CA1308707C - 20- and 21-amino steroids - Google Patents

Abstract

ABSTRACT
Disclosed are 20-, 21- and 22-amino substituted steroids (XI), more particularly amino steroids (Ia and Ib), aromatic steroids (II), .DELTA.16-steroids (IIIa and IIIb), reduced A-ring steroids (IV), .DELTA.17(20)-steroids (Va and Vb) and .DELTA.9(11)-steroids (VI) which are useful as pharmaceutical agents for treating a number of conditions:

(XI) (Ia) (Ib) (II) (IIIa) (IIIb) (IV) (Va)

Description

~ 4236.1 2 1 3r"'~707 BACKCROUND OF THE INVENTION

Yarious amino (subst~tuted) steroids are known ~ith the amine 3ubstltution on elther the steroidal ring ~ystem or on the ~ide chain of the D-ring at C17 U.S. Patent 4,456,602 discloses steroidal 21-e~ters in whic~ there is an amino function in the non-steroidal portion of the ester.
In the 3~-hydroxy series, U.S. Patent 3,998,829 discloses 21-aminomethyl steroids and U.S. Patent 3,983,111 discloses 21-amino steroids where the amino group 13 cyclized. These patents also disclo~e reduced A-ring steroids as uell as steroids ~ith a hydrogen atom at Ct7 and two hydrogen atoms at C11.
20-Amino steroids are known in the ~4-3-keto series with no subst-ltution at C11 and C17, see Can. J. Chem., 47, 160 (1969); J. Med.
Chem., 27, 1690 (1983); U.S. Patents 4,377,584 and 4,191,759;
Chem.-Blol. Interact., 46, 1 (1983); J. Steroid Biochem., 20, 1095 (1984); Inorg. Chim. Acta, 91, 257 (1984), with substltution at C11, -~ee Steroids 35, 265 (1980) and Blochim. Biophys. Acta, 623, 280 (1980) as ~ell as wlth substltution at both C11 and C17, see Steroids, ~upra.
20-Amino steroids are known ln the ~1-4-3-keto series with an 11B-hydroxyl sub~tltution, see Steroids, ~upra, as uell a~ ~Ith 11B,17~-dihydroxy ~ubstltution, see Protldes Biol. Fluids, 29, 393 (1982); J. Clln. Che~. Clln. Biochem., 22, 209 (1984); Eur. J.
Biochem., 108, 47 (19ôO); J. Sterold Biochem., 14, 697 (1981), Nature ~London) 279, 158 (1979) and Eur. J. aiochem., 131, 333 (1983) and uith 11~,17~- dihyaroxy sub~tltutlon, ~ee J. Clin. Chem. Clin. Biocnem., 21, 69 ~1983). US Patent 4,1g1,759 disc~oses 20-amino-~1-4-3-~eto s~eroS~ ~lthOUt any ~ub3tlSutlon at the 11 position uhere the amlne ~ub~titutent ls morpholine or piperazine.
21-Amlno ~teroia~ are kno~n ln the ~4-3-keto ~eri2~ ~Sth no ~ub-' 1 3''~`7n7 -2- 4236.1.2 stitutlon at C11, 9ee J. Org. Chem., 45, 3084 (1980); J. Org. Chem., 26, 1223 and 5052 (1961); J. Chem. Soc., Perkin Trans. 1, 502 (t972);
Great Brltain Patent 954,146; Austrlan Patent 249,883; Arch. Blochem.
Biophys., 182, 197 (1977) and ~him.-Farm. 2, 26 (1968~. In addltlon 21-amino -~terolds are known ln the ~1-4-3-keto serie~ substltuted wlth 11g-hydroxyl, ~ee Arch. Biochem. Blophys., 182, 197 (1977); Int. Conf.
Chem. 8iotechnol. Blol. Act. Nat. Prod. 2, 135-49 (1981); Analyst (London) 98, 519 (1972); U.S. Patents 3,705,150, 4,076,737 and 2,920,999; Nature 191,607 (1961); Hungarlan Patent 150,350 and J. Org. Chem., 45, 3084 (1980). For example Hungarian Patent 150,350 discloses dlpersolone, 113,17~-dihydroxy-21-(4-methyl-1-piperazlnyl)-pregna-1,4-dlene-3,20-dione. Further; U.S. Patent 3,705,150 dlscloses 21-[N-(N'-methyl)piperazinyl]prednisolone.
In the 20-amlno and 21-amino steroids above, the amine function was substituted with simple alkyl (methyl, propyl, dimethyl, diethyl, dipropyl), simple aralkyl (benzyl), substituents containing hetero atoms (sulfur), esters, acids, amino substituted alkyl, alcohols, ethynyl groups and complex combinatlons and ~ubstltuents. The~e amines include 4-~hydroxyethyl~-1-piperidine, 4-thYdroxYethYl]-1-piperazine, 4-methylpiperazine, 4-acetylplperazine and 4-formylpiperazine. Some of the free amines Or the 20- or 21-amino substituent of the amino subst-ituted steroids (I-VI) of the present invention are known. See, for example, U.S. Patent 4,492,696. The amlno substituted steroids (I-VI) o~ the present i m ention differ markedly from the amino steroids of the prior art.
Japanese published application J8 5043068 discloses azepino-(1,2,3-1H)-B-carboline deri~atives whlch inhlblt llpld peroxidation and are useful in inhibiting the aging of livlng bodies.
US Patent 3,697,509 discloses ~17(20)-21-quaternary amino steroid salts, The ~17(Z0)-21-amino steroids (V) of the present im ention include pharmaceutlcally acceptable salts, but not quaternary amine ~alts.
A number of 20-amlno ~teroids are known where the 20-amlno group is of the general type -NH-(CH2)x-N(R1)(R2) where x i~ 2 or 3 and R1 and R2 are methyl or ethyl. See, for example, Arch. Farmacol. Toxicol.
4, 265 (1978), Llpids 2, 5 (1g67), J. Med. Chem. 15, 1129 (1972)~ lbld 15, 1284 (1972), French Patent 90805, Lipids 11, 616 (1976), US Patent ;:

; 1 3~`7Q7 ~3- 4236.1.2 3,558,608, Chem. Ab~t. 62, 14784a, lbid 64, 14573e, ibld 65, 2334d, lbid 56, 15583a, b, and l, lbid 57, 12574d, ibid 57, 6225d.
Many 20-amlno and 21-amino sterolds are known ~here the amlne function l~ sub3tltuted wlth slmple alkyl (C1-C3), ~imple aralkyl (benzyl), ~ubstltuents contalning hetero atoms (sulfur), e~ters, acld3, amino sub~tltuted alkyl, alcohols, ethynyl groups, etc. Other 20-amlno sterold~ are known where the amlno group 19 a ~lmple amlne lncluding very slmple cycllc and heterocycllc amlne~, unlike the complex amine substitutent~ of the present in~ention, see US Patents 3,523,942 and 4,191,759. Also known are 21-amino substituted steroids where the amlne 19 a simple (~ubstituted) cycllc amine such a~ 4-(2-hydroxyethyl)-1-plperazinyl ~CA 65;20189g]; 4-(2-hydroxyethyl)-1-piperidinyl t83544~ 0]; 4,4-dlmethyl-1-plperazinyl, 3-hydroxyethyl-1-plperidlnyl, 4-hydroxy-1-piperidinyl, 4-carboxy-1-piperldinyl, 3-hydroxy-1-piperldinyl, 3-carboxy-1-piperidinyl, piperazlnyl, bls(hydroxyethyl)amino, 4-acetyl-1-piperazlnyl, 4-carboxaldehyde-1-piperazinyl, 1-plperidlnyl, tInt. Conf. Chem. Blotechnol. Blol. Act.
Nat. Prod. [Proc.] 1st. Vol. 2, p. 135, 1981]; 4-methyl-1-plperazlnyl tGreat Brltln Patent 2,136,293]; 3,6-dlhydro-2,6-dloxo-1(2H)-pyrlmldlnyl, 5-rluoro-3,6-dlhydro-2,6-dioxo-1(2H)-pyrlmidinyl, 5-rluoro-3,4-dlhydro-2,4~dloxo-1(2H)-pyrlmldlnyl, 3,4-dihydro-2,4~dloxo-1(2H)-pyrlmidlnyl, 3,4-dihydro-5-methyl-2,4-dioxo-1(2H)-pyrimidlnyl [J. Steroid Blochem. 9, 1155 (1978)]; and 4-morphollnyl tJ. Chem. Soc.
Perkin ~ran~ I, 502 (1972)].
While some of the free amines of the amlno ~terolds of the pre~ent invention are known, ~uch a~ 2-carboxy-1-piperldine [Aldrlch, ltem P4,585-o], 4-(2-pyridinyl)piperazine 8tFrench Patent 7253 M]l 4-(2-2,0 ,575 A, publiqhed Aprll 15, 1982 pyrldinylmethyl)piperazlne t Briti8n Patent applicatlon / ], 4-(6-methoxy-2-pyridinyl)piperazlne ~Canadian Patent 979,8943, 4-(2-pyrlmidlnyl)piperazlne [US Patent 4,409,223], 4-(3,6-dimethylpyrazlnyl)piperazine tCanadlan Patent 979,894], 4-(2-methoxyphenyl)piperazlne tAldrlch, ltem M2,260~1], 4-(4-methoxyphenyl)plperazine [Aldrlch ltem M2,300-4], 4-t(3,4-dimethoxyphenyl)methyl]plperazine tFrench Patent 7031 M], 4-t4-~5 fluorophenyl)piperazine tAldrlch, ltem 19,133-7], 4-~t4-(dimethylamlno)phenyl]methyl]plperazlne tUS Patent 4,421,753], 4-hydroxy-4-t4-(trifluoromethyl)phenyl]plperazlne [US Patent 1 3r~7n7 ~4~ 4236.1.2 3,936,464], (2-dlethylamlnoethyl)amlne ~Aldrich, ltem 12,694-2], ~2-(3,4-dimethoxyphenyl)ethyl~amine ~Aldrich, item D13,620-4], ~2-(2,4-dimethoxyphenyl)-1-methylethyl]amlne ~J. Pharm. Scl. 60, 1232 (1971)], [2-(3,4-dimethoxyphenyl)ethyl]~[4-dimethylamlno)phenyl]-~ethyl]amine ~Chem. Abst. 65:7001-] and (2-pyridinyl)methylamine ~Aldrlch, ltem A6~520-4], most are novel.
Most of the steroldal 21- (hydroxy derivatl~e) halo (bromlne or iodine), mesylate or tosylate ~tartlng materials are known, 3uch a3 21-bromo-17a-hydroxypregna-4,9-dlene-3,20-dione [US 4,041,055 (Ex 59)~, 21-bromo-173-hydroxyprsgn-4-ene-3,11,20-trione [J. Chem. Soc. B., 4, 748 (1970)], 11a,21-dihydroxypregn-4-ene-3,20-dione [US Patent 4,013,688], 21-bromo-17a-hydroxypregn-4-ene-3,20-dione [US Patent 4,500,461], 21-bromopregn-4-ene~3,11,20-trione [US Patent 3,983,111], 21-hydroxy-pregna-4,9(11),16-triene-3,20-dione [Tetrahedron Lett. 25, 2581 (1984)], 21-iodopregna-4,9(11)-dlene-3,20-dione ~95288-91-8], 21-bromopregn-4-ene-3,20-dione [J. Org. Chem., 50, 81 (1985), 11B,17a-dlhydroXy~21~lodo-6a-methylpregna~1,4-dlene~3,20~dlone ~J. iharD. Soc., 74, 36~ (1985)], 21-bromo-11B,17~-dlhydroxypregna-1,4-diene-3,20-dione ~US Patent 3,856,~56], 17a~hydroxy-21~iodo~16a~
methylpregna-1,4,9(11)-triene-3,20-dione [US Patent 3,455,968], 17~,21-dihydroxy-6a-methylpregna-1,4,9(11)-triene-3,20-dione tWe~t German DE 3,322,120], 17a-Hydroxy-21-iodopregna~1,4-diene-3,11,20-trione tJ. Med. Chem., 28, 171 (1985)], 21-bromopregna-1,4-dlene-3,20-dione ~Bull. Chem. Soc. Jpn. 58, 9~1 (198~)~, 17~,21-dihydroxy~
pregna-1,4,9(11)-triene-3,20-dione ~West German DE 3,322,120], 17a,21-dihydroxy-16B-methyl-5a-pregn-9(11)-ene-3,20-dione ~US Patent 4,336,200] and 21-bromo-3a,17-dihydroxy-5B-pregnane-11,20-dione t95044-38-5], howerer ~ome are norel.
SUMMARY OF THE INVENTION
The amino substituted steroids (XI) encompass the amlno steroids (Ia and Ib~, aromatic steroids (II), ~16-steroids ~IIIa and IIIb), reduced A-ring sterolds (IV) and h17(20)-steroid~ (Va and ~b).
Di~clo3ed is an amlno substituted ~teroid of formula (XI) where:

