US4732912A — Phenol derivatives

Claim 1

Independent Claim 347 words

A phenol derivative of the formula: NU--A--X--R.sup.1 where NU is a bis-phenolic nucleus of the general formula ##STR35## wherein one of R 13 and R 23 , and one of R 33 and R 43 , has the formula R 3 0-, wherein each R 3 , which may be the same or different, is hydrogen or alkyl, cyaloalkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl, or aroyl each of up to 10 carbon atoms, and wherein the other of R 13 and R 23 , and the other of R 33 and R 43 , is hydrogen: wherein R 4 and R 14 , which may be the same or different, each is hydrogen or alkyl of up to 5 carbon atoms, or R 4 and R 14 are joined together so that CR 4 -CR 14 is an olefinic double bond; wherein R 5 and R 6 together form a direct link or --CH 2 --, --CH(CH 3 )--, --CH 2 CH 2 --, --(CH 2 ) 3 -- or --CH═CH--, and R 15 is hydrogen; and wherein the aromatic rings B and C each is unsubstituted or substituted with one or more halogen or methyl or ethyl substituents; where A is straight- or branched-chain alkylene, alkenylene or alkynylene each of from 4 to 12 carbon atoms; or A has the formula: --A.sup.1 --Y.sup.3 --A.sup.21 -- wherein A 1 is alkylene or alkenylene and A 21 is a direct link or alkylene, alkenylene or cycloalkylene, such that A 1 and A 21 together have a total of 2 to 10 carbon atoms, and Y 3 is phenylene or naphthylene which is unsubstituted or substituted with one or more halogen or methyl or ethyl substituents; wherein R 1 is alkyl, alkenyl, cycloalkyl, halogenoalkyl, each of up to 10 carbon atoms, phenyl, chlorophenyl, o-ethylphenyl, p-cyanophenyl, p-hydroxyphenyl, p-methoxyphenyl, alkyl of 1 to 3 carbon atoms which bears a phenyl, tolyl, halogenophenyl or trifluoromethylphenyl substituent, α-methylbenzyl, 3,4-dichlorobenzyl, p-cyanobenzyl or p-methylthiobenzyl; and wherein X is --S--, --SO-- or --SO 2 --; or a pharmaceutically acceptable salt of a compound wherein R 3 is carboxyalkanoyl.

Claim 2

Dependent Claim 347 words

A phenol derivative of the formula: NU--A--X--R.sup.1 where NU is a bis-phenolic nucleus of the general formula ##STR35## wherein one of R 13 and R 23 , and one of R 33 and R 43 , has the formula R 3 0-, wherein each R 3 , which may be the same or different, is hydrogen or alkyl, cyaloalkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl, or aroyl each of up to 10 carbon atoms, and wherein the other of R 13 and R 23 , and the other of R 33 and R 43 , is hydrogen: wherein R 4 and R 14 , which may be the same or different, each is hydrogen or alkyl of up to 5 carbon atoms, or R 4 and R 14 are joined together so that CR 4 -CR 14 is an olefinic double bond; wherein R 5 and R 6 together form a direct link or --CH 2 --, --CH(CH 3 )--, --CH 2 CH 2 --, --(CH 2 ) 3 -- or --CH═CH--, and R 15 is hydrogen; and wherein the aromatic rings B and C each is unsubstituted or substituted with one or more halogen or methyl or ethyl substituents; where A is straight- or branched-chain alkylene, alkenylene or alkynylene each of from 4 to 12 carbon atoms; or A has the formula: --A.sup.1 --Y.sup.3 --A.sup.21 -- wherein A 1 is alkylene or alkenylene and A 21 is a direct link or alkylene, alkenylene or cycloalkylene, such that A 1 and A 21 together have a total of 2 to 10 carbon atoms, and Y 3 is phenylene or naphthylene which is unsubstituted or substituted with one or more halogen or methyl or ethyl substituents; wherein R 1 is alkyl, alkenyl, cycloalkyl, halogenoalkyl, each of up to 10 carbon atoms, phenyl, chlorophenyl, o-ethylphenyl, p-cyanophenyl, p-hydroxyphenyl, p-methoxyphenyl, alkyl of 1 to 3 carbon atoms which bears a phenyl, tolyl, halogenophenyl or trifluoromethylphenyl substituent, α-methylbenzyl, 3,4-dichlorobenzyl, p-cyanobenzyl or p-methylthiobenzyl; and wherein X is --S--, --SO-- or --SO 2 --; or a pharmaceutically acceptable salt of a compound wherein R 3 is carboxyalkanoyl.

