EP0800517A1 - Acetylen-derivate substituiert mit 5-oder 8-substituierten tetrahydronaphthyl oder dihydronaphthyl sowie mit aryl-oder heteroaryl-gruppen mit retinoid artiger wirkung - Google Patents

Acetylen-derivate substituiert mit 5-oder 8-substituierten tetrahydronaphthyl oder dihydronaphthyl sowie mit aryl-oder heteroaryl-gruppen mit retinoid artiger wirkung

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Publication number
EP0800517A1
EP0800517A1 EP95943828A EP95943828A EP0800517A1 EP 0800517 A1 EP0800517 A1 EP 0800517A1 EP 95943828 A EP95943828 A EP 95943828A EP 95943828 A EP95943828 A EP 95943828A EP 0800517 A1 EP0800517 A1 EP 0800517A1
Authority
EP
European Patent Office
Prior art keywords
carbons
compound
alkyl
group
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95943828A
Other languages
English (en)
French (fr)
Inventor
Vidyasagar Vuligonda
Min Teng
Richard L. Beard
Alan T. Johnson
Yuan Lin
Roshantha A. Chandraratna
Tae K. Song
Harold N. Wong
Tien T. Duong
Samuel J. Gillett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Allergan Sales LLC
Original Assignee
Allergan Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/366,167 external-priority patent/US5618943A/en
Priority claimed from US08/366,172 external-priority patent/US5543534A/en
Priority claimed from US08/366,183 external-priority patent/US5618931A/en
Priority claimed from US08/366,169 external-priority patent/US5599967A/en
Priority claimed from US08/366,168 external-priority patent/US5514825A/en
Priority claimed from US08/366,182 external-priority patent/US5489584A/en
Priority claimed from US08/366,193 external-priority patent/US5648514A/en
Application filed by Allergan Inc filed Critical Allergan Inc
Publication of EP0800517A1 publication Critical patent/EP0800517A1/de
Withdrawn legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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 novel compounds having retinoid-like activity. More specifically, the present invention relates to compounds having an acetylene portion which is substituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl and by a substituted aryl or substituted heteroaryl group having an acid function.
  • the acid function may also be converted to an alcohol, aldehyde or ketone or derivatives thereof, or may be reduced to -CH 3 .
  • retinoid-like activity is well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions.
  • compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non ⁇ inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy) , as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
  • skin-related diseases including, actinic keratoses, arsenic keratoses, inflammatory and non ⁇ inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin,
  • Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma.
  • premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of
  • retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR) , retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA) .
  • PVR proliferative vitreoretinopathy
  • TPA tissue plasminogen activator
  • retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV) , including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T- Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil R , diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
  • HPV human papilloma virus
  • various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease
  • R-_ is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 4;
  • R 4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C-* ⁇ - C 10 -alkylphenyl, naphthyl, C- - C 10 -alkyl- naphthyl, phenyl-C-* ⁇ - C 10 alkyl, napthyl-C-* ⁇ - C 10 alkyl; CN, or (CH 2 ) p C0 2 R 8 where p is an integer between 0 to 10;
  • R 5 is hydrogen, alkyl of 1 to 10 carbons, fluoro- substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbo- cyclic aryl selected from the group consisting of phenyl, C - C 10 -alkylphenyl, naphthyl, C - Ch ⁇ alkylnaphthyl, phenyl-C-L - C 10 alkyl, napthyl-C j L - C 10 alkyl; Si(R 2 ) 3 , COR 14 , camphanoyl, C(R 15 ) (R 16 )XR 17 ;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 car ⁇ bons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR g R 10 , -CH 2 OH, CH 2 OR 1:L , CH 2 0C0R 1:L , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR-,, CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsily- lalkyl where the alkyl group has 1 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphen
  • R A is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 car ⁇ bons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , -CH 2 OH, CH 2 OR 1:L , CH 2 OCOR 1:L , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR ? , CR 7 (OR 12 ) 2 , CR ?
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • ⁇ l is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • X is O or S
  • R.* ⁇ is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, C00R 8 , CONR 9 R 10 , -CH 2 0H, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 0, -C0R ?
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of l to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R ⁇ i i s lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • R 19 is independently hydrogen, alkyl of l to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C-* ⁇ - C 10 -alkylphenyl, naphthyl, c l ⁇ C 10 -alkylnaphthyl, phenyl-C-L - C 10 alkyl, naphthyl-
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 4; Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 1Q , -CH 2 OH, CH 2 OR ⁇ , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR ?
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of l to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 1:L is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons; the wavy line represents a single valence bond around which the configuration can be syn or anti, and
  • Z is OW ⁇ , is phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, OSi(R 2 ) 3 , 0C0R 14 , 0C(R 15 ) (R 16 )XR 17 , N(R 14 ) 2 , NHCON(R 14 ) 2 , NHCSN(R 14 ) 2 , where X is O or S;
  • R 14 is hydrogen, alkyl of l to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C ⁇ - C 10 -alkylphenyl, naphthyl, C-L - C 10 -alkylnaphthyl, phenyl-C- ⁇ - C 10 alkyl, naphthyl- c l ⁇ ' R
  • R A is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the tetrahydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 4;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , -CH 2 OH, CH 2 OR 11 , CH 2 OCOR 1;L , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR ?
  • R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R 11 is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C - C 10 -alkylphenyl, naphthyl, C ⁇ - C 10 -alkyl- naphthyl, phenyl-C x - C 10 alkyl, naphthyl-C-L - C 10 alkyl, or R 14 is C0R 8 , or the two R 14 groups together with the N jointly form a 5 or 6 membered ring, compounds of Formula 6
  • n is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 3;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazi- nyl pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 car ⁇ bons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR g R 10 , -CH 2 OH, CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR ? , CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or tri-lower alkylsilyl, where R 7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl, R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 1:L is lower alkyl, phenyl or lower
  • X is O, S, SO or S0 2 and
  • R 20 is Si(R 2 ) 3 , R 14 , COR 14 , S0 2 R 21 , where R 14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C-* ⁇ - C 1Q - alkylphenyl, naphthyl, C- ⁇ - C 10 -alkylnaphthyl, phenyl- c l ⁇ - C 10 alkyl, or R 20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons; and R 21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C- ⁇ - C 1Q - alkylpheny
  • R A is hydrogen or alkyl of 1 to 10 carbons
  • R 2 and R 3 are hydrogen, or alkyl of 1 to 6 carbons and the substituted ethynyl group occupies either the 2 or the 3 position of the dihydronaphthalene nucleus; m is an integer having the value of 0 - 3; o is an integer having the value 0 - 3;
  • Y is a phenyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R 2 groups;
  • A is (CH 2 ) n where n is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
  • B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, C00R 8 , CONR 9 R 10 , -CH 2 OH, CH 2 0R l:L , CHO, CH(OR 12 ) 2 , CHOR 13 0, -COR ? , CR 7 (OR 12 ) 2 , CR 7 OR 13 0, or tri-lower alkylsilyl, where R ?