(A-I) R6 i9 ~-R61 3-R62- Rlo i8 ~-RlOl:B-R102 and R7 is ~-H:B-H, where one of R61 and R62 is -H, and the other is ~H, -F, or C1-C3 ~alkyl~ R102 i3 -CH3, R101 and R5 taken togsther are -(CH2)2-C(-R33)~CH~
or -CH-CH-CO-CH-, where R33 is -O or ~-H:B-OR34 or a~OR34:B~H, where 7n7 ~5~ 4236.1.2 R34 ls -H, -CO-CH3, -CO-C2Hs, -CO-C6Hs, -CO-O-C~3 or -CO-O-c2H5;
(A-II) Rs is ~-Rs3:B-Rs4~ R6 i9 a-R63:B-R64~ Rlo i9 ~-R103:B R104 and R7 is a-H:B-H, where one of R63 and R64 is -H, and the other taken together wlth one of R53 and R54 forms a second bond between Cs and C6, R104 i9 -CH3, R103 and the other of Rs3 and Rs4 taken together are -(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 i9 a-R65:B-R66 where one of R~5 and R66 is -H, and the other is -H, -F, or C1-C3 al~yl and R7 is a-H:~-H;
(A IV) R5 i9 -R57:~-R58- R6 is a-R67:~-R63~ R7 i~ a-H:B-H and R10 ~9 a-R107:B-R108, where one of Rs7 and Rs8 i9 -H, R107 and the other of Rs7 and Rs8 taken together are -(CH2)2-C(~R33)-CH2~ where R33 is as defined abore, R108 is -CH3, where one of R67 and R68 is -H and the other is -H, -F, or C1-C3 alkyl;
(A V) R6 i9 R69:R610. R7 i9 R7g:R710~ R10 is a-R10g:R1olo~ where one o~ R69 and R610 i9 -H and the other taken together with one of R79 and R710 rorms a second bond between C6 and C7, and the other of R7g and R710 i9 -H, R10tO 19 -CH3, R109 and Rs taken together are -(CH2)2-C(~R33)-CH~ or -CH-CH-CO-CH-, where R33 is as defined above;
where:
(C-I) R11 l~ a-R111:B-R112- where one of R111 and R112 is taken together with Rg to form a second bond between Cg and C11 and the other f R111 and R112 is -H;
~C-II) Rg is -Cl and R11 is ~0 or ~-H:B-R114 where R114 is -Cl or -OH;
(C-III) Rg is -H or -F and R11 is -O or a~R11s:3~R116, where one of R11s and R116 is -H, and the other of R11s and R116 is -H, -OH or C1-C12 alkoxy;
(C-IY) Rg is -~ or -F and R11 i9 a~O~CO~R117:~~H, ~here R117 i9 (A) C1-C3 alkyl, (B) C1-C12 alkoxy, (C) furanyl, (D) -NR122R123- where one of R122 and R123 i~ -H, methyl or ethyl and the other is -H, C1-C4 alkyl or phenyl, (E) -X3-X1, where X3 i3 -O- or a valence bond, where X1 i9 phenyl optionally sub~tituted with 1 through 2 -Cl, -~r, C1-C3 alkoxy, 1 3 C ! 7 0 7 -6- 4236.1.2 COOH~ -NH2, Cl-C3 alkylamlno, di(Cl-C3)alkylamlno, ~here the alkyl groups are the same or di~ferent, l-pyrrolidinyl-, 1-piperldinyl, 1-hexamethylenlmlno-, 1-heptamethylenlmino-, C2-C4 acylamino and -NH-CH0 or ~lth 1 -F or -CF3;
where:
(D-I) R16 iQ R161 :R162 and R17 19 Rl7l :R172~ where one of R161 and R162 l9 -H or -CH3 and the other taken together wlth one of R171 and R172 forms a second bond between C16 and C17, and the other of R171 and R172 i9 -C ( ~Z )- ( CH2)n-NR2lR2lo~ where Z is -0, -CH2 or R17g:-H where R179 i9 -H or -CH3, where n 19 0, 1 or 2~ where (A) R21 ls (1~ (CH2)m~NR21t~X2. where m is 2, 3 or 4, where R21l is -H or C1-C3 alkyl, where X2 is:[A]
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substltuted by 1 or 2 R212, being the same or d~fferent, where A212 is (l) -F, ~il) -Cl, (lll) -Br, ~iv) C1-Cs alkyl, ( v ) -CH2-CH-CH2 .
(Yi) -X1, where X1 is as defined above, (vii) -NR213R213 where the R213~s are the same or dlfferent and are -H, C1-C3 alkyl or -CH2-CH~CH2-25(viiia) *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, (viilB) *CH2-CH2-(CH2)C-G-(cH2)d-cH2-cH2-N ~
where the atoms ~arked with an asterisk (*) are bonded to each other 30resulting in the formation of a ring, where G is -0-, -S-, -S0-, -S02-or -NHR214, where R214 is -H, C1-C3 alkyl, or X1 as defined above, where c and d are the same or dir~erent and are 0 through 2 with the proviso that the total number Or ring carbon atom~ 18 4, 5 or 6, ~a]
(ix) 3-pyrrolin-1-yl, ~b]
35(x) pyrrol~ yl optionally substituted with C1-C3 alkyl, ~c]
(xi) piperidin-1~ yl optionally substituted -` 1 3c"7n7 -"
-7- 4236.1.2 wlth l or 2 Cl-C3 alkyl, ~d]
(xil) l,2,3,6-tetrahydropyrldln-1-yl, ~e]
(xill) l-hexamethyleneimino containing a 3- or 4~ double bond or 3- and 5- double bonds, ~f]

5(xl~) l,4-dlhydro-1-pyrldlnyl substituted ln the 4 posltlon by two Cl-C3 alkyl being the same or dlfferent, ~g]
(xY) -OH, (x~l) Cl-C3 alkoxy, (xil) ~NR2l7-(CH2)e-Q where Q i9 2-pyrldlnyl 10where R217 i9 -H or Cl-C3 alkyl and e 19 0 through 3, (1) (b) 1,3,5-trlazln-4-yl or the N-oxide thereof optlonally substltuted at the 2- and~or 6- po~ltion with R212 i~ as defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereof optlonal-ly sub~tltuted at the 2- and/or 6- posltlon with R212 is as deflned abo~e, (5) (d) pyrimidin-2-yl optionally substituted at 4 and/or 6- po~itlon wlth t or 2 R212 as 19 deflned abo~e, ~6) ~e~ pyrazin-2-yl optlonally ~ub~tltuted wlth 1 or 2 20R212 a9 19 deflned abo~e, ~7) (f) lmidazol-2-yl optionally ~ubstitututed in the 1 positlon with C1-C3 alkyl or -Xl, where X1 1~ as defi~ed above, and further optionally substituted with 1 or 2 R212 as defined above, (8) (g) 1,3,4-triazol-2-yl optlonally sub~tituted ln 25the 1 posltlon with C1-C3 alkyl or -X1, where X1 19 a~ de~ined above, and rurther optlonally substituted with R212 as defined abo~e, (9) (h) lmldazol-4- or 5-yl optionally ~ubstituted ln ~ the 1 positlon with C1-C3 alkyl or -Xl, where %1 is as defined abo~e, : 30and further opt~onally substituted with 1 or 2 R212 as defined above, (10) ; (1) benzo~b]thien-2-yl, (12a) ) lndol-2-yl, (12b) (k) benzo~b]thiazol-2-yl, (12c) ~l) benzlmidazol-2-yl, (12d) (m) 4-~2-~4-~2,6-bl~(1-pyrrolldinyl)-4-pyrlmidlnyl]-1-piperazinyl]ethyl~plperazinyl, (13) ~: :
~, ' :13r~ ,7n7 -8-~ 423~.1.2 (2) (1-plperazinyl)-(C2-c4)alkyl optlonally sub~tltuted in the 4- positlon with -Xl or -X2 as deflned abo~e, C8]
~3) -X2, a~ defined abo~e, tO]
(4) -tCH2)m-X4 ~here m 19 as defined abo~e and where X4 S is (a) O CH2CH2-Y, where Y i9 Cl-C3 alkylamino, di(cl-c3)alkylamino where the alkyl groups are the same or d1fferent, C3-C6 alkylenelmlno, optlonally substltuted wlth 1 or 2 Cl-C3 alkyl, (b) -NR220CH2CH2-Y, where R220 is -H or C1-C3 alkyl 10and Y is as defined above~
(c) -(CH2)g-N(R220)-X2, where ~ i9 2, 3 or 4, and where R220 and X2 are a~ deflned above, CH]
(5) ~(CH2)m~NR222R223, where R222 is -H or Cl-C3 alkyl and R223 i~ -Xl or -X2 as defined above, or R222 and R223 15are taken together with the attached nitrogen atom to form a ~aturated mono-nltrogen C3-C6 heterocyclic ring and where m i~ as defined above, ~I]

(6) (CHCH3)b-(CH2)~-R224~ where b is O and f Ls 1 through 3 or b 19 one and r 19 0 through 3, where R224 is phenyl 203ubstituted wlth 1 through 3 -OH, Cl-C3 alkoxy, -NR225R226 where R225 and R226 are the same or dirferent and are -H, Cl-C3 alkyl or are taken together with the attached nitrogen atom to form a C4_C7 cyclicamino rlng,[J~

(7) (CH2)i-X2. ~here i i9 1 through 4 and X2 is as derlned above, tX]

(8) tl-piperazlnyl)acetyl substltuted ln the 4- posltlon by X2 where X2 18 as derlned above, ~L]

(9) (1-plperazlnyl)carbonylmethyl sub~tltuted ln the 4- posltion by -X2 where X2 is as derined a~ove, and ~M]
(B) R210 i9 (1) -H, (2) C1-C3 alkyl, (3) Cs-C7 cycloalkyl, ~ (4) -~CH2)m-NR211-X2, where m, R211 and X2 are as ; defined abo~e, tA]
~5) (1-plperazinyl)-(C2-C4)alkyl optionally substituted in the 4- positlon wlth -Xl or -X2 a3 de~ined above, ~B]
(6) -(CH2)m-%4, w~ere m and X4 are a3 deflned above, CH]

' ~
4236.1-2 t7) (cH2)m-NR222R223~ where m, R222 and R2z3 are as deflned above, [I~
(8) -(CHCH3)b-(CH2)f-R224, where b, f and R224 are as defined above, ~J]
(C) R21 and R210 are taken together with the attached nltrogen atom to form a heterocycllc rlng selected from the group consistlng of (1) 2-(carboxy)-1-pyrrolldinyl optlonally as the C1-C3 alkyl ester or as a pharmaceutlcally acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperldinyl optionally a9 the C1-C3 alkyl ester or as a pharmaceutlcally acceptable salt, [C-2]
(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable ~alt, [C-3]
(4) 2-(carboxy)-1~heptamethylenei~ino optionally a~ the 15C1-C3 alkyl ester or as a pharmaceutlcally acceptable salt, ~C-4]
(5) 1-piperazinyl sub~tituted in the 4- position with R228-CO-(CH2)~- where R228 i9 -X1, -NR22gxl and 2-furanyl, where R229 is -H or C1-C3 alkyl, where ~ l~ O through 3 and X1 is as defined above, ~D]
~6) 1-piperazlnyl substituted in the 4- position with X2-(CH2)~-, where X2 and ~ are a~ deflned above, ~E]
(7) 1-piperazinyl sub~tltuted in the 4- position with X1-(CH2)~-, where X1 and ~ are as deflned above, [F]
(8) 4-hydroxy-1-piperidinyl substitut~d in the 4-25position with X1 as defined above, [G]
(9) 1-piperazinyl ~ubstituted ln the 4~ po~ition wlth X2-NR22g-co-(cH2)i-~ where X2, R229 and i are as defined above; ~N~
(D II~ R16 i9 a-R163:B-R164 where one of R163 and R164 is -H and the other is -H, -F, -CH3 or -OH, and R17 i9 -CH-(CH2)p-NR21R210~ where 30p 19 1 or 2, where R21 and R210 are as defined above;
(D-III) R16 i~ ~-R16s:B-R166 and R17 i9 ~-R175:B-R176~ wher~ R165 i9 -H, -OH, -F or -CH3 and R166 l~ -H, -OH, -F, or -CH3, wlth the provi~o that at least one Or R165 and R166 l~ -H, where R17s 19 -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, where X1 is as 35defined above, and where R176 is ~C(~Z)-(CH2)n-NR21R210~ where Z, n, R21 and R210 are a9 defined above;
(D-IV) the 16,17-acetonide of a compound where R165 is -OH, R166 1 3"''`7Q7 -10- 4236.1.2 19 -H, R17s i9 ~OH and R176 l~ ~C(-Z)-(CH2)n-NR~lR2l0~ whore Z, n, R
and R210 are as defined above;
and pharmaceutically acceptable salts thsreof, and hydrates and ~ol~ates thereof;
w1th the followlng o~erall provisos that:
(I) one of R161 or R162 i9 taken together wlth one Of R171 or R172 to rorm a second bond between C16 and C17, only when R1o is a R101:3-R102. a-R103:B-R104, a~R107:B-Rlo8 or a-R1og:~-R1o1o, (II) R17 is 'CH-(CH2)p-NR2lR2l0~ only when R1o i9 a-R101:
B-Rl02~ a-R103:B-Rl04~ a-Rlo7:B-Rlo8 or -R109:B-R1010-(III) R5 and R1o taken together are -CH-CH-C(OR3)-CH-, only when R17 i9 a R17s:B-R176 or the 16,17-acetonide of a compound where R16 i9 a~OH:B-H and R17 i9 a-OH:B-C(-Z)-(CH2)n-NR2lR2l0~ and (IV) Rs is a~Rs7:B~Rsg, only when R1? i9 a-Rl75:B-Rl76 or a-OH:B-C-(~Z)~(CH2)n-NR21R210, or the 16,17-acetonide thereof.
Preferred compounds of formula (XI) are the amino substituted steroids where:
(A I) R6 i9 a-R61:B-R62- R10 i9 a-Rlo1:B-R1o2 and R7 i9 a~H:B-H, where one of R61 and R62 is -H, and the other 19 -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 ~0 or a-ff:B-OR34 or a~OR34:B-H, where R34 i9 -H, -CO-CH3, -CO-C2Hs, -CO-C6Hs, -cO-O-cH3 or -CO-O-c2H5;
(A-II) Rs is a-Rs3:B-Rs4, R6 i8 a-R63:B-R64~ R10 i9 a R103:B R104 and R7 i~ a~H:B~H, where one Or R63 and R64 is -H, and the other taken together with one Or Rs3 and Rs4 rOrms a second bond between Cs and C6, R104 i9 -CH3, R103 and the other o~ Rs3 and Rs4 taken together are -(OH2)2-C(H)(OH)-CH2-;
(A-III) R1~ and Rs taken together are -CH-CH-C(OR3)-CH- where R3 i~ -H, C1-C3 alkyl, -CO-H, C2-C4 alkanoyl or benzyl, R6 i9 a-R65:B-R66 where one Or R65 ard R66 i9 -H, and the other i9 -H, -F, or C1-C3 alkyl :~ and R7 is a~H:B~H;
(A-IV) R5 i~ a~R57 B-Rs8. R6 i9 a-R67:B-R6g. R7 is a-H:B-H and Rlo i9 a-R107:B-R108. ~here one of R57 and R58 i9 -H, R107 and the other of R57 and Rs8 taken together are -(CH2)2-C(~R33)-CH2~ where R33 is as defined above, R108 is -CH3, where one Or R67 and R68 19 -H and the other is -H, -F, or C1-C3 alkyl;
: tA-V) R6 is R6g:R610~ R7 is R7g:R710, R10 i9 a~R10g:R1o1o~ where ~ ' 1 3~1707 -11 4236.1.2 on~ of R69 and R610 i~ -H and the other taken together with one of R7g and R710 forms a ~econd bond between C6 and C7, and the other of R7g and R710 19 -H, RlO10 i9 -CH3, Rlog and R5 taken together are -(~H2)2-C(~R33)-CH~ or -CH~CH-CO-CH-, where R33 ls as de~ined above;
where:
(C-I) Rll 19 ~-Rlll:B-R112. where one of Rlll and R112 is taken together wlth Rg to rOrm a second bond between Cg and C11 and the other of Rlll and R112 ls -H;
(C-II) Rg i~ -Cl and Rll is -O or ~-H:B-R114 where R114 is -Cl or -OH;
(C-III) Rg ls -H or -F and Rll ls DO or a-R11s:B~Rlt6, where one of Rl 15 and Rl 16 is -H, and the other of Rl 15 and Rl 16 ls -H, -OH or Cl-C12 alkoxy;
(C-IV) Rg is -H or -F and R11 i9 ~-0-CO-R117:B-H, where R117 i9 (A) Cl-C3 alkyl, (B) Cl-C12 alkoxy, (C) furanyl, (D) NR122R123. where one of R122 and R123 1~ -H, methyl or ethyl and the other is -H, C1-C4 alkyl or phenylD
(E) -%3~X1, where X3 ls -O- or a valence bond, where X1 19 phenyl optlonally substltuted with 1 through 2 -Cl, C1-C3 alkoxy, -NH2- Cl-C3 alkylamino, di(C1-C3)alkylamino~ where the alkyl groups are the same or dl~ferent, 1-pyrrol$dinyl-, 1-plperidinyl, C2-C4 acylamino and -NH-CHO;
where:
(D-III) R16 is ~-R16s:B-R166 and R17 is ~-R175:B-R176- where R165 i9 -H, -OH, -F or -CH3 and R166 is -H, -OH, -F, or -CH3, with the proviso that at least one of R16s and R166 is -H, where R17s i9 -H, -OH, -CH3, -CH2CX3, C2-C7 alkanoyloxy or -O-CO-Xl, where Xl is as defined aboYe, and where R176 is -C(~Z)-(CH2)n-NR21R210~ where Z i9 -O, -CH2 or R179:-H- where R179 is -H or -CH3, where n i9 1, where (C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring sele¢ted from the group con~istlng of (6) 1-p$peraz$nyl substituted in the 4- posltion with X2-(CH2)j~, where ~ i~ O and where X2 is:
(a) pyridln-2-, 3- or 4-yl or the N-oxlde thereof ' l 3~7n7 -12- 4236.1.
optionally substituted by 1 or 2 R2l2, being the ~ame or dlfferent, where R212 19 (iv) Cl-C3 alkyl, ( v ) -CH2-CH-CH2 ~
(v1) -%1, where X1 is as defined above, ~vii) -NR213R213 where the R2l3's are the same or difrerent and are -H, Cl-C3 alkyl or -C~2-C~-CH2-(riii~) *cH2-(cH2)q-cH2~N*~ where the atom~
marked with an asiterisk (*) are bonded to each other resulting in the 0 formation of a ring, where q i~i 1 through 3, (viliB) *CH2-CH2-(CH2)C-G-(cH2)d-cH2-cH2-N ~
where the atoms mar~ed with an a~terisk (~) are bonded to each other resulting in the formation of a ring, ~here G i~ -0-, -S-, S0-, -S02-or NHR214- where R214 i9 -H, Cl-C3 alkyl, or Xl as defined above, where c and d are the ~iame or dlfferent and are 0 through 2 with the proviso that the total number of ring carbon atoms is 4 or ~, [a3 (ix) 3-pyrrolin-1-yl, [b]
(x) pyrrol-1-yl optionally substituted with C1-C3 alkyl, ~c]
~xi) piperidin-1-yl optionally sub~tituted with 1 or 2 C1-C3 alkyl, [d]
(xii) 1,2,3,6-tetrahydropyridin-1-yl, ~e]
(xiv) 1,43d1hydro-1-pyridinyl substituted in the 4 position by two C1-~3 alkyl being the ~ame or difrerent, ~g]
(xvl) C1-C3 alkoxy, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and~or 6- position with R212 i9 a8 defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereor optional-ly substituted at the 2- and/or 6- po~ition with R212 is as def$ned above, (5) (d) pyrimidin-2-yl optionally substituted at 4-and/or 6- position with 1 or 2 R212 a~ 19 derlned above, (6) ~E]
(7) 1-piperazinyl substituted ln the 4- posltion with 35X1-(CH2)~-~ where %1 and ~ are as deflned above, ~F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4-position with X1 as deflned above, [G]

