Novel alkane and alkene derivatives and their preparation and use

Claim 2

A compound of the general formula: or wherein R 1 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, allyloxy, 2,3-epoxypropoxy, 2,3-dihydroxypropoxy, methoxymethoxy, ethoxymethoxy or R 5 I -O-CH 2 (CH 2 ) m -N-R 6 wherein one of R 5 and R 6 is hydrogen or R5 and R 6 are alkyl groups of 1-4 carbon atoms which may be the same or different or the -NR 5 R 6 group stands for a nitrogen containing 5 to 7 membered heterocyclic radical and m is 1 or 2; R 2 is an alkyl of 1 to 4 carbon atoms or wherein R 7 has the same meanings as R 1 except that R 7 and R 1 cannot simultaneously be the same; R 3 is an alkyl of 2 to 4 carbon atoms, cyclopentyl or hydroxycyclopentyl; R 4 is hydrogen or hydroxy and n is 0 to 3 provided that when R 4 is hydrogen, then R 2 and R 3 are not simultaneously lower alkyl containing up to 4 carbon atoms and its non-toxic pharmaceutically acceptable salts and esters.

Claim 3

A compound of formula (I) according to claim 1 wherein it is an (E)-isomer, (Z)-isomer or a mixture thereof.

Claim 4

A compound of formula (I) according to the claims 1 - 2 wherein R 2 is and R 7 is as defined in claim 1.

Claim 5

A compound according to claim 3 wherein R 3 is cyclopentyl or hydroxycyclopentyl.

Claim 6

A compound according to claim 4 wherein R 4 is hydrogen and n is 1.

Claim 7

A compound of formula (I) according to the claims 1 - 2 wherein R 2 is phenyl.

Claim 8

A compound according to claim 6 wherein R 3 is cyclopentyl or hydroxycyclopentyl.

Claim 9

A compound according to claim 7 wherein R 4 is hydrogen and n is 1.

Claim 10

A compound of formula (II) according to claim 1 wherein R 2 is and R 7 is as defined in claim 1.

Claim 11

A compound according to claim 9 wherein R 3 is cyclopentyl or hydroxycyclopentyl.

Claim 12

A compound according to claim 10 wherein R 4 is hydrogen and n = 1.

Claim 13

A compound of formula (II) according to claim 1 wherein R 2 is phenyl.

Claim 14

A compound according to claim 12 wherein R 3 is cyclopentyl or hydroxycyclopentyl.

Claim 15

A compound according to claim 13 wherein R 4 is hydrogen and n is 1.

Claim 16

2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-methoxyphenyl)-1-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 17

2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-methoxyphenyl)-1-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 18

2-cyclopentyl-l-(p-methoxyphenyl)-l-phenyl-l-butene and its (E)-isomer, (Z)-isomer or a mixture thereof.

Claim 19

2-cyclopentyl-l-(p-methoxyphenyl)-l-phenyl-l-butene and its (E)-isomer, (Z)-isomer or a mixture thereof.

Claim 20

2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene and its (E)-isomer, (Z)-isomer or a mixture thereof, and its esters and salts.

Claim 21

2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene and its (E)-isomer, (Z)-isomer or a mixture thereof, and its esters and salts.

Claim 22

2-cyclopentyl-l-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-l-phenyl-1-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 23

2-cyclopentyl-l-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-l-phenyl-1-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 24

2-ethyl-3-(p-methoxyphenyl)-3-phenyl-2-propen-l-ol,its (E)-isomer, (Z)-isomer or a mixture thereof and its esters.

Claim 25

2-ethyl-3-(p-methoxyphenyl)-3-phenyl-2-propen-l-ol,its (E)-isomer, (Z)-isomer or a mixture thereof and its esters.

Claim 26

2-ethyl-3-(p-hydroxyphenyl)-3-phenyl-2-propen-l-ol,its (E)-isomer, (Z)-isomer or a mixture thereof and its esters and salts.

Claim 27

2-ethyl-3-(p-hydroxyphenyl)-3-phenyl-2-propen-l-ol,its (E)-isomer, (Z)-isomer or a mixture thereof and its esters and salts.

Claim 28

2-cyclopentyl-1-(p-methoxyphenyl)-1-phenylbutane.

Claim 29

2-cyclopentyl-1-(p-methoxyphenyl)-1-phenylbutane.

Claim 30

2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenylbutane and its esters and salts.

Claim 31

2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenylbutane and its esters and salts.

Claim 32

3-cyclopentyl-4-(p-methoxyphenyl)hexane

Claim 33

3-cyclopentyl-4-(p-methoxyphenyl)hexane

Claim 34

3-cyclopentyl-4-(p-hydroxyphenyl)hexane and its esters and salts.