  • R 8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8 is phenyl or lower alkylphenyl
  • R 9 and R 10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl
  • R ⁇ is lower alkyl, phenyl or lower alkylphenyl
  • R 12 is lower alkyl
  • R 13 is divalent alkyl radical of 2-5 carbons
  • R 22 is hydrogen, alkyl of 1 to 10 carbons, fluoro- substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbo ⁇ cyclic aryl selected from the group consisting of phenyl, C ⁇ - C 10 -alkylphenyl, naphthyl, C- ⁇ - C 1Q - alkylnaphthyl, phenyl-C-- ⁇ - C 10 alkyl, naphthyl-C 1 - C 10 alkyl, C- ⁇ - C 10 -alkenylphenyl having 1 to 3 double bonds, C ⁇ - C 10 -alkynylphenyl having 1 to 3 triple bonds, phenyl-C- ⁇ - C 10 alkenyl having 1 to 3 double bonds, phenyl-C-- ⁇ - C 1Q alkynyl having
  • this invention relates to the use of the compounds of Formula 1 through Formula 7 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin.
  • skin-related diseases including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis
  • the compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma.
  • premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's
  • the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR) , retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA) .
  • PVR proliferative vitreoretinopathy
  • TPA tissue plasminogen activator
  • Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV) , including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil", diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
  • HPV Human papilloma virus
  • various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease
  • This invention also relates to a pharmaceutical formulation comprising a compound of Formula l through Formula 7 in admixture with a pharmaceutically acceptable excipient.
  • this invention relates to processes for making a compound of Formula 1 through Formula 7 which process comprises reacting a compound of Formula 8 with a compound of Formula 9, in the presence of cuprous iodide and Pd(PQ 3 ) 2 Cl 2 (Q is phenyl) or a similar complex, or reacting the zinc salt of the compound shown in Formula 8 with a compound of Formula 9 in the presence of Pd(PQ 3 ) 4 (Q is phenyl) or similar complex.
  • STHN represents a tetrahydronaphthalene or dihydronaphthalene nucleus which is appropriately substituted to provide the compounds defined in Formulas 1 through 7, or said tetrahydronaphthalene or dihydronaphthalene nucleus is appropriately substituted to provide such precursors of compounds of the Formulas 1 through 7 from which the target compounds can be readily obtained by organic reactions well known in the art.
  • X.* ⁇ is halogen
  • B 1 is H, or a protected acid, alcohol, aldehyde, or ketone.
  • B' is either the desired B group of Formulas 1 through 7, or B 1 is a precursor from which the B group can be readily obtained by reactions well known in the art.
  • the present invention relates to such reactions performed on the compounds of Formula l through 7 which cause transformations of the A-B group or of the substituents on the tetrahydro- or dihydronaphthalene moiety, while the reaction product still remains within the scope of Formulas X through 7,
  • alkyl refers to and covers any and all groups which are known as normal alkyl, branched-chain alkyl and cycloalkyl.
  • alkenyl refers to and covers normal alkenyl, branch chain alkenyl and cycloalkenyl groups having one or more sites of unsaturation.
  • alkynyl refers to and covers normal alkynyl, and branch chain alkynyl groups having one or more triple bonds.
  • Lower alkyl means the above-defined broad definition of alkyl groups having 1 to 6 carbons in case of normal lower alkyl, and as applicable 3 to 6 carbons for lower branch chained and cycloalkyl groups.
  • Lower alkenyl is defined similarly having 2 to 6 carbons for normal lower alkenyl groups, and 3 to 6 carbons for branch chained and cyclo- lower alkenyl groups.
  • Lower alkynyl is also defined similarly, having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6 carbons for branch chained lower alkynyl groups.
  • esters refers to and covers any compound falling within the definition of that term as classically used in organic chemistry. It includes organic and inorganic esters. Where B (of Formula 1 through 7) is -COOH, this term covers the products derived from treatment of this function with alcohols or thiols preferably with aliphatic alcohols having 1-6 carbons.
  • ester is derived from compounds where B is -CH 2 OH
  • this term covers compounds derived from organic acids capable of forming esters including phosphorous based and sulfur based acids, or compounds of the formula -CH OCOR ⁇ :L where R 1:L is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably with 1-6 carbons in the aliphatic portions.
  • preferred esters are derived from the saturated aliphatic alcohols or acids of ten or fewer carbon atoms or the cyclic or saturated aliphatic cyclic alcohols and acids of 5 to 10 carbon atoms.
  • Particularly preferred aliphatic esters are those derived from lower alkyl acids and alcohols.
  • Also preferred are the phenyl or lower alkyl phenyl esters.
  • Amides has the meaning classically accorded that term in organic chemistry. In this instance it includes the unsubstituted amides and all aliphatic and aromatic mono- and di- substituted amides. Unless stated otherwise in this application, preferred amides are the mono- and di-substituted amides derived from the saturated aliphatic radicals of ten or fewer carbon atoms or the cyclic or saturated aliphatic-cyclic radicals of 5 to 10 carbon atoms. Particularly preferred amides are those derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono- and disubstituted amides derived from the substituted and unsubstituted phenyl or lower alkylphenyl amines. Unsubstituted amides are also preferred.
  • Acetals and ketals include the radicals of the formula-CK where K is (-OR) 2 .
  • R is lower alkyl.
  • K may be -OR 7 0- where R 7 is lower alkyl of 2-5 carbon atoms, straight chain or branched.
  • a pharmaceutically acceptable salt may be prepared for any compounds in this invention having a functionality capable of forming a salt, for example an acid functionality.
  • a pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
  • Pharmaceutically acceptable salts may be derived from organic or inorganic bases.
  • the salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium.
  • Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Where there is a nitrogen sufficiently basic as to be capable of forming acid addition salts, such may be formed with any inorganic or organic acids or alkylating agent such as methyl iodide.
  • Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any of a number of simple organic acids such as mono-, di- or tri- acid may also be used.
  • 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.
  • Still further oxime and related compounds of the present invention may exist in syn and anti isomeric 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 syn and anti isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. In the present application when no specific mention is made of the configuration (cis.
  • trans syn or anti 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.
  • a straight line representing a valence bond is drawn to an asymmetric carbon, then isomers of both R and S configuration, as well as their mixtures are intended.
  • stereochemistry about an asymmetric carbon is indicated in the formulas (where applicable) by a solid triangle showing ⁇ configuration, or by a hashed line showing a configuration.
  • the preferred compounds of the invention are those where Y is phenyl, pyridyl, thienyl or furyl. Even more preferred are compounds where Y is phenyl or pyridyl. As far as substititutions on the Y (phenyl) and Y (pyridyl) groups are concerned, compounds are preferred where the phenyl group is 1,4 (para) substituted, and where the pyridine ring is 2,5 substituted. (Substitution in the 2,5 positions in the "pyridine” nomenclature corresponds to substitution in the 6-position in the "nicotinic acid” nomenclature.) In the preferred compounds of the invention there is no optional R 2 substituent on the Y group.
  • the A-B group of the preferred compounds is (CH 2 ) n -COOH or (CH ) n -COOR 8 , where R 8 is defined as above. Even more preferably n is zero and R 8 is lower alkyl.
  • the aromatic portion of the tetrahydronaphthalene or dihydronaphthalene moiety is preferably substituted only by the acetylene function.