,,' ' 1 3""707 -13- 4236.1 2 and pharmaceutlcally acceptable salt~ thereof, and hydrates and ~ol~ates thereo~.
More preferred compounds of formula (XI) are the amino substituted steroids where:
(A-I) R6 i9 -R6l: B-R62. Rlo i9 a-Rlol: 3-R102 and R7 i9 a-H:B-H, where one of R61 and R62 i9 -H, and the other i9 -H, -F, or C1-C3 alkyl~ R102 i9 -CH3, R10l and Rs taken together are -(CH2)2-C(-R33)-CH~
or -CH-CH-CO-CH-, where R33 is -0;
where:
(C-I) R11 i9 a-R111:B-R112, where one of R111 and R112 is taken together with Rg to form a second bond between Cg and C11 and the other f R111 and R112 i9 -H;
(C-III) Rg is -H and R11 is a~R11s:B-R116~ where both R11s and R116 are -H;
lS where:
(D-III) R16 is a-R16s:B-R166 and R17 i9 a-R17s:B-R176~ where R165 is -H, -OH, -F or -CH3 and R166 is -H, -OH, -F, or -CH3, with the proviso that at lea9t one of R16~ and R166 i9 -H, where R17s i9 -K, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -0-CO-X1, where X1 19 as deflned abo~e, and where R176 i8 ~C(-Z)-(CH2)n-NR21R210~ where Z i3 -O, -CH2 or R17g:-H, where R1~g is -H or -CH3, where n is 1, where (C) R21 and R210 are taken together with the attached nitrogen atom to rorm a heterocyclic ring selected from the group consi~ting Or (6) 1-piperazlnyl substituted in the 4- position with X2-~CH2)~-, where J i9 0 and where X2 is:
: ~a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R212~ being the same or different, where R212 is ~i~) C1-C3 alkyl, ( ~,r) -CH2-CH-CH2 ~
(vi) -%1, where %1 is as derined above, ~ vii) -NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CHz-CH~CH2, (viiia) *CH2~(CH2)q~CH2~N*~ where the atoms ~arked with an asterisk (*) are bonded to each other re~ulting in the formation of a ring, where q i~ 1 through 3, ~``` 1 3~`707 -14- 4236.1.2 ~viliB) ~CH2-CH2-(CH2)C-G-~cH2)d-cH2-cH2-N -~here the atoms marked with an asterisk (~) are bonded to each other resultlng in th0 formation of a ring, where G ~9 -O-, -S-, -S-, -S2-or -NHR214~ where R214 is -H, C1-C3 alkyl, or X1 a~ defined above, 5~here c and d are the same or different and are 0 through 2 with the proviso that the total number of rlng carbon atoms i-~ 4 or 5, [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]
(XiY) 1 ,4-dihydro-1-pyridinyl 9ubstituted in the 4 position by two C1-C3 alkyl being the same or different, Cg]
(xvi) C1-C3 alkoxy, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 is as defined above, (4) ~ c) pyrimldin-4-yl or the N-oxide thereof optional-ly ~ubstituted at the 2- and/or 6- po81tlon with R212 is as derlned above, (5) (d) pyrlmidln-2-yl optionally substituted at 4-and/or 6- position with 1 or 2 R212 as i3 derined a~ove, (6) ~E]
(7) 1-piperazinyl substituted in the 4- positlon with X1-~CH2)~-, where X1 and J are as de-ined abo~e, ~F]
(8) 4-hydroxy-1-plperidlnyl substituted in the 4-position with X1 as defined above, tG]
and pharmaceutically acceptable salts thereof, and hydrates and solvates thereof.
Also disclosed is the amino steroid of formula (Ia and Ib) vhere:
R6 is a~R61:B-R62 and R10 is -R101:B-Rlo2~ where one Or R61 and R62 is -H, and the other i~ -H, -F or C1-C3 alkyl, R102 i9 -CH3, R101 and R5 taken together are -(CH2)2-C(~R33)-CH- or -CH~CH-CO-CH~, ~here R33 is ~0 or -H:B-OR34 or a-OR34:B~H, where R34 i9 -H, -C0-CH3, -CO-C2H5--CO-C6Hs, -CO-O-CH3 or -CO-O-C2Hs or Rs i~ a~R~3:B~R54- R6 i~ ~-R63:
B-R64 and R1o is a~R103:B-R1o4 where one of R63 and R64 is -~, and the other taken together with one of Rs3 and Rs4 forms a second bond 1 3r ~7 07 -15- 4236.1.2 between C5 and C6, R104 i9 -CH3, R103 and the other oS R53 and R54 taken together are -CH2)2-C(H)(OH)-CH2-, R7 i9 a-H:B~H and R16 i_ a R165:B-R166 and R17 i9 a-R175 3-R176- where R16s i9 -H, -OH, -F or -C~3 and R166 i~ -H, -OH, -F, or -CH3, with the proviso that at least one of R165 and R166 mu9t be H, where R17s i_ -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, and where R176 i9 -C('Z)~(cH2)n-NR21R-210; where .... is a single or double bond and r~lndicates that there are 2 poss1ble orientations for the attached group, (1) a or B when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond.
Disclosed are the amino steroids of EXAMPLES 1, 4-8, 10-43, 45-57, 59-70, 72-91, 94-98, 103-108, 111, 112, 114-124, 126-128 and 132.
The preferred amine is 16a-methyl-21-~4~~2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione. More preferred is 16a-methyl-21-~4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethane~ulfonate, 16-methyl-21-[4-~2,6-bis-(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione bismethanesul~onate and 16~-methyl-21-~4-[2,6-bis-(pyrrolidino)-4-pyrimidlnyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dlone hydrochlorlde. Most preferred i9 16a~
methyl-21-[4-~2,6-bis(pyrrolidlno)-4-pyrimldinyl]-1-piperazinyl]pregna-1,4,9(11)-trlens-3,20-dlone monomethanesulronate.
Further disclosed is an aromatic amino steroLd Or formula (II) where: R10 and Rs taken together are -CH-CH-C(OR3)-CH~ where R3 is -H, C1-C3 alkyl, -CO-H, C2-C4 alkanoyl or benzyl, R6 is a-R6s:B-R66 where one Or R6s and R66 is -H, and the other iq -H, -F or C1-C3 alkyl, R7 i9 ~-H:B-H and R16 is a~R16s:B~R166 and R17 i9 a-R17s:B-R176~ where R165 is -H, -OH, -F or -CH3 and R166 is -H, -OH, -F, -CH3, with the pro~iso that at least one Or R165 and R166 mu~t be -H, ~here R175 is -H, -OH, -CH3, -CH2CH3, Cz-C7 alkanoyloxy or -0-CO-X1, and where R176 is ~C(-Z)~ (cH2)n-NR21 R210-Additionally di~closed is a ~16 amino steroid of ~ormula (IIIa and IIIb) where: R6 is a-R6t:B-R62 and R10 is a-R101:B-R102, where one Or R61 or R62 is -H, and the other 19 -H, -OH, -F, C1-C3 alkyl or phenyl, R102 i9 -CH3, R101 and R5 taken together are -(CH2~z-C(-R33)-CH~ or -CH~CH-CO-CH-, where R33 is -O or a~H:B-OR34 or a~OR34:B-H, where R34 i~ -H, -CO-CH3, -CO-C2Hs, -CO-C6Hs, -CO-O-CH3 or -CO-O-C2Hs or Rs is ~ 3~ 7-Q7 4236.1.2 a R53:B R54, R6 i9 a-R63:B-R64 and Rlo 19 a-R103:B-R104 where one of R63 and R64 19 -H, and the other taken together with one of Rs3 and Rs4 forms a second bond between Cs and C6, R104 19 -CH3, R103 and the other of Rs3 and Rs4 taken together are -~CH2)2-C(H)(OH)-CH2-, R7 is a~H:B-H
and R16 i9 R161:R152 and R17 i9 R171 :R172- where one of R161 and R162 i9 -H or -CH3 and the other taken together with one Or R171 and R172 forms a second bond between C16 and C17, and the other of R171 and R172 i9 C(-z) (CH2)n-NR2lR2l0; where is a 3ingle or double bond and where ~ lndlcate~ that there are 2 possible orientations for the attached group, (1) a or B when attached to the sterold rlng and (2) cls or trans when attached to a carbon atom of a double bond.
Also dlsclosed 19 a reduced rlng amino steroid oS formula (IV) where R5 19 a~57:3-R58- R6 is a-R67:B-R6g and Rlo 19 a R107 ~ R108, where one of Rs7 and Rs8 19 -H, R107 and the other of Rs7 and Rs8 taken together are -(CH2)2-C(R33)-CH2, where R33 i9 ~0 or a-H:B-OR34 or a-OR34:B-H, where R34 19 -H, -CO-CH3, -CO-C2Hs, -CO-C6Hs, -CO-O-CH3 or -CO-O-C2H5- R108 i~ -CH3, where one of R67 and R68 is -H and the other is -H, -F or Cl-C3 alkyl, R7 19 a~H:B-H and R16 19 a-R165:B-Rl66 and R17 19 a-R175:B-R176. where R165 19 -H, -OH, -F or -CH3 and R166 19 -H, -OH, -F or -CH3, wlth the provlso that at least one oS R16s and R166 must be -H, where R17s ls -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, and where R176 i8 -C(-Z)-(CH2)n-NR21R21o; where ........ is a single or double bond and where ~ indicateq that there are 2 posslble orlentations for the attached group, (1) a or B when attached to the steroid ring and (2) cls or tran~ when attached to a carbon atom o~ a double bond.
Further dlsclosed is a ~17 am$no steroid of rormula (Va and Vb) where: R6 19 a-R6l:B-R62 and R10 i9 a-R1o1:B-R1o2~ where one of R61 and R62 is -H, and the other i9 -H, -F or C1-C3 alkyl, R102 i-~ -CH3, R101 and R5 taken together are -(CH2)2-C(~R33)-CH~ or -CH~CH-CO-CH-, where R33 is ~0 or a~H:B~OR34 or a-OR34:B-H, where R34 is -H, -CO-CH3, -CO-C2H5, -CO-C6Hs, -CO-O-CH3 or -CO-O-C2Hs or R5 i8 ~-R53:B-R54, R6 i9 a-R63:B-R64 ard R10 19 a-R1o3:B-R1o4 where one of R63 and R64 i~ -H, and the other taken together wi~h one of Rs3 and Rs4 rorms a second bond between Cs and C6, R104 is -CH3, R103 and the other or R~3 and Rs4 taken together ars -(CH2)2-C(H)(OH)-CH2-, R7 is ~-H:B-H and R16 is a-R163:B-R164 where one of R163 and R164 i9 -H and the other is -H, l 3~ 707-17- 4236.1.~
-OH, -F or ~CH3, and Rl7 is -CH-(CH2)p-NR21R2l0~ where p i9 1 or 2, where .... 19 a ~lngle or double bond and where " indicates that there are 2 posslble orientatlon3 for the attached group, (1) or B when attached to the steroid rlng and (2) Ci9 or trans ~hen attached to a carbon atom of a double bond.
Disclosed are ~9(11 )-steroids of formula (VI) where: (A-I) E6 1 ~-E61:B-E62 and E10 i9 a-Elol:B-Elo2~ where one of E61 and E62 i9 -H, and the other is -H, F, -Cl, -Br or ~1-C3 alkyl, Elo1 and Es taken together are (CH2)2-C(-E33)-C~. or -CH-CH-CO-CH,, where E33 i~ ~O or a~H:B-OE34 or a~OE34:B-H, where E34 i9 -H, -CO-C~3, -CO-C2H5- -CQ-C6H5, -CO-O-CH3 or -CO-O-C2Hs, where E102 i~ -CH3; (A-II) Es i~ l-Es3:3-Es4, E6 i9 a-E63:B-E64 and E10 i9 ~-E1o3:B-Elo4~ where one of E63 and E64 is -H, and the other taken together with one of Es3 and Es4 forms a -~econd bond between Cs and C6, E104 is -CH3, E103 and the other of Es3 and Es4 taken together are -(CH2)2-C(H)(OH)-CH2-;
(A IY) E5 i9 a E57:a-E58- E6 i9 -E67:B-E6g and E10 i9 a-E107 B-E108~ where one of Es7 and Es8 i3 -H, E107 and the other of Es7 and E58 taken together are -(CH2)2-C(~E33)-CH2, where E33 is as defined abo~e~ E108 i9 -CH3, where one of E67 and E68 is -H and the other is -H, -F or C1-C3 alkyl;
where:
(D-I) E16 19 -E161;B-E16z~ where one Or E161 and E162 is -H and the other i9 -H, -F, -CH3 or -OH;
(D-II) E17 is -H, -CH3, -CH2Hs, -OH or -~C-E171- ~here E171 i9 C1-C6 alkyl or Xl, where %1 ig phenyl optionally substituted with 1 through 2 -Cl, -3r, C1-C3 alkoxy, -COOH, -NH2, C1-C3 alkylamino, di(C1-C3)alkylamino, where the alkyl groups are the same or difi~erent, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylen-imino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3;
(D-III) Z i9 -O, -C~2, E20:-H where E20 is -H or -CH3;
(D-IV) J i9 - 1-(4-methyl)-piperazinyl, ~J-1]
1-(4~acetyl)-piperazinyl, ~J-2]
1-(4-hydroxy)-piperidinyl ~J-3]
1-piperidlnyl optionally ~ubstituted with 2-hydroxyethyl, ~J-4]
4-morpholinyl ~J-5]

