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Pyrazinylpiperazinyl steroids

  • US 5,382,661 A
  • Filed: 12/01/1992
  • Issued: 01/17/1995
  • Est. Priority Date: 09/12/1985
  • Status: Expired due to Term
First Claim
Patent Images

1. An amino substituted steroid of formula XI ##STR41## where:

  • (A-I) R6 is α

    -R61 ;

    β

    -R62, R10 is α

    -R101 ;

    β

    -R102 and R7 is α

    -H;

    β

    -H, where one of R61 and R62 is --H, and the other is --H, --F, or C1 -C3 alkyl, R102 is --CH3, R101 and R5 taken together are --(CH2)2 --C(═

    R33)--CH═

    or --CH═

    CH--CO--CH═

    , where R33 is ═

    O or α

    -H;

    β

    -OR34 or α

    -OR34 ;

    β

    -H, where R34 is --H, --CO--CH3, --CO--C2 H5, --CO--C6 H5, --CO--O--CH3 or --CO--O--C2 H5 ;

    (A-II) R5 is α

    -R53 ;

    β

    -R54, R6 is α

    -R63 ;

    β

    -R64, R10 is α

    -R103 ;

    β

    -R104 and R7 is α

    -H;

    β

    -H, where one of R63 and R64 is --H, and the other taken together with one of R53 and R54 forms a second bond between C5 and C6, R104 is --CH3, R103 and the other of R53 and R54 taken together is --(CH2)2 --C(H)(OH)--CH2 --;

    (A-III) R10 and R5 taken together are ═

    CH--CH═

    C(OR3)--CH═

    where R3 is --H, C1 -C3 alkyl, --CO--H, C2 -C4 alkanoyl or benzyl, R6 is α

    -R65 ;

    β

    -R66 where one of R65 and R66 is --H, and the other is --H, --F, or C1 -C3 alkyl and R7 is α

    -H;

    β

    -H;

    (A-IV) R5 is α

    -R57 ;

    β

    -R58, R6 is α

    -R67 ;

    β

    -R68, R7 is α

    -H;

    β

    -H and R10 is α

    -R107 ;

    β

    -R108, where one of R57 and R58 is --H, R107 and the other of R57 and R58 taken together are --(CH2)2 --C(═

    R33)--CH2, where R33 is as defined above, R108 is --CH3, where one of R67 and R68 is --H and the other is --H, --F, or C1 -C3 alkyl;

    (A-V) R6 is R69 ;

    R610, R7 is R79 ;

    R710, R10 is α

    -R109 ;

    R1010, where one of R69 and R610 is --H and the other taken together with one of R79 and R710 forms a second bond between C6 and C7, and the other of R79 and R710 is --H, R1010 is --CH3, R109 and R5 taken together are --(CH2)2 --C(═

    R33)--CH═

    or --CH═

    CH--CO--CH═

    , where R33 is as defined above;

    (C-I) R11 is α

    -R111 ;

    β

    -R112, where one of R111 and R112 is taken together with R9 to form a second bond between C9 and C11 and the other of R111 and R112 is --H;

    (C-II) R9 is --Cl and R11 is ═

    O or α

    -H;

    β

    -R114 where R114 is --Cl or --OH;

    (C-III) R9 is --H or --F and R11 is ═

    O or α

    -R115 ;

    β

    -R116, where one of R115 and R116 is --H, and the other of R115 and R116 is --H, --OH or C1 -C12 alkoxy;

    (C-IV) R9 is --H or --F and R11 is α

    -O--CO--R117 ;

    β

    -H, where R117 is(A) C1 -C3 alkyl,(B) C1 -C12 alkoxy,(C) furanyl,(D) --NR122 R123, where one of R122 and R123 is --H, methyl or ethyl and the other is --H, C1 -C4 alkyl or phenyl,(E) -X3 -X1, where X3 is --O-- or a valence bond, where X1 is phenyl optionally substituted with 1 through 2 --Cl, --Br, C1 -C3 alkoxy, --COOH, --NH2, C1 -C3 alkylamino, di(C1 -C3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C2 -C4 carboxylic acid acylamino and --NH--CHO or with 1 --F or --CF3 ;

    (D-I) R16 is R161 ;

    R162 and R17 is R171 ;

    R172, where one of R161 and R162 is --H or --CH3 and the other taken together with one of R171 and R172 forms a second bond between C16 and C17, and the other of R171 and R172 is --C(═