  • R 2 substituent other than hydrogen
  • R 3 substituent other than hydrogen
  • the R substituent of the compounds of the invention is preferably lower alkyl, and even more preferably methyl.
  • the R 4 substituent is preferably hydrogen, CN or CH 2 COOR 8 where R 8 is preferably methyl or ethyl.
  • the 5 substituent is preferably hydrogen, alkyl, cycloalkyl, of the structure Si(R 2 ) 3 , C0R 14 , and C(R 15 ) (R 16 )XR 17 (as these are defined in connection with Formula 1) .
  • R 5 is hydrogen, cyclohexyl, trimethylsilyl, -CH 2 OCH 3 (methoxymethyl), 2'-tetrahydropyranyl, acetyl, benzoyl or camphanoyl.
  • Specific preferred compounds in accordance with Formula 1 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently roost preferred compounds of the invention in accordance with Formula 1 are indicated in Table 1 below, with reference to Formula 1A.
  • the tetrahydronaphthalene system is numbered in accordance with the example shown for Compound l TMS represents trimethylsilyl diastereomeric mixture
  • X is sulphur and R 18 is an alkyl group; even more preferably X is sulphur and the two R 18 groups jointly represent methylene groups which together with the two sulphur atoms and the Cg carbon of the tetrahydronaphthalene nucleus form a 6 membered ring.
  • Specific preferred compounds in accordance with Formula 2 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently most preferred compounds of the invention in accordance with Formula 2 are indicated in Table 2 below, with reference to Formula 2A.
  • the two R 18 groups jointly form a (CH 2 ) 3 bridge.
  • TMS represents trimethylsilyl
  • the R 19 groups preferably are hydrogen, alkyl of 1 to 10 carbons, cyano (CN) or COOR 8 . Even more preferably the 19 groups are H, CN, COOEt or lower alkyl.
  • the two R 19 groups jointly form a -(CH 2 )_- radical, (q is an integer having the values of 3 to 7) whereby a cycloalkyl ring is formed, most preferably a cyclohexyl ring.
  • Specific preferred compounds in accordance with Formula 3 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently most preferred compounds of the invention in accordance with Formula 3 are indicated in Table 3 below, with reference to Formula 3A.
  • the CN group is in the E (trans) configuration.
  • the CN group is in Z. (cis) configuration.
  • the Z group preferably represents OR 1; where the R ⁇ group is preferably hydrogen or lower alkyl. Alternatively, Z is preferably 2-tetrahydropyranyloxy.
  • R ⁇ group is preferably hydrogen or lower alkyl.
  • Z is preferably 2-tetrahydropyranyloxy.
  • R 14 groups are hydrogen or lower alkyl, even more preferably hydrogen.
  • the presently most preferred compounds of the invention in accordance with Formula 5 are indicated in Table 5 below, with reference to Formula 5A, and the synthesis of these compounds is described in the Specific Examples.
  • R 20 group is preferably R j4 , COR 14 , S0 2 R 21 or Si(R 2 ,) 3 where R 14 is preferably phenyl, benzyl or lower alkyl, even more preferably ethyl, R 21 is preferably fluorinated lower alkyl, even more preferably CF 3 , and R 2 , is preferably lower alkyl, even more preferably methyl.
  • R 14 is preferably phenyl, benzyl or lower alkyl, even more preferably ethyl
  • R 21 is preferably fluorinated lower alkyl, even more preferably CF 3
  • R 2 is preferably lower alkyl, even more preferably methyl.
  • R 22 is preferably hydrogen, alkyl of 1 - 10 carbons, alkynyl of 2 to 10 carbons having 1 triple bond, alkylphenyl having 1 to 10 carbons in the alkyl group, phenylalkyl having 1 to 10 carbons in the alkyl group, phenylalkynyl having 2 to 10 carbons in the alkynyl group, CH 2 C0 2 R 8 , hydroxyalkyl having 1 to 10 carbons in the alkyl group, hydroxyalkynyl having 2 to 10 carbons in the alkynyl group, cyano (CN) , CONH 2 or heteroaryl.
  • heteroaryl groups 5 or 6 membered rings having 1 or 2 heteroatoms are particularly preferred.
  • Compounds where the R 22 group is 2-thiazolyl, 2-furyl, 2-thienyl or 2-pyridyl are especially preferred.
  • Specific preferred compounds in accordance with Formula 7 and their synthesis are described below in the section of this application titled "Specific Examples”. The presently most preferred compounds of the invention in accordance with Formula 7 are indicated in Table 7 below, with reference to Formula 7A.
  • the compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
  • any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example. Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form.
  • the drug may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration.
  • the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
  • medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
  • Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention.
  • a therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards it expansion.
  • the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
  • a useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
  • retinoic acid-like activity of these compounds is confirmed through the classic measure of retinoic acid activity involving the effects of retinoic acid on ornithine decarboxylase.
  • the original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated.
  • TPA 12-0-tetradecanoylphorbol-l3- acetate
  • Retinoic acid inhibits this induction of ODC activity by TPA.
  • An assay essentially following the procedure set out in Cancer Research: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC by compounds of this invention.
  • Activity of exemplary compounds of the present invention in the above- described ODC assay is disclosed in Table 8 which provides the IC 80 concentration for the respective exemplary compound.
  • IC 80 is that concentration of the test compound which causes 80% inhibition in the
  • IC 60 concentration of the test compound which causes 60% inhibition in the ODC assay.
  • Reaction Scheme 1 a synthetic route leading to the compounds of Formula 1 and of Formula 2 is illustrated.
  • a 6- or 7-bromo substituted 3,4-dihydro- naphthalen-l(2H)-one (numbering as shown for Compound G) of Formula 10 is the starting material.
  • the compounds of Formula 10 already carry the desired ⁇ L l r R 2 and R 3 substituents, as these are defined above in connection with Formula 1.
  • the compounds of Formula 10 are reacted with (trimethylsilyl)acetylene to provide the 6- or 7-trimethylsilylethynyl- substituted 3,4- dihydro-naphthalen-l(2H)-one compounds of Formula 11.
  • the reaction with (trimethylsilyl)acetylene is typically conducted under heat (approximately 100 ° C) in the presence of cuprous iodide, a suitable catalyst, typically having the formula Pd(PPh 3 ) C1 2 , an acid acceptor (such as triethylamine) under an inert gas (argon) atmosphere.
  • Typical reaction time is approximately 24 hours.
  • the 6- or 7- (trimethylsilyl)ethynyl- substituted 3,4-dihydro- naphthalen-l(2H)-one compounds of Formula 11 are then reacted with base (potassium hydroxide or potassium carbonate) in an alcoholic solvent, such as methanol, to provide the 6- or 7-ethynyl substituted 3,4-dihydro-l-naphthalen-l(2H)ones of Formula 12.
  • Compounds of Formula 12 are then coupled with the aromatic or heteroaromatic reagent X 1 -Y(R 2 )-A-B' (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh 3 ) 2 C1 2 , an acid acceptor, such as triethylamine, under inert gas (argon) atmosphere.
