Claims for Patent: 4,659,516

Summary for Patent: 4,659,516

Title:	Steroid derivatives
Abstract:	A steroid derivative of the formula: ST-A-X-R1 wherein ST is a 7 alpha -linked steroid nucleus of the general formula: wherein the double bond(s) between carbon atoms 6 and 7 and/or carbon atoms 8 and 9 are optional; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R3 is hydrogen, alkyl, or acyl; wherein R16 is hydrogen, alkyl or hydroxy; wherein either R17 is hydroxy or acyloxy and R27 is hydrogen, alkyl, alkenyl or alkynyl, or R17 and R27 together form oxo (=O); wherein R18 is alkyl; wherein A is alkylene, alkenylene or alkynylene optionally fluorinated and optionally interrupted by -O-, -S-, -SO-, -SO2-, -CO-, -NR-, -NRCO-, -CONR-, -COO-, -OCO- or phenylene, wherein R is hydrogen or alkyl; wherein R1 is hydrogen, alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, or dialkylaminoalkyl, or R1 is joined to R2 as defined below; and wherein X is -CONR2-, -CSNR2-, -NR12CO-, -NR12CS-, -NR12 CONR2-, -SO2NR2- or -CO-; or, when R1 is not hydrogen, is -O-, -NR2-, -(NO)R2-, -(PO)R2-, -NR12COO-; -NR12SO2-, -S-, -SO- or -SO2-; wherein R2 is hydrogen or alkyl or R1 and R2 together form alkylene or halogenoalkylene; wherein R12 is hydrogen or alkyl and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate.
Inventor(s):	Jean Bowler, Brian S. Tait
Assignee:	AstraZeneca UK Ltd , Syngenta Ltd
Application Number:	US06/656,466
Patent Claims:	1. 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 R3 is hydrogen or alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl each of up to 10 carbon atoms; wherein R16 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 R17 (in the β-configuration) is hydroxy or alkanoyloxy, carboxyalkanoyloxy or aroyloxy each of up to 10 carbon atoms; and R27 (in the α-configuration) is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; or R17 and R27 together form oxo (═0); wherein R18 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 A1 and A11 are each alkylene or alkenylene, optionally fluorinated, having together a total of 2 to 13 carbon atoms and Y is --O--, --S--, --SO--, and --SO2 --, --CO-- or --NR-- wherein R is hydrogen or alkyl of up to 3 carbon atoms; or A1 is alkylene or alkenylene, optionally fluorinated, and A11 is a direct link or alkylene or alkenylene, optionally fluorinated, such that A1 and A11 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 R1 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 R1 is joined to R2 as defined below; and wherein X is --CONR2 --, --CSNR2 --, --NR12 --CO--, ##STR26## --NR12 --CS--, --NR12 --CONR2 --, --SO2 NR2 -- or --CO--; or, when R1 is not hydrogen, is --O--, --NR2 --, --(NO)R2 --, --(PO)R2 --, --NR12 --COO--; --NR12 --SO2 --, --S--, --SO-- or --SO2 --; wherein R2 is hydrogen or alkyl of up to 6 carbon atoms, or R1 and R2 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 R12 is hydrogen or alkyl of up to 6 carbon atoms; and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate. 2. A steroid derivative as claimed in claim 1 which has the formula: ##STR27## wherein R17 is hydroxy and R27 is hydrogen or ethynyl, or R17 and R27 together form oxo;wherein --A-- is --(CH2)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 R1 is alkyl, fluoroalkyl or cycloalkyl each of up to 10 carbon atoms, or phenyl, chlorophenyl or benzyl, or is linked to R2 as stated below; wherein X is --CONR2 --, --NR12 CO--, --S--, --SO-- or --SO2 --, wherein R2 is hydrogen or alkyl of up to 3 carbon atoms or together with R1 forms alkylene of 5 or 6 carbon atoms, and wherein R12 is hydrogen or alkyl of up to 3 carbon atoms. 3. A steroid derivative as claimed in claim 2 wherein the number of carbon atoms in the two groups A and R1 adds up to between 12 and 16 inclusive. 4. A process for the manufacture of a steroid derivative claimed in claim 1, which comprises:(a) when X has the formula --CONR2 --, --CSNR2 -- or --SO2 NR2 --, the reaction of a compound of the formula ST1 --A--Z1, wherein A has the meaning stated in claim 1, wherein ST1 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 Z1 is an activated group derived from a carboxylic, thiocarboxylic or sulphonic acid, with an amine of the formula HNR1 R2, wherein R1 and R2 have the meanings stated in claim 1; or (b) when X has the formula --CO--, the reaction of an acid of the formula ST1 --A--COOH, wherein ST1 and A have the meanings stated above, with an organometallic compound of the formula R1 --M, wherein R1 has the meaning stated above and M is a metal group; or (c) when X has the formula --S--, --O--, --NR2 -- or (PO)R2 the reaction of a compound of the formula ST1 --A--Z2, wherein ST1 and A have the meanings stated above and wherein Z2 is a displaceable group, with a compound of the formula R1 SH, R1 OH, HNR1 R2 or R1 R2 P--C6 H5, wherein R1 and R2 have the meanings stated above, whereafter a phosphonium salt is hydrolysed to the phosphinyl compound; or (d) when X has the formula --NR12 CO--, --NR12 CS--, --NR12 CONR2 --, ##STR29## --NR12 COO-- or --NR12 SO2 --, the reaction of a compound of the formula ST1 --A--NHR12, wherein ST1, A and R12 have the meanings stated above, with an acylating agent derived from an acid of the formula R1 COOH, R1 CSOH, R1 OCOOH or R1 SO2 OH; or, for the manufacture of a urea, with an isocyanate of the formula R1 NCO; or, for the manufacture of a guanidine, with a cyanamide of the formula R1 NR2 --CN; or (e) when --A-- is alkenylene of the formula --A3 --CH═CH--A4 --, the reaction of a compound of the formula: ST.sup.1 --A.sup.3 CHO wherein ST1 and A3 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 R1, X and A4 have the meanings stated above and wherein Q- is an anion; wherafter: (i) any protecting group in ST1 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 R27 is alkyl, alkenyl or alkynyl); or (iii) a steroid derivative wherein R3 and/or R17 are other than hydrogen may be obtained from the corresponding compound wherein R3 and/or R17 are hydrogen by a conventional etherification or esterification process; or (iv) a steroid derivative wherein R3 and/or R17 are hydrogen may be obtained by hydrolysis of the corresponding compound wherein R3 and/or R17 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 --CH2 NR2 -- or --NR2 CH2 -- may be obtained by the reduction of the corresponding compound wherein --X-- is --CONR2 -- or --NR2 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)R2, --SO-- or --SO2 -- may be obtained by the oxidation of the corresponding compound wherein X is --NR2 -- or --S--. 5. A pharmaceutical composition comprising a steroid derivative, claimed in claim 1, together with a pharmaceutical acceptable diluent or carrier. 6. 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. 7. 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. 8. 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.