The preparation of retinoid of formula II wherein X is a nitrogen may be prepared by reductive amination of the ketones of type XXXa or b to lead to the amines XXXIa or b.
When it is desired to have a retinoid of formula I wherein R is not a hydrogen or an alkyl group, the compounds of type XXVIIIa to o may be oxidized to afford the ketones XXVIIIa to o (Scheme 11). Subsequently, this ketone may be converted to the ketal XXVIIIa to o under conditions known in the art. Alternatively, a Wittig type reaction affords the dienes of formula XXVIIIa to o.
When it is desired to have a retinoid of type I wherein R1 is an α- keto-carboxylic acid, (Scheme 12) the side chain is preferably introduced from intermediates XXVIIIa to o bearing a halide group at position 1, via cross-coupling under conditions known in the art. The resulting α-keto- ester intermediates XXVIIIa to o may then be converted to the corresponding oxime derivatives as shown in Scheme 12. The same reactions apply also to the preparation of retinoid of type II wherein R1 is an α-keto-carboxylic acid or an α-hydroxy-imino-carboxylic acid as shown in Scheme 12 from intermediate XXXI a to o.
Finally, the protected intermediates XXVIIIa to o (Scheme 13) wherein R17 is not a halide or an alkyl group are advantageously
converted to the retinoid of type I under hydrolytic conditions known by those skilled in the art. Similarly, the protected intermediates XXXIa to o wherein R17 is not a halide or an alkyl group are converted to the retinoid of type II using hydrolytic conditions known by those skilled in the art.
SCHEME 1 Preparation of intermediates
When R5 ≠ H
When ff ≠ H; and Y = halogen; Route A:
Aromatic
Grignard type halogenation
reaction
VII, Y = halogen VIII, Y = halogen
Cross-coupling or Heck coupling
or aromatic
Vb R5 ≠ H substitution
IX, Y = halogen
When R? ≠ H;X = halogen or alkyl Route B:
en or
SCHEME 2 Preparation of intermediates
Alkylation
Va, b Xllla, b
A = O, S, NR 2
Friedel-
Crafts reaction
Xlllc, A = O, S, NR 2
Alkylation oxidation A = S
XIVc, d XIII d, A = SO or SO 2
WhenR7≠H
Y = halogen
XlVa to d XVIIa, R6 = H XIVe,R7≠H l6≠H Enone Michael addition , formation ' 1
0 II 0
VYYV Michael addition
R3 R2 "XXX
XV lib, R6≠H XlVf, R7≠H
SCHEME 3 Preparation of intermediates
When R4 = C-i-g alkyl, C^polyfluoroalkyl, substituted phenyl or heteroaryl, Q-g alkylthio, C,^ alkoxy
When R4 = -COR13, -C(OR14)2R13 , -C(SR1 )2R13 , -CfSCHjCHjSJR13 or -C(OCH2CH2θ)R13
Acetal / ketal formation. Thioacetal formation
R4 = -C(OR14)2R13 or R4 = -C(SR14)2R13 or -C(OCH2CH2θ)R13 -C(SCH2CH2S)R13
SCHEME 4 Preparation of intermediates
Grignard type reaction
XlVa to f XXIIa to f XXa to f
Reductive Rb=H,X = S
Ketal formation amination
Alkylation
SCHEME 5 Preparation of intermediates
When R17---CO,R1δ
jy XXIII, R16
Y = halogen R1β, R1β=C1.6alkyl
When R17 = -(CH=CH)p-C02R16 and -(CH--CH)p-C02R16
XXIII, R20≠H Y = halogen
SCHEME 6
R17 = -(CH--CHp-Cθ2R16, -(C-CJp-COjR16, -(CH^p^R16, C^ alkyl and halogen
Wittig type Epoxide reaction - formation Alkylation
XXVIIIb XXVIIIc XXVIIIe
XXVIIIa XXVIIIf XXVIIIg Imine formation Ketal formation
SCHEME 7
R »117' . = -(CH=CH)p-C02R >1160, -(C--C)p-Cθ2R 1160, -(CH2)pC02R ,16 , C^ alkyl and halogen
XXVIIIh, R' = R" = -S(CH2)2S- XXVIIIk
XXVIIId XXVIIIm Reductive alkylation
XXVIIIn
SCHEME 8
Ketal formation
XXXIa
W
SCHEME 9
R17 = -(CH--CHp-Cθ2R16, -(C-C)p-Cθ2R16, -(CHipCO∑R16, Ci-e alkyl and halogen
R", R' contain O or S
SCHEME 10
R17=-(CH=CH)p-C02R16, (C--C)p-C02R ,1160,-(CH2)pC02R 1160a, nd C^ alkyl
XXXIi, R' = R" = -S(CH 2)2S- XXXIm
XXXId XXXIn Reductive alkylation
XXXIo
XXXIa XXXIb
XXXa or b XXXIa or b
SCHEME 11
R17= -(CH--CH)p-C02R16, -(C--C)p-C02R16, -(CH2)pCθ2R 6and C .6 alkyl
oxidation
XXVIIIa to o XXVIIIa to o
Wittig type reaction ketal formation
XXVIIIa to o XXVIIIa to o Z, Y = H or Me X = O or S
B = alkyl or cycloalkyl
SCHEME 12
NH2O 10
XXXIa to o, R ,1"7 . = halogen
^3
SCHEME 13
R17= -(CH = CH)p-C02R16, -(C≡CJp-COzR16, -(CH2)pC02R16, -COC02R16, -C=N(OR12)C02R16.
XXVIIIa to o I a too
A = C, N, O, S
DESCRIPTION OF SPECIFIC EMBODIMENTS
The specific examples which follow illustrate the synthesis of representative compounds of the present invention. The procedures may be adapted to variations in order to produce compounds within the scope of the invention but not specifically disclosed.
All temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics
refer to chemical shifts (δ) expressed in parts per million (ppm) versus
tetramethylsilane (TMS) as reference standards. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet (q), quintet (qi), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quarter (dq). The solvents employed for taking NMR spectra are DMSO-d6 (perdeuterodimethylsulfoxide), D20 (deuterated water), CDC13 (deuterochloroform) and other conventional deuterated solvents. The infrared (IR) spectral description include only absorption wave numbers (cm"1) having functional group identification value. All melting points were not corrected.
EXAMPLE 1
4-ri- 8-Methoxy-5,5,8-trimethyl-5.6,7.8-tetrahydro-2- naphthalenyPethenyllbenzoic acid
7-Bromo-l-hydroxy-1.4.4-trimethyl-1.2.3.4-tetrahydronaphthalene
In a three-necked flask, cerium(III) chloride heptahydrate (6.7 g, 17.8 mmol) was dried for 2 hours at = 145°C under vaccum (for more details on the drying procedure see J. Am. Chem. Soc. vol. Ill, p. 4392-4398
(1989)). While still hot, argon was introduced and the flask was cooled to 0-5°C and tetrahydrofuran (60 mL) was quickly added with vigorous stirring. The ice-bath was removed and the solution was stirred overnight (=18 h) at room temperature. The solution was then cooled down to 0-5°C again and methyl magnesium bromide (6 mL, 3M solution in ethyl ether, 17.8 mmol) was added dropwise and the mixture was vigorously stirred for 1.5 hours. A solution of 7-bromo-4,4-dimethyl-l- oxo-l,2,3,4-tetrahydronaphthalene (U.S. Patent 5,618,839 and EP 661,259) (3.0 g, 11.0 mmol) in tetrahydrofuran (15 mL) was then added dropwise to this mixture and the resulting mixture was stirred for 45 minutes at 0-5°C. Acetic acid (10%, 100 mL) was slowly added and the mixture was extracted with ethyl ether (=100 mL). The organic phases were washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (4.5 x 15 cm, toluene then 5, 10, 15% ethyl acetate /toluene) to give a solid which was triturated in hexanes. The title material was obtained (3.08 g, 96%) as a beige solid. IR (KBr) υmax (cm"1): 3300 (br, OH), 2985, 2930, 2860.
IH NMR 400 MHz (CDCI3) δ (ppm): 7.72 (IH, d, J=2.2 Hz, H-8), 7.33 (IH, dd, J=8.5 and 2.2 Hz, H-6), 7.17 (IH, d, J=8.5 Hz, H-5), 1.96 (2H, dd, J=6.6 and 5.7 Hz, H-2 or H-3), 1.82-1.69 (2H, m, H-2 or H-3), 1.71 (IH, s, exchangeable with D2O, -OH), 1.54 (3H, s, -CH3-I), 1.28 and 1.29 (2 x 3H, 2 s, 2 x -CH3-4).
7-Bromo-l-methoxy-l,4,4-trimethyl-1.2.3,4-tetrahydronaphthalene
To a stirred solution of 7-bromo-l-hydroxy-l,4,4-trimethyl-l,2,3,4- tetrahydronaphthalene (0.270 g, 1 mmol) in tetrahydrofuran (3 mL) was added dropwise a suspension of 60% sodium hydride (48 mg, 1.2 mmol) in tetrahydrofuran (3 mL). The mixture was stirred for 30 minutes at room temperature, then iodomethane (0.125 mL, 2 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours, then after cooling to 0-5°C, IN hydrochloric acid was added. The mixture was diluted with ethyl ether and the organic phase was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (2 x 17 cm, hexane, then toluene /hexane 20, 40, 80%, then toluene) to give the title compound (0.250 g, 88%) as a colorless oil.
IR (film) υmax (cm"1): 2950, 2860.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.58 (IH, d, J=2.2 Hz, H-8), 7.32 (IH, dd, J=2.2 and 8.4 Hz, H-6), 7.17 (IH, d, J=8.4 Hz, H-5), 3.10 (3H, s, -OMe), 2.30- 2.23 (IH, m, H-2 or H-3), 1.77-1.74 (2H, m, H-2 or H-3), 1.66 (IH, ddd, J=13.5, 4.9 and 4.0 Hz, H-2 or H-3), 1.48 (3H, s, -CH3-I), 1.30 (3H, s, -CH3-4), 1.25 (3H, s, -CH3-4).
Anal. Calcd. for Ci4Hi9BrO: C 59.37; H 6.76.
Found: C 59.37; H 6.61.
Methyl 4-[.8-methoxy-5.5.8-trimethyl-5.6.7,8-tetrahydro-2-naphthalenylV carbonyl]benzoate
To a stirred suspension of 60 mg. magnesium in tetrahydrofuran (1 mL) was added a solution of 7-bromo-l-methoxy-l,4,4-trimethyl-l,2,3,4- tetrahydronaphthalene (0.537 g, 1.9 mmol) in tetrahydrofuran (2 mL). 1,2- Dibromo-ethane (0.01 mL) was then added and the mixture was heated up to =55°C under argon for 1 hour. When TLC showed that the reaction was completed, the mixture was cooled down to room temperature.