  • a zinc salt (or other suitable metal salt) of the compounds of Formula 12 can be coupled with the reagents of Formula 9 in the presence of Pd(PPh 3 ) 4 or similar complex.
  • the coupling reaction with the reagent X 1 -Y(R 2 )-A-B » (Formula 9) is conducted at room or moderately elevated temperature.
  • the compounds of Formula 13 are compounds of the invention within the scope of Formula 2, or a derivative thereof protected in the B' group, from which the protecting group can be readily removed by reactions well known in the art.
  • the compounds of Formula 13 can also be converted into ketals or thioketals, within the scope of Formula 2, by reactions generally well known in the art.
  • the compounds of Formula 13 can also be converted into further compounds of the invention by such reactions and transformations which are well known in the art.
  • the halogen substitituted aryl or heteroaryl compounds of Formula 9 can, generally speaking, be obtained by reactions well known in the art.
  • An example of such compound is ethyl 4-iodobenzoate which is obtainable, for example, by esterification of 4- iodobenzoic acid.
  • Another example is ethyl 6- iodonicotinate which can be obtained by conducting a halogen exchange reaction on 6-chloronicotinic acid, followed by esterification.
  • derivatization of compounds of Formula 13 and/or the synthesis of aryl and heteroaryl compounds of Formula 9 which can thereafter be reacted with compounds of Formula 12 to yield compounds of the invention the following well known and published general principles and synthetic methodology can be employed.
  • Carboxylic acids are typically esterified by refluxing the acid in a solution of the appropriate alcohol in the presence of an acid catalyst such as hydrogen chloride or thionyl chloride.
  • an acid catalyst such as hydrogen chloride or thionyl chloride.
  • the carboxylic acid can be condensed with the appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine.
  • the ester is recovered and purified by conventional means. Acetals and ketals are readily made by the method described in March, "Advanced Organic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810) .
  • Alcohols, aldehydes and ketones all may be protected by forming respectively, ethers and esters, acetals or ketals by known methods such as those described in McOmie, Plenum Publishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley & Sons, 1981.
  • aromatic or heteroaromatic carboxylic acids are subjected to homologation by successive treatment under Arndt-Eistert conditions or other homologation procedures.
  • derivatives which are not carboxylic acids may also be homologated by appropriate procedures.
  • the homologated acids can then be esterified by the general procedure outlined in the preceding paragraph.
  • Compounds of Formula 9, (or of the invention as set forth in Formulas 1 through 7, as applicable) where A is an alkenyl group having one or more double bonds can be made for example, by synthetic schemes well known to the practicing organic chemist; for example by Wittig and like reactions, or by introduction of a double bond by elimination of halogen from an alpha- halo-arylalkyl-carboxylic acid, ester or like carbox- aldehyde.
  • Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where the A group has a triple (acetylenic) bond can be made by reaction of a corresponding aromatic methyl ketone with strong base, such as lithium diisopropyl amide, reaction with diethyl chlorophosphate and subsequent addition of lithium diisopropylamide.
  • strong base such as lithium diisopropyl amide
  • esters The acids and salts derived from compounds of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) are readily obtainable from the corresponding esters.
  • Basic saponification with an alkali metal base will provide the acid.
  • an ester of Formula 13 (or other compounds of the invention as set forth in Formulas 1 through 7, as applicable) may be dissolved in a polar solvent such as an alkanol, preferably under an inert atmosphere at room temperature, with about a three molar excess of base, for example, lithium hydroxide or potassium hydroxide.
  • the solution is stirred for an extended period of time, between 15 and 20 hours, cooled, acidified and the hydrolysate recovered by conventional means.
  • the amide may be formed by any appropriate amidation means known in the art from the corresponding esters or carboxylic acids.
  • One way to prepare such compounds is to convert an acid to an acid chloride and then treat that compound with ammonium hydroxide or an appropriate amine.
  • the ester is treated with an alcoholic base solution such as ethanolic KOH (in approximately a 10% molar excess) at room temperature for about 30 minutes.
  • the solvent is removed and the residue taken up in an organic solvent such as diethyl ether, treated with a dialkyl formamide and then a 10-fold excess of oxalyl chloride. This is all effected at a moderately reduced temperature between about -10 degrees and +10 degrees C.
  • Alcohols are made by converting the corresponding acids to the acid chloride with thionyl chloride or other means (J. March, "Advanced Organic Chemistry", 2nd Edition, McGraw-Hill Book Company) , then reducing the acid chloride with sodium borohydride (March, Ibid, pg. 1124) , which gives the corresponding alcohols.
  • esters may be reduced with lithium aluminum hydride at reduced temperatures.
  • Alkylating these alcohols with appropriate alkyl halides under Williamson reaction conditions (March, Ibid, pg. 357) gives the corresponding ethers.
  • These alcohols can be converted to esters by reacting them with appropriate acids in the presence of acid catalysts or dicyclohex- ylcarbodiimide and dimethylaminopyridine.
  • Aldehydes can be prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. .399, 1979) . or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K. , Swern, D. , Tetrahedron. 1978. 34. 1651).
  • mild oxidizing agents such as pyridinium dichromate in methylene chloride (Corey, E. J., Schmidt, G., Tet. Lett.. .399, 1979) . or dimethyl sulfoxide/oxalyl chloride in methylene chloride (Omura, K. , Swern, D. , Tetrahedron. 1978. 34. 1651).
  • Ketones can be prepared from an appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent followed by oxidation.
  • Acetals or ketals can be prepared from the corresponding aldehyde or ketone by the method described in March, Ibid, p 810.
  • Compounds of Formula 9 (or of the invention as set forth in Formulas 1 through 7, as applicable) where B is H can be prepared from the corresponding halogenated aromatic or heteroaromatic compounds, preferably where the halogen is I.
  • the 5-hydroxy function of the compounds of Formula 14 is then acylated with a suitable acylating agent (such as a carboxylic acid chloride or anhydride) , or converted into an ether with a suitable reagent (such as an alkyl bromide under basic conditions, or dihydropyran under acidic conditions) or converted into a trialkylsilyl ether (with trialkylsilyl chloride or other "silylating" agent) to provide compounds of Formula 15.
  • a suitable acylating agent such as a carboxylic acid chloride or anhydride
  • a suitable reagent such as an alkyl bromide under basic conditions, or dihydropyran under acidic conditions
  • a trialkylsilyl ether with trialkylsilyl chloride or other "silylating" agent
  • the compounds of Formula 13 can also be reacted with a Reformatsky reagent derived from an a halocarboxylic acid ester (such as ethyl bromoacetate) , or with a Grignard reagent, optionally followed by acylation or ether formation on the resulting tertiary hydroxyl group on the 5-position of the tetrahydronaph ⁇ thalene nucleus, to yield compounds of Formula 16.
  • the compounds of Formula 13 are reacted with cyanotrimethylsilane in the presence of boron trifluoroetherate to yield compounds in accordance with Formula 16.
  • the compounds of Formula 16 are compounds of the invention within the scope of Formula l, (or protected derivatives thereof) and can be converted into further homologs and derivatives within the scope of the invention.
  • Reaction Scheme 2 illustrates another synthetic route to the compounds of the invention in accordance with Formula 1.