    Z)--(CH2)n --NR21 R210, where Z is ═

    O, ═

    CH2 or R179 ;

    --H where R179 is --H or --CH3, where n is 1 through 6, where R21 and R210 are taken together with the attached nitrogen atom to form (6) 1-piperazinyl substituted in the 4-position with X2 --(CH2)j --[E]where j is 0 thru 3 and where X2 is(1) pyrazin-2-yl optionally substituted with 1 or 2 R212 where the R212 '"'"'s (7)are the same or different and are(i) --F,(ii) --Cl,(iii) --Br,(iv) C1 -C5 alkyl,(v) --CH2 --CH═

    CH2,(vi) --X1, where X1 is as defined above,(vii) --NR213 R213 where the R213 '"'"'s are the same or different and are --H, C1 -C3 alkyl or --CH2 --CH═

    CH2,(viiiα

    ) *CH2 --(CH2)q --CH2 --N*-- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 5,(viiiβ

    ) *CH2 --CH2 --(CH2)c --G--(CH2)d --CH2 --CH2 --N*-- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where G is --O--, --S--, --SO--, --SO2 -- or --NHR214, where R214 is --H, C1 -C3 alkyl, or X1 as defined above, where c and d are the same or different and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4, 5 or 6, [a](ix) 3-pyrrolin-1-yl, [b](x) pyrrol-1-yl optionally substituted with C1 -C3 alkyl,[c](xi) piperidin-1-yl optionally substituted with 1 or 2 C1 -C3 alkyl, [d](xii) 1,2,3,6-tetrahydropyridin-1-yl, [e](xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, [f](xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C1 -C3 alkyl being the same or different, [g](xv) --OH,(xvi) C1 -C3 alkoxy,(xvii) --NR217 --(CH2)e --Q where Q is 2-pyridinyl where R217 is --H or C1 -C3 alkyl and e is 0 through 3,(1)(xviii) pyridin-2-, 3- or 4-yl,(D-II) R16 is α

    -R163 ;

    β

    -R164 where one of R163 and R164 is --H and the other is --H, --F, --CH3 or --OH, and R17 is ═

    CH--(CH2)p --NR21 R210, where p is 1 or 2, where R21 and R210 are as defined above;

    (D-III) R16 is α

    -R165 ;

    β

    -R166 and R17 is α

    -R175 ;

    β

    -R176, where R165 is --H, --OH, --F or --CH3 and R166 is --H, --OH, --F, or --CH3, with the proviso that at least one of R165 and R166 is --H, where R175 is --H, --OH, --CH3, --CH2 CH3, C2 -C7 alkanoyloxy or --O--CO--X1, where X1 is as defined above, and where R176 is --C(═

    Z)--(CH2)n --NR21 R210, where Z, n, R21 and R210 are as defined above;

    (D-IV) the 16,17-acetonide of a compound where R165 is --OH, R166 is --H, R175 is --OH and R176 is --C(═

    Z)--(CH2)n --NR21 R210, where Z, n, R21 and R210 are as defined above; and

    pharmaceutically acceptable salts, hydrates and solvates thereof;

    with the following overall provisos that;

    (I) one of R161 or R162 is taken together with one of R171 or R172 to form a second bond between C16 and C17, only when R10 is α

    -R101 ;

    β

    -R102, α

    -R103 ;

    β

    -R104, α

    -R107 ;

    β

    -R108 or α

    -R109 ;

    β

    -R1010,(II) R17 is ═

    CH--(CH2)p --NR21 R210, only when R10 is α

    -R101 ;

    β

    -R102, α

    -R103 ;

    β

    -R104, α

    -R107 ;

    β

    -R108 or α

    -R109 ;

    β

    -R1010,(III) R5 and R10 taken together are ═

    CH--CH═

    C(OR3)--CH═

    , only when R17 is α

    -R175 ;

    β

    -R176 or the 16,17-acetonide of a compound where R16 is α

    -OH;

    β

    -H and R17 is α

    -OH;

    β

    -C(═

    Z)--(CH2)n --NR21 R210, and(IV) R5 is α

    -R57 ;

    β

    -R58, only when R17 is α

    -R175 ;

    β

    -R176 or α

    -OH;

    β

    -C--(═

    Z)--(CH2)n --NR21 R210, or the 16,17-acetonide thereof.

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