A solution of distilled terephthalic acid monomethyl ester chloride (380 mg, 1.9 mmol) in tetrahydrofuran (10 mL) at -20°C under argon was treated dropwise with tributylphosphine (0.522 mL, 2.1 mmol). The mixture was stirred for 30 minutes at -20°C, then the magnesium salt solution prepared above was added to it (internal temperature: -15°C). The flask containing the magnesium salt solution was rinsed with tetrahydrofuran (2 x 1 mL). The resulting mixture was stirred at
-15°C/-20°C for 30 minutes and was allowed to reach room temperature over a 1 hour period. 10% Cold ammonium chloride (20 mL) was then added and the mixture was extracted with ethyl ether. The organic phase was washed with IN cold hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3 x 15 cm, 0, 2, 4, 6% ethyl acetate /toluene) to give the title compound which was triturated in hexane and was obtained (0.422 g, 61%) as a white solid.
IR (KBr) υmax (cm"1): 2960, 2940, 1713 and 1720 (C=0), 1650. lH NMR 400 MHz (CόDό) δ (ppm): 8.18 (IH, d, J---1.8 Hz, H-l'), 8.03 (2H, d,
J=8.4 Hz, H-2 and H-6), 7.73 (IH, dd, J=8.3 and 1.8 Hz, H-3'), 7.70 (2H, d, J=8.4 Hz, H-3 and H-5), 7.14 (IH, d, J=8.3 Hz, H-4*), 3.46 (3H, s, -OCH3), 2.90 (3H, s, -OCH3), 2.14-2.07 (IH, m, H-6' or H-7'), 1.57-1.54 (2H, m, H-6' or H-
7), 1.51-1.44 (IH, m, H-6' or H-7'), 1.39 (3H, s, -CH3), 1.14 (3H, s, -CH3), 1.12
(3H, s, -CH3).
Anal. Calcd. for C23H26O4: C 75.38; H 7.15. Found: C 75.29; H 6.93.
Methyl 4-.1- ( 8-methoxy-5.5.8-trimethyl-5. .7.8-tetrahydro-2-naphthalenyl .- ethenyl]benzoate
To a vigorously stirred solution of methyl 4-[(8-methoxy-5,5,8-trimethyl- 5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoate (0.250 g, 0.682 mmol) in tetrahydrofuran (8 mL) at -78°C was added the Nysted reagent (4 mL, 0.52 mmol/mL, 3 eq, (Aldrich)) followed by titanium(IV) chloride (lmL, 1 mmol, solution 1M in dichloromethane). The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was slowly poured into saturated sodium bicarbonate and ethyl ether was added followed by celite. The resulting slurry was stirred, filtered and concentrated. The residue was purified on silica gel chromatography (3 x 15 cm, 50,70,100% toluene /hexane then 2, 4, 6% ethyl acetate /hexane) to give the title material which was triturated in hexane (0.150 g, 60%) and was obtained as a white solid.
IR (KBr) υmaχ (cm"1): 2970, 2930, 1720 (C=0), 1610.
!H NMR 400 MHz (CόDβ) δ (ppm): 8.10 (2H, d, J=8.1 Hz, H-2 and H-6), 7.69
(IH, s, H-l'), 7.31 (2H, d, J=8.1 Hz, H-3 and H-5), 7.21-7.17 (2H, m, H-3' and H-4'), 5.48 and 5.34 (2 x IH, 2 br s, ethenyl H), 3.50 (3H, s, -OCH3), 2.96 (3H, s, -OCH3), 2.21-2.15 (IH, m, H-6' or H-7'), 1.59-1.46 (3H, m, H-6' and H-7'), 1.47 (3H, s, -CH3), 1.20 (3H, s, -CH3), 1.18 (3H, s, -CH3).
Anal. Calcd. for C24H28θ3- 0.2 H2O: C 78.31; H 7.78.
Found: C 78.35; H 7.64.
4-[.8-Methoxy-5.5.8-trimethyl-5.6.7.8-tetrahydro-2- naphthalenyl.ethenyl]benzoic acid
A solution of methyl 4-[(8-methoxy-5,5,8-trimethyl-5,6,7,8-tetrahydro-2- naphthalenyl)ethenyl]benzoate (0.138 g, 0.379 mmol) in tetrahydrofuran (3 mL) and ethanol (3 mL) was treated dropwise with sodium hydroxide (ION, 0.55 mL) and stirred at room temperature for 18 hours. The solution was then cooled down to 0-5°C and IN hydrochloric acid (~7 mL) was added dropwise with a vigorous stirring. After stirring for 15 minutes at 0-5°C, the resulting white precipitate was filtered, washed with water and dried. The white solid was dissolved in dichloromethane /ethanol and filtered and the filtrate was partially concentrated. Ethanol was added and the solution was concentrated to =3 mL. Water was added (=3 mL) and the compound was precipitated at 5°C over 1 hour. The white solid was filtered, washed with water/ethanol (1:1, 3 mL) and water (3 mL) and dried. The title material was obtained (0.127 g, 96%) as a white solid.
IR (KBr) υmaχ (cm"1): 3650-3300 (br), 2960, 1715 (C=0).
IH NMR 400 MHz (DMSO-d6) δ (ppm): 7.94 (2H, d, J=8.3 Hz, H-2 and H-6),
7.42 (2H, d, J=8.3 Hz, H-3 and H-5), 7.38 (IH, d, J=8.0 Hz, H-4'), 7.21-7.18 (2H, m, H-l' and H-3'), 5.56 (2H, br s, ethenyl H), 2.92 (3H, s, -OCH3), 2.33-2.17
(IH, m, H-6' or H-7'), 1.73-1.68 (2H, m, H-6' or H-7'), 1.59-1.55 (IH, m, H-6' or H-7'), 1.34, 1.29 and 1.24 (3 x 3H, 3 s, 3 x -CH3).
Anal. Calcd. for C23H26O3: C 78.82; H 7.48.
Found: C 79.18; H 7.61.
EXAMPLE 2
4-fl-(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethenynbenzoic acid
7-Bromo-l-phenyl-4.4-dimethyl-3.4-dihydronaphthalene
7-Bromo-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydronaphthalene (0.506 g, 2.0 mmol) was reacted as described in Example 1 for the preparation of 7- bromo-l-hydroxy-l,4,4-trimethyl-l,2,3,4-tetrahydronaphthalene, by using phenyl magnesium bromide (3M in ether) instead of methyl magnesium bromide.
The crude product obtained from the Grignard reaction was then dissolved in toluene (15 mL) and treated with p-toluenesulfonic acid (=15 mg). The mixture was heated to 70°C for 30 minutes, then concentrated and the residue was purified by silica gel chromatography (3 x 15 cm, 0-1% ethyl acetate /hexane) to give the title material (0.52 g, 83%) as a colorless oil.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.53-7.32 (6H, m, H-6 and H phenyl),
7.23 (IH, d, J=8.2 Hz, H-5), 7.14 (IH, d, J=2.0 Hz, H-8), 6.02 (IH, t, J=4.7 Hz, H-2), 2.36 (2H, d, J=4.7 Hz, H-3), 1.33 (6H, s, 2 x -CH3).
Methyl 4-f(8-phenyl-5.5-dimethyl-5.6-dihydro-2- naphthalenyl.carbonyl]benzoate
7-Bromo-l-phenyl-4,4-dimethyl-3,4-dihydronaphthalene (0.560 g, 1.8 mmol) was reacted as described in Example 1 for the preparation of methyl 4-[(8-methoxy-5,5,8-trimethyl-5,6,7,8-tetrahydro-2- naphthalenyl)carbonyl]benzoate. The title material was obtained (0.380 g, 51%) as a white solid.
IR (KBr) υmax (cm"1): 3030, 2970, 2950, 2930, 1725, 1655 (C=0). IH NMR 400 MHz (CDCI3) δ (ppm): 8.09 (2H, d, J=8.3 Hz, H-2 and H-6), 7.80 (2H, d, J=8.3 Hz, H-3 and H-5), 7.66 (IH, dd, J=8.0 and 1.9 Hz, H-3'), 7.51-7.27 (7H, m, H-l', H-4' and H phenyl), 6.08 (IH, t, J=4.7 Hz, H-7'), 3.97 (3H, s, -OCH3), 2.41 (2H, d, J=4.7 Hz, H-6'), 1.40 (6H, s, 2 x -CH3).
Methyl 4-fl-.8-phenyl-5.5-dimethyl-5.6-dihydro-2- naphthalenyl.ethenyl"|benzoate
Methyl 4-[(8-phenyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)carbonyl]benzoate (0.30 g, 0.727 mmol) was reacted as described in Example 1 for the preparation of methyl 4-[(8-methoxy-5,5,8- trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-ethenyl]benzoate. The title material (0.230 g, 79%) was obtained as a white solid.
IR (KBr) υmaχ (cm"l): 3020, 2955, 2920, 1720 (C=0), 1605. IH NMR 400 MHz (CDCI3) δ (ppm): 7.97 (2H, d, J=8.4 Hz, H-2 and H-6), 7.39 (2H, d, J=8.4 Hz, H-3 and H-5), 7.36-7.23 (6H, m, H-4' and H phenyl), 7.11 (IH, dd, J=8.0 and 2.0 Hz, H-3'), 7.07 (IH, d, J=1.9 Hz, H-l'), 6.03 (IH, t, J=4.7 Hz, H-7'), 5.43 (IH, d, J=0.8 Hz, ethenyl H), 5.40 (IH, d, J=0.8 Hz, ethenyl H), 3.93 (3H, s, -OCH3), 2.38 (2H, d, J=4.8 Hz, H-6'), 1.37 (6H, s, 2 x -
CH3).
Anal. Calcd. for C28H26O2: C 85.25; H 6.64. Found: C 84.92; H 6.57.
4-[l-.5.6-Dihydro-5.5-dimethyl-8-phenyl-2-naphthalenyl.ethenyl]benzoic acid
Methyl 4-[(8-phenyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate (0.200 g, 0.487 mmol) was saponified as described in Example 1 for the preparation of 4-[(8-methoxy-5,5,8- trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoic acid. The title material (0.177 g, 96%) was obtained as a white solid. IR (KBr) υmax (cm"1): 3300-2300 (br), 1690 (C=0), 1605.