  • 6- or 7-Bromo substituted 1,2,3,4- tetrahydro naphthalene derivatives of Formula 17 (numbering as exemplified for Compound F) are reacted with trimethylsilylacetylene as described above in connection with Reaction Scheme 1 (cuprous iodide, Pd(PPh 3 ) 2 C1 2 , catalyst and triethylamine under inert atmosphere) and thereafter with base (potassium hydroxide or potassium carbonate in an alcoholic solvent, such as methanol) to provide the 6- or 7- ethynyl 1,2,3,4-tetrahydronaphthalene derivatives of Formula 18.
  • Compounds of Formula 18 are coupled with the aromatic or heteroaromatic reagent ⁇ YCR j )-A-B' (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh 3 ) 2 C1 2 , an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, to yield compounds of Formula 19.
  • a suitable catalyst typically Pd(PPh 3 ) 2 C1 2
  • an acid acceptor such as diethylamine
  • the zinc salts of the compounds of Formula 18 can also be coupled with the reagents of Formula 9, in the presence of Pd(PPh 3 ) 4 or similar complex.
  • R 5 and X groups are defined as in connection with Formula l, typically R g XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
  • R g XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol or thiol.
  • the product of the latter nucleophilic displacement reaction is a compound in accordance with Formula 21, which is within the scope of Formula 1.
  • the compounds of Formula 21 can be converted into further homologs and derivatives, as is described above in connection with compounds of Formulas 13, 15 and 16.
  • Reaction Scheme 3 discloses still another synthetic route to the compounds of the invention within the scope of Formula 1.
  • a 6- or 7-bromo-l,2,3,4-tetrahydronaphthalene derivative of Formula 17 (numbering as shown for Compound F) is brominated with a suitable brominating agent (such as N.-bromosuccinimide (NBS) and benzoyl peroxide in carbontetrachloride) to yield the corresponding 4- and 6- or 7- dibromo-1,2,3,4- tetrahydronaphthalene derivatives of Formula 22.
  • NBS N.-bromosuccinimide
  • benzoyl peroxide in carbontetrachloride benzoyl peroxide in carbontetrachloride
  • the dibromo compounds of Formula 22 are then reacted with a nucleophilic reagent having the formula R 5 XH, in the presence of base.
  • the R 5 and X groups are defined as in connection with Formula 1; typically R 5 XH is the salt of a thiocarboxylic acid (such as potassium thioacetate) or the sodium derivative of an alcohol (such as the sodium salt of cyclohexanol) , or thiol.
  • the product of the latter reaction is a 6- or 7-bromo tetrahydronaphthalene derivative of Formula 23 which has the desired R 5 X substituent in the 4-position.
  • the 6- or 7- bromo compound of Formula 23 is then reacted with trimethylsilylacetylene, followed by base (such as potassium carbonate) to yield the 6- or 7-ethynyl- 1,2,3,4-tetrahydronaphthalene derivatives of Formula 24.
  • base such as potassium carbonate
  • the latter two reactions involving introduction of the ethynyl group into the 6 or 7 position of the tetrahydronaphthalene nucleus are conducted under conditions substantially similar to the analogous reactions described above in connection with Reaction Schemes 1 and 2.
  • the ethynyl compounds of Formula 24 are then coupled with the reagent X 1 -Y(R 2 )-A-B » (Formula 9) under conditions which are described above for the analogous reactions of Reaction Schemes l and 2, to provide compounds of Formula 21.
  • the compounds of Formula 21 are within the scope of Formula 1 or are such protected derivatives thereof which can be readily converted into compounds of the invention by chemical reactions well known in the art. These and similar reactions of the compounds of Formula 21 within the state of the art, are symbolized in Reaction Scheme 3 by conversion into "homologs and derivatives".
  • this coupling reaction can be conducted with 6- or 7- substituted ethynyl compounds which either already have a substituent desired for the present invention in the 4- position (as in Reaction Scheme 3) or have a precursor suitable for introduction of such desired substituent (as in Reaction Schemes 1 and 2) .
  • Reaction Scheme 4 In the preferred compounds of the invention the two R ⁇ substituents are methyl, and the R 2 and R 3 substituents are hydrogen.
  • Reaction Scheme 4 illustrates a synthetic process for preparing 7-bromo- 3,4-dihydro-4,4-dimethylnaphthalen-l-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention.
  • Compound G 7-bromo- 3,4-dihydro-4,4-dimethylnaphthalen-l-one
  • Reaction Scheme 4 illustrates a synthetic process for preparing 7-bromo- 3,4-dihydro-4,4-dimethylnaphthalen-l-one (Compound G) which serves as a starting material for the synthesis of several preferred compounds of the invention.
  • ethyl 3-bromophenylacetate Compound B, made by esterification of 3-bromophenylacetic acid
  • DIBAL H diisobutylaluminum hydride
  • Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3- bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R 1 substituent in the resulting compounds of the invention.)
  • Compound E is then treated with acid to cyclize it and to form 6-bromo-l,2,3,4-tetrahydro-l,1- dimethylnaphthalene (Compound F) .
  • Compound F is in the scope of Formula 17, and in accordance with Reaction Schemes 2 and 3 serves as the starting material in the synthesis of several preferred compounds of the invention.
  • Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4- dimethylnaphthalen-l(2H)-one (Compound G) .
  • Compound G is covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
  • Compound H 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-l(2H)- one (Compound H) is isomeric with Compound G, and can be obtained, starting with ethyl (4- bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction scheme 4 for Compound G.
  • Compound H 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-l(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985) .
  • Compound H is also covered by Formula 10 and in accordance with Reaction Scheme 1 serves as a starting material in the synthesis of several preferred compounds of the invention.
  • Reaction Scheme 5 Compounds of Formula 3 can be synthesized in accordance with the synthetic steps illustrated in Reaction Schemes 5, 6 and 7.
  • the 1-oxo 6- or 7-bromo 1,2,3,4- tetrahydronaphthalene derivative (numbering as exemplified for Compound G) of Formula 10 is reacted with a ketone or aldehyde compound of Formula 25 wherein the R 19 groups are defined as in connection with Formula 3.
  • the reaction (McMurry coupling) is conducted at elevated temperature in the presence of lithium metal and titanium trichloride, in an inert ether type solvent, for example in refluxing 1,2- dimethoxyethane (DME) .
  • DME 1,2- dimethoxyethane
  • the resulting compounds of Formula 26 are then reacted with trimethylsilylacetylene as described above in connection with Reaction Scheme l (cuprous iodide, Pd(PPh 3 ) 2 Cl 2 , catalyst and triethylamine under inert atmosphere) and thereafter with base (potassium hydroxide or potassium carbonate in an alcoholic solvent, such as methanol) to provide the 6- or 7- ethynyl 1,2,3,4-tetrahydronaphthalene derivatives of Formula 27 which have the R ig R i gC- 3 group attached to the tetrahydronaphthalene nucleus.
  • Compounds of Formula 27 are then coupled with the aromatic or heteroaromatic reagent X 1 -Y(R 2 )-A-B « (Formula 9) in the presence of cuprous iodide, a suitable catalyst, typically Pd(PPh 3 ) 2 C1 , an acid acceptor, such as diethylamine, under inert gas (argon) atmosphere, as described above in connection with Reaction Scheme 1, to yield compounds of Formula 28.
