Steroid derivatives

Claim 2

A steroid derivative of the formula: ST--A--X--R.sup.1 wherein ST is a 7α-linked steroid nucleus of the general formula: ##STR25## wherein the dotted lines between carbon atoms 6 and 7, and carbon atoms 8 and 9, of the steroid nucleus indicate that there is an optional double bond between carbon atoms 6 and 7, or that there are two optional double bonds between carbon atoms 6 and 7 and carbon atoms 8 and 9; wherein the aromatic ring A may optionally bear one or two of a member selected from the group consisting of halogen and alkyl substituents; wherein R 3 is hydrogen or alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl each of up to 10 carbon atoms; wherein R 16 is hydrogen, alkyl of up to 6 carbon atoms which is preferably in the β-configuration, or hydroxy which is preferably in the α-configuration; wherein either R 17 (in the β-configuration) is hydroxy or alkanoyloxy, carboxyalkanoyloxy or aroyloxy each of up to 10 carbon atoms; and R 27 (in the α-configuration) is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; or R 17 and R 27 together form oxo (═0); wherein R 18 is alkyl of up to 6 carbon atoms; wherein A is straight-or branched-chain alkylene, alkenylene or alkynylene each of from 3 to 14 carbon atoms, which may have one or more hydrogen atoms replaced by fluorine atoms, or has the formula --A.sup.1 --Y--A.sup.11 -- wherein A 1 and A 11 are each alkylene or alkenylene, optionally fluorinated, having together a total of 2 to 13 carbon atoms and Y is --O--, --S--, --SO--, and --SO 2 --, --CO-- or --NR-- wherein R is hydrogen or alkyl of up to 3 carbon atoms; or A 1 is alkylene or alkenylene, optionally fluorinated, and A 11 is a direct link or alkylene or alkenylene, optionally fluorinated, such that A 1 and A 11 together have a total of 1 to 12 carbon atoms, and Y is --NRCO--, --CONR--, --COO--, --OCO-- or phenylene wherein R has the meaning stated above; wherein R 1 is hydrogen, or alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl or arylalkyl each of up to 10 carbon atoms, or dialkylaminoalkyl wherein each alkyl is of up to 6 carbon atoms, or R 1 is joined to R 2 as defined below; and wherein X is --CONR 2 --, --CSNR 2 --, --NR 12 --CO--, ##STR26## --NR 12 --CS--, --NR 12 --CONR 2 --, --SO 2 NR 2 -- or --CO--; or, when R 1 is not hydrogen, is --O--, --NR 2 --, --(NO)R 2 --, --(PO)R 2 --, --NR 12 --COO--; --NR 12 --SO 2 --, --S--, --SO-- or --SO 2 --; wherein R 2 is hydrogen or alkyl of up to 6 carbon atoms, or R 1 and R 2 together form alkylene or halogenoalkylene such that, with the adjacent nitrogen atom, they form a heterocyclic ring of 5 to 7 ring atoms, one of which atoms may be a second heterocyclic atom selected from oxygen, sulphur and nitrogen; wherein R 12 is hydrogen or alkyl of up to 6 carbon atoms; and wherein R 22 is hydrogen, cyano or nitro; or a salt thereof when appropriate.

Claim 3

A steroid derivative as claimed in claim 1 which has the formula: ##STR27## wherein R 17 is hydroxy and R 27 is hydrogen or ethynyl, or R 17 and R 27 together form oxo; wherein --A-- is --(CH 2 ) n --, wherein n is an integer from 3 to 14, or --A-- is: ##STR28## wherein m is an integer from 2 to 9 and p is 0 to 2; wherein R 1 is alkyl, fluoroalkyl or cycloalkyl each of up to 10 carbon atoms, or phenyl, chlorophenyl or benzyl, or is linked to R 2 as stated below; wherein X is --CONR 2 --, --NR 12 CO--, --S--, --SO-- or --SO 2 --, wherein R 2 is hydrogen or alkyl of up to 3 carbon atoms or together with R 1 forms alkylene of 5 or 6 carbon atoms, and wherein R 12 is hydrogen or alkyl of up to 3 carbon atoms.

Claim 4

A steroid derivative as claimed in claim 2 wherein the number of carbon atoms in the two groups A and R 1 adds up to between 12 and 16 inclusive.