!H NMR 400 MHz (DMSO-dό) δ (ppm): 7.90 (2H, d, J=8.3 Hz, H-2 and H-6), 7.42 (IH, d, J=8.0 Hz, H-4'), 7.38 (2H, d, J=8.3 Hz, H-3 and H-5), 7.35-7.25 (5H, m, H phenyl), 7.21 (IH, dd, J=8.0 and 1.8 Hz, H-3'), 6.83 (IH, d, J=1.8 Hz, H- 1'), 6.03 (IH, t, J=4.7 Hz, H-7'), 5.52 and 5.42 (2 x IH, 2 br s, ethenyl H), 2.34 (2H, d, J=4.7 Hz, H-6'), 1.31 (6H, s, 2 x -CH3).
Anal. Calcd. for C27H24O2: C 85.23; H 6.36.
Found: C 85.11; H 6.46.
EXAMPLE 3
4 l-(5f6-Dihydro-5,5-dimethyl-8-isopropyl-2-naphthalenyl. ethenyl! benzoic acid
7-Bromo-l-isopropyl-4.4-dimethyl-3.4-dihydronaphthalene
7-Bromo-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydronaphthalene (1.5 g, 6.0 mmol) was reacted as described in Example 2 for the preparation of 7- bromo-l-phenyl-4,4-dimethyl-3,4-dihydronaphthalene using isopropylmagnesium chloride instead of phenylmagnesium bromide. The title material (=0.40 g, 25%) was obtained along with 7-bromo-4,4- dimethyl-3,4-dihydronaphthalene (red. comp.) (=0.22 g, 15%) as a non- separable mixture and 7-bromo-4,4-dimethy 1-1 -hydroxy- 1,2,3,4- tetraydronaphthalene (0.20 g, 10%).
!H NMR 400 MHz (CDCI3) δ (ppm) (mixture 7:3 title material/red. comp.): 7.44 (IH, d, J---1.9 Hz, H-8), 7.31 (IH, dd, J=8.2 and 1.9 Hz, H-6), 7.29-7.27 and 7.19-1.15 (3H, 2m, H-l, H-6 and H-5 red. comp.), 7.18 (IH, d, J=8.2 Hz, H-5), 6.39 (IH, d, J=9.6 Hz, H-l red. comp.), 5.99 (IH, dt, J=9.6 and 4.4 Hz, H-2 red. comp.), 5.82 (IH, t, J=4.5 Hz, H-2), 2.90 (IH, m, J=6.6 Hz, -CH(CH3)2), 2.25
(2H, dd, J=4.3 and 1.8 Hz, H-3 red. comp.), 2.19 (2H, d, J=4.5 Hz, H-3), 1.26 (6H, s, 2 x -CH3 red. comp.), 1.22 (6H, s, 2 x -CH3), 1.17 (6H, d, J=6.7 Hz, -
CH(CH3)2)-
Methyl 4-[.8-isopropyl-5.5-dimethyl-5.6-dihydro-2- naphthalenyl.carbonyl]benzoate
A mixture of 7-bromo-l-isopropyl-4,4-dimethyl-3,4-dihydronaphthalene and 7-bromo-4,4-dimethyl-3,4-dihydronaphthalene (0.620 g, =2.6 mmol) was reacted as described in Example 2 for the preparation of methyl 4-[(8- phenyl-5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoate. The title material was obtained (0.183 g, 19%) as a white solid.
IR (film) υmax (cm"1): 2960, 2930, 2870, 1725 and 1660 (C=0), 1595.
*H NMR 400 MHz (CDCI3) δ (ppm): 8.16 (2H, d, J=8.4 Hz, H-2 and H-6), 7.87 (2H, d, J=8.4 Hz, H-3 and H-5), 7.80 (IH, d, J=1.7 Hz, H-l'), 7.63 (IH, dd, J=8.0 and 1.7 Hz, H-3'), 7.44 (IH, d, J=8.0 Hz, H-4'), 5.87 (IH, t, J=4.6 Hz, H- 7), 3.99 (3H, s, -OCH3), 2.95 (IH, m, J=6.7 Hz, -CH(CH3)2), 2.25 (2H, d, J=4.6 Hz, H-6'), 1.29 (6H, s, 2 x -CH3), 1.17 (6H, d, J=6.7 Hz, -CH(CH3)2).
Methyl 4-[(8-isopropyl-5.5-dimethyl-5.6-dihydro-2- naphthalenyl.ethenyllbenzoate
Methyl 4-[(8-isopropyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)carbonyl]benzoate (0.183 g, 0.505 mmol) was reacted as described in Example 2 for the preparation of .methyl 4-[(8-phenyl-5,5- dimethyl-5,6-dihydro-2-naphthalenyl)ethenyl]benzoate. The title material was obtained (0.108 g, 59%) as an oil which solidified.
IR (film) υmax (cm"1): 2950, 2870, 1720 (C=0), 1605.
!H NMR 400 MHz (CDCI3) δ (ppm): 8.02 (2H, d, J=8.4 Hz, H-2 and H-6),
7.46 (2H, d, J=8.4 Hz, H-3 and H-5), 7.30 (IH, d, J=8.0 Hz, H-4'), 7.27 (IH, br s,
H-l'), 7.15 (IH, dd, J=7.9 and 1.8 Hz, H-3'), 5.80 (IH, t, J=4.5 Hz, H-7'), 5.55 (IH, d, J=0.7 Hz, ethenyl H), 5.52 (IH, br s, ethenyl H), 3.94 (3H, s, -OCH3), 2.86 (IH, m, J=6.7 Hz, -CH(CH3)2), 2.22 (2H, d, J=4.5 Hz, H-6"), 1.27 (6H, s, 2 x -CH3), 1.12 (6H, d, J=6.7 Hz, -CH(CH3)2).
4-[l-('5.6-Dihydro-5.5-dimethyl-8-isopropyl-2-naphthalenyl.ethenyl]benzoic acid
Methyl 4-[(8-isopropyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate (0.050 g, 0.139 mmol) was saponified as described in Example 2 and afforded the title material (0.041 g, 85%) as a white solid.
IR (KBr) υmax (cm"l): 3300-2300 (br), 1680 (C=0), 1605. H NMR 400 MHz (DMSO-d6) δ (ppm): 12.93 (IH, br s, -CO2H), 7.94 (2H, d, J=8.3 Hz, H-2 and H-6), 7.44 (2H, d, J=8.3 Hz, H-3 and H-5), 7.34 (IH, d, J=7.9 Hz, H-4'), 7.19 (IH, d, J=1.7 Hz, H-l'), 7.14 (IH, dd, J=7.9 and 1.7 Hz, H-3'), 5.80 (IH, t, J=4.4 Hz, H-7'), 5.58 (2H, 2 br d, JAB undetermined, ethenyl H), 2.82 (IH, m, J=6.7 Hz, -CH(CH3)2). 2.16 (2H, d, J=4.3 Hz, H-6'), 1.21 (6H, s, 2 x -CH3), 1.06 (6H, d, J=6.7 Hz, -CH(CH3)2).
Anal. Calcd. for C24H26O2 • 0.3 H2O: C 81.92; H 7.62.
Found: C 81.90; H 7.55.
EXAMPLE 4
4-f(8-Methoxy-5.5.8-trimethyl-5.6.7.8-tetrahydro-2-naphthalenyl)- carbonyllbenzoic acid
Methyl 4-[(8-methoxy-5,5,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)- carbonyl]benzoate prepared in Example 1 (0.140 g, 0.382 mmol) was saponified as described in Example 1 and afforded the title compound (0.127 g, 94%) as a white solid.
IR (KBr) υmax (cm-1 ): 3300-2300 (br), 1680, 1655 (C=0), 1605.
!H NMR 400 MHz (DMSO-dβ) δ (ppm): 8.10 (2H, d, J=8.3 Hz, H-2 and H-6),
7.80 (2H, d, J=8.3 Hz, H-3 and H-5), 7.72 (IH, d, J---1.8 Hz, H-l'), 7.62 (IH, dd, 1=8.2 and 1.8 Hz, H-3'), 7.57 (IH, d, J=8.2 Hz, H-4'), 3.31 (3H, s, -OCH3), 2.26- 2.18 (IH, m, H-7'), 1.77-1.75 (2H, m, H-6'), 1.64 (IH, dt, J=13.2 and 4.3 Hz, H- 7), 1.40, 1.33, 1.27 (3 x 3H, 3 s, 3 x -CH3).
Anal. Calcd. for C22H24O4 . 0.3 H2O: C 73.84; H 6.93.
Found: C 73.79; H 6.70.
EXAMPLE 5
4 l-(5,6-Dihydro-5,5,8-trimethyl-2-naphthalenyl)ethenyllbenzoic acid
7-Bromo-1.4,4-trimethyl-3,4-dihydronaphthalene
7-Bromo-4,4-dimethyl-l-oxo-l,2,3,4-tetrahydronaphthalene (1.35 g, 5.0 mmol) was reacted as described in Example 2 for the preparation of 7-
bromo-l-phenyl-4,4-dimethyl-3,4-dihydronaphthalene by using methylmagnesium bromide instead of phenylmagnesium bromide. The title material was obtained (1.17 g, 93%) as a colorless oil.
IR (film) υmax (cm-1): 2960, 2920, 2860, 2820.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.35 (IH, d, J=2.1 Hz, H-8), 7.32 (IH, dd,
J=8.2 and 2.1 Hz, H-6), 7.17 (IH, d, J=8.2 Hz, H-5), 5.81 (IH, br tq, J=4.4 and =1.3 Hz, H-2), 2.20 (2H, br d, J=4.4 Hz, H-3), 2.05 (3H, d, J=1.6 Hz, -CH3-I), 1.24 (6H, s, 2 x -CH3-4).
Methyl 4- \ ( 5.5 ,8-trimethy 1-5.6-dihy dro-2-naphthaleny 1. carbonyl]benzoate
7-Bromo-l,4,4-trimethyl-3,4-dihydronaphthalene (0.502 g, 2.0 mmol) was reacted as described in Example 2 for the preparation of methyl 4-[(8- phenyl-5,5-dimethyl-5,6-dihydro-2-naphthalenyl)carbonyl]benzoate. The title material was obtained (0.430 g, 64%) as a white solid.
IR (KBr) υmaχ (cm-1): 2960, 2915, 2860, 2820, 1715 and 1650 (C=0). !H NMR 400 MHz (Benzene-d6) δ (ppm): 8.07 (2H, d, J=8.3 Hz, H-2 and H- 6), 7.92 (IH, d, J---1.8 Hz, H-l'), 7.70 (2H, d, J=8.4 Hz, H-3 and H-5), 7.63 (IH, dd, J=8.0 and 1.8 Hz, H-3'), 7.16 (IH, d, J=8.0 Hz, H-4'), 5.58 (IH, br t, J=4.2 Hz, H-7'), 3.47 (3H, s, -OCH3), 2.01 (2H, br d, J=4.3 Hz, H-6'), 1.85 (3H, d, J=1.6 Hz, -CH3-8'), 1.16 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C22H22O3: C 79.01; H 6.63.