1 3 ` 7-18- 4236.1.2 and the 16,17-acetonlde t~ereor when E161 and E17 are both -OH;
and pharmaceutlcally acceptable salts thereof, and hydrate~ and ~ol~ates thereof.
Also disclosed are the amines of PREPARATIONS A-1, A-3, A-9 thru A-11, A-13 thru A-24, A-26, A-28, A-29, A-34, A-40, A~42, A-44 5thru A-48. The preferred amlnes are A-22, A-23, A-26, A-45, A-46 and A-47. Most prererr~d is A-22 and A-47.
Further disclosed are the terolds Or PREPARATIONS S-3, S-10, S-16, S 22 thru S-24, S-28, S-29, S-31 thru S-35 and S-41. More preferred is the steroids S-22 and S-24.
DETAILED DESCRIPTION OF THE INVENTION
The invention is amino substituted steroids (XI~, namely the amino steroids (Ia and Ib), aromatic steroids (II), ~16-steroid~ (IIIa and IIIO), reduced A-ring steroids (IV) and ~17(20)-steroids (Va and Vb) a~
well as the ~9(11)-steroids (VI). Also included are the novel amine 15and ~teroldal reactants used to prepare the amino substituted steroid3 (XI), ~ee PREPARATIONS "A" (amines) and ~'S" (steroid~) respectiYely.
With the aromatic steroids tII) the A-ring functionality at C3 is a hydroxy group or substituted hydroxy group (ether or ester).
However, with the amino ~teroids (Ia and Ib), ~16-steroids (IIIa and 20IIIb), redu¢ed A-rlng steroids (IV), Q17(20)-sterolds (Va and Vb) and ~9(11)-sterolds (VI) the A-rlng functionality at C3 is either hydroxyl or ketone. When the k-ring functionality at C3 is hydroxy, the hydroxyl group can be in either the ~ or B configuration. When the A-ring functionallty at C3 i~ hydroxy, there will be either a reduced 25A-ring, ~4 or ~5 double bond present but no double bond at C1 for the sterolds or formulas (Ia, Ib, IIIa, IIIb, Va, Vb and VI). When the A-ring functlonality at C3 is a ketone, then there will be a reduced A-ring or a Q4 double bond present and no ~5 double bond or there will be a ~1-4-diene A-ring functionality. The reduced A-ring steroids Or 30formula tI~) have no double bond in either rlngs A or B and ha~e at C3 either a hydroxyl group or a ketone.
The amino substituted steroid9 (XI) and ~9(11)-steroids (VI) of the present invention are prepared by methods known to those skilled in the art from steroidal and amine reactant9 which are either known to 35those ~killed in the art or which are readily prepared rrom compounds known to those skilled in the art by method9 known to tho9e skilled in l 3 `707-19- 4236.1.2 the~art.
The amlno 3ubstltuted ~teroids (XI), when n 19 1 or 2, and the Q9(1~ terolds (VI) are produced in a preferred proce~s by reacting a ~terold corre~pondlng to the desired amino steroid ~Ia and Ib), aromatic steroid (II), Q16-steroid (IIIa and IIIb~, reduced A-ring steroid (IY), Q17(20)-~teroid (Va and Vb) and the ~9(11)stero1d (VI) but ha~ing a ~ubstituent at C21 (n - l) or C22 (n - 2) such a~ a halogen atom (chlorine, bromine or lodine), a mesyl or to~yl group, wlth the desired amine in an aprotic solvent (DMF, THF, methylene chloride, acetonitrile, DMA, ether) containing a ba3e (carbonate, bicarbonate, triethylamine, diisopropylethylamine) a~ i9 known to tho~e s~illed in the art ror the formation of amine~. The 21-/22 halo, me~yl or tosyl substituted 3teroids are known to tho~e ~killed in the art or are readily prepared from compounds known to those skilled in the art by methods known to those skilled in the art. It i~ preferred that the 21-/22-halo substituent be a bromine atom but an iodine or chlorine atom is suitable.
The derivatlves of the 3(a/B)-hydrOxy ~teroids are prepared by methods known to those skilled in the art. When the 3-hydroxy ~teroid starting materials contain other free hydroxy or amlno functionality the~e groups must be protected a~ i~ known to those skllled in the art.
The rree hydroxy group~ are prote¢ted, ror example, a~ the THP
derlvatives and the free amino are protected, for example, as the t-butyloxycarbonyl derivatives. The 3-0-acyl deriYatives (steroid-O-COR) are prepared by first dissol~ing the the 3-hydroxy compound in a ~olYent such a~ pyridine or methylene chloride and with a base such as triethylamlne present. The mixture is cooled in an ice bath and treated with the acylating agent such as acetyl chloride, acetic anhydride, propionyl chloride, benzoyl chloride, etc. The reaction mixture i9 then partitioned between an organic solvent such as ~ethylene chloride and aqueous bicarbonate. The organic phase is separated, dried, concentrated and puri~ied, for example by chromatography. Likewi~e, 3-carbonates are produced by reactlng the 3-hydroxy ~teroid with a reagent such as RO-CO-Cl, The Q4,6 and Ql,4,6 derivat'~es are prepared by reactlng the corresponding Q4 starting material wlth a reagent such as chloranll followlng the general procedure of Campbell and Babcock, J. Am. Chem.

.

1 7, r~ ~l ? 0 7 ^20- 4236.1,2 Soc. 81, 4069 (1959). If a ~1,4,6 derivatiYe l~ desired, the ~1 double bond is 3ubsequently added by methods well known to tho~e skilled in the art ~uch as by fermentation or with DDQ.
When n is O, the amino substituted steroids (XI) are amides and are produced ln a preferred proces~ by ~tarting ~ith the acid (-COOH at C17) and reacting it f1rst with a conden~ing reagent ~uch as carbonyldiimidazole or DCC in the pre~ence of HOBT, followed by reaction with the free amine corresponding to the desired amine substituent as is known to those ~killed in the art, see for example US
Patent 4,438,130; ~ee EXAMPl,ES 56, 57 AND 103. The amine starting materials are either known to those skilled in the art or are readily prepared from compounds known to those skilled in the art by methods known to those skilled in the art. Suitable 30lvents include, acetonitrile, DMF, dioxane, l~F, methylene chloride, and mixtures thereof.
When the substitutent at C17~ is a methyl or ethyl group and the ~ubstitutents at C16 are hydrogen atoms, the compounds are prepared by first treatlng the corresponding ~16-steroid wlth lithium in liquid ammonla and then trapplng the enolate wlth methyl or ethyl iodide.
~uring this methylation the A-rlng must be protected as i~ known to those skllled in the art. When the ~ub9titutent at C16a is a methyl group and at C16B i~ a -H, the compounds are prepared by first adding methyl magne~lum chloride in the presence of a copper proplonate and trapping the enolate with methyl or ethyl iodide.
Alternatively, ln principle, a form of the steroid not necessarily desired a~ the final product (Xl), can be reacted in its 21-halo, 21-mesyl or 21 tosyl form with the appropriate amine to form a 21-amino steroid. Following this, the steroid nucleus itself can be modified.
While thi3 is an alternative proces~, in principle, to produce the amino ~ubstituted steroid~ (XI), of the present invention, in practice it is an undesirable method compared to the pre~rered process of reacting the 21-halo, tosyl or mesyl analog corre~ponding to the stero~dal portion of de~ired amino substituted ~teroids (XI), with the amine corresponding to the amine portion of the desired amino sub~tituted ~teroids (XI) as i~ apparent to one skilled in the art -with the exception of the e~ters of the 11a-hydroxy steroids, see EXAMPLES 28, 31 AND 32.

1 3 ~1 7 0 7 -21- 4236.l.2 Yst another alternatlve procedure, ln princlple, to produce some of t~e sterolds o~ the lnventlon lnvol~lng amino substituents whlch can be thought of as ha~lng 2 or more components, can be produced by first reactlng the 21-halo, tosyl or mesyl sterold with a portlon of the deslred amlne substltuent to form a steroid in whlch there is an amlne substltuent at the 21-positlon followed by further reactlon of the amlno portlon of the amlno substltuted sterold to produce the complete sub~tltuent at the 21-posltlon. For some sterolds of this lnvention (EXAMPLES 9 and 10) thls method 19 preferable, but a~ stated a~ove for the other alternati~e procedure, while this is an alternatlve proce~s ln prlnclple, ln practice lt i~ usually undesira~le compared to the preferred proce~s.
For the amino substituted ~teroids (XI), it i preferred that the steroid be the amlno steroid (Ia and Ib), more preferably the amino steroid (Ia). It is preferred that the A-ring be ~4-3-keto or ~1,4-3-keto. At C6, it l~ preferred that R61, R65 and R67 be -H and R62, R66 and R68 be -H or -CH3. It is preferred that R7 be ~-H:B-H. For the C-ring it ls preferred that Rg be -H or the C-ring be ~9(11), more preferrably ~9(11 ) . It ls preferred that the substltutent(s) at C16 be -H l~ only one substltutent, or l~ two substitutent3, elther two -H's or a -H and a -CH3. If -CH3 it ls preferred that it be in the a configuration. It i9 preferred that R175 be a -H, -OH, C2-C7 alkanoyloxy or -O-CO-Xl; it is more preferred that R17s be -H. Wlth regard to the slde chain at C17, it is preferred that it be ~C('Z)~(CH2)nNR21R210. It i9 preferred that Z be -O. It is prererred that n be 1. Regardlng R21 and R210 lt i~ preferred that R21 and R210 are taken together with the attached nitrogen atom to rorm a cyclic amino substitutent selected rrOm 1-piperazlnyl substituted in the 4- position with X2-(cH2)~- tE] and l-piperazinyl ~ubstituted in the 4-position with Xl-(CH2)j- [F~. It is preferred that ~ be 0.
With the substitutent ~E] it is preferred that X2 be selected from the group consisting Or 1,3,5-triazin-4-yl substituted in the 2- and/or 6-position with -CH2-CH.CH2, pyrimidin-4-yl substltuted ln the 2- and/or 6- position with 1-pyrrolidlnyl, pyrimldln-4-yl sub~tituted ln the 2-and/or 6- position with 4-morpholinyl, 1,3,5~triazln-4-yl substltuted in the 2- and 6- position with l-pyrrolldlnyl and pyrldlnyl ~ubstltuted in the 3- position with -NR213R213 where one of R213 is -H and ths .

~ 1 3 ~, V 7 7 -22- ~` 4236.1.2 other l~ C2 alkyl. It i~ preferred that the compounds not be the N-oxlde. With the sub~tltutent ~F], it i9 preferred that X1 be phenyl optionally ~ub3tituted with 1,2 or 3 methoxy group3.
It i9 preferred that the amino sub-~tltuted steroid (XI) be selected from the group consistlng of 17a-hydroxy-21-[4-(2-pyrldinyl)-1-piperazinyl]pregna-4,9(11)diene-3,20-dlone, 21-[4-[2-amlno-6-(diethylamino)-4-pyrimldinyl]-1-piperazinyl]-17a-hydroxypregna-4,9(11)-dlene-3,20-dione, 17a-hydroxy-2l-[4-[2~6-bi~(dlethylamino)-4-pyrimidinyl]
piperazinyl]pregna-4,9(11)-diene-3,20-dione, 2t-[4-t2,6-bls(diethylamino)-4-pyrimldinyl]-1-piperazlnyl]-17a-hydroxy-16a-methylpregna-1,4,9(11)-trlene~3,20-dione, 21-t4-(2-pyrldinyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 21-[4-~2,6-bis(dlethylamino)-4-pyrimidinyl]-1-piperazlnyl]-1 la, 17a1dihydroxypregn-4~ene-3,20-dlone, 17a-hydroxy-16a-methyl-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrlmldinyl]-1-piperazinyl]pregna-t,4,9(11)-trlene-3,20-dione, 17a-hydroxy-21-[4-[2,6-bis-(1-pyrrolldlnyl)-4-pyrimldlnyl]-1-plperazinly]pregna-1,4,9(11)-trlene-3,20-dlone, 16-methyl-21-~4-~2,6-bls(pyrrolidlno)-4-pyrlmldinyl]-1-plperazlnyl]pregna-1,4,9~11)-triene-3,20-dione, 11a-hydroxy-16a-methyi-21-[4-~2,6-bis(pyrrolidino)-4-pyrlmldinyl]-1-piperazlnyl]pregna-1,4-diene-3,20-dione, 16a~methyl 21-~4-~2~6-bis(w rrolldino)-4-pyrimldinyl]-1-piperazinyl]-pregna-1,4-diene-3,20-dione, 16a-methyl-21-[4~[2,6~bi~(morphollno)-4-pyrimldlnyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione, 11a-hydroxy-16a-methyl-21-t4-[2,6-bis(morphollno)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4-diene-3,20-dione, 16a-methyl-21-[4-[2,6-bls(morpholino)-4-pyrlmidlnyl]~1-piperazinyl]-pregna-1,4-dlene-3,20-dione, 21-t4-t3,6-bl~-(dlethylam$no)-2-pyrldinyl]-1-plperazinyl]-16a-methyl-pregnA-1,4,9(11)-triene-3,20-dione 21-t4~[6-(ethylamino)-2-pyrid$nyl]piperazinyl]-16a-methyl-pregna-1,4,9(11)-triene-3,20-dione and pharmaoeutically a¢ceptable ~alts thereof.
.
'~'~ ' ., : ' . . ..