  • a suitable catalyst typically Pd(PPh 3 ) 2 C1
  • an acid acceptor such as diethylamine
  • argon inert gas
  • the zinc salts of the compounds of Formula 27 are coupled with the reagents of Formula 9, in the presence of Pd(PPh 3 ) 4 or similar complex.
  • Compounds of Formula 28 are within the scope of Formula 3. They can be converted to further homologs and derivatives which are still within the scope of the invention, as is described above in connection with compounds of Formulas 13, 15 and 16.
  • Reaction Scheme 6 synthesis of those compounds of Formula 3 is illustrated where one of the R 19 groups represents hydrogen and the other is cyano (CN) .
  • These compounds are obtained by reacting a 5-oxo 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8- tetrahydronaphthalene compound of Formula 13 (numbering as exemplified for Compound 1) with diethyl cyanometh- ylphosphonate and potassium bis(trimethylsilyl)amide in an inert ether type solvent, such as tetrahydrofuran.
  • the resulting compounds of Formula 29 can be converted into further homologs and derivatives, as described above.
  • the cyano derivative (Formula 29) can be converted into the corresponding aldehyde by reduction with diisobutylaluminum hydride.
  • Reaction Scheme 7 illustrates synthesis of those compounds of Formula 3 wherein one of the R 19 groups is hydrogen and the other is a carboxylic acid ester (or derivative thereof) .
  • the starting compounds for these syntheses are compounds of Formula 30, which are within the scope of Formula 1 and can be obtained in accordance with the synthetic procedures leading to compounds of Formula 1. Dehydration (elimination of the hydroxy group) of compounds of Formula 30 with a suitable reagent such as
  • oxi es are readily formed by reacting the compounds of Formula 13 with hydroxylamine hydrochloride in a polar solvent, such as a lower alkanol, in the presence of a buffering agent, such as sodium acetate.
  • a reagent of the formula NH 2 OR 1 or its salt such as methoxylamine hydrochloride or ethoxylamine hydrochloride
  • Z is OR ⁇ (R ⁇ ⁇ is defined as in connection with Formula 4)
  • the reagent H 2 N-Z is a primary amine (Z is R 1; phenyl or benzyl) then the reaction between the compounds of Formula 13 and the primary amine is the formation of an imine.
  • the hydrochloride salt of of the reagent is reacted with the compound of Formula 13 in an alcoholic solvent, in the presence of sodium acetate.
  • oxime derivatives of the structure shown by Formula 34 is illustrated.
  • an oxime derivative of the Formula 33 is first prepared in accordance with the reaction described above.
  • the oxime derivative of Formula 33 is thereafter reacted with 3,4-dihydro-2H- pyran (DHP) in an inert solvent (such as dichloromethane) in the presence of acid, typically pyridinium p-tolunesulfonate (PPTS) .
  • DHP 3,4-dihydro-2H- pyran
  • PPTS pyridinium p-tolunesulfonate
  • This reaction is typically conducted in the cold, or at ambient temperature.
  • the resulting product of Formula 34 is usually isolated by chromatography.
  • Compounds of Formula 4 where the Z group represents OC(R 15 ) (R 16 )XR 17 other than tetrahydropyranyl, (for example tetrahydrothiopyranyl) can be prepared in reaction steps analogous to the ones described above for the preparation of compounds of Formula 34.
  • the oxime derivatives of Formula 33 can also be reacted with an appropriate reagent (such as an acyl chloride R 14 C0C1) to introduce the R 14 CO group, to provide the compounds of Formula 35.
  • the compounds of Formula 4, 33, 34 and 35 can be converted into further homologs and derivatives as is described above for compounds of Formulas 13, 15 and 16, and shown in Reaction Scheme 8.
  • the compounds of Formula 4 can also be obtained, generally speaking, by first forming an oxime, alkoxyoxime, imine, hydrazone, semicarbazone etc. from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in the resulting oximes, alkoxyoxime etc. with an ethynyl group and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B « (Formula 9) .
  • Reaction Scheme 9 Compounds of Formula 5 can be prepared by the reactions illustrated in Reaction Scheme 9.
  • the 5-oxo 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 are reduced in the 5 position and aminated by reaction with ammonium acetate and sodium cyanoborohydride (NaBH 3 CN) .
  • the latter reaction provides the 5-amino 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 36.
  • Compounds of Formula 36 where the NH 2 group is not substituted comprise the presently preferred compounds of Formula 5.
  • Compounds of Formula 5 where R 14 is an alkyl, alkenyl, alkynyl or aryl group are prepared by reaction of compounds of Formula 36 with a reagent of the formula R i4 ⁇ X 1 , where X ⁇ is halogen.
  • R 14 is an alkyl group then the reagent is an alkyl halide.
  • Compounds of Formula 5 where R 14 is alkyl, alkenyl, alkynyl or aryl group can also be obtained from the 5-oxo 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reacting compounds of Formula 13 with the corresponding amine (R 14 NH 2 ) and thereafter reducing the resulting imine compounds with hydrogen or other suitable reducing agent.
  • a second R 14 9 rou P which is alkyl, alkenyl, alkynyl or aryl, or which is R 8 CO (acyl) can be introduced into the latter compounds by reaction with the reagent R 14 -X 1 (X j ⁇ is halogen) , or R g COCl.
  • the compounds of Formula 5 can also be obtained, generally speaking, by first forming the 5-amino, 5- alkylamino or 5-acylamido derivative from the ketone compounds of Formula 10 (see Reaction Scheme 1) and thereafter performing the synthetic steps of replacing the 6 or 7-bromo substituents in these compounds with an ethynyl group, and subsequently coupling the ethynyl compounds with the reagent X 1 -Y(R 2 )-A-B » (Formula 9).
  • Reaction Scheme 10 Compounds of Formula 6 are obtained in accordance with Reaction Scheme 10, starting with the 5-oxo 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaph ⁇ thalene compounds of Formula 13 (numbering as exemplified for Compound 1) .
  • the ketone derivatives of Formula 13 are reacted with a reagent which "enolizes” the ketone function of the tetrahydronaphthalene nucleus.
  • the resulting "enol” compound then reacts with a reagent which introduces the R 20 group into the enol function.
  • the group R 20 is defined in connection with Formula 6.
  • Suitable reagents for the purpose of introducing the R 20 function include a reactive leaving group L.
  • the reagents used in this reaction have the general formula R 20 -L, R 14 -CO-L, R ⁇ -L, and R21" 1 * ' wnere tne R 14 and R 21 groups are defined as in connection with Formula 6.
  • Examples of the reagents, and/or reaction conditions which are used for the synthesis of the preferred compounds of the invention within the scope of Formula 6 include: reacting compounds of Formula 13 with sodium bis(trimethylsilyl)amide and 2-[N,N- bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C) to obtain the 5- trifluoromethylsulfonyloxy-7,8-dihydronaphthalene derivative; reacting compounds of Formula 13 with acetic anhydride and p-toluenesulfonic acid at elevated temperature (80 °C) to obtain the 5-acetoxy-7,8- dihydronaphthalene derivative; and reacting compounds of Formula 13 with cyanotrimethylsilane in the presence of zinc iodide at ambient temperature to obtain the 5- trimethylsilyloxy-7,8-dihydronaphthal
  • Compounds of Formula 38 obtained in the above- described manner are such compounds of Formula 6 where the X is oxygen.