Found: C 79.02; H 6.78.
Methyl 4- [ (5 ,5 ,8-trimethyl-5 ,6-dihy dro-2-naphthalenyl . ethenyllbenzoate
Methyl 4-[(5,5,8-trimethyl-5,6-dihydro-2-naphthalenyl)carbonyl]benzoate (0.250 g, 0.747 mmol) was reacted as described in Example 2 for the preparation of methyl 4-[(8-phenyl-5,5-dimethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate. The title material was obtained (0.181 g, 73%) as a white solid.
IR (KBr) υmax (cm"!): 2950, 2905, 1712 (C=0), 1610. !H NMR 400 MHz (Benzene-d6) δ (ppm): 8.16 (2H, d, J=8.3 Hz, H-2 and H-
6), 7.42 (IH, br s, H-l'), 7.39 (2H, d, J=8.4 Hz, H-3 and H-5), 7.26 and 7.25 (2H, 2 d, JAB=8.1 HZ, H-3' and H-4'), 5.67 (IH, br tq, J=4.4 and =1.4 Hz, H-7'), 5.52
(IH, d, J=0.9 Hz, ethenyl H), 5.42 (IH, d, J=0.9 Hz, ethenyl H), 3.55 (3H, s, - OCH3), 2.12 (2H, br d, J=4.4 Hz, H-6'), 1.94 (3H, d, J=1.6 Hz, -CH3-8'), 1.27 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C23H24O2: C 83.10; H 7.28.
Found: C 83.40; H 7.32.
4-[l-.5.6-Dihydro-5.5.8-trimethyl-2-naphthalenyl.ethenyl1benzoic acid
Methyl 4-[(5,5,8-trimethyl-5,6-dihydro-2-naphthalenyl)ethenyl]benzoate (0.160 g, 0.481 mmol) was saponified as described in Example 2 and afforded the title material (0.139 g, 90%) as a white solid.
IR (KBr) υmaχ (cm"1): 2960, 1685 (C=0), 1610.
!H NMR 400 MHz (DMSO-d6) δ (ppm): 7.94 (2H, d, J=8.2 Hz, H-2 and H-6),
7.43 (2H, d, J=8.3 Hz, H-3 and H-5), 7.33 (IH, d, J=7.8 Hz, H-3' or H-4'), 7.15
(IH, s, H-l'), 7.10 (IH, d, H-4' or H-3'), 5.82 (IH, br s, H-7'), 5.58 (2H, br s, JAB undetermined, ethenyl H), 2.17 (2H, br s, H-6'), 1.97 (3H, s, -CH3-8'), 1.22 (6H, s, 2 x -CH3).
Anal. Calcd. for C22H22O2: C 82.98; H 6.96.
Found:C 82.86; H 6.90.
EXAMPLE 6
4 (5 5,8-Trimethyl-5,6-dihydro-2-naphthalenyl)carbonyl1benzoic acid
Methyl 4-[(5,5,8-trimethyl-5,6-dihydro-2-naphthalenyl)carbonyl]benzoate prepared in Example 5 (0.156 g, 0.466 mmol) was saponified as described in Example 5 and afforded the title compound (0.125 g, 84%). as a white solid.
IR (KBr) υmax (cm"l): 3300-2000 (br), 1690, 1650 (C=0). iH NMR 400 MHz (DMSO-dό) δ (ppm): 13.25 (IH, br s, -CO2H), 8.09 (2H, d, J=8.2 Hz, H-2 and H-6), 7.83 (2H, d, J=8.2 Hz, H-3 and H-5), 7.62-7.58 (2H, m, H-3' and H-l'), 7.51 (IH, d, J=7.9 Hz, H-4'), 5.91 (IH, br s, H-7'), 2.22 (2H, d, J=2.1 Hz, H-6'), 2.03 (3H, s, -CH3-8'), 1.25 (6H, s, 2 x -CH3).
Anal. Calcd. for C21H20O3 . 0.1 EtOH: C 78.35; H 6.39.
Found: C 78.11; H 6.36.
EXAMPLE 7
4-ri-(5,6-Dihydro-5,5,7,8-tetramethyl-2-naphthalenyl)ethenynbenzoic acid
1.2.3,4-Tetrahydro-2.4.4-trimethyl-l-oxo-7-bromo-naphthalene
To a suspension of potassium hydride (35% in oil, 4.6 g, 40 mmol) in ethyl ether (50 mL) was added dropwise a solution of 7-bromo-4,4- dimethyl-l-oxo-l,2,3,4-tetrahydro-naphthalene (5.06 g, 20 mmol) in ether (10 mL). The mixture was stirred at room temperature for 2 hours, then cooled down to -30°C. Methyl triflate (3.4 mL, 30 mmol) was added and the mixture was stirred at -30°C for 1 hour and 30 minutes at room temperature. The mixture was cooled down to 0°C and IN hydrochloric acid was slowly added. The organic phase was separated and the aqueous phase was extracted with ethyl ether. The combined organic phases were washed with water, saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (4.5 x 15 cm, 30 to 100% hexane /toluene) and triturated in hexane (3.9 g, 73%) as a white solid.
IR (KBr) υmax (cm"1 ): 2960, 2915, 2860, 1685 (C=0).
ΪH NMR 400 MHz (CDCI3) δ (ppm): 8.12 (IH, d, J=2.2 Hz, H-8), 7.62 (IH, dd,
J=8.4 and 2.2 Hz, H-6), 7.30 (IH, d, J=8.4 Hz, H-5), 2.87-2.78 (IH, m, H-2), 1.92-1.86 (2H, m, H-3), 1.42 and 1.38 (2 x 3H, 2 s, CH3-4), 1.26 (3H, d, J=6.6 Hz, CH3-2).
Anal. Calcd. for Ci3Hi5BrO: C 58.44; H 5.66.
Found: C 58.59; H 5.62.
7-Bromo-l,2,4,4-tetramethyl-3.4-dihydronaphthalene
l,2,3,4-Tetrahydro-2,4,4-trimethyl-l-oxo-7-bromo-naphthalene (0.535 g, 2.0 mmol) was reacted as described in Example 2 for the preparation of 7- bromo-l-phenyl-4,4-dimethyl-3,4-dihydronaphthalene by using methylmagnesium bromide instead of phenylmagnesium bromide. The title material was obtained (0.596 g, 92%) as a white solid.
IR (KBr) υmax (cm"1): 2930, 2900, 2840, 2800. iH NMR 400 MHz (CDCI3) δ (ppm): 7.36 (IH, d, J=2.0 Hz, H-8), 7.27-7.25 (IH, dd overlapped by CDCI3, H-6), 7.14 (IH, d, J=8.2 Hz, H-5), 2.14 (2H, s, H-3), 2.01 and 1.91 (2 x 3H, 2 s, -CH3-2 and -CH3-I), 1.21 (6H, s, 2 x -CH3-4).
Anal. Calcd. for Ci4Hχ7Br: C 63.41; H 6.46. Found: C 63.30; H 6.46.
Methyl 4-[.5.5.7.8-tetramethyl-5.6-dihydro-2- naphthalenyl)carbonyl]benzoate
7-Bromo-l,2,4,4-tetramethyl-3,4-dihydronaphthalene (0.265 g, 1.0 mmol) was reacted as described in Example 2 for the preparation of methyl 4-[(8- phenyl-5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]benzoate. The title material was obtained (0.162 g, 46%) as a white solid.
IR (KBr) υmax (cm'1): 2960, 2920, 2860, 1722 and 1655 (C=0).
!H NMR 400 MHz (CD3OD) δ (ppm): 8.08 (2H, d, J=8.2 Hz, H-2 and H-6),
7.76 (2H, d, J=8.2 Hz, H-3 and H-5), 7.62 (IH, d, J=1.6 Hz, H-l'), 7.47 (IH, dd, J=8.0 and 1.6 Hz, H-3'), 7.37 (IH, d, J=8.0 Hz, H-4"), 3.87 (3H, s, -OCH3), 2.12
(2H, s, H-6'), 1.95 and 1.85 (2 x 3H, 2 s, -CH3-7' and -CH3-8'), 1.18 (6H, s, 2 x - CH3-5').
Anal. Calcd. for C23H24 3: C 79.28; H 6.94. Found: C 79.31; H 7.08.
Methyl 4-..5.5.7.8-tetramethyl-5.6-dihydro-2- naphthalenyl.ethenyl]benzoate
Methyl 4-[(5,5,7,8-tetramethyl-5,6-dihydro-2- naphthalenyl)carbonyl]benzoate (0.150 g, 0.430 mmol) was reacted as described in Example 2 for the preparation of methyl 4-[(8-phenyl-5,5- dimethyl-5,6-dihydro-2-naphthalenyl)ethenyl]benzoate. The title material was obtained (0.092 g, 62%) as a white solid.
IR (KBr) υmax (cm"l): 2955, 2900, 1718 (C=0), 1645. iH NMR 400 MHz (CD3OD) δ (ppm): 7.93 (2H, d, J=8.2 Hz, H-2 and H-6),
7.38 (2H, d, J=8.2 Hz, H-3 and H-5), 7.21 (IH, d, J=7.9 Hz, H-4'), 7.10 (IH, br s, H-l'), 7.00 (IH, br d, J=7.9 Hz, H-3'), 5.46 (2H, br d, JAB undetermined, ethenyl H), 3.85 (3H, s, -OCH3), 2.08 (2H, s, H-6'), 1.88 and 1.84 (2 x 3H, 2 s , - CH3-7' and -CH3-8'), 1.17 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C24H26O2: C 83.20; H 7.56.
Found: C 83.29; H 7.28.
4-[l-(5,6-Dihydro-5.5.7.8-tetramethyl-2-naphthaleny ethenyl1benzoic acid
Methyl 4-[(5,5,7,8-tetramethyl-5,6-dihydro-2- naphthalenyl)ethenyl]benzoate (0.082 g, 0.237 mmol) was saponified as described in Example 2 and afforded the title compound (0.072 g, 92%).
IR (KBr) υmax (cm"1): 3300-2000, 1675 (C=0). iH NMR 400 MHz (DMSO-d6) δ (ppm): 7.94 (2H, d, J=8.3 Hz, H-2 and H-6), 7.43 (2H, d, J=8.3 Hz, H-3 and H-5), 7.28 (IH, d, J=7.9 Hz, H-4'), 7.14 (IH, d, J=1.7 Hz, H-l'), 7.04 (IH, dd, J=7.9 and 1.7 Hz, H-3'), 5.57 (2H, br s, ethenyl H), 2.13 (2H, s, H-6'), 1.93 and 1.88 (2 x 3H, 2 s, -CH3-7' and -CH3-8'), 1.19 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C23H24O2 • 0.06 EtOH: C 82.84; H 7.32. Found: C 82.67; H 7.16.