7 !~ 7 ~-7 -23- 4236.1.2 It 1s more preferred the amlno sub3tituted steroid (XI) be 16~-methyl-21-~4-~,6-bl~(pyrrolldino)-4-pyrimidinyl]-1-piperazlnyl]-pregna-1,4,9(11)-triene-3,20-dione or 21-[4-[3-(ethylamino)-2-pyridinyl]piperazinyl]-16a-methyl~pregna-1,4,9(11)~triene-3,20-dione.
The amino sub~tituted steroids (XI) and the ~9(11 )steroids (VI) of the present inventlon are reacted with acids to form amlne salts by methods known to those skilled ln the art and the resulting salts are more water soluble and therefore preferable to use when an aqueous formulation is desired ~uch as a solution for IV use. &enerally the a~lno substituted steroids (XI) and the ~9(1l)steroid~ (VI) possess one or more basic nitrogen atoms to be converted to an acid addition pharmaceutically acceptable salt. Ho~ever, when n is 0 and Z is ~0 (i.e. amides) and the compound does not contain another nitrogen atom, they will not form salts suitable as pharmaceuticals. The pharmaceutically acceptable salt rorms of the amino substituted steroids (XI and VI) are generally preferred over the free base form since the salts have greater water solubility and form crystals more suitable for pharmaceutical purpose~. An acid addition ~alt of the amino Rubstituted steroids (XI) and the ~9(11)steroids (VI) can be converted to the free base, which can be converted to any desired pharmaceutlcally acceptable acid addltlon salt by methods known to those skllled in the art. It is preferred that the acid addition salt be prepared by reacting the free base of the amino substituted sterolds (%I) and the ~9(11)~terolds (VI) with an approximately ~toichlometric amount of an acid, such as hydrochloric, hydrobromic, hydroiodiic, sulfuric, phosphoric, acetic, lactic, citric, succinic, benzoic, salicyclic, pamoic, cyclohexanesulramic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, oxalic acid and the like. It is preferred that the acid be selected from the group consi~ting of hydrochloric, maleic, methanesulfonic and fumaric acids~
The amino substltuted 3teroids (%I) and the ~9(11)steroids (VI) and acid addition salts can be i~olated as hydrates or 30lvates, and ~uch forms are regarded as equivalent to the corresponding amino substituted steroids (XI) and the ~9(11)steroids (VI) not contalning water or solvent.
The a~ino substituted steroid9 (XI) and the ~9(11)steroids (VI) of the present invention are useful pharmaceutlcal agents in treating a 1 7 ~ ~ 7 ~ 7 I J ~ 24- 4236.1.2 num~er of dlfferent ~edlcal conditions in human3 and useful warm blooded anlmal~.
In human~, the amino sub~tituted ~terolds (XI) and the ~9(11)_ sterolds (VI) of the present invention are userul in treating spinal trauma, ~ild and/or moderate to severe head in~ury, subarachnoid hemorrhage and subsequent cerebral Yasospasm, ischemic (thromboembolic) stroke, excess mucous ~ecretion, asthma, mu3cular dystrophy, adriamycin-lnduced cardlac toxicity, Parkinsonism, Alzheimer's di3ease, other degenerative neurological disorders, multiple sclerosi~, organ damage during reperfusion after transplant, 3kin graft re~ection, hemorrhagic, traumatic and ~eptic shock, and conditions such a~ ~evere burns, ARDS, inflammatory diseases such as osteo- or rheumatoid arthriti~, nephrotic syndrome (immunological), 3ystemic lupu9 erythematosis, allergic reactions, athero~clerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, cancer (limit metastasls, limlt tumor growth), stre~s induced ulcers, cluster headaches, complications from brain tumors, radiatlon damage and damage after MI. Amino substituted steroids (XI) having the amine functionality 4-~2,6-bis(4-al~yl-1-piperazinyl)-4-pyr-imidinyl]-1-plperazinyl are use~ul in treating burn vlctims for burn healing, userul ln promoting wound healing and for post MI heart recovery.
In humans, the amino ~ubsti~uted steroids (XI) and the ~9(11)-ste~oids (VI) are useful ln preventing damage rollowing cardiopulmonary resuscltation, neurological or cardiovascular surgery and rrom cardiac infarction.
Generally, the amino substituted steroids (XI) and the ~9(11)_ steroid~ (VI) are useful in the same way as glucocorticoid pharmaceutical~ for the treatment Or the above human conditions a~ well as the animal condition~ listed below. While the amino 3ubstituted ~ steroids (XI) and the ~9(11)steroids (VI) are useful in both humans and animal~ in treating many of the same conditions and preYenting damage from the same problems as the glucocorticoids, the amino substituted 3teroids (XI) and the ~9(11)steroids (VI) are userul in treating a number of condltions and preventing damage from conditions where the glucocorticoids are not userul. The amino substituted steroids (XI) and the ~9(11)steroid9 (VI) have diminished glucocorticoid activity and `` 1 3~ ^7~7 -25- 4236.l.2 th~nefore, unllke the glucocortlcolds, they can be ~lYen daily for long periods of time ~used chronlcally) without the ~lde effect~ assoclated with the glucocorticoids. Thi~ i~ a di~tinct advantage.
It i9 to be understood that each of the amino substituted steroids (XI) and the a9(1l)~teroids (VI) i~ useful for a number of the above conditlon~ but not each and every compound i~ useful for each and every condltion. It 19 well within the ability of those skilled in the art to easlly determlne which particular amino substituted ~terolds (XI) and the ~9(l1)~teroids (YI) are u~eful for each particular condition without undue experimentation. For example, the fertile egg or chick embryo assay of Folkman, Nature 288, 551 (1980) or Science 221, 719 (1983), dl~closes an a~say to determlne antiangiogenic activlty whlch i3 indicative of inhibition of tumor growth and anti-cancer utility.
Because of the ability of the compound~ which are active in the Folkman embryo test to inhlbit tumor growth, they are useful in the treatment of variou~ di3eases and conditions, e~pecially variou~ form~ of cancer. Accordingly, they are admini~tered to animals and humans to prolong survival or reduce pain and/or dl~comfort secondary to tumor growth and the allke. Further, the arachidonlc acld LDso te~t Or Kohler, Thrombosi~ Res., 9, 67 (1976), identlf1es compounds which are antioxidants, which inhlbit llpld peroxldatlon, and~or which inhibit the prostaglandin cascade and are userul in treating spinal trauma, mild and/or moderate to severe head in~ury, degenerative neurological disorders, etc. Another method u~eful for determining which particular compounds inhibit lipid peroxidation and whlch are therefore u~eful in treating spinal trauma, mild cmd/or moderate to ~evere head in~ury, degenerative neurological di~orders, etc 19 described by Pryor ln Method~ Or Enzymology 105, 293 (1984). Further, the mouse head ln~ury a~say of Hall, J. Neurosurg., 62, 882 (1980) discloses an assay from which one skilled in the art can readily determine which particular amino substituted ~teroids (XI) and the ~9(~ teroids (YI) are useful $n the acute treatment of ~p~nal trauma or mild and~or moderate to severe head in~ury. Additionally, the cat 48 hr motor nerve degerneration model of Hall et al, Exp. Neurol., 79, 488 (1983) d$scloses a routine assay from which one qkilled in the art can readily determine whlch partlcular amino substituted 3teroids (XI) and the ~9(1l)steroid~ (VI) are u~eful in treatlng chronic degenerative 1 3~ ~ n 7~26- 4236.1,2 neurological dlsorders ~uch as Parkinsonlsm, Alzheimer`s dlsaase etc.
H. Johnson ln Int. Arch. Allergy Appl. Immunol., 70, 169 (1983) has de~crlbed the a3carla~ sen~1tized rhe-~us monkey as~ay for anti-asthma drug~.
The standard cond1tions for treatment are to gi~e the amino sub-~tltuted steroids (XI) and the ~9(11)steroids (VI) orally or parenterally, e.g. IV (that 19 by in~ection, infu~ion or continuous drip) or IM, with a standard dose of about 0.05 to about 100 mg/kg/day, one to four times dally.
For Sreating spinal trauma, mild and moderate to severe head ln~ury, damage followlng cardiopulmonary resu~citatlon, cardiac infarction, organ damage during reperfusion after transplant, hemorrhagic, traumatic and ~eptic ~hock, severe burns, ARDS, and nephrotic syndrome and prevent$ng ~kin graft rejection, the standard condltions are u~ed. Typical treatment will involve an initial loading dose, e.g. an IY dose of 0.01 mg to 1 mg/kg followed by maintaince dosing e.g. IV infu~ion for a day to a week depending on the particular condition of the patient and the particular compound u~ed. Thi~ may be ~upplemented with IM or oral dosing for days, ~eek~ or months to prevent delayed neuronal degeneration in neurological appllcations (eg ~pinal trauma, head ln~ury).
In treatlng subarachnoid hemorrhage and subsequent cerebral vasospasm or lschemlc (thromboembollc) stroke the standard condltlon~
are used and patlents at risk are pre-treated orally.
In treating exce~s mucou~ secretion and asthma the amino 3ub~tituted steroid~ (XI) and the ~9(11)steroids (VI) are administered orally, IV and by Inhalation in the standard dose. In treating exce~s mucous secretions the dose of the amino substituted ~teroids (XI) and the ~9(11)steroids (VI) u3ed i3 fro~ about 0.05 to about 100 mg/kg/day. The frequency of administration is one through 4 times daily. The oral administration of the amino sub-~tituted steroids (XI) and the ~9(11)steroids (VI) to treat excess mucou~ secretions may go on for months or even year~. The ~usceptlble lndlvldual~ can be pre-treated a few hour~ before an expected problem. The IV dose is about 0.05 to about 50 mg/kg/day. The aerosol formulatlon contains about 0.05 to about 1.0S of the amino ~ub~tltuted sterolds (XI) and the ~9(11)steroids (VI) and is administered or u~ed about four times dally 1 3~i~7n7 -27- 4236.1.2 a3 ~eeded.
In treating cancer, muscular dystrophy, Parkinsonlsm, Alzhelmer's disease and other degenerative neurologlcal disorders (amyotrophlc lateral sclerosis; multiple sclerosis) the amlno substituted steroids (XI) and the ~9(tl )steroids (YI) are adminlstered orally using a dose of about 0.05 to about 100 mg/kg/day, adminlstered or used one to four tlmes a day. The treatment may go on rOr years.
In addltion, utility in cancer as well as other disorders or physlologlcal phenomena dependent on angiogenesis or neovascularization such as embryo implantation (antifertility), arthritis, and atherosclerosis ls exhlbited with the amino substltuted steroids (XI) and the ~9(11)steroids tVI) with or wlthout co-administered oral heparln or systemlc heparln fragments, see Science 221, 719 (1983).
In treating adriamycin-induced cardlac toxicity the amino substituted steroids (XI) and the ~9(11)steroids (VI) are admlnistered orally or IV using a dose of about 0.05 to about 100 mg/kg/day (orally) or (IV). The amino substituted steroids (XI) and the ~9(11)sterolds (VI) are preferably given concomitantly with IV adrlamycin or the individual is pre-treated with the amlno substituted sterolds (XI) and the ~9(~ teroids (VI).
For prophylaxis prlor to and preventing damage after neurological or cardiovascular surgery the amino substituted steroids (%I) and the ~9~11)steroids (VI) are u~ed according to the standard conditions. The patient can be pretreated with a single IV or IM dose ~ust prior to surgery or orally before and arter surgery.
In treatinB osteo- or rheumatoid arthritis and other inflammatory disease~ the amino substituted steroids (XI) and the Q9(11)steroids (VI) are gi~en orally or IM in do~es of about 0.05 to about 100 mg~kg/day, one to four times dally. Orally the drug will be glven over a period of months or years alone or with other steroidal agents. The initial dose with some severe rheumatoid patlents may be given IV and followed wlth an IV drip for up to 24 hr or more. In addition, intra-articular administratlon may be employed.
In treating drug allergic reactlon~ the amlno substituted steroids (XI) and the ~9(11)steroids (VI) are given orally or IV in a dose of about 0.05 to 100 mg/kg/day, admlni3tered one to four times daily orally and IV. Typical treatment would be an initial IV loading dose 1 3 `707 -28- 4236.l.2 ~ollowed Oy oral dosing for a few days or more.
In treating atherosclerosls and emphyse~a the amino substltuted ~teroids (XI) and the ~9(l1)sterolds (VI) are 8iren orally in a dose of about 0.05 to about lOO mg/kg~day, one to four times dally for months or years.
In treating dermatolcgical inflammatory conditions lncluding psoriasis the amlno substituted steroids (XI) and the ~9(11)steroids tVI) are given orally in a dose of about 0.05 to about 100 mg/kg~day, one to four tlmes dally or applied topically as a cream, ointment or lotlon or equl~ralent dosage form in a concentration of about 0.05 to about 5S as long as needed. In treating these condition~ the amino substituted steroids (XI) and the ~9(l1)steroids (VI) can be used with other steroidal agents.
In promoting burn healing and wound healing the amino substituted steroid~ (XI) and the ~9t11)steroids (VI) are given orally or IV in a dose Or about 0.05 to about tOO mg/kg/day admini~tered one to four times daily orally and IV. Typical treatment ~lould be an initial Il~
loading dose of 0.01 to 1 mg/kg followed by oral dosing for a few days.
The amlno substituted steroids (XI) and the ~9(~ teroids (VI) are useful ln the preventlon and treatment of stress ulcers and of gastri¢ intoleranoe oaused by drugs such as nonsteroldal anti-inflammatory oompounds (NOSAC). Stress ulcers are ulcers that develop after exposure to severe condltions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. Patients in intensive care units are particularly prone to develop stress ulcers.
Stress ulcers also lnclude leslons that can lead to upper gastrointestinal bleedlng such bleeding is likely to be pre~ented or stopped by thess compounds. NOSAC includes drugs such as ibuprofen, aspirin, indomethacin, naproxen, piroxicam lnd the like that are usually taken for analgesia, and that are often associated with gastrointestinal intolerance characterized by pain and lesions that may lead to bleeding. The amlno substituted steroids (XI) and the ~9(1~)-steroid~ (lII) will be administered preferentially by the oral route either as tablets, capsules or llquids, in doses ranglng rrom 5 to 500 mg, two to four times a day. The treatment would be elther preventive, i.e., starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ul¢ers have 1 3 ~i ! 7 ~ 7 - 29- 4236.1.2 formed. In patlents wno3e cllnical condltlon precludes swallowlng the oral do~age ~orms, the amlno substltuted sterolds (XI) and the Q9(11)-sterolds (VI) would be glven slther thru a nasogastric tube, or parenterally, ~.e., IV or IM. The parenteral doses would range from about 1 to about 100 mg and be admlnistered one to four times a day or by IV.
In dogY, the amlno substituted ~teroids (XI) and the ~9(11)_ steroids (VI) are u~eful in Sreatlng head and spinal trauma, intervertebral diseases (sllpped dlsk), traumatic shock, flea bite and other allergies.
1~In horses, the amino substituted steroid~ (XI) and the Q9(1 1)-steroids (YI) are useful in treating endotoxic or ~eptic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (lamlnltis).
In cattle, the amino sub3tituted steroids (XI) and the ~9(11)_ 15steroids (YI) are useful in treating acute coliform ma~titi~, bovine mastitis and acute allergic reaction to feed lot vaccination.
In pigs, the amino substituted steroidq (XI) and the Q9(~
~terolds (VI) are useful in treating porcine ~tres~ syndrome and thermal ~tress syndrome.
20The term treatment or treating as used in this patent i9 u~ed broadly and includes both treatment Or an existing condition as well a~
pr~venting the same condition rrom occurring where such i~ posslble as is well known to those ~killed ln the art. For example, the amino substituted steroids (XI) and the Q9(11)steroids (VI) can be u~ed to 25treat existing asthma conditions and to prevent ruture ones from occurring. For example, the amino substituted steroids (XI) and the ~9(11)steroid~ (VI) treat spinal trauma and prevent re~ection of skin grarts .
The exact ao~age and frequency of adminlstration depends on the 30particular amino ~ubstituted steroids (XI) and the Q9(11)steroid~ (VI) used, the particular condition being treated, the severity Or the condition being treated, the age, weight, general phy~ical ¢ondition Or the particular patient, other medication the individual may be taking a~ i~ well known to those ~killed in the art and can be more accurately 35determlned by measuring the blood level or concentratlon of the amino ~teroid (I), aromatic ~teroid (II~, Ql~-steroid (III), reducsd A-rlng 1 3 7 C7 _30_ 4236.1.~

