Patent EP-0221705-A1 (EP)
Inventor: ARISTOFF PAUL A
IPC: C07J41/00
Filed: 1986-10-16
Abstract: This invention provides novel tetrahydro steroids which are useful in inhibiting angiogenesis and have the following structure: 
     A compound of the formula:
      wherein R₁ is β-CH₃ or β-CH₂H₅; 
wherein R₂ is H, and R₃ is =0, -OH, -0-alkyl(C₁-C₁₂), -OC(=0)-­alkyl(C₁-C₁₂), -OC(=0)aryl, -OC(=0)N(R)₂, or -OC(=0)OR₇, wherein aryl is furyl, thienyl, pyrrolyl, or pyridyl wherein each of said hetero moiety is optionally substituted with one or two (C₁-C₄)alkyl groups or aryl is -(CH₂) f -phenyl wherein f is 0 to 2 and wherein the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C₁-C₃), alkoxy(C₁-C₃), thioalkoxy-­(C₁-C₃), Cl₃C-, F₃C-, -NH₂ and -NHCOCH₃ and wherein R is hydrogen, alkyl(C₁-C₄), or phenyl and each R can be the same or different; and wherein R₇ is aryl as herein defined or alkyl(C₁-C₁₂); or wherein R₂ is α-Cl and R₃ is β-Cl, or 
wherein R₂ and R₃ taken together are oxygen (-0-) bridging positions C-9 and C-11; or 
wherein R₂ and R₃ taken together form a double bond between positions C-9 and C-11; 
or R₂ is α-F and R₃ is β-OH; 
wherein R₄ is H, CH₃, Cl or F; 
wherein R₅ is H, OH, F, Cl, Br, CH₃, phenyl, vinyl or allyl; 
wherein R₆ is H or CH₃; 
wherein R₉ is H, OH, CH₃, F or =CH₂; 
  wherein R₁₀ is H, OH, CH₃ or R₁₀ forms a second bond between positions C-16 and C-17; 
wherein R₁₂ is -H or forms a double bond with R₁₄; 
wherein R₁₃ is H, -OH, -OH, =0, -0-P(0)(OH)₂, or -0-C(=0)-(CH 2)t COOH where t is an integer from 2 to 6; 
wherein R₁₄ is H or forms a double bond with R₁₂; 
wherein R₁₅ is =0 or -OH; 
wherein R₂₃ with R₁₀ forms a cyclic phosphate of the formula
      wherein R₉ and R₁₅ have the meaning defined above; or wherein R₂₃ is -OH, O-C(=0)-R₁₁, -0-P(0)(OH)₂, or -0-C(=0)-(CH₂) t COOH wherein t is an integer from 2 to 6; and R₁₁ is -Y-(CH₂) n -X-(CH₂) m -SO₃H, -Y'-(CH₂) p -X'-(CH₂) q -NR₁₆R₁₇ or -Z(CH₂) r Q, wherein Y is a bond or -0-; Y; is a bond, -0-, or -S-; each of X and X' is a bond, -CON(R₁₈)-, -N(R₁₈)CO-, -0-, -S-, -S(0)-, or -S(0₂)-; R₁₈ is hydrogen or alkyl(C₁-C₄); each of R₁₆ and R₁₇ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R₁₆ and R₁₇ taken together with the nitrogen atom to which each is attached forms a monocyclic heterocyclic selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkylpiperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -0-; r is an integer of from 2 to 9; and Q is
     (1) -R₁₉-CH₂COOH wherein R₁₉ is -S-, -S(0)-, -S(0)₂-, -SO₂N(R₂₀)-, or -N(R₂₀)SO₂-; and R₂₀ is hydrogen or lower alkyl(C₁-C₄); with the proviso that the total number of carbon atoms in R₂₀ and (CH₂) r  is not greater than 10;   (2) -CO-COOH; or   (3) -CON(R₂₁)CH(R₂₂)COOH wherein R₂₁ is H and R₂₂ is H, CH₃, -CH₂COOH, -CH₂CH₂COOH, -CH₂OH, -CH₂SH, -CH₂CH₂SCH₃, or -CH₂Ph-OH   wherein Ph-OH is p-hydroxyphenyl; or R₂₁ is CH₃ and R₂₂ is H; or R₂₁ and R₂₂ taken together are -CH₂CH₂CH₂-; or -N(R₂₁)CH(R₂₂)COOH taken together is -NHCH₂CONHCH₂COOH; and pharmaceutically acceptable salts thereof; with the further provisos that:
   (a) when n is 2, R₁₈ is other than hydrogen;   (b) the sum of m and n is not greater than 10;   (c) the sum of p and q is not greater than 10;   (d) when X is a bond the sum of m and n is from 5 to 10;   (e) when X' is a bond the sum of p and q is from 4 to 9;   (f) when R₄ is Cl or F, the C-1 position is saturated; and   (g) when R₉ is =CH₂, R₁₀ is other than a second bond between positions C-16 and C-17; and mono and bis salts thereof; excepting the following compound: 3α,11β,17α,21-tetrahydroxy-5β-­pregnane-20-one, and with the proviso that except for the compound 21-phosphate-6α-fluoro-17-hydroxy-16β-methyl(pregna-4,9(11))-diene)-­3,20-dione, R₁₃ is =0 only when R₂₃ with R₁₀ forms the above described cyclic phosphate.