  • Compounds of Formula 6 where X is sulfur can be obtained by analogous reactions of the 5- thio analogs of the oxo compounds of Formula 13.
  • Compounds of Formula 6 where X is S and R 20 is R 14 are preferably obtained by reacting compounds of Formula 13 with titanium tetrachloride and a thiol of the formula R 14 SH in an inert ether type solvent (such as tetrahydrofuran) in the presence of base (such as triethylamine) .
  • an inert ether type solvent such as tetrahydrofuran
  • base such as triethylamine
  • the latter reaction is shown in Reaction Scheme 10, and gives rise to compounds of Formula 38A.
  • the thienol ether compounds of Formula 38A can be oxidized to sulfoxides or with a suitable oxidizing agent, such as 3-chloroperoxybenzoic acid (MCPBA) to the corresponding sulfones of Formula 38B.
  • MCPBA 3-chloroperoxybenzoic acid
  • Reaction Scheme 11 discloses synthetic steps for the preparation of those compounds of Formula 7 where the R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
  • R 22 group is alkyl, alkenyl, alkynyl, carbocyclic aryl or heteroaryl, as these groups are broadly defined in Formula 7.
  • 5-trifluoromethylsulfonyloxy 2- or 3- (aryl or heteroaryl)ethynyl 7,8-dihydronaphthalene compounds of Formula 39 serve as starting materials.
  • the compounds of Formula 39 can be obtained from the 5-oxo 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 13 by reaction with sodium bis(trimethylsilyl)amide and 2-[N,N-bis(trifluoro ⁇ methylsulfonyl)amino]-5-chloropyridine in an inert ether type solvent such as tetrahydrofuran at low temperatures (-78 °C and 0 °C) . This is described in connection with Reaction Scheme 10.
  • Compounds of Formula 39 are reacted with an organometal derivative derived from the alkane, alkene, alkyne, or aryl or heteroaryl compound R 22 H, such that the formula of the organometal derivative is R 22 Met (Met stands for metal) , preferably R 22 Li.
  • the reaction with the organometal derivative, preferably lithium derivative of the formula R 22 Li is usually conducted in an inert ether type solvent (such as tetrahydrofuran) in the presence of either (1) cuprous cyanide (cuCN) and lithium chloride (Licl) , or in the presence of zinc chloride (ZnCl 2 ) and tetrakis(triphenylphosphine)- palladium(O) (Pd(PPh 3 ) 4 ).
  • the organolithium reagent R 22 Li if not commercially available, can be prepared from the compound R 2 H (or its halogen derivative R 22 - X where X ⁇ is halogen) in an ether type solvent in accordance with known practice in the art.
  • the temperature range for the reaction between the reagent R 22 Li and the compounds of Formula 39 is, generally speaking in the range of approximately -78 °C to 50 °C.
  • the lithium compounds which are used in the just described reaction are lithium salts derived from straight and branch chained alkanes, such as methyl lithium, butyllithium, t-butyllithium, lithium salts derived from carbocyclic aryl compounds, such as phenyl lithium, and lithium salts derived from heteroaryl compounds, such as 2-thiazolyllithium, 2-furyl lithium, 2-thienyllithium, and 2-pyridyllithium.
  • R 23 is defined as R 22 of Formula 7 minus a two carbon fragment, so that the alkyne reagent R 23 CsCH is within the applica ⁇ ble definition of R 22 of Formula 7; namely R 23 C- ⁇ CH is alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, phenyl-C-L - C 1Q alkynyl having 1 to 3 triple bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds.
  • Compounds of Formula 41 are obtained by the reaction compounds of Formula 39 with the reagent R 23 CsCH in an inert ether type solvent, or dimethylformamide, or without solvent, in the presence of a mild base (such as diethylamine) , cuprous iodide (Cul) , and bis(triphenylphosphine)palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 ) in an inert gas (argon) atmoshere.
  • a mild base such as diethylamine
  • Cul cuprous iodide
  • Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)palladium(II) chloride
  • argon inert gas
  • Reaction Scheme 12 According to this reaction scheme, derivatives of 5-hydroxy, 2- or 3- (aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalene compounds of Formula 42 serve as the starting materials.
  • Compounds of Formula 42 are within the scope of Formula 1, and can be prepared in accordance with the procedures set forth for the preparation of compounds of Formula l.
  • the group R 22 is defined as in connection with Formula 7, and R 24 is hydrogen, or trialkylsilyl (preferably trimethylsilyl) , or any other group which is suitable to form a leaving group including the R2 ° ⁇ element, in the elimination reaction which is shown in the reaction scheme.
  • the product of the elimination reaction is a compound of Formula 7.
  • reaction Scheme 12 is presently preferred for the preparation of compounds of Formula 7 where the R 22 group is hydrogen, cyano (CN) and CH COOEt.
  • R 22 is hydrogen, cyano (CN) and CH COOEt.
  • the elimination reaction which results in compounds where R 22 is CH 2 COOEt also gives rise to isomers where the double bond is exterior to the condensed 6-membered ring. The latter compounds are within the scope of Formula 3 and are not shown in this reaction scheme.
  • Ethyl 4-r (5.6.7.8-tetrahvdro-8.8-dimethyl-5- (oxime)naphth-3-yl)ethynyl1benzoate (Compound 19)
  • Ethyl 4-r (5.6.7.8-tetrahvdro-8.8-dimeth ⁇ l-5-anti-(Q- ethyl oxime) naphth-2-yl)ethvn ⁇ llbenzoate (Compound 24) and Ethyl 4-r (5.6.7.8-tetrahvdro-8.8-dimeth ⁇ l-5-syn-(0- ethyl oxime)naphth-2-yl)ethvnyl1benzoate (Compound 25)
  • a solution of 2-lithiothiazole was prepared by the addition of 41.2 mg (0.42 ml, 0.63 mmol) of n-butyl- lithium (1.5M solution in hexanes) to a cold solution (-78 °C) of 53.4 mg (0.63 mmol) of thiazole in 1.0 ml of THF. The solution was stirred at for 30 minutes and then a solution of 113.9 mg (0.84 mmol) of zinc chloride in 1.5 ml of THF was added.
  • Ethyl 4-r (7.8-dihvdro-8.8-dimethyl-5-(2- thiazolyl)naphth-2-yl)ethynyl1benzoate (Compound 88) Employing the same general procedure as for the preparation of ethyl 4-[ (7,8-dihydro-8,8-dimethyl-5-(2- thiazolyl)napth-3-yl)ethynyl]benzoate (Compound 67) ,400 mg (0.84 mmol) of ethyl 4-[(5- trifluoromethylsulfonyloxy-7,8-dihydro-8,8- dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) in 2 ml of THF was converted into the title compound (white solid) using a solution of 82 mg (1.26 mmol) of thiazole in 2 ml of THF, 81 mg (0.84
  • Ethyl 4-r (5-cvano-7.8-dihvdro-8.8-dimethylnaphth-2- yl)ethvnyl1benzoate (Compound 108)
  • ethyl 4-[ (5-cyano-5,6,7,8-tetrahydro-8,8-dimethyl-5-tri- methylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 107) was added 0.5 ml of pyridine and 3 drops of phosphorous oxychloride. The resulting dark mixture was gently refluxed at 115 °C for 30 minutes, cooled to room temperature and poured into crushed ice.