sterold (IV), ~17(20)-~terold (V) and ~9(~ sterold (VI) in the patient'~ blood and/or the patlents response to the particular conditlon belng treated.
DEFINITIONS AND CONVENSIONS
The deflnitions and explanations below are for the terms as used throughout thls entlre document lncluding both the ~pecificatlon and the claims.
I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES
The chemlcal formulas reprRsentlng various compounds or molecular fragments in the specification and claim~ may contain variable substitutents ln addltion to expre~sly derined structural features.
These variable substitutents are identified by a letter or a letter followed by a numerical subscript, for example, "Zl or "Ri" where "i"
is an integer. These varia~le substitutents are either monovalent or bivalent, that is represent a group attached to the formula by one or two chemlcal bonds. For example, a group Z would represent a bivalent variable i~ attached to the formula CH3-C(~z)H. Groups Ri and R~ would represent monovalent varlable substitutents if attached to the formula CH3-C~2-C(Ri)(R~)H2. When chemlcal formula~ are drawn in a linear fashlon, su¢h a~ those above, varlable substitutents contained in parenthese~ are bonded to the atom immediately to the left of the varlable substitutent enclosed ln parenthesis. When two or more consecutivc variable substltutents are enclosed in parenthe~es, each of the con~ecutlve varlable substitutents is bonded to the immedlately precedlng atom to the left which i~ not enclosed in parentheses. Thus, in the ~ormula above, both Ri and R~ are bonded to the precedlng carbon atom. Also. ror any molecule wlth an established system of carbon atom numbering, such as steroids, these carbon atoms are deslgnated as Ci, where "i~ Ls the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally deslgnated by tho~e s~llled ln the art of sterold chemlstry. Likewl9e the term "R6n represents a variable substitutent (either monovalent or blvalent) at the C6 positlon.
Chemical formulas or portlons thereof drawn ln a llnear ~ashlon represent atoms in a linear chain. The 3ymbol n_n ln general represents a bond between two atoms ln the chain, more specirlcally lt represents a carbon-carbon bond. Th w CH3-0-CH2-C(Rl)H-CH3 represents 1 3^S707 -31- 4236.12 a 2-substltuted-1-methoxypropane compound. In a ~lmilar fashion, the symbol n_n represents a double bond, e.~., CH2.C(Ri)-o-CH3, and the symbol n~ repregents a triple bond, e.g., HC-C-CH(Ri)-CH2-CH3.
Carbonyl groups are represented in either one of two ways: -C0- or -C(~0)-, wlth the former being preferred for simplicity.
Chemlcal rorumlas Or cyclic (rlng) compounds or molecular rragments can be represented ln a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear rashion by N~-C(CH3)-C~.CCl-CH.C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N*-(CH2)2-N(C2Hs)-CH2-C*H2.
A cyclic (ring) structure for any campound herein defines an orientation with respect to the plane of the ring for ~ubstituents attached to each carbon atom Or the cyclic compound. In formulas depicting such compounds, a ~ubstituent attached to a carbon atom below the plane Or the ring is identified as being in the alpha (a) configuration and is indicated by a broken, dashed or dotted line attach~ent to the carbon atom, ~.e " by the symbol n_ - _1~ or ll,.,,n, The correspondlng 8ubstltuent attached above the plane Or the rlng i9 identlfied as being ln the beta ~B) conriguration. When a varlable substitutent is bivalent, the valences may be taken together or separately or both in the definition Or the variable. For example, a variable Rl attached to a carbon atom as -C(-Ri)- might be bivalent and be deflned as oxo or keto (thus rormlng a carbonyl group (-C0-) or as two separately attached monovalent varlable 9UbstitUtent9 a-Ri~ and B-Rik. When a bivalent variable, Ri, is defined to consist of two monovalent variable substitutents, the convention used to define the bivalent variable is o~ the form "a~Ri~:B-Rikn or some varlant thereof. In such a case both a-RiJ and B-Rik are attached to the - carbon atam to yleld -C(a-Ri~)(B-ik)-. For exa~ple, when the blvalent variable ~6, -C(-R6)-is defined to consist Or two monovalent variable substitutents, two monovalent variable ~Ub9titutents are a-R61:B-R62, .... a~R6g:B-R610~ etc, yieldlng -C~a~R61)(B-R62)~ -- -C(a-R69)(B-R610)-~ etc. Likewise, for the blvalent variable R11, -C(-R11)-, two monovalent variable substitutents are a~R111:B-R112. For a ring substituent for which separate a and B orientations do not exl~t (e.z.

`~`` 1 3`~`707 ``

due to the presence Or a carbon carbon double bond ln the ring), and for a suOstitutent bonded to a carbon atom which i~ not part of a ring the above convention is still used, but the ~ and B designations are omitted.
Just as a bivalent variable may be defined as two ~eparate monovalent variable substitutents, two separate monoYalent variable substitutents may be derined to be taken together to form a bivalent variable. For example, in the formula -cl(Ri)H-c2(R~)H- (Cl and C2 define arbitrarily a rirst and second carbon atom, respectively) Ri and R; may be defined to be taken together to form (1) a second bond between C1 and C2 or (2) a bivalent group ~uch a~ oxa ~-0-) and the for~ula thereby describes an epoxide. When Ri and R~ are taken together to form a more complex entity, ~uch as the group -X-Y-, then the orientation of the entity is such that Cl in the above formula is bonded to X and C2 is bonded to Y. ~hus, by convention the designation ",.. Ri and RJ are taken together to form -C~2-CH2-0-C0- ..." means a lactone in which the carbonyl is bonded to C2. However, when designated ".., R~ and Ri are taken together to form -CH2-CH2-0-C0- the conrention means a lactone in which the carbonyl is bonded to C1, The carbon atom content of rariable sub~titutents is indicated in one Or two ways. The flrst method uses a prefix to the entire name of the variable such as "C1-C4", where both "1 n and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated rrom the variable by a space. For example, "Cl-C4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including iso~eric form~ thereof unless an expre~s indication to the contrary i~ given). Whenever this single prefix is given, the prefix ind$cates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3-(C~2)n-0-CO-where n is zero, one or 2. By the second method the carbon atom content of only each portion Or the definition is indicated separatély by enclosing the "Ci-C~" designation in parentheses and placing it immediately (no intervening space) before the portion of the definltion being defined. By this optional convention (C1-C3)alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the ~C1-C3~rerers only to the carbon atom ¢ontent of the alkoxy 8roup. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)alkoxy(C1-C3)alky1 de~ine alkoxyalkyl 1 3C~J707 33~ 4236.1.2 groups containing from 2 to 6 carbon atoms, the t~o definitlons dlffer s1nce the ~ormer deflnitlon allows elther the alkoxy or alkyl portion alone to contaln 4 or 5 carbon atoms whlle the latter definltion limits either of these groups to 3 carbon atoms.
When the clalms contaln a (cyclic) substitutent, at the end Or the phrase naming/designating that particular substitutent will be a notation in ~brackets] or in (parentheses) whlch will correspond to the same name/designation in one of the CHARTS which ~ill also set forth the chemlcal structural formula of that particular substitutent.
II. DEFINITIONS
All temperatures are in degree~ Centigrade.
TLC refers to thin-layer chromatography.
THF rerers to tetrahydrofuran.
DMF refers to dimethylformamide.
DMA refers to dimethylacetamide.
D8U rerers to 1,5-diazabicyclo[5.4.0]undec-5-ene.
DBN rerers to 1,5-diazabicyclot3.4.0~non-5-ene.
DCC refers to dlcyclohexylcarbodlimide.
DDQ refers to 2,3~dichloro^5,6-dicyano-1-4-benzoqulnone.
HOBT refers to 1-hydroxyben20triazole.
DMSO re~ers to dlmethrlsulroxide.
Saline refer~ to an aqueous saturated sodium chloride solution.
Physiological (normal) saline rerers to O.9S aqueous sodlum chloride solution.
W refers to ultraviolet spectroscopy.
IR rerers to lnrrared spsctroscopy.
NMR re ers to nuclear (proton) magnetic resonance spectroscopy, chemlcal shifts are reported ln ppm (~) downfield from tetramethylsilane.
3~ MS re~ers to mass spectrometry expressed as m/e or mass/change unit. ~M + H]+ rerers to the positlve ion Or a parent plus a hydrogen atom.
dec rerers to decomposition.
Amlno substltuted steroids (XI) refer to the amino steroids (Ia and Ib), aromatic steroids (II), ~16-steroids ~IIIa and IIIb), reduced A-rlng steroids (IV) and ~17(20)-sterolds (Va and Vb) and pharmaceutically acceptable salts thereo~ and hydrates thereof.
; :

.

1 3 ~ 7 r~ 7 -34- 4236.1.2 The ~terolds of the Examples were chromatographed on 40-60 mlcron sllica gel by flash chromatoBraphy.
The hplc ~ystem used ln the Examples 19 a paired ion, gradient, C-l 8 system. Solvent A is t-butylammonium phosphate (1 g) in buffer (pH 3, 900 ml) and acetonitrile (100 ml). Solvent B ls t-butylammonium phosphate (1 g) ln acetonitrile (1000 ml). The flow 1~ 1.5 ml/min.
The gradient is 90% Or A to 80S of B over 25 min. Detection is by UV
light at 254 nm.
Fumaric acid refers to (E)-2-butanedioic acid.
Ether refers to diethyl ether.
Alcohol refer~ to ethyl alcohol.
Allyl refers to 2-propen-1-yl.
ARDS refers to acute/adult resplratory di3tre~ syndrome.
IY refers to intravenous, including injection, infuslon and continuou~ drlp.
IM refers to intramuscular .
IA re~ers to lntra-arterial.
Pharmaceutically acceptable refer~ to those propertie~ and/or substances which are acceptable to the patient from a pharmacologlcal/-toxlcologi¢al polnt of view lncluding bioavallability and patient acceptance or to the manufacturing chemist from a physlcal-chemical polnt Or vlew regardlng composltlon, formulation, stablllty and isolat-ability.
When sol vent pairs are used, the ratios of ~olvents used are volume/qolume (v/v).
~ lndlcates that there are 2 possible orlentations for the attached group, (1) a or 3 when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond.
Aqueous workup (organic ~olvent, drylng agent) refer~ to quenching the reaction mixture with water, dilution with the indicated organic ~olvent, 3eparation of the organic layer, extraction of the aqueous layer qeveral times with the organic ~olvent, drying the combined organic layers with the indicated drying agent and removal of the organic ~olvent using a rotary evaporator under reduced pressure.
Basic workup (organic ~olvent, aqueou3 ba3e, drying agent) re~ers to a workup procedure ~imilar to aqueous workup, except the indicated aqueous base is used in~tead of water.