EXAMPLE 8
4-ri-(5,6-Dihydro-3.5.5-trimethyl-8-isopropyl-2- naphthalenyl)ethenyn benzoic acid
1. Preparation of 1.2.3,4-tetrahydro-4.4,6-trimethyl-7-bromo-l-oxo- naphthalene
Methyl 4-.p-tolyl.-butyrate
A solution of 4-(p-tolyl)-butyric acid (10.0 g, 56.11 mmol) in methanol (680 mL) was treated with concentrated sulfuric acid (5.4 mL). The reaction
was stirred at room temperature for 18 hours. Sodium bicarbonate (=15 g) was added and the mixture was stirred for 15 minutes, then concentrated. The residue was dissolved in ethyl acetate /water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (10.8 g, 100% crude) as an oil which was used for the next reaction.
iH NMR 400 MHz (CDCI3) δ (ppm): 7.11 (2H, d, JAB=8.2 Hz, H-2 and H-6), 7.03 (2H, d, JAB=8,2 HZ, H-3 and H-5), 3.68 (3H, s, -OCH3), 2.62 (2H, t, J=7.5 Hz, -CH2-Cθ2Me), 2.34 (2H, t, J=7.5 Hz, Ar-CH2-), 2.33 (3H, s, -CH3), 1.95 (2H, qi, J=7.5 Hz, -CH2-CH2-CH2-).
2-methyl-5-.p-tolyl.-pentan-2-ol
A solution of methyl 4-(p-tolyl)-butyrate (10.8 g, 56.2 mmol) in ether (215 mL) and benzene (215 mL) was treated dropwise (=15 minutes) with methylmagnesium bromide (3M in ethyl ether, 45 mL, 135 mmol). The mixture was stirred at room temperature for 1.5 hours, then cooled down to 0°C and treated with 10% aqueous ammonium chloride (100 mL). The pH was then adjusted to 6.5-7 with concentrated hydrochloric acid and the mixture was diluted with ethyl acetate (=200 mL). The organic phase was separated and washed with brine/water 1:1, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material(10. 4 g, 96%) as a yellowish oil which was used for the next reaction.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.10 (4H, s, H-2, H-3, H-5 and H-6), 2.60 (2H, t, J=7.6 Hz, Ar-CH2-), 2.33 (3H, s, Ar-CH3), 1.73-1.65 and 1.54-1.50 (2 x 2H, 2m, -CH2-CH2-). 1.22 (6H, s, 2 x -CH3).
1.2.3.4-Tetrahydro-l .1.7-trimethyl-naphthalene
A solution of 2-methyl-5-(p-tolyl)-pentan-2-ol (10.4 g, 54.1 mmol) in ethyl ether (100 mL) at 0°C was treated with concentrated sulfuric acid (64 mL). The mixture was stirred at 0°C for 1.5 hours, and then poured into a mixture of ice /water. The mixture was diluted with ethyl ether, the organic phase was separated, washed with water (2 x), saturated sodium bicarbonate and brine. The aqueous phase was extracted with ethyl ether and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (9.6 g, 100% crude) as a yellowish oil which was used for the next reaction.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.14 (IH, br s, H-8), 6.96 (IH, d, J=7.7
Hz, H-5), 6.91 (IH, br d, J=7.7 Hz, H-6), 2.74 (2H, t, T=6.3 Hz, H-4), 2.32 (3H, s, -CH3-7), 1.83-1.77 and 1.68-1.65 (2 x 2H, 2m, H-3 and H-2), 1.29 (6H, s, 2 x -
CH3-I).
l,2,3.4-Tetrahydro-4,4,6-trimethyl-l-oxo-naphthalene
A solution of l,2,3,4-tetrahydro-l,l,7-trimethyl-naphthalene (9.60 g, 55 mmol), potassium bromate (9.17 g, 55 mmol), cerium ammonium nitrate (1.50 g) in water (28 mL) and dioxane (44 mL) was heated under argon at 85°C for 6 hours. The mixture was then cooled down to 0°C, diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water (2 x), saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The
residue was purified by silica gel chromatography (6.5 x 17 cm, 10% ethyl acetate /hexane) to give the title material (9.2 g, 89%) as a colorless oil. IR (film) υmax (cm"1): 2940, 2910, 2840, 1670 (C=0), 1600.
!H NMR 400 MHz (CDCI3) δ (ppm):7.94 (IH, d, J=8.0 Hz, H-8), 7.22 (IH, br s, H-5), 7.12 (IH, dd, J=8.0 and 0.8 Hz, H-7), 2.71 (2H, t, J=6.8 Hz, H-2), 2.41 (3H, s, -CH3-6), 2.02 (2H, t, J=6.8 Hz, H-3), 1.39 (6H, s, 2 x -CH3-4).
MS DCI: 189 (MH)+
1.2.3 ■4-Tetrahydro-4.4.6-trimethyl-7-bromo-l-oxo-naphthalene
To a stirred suspension of aluminum trichloride (l.lg, 8.1 mmol) in dichloromethane (2.5 mL) was added a solution of l,2,3,4-tetrahydro-4,4,6- trimethyl-1-oxo-naphthalene (0.564 g, 3 mmol) in dichloromethane (1 mL) at 0°C. The mixture was stirred at this temperature for 45 minutes and then at room temperature for 45 more minutes. Bromine (0.185 mL, 3.6 mmol) was then added and the resulting mixture was stirred 2 hours at room temperature. The mixture was poured into a mixture of ice (=50 mL), concentrated hydrochloric acid (=1.5 mL) and ethyl ether (=50 mL). The organic phase was separated and washed with IN hydrochloric acid, saturated sodium bicarbonate, aqueous sodium thiosulfate and brine. The aqueous phases were extracted with ethyl ether and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5 x 17 cm, 0 to 5% ethyl acetate /toluene) to give the title material which was triturated in cold hexane (0.700 g, 87%). IR (KBr) υ^ (cm'1): 2960, 2930, 2860, 1675 (C=0).
Η NMR 400 MHz (CDC13) δ (ppm): 8.17 (IH, s, H-8), 7.28 (IH, s, H-5), 2.72 (2H, t, J=6.8 Hz, H-2), 2.02 (3H, s, -CH3-6), 2.01 (2H, t, J=6.8 Hz, H-3), 1.38 (6H, s, 2 x -CH3-4).
Anal. Calcd. for C13H15BrO: C 58.44; H 5.66. Found: C 58.12; H 5.78.
2. Preparation of ethyl 4-(l-.tributylstannyl.-2-(trimethylsilyl.-ethen-l-yl.- benzoate
Ethyl 4-ethynyl-benzoate
A solution of ethyl 4-iodo-benzoate (55.2 g, 0.2 mol) in triethylamine (800 mL) was purged with argon. Copper iodide (1.1 g) and bis(triphenylphosphine)palladium(II) dichloride (7.0 g) were then added and the mixture was purged again. Trimethylsilylacetylene (42 mL, 0.3 mol) was then added at 0°C for 30 minutes and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated, triturated in hexane and filtered. The filtrate was concentrated to give ethyl 4-(2-trimethylsilylethen-l-yl)-benzoate (51.5 g, 100% crude) as a black oil.
!H NMR 400 MHz (CDCI3) δ (ppm): 7.98 (2H, d, J=8.4 Hz, H-2 and H-6), 7.52 (2H, d, J=8.4 Hz, H-3 and H-5), 4.38 (2H, q, J=7.1 Hz, -OCH2-), 1.40 (3H, t, J=7.1 Hz, -CH3), 0.27 (9H, s, -Si(CH3)3)-
The crude silated material was diluted in ethanol (500 mL) and potassium carbonate (2.4 g) was added. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was
triturated in hexane and filtered. The filtrate was concentrated and the residue was purified by Kugelrohr distillation (=0.1 mm Hg, bath =70- 80°C) and afforded the title material (27.2 g, 78%) as a colorless oil which solidifies.
IR (KBr) υmax (cm"1): 3300 (≡C-H), 2980, 2940, 2910, 2110 (-C---C-), 1715
(C=0).
iH NMR 400 MHz (CDCI3) δ (ppm): 8.01 (2H, d, J=8.2 Hz, H-2 and H-6), 7.56 (2H, d, J=8.2 Hz, H-3 and H-5), 4.40 (2H, q, J=7.1 Hz, -OCH2-), 3.24 (IH, s, sC-H), 1.41 (3H, t, J=7.1 Hz, -CH3).
Ethyl 4-(l-(tributylstannylV2-(trimethylsilyl)-ethen-l-y -benzoate
A mixture of ethyl 4-ethynyl-benzoate (27.0 g, 0.155 mol), trimethylsilyltributyltin (65 mL, 0.186 mol), tetrakis(triphenylphosphine)palladium(0) (2.9 g, 2.51 mmol) in dioxane
(270 mL) was purged with argon, and then heated to 85°C for 1.5 hours.
The mixture was cooled down to room temperature and concentrated. The residue was purified by silica gel pad chromatography (10.5 x 15 cm, 0 to 5% ethyl acetate /hexane) to give the title material (83.0g, 100%) as a slightly yellowish oil.
iH NMR 400 MHz (CDCI3) δ (ppm): 7.95 (2H, d, J=8.2 Hz, H-2 and H-6), 7.03 (2H, d, J=8.3 Hz, H-3 and H-5), 6.57 (IH, s, ethenyl H), 4.38 (2H, q, J=7.1 Hz, -OCH2-), 1.41 (3H, t, J=7.1 Hz, -OCH2CH3), 1.41 (6H, m, 3 x -CH2-), 1.26 (6H, m, J=7.3 Hz, 3 x -CH2-CH2-CH3), 0.91 (6H, m, 3 x -SnCH2-), 0.86 (9H, t, J=7.3 Hz, 3 x -CH2-CH3). 0.19 (9H, s, -Si(CH3)3).