Claim 35

3-cyclopentyl-4-(p-hydroxyphenyl)hexane and its esters and salts.

Claim 36

2-ethyl-3-(p-methoxyphenyl)-l-pentanol and its esters.

Claim 37

2-ethyl-3-(p-methoxyphenyl)-l-pentanol and its esters.

Claim 38

2-ethyl-3-(p-hydroxyphenyl)-1-pentanol and its esters and salts.

Claim 39

2-ethyl-3-(p-hydroxyphenyl)-1-pentanol and its esters and salts.

Claim 40

2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-hydroxyphenyl)-l-butene, its (E)-isomer,(Z)-isomer or a mixture thereof and its esters and salts.

Claim 41

2-cyclopentyl-1-[p-(N,N-dimethyl-2-aminoethoxy)phenyl]-1-(p-hydroxyphenyl)-l-butene, its (E)-isomer,(Z)-isomer or a mixture thereof and its esters and salts.

Claim 42

2-cyclopentyl-1-[p-(N,N-diethyl-2-aminoethoxy)phenyl]-1-phenyl-I-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 43

2-cyclopentyl-1-[p-(N,N-diethyl-2-aminoethoxy)phenyl]-1-phenyl-I-butene, its (E)-isomer, (Z)-isomer or a mixture thereof and its salts.

Claim 44

2-cyclopentyl-1-(p-(N -methyl-2-aminoethoxy)phenyl]-1-phenyl-1-butene, its (E)-isomer,(Z)-isomer or a mixture thereof and its salts.

Claim 45

2-cyclopentyl-1-(p-(N -methyl-2-aminoethoxy)phenyl]-1-phenyl-1-butene, its (E)-isomer,(Z)-isomer or a mixture thereof and its salts.

Claim 46

2-(3-hydroxy-1-cyclopentyl)-1-(p-methoxyphenyl)-1-phenyl-1-butene and its esters.

Claim 47

2-(3-hydroxy-1-cyclopentyl)-1-(p-methoxyphenyl)-1-phenyl-1-butene and its esters.

Claim 48

2-(3-hydroxy-1-cyclopentyl)-1-(p-hydroxyphenyl)-1-phenyl-1-butene and its esters.

Claim 49

2-(3-hydroxy-1-cyclopentyl)-1-(p-hydroxyphenyl)-1-phenyl-1-butene and its esters.

Claim 50

2-(3-hydroxy-1-cyclopentyl)-1-[p-(N,N-dimethyl-2-amino- ethoxy)phenyl]-1-phenyl-1-butene and its salts and esters.

Claim 51

2-(3-hydroxy-1-cyclopentyl)-1-[p-(N,N-dimethyl-2-amino- ethoxy)phenyl]-1-phenyl-1-butene and its salts and esters.

Claim 52

A compound of the general formula or wherein R 1 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, allyloxy, 2,3-epoxypropoxy, 2,3-dihydroxypropoxy, methoxymethoxy, ethoxymethoxy or -O-CH 2 (CH 2 ) m - -R 6 wherein one of R 5 and R 6 is hydrogen or R 5 and R 6 are alkyl groups of 1-4 carbon atoms which may be the same or different or the -NR 5 R 6 group stands for a nitrogen containing 5 to 7 membered heterocyclic radical and m is 1 or 2; R 2 is an alkyl of 1 to 4 carbon atoms or wherein R 7 has the same meanings as R 1 except that R 7 and R 1 Cannot simultaneously be the same; R 3 is an alkyl of 2 to 4 carbon atoms, cyclopentyl or hydroxycyclopentyl; R 4 is hydrogen or hydroxy and n is 0 to 3 provided that when R 4 is hydrogen, then R 2 and R 3 are not simultaneously lower alkyl containing up to 4 carbon atoms and its non-toxic pharmaceutically acceptable .salts and ester for use in.therapy in the treatment of hormonedependent tumours.

Claim 53

A compound of the general formula or wherein R 1 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, allyloxy, 2,3-epoxypropoxy, 2,3-dihydroxypropoxy, methoxymethoxy, ethoxymethoxy or -O-CH 2 (CH 2 ) m - -R 6 wherein one of R 5 and R 6 is hydrogen or R 5 and R 6 are alkyl groups of 1-4 carbon atoms which may be the same or different or the -NR 5 R 6 group stands for a nitrogen containing 5 to 7 membered heterocyclic radical and m is 1 or 2; R 2 is an alkyl of 1 to 4 carbon atoms or wherein R 7 has the same meanings as R 1 except that R 7 and R 1 Cannot simultaneously be the same; R 3 is an alkyl of 2 to 4 carbon atoms, cyclopentyl or hydroxycyclopentyl; R 4 is hydrogen or hydroxy and n is 0 to 3 provided that when R 4 is hydrogen, then R 2 and R 3 are not simultaneously lower alkyl containing up to 4 carbon atoms and its non-toxic pharmaceutically acceptable .salts and ester for use in.therapy in the treatment of hormonedependent tumours.