Claim 5

A process for the manufacture of a steroid derivative claimed in claim 1, which comprises: (a) when X has the formula --CONR 2 --, --CSNR 2 -- or --SO 2 NR 2 --, the reaction of a compound of the formula ST 1 --A--Z 1 , wherein A has the meaning stated in claim 1, wherein ST 1 either has the same meaning as stated in claim 1 for ST, or is an equivalent 7α-linked steroid nucleus which bears one or more protecting groups for functional derivatives, and wherein Z 1 is an activated group derived from a carboxylic, thiocarboxylic or sulphonic acid, with an amine of the formula HNR 1 R 2 , wherein R 1 and R 2 have the meanings stated in claim 1; or (b) when X has the formula --CO--, the reaction of an acid of the formula ST 1 --A--COOH, wherein ST 1 and A have the meanings stated above, with an organometallic compound of the formula R 1 --M, wherein R 1 has the meaning stated above and M is a metal group; or (c) when X has the formula --S--, --O--, --NR 2 -- or (PO)R 2 the reaction of a compound of the formula ST 1 --A--Z 2 , wherein ST 1 and A have the meanings stated above and wherein Z 2 is a displaceable group, with a compound of the formula R 1 SH, R 1 OH, HNR 1 R 2 or R 1 R 2 P--C 6 H 5 , wherein R 1 and R 2 have the meanings stated above, whereafter a phosphonium salt is hydrolysed to the phosphinyl compound; or (d) when X has the formula --NR 12 CO--, --NR 12 CS--, --NR 12 CONR 2 --, ##STR29## --NR 12 COO-- or --NR 12 SO 2 --, the reaction of a compound of the formula ST 1 --A--NHR 12 , wherein ST 1 , A and R 12 have the meanings stated above, with an acylating agent derived from an acid of the formula R 1 COOH, R 1 CSOH, R 1 OCOOH or R 1 SO 2 OH; or, for the manufacture of a urea, with an isocyanate of the formula R 1 NCO; or, for the manufacture of a guanidine, with a cyanamide of the formula R 1 NR 2 --CN; or (e) when --A-- is alkenylene of the formula --A 3 --CH═CH--A 4 --, the reaction of a compound of the formula: ST.sup.1 --A.sup.3 CHO wherein ST 1 and A 3 have the meanings stated above, with a triphenylphosphonium salt of the formula: R.sup.1 X--A.sup.4 --CH.sub.2 --P.sup.+ (Ph).sub.3 Q.sup.- wherein R 1 , X and A 4 have the meanings stated above and wherein Q - is an anion; wherafter: (i) any protecting group in ST 1 is removed by conventional means; or (ii) a steroid derivative wherein ST is a 17-hydroxy-steroid derivative may be converted by conventional reactions into the corresponding 17-keto steroid derivative, and thence to the corresponding 17-hydroxy-17-hydrocarbyl steroid derivative (that is, a steroid derivative wherein R 27 is alkyl, alkenyl or alkynyl); or (iii) a steroid derivative wherein R 3 and/or R 17 are other than hydrogen may be obtained from the corresponding compound wherein R 3 and/or R 17 are hydrogen by a conventional etherification or esterification process; or (iv) a steroid derivative wherein R 3 and/or R 17 are hydrogen may be obtained by hydrolysis of the corresponding compound wherein R 3 and/or R 17 are other than hydrogen; or (v) a steroid derivative wherein A is alkenylene may be hydrogenated to provide the corresponding compound wherein A is alkylene; or (vi) a steroid derivative wherein --X-- is --CH 2 NR 2 -- or --NR 2 CH 2 -- may be obtained by the reduction of the corresponding compound wherein --X-- is --CONR 2 -- or --NR 2 CO--; or (vii) a steroid derivative wherein --X-- is --CSNH-- or --NHCS-- may be obtained by the reaction of the corresponding compound wherein X is --CONH-- or --NHCO-- with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide; or (viii) a steroid derivative wherein X is --(NO)R 2 , --SO-- or --SO 2 -- may be obtained by the oxidation of the corresponding compound wherein X is --NR 2 -- or --S--.

Claim 6

A pharmaceutical composition comprising a steroid derivative, claimed in claim 1, together with a pharmaceutical acceptable diluent or carrier.

Claim 7

A composition as claimed in claim 5 which is suitable for oral administration and which contains from 5 to 500 mg. of a steroid derivative.

Claim 8

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 steroid derivative as claimed in claim 1.

Claim 9

A compound selected from the group consisting of N-n-butyl-N-methyl-, N-2,2,3,3,4,4,4-heptafluorobutyl-N-methyl- and N,N-(3-methylpentamethylene)-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)undecamide; N-n-butyl- and N-2,2,3,3,4,4,4-heptafluorobutyl-3-p-[4-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)butyl]phenylpropionamide; 7α-(10-p-chlorophenylthiodecyl)-, 7α-(10-p-chlorophenylsulphinyldecyl)-,7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]-, 7α-[10-[4,4,4-trifluorobutylsulphinyl)decyl]- and 7α-[10-p-chlorobenzylsulphinyl)-decyl]oestra-1,3,5(10)-triene-3,17.beta.-diol; and 7α-(9-n-heptylsulphinylnonyl)oestra-1,3,5(10)-triene-3,17β-diol.

Claim 10

A compound selected from the group consisting of N-n-butyl-N-methyl-, N-2,2,3,3,4,4,4-heptafluorobutyl-N-methyl- and N,N-(3-methylpentamethylene)-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)undecamide; N-n-butyl- and N-2,2,3,3,4,4,4-heptafluorobutyl-3-p-[4-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)butyl]phenylpropionamide; 7α-(10-p-chlorophenylthiodecyl)-, 7α-(10-p-chlorophenylsulphinyldecyl)-,7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]-, 7α-[10-[4,4,4-trifluorobutylsulphinyl)decyl]- and 7α-[10-p-chlorobenzylsulphinyl)-decyl]oestra-1,3,5(10)-triene-3,17.beta.-diol; and 7α-(9-n-heptylsulphinylnonyl)oestra-1,3,5(10)-triene-3,17β-diol.