Claim 3

Dependent Claim 254 words

A phenol derivative as claimed in claim 1 wherein R 15 , R 23 and R 43 are all hydrogen; wherein R 13 and R 33 both have the formula R 3 O- wherein R 3 is hydrogen or alkanoyl or alkoxycarbonyl each of up to 5 carbon atoms; wherein either R 4 is hydrogen and R 14 is hydrogen, methyl or ethyl, or R 4 and R 14 are joined together so that CR 4 --CR 14 is an olefinic double bond; wherein R 5 and R 6 together form --CH 2 --, --CH(CH 3 )--, --CH 2 CH 2 --, or --CH═CH--; wherein the aromatic rings B and C either bear no further substituent or bear one or more fluoro, methyl or ethyl substitutents; wherein the group --A-- is a straight chain alkylene group of the formula --(CH.sub.2).sub.n -- wherein n is an integer of from 4 to 12 or the group A is a group of the formula: --A.sup.1 --Y.sup.3 --A.sup.21 -- wherein A 1 is straight-chain alkylene of 2 to 9 carbon atoms, --Y 3 -- is meta- or para-phenylene and A 21 is a direct link, methylene, ethylene, or trimethylene; wherein X is --S--, --SO-- or --SO 2 --; and wherein R 1 is n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, t-pentyl, 2,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, n-hexyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, n-heptyl, n-decyl, cyclopentyl, cyclohexyl, phenyl, o-ethylphenyl, p-chlorophenyl, m-chlorophenyl, p-cyanophenyl, p-hydroxyphenyl, p-methoxyphenyl, benzyl, α-methylbenzyl, p-chlorobenzyl, p-methylbenzyl, 3,4-dichlorobenzyl, p-cyanobenzyl, p-methylthiobenzyl, p-trifluoromethylbenzyl, phenethyl, p-fluorophenethyl, p-chlorophenethyl, 1H, 1H, -heptafluorobutyl, 4,4,5,5,5-pentafluoropentyl or 1H, 1H, 2H, 2H, 3H, 3H-heptafluorohexyl.

Claim 4

Dependent Claim 81 words

A phenol derivative as claimed in claim 1 wherein the number of carbon atoms in the two groups A and R 1 adds up to 14 to 16 if neither R 1 nor A contains a phenyl or phenyl group, 17 or 19 if there is either a phenylene group in --A-- or a phenyl group in R 1 , and 19 to 21 if there are both a phenylene group in --A-- and a phenyl group in R 1 .

Claim 5

Dependent Claim 134 words

A phenol derivative as claimed in claim 1 wherein: NU is 6-hydroxy-2-p-hydroxyphenylnaphth-1-yl and A is --(CH 2 ) 10 --, --(CH 2 ) 11 -- or --(CH 2 ) 5 --(1,4-phenylene)--(CH 2 ) 2 --; or NU is (1RS, 2RS)-- or (1RS, 2SR)--1,2,3,4-tetrahydro-6-hydroxy-2-p-hydroxyphenylnaphthyl-1-yl, or NU is (1RS, 2RS)-- or (1RS,2SR)- 1,2,3,4,-tetrahydro-6-hydroxy-2-p-hydroxyphenyl-2-methylnaphth-1-yl, and A is --(CH 2 ) 10 --, --(CH 2 ) 10 --, --(CH 2 ) 11 -- or --(CH 2 ) 4 -(1-4-phenylene)-(CH 2 ) 2 --; or NU is (1RS, 2RS)-5-hydroxy-2-p-hydroxy-phenylindan-1-yl or (1RS, 2RS)-5-hydroxy-2-p-hydroxy-phenyl-2-methylindan-1-yl and A is --(CH 2 ) 10 --, --(CH 2 ) 11 -- or --(CH 2 ) 4 --(1,4-phenylene)--(CH 2 ) 2 --; and wherein XR 1 is --SR 1 , SOR 1 or --SO 2 R 1 wherein R 1 is n-pentyl, n-hexyl, 4,4,5,5,5-pentafluoropentyl or 1H,1H,2H,2H,3H,3H-heptafluorohexyl.