Claim 54

A pharmaceutical composition comprising a compound as claimed in anyone of the claimsl to 32 or a non-toxic pharmaceutically acceptable salt or ester thereof and a compatible pharmaceutically acceptable carrier therefor.

Claim 55

A process for the preparation of a compound of formula (I) as claimed in claim 1 which comprises dehydrating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined in claim 1.

Claim 56

A process for the preparation of a compound of formula (I) as claimed in claim 1 which comprises 0-alkylating the corresponding phenolic compound of the formula wherein R 2 , R 3 , R 4 and n are as befure, in basic conditions with an alkyl or a benzyl halide of the formula R 8 X, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen.

Claim 57

A process for the preparation of a compound of formula (I) as claimed in claim 1 wherein n is 0 and R 4 is OH which comprises reducing an ester of the formula wherein R 1 , R 2 and R 3 are as defined in claim 1.

Claim 58

A process for the preparation of a compound of formula (I) as claimed in claim 1 wherein R 4 is OH and n is 1 to 3, which comprises reacting a compound of the formula wherein R 1 , R 2 and R 3 are as in claim 1 and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide.

Claim 59

A process for the preparation of a compound of formula (I) as claimed in claim 1 which comprises dehydrating a compound of the formula wherein R 1 , R 2 . R 3 , R 4 and n are as defined in claim 1.

Claim 60

A process for the preparation of a compound of formula (II) as claimed in claim I, which comprises catalytically hydrogenating a compound of the formula (1).

Claim 61

A process for the preparation of a compound of formula (11) as claimed in claim 1, which comprises hydrogenating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined in claim 1, in an acidic medium.

Claim 62

A process for the preparation of a compound of formula (II) as claimed in claim 1, which comprises 0-alkylating the corresponding phenolic compound of the formula wherein R 2 , R 3 , R 4 and n are as before in basic conditions with an alkyl or a benzyl halide of the formula R 8 X, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen.

Claim 63

A process for the preparation of a compound of formula (II) as claimed in claim 1 wherein n is 0 and R 4 is OH, which comprises reducing an ester of the formula wherein R 1' R2 and R 3 are as defined in claim 1.

Claim 64

A process for the preparation of a compound of formula (11) as claimed in claim 1 wherein R 4 is OH which comprises reacting a compound of the formula wherein R 1 , R 2 and R 3 are as defined in claim 1 and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide.

Claim 65

A process for the preparation of a compound of the formula or wherein R 1 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, allyloxy, 2,3-epoxypropoxy, 2,3-dihydroxypropoxy, methoxymethoxy, ethoxymethoxy or -O-CH 2 (CH 2 ) m - -R 6 wherein one of R 5 and R 6 is hydrogen or R 5 and R b are alkyl groups of 1-4 carbon atoms which may be the same or different or the -NR 5 R 6 group stands for a nitrogen containing 5 to 7 membered heterocyclic radical and m is 1 or 2; R 2 is an alkyl of 1 to 4 carbon atoms or wherein R 7 has the same meanings as R 1 except that R 7 and R 1 cannot simultaneously be the same; R 3 is an alkyl of 2 to 4 carbon atoms, cyclopentyl or hydroxycyclopentyl; R 4 is hydrogen or hydroxy and n is 0 to 3 provided that when R 4 is hydrogen, then R 2 and R 3 are not simultaneously lower alkyl containing up to 4 carbon atoms and its non-toxic pharmaceutically acceptable salts and esters which comprises a) dehydrating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or wherein R 1 and/or R 4 contain protecting groups, which are removed to give a compound of formula (I) b) 0-alkylating the corresponding phenolic compound of the formula wherein R 2' R 3 , R 4 and n are as before or where R 4 contains a protecting group which is removed, in basic conditions with an alkyl or a benzyl halide of the formula RgX, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen, to give a compound of formula (I) c) reducing an ester of the formula wherein R 1 , R 2 and R 3 are as defined above or where R 1 contains a protecting group which is removed, to give a compound of formula (I) wherein n is 0 and R 4 is OH d) reacting a compound of the formula wherein R1 , R2 and R3 are as above or where R 1 contains a protecting group which is removed and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide, to give a compound of formula (I) wherein R 4 is OH and n is 1 to 3 e) dehydrating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or where R 1 and/or R 4 contain protecting groups which are removed, to give a compound of formula (I) f) catalytically hydrogenating a compound of the formula (I), to give a compound of formula (II) g) hydrogenating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or wherein R 1 and/or R 4 contain protecting groups which are removed, to give a compound of formula (II) h) 0-alkylating the corresponding phenolic compound of the formula wherein R 2 , R 3 , R 4 and n are as before or wherein R 4 contains a protecting group which is removed, in basic conditions with an alkyl or a benzyl halide of the formula R 8 X, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen, to give a compound of formula (II) i) reducing an ester of the formula wherein R 1 , R2 and R 3 are as defined above or wherein R 1 contains a protecting group which is removed, to give a compound of formula (II) wherein n is 0 and R 4 is OH j) reacting a compound of the formula wherein R 1 , R 2 and R 3 are as defined above or R 1 contains a protecting group which is removed and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide, to give a compound of formula (II) wherein R 4 is OH and n is lto3 k) alkylating a phenolic compound of the formula with a dihaloalkane of the formula wherein m is as defined before, to give a p-haloalkoxy- phenylalkene of the formula whereafter X is replaced by a primary or secondary amino group wherein R 5 and R 6 are as above, to give a compound of formula (I) wherein R 1 is -0-CH 2 (CH 2 ) m