3. Preparation of 4-f -L-(5.6-dihydro-3,5.5-trimethyl-8-isopropyl-2- naphthalenyDethenyllbenzoic acid
Ethyl 4-ri-.5.6.7.8-tetrahydro-3.5.5-trimethyl-8-oxo-2-naphthaleny -2- trimethylsilyl-ethenyl benzoate
A solution of l,2,3,4-tetrahydro-4,4,6-trimethyl-l-oxo-7-bromo- naphthalene (8.5 g, 31.8 mmol) in 318 mL of N-methyl pyrrolidone was purged with argon (2 x). Lithium chloride (4.0 g), copper iodide (0.860 g), tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.6 mmol) and ethyl 4-(l- (tributylstannyl)-2-(trimethylsilyl)-ethen-l-yl)-benzoate (24.0 g, 44.5 mmol) were then added and the resulting mixture was again purged with argon. The mixture was heated to 80°C for =4 hours, and then cooled down to room temperature. The mixture was poured into cold water (1L) and was diluted with ethyl ether. The organic phase was separated, washed with cold water (2 x 1L), saturated sodium bicarbonate (1L), brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8 x 15 cm, 0 to 5% ethyl acetate /toluene) to give the title material which was triturated in hexane (12.2 g, 88%).
iH NMR 400 MHz (CDCI3) δ (ppm): 7.94 (2H, d, J=8.3 Hz, H-2 and H-6),
7.85 (IH, s, H-l"), 7.31 (2H, d, J=8.3 Hz, H-3 and H-5), 7.22 (IH, s, H-4'), 6.53 (IH, s, ethenyl H), 4.37 (2H, q, J=7.1 Hz, -OCH2-), 2.76 (2H, t, J=6.7 Hz, H-7'), 2.03 (2H, t overlapped by -CH3-3', H-6'), 2.03 (3H, s, -CH3-3'), 1.43 (6H, br s, 2 x -CH3-5'), 1.39 (3H, t, J=7.1 Hz, -CH2-CH3), -0.17 (9H, s, -Si(CH3)3).
Anal. Calcd. for C27H34O3S C 74.61; H 7.89.
Found: C 75.08; H 7.94.
Ethyl 4-[l-.5.6.7.8-tetrahydro-3.5.5-trimethyl-8-oxo-2-naphthalenylV ethenyl]benzoate
A solution of ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2- naphthalenyl)-2-trimethylsilyl-ethenyl]benzoate (12.0 g, 27.6 mmol) in dichloromethane (900 mL) was treated with trifluoroacetic acid (100 mL) at 0°C. The mixture was stirred for 18 hours and allowed to reach room temperature. The mixture was then diluted with toluene (=100 mL) and concentrated. The residue was purified by silica gel chromatography (8 x 15 cm, 0 to 5% ethyl acetate /toluene) and gave the title material as a yellowish solid which was triturated in hexane (9.7 g, 97%). An analytical sample was recrystallized in hexane.
IR (KBr) υmax (cm"l): 2970, 2950, 2910, 2875, 1712 and 1685 (C=0), 1605. !H NMR 400 MHz (CDCI3) δ (ppm): 7.97 (2H, d, J=8.4 Hz, H-2 and H-6), 7.91 (IH, s, H-l'), 7.31 (2H, d, J=8.4 Hz, H-3 and H-5), 7.22 (IH, s, H-4'), 5.86 (IH, d, J=0.6 Hz, ethenyl H), 5.35 (IH, br s, ethenyl H), 4.38 (2H, q, J=7.1 Hz, - OCH2-), 2.76 (2H, t, J=6.8 Hz, H-7'), 2.05 (3H, s, -CH3-3'), 2.07-2.04 (2H, t overlapped by -CH3-3', H-6'), 1.43 (6H, s, 2 x -CH3-5'), 1.40 (3H, t, J=7.1 Hz, - CH2-CH3).
Anal. Calcd. for C24H26O3: C 79.53; H 7.23.
Found: C 79.26; H 7.30.
Ethyl 4-r ( 3.5,5-trimethyl-5.6-dihydro-8-isopropyl-2- naphthalenyl.ethenyl"lbenzoate
Ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2-naphthalenyl)- ethenyljbenzoate (9.06 g, 25 mmol) was reacted as described in Example 2 for the preparation of 7-bromo-l-phenyl-4,4-dimethyl-3,4- dihydronaphthalene except that isopropylmagnesium chloride was used instead of phenylmagnesium bromide. The title material was obtained (6.1 g, 63%) as a white solid along with the starting material (1.0 g, 11%) and ethyl 4-[(3,5,5-trimethyl-5,6-dihydro-8-hydroxy-2- naphthalenyl)ethenyl]benzoate (1.0 g, 11%).
IR (KBr) υmax (cm"l): 2970, 2960, 2950, 2920, 2870, 1710 (C=0), 1605. !H NMR 400 MHz (CDCI3) δ (ppm): 7.98 (2H, d, J=8.3 Hz, H-2 and H-6), 7.37 (2H, d, J=8.3 Hz, H-3 and H-5), 7.18 and 7.12 (2 x IH, 2 s, H-l' and H-4'), 5.85 (IH, br s, ethenyl H), 5.77 (IH, t, J=4.6 Hz, H-7'), 5.35 (IH, br s, ethenyl H), 4.38 (2H, q, J=7.1 Hz, -OCH2-), 2.95 (IH, m, J=6.7 Hz, -CH(CH3)2), 2.22 (2H, d, J=4.6 Hz, H-6'), 2.01 (3H, s, -CH3-3'), 1.40 (3H, t, J=7.1 Hz, -CH2-CH3), 1.27 (6H, s, 2 x -CH3-5'), 1.16 (6H, d, J=6.8 Hz, -CH(CH3)2).
Anal. Calcd. for C27H32O2: C 83.46; H 8.30.
Found: C 83.27; H 7.67.
4-ri-.5.6-Dihydro-3.5.5-trimethyl-8-isopropyl-2- naphthalenyl.ethenyllbenzoic acid
Ethyl 4-[(3,5,5-trimethyl-5,6-dihydro-8-isopropyl-2- naphthalenyl)ethenyl]benzoate (3.9 g, 10 mmol) was saponified as described in Example 2 and afforded the title compound (3.1 g, 86%) as a white solid.
IR (KBr) υmaχ (cm"l): 3330-2300 (br), 1690 (C=0), 1605. !H NMR 400 MHz (DMSO-d6) δ (ppm): 7.90 (2H, d, J=8.4 Hz, H-2 and H-6), 7.36 (2H, d, J=8.4 Hz, H-3 and H-5), 7.18 and 7.08 (2 x IH, 2 s, H-l' and H-4'), 5.96 (IH, s, ethenyl H), 5.75 (IH, t, J=4.4 Hz, H-7'), 5.32 (IH, s, ethenyl H), 2.89 (IH, m, J=6.7 Hz, -CH(CH3)2), 2.15 (2H, d, J=4.3 Hz, H-6'), 1.96 (3H, s, - CH3-3'), 1.21 (6H, s, 2 x -CH3-5'), 1.09 (6H, d, J=6.7 Hz, -CH(CH3)2).
Anal. Calcd. for C25H28O2: C 83.29; H 7.83.
Found: C 83.24; H 8.37.
EXAMPLE 9
4-ri-(5.6-Dihydro-3,5.5-trimethyl-8-t-butyl-2- naphthalenyl)ethenyn benzoic acid
Ethyl 4-\( .5.5-trimethyl-5.6-dihydro-8-t-butyl-2- naphthalenv ethenyllbenzoate
Ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2-naphthalenyl)- ethenyl]benzoate (1.025 g, 2.82 mmol) was reacted as described in Example
2 for the preparation of 7-bromo-l-phenyl-4,4-dimethyl-3,4- dihydronaphthalene except that t-butylmagnesium chloride was used instead of phenylmagnesium bromide. The title material was obtained
(0.319 g, 28%) as a white solid along with the starting material (0.30 g, 29%).
IR (KBr) υmax (cm"l): 2980, 2955, 2925, 2875, 1715 (C=0), 1605. iH NMR 400 MHz (CDCI3) δ (ppm): 7.98 (2H, d, J=8.4 Hz, H-2 and H-6), 7.52 (IH, s, H-l'), 7.39 (2H, d, J=8.4 Hz, H-3 and H-5), 7.12 (IH, s, H-4'), 5.94 (IH, t, J=5.0 Hz, H-6'), 5.85 (IH, d, J=l.l Hz, ethenyl H), 5.36 (IH, br s, ethenyl H), 4.38 (2H, q, J=7.1 Hz, -OCH2-), 2.18 (2H, d, J=5.0 Hz, H-6'), 2.00 (3H, s, -CH3-3'), 1.40 (3H, t, J=7.1 Hz, -CH2-CH3), 1.30 (9H, s, -tBu), 1.25 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C28H34O2: C 83.54; H 8.51.
Found: C 83.56; H 8.60.
4-[l-.5.6-Dihydro-3.5.5-trimethyl-8-t-butyl-2-naphthalenyl.ethenyl]benzoic acid
Ethyl 4-[(3,5,5-trimethyl-5,6-dihydro-8-t-butyl-2- naphthalenyl)ethenyl]benzoate (0.605 g, 1.50 mmol) was saponified as described in Example 2 and afforded the title material (0.525 g, 93%) as a white solid.
IR (KBr) υmaχ (cm"1): 3500-2200, 1680 (C=0), 1615. iH NMR 400 MHz (DMSO-d6) δ (ppm): 12.92 (IH, s, -CO2H), 7.91 (2H, d,
J=8.4 Hz, H-2 and H-6), 7.38 (2H, d, J=8.4 Hz, H-3 and H-5), 7.38 (IH, s, H-l'),
7.17 (IH, s, H-4'), 5.95 (IH, s, ethenyl H), 5.93 (IH, t, J=4.9 Hz, H-6'), 5.32 (IH, s, ethenyl H), 2.12 (2H, d, J=4.9 Hz, H-6'), 1.97 (3H, s, -CH3-3'), 1.25 (9H, s, t-Bu), 1.20 (6H, s, 2 x -CH3-5').
Anal. Calcd. for C26H30O2 . 0.5 H2O: C 81.42; H 8.15.
Found: C 81.50; H 8.10.
EXAMPLE 10
4-ri-.5.6-Dihydro-3,5.5-trimethyl-8-(l-methyl-l-ethane-thio)-2- naphthalenyDethenyllbenzoic acid
Potassium 1-methyl-l-ethane-thiolate
To a stirred solution of 1-methyl-l-ethanethiol (0.152 g, 2.0 mmol) in hexane (5 mL) was added dropwise potassium bis(trimethylsilyl)amide (0.5 M in toluene, 4.0 mL, 2.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. A viscous suspension was formed. The solid was filtered, washed with hexane (3 x) and dried under vaccum.
Ethyl 4-[l-.5,6-dihydro-3.5.5-trimethyl-8-trifluoromethanesulfonyloxy-2- naphthalenyl.ethenyl]benzoate
A solution of ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2- naphthalenyl)-ethenyl]benzoate prepared in Example 8 (0.300 g, 0.828 mmol) in tetrahydrofuran (10 mL) at -78°C was treated dropwise with a solution of lithium bis(trimethylsilyl)amide (1.0M in tetrahydrofuran,
1.16 mL, 1.16 mmol). The solution was stirred for 30 minutes then treated with a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]pyridine (0.593 g, 1.656 mmol) in tetrahydrofuran (3 mL). The mixture was stirred overnight and was allowed to reach room temperature. The mixture was cooled down to 0-5°C , diluted with water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography in ethyl acetate/hexane and triturated in hexanes to give the title material (0.340, 83%).