1 3"`"`'07 -35- 4236.1.2 Acidlc workup torganlc ~olvent, organlc solvent, drylng agent) rerers to dilution of the reaction mixture with the first indicated organic solvent, extraction of the organic mixture several times with hydrochloric acid (1 N), basification Or the combined acidic layer3 with solid ~odlum or potassium hydroxide, extraction of the basic mixture with the second indicated organic solvent several times, drying the organic phases with the indicated drying agent and removal of the solvent with a rotary evaporator under reduced pre3sure.
~NNNNNN-NN N] rerers to Chemical Abstract3 Service (CAS, Columbus, Ohio) registry numbers where each N is an integer from O thru 9, but deleting leading zeros Ln the 6-digit portion Or the number. Regi~try numbers are ass$gned to a particular chemical compound by CAS only when there is ~ufricient proof according to CAS criteria that the compound has been found to exist and it has been characterized in some way.
Compounds published from approximately 1967 to the present are regis-tered publicly and the registry number is the key to ~indin8 references ln the CAS data base rOr such a regl~tered compound. The CAS database 19 publicly available ~rom several database vendors such as STN
International, System Development Corporation tSDC) Orbit Search Servlce, Lockheed Dialog, Bibliographic Retrieval Systems, Questel, etc. CAS rsgistry numbers are included in the EXAMPLES rOr some of the compounds whLch have been reg$stered.
Aldrich item rerers to an ltem listed for sale by Aldrich Chemical Co., P.O. Box 35~, Milwaukee, Wisconsin, 53201, USA in their 1984-1985 catalog.
EXAMPLES
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to it~ fulle8t extent. The following detailed examples describe how to prepare the various compounds and/or perform the various proces3es of the invention and are to be construed as merely illu~trative, and not limitations Or the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognlze appropriate variations from the procedures both as to reactants and as to reaction condltions and technlques.
PREPARATION A-1 Methyl[2-(methyl-2-pyridinylamino)ethyl]amine A mixture of N,N'-dimethylethylene-diamine (25 g) and 2-chloropyr-- 1 3 ~ ~. 7 ~i7 `--36- 4236.1.2 idine (1.3 g) 19 warmed at 85 wlth ~tirrlng ror 18 h. The excess dlmethylethylenediamlne ls removed by dlstlllatlon at reduced pre~sure. The dl~tlllation resldue 1~ dl~tr1buted between ethyl acetate (150 ml) and water (100 ml). The organlc phase is separated, dr~ed over sodlum sulfate and the organic solvent removed under reduced pressure to glve the tltle compound.
PREPARATION A-2 2-Carboxy-l-piperidine [S35-75-1], ~ee Aldrlch, ltem P4,585-0.
PREPARATION A-3 4~-(2-Furonylcarbonyl)plperazine, See Example 6B.
PREPARATION A~6 4-(2-Pyrldlnyl)plperazlne [34803-66-2], see French Patent 7253 M.
PREPARATION A-7 4-~2-Pyrldlnylmethyl)piperazine [55579-01-6], ~ee British Patent appllcation 2,084,575 A, published PREPARATION A-8 4-(6-Methoxy-2-pyridinyl)p$perazlne t510~7-54-2~, ses Canadian Patent 979,894.
PREPARATION A-9 4-~(3-Hydroxy-2-pyrldinyl)methyl]piperazine A mixture Or t-butyloxycarbonylpiperazine (2.3 g), 3-hydroxypyrld-lne ~o.g8 g)~ formaldehyde (37%, 2.0 ml) and absolute ethanol (25 ml) are heated at 780 for 44 hr. The ethanol is removed under reduced pre3sure and the residue distributed betweeen chloroform (150 ml) and sodium carbonate (0.1 N, 100 ml). The aqueous phase is extracted with chloroform (100 ml). The organic phases are combined and washed with saline, dried over sodium sulfate and concentrated to a solld. The solid is dissolved in chloroform and chromatographed on a flash column u~ing silica gel (150 g) eluting with ethyl acetate/methanol/ammonium hydroxide (9.9/0.8/0.2). The appropiate fraction~ are pooled and concentrated to gi~e 4-[(3-hydroxy-2-pyridinyl)methyl]-1-piperazine-carboxylic acid t-butyloxy ester. This material is dissolved in methylene chloride (10 ml), cooled to 0 in an ice/water bath.
Trifluoroacetic acid (10 ml) is added over 3 min. The mixture is stirred at 0 for 30 mln and then allowed to warm to 20-25 for 1 hr.
The solvents are removed under reduced pressureand the residue ls distrlbuted between chloroform (100 ml) and saturated sodium bicarbon-ate (100 ml). The aqueou~ phase is extracted (~x) wilth chloroform (75 ml). The organic phases are combined, dried over sodium sulfate and concentrated to an oil. The aqueous bicarbonate phase is extracted ith ethyl acetate ror 48 hr. The ethyl acetate 1~ re=oved under . 1 3 `~707 ; ~ 1 .

-37- 4236.1.2 reduced pressure to leaYe an oll. Theqe oilq are comblned to glve the title compound.
., PREPARATION A-10 4-[6-(1-Pyrrolldinyl)-2-pyridinyl]piperazine A ~olutlon Or 2,6-dichloropyrldlne (10 g) and piperazine (25 g) in pyrldlne (30 ml) i~ stlrred at 65 for 3 h and at 20-25 overnight.
The reaction mlxture 19 concentrated, the resldue 19 partitloned between ether and aqueous pota~ium carbonate. The organic phase i~
separated, washed with saline, drled over sodium sulfate and concen-trated. The residue iq added to pyrrolldine (15 g), pyridine (100 ml) and heated at 100 for 6 days. The reaction mixture i~ concentrated.
The re~idue is partitioned between methylene chloride and ~queous sodium bicarbonate. The organic phase is separated, dried and concen-trated. The residue i~ chromatographed on silica gel, eluting with methanol/ammonium hydroxide/methylene chloride (15/1/84). The appro-priate fraction~ are pooled and concentrated to give the title com-pound.
PPEPARATION A-11 4-[3-Amino-6-(diethylamino)-2-pyridinyl]piperazine Dlethylamine ~3.29 ml) i~ added dropwise o~er l hr to a mlxture of 2,6-dichloro-3-nltropyridlne (6.13 g), acetonitrile (100 ml) and 2~ potassium carbonate (5.2 g) precooled to 0. The resulting mixture is allowed to slowly warm to 20-25 and is stlrred for 16 hr. The mixture is filtered, the ~iltrate combined with piperazine (12.2 g) and potassium carbonate (6.0 g). The re~ulting mixture is heated at reflux for 24 hr and allowed to cool to 20-25. Aqueous workup (methylene chloride, water wa~h of organic layerq and potasslum carbonate) and purification by rlash chromatography over silica gel eluting with methylene chloride/methanol (20/1 to 5/1), pooling and concentration of the approprlate fraction~ giYes 6-N,N-diethylamino-3-nitro-2-(1-piperazinyl)piperidine.
A mixture of 6-N,N-diethylamino-3-nitro-2-(1-piperazinyl)piperid-ine (21.8 g), ethanol (275 ml), hydrochloric acid (1.2 N, 27 ml) and palladium on charcoal (10S, 5.25 g) is exposed to hydrogen at 50 psi in a Parr fla~k. After 16 h the resldue is riltered through celite*
concentrated and partitioned between chloroform and 5% sodium hydrox-ide. The organic phase is separated, drled o~er potasslum carbonate, concentrated and the res$due pa~sed through a plug of silica gel r. eluting with chloroform/methanol/ammonium hydroxlde (4/1/0.25). The * trade mark 1 31'`r'`707 . _, I
-38- 4236.1.2 approprlate fraction~ are pooled and concentrated to give the title compound, IR (nu~ol) 3309, 2967, 2828, 1581, 1474, 1451, 1258 and 803 cm~1; NMR (CDC13) 1.05, 2.9-3.1, 3.2, 3~2-3.4, 6.25 and 6.94 ~; MS
(electron lmpact) 2.49, 2.20, 207, 193, 177 and 163.
PREPARATION A-13 4-[6-(Dlethylamlno)-3-(dimethylamino)-2-pyridinyl]-plperazlne Sodium cyanoborohydrlde (0.5 g) ls added to a mlxture of 3-amlno-6-N,N-diethylamino-2-((4-t-butylcarbamate)plperazln-1-yl)plperidlne (1.1 g), formalyn (37%, 11 ml) and acetonltrile (33 ml). The mixture 0 i9 stirred for 24 h at 20-25, basic workup (chloroform, sodium carbonate, sodium sulrate) and fla~h chromatography over slllca gel elutlng with hexane ethyl acetate (4~1) provides the protected form of the title compound. The protected amine (967 ml), ethyl acetate (20 ml) and hydrochloric acid (3.0 N, 50 ml) is stirred rOr 3 h at 20-25~.
~aRic workup (chloroform, 10~ sodium hydroxide, Rodium carbonaSe) glves the title compound, IR (nu~ol~ 3289, 2935, 2820, 1589, 1566, 1479, 1445, 1429, 1373, 1263, 1236 and 940 cm~1; NMR (CDCl3) 2.9-3.1, 3.3-3.5, 3.51, 6.06 and 7.10 ~.
PREPARATION A-14 4-~4,6-Bls(2~propenylamino)-1,3,5-trlazln-2-yl]-plperazine A 30lution Or 2-chloro-4,6-bis(2-propenylamino)-1,3,5-triazine (10.44 g) and 15.95 g Or piperazine in 150 ml Or DMF is heated under reflux for about 18 hour~. The reaction mixture is cooled and stored at 5 and crystals are depo~ited. The soluble fraction ls concentrated and the residue is extracted with ethyl acetate. The extracts are washed with aqueous potassium carbonate, 50S saline and saline and dried over magnesium sulrate and concentrated to give a gum. Chromato-graphy on silica gel (400 g) and elution (200 ml fractions) wlth 20S
acetone-methylene chloride gives the formamlde. The formamlde (9.2 g) ln 200 ml Or methanol ls heated to reflux, then cooled under nitrogen and mixed with 4 ml Or 45% potasRlum hydroxide solution. The mixture is heated under reflux for about 20 hours, then cooled and concen-trated. The resldue i~ partitloned between ethyl acetate and water.
The organlc extracts are washed with water and saline, drled over magneslum sulfate and concentrated to glYe a gum. Crystalllzatlon from 50 ml of carbon tetrachloride glves the title compound, mp 93-94.5.
PREPARATION A-15 4-t2~6-Bis(diethylamlno)-4-pyrimidinyl~piperazlne * trade ~ark `` 13r,`~,,707 ! 39 4236.1.2 See Example 0.
P~EPARATION A-16 4-[6-Amino-4-(diethylamino)-2-pyrimidinylpiperazine Dry plperazine (3.59 g) and 2~amino-4-diethylamino-6-chloro-pyrimidine (1.55 g) are heated at 100 in ethylene glycol (20 ml) for 4 h. The mlxture is partitioned between methylene chloride and aqueous 30dlum bicarbonate. The phases are ~eparated, the organic phaae is dried with sodium sulrate and concentrated. The re~iidue is chromato-graphed on silica gel eluting with ethyl acetate to 1% methanol/ethyl acetate to 20% methanolJlS ammonia/ethyl acetate. The approprlate rractions are pooled and concentrated to give the title compound.
PREPARATION A-17 4~2,6-Bi~(dimethylamino)-4-pyrimidinyl]piperazine A mixture of dimethylamlne (16.6 g, 25S in water), triethylamine (20 g) and 1,3,5-trichloropyrimidine (8.3 g) in ethanol (100 ml) i~
stirred at 20-25 rOr 2 h. The mixture 19 stored at 0 overnight.
Additional dimethylamine solution (2 g) i~i added and the reaction is-stirred at 20-25 rOr 2 h. The mixture is partitioned between methyl-ene chloride and aqueous sodium bicarbonate. The organic phaae is dried over ~odlum sulrate and concentrated. The residue 18 chromato-graphed over slllca gel elutlng wlth 10~ ethyl acetate/hexane to give pure 2,4-bi~dimethylamlno]-6-¢hloropyrlmidine. This bis-adduct la heated wlth plperazine (2.6 g) in ethanol (100 ml) for 1 h. The mlxture is partitloned between methylene chloride and aqueQus sodium bicarbonate. The phases are separated, the organic phase ls dried o~er sodium sulrate and concentrated. The residue i9 crystallized rrom ether and hexane to gi~e the title compound.
PREPARATION A-18 4-~2-(Diethylamino)-6-(1-pyrrolldinyl)-4-pyrlmidl-nyl]piperazine A olution Or 2-diethylamino-4-piperazino-6-chloropyrimidlne (4.10 g) ln pyrrolidine (4.10 g) i~ heated at 100 rOr 12 h. The mlxture 18 concentrated and the resiidue is partitioned between aqueous sodium bicarbonate and methylene chloride. The phasies are ~eparated and She organic pha~e is dried and concentrated to gi~e the title compo~nd.
PREPARATION A-l9 4-C2,6-Bia(4-methYl-l-piperazLnyl)-4-pyrimidinyl]-piperazine Trichloropyrimidine is added ln portions to an ice cool solution o~ N-methylpiperazine (40 g) in ethanol (200 ml). The mixture is then heated at 60 ~or 2 h. The mixture is concentrated and chromatographed .