Claim 66

A process for the preparation of a compound of the formula or wherein R 1 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, benzyloxy, allyloxy, 2,3-epoxypropoxy, 2,3-dihydroxypropoxy, methoxymethoxy, ethoxymethoxy or -O-CH 2 (CH 2 ) m - -R 6 wherein one of R 5 and R 6 is hydrogen or R 5 and R b are alkyl groups of 1-4 carbon atoms which may be the same or different or the -NR 5 R 6 group stands for a nitrogen containing 5 to 7 membered heterocyclic radical and m is 1 or 2; R 2 is an alkyl of 1 to 4 carbon atoms or wherein R 7 has the same meanings as R 1 except that R 7 and R 1 cannot simultaneously be the same; R 3 is an alkyl of 2 to 4 carbon atoms, cyclopentyl or hydroxycyclopentyl; R 4 is hydrogen or hydroxy and n is 0 to 3 provided that when R 4 is hydrogen, then R 2 and R 3 are not simultaneously lower alkyl containing up to 4 carbon atoms and its non-toxic pharmaceutically acceptable salts and esters which comprises a) dehydrating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or wherein R 1 and/or R 4 contain protecting groups, which are removed to give a compound of formula (I) b) 0-alkylating the corresponding phenolic compound of the formula wherein R 2' R 3 , R 4 and n are as before or where R 4 contains a protecting group which is removed, in basic conditions with an alkyl or a benzyl halide of the formula RgX, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen, to give a compound of formula (I) c) reducing an ester of the formula wherein R 1 , R 2 and R 3 are as defined above or where R 1 contains a protecting group which is removed, to give a compound of formula (I) wherein n is 0 and R 4 is OH d) reacting a compound of the formula wherein R1 , R2 and R3 are as above or where R 1 contains a protecting group which is removed and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide, to give a compound of formula (I) wherein R 4 is OH and n is 1 to 3 e) dehydrating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or where R 1 and/or R 4 contain protecting groups which are removed, to give a compound of formula (I) f) catalytically hydrogenating a compound of the formula (I), to give a compound of formula (II) g) hydrogenating a compound of the formula wherein R 1 , R 2 , R 3 , R 4 and n are as defined above or wherein R 1 and/or R 4 contain protecting groups which are removed, to give a compound of formula (II) h) 0-alkylating the corresponding phenolic compound of the formula wherein R 2 , R 3 , R 4 and n are as before or wherein R 4 contains a protecting group which is removed, in basic conditions with an alkyl or a benzyl halide of the formula R 8 X, wherein R 8 is lower alkyl, benzyl, 2,3-dihydroxypropyl, alkoxyalkyl, allyl, 2,3-epoxypropyl or substituted aminoalkyl and X is halogen, to give a compound of formula (II) i) reducing an ester of the formula wherein R 1 , R2 and R 3 are as defined above or wherein R 1 contains a protecting group which is removed, to give a compound of formula (II) wherein n is 0 and R 4 is OH j) reacting a compound of the formula wherein R 1 , R 2 and R 3 are as defined above or R 1 contains a protecting group which is removed and X is halogen, with Mg, whereafter the Grignard compound obtained further is reacted with formaldehyde, ethylene oxide or trimethylene oxide, to give a compound of formula (II) wherein R 4 is OH and n is lto3 k) alkylating a phenolic compound of the formula with a dihaloalkane of the formula wherein m is as defined before, to give a p-haloalkoxy- phenylalkene of the formula whereafter X is replaced by a primary or secondary amino group wherein R 5 and R 6 are as above, to give a compound of formula (I) wherein R 1 is -0-CH 2 (CH 2 ) m