Ethyl 4-[l-(5.6-dihydro-3.5.5-trimethyl-8- -methyl-l-ethane-thioV2- naphthalenyl)ethenyl]benzoate
To a suspension of potassium 1-methyl-l-ethane-thiolate (78 mg, 0.688 mmol) in tetrahydrofuran (3 mL) was added benzene (3 mL), followed by ethyl 4-[l-(5,6-dihydro-3,5,5-trimethyl-8-trifluoromethanesulfonyloxy-2- naphthalenyl)ethenyl]benzoate (0.170 g, 0.344 mmol) and tetrakis(triphenylphosphine)palladium(0) (68 mg). The reaction mixture was stirred at 60°C for 30 minutes, then diluted with ethyl acetate. The organic phase was washed with water, 10% sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography in ethyl acetate/hexane and afforded the title material (0.065 g, 45%).
!H NMR 400 MHz (CDCI3) δ (ppm): 7.97 (2H, d, J=8.5 Hz, H-2 and H-6), 7.36 (2H, d, J=8.5 Hz, H-3 and H-5), 7.64 and 7.12 (2 x IH, 2 s, H-l' and H-4'), 6.30 (IH, t, J=4.8 Hz, H-7'), 5.86 (IH, d, J=1.0 Hz, ethenyl H), 5.35 (IH, d,
J=l.l Hz, ethenyl H), 4.38 (2H, q, J---7.1 Hz, -OCH2-), 3.14 (IH, m, J=6.6 Hz, - CH(CH3)2), 2.34 (2H, d, J=4.8 Hz, H-6'), 2.02 (3H, s, -CH3-3'), 1.40 (3H, t, J=7.1 Hz, -CH2CH3), 1.32 (6H, s, 2 x -CH3), 1.26 (6H, d, J=6.6 Hz, -CH(CH3)2).
4-fl-f5.6-Dihydro-3.5.5-trimethyl-8-(l-methyl-l-ethane-thioV2- naphthaleny ethenyllbenzoic acid
Ehyl 4-[l-(5,6-dihydro-3,5,5-trimethyl-8-(l-methyl-l-ethane-thio)-2- naphthalenyl)ethenyl]benzoate was saponified as described in Example 2.
iH NMR 400 MHz (DMSO-d6) δ (ppm): 7.91 (2H, d, J=8.4 Hz, H-2 and H-6),
7.42 and 7.22 (2 x IH, 2 s, H-l' and H-4'), 7.36 (2H, d, J=8.4 Hz, H-3 and H-5), 6.27 (IH, t, J=4.7 Hz, H-7'), 5.97 (IH, d, J=0.6 Hz, ethenyl H), 5.32 (IH, br s, ethenyl H), 3.10 (IH, m, J=6.7 Hz, -CH.(CH3)2), 2.30 (2H, d, J=4.7 Hz, H-6'), 2.00 (3H, s, -CH3-3'), 1.26 (6H, s, 2 x -CH3), 1.18 (6H, d, J=6.7 Hz, -CH(CH3)2). MS (ESI): 391.2 (M-H)".
HRMS (ESI): calculated for C25H27S02: 391.1732
Found: 391.1751
EXAMPLE 11
4-fl-(5,6,7,8-Tetrahydro-3,5,5-trimethyl-8-(cyclopropylamino)-2- naphthalenyl.ethenyllbenzoic acid
Ethyl 4-fl-.5.6.7.8-tetrahydro-3.5.5-trimethyl-8-.cyclopropylaminoV2- naphthalenyl.ethenyl]benzoate
A powdered form of ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-oxo-2- naphthalenyl)-ethenyl]benzoate (110 mg, 0.3035 mmol) was placed into a 7 mL vial equipped with a stirrer. EtOH (1.7 mL), THF (0.6 mL), Ti(0-iPr) (0.40 mL) and cyclopropyl amine (0.1 mL, 1.443 mmol) were sequentially added. The vial was capped and stirred at room temperature for 3.5 hrs, and heated for 5 hrs with an oil bath equilibrated at 40 °C. The vial was removed from the heating bath, and NaBHj (26.0 mg, 0.6869 mmol) was added in one batch. The reaction mixture was then stirred for an additional 14 hrs at room temperature.
KOH solution (1 mL of 1.76 M/H2O) was added to the reaction mixture. The mixture was diluted with CH2CI2 (10 mL), stirred for a few minutes and the precipitate was filtered. The filterate was diluted with additional CH2CI2, washed with water and brine. The organic layer was dried with Na2Sθ4, filtered and the filterate was evaporated in vacuo. The resulting crude amine was purified with flash chromatography (sample was loaded as a silica gel mesh; 7.5% EtOAc/hexanes) to afford the amine as a white solid (109 mg, 89%).
!H NMR 400 MHz (CDCI3) δ (ppm): 7.97 (d, J = 8.6 Hz, 2 H, Ar-H), 7.35 (d, J
= 8.6 Hz, 2H, Ar-H), 7.15 (s, IH, Ar-H), 7.12 (s, IH, Ar-H), 5.83 (d, J = 1.3 Hz, IH, =CH2), 5.33 (d, J = 1.3 Hz, IH, =CH2), 4.39 (q, J = 7.1 Hz, 2H, OCH2), 3.82 (app t, <J> = 4.7 Hz, IH, CCHNH), 2.28-2.18 (m, IH), 2.10- 1.85 (m, 3H), 1.97 (s, 3H, ArCH3), ~ 1.57 (m, IH), 1.40 (t, J = 7.1 Hz, 3H, CH2CH3), 1.36 (s, 3H, CH3), 1.29 (s, 3H, CH3), 0.58-0.32 (m, 4H, CHCH2CH2). MS: (ESI) = 404.3 (M+H)+.
4-[l-.5.6.7.8-Tetrahydro-3,5.5-trimethyl-8-(cyclopropylamino.-2- naphthalenyl.ethenyl]benzoic acid
Ethyl 4-[l-(5,6,7,8-tetrahydro-3,5,5-trimethyl-8-(cyclopropylamino)-2- naphthalenyl)ethenyl]benzoate (107.0 mg, 0.2650) was treated with EtOH (3 mL) and KOH (0.30 mL of 1.76 M/H2O), and the resulting mixture was heated with a 75 °C oil bath for 1 hr. The reaction mixture was diluted with water (15 mL) and acidified with 5% HC1 to a pH near 4.0. The resulting milky solution was treated with saturated NH4CI solution (2 mL), and extracted with EtOAc. The organic layer was washed with brine, dried with MgSθ4, filtered and evaporated in vacuo to afford the title compound as a white solid (98.0 mg, 98%).
iH NMR 400 MHz (DMSO-d6) δ (ppm): 7.58 (br d, J = 7.70 Hz, 2H, Ar-H), 7.41 (s, IH, Ar-H), 7.20 (s, IH, Ar-H), 6.99 (br d, J = 7.70 Hz, 2 H, Ar-H), 5.72 (s, IH, =CH2), 5.25 (s, IH, =CΑ_), 4.43 (s, IH, CCHNH), 2.60-2.38 (m, 2H), 2.35-2.10 (m, 2H), 1.95 (s, 3H, Ar-H), 1.77-1.57 (m, IH), 1.49 (s, 3H, CCH3), 1.29 (br s, 5H, CCH3 and 2 cyclopropyl CH), 0.82-0.60 (m, 2H, NHCHCH2CH2). MS: (ESI) = 374.3 (M-H)".
A series of 8-amino derivatives was prepared according to the procedures described in Example 11. During the reductive amination, only 2 equivalents of amine was employed for the less volatile ones. After saponification, the acids that contained impurities were dissolved in DMF and purified with a reverse phase HPLC by employing the following conditions:
Column = YMC S5 ODS 20X100 MM Solvent A = 10 CH3OH: 90 H2O : 0.1 TFA Solvent B = 90 CH3OH: 10 H2O: 0.1 TFA Initial Solvent = 30% A: 90% B Final Solvent = 100% B
Flow Rate = 20 mL/min Wavelength = 220 nM.
The compounds prepared are the following:
4- [ 1 - (5,6-Dihy dro-3,5,5-trimethy 1-8-pr opy lamino-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2-methylpropyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-butylamino-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2,2-dimethyl-propyl-l- amino)-
2-naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(3-methyl-butyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2-methyl-butyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid; and
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(cyclohexylmethylamino)-2- naphthalenyl)ethenyl]benzoic acid.
Claims
1. A retinoid compound having the formula:
or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which,
R' and R" are independently hydrogen, Cι_6 alkyl, hydroxy,
Ci-6 alkoxy or Cχ-6 alkylthio; or when taken together are =0, =S, =NR15, =CR10R11, C3-6 cycloalkyl, epoxy, thioepoxy,
-0(CH2)mO-, -0(CH2)mS- or -S(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Cχ-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur atom;
R1 is -(CH=CH)p-C02Z, -(C-- )p-C02Z, -(CH2)p
-C02Z, Ci-6 alkyl, -CH2OH, -CONHR12, -CHO, -COCO2Z or -C=N(OR12)-C02Z; R2 and R3 are independently hydrogen or Ci-6 alkyl when
A is carbon or nitrogen; independently oxygen or nil when A is sulfur and nil when A is oxygen;
R4 is hydrogen, Ci-io alkyl, C3-10 cycloalkyl, alkyl
Cι-10 polyfluoroalkyl, Ci-10 alkylthio, C3-10 cycloalkylthio, Ci-io alkylsulfoxy, C3-10 cycloalkylalkylsulfoxy, Cι_ιo alkylsulfone, C3-10 cycloalkylsulfone, Ci-io alkoxy, C3.10 cycloalkoxy, Ci-io alkylamino, C3-10 cycloalkylamino, -COR13, -C(OR1 )2R13, -C(SR14)2R13, phenyl or heteroaryl, wherein the phenyl or the heteroaryl radicals can be substituted by Ci-6 alkyl, halogen, Ci-6 alkoxy, Ci-6 alkylthio, -C02R13, -COR13 or
-NR13R14;
R5 is hydrogen, Ci-6 alkyl, Ci-6 alkoxy or Ci-6 alkythio, C2-6 alkenyl or C2-6 alkynyl;
R6 is hydrogen or Ci-6 alkyl;
R7 is independently hydrogen, Cχ-6 alkyl, hydroxy, carbonyl, Ci-6 alkyloxy, C\.(, alkylthio, fluoride; but when n is one, R6 and R7 together can form a radical of the formula 
7 and when n is two, both R taken together can be =0, =S, =CH2, =C(CH3)2, =CH(CH3), -0(CH2)20-, -S(CH2)20- or -S(CH2)20-;
R8 and R9 are independently hydrogen, halogen, Ci-β alkyl, hydroxy, azido, cyano, Ci-6 alkoxy or nitro;
R10, R11, R12, R13 and R14 are independently hydrogen or Ci-6 alkyl;
R13 is OH, Ci-6 alkyl, aryl or heteroaryl;
n is 0 to 2;
m is 2 to 5;
p is 0 to 2;
Z is Ci-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation.