  • Ethyl 4-r (7.8-dihvdro-8.8-dimethyl-5- carboethoxymethylnaphth-3-yl)ethvnyl1benzoate (Compound 120) and Ethyl 4-r (5-carboethoxymethylidene-7.8- dihydro-8.8-dimethylnaphth-3- ⁇ l)ethvnyl1benzoate (Compound 121)
  • Ethyl 4-r (5-acetoxy-7.8-dihvdro-8.8-dimethylnaphth-3- yl)ethynyl1benzoate (Compound 126)
  • ethyl 4-[ 5-acetoxy-7,8-dihydro-8,8- dimethylnaphth-2-yl)ethynyl]benzoate (Compound 105)
  • 90.0 mg (0.26 mmol) of ethyl 4-[ (5,6,7,8-tetrahydro- 8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow powder) using 0.06 ml (0.78 mmol) of acetic anhydride and 5 mg (0.03 mmol) of p.- toluenesulfonic acid.

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EP95943828A 1994-12-29 1995-12-14 Acetylen-derivate substituiert mit 5-oder 8-substituierten tetrahydronaphthyl oder dihydronaphthyl sowie mit aryl-oder heteroaryl-gruppen mit retinoid artiger wirkung Withdrawn EP0800517A1 (de)

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Application Number Priority Date Filing Date Title
US366168 1989-06-14
US366193 1994-12-29
US08/366,167 US5618943A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 OXO substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US366183 1994-12-29
US366172 1994-12-29
US08/366,172 US5543534A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US366169 1994-12-29
US08/366,183 US5618931A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted dihydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,169 US5599967A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl of heteroaryl group having retinoid-like biological activity
US366182 1994-12-29
US08/366,168 US5514825A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,182 US5489584A (en) 1994-12-29 1994-12-29 Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity
US08/366,193 US5648514A (en) 1994-12-29 1994-12-29 Substituted acetylenes having retinoid-like biological activity
PCT/US1995/016367 WO1996020930A1 (en) 1994-12-29 1995-12-14 Acetylenes disubstituted with a 5 or 8 substituted tetrahydronaphthyl or dihydronaphthyl group and with an aryl or heteroaryl groups having retinoid-like biological activity
US366167 1999-08-03

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US5931969A (en) * 1994-07-29 1999-08-03 Baxter International Inc. Methods and apparatuses for treating biological tissue to mitigate calcification
US5760276A (en) * 1997-03-06 1998-06-02 Allergan Aryl-and heteroarylcyclohexenyl substituted alkenes having retinoid agonist, antagonist or inverse agonist type biological activity
US6166244A (en) * 1999-05-07 2000-12-26 Allergan Sales, Inc. Oxygen, sulfur and nitrogen substituted cyclohexene and cyclohexane derivatives having retinoid-like biological activity
US6313107B1 (en) * 2000-08-29 2001-11-06 Allergan Sales, Inc. Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI
ES2256288T3 (es) * 2000-08-29 2006-07-16 Allergan, Inc. Compuestos con actividad como inhibidores de citocromo p450rai.
US7482366B2 (en) 2001-12-21 2009-01-27 X-Ceptor Therapeutics, Inc. Modulators of LXR
EP1465869B1 (de) 2001-12-21 2013-05-15 Exelixis Patent Company LLC Modulatoren von lxr
WO2004045595A1 (en) * 2002-11-15 2004-06-03 Galderma Research & Development, S.N.C. USE OF AN RAR RECEPTOR ANTAGONIST FOR POTENTIATING THE ACTION OF TGFβ
FR2847167A1 (fr) * 2002-11-15 2004-05-21 Galderma Res & Dev UTILISATION D'UN ANTAGONISTE DES RECEPTEURS RARs POUR POTENTIALISER L'ACTION DU TGFb
US7662821B2 (en) 2003-10-08 2010-02-16 Bayer Schering Pharma Ag Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
WO2005034939A1 (de) 2003-10-08 2005-04-21 Schering Aktiengesellschaft Tetrahydronaphthalinderivate, verfahren zu ihrer herstellung und ihre verwendung als entzündungshemmer
US7638515B2 (en) 2003-10-08 2009-12-29 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
US7226951B2 (en) * 2003-12-17 2007-06-05 Allergan, Inc. Compounds having selective cytochrome P450RAI-1 or selective cytochrome P450RAI-2 inhibitory activity and methods of obtaining the same
US20080153859A1 (en) 2004-04-05 2008-06-26 Hartmut Rehwinkel Multiply-substituted tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents
DE102004044680B3 (de) * 2004-09-09 2006-06-08 Schering Ag Alkyliden-Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer sowie diese enthaltende pharmazeutische Präparate
EP1834948A1 (de) 2006-03-15 2007-09-19 Bayer Schering Pharma Aktiengesellschaft Tetrahydronaphthalinderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Entzündungshemmer

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3434946A1 (de) * 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen Diarylacetylene, ihre herstellung und verwendung
US5149705A (en) * 1987-03-13 1992-09-22 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a tetralin group and having retinoid like activity
CA1305480C (en) * 1987-03-20 1992-07-21 Roshantha A.S. Chandraratna Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US4810804A (en) * 1987-03-26 1989-03-07 Allergan, Inc. Acetylenes disubstituted with a phenyl group and a heterobicyclic group having retinoid-like activity
DE3726806A1 (de) * 1987-08-12 1989-02-23 Basf Ag Arylphosphorderivate, ihre herstellung und verwendung
DE3926148A1 (de) * 1989-08-08 1991-02-28 Basf Ag Diarylacetylene, ihre herstellung und verwendung
US4980369A (en) * 1989-09-19 1990-12-25 Allergan, Inc. Acetylenes disubstituted with a phenyl group and a 2-substituted chromanyl or thiochromanyl group having retinoid-like activity
US5013744B1 (en) * 1989-12-29 1994-09-20 Allegran Inc Acetylenes disubstituted with a pyridinyl group and a substituted phenyl group having retinoid like activity
EP0617020A1 (de) * 1992-04-02 1994-09-28 Shudo, Koichi, Prof. Dr. Carbonsäure mit retinsäure-ähnlicher Wirkung
EP0983991B1 (de) * 1992-04-22 2003-12-17 Ligand Pharmaceuticals, Inc. Verbindungen mit Retinoid x receptorselektivität
FR2713635B1 (fr) * 1993-12-15 1996-01-05 Cird Galderma Nouveaux composés propynyl bi-aromatiques, compositions pharmaceutiques et cosmétiques les contenant et utilisations.
CA2138000A1 (en) * 1994-01-03 1995-07-04 John E. Starrett, Jr. Retinoid-like compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9620930A1 *

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