Claim 6

Dependent Claim 26 words

A pharmaceutical composition having antiestrogenic activity comprising an effective amount of a phenol derivative, claimed in claim 1, together with a pharmaceutically acceptable diluent or carrier.

Claim 7

Dependent Claim 27 words

A composition as claimed in claim 5 which contains, in addition to the phenol derivative an effective amount of one or more antiandrogenic agents or antiprogestational agents.

Claim 8

Dependent Claim 36 words

A method for producing an antioestrogenic effect in a warm-blooded animal in need of such treatment, which comprises administering to said animal an effective amount of at least one phenol derivative as claimed in claim 1.

Claim 9

Dependent Claim 188 words

A phenol derivative as claimed in claim 1 wherein R 15 , R 23 and R 43 are all hydrogen, wherein R 13 and R 33 both have the formula R 3 O-- wherein R 3 is hydrogen, wherein either R 4 is hydrogen and R 14 is hydrogen, methyl or ethyl, or R 4 and R 14 are joined together, wherein R 5 and R 6 together form --CH 2 --, --CH 2 CH 2 --, --CH(CH 3 )--, or --CH═CH--, wherein --A-- is --(CH 2 ) n --, wherein n is an integer from 4 to 12, or --A--is ##STR36## wherein p is an integer from 2 to 9, q is 0 to 3, and the --(CH 2 ) q -- group is in the meta- or para-position; wherein R 1 is alkyl or fluoroalkyl each of 4 to 10 carbon atoms, or phenyl or chlorophenyl, or alkyl of 1 to 3 carbon atoms which bears a phenyl, tolyl, halogenophenyl or trifluoromethylphenyl substituent, wherein X is --S--, --SO-- or --SO 2 --; and wherein ring C is unsubstituted or substituted with one or two methyl substituents.

Claim 10

Dependent Claim 51 words

The compound: (1RS, 2RS)-1-{4-[p-(2-n-hexylthioethyl)phenyl]butyl}-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol or the corresponding 4,4,5,5,5-pentafluoropentylthio derivative, or the corresponding hexylsulphinyl, hexylsulphonyl or pentafluoropentylsulphinyl derivative; 2-p-hydroxyphenyl-1-{5-[p-(3-n-hexylthioethyl)-p-pentyl]pentyl}naphth-6-ol or the corresponding hexylsulphinyl derivative; (1RS, 2RS)-1-{4-[p-(2-hexylthioethyl)phenyl]butyl}-2-p-hydroxyphenyl-2-methyl-1,2,3,4-tetrahydronaphth-6-ol or the corresponding 4,4,5,5,5-pentafluoropentylthio derivative, or the corresponding hexylsulfinyl, hexylsulphonyl or pentafluoropentylsulphinyl derivative, or the corresponding (1RS, 2SR) isomer of either the hexylthio or hexylsulphinyl derivative.

Claim 11

Dependent Claim 51 words

The compound: (1RS, 2RS)-1-{4-[p-(2-n-hexylthioethyl)phenyl]butyl}-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol or the corresponding 4,4,5,5,5-pentafluoropentylthio derivative, or the corresponding hexylsulphinyl, hexylsulphonyl or pentafluoropentylsulphinyl derivative; 2-p-hydroxyphenyl-1-{5-[p-(3-n-hexylthioethyl)-p-pentyl]pentyl}naphth-6-ol or the corresponding hexylsulphinyl derivative; (1RS, 2RS)-1-{4-[p-(2-hexylthioethyl)phenyl]butyl}-2-p-hydroxyphenyl-2-methyl-1,2,3,4-tetrahydronaphth-6-ol or the corresponding 4,4,5,5,5-pentafluoropentylthio derivative, or the corresponding hexylsulfinyl, hexylsulphonyl or pentafluoropentylsulphinyl derivative, or the corresponding (1RS, 2SR) isomer of either the hexylthio or hexylsulphinyl derivative.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1991-03-22	1991-09-21	1992-03-22	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1995-03-22	1995-09-21	1996-03-22	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	1999-03-22	1999-09-21	2000-03-22	$7700.00	Window Closed / Lapsed

Phenol derivatives

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