2. A retinoid having the formula:
R' and R" are independently hydrogen, Ci-6 alkyl, hydroxy, Ci-6 alkoxy or Cχ-6 alkylthio; or when taken together are =0, =S, =NR15, =CR10R11 / C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -0(CH2)mS- or S(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Ci-6 alkyl, phenyl, alkoxyphenyl or halogen;
A is carbon, nitrogen, oxygen or sulfur atom;
R1 is -(CH=CH)p-C02Z, -(C---C)p-C02Z, -(CH2)p
-C02Z, Ci-6 alkyl, -CH2OH, -CONHR12, -CHO, -COCO2Z or -C=N(OR12)-C02Z;
R2 and R3 are independently hydrogen or Ci-6 alkyl when A is carbon or nitrogen; independently oxygen or nothing when A is sulfur and nothing when A is oxygen;
R5 is hydrogen, Ci-6 alkyl, Cχ-6 alkoxy or -6 alkythio, C2-6 alkenyl or C2-6 alkynyl;
R6 is hydrogen or Ci-6 alkyl; R7 is independently hydrogen, Cχ-6 alkyl, hydroxy, carbonyl, Ci-6 alkyloxy, Ci-6 alkylthio, fluoride; but when n is one, R6 and R7 together can form a radical of the formula
7 and when n is two, both R taken together can be =0, =S, =CH2, =C(CH3)2, =CH(CH3), -0(CH2)20-, -S(CH2)20- or -S(CH2)20-;
R8 and R9 are independently hydrogen, halogen, Ci-6 alkyl, hydroxy, azido, cyano, Ci-6 alkoxy or nitro;
R10, R11 and R12 are independently hydrogen or Ci-6 alkyl;
R15 is OH, Ci-6 alkyl, aryl or heteroaryl;
Ra is hydrogen, Ci-6 alkyl, Ci-6 alkoxy or Ci-6 alkylthio;
Rb is hydrogen, Ci-6 alkyl, C3.6 cycloalkyl or Ci-6 alkyl- C3.6 cycloalkyl;
X is O, S or N;
n is 0 to 2;
m is 2 to 5; p is 0 to 2;
Z is Ci-6 alkyl, allyl, trichloroethyl, trimethylsilylethyl, hydrogen or a pharmaceutically acceptable cation.
3. A retinoid compound of claim 1 wherein R1 is -CO2Z and Z is hydrogen or Ci-6 alkyl.
4. A retinoid compound of claim 2 wherein R1 is -CO2Z and Z is hydrogen or Ci-6 alkyl.
5. A retinoid compound of claim 3 wherein R8 and R9 are both hydrogen.
6. A retinoid compound of claim 4 wherein R8 and R9 are both hydrogen.
7. A retinoid compound of claim 3 wherein R6 is a hydrogen or C._6 alkyl and R7 is a hydrogen.
8. A retinoid compound of claim 4 wherein R6 is a hydrogen or Cα_6 alkyl and R7 is a hydrogen.
9. A retinoid compound of claim 5 wherein R6 is a hydrogen or C..6 alkyl and R7 is a hydrogen.
10. A retinoid compound of claim 6 wherein R6 is a hydrogen or C^6 alkyl and R7 is a hydrogen.
11. A retinoid compound of claim 3 wherein R2 and R3 are methyl.
12. A retinoid compound of claim 4 wherein R2 and R3 are methyl.
13. A retinoid compound of claim 3 wherein R5 is methyl.
14. A retinoid compound of claim 4 wherein R5 is methyl.
15. A retinoid compound of claim 9 wherein R2 and R3 are methyl.
16. A retinoid compound of claim 10 wherein R2 and R3 are methyl.
17. A retinoid compound of claim 15 wherein R5 is methyl.
18. A retinoid compound of claim 16 wherein R5 is methyl.
19. A retinoid compound of claim 17 wherein R6 is hydrogen.
20. A retinoid compound of claim 18 wherein R6 is hydrogen.
21. A retinoid compound of claim 19 wherein R' and R" are, when taken together =0, =S, =NR15, =CR10R1:l, C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -0(CH2)mS- or -S(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Ci-6 alkyl, phenyl, alkoxyphenyl or halogen;
22. A retinoid compound of claim 20 wherein R' and R" are, when taken together, =0, =S, =NR15, =CR10R11, C3-6 cycloalkyl, epoxy, thioepoxy, -0(CH2)mO-, -0(CH2)mS- or -S(CH2)mS- wherein the cycloalkyl, the epoxy or the thioepoxy can be substituted with Ci-6 alkyl, phenyl, alkoxyphenyl or halogen;
23. A retinoid compound of claim 1 selected from the group consisting of:
4-[l-(5,6-Dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-5,5-dimethyl-8-isopropyl-2-naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-5,5,8-trimethyl-2-naphthalenyl)ethenyl]benzoic acid;
4-[(5,5,8-Trimethyl-5,6-dihydro-2-naphthalenyl)carbonyl]benzoic acid;
4-[l-(5,6-Dihydro-5,5,7,8-tetramethyl-2-naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-isopropyl-2- naphthaleny 1) ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-t-butyl-2-naphthalenyl)ethenyl]benzoic acid; and 4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(l-methyl-l-ethane-thio)-2- naphthalenyl)ethenyl]benzoic acid; or a pharmaceutically acceptable salt thereof.
24. A retinoid compound of claim 2 selected from the group consisting of:
4-[l-(8-Methoxy-5,5,8-trimethyl-5,6,7,8-tetrahydro-2- naphthalenyl)ethenyl]benzoic acid;
4-[(8-Methoxy-5,5,8-trimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)- carbonyljbenzoic acid;
4-[l-(5,5,8-Trimethyl-5,6,7,8-tetrahydro -8-cyclopropylamino-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-propylamino-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2-methylpropyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-butylamino-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2,2-dimethyl-propyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid; 4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(3-methyl-butyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid;
4-[l-(5,6-Dihydro-3,5,5-trimethyl-8-(2-methyl-butyl-l-amino)-2- naphthalenyl)ethenyl]benzoic acid; and
4-[l-(5,6-Dihydro~3,5,5-trimethyl-8-(cyclohexylmethylamino)-2- naphthalenyl)ethenyl]benzoic acid; or a pharmaceutcally acceptable salt thereof.
25. A method for treating in a host mammal, one or more of the conditions and diseases selected from the group consisting of chronic skin inflammatory diseases, rheumatic diseases, non-malignant proliferative skin conditions and malignant tumors, which comprises administering to said host an effective therapeutic amount of a compound of claim 1 or claim 2, or a pharmaceutical composition thereof.
26. A method for the minimization or prevention of a post-surgical adhesion formation between organ surfaces comprising administering to an animal host an effective amount of a compound of claim 1 or claim 2 for a period of time sufficient to permit tissue repair.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or claim 2 and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU37706/00A AU3770600A (en) | 1999-04-06 | 2000-03-23 | Selective retinoic acid analogs |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12797699P | 1999-04-06 | 1999-04-06 | |
| US60/127,976 | 1999-04-06 | ||
| US13054299P | 1999-04-22 | 1999-04-22 | |
| US60/130,542 | 1999-04-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000059861A1 true WO2000059861A1 (en) | 2000-10-12 |
Family
ID=26826140
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2000/007751 WO2000059861A1 (en) | 1999-04-06 | 2000-03-23 | Selective retinoic acid analogs |
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| Country | Link |
|---|---|
| AU (1) | AU3770600A (en) |
| WO (1) | WO2000059861A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7196099B2 (en) | 2001-09-14 | 2007-03-27 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
| JP2008179570A (en) * | 2007-01-25 | 2008-08-07 | R&R Inc | Medicine for preventing and/or treating internal organ adhesion |
| JP2017537140A (en) * | 2014-10-10 | 2017-12-14 | ハイ フォース リサーチ リミテッド | Fluorescent synthetic retinoid |
| CN109503446A (en) * | 2007-01-15 | 2019-03-22 | 于崇曦 | The prodrug of V-A acidic and biostearin acid compound |
| WO2020212543A1 (en) | 2019-04-18 | 2020-10-22 | Merck Patent Gmbh | Compounds for optically active devices |
| CN115504862A (en) * | 2021-06-07 | 2022-12-23 | 南通新世元生物科技有限公司 | Preparation method of cannabigerol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6034110A (en) * | 1998-01-12 | 2000-03-07 | Allergan Sales, Inc. | Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid and a PPARγ ligand |
-
2000
- 2000-03-23 WO PCT/US2000/007751 patent/WO2000059861A1/en active Application Filing
- 2000-03-23 AU AU37706/00A patent/AU3770600A/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6034110A (en) * | 1998-01-12 | 2000-03-07 | Allergan Sales, Inc. | Method for preventing onset of restenosis after angioplasty employing an RXR-specific retinoid and a PPARγ ligand |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7196099B2 (en) | 2001-09-14 | 2007-03-27 | Aventis Pharmaceuticals Inc. | Compounds and compositions as cathepsin inhibitors |
| CN109503446A (en) * | 2007-01-15 | 2019-03-22 | 于崇曦 | The prodrug of V-A acidic and biostearin acid compound |
| CN109503446B (en) * | 2007-01-15 | 2021-08-20 | 于崇曦 | Prodrugs of retinoids and retinoid-like compounds |
| JP2008179570A (en) * | 2007-01-25 | 2008-08-07 | R&R Inc | Medicine for preventing and/or treating internal organ adhesion |
| JP2017537140A (en) * | 2014-10-10 | 2017-12-14 | ハイ フォース リサーチ リミテッド | Fluorescent synthetic retinoid |
| US10759762B2 (en) | 2014-10-10 | 2020-09-01 | High Force Research Limited | Fluorescent synthetic retinoids |
| JP7178781B2 (en) | 2014-10-10 | 2022-11-28 | ハイ フォース リサーチ リミテッド | Fluorescent synthetic retinoid |
| WO2020212543A1 (en) | 2019-04-18 | 2020-10-22 | Merck Patent Gmbh | Compounds for optically active devices |
| CN115504862A (en) * | 2021-06-07 | 2022-12-23 | 南通新世元生物科技有限公司 | Preparation method of cannabigerol |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3770600A (en) | 2000-10-23 |
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