i 1 3r~71~7 ~40' 4236.1.
on silica gel with 2-5S methanol and methylene chlorlde to give 2,4-bis-t4-methylpiperazino]-6-chloropyrimidine. Thi9 materlal is heated at 130 in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 h. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organlc phase is drled over sodium sulfate and concentrated to give the title compound.
PREPARATION A-20 4-[2-(Diethylamino)-6-(4-methyl l-piperazinyl)-4-pyrimidinyl]piperazine 2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at rerlux for 2 hr. The mixture i~ concentrated and the product isolated by silica gel chromat-ography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-plperazino-6-chloropyrimidine (8 g) and N-methylpiper-azine (8 g) is heated neat at 70 for ~6 hr. Then water (2.5 ml) i~
added and the mixture is heated at 100 rOr 50 hr. The mixture i9 chromatographed on silica gel, the appropriate ~ractions are pooled and concentrated to give the title compound.
PREPARATION A-21 4-t2-(Diethylamlno)-6-(1-piperidlnyl)-4-pyrimidln-yl~piperazlne A solutlon Or 2-dlethylamlno-4,6-dichloropyrimidine (4 g) in piperidine (6 g) is heated at 80 for 20 min. The mixture is stirred at 20-25 rOr 15 h and then partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated, the organic phase is dried over sodium sulrate and concentrated. The residue and plperazine (8 g) are rerluxed in pyridine (100 ml) ~or 6 h. The reactlon i9 partitioned between methylene chloride and aqueous potas-~ium carbonate. The organic phase is dried over sodlum sul~ate, concentrated to a re~idue which is chromatographed on silica gel elutlng with methylene chloride to 6S methanol/1S ammonium hydroxide/-methylene chloride. The appropriate rractiOns are pooled and concen-trated to give the title compound.
PREPARATION A-22 4-t2,6-Bi9(1-pYrrolidinyl)-4-pyrimidinyl]piperazine ~; A solution Or pyrrolidine (80 g) in THF (500 ml) is chilled in an ice wa~er bath and stlrred mechanically under nitrogen. With a syringe pump Or 2,4,6-trichIoropyrimidine (50 g) is added over 35 minutes. The reaction l~ stirred in the ice bath for 1 hour and is then warmed to 20-25 over 4 h. Pyridine (100 ml) is added to the reaction and the 1 3r"707 -41- 4236.1.2 mixture stlrred at 20-25 overnlght. The reactlon is concentrated.
The residue i3 partltioned bet~een methylene chloride and aqueou~
sodium bicarbonate. The organlc phase i9 concentrated and the residue chromatographed on 3111ca gel (10% ethyl acetate/hexane) to yield 51 g Or crystalline 2,4-bis~pyrrolldino]-6-chloropyrlmldlne. Immedlately arter the lnitial addltlon o~ reagents, t~o spots are seen ~lth 25S
ethyl acetate on a silica gel plate. These are the 2 and the 4-adducts. The bls product rorm~ over tlme. It move~ between these flr~t two spot~. The 51 g Or product i3 reacted wlth plperazlne (40 g) ln 100 ml o~ dry pyridine at 100 rOr 50 h. The reaction i~ concen-~rated. The re~idue is partltioned between methylene chlorlde and 30dlum bicarbonate solution. The organic phase i9 dried and concentrated. The resldue 1~ chromatographed on ~ilica gel eluting with methylene chlorlde to 10S methanol/l~ ammonla~methylene chloride to g$ve the title compound.
PREPARATION A-23 4-~2,6-Bis(morpholino)-4-pyrimidinyl]piperazine A solution Or 160 g of morpholine in 1000 ml Or methylene chloride is treated dropwlse wlth 100 g Or 2,4,6-trlchloropyrimidlne. The reactlon 19 immersed ln an i¢e water bath. Arter 1 h, 300 ml of pyrldine i8 added. The reaction is stirred rOr two days and concen~
trated. The re3idue is partltloned between methylene chloride and aqueous ~odlum bicarbonate. The resldue i9 chromatographed on silica gel (10S ethyl acetate/hexane to 25S to methylene chloride) to give 2,4-t~is-morpholino]-6-chloropyr'midine. A solution Or 40 g Or 2,4-~bl~-m~rpholino~ 6-chloropyrimidine and 34 g Or piperazlne ln 60 g Or pyridine 1~ heated at 100 ~or 24 h. The mixture is partltioned between methylene chloride and aqueou~ potassium carbonate. Tbe organic phase i9 filtered through ~odium ~ul~ate and concentrated. The residue i~ chromatographed (methylene chloride to 4S methanol/1S
ammonium hydroxide/methylene chlorlde) to glve the title compound.
PREPARATION A-24 4-~2,6-8is(allylamlno)-4-pyrlmidinyl]piperazlne Following the general procedure for PREPARATION A-22, and making non-critical Yariation but ~ubstltuting allylamine ror pyrrolldlne the title compound 19 obtalned.
PREPARATION A-25 4-(2-Pyrimldinyl)piperazine ~20980-22-7], see US
Patent 4,409,223.
PREPARATION A-26 4-~4,6-Bis(diethylamino)-2-pyrimidinyl~piperazine "- 1 3"~7~7 -_ -42- 4236.1.2 Dlethylamine (80 g) 19 reacted ~lth trlchloropyr~mldine t50 g) in THF. The reactlon a~ter chromatography yields a mixture of the mono-and dl-adduct. This materlal is dissolved in pyridine (58 g) and reacted with diethylamine (35 g) at 50 for 3 h. The reactlon is concentrated to a resldue. The residue ls partltloned between methyl-ene chlorlde and aqueous sod~um blcarbonate. The organic phase i~
separated and concentrated. The resldue 1~ chromatographed on slllca gel, eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to glYe 2,4-bis[diethylamlno]-6-chloropyrimidine. This material i~ dissol~ed in pyridine (100 g) and reacted with piperazine (40 g) at 100 for 50 h. Following the above workup procedure the title compound is obtained.
PREPARATION A-27 4-(3,6-Dimethylpyrazinyl)piperazlne [59215-42-8], ~ee Canadlan Patent 979,894.
PREPARATION A-28 4-(t5-Methyl)-4-phenyl~4H-1,2,4-trlazol-3-yl)plper-azlne A mixture Or 3~bromo-5-methyl-4-phenyl-4H-1,2,4-trlazole (4.16 g), 15.07 g Or piperazlne and 20 ml Or pyrldine is stlrred at 100 under nltrogen for 22 h. The reaction $9 monitored by TLC ~8% methanol/meth-ylene chlorlde) and after this period of tlme no change occurrs. The mixture is subsequently placed in a Parr bomb and heated in an oil bath at 180 for 24 h. Bomb pressure increases by 40 psi. The mixture is worked up by partitioning between chloroform and water. The organic phase 18 washed with saturated aqueous ~odlum bicarbonate (2 x) and with sallne (2 x), dried over sodium sulrate and concentrated to a solid, the product is recrystallized in ethyl acetate. MS [M ~ H]' 243.1484 PREPARATION A-29 4-Benzo(b)thien-2 yl)piperazine 2-Chlorobenzothiazole (5 g) is heated in ethanol (75 ml) with piperazine (3.05 g) for 20 h. The mixture is partitioned between methylene chloride/ether and aqueous sodium bicarbonate. The organic phase is separated, dried with sodium sulfate and concentrated to giYe the title compound.
PREPARATION A-30 4-(2-Methoxyphenyl)piperazine ~35386-24-4], see Aldrich item M2,260-1.
PREPARATION A-31 4-(4~Methoxyphenyl)piperazine [70849-64-8], see Aldrich item M2,300-4.

... ... . . . . . . . . .

` 1 3 ~ ~ 7 C 7 `

-43- 4236.1.2 PREPARATION A~32 4-[(3,4-Dlmethoxyphenyl)methyl]piperazlne See French Patent 7031 M.
PREPARATION A-33 4-(4-Fluorophenyl)plperazine [2252-63-3], see Aldrlch ltem 19,133-7.
PREPARATION A-34 4~[2-Amino-5-(1-pyrrolldinyl)phenyl]plperazine Pyrrolidlne (2.0 ml) 19 added to a mixture of 2,4-dichloronitro-benzene (4.50 g), acetonltrlle (25 ml~ and potassium carbonate 4.90 g). After ~tlrrlng for 48 hr at 20-25 ba~lc workup gi~e3 1-nitro-2-piperazlnyl-4-pyrrolldlnylbenzene.
A mixture Or 1-nitro-2-plperazlnyl-4-pyrrol~dlnylbenzene (4.57 g), ethanol (110 ml), hydrochlorlc acld (1.2 N, 6 ml) and palladium on carbon (10S, 1 g) l~ exposed to hydrogen 51 p~i at 20-25 in a Parr flask. After 16 h (49 psi total uptake) the mixture i9 r~ltered.
Basic workup (chloroform, potassium carbonate) and column chromato-graphy sllica gel (50 g) eluting wlth chloroform/methanol (4/1) gl~e~
the title compound as an oil, IR (nu~ol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm~1; NMR (CDCl3) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 6; MS
(electron lmpact~ 246, 204 and 189.
PREPARATION A-35 4-[~4-(dimethylamlno)phenyl]methyl]piperazlne See US Patent 4,421,753.
PREPARATION A~36 4-Hydroxy-4-[4-(trl~luoromethyl)phenyl]plperazine [39157~71-6], see US Patent 3,936,464.
PREPARATION A-37 (2-Dlethylamlnoethyl)amine ~111-74-0], ~ee Aldrich item 12,694-2.
PREPARATION A-38 [2-(3,4-Dimethoxyphenyl)ethyl]amine [120-20-7], siee Aldrich item D13,620-4.
PREPARATION A~39 t2-(2,4-Dimethoxyphenyl)-1-methylethyl]amine See J. Pharm. Sci. 60, 1232 (1971).
PREPARATION A-40 [2-(3,4-Dimethoxyphenyl)ethyl]~3,4,5-trimethoxy-phenyl)-methyl]amine A mixture of 3,4-dlmethoxyphenylamine (2.87 g), 3,4,5-trimethoxy-benzaldehyde (3.15 g), benzene (100 ml) and p-TSA (276 ml) is heated at reflux in a Dean Stark apparatusi. Arter 16 hours, the mixture i~
allowed to oool to 20-25. aa~ic workup (methylene chloride, sodium bicarbonate, magne~ium sulfate) gi~es an ~m~ne. Sodium borohydr~de (1.2 g) is added in ~everal portlon~ over 2 hour3 to the ~mlne ln methanol (65 ml) and hydrochloric a¢id (1.2 N, 7.4 ml). After 3 hour~, * trade mark .. , i 1 3f~"7n7 -44- 4236.1.2 acldic workup (ether, chloroform, sodlum carbonate) gives the title compound as an o1l~ IR (nu~ol) 2939, 1591, 1516, 1463, 1420, 1236 and 1128 cm~1; NMR (CDC13) 2.7-3.0, 3.7 4.0 and 6.5-6.9 ~; MS (chemical lonizatlon) tM ~ H]+ 360, 199, 182, 181.
PREPARATION A-41 [2-(3,4~Dimethoxyphenyl)ethyl]~[4-(dimethylamino) phenyl]methyl]amine [13159-97-2], see Chem. Abst. 65:7001f.
PREPARATION A-42 [(3,4-Dihydroxyphenyl)methyl]t2 (3,4-dimethoxy-phenyl~-ethyl]amlne A mixture of 3,4-dihydroxybenzaldehyde (1.25 g) t-butyldimethyl-silyl chloride (3.5 g), dlmethylformamide (10 ml) and imidazole (1.54 g) is st~rred for 18 h at 20~25. The mixture is diluted with ether and wa~hed successively uith dilute hydrochloric acid and dilute sodium bicarbonate. The organic phase 1g separated and drled over magnesium sulrate and concentrated to giYe an oil homogeneous by TLC. The oil (3.3 g), 3,4-dlmethoxyethylamlne (1.77 g) toluene (50 ml) and p-TSA
(150 ml) i~ heated at re n ux ln a Dean Stark apparatus rOr 24 h.
Afterwards the solution is permltted to cool to 20-25, methanol (35 ml), hydrochloric acld (1.2 N, 4.2 ml) and sodium borohydride (1 g) are added. After 2 h the mixture is concentrated, basic workup (chloro~
rorm, aod$um carbonate, sodium ~ulrate) gives a compound which is puriried by ~lash chromatography over silica gel diluting with chloro-rorm/methanol (30J1). The appropriate rractions are pooled and concentrated to give the title compound as an oil, IR (nu~ol) 2931, 2858, 1511, 1297, 1259, 909, 840 and 782 cm~1; NMR (CDCl3) 0.19, 0.99, 2.7-2.9, 3.68, 3.87, and 6.6-6.9 ~; MS (chemical ionization) [M ~ H]~
532, 386, 351.
PREPARATION A~43 (2-Pyridinyl)methyl [3731-51-9], see Aldrich item A6,520-4.
PREPARATION A-44 4-[2-[4-[2,6-dl-(1-Pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]ethyl]piperazine Several batches Or di-t-butyl dicarbonate (17.7 g) is added to a stirred mixture of 2-hydroxyethylpiperazine (10.6 g) in ether (300 ml). The mlxture is stlrred at 20-25 ~or 1.5 hr and then washed with sodium hydroxide (5%, 200 ml), 3ailne (200 ml), dried over sodium sulfate, and ~iltered. The organlc solvent 19 removed under reduced ''! pre~sure to glve an oil. The oil i~ rla~hed chromatographsd on silica * trade mark ... . . . . . . . .... ... . ... .. . . . . .

1 3r~ 7~7 -45- 4236.1.2 gel (100 g~, elutlng with ethyl acetate/methanol/ammonium hydroxlde (9.5/0.4/0.1). The appropriate ~ractions are pooled and concentrated ~o give and the N-protected 2-hydroxyethylpiperazine.
The N-protected 2-hydroxyethylpiperazlne (3.0 g), triethylamine (1.42 g) and methylene chlorlde (30 ml) is cooled to 0 in an lce bath under nitrogen. A mixture Or methanesulfonyl chloride (1.64 g) in ln methylene chloride (30 ml) i~ added dropwise over 10 min. The cooling bath is removed and the mlxture allowed to warm to 20-25 for 30 mln.
The mixture i9 then washed wlth water (60 ml), dried over sodium sulfate and the solvent removed to give crude mesylate. 4-[2,6-Di-(l-pyrrolidinyl)-4-pyrimidlnyl]piperazlne (4.23 g), potas~ium carbonate (1.93 g) and acetonitrile (150 ml) are added to the crude me~ylate.
The mlxture i~ heated at reflux for 18 hr. The acetonitrlle i~ removed under reduced pressure and the residue distributed between chloroform S (200 ml) and water (200 ml). The phase~ are separated, the organlc phase is washed with saline, dried over sodium sulrate and the 30lvent removed under reduced pressure to gl~e an oil. The oll i9 rlash chrom-atographed on sllica gel (200 g) with ethyl acetate/methanol/ammonium hydroxlde (9.5/0.4/0.1). The approprlate rractions are pooled and con¢entrated to giYe the N-protected rorm oS the title compound as a solld, mp 148-14~o.
This solLd (0.75 g) in methylene chlorlde (10 ml) is stirred and cooled to 0 in an ice~water bath. Tri n uoroacetlc acid (10 ml) is added dropwise over 5 min. The cooling bath 19 removed and the mixture is ~tirred at 20-25 ~or 1 hr. The organic solvent ls removed under reduced pressure and the resldue is distributed between methylene chloride (50 ml) and sodium hydroxide (10S, 50 ml). The organic phase is separated. and dried over sodium 3ulfate. The ~ol~ent i9 removed to give the title compound.
PREPARATION A-45 4't4,6-Bi~(1-pyrrolidinyl)-1,3,5-triazln-2-yl]-1-piperazine Pyrrolidine (28.5 g) is cooled on an ice bath. 1,3,5-trichloro-triazine (10.4 g) is added with vigorous ~tlrring. After 1-1.5 h the mixture 19 permitted to warm to 20-25. The ~olid is ~l;tered and 3~ rin~ed several times with water and dried under reduced pressure to give the monochloro-bis(1-pyrrolidinyl)triazine.
Thi~ material (23.18 g) in piperazine (31.55 g) at DMF (295 ml) i~

1 3`"" I~7 -46- 4236.1.2 refluxed under nitrogen. ~hen the reaction i~ complete (TLC) the 301~ent is removed under reduced pressure. The mixture is transrerred to a separatory runnel contalning ethyl acetate (100 ml) and pota~sium carbonate (100 ml). ~ne layers are separated, the organic layer ia washed ~lth 3aline (100 ml) and back-washed with ethyl acstate (2 x 100 ml). The organic layers are combined, drled over magne3ium sulrate at room temperature, riltered and concentrated under reduced pressure.
This material is chromatographed on a allica gel column (500 g) eluting with acetone/methylene chloride (5~95). The appropriate rractions (500 ml) are pooled and concentrated to give a solid.
The solid (10.13 g) is refluxed in methanol (200 ml) and cooled under nitrogen. Potassium hydroxide (45% aqueoua, 4 ml) ia added, the mixture degas3ed with nitrogen and heated to re~lux. After 8 h the mixture is cOoled to room temperature and concentrated under reduced preaaure. The solid ia trans~erred to a aeparatory runnel containing ethyl acetate (200 ml) and water (100 ml). The phases are separated, the organic layer i9 washed with water (2 x 100 ml) and 50S brine (100 ml) rollowed by brine (2 x 100 ml). Tne aqueous wa~shes are back-washed with 200 ml of ethyl aceta~e, the organic phases are combined, dried over magnesium sulrate, riltered, concentrated under reduced pressure to glve the title compound.
P~EPARATION A-46 4 ~5,6-Bis(diethylamino)-2-pyridinyl~piperazine Diethylamine (3.29 ml) is added dropwise oYer 1 h to a mixture of 2,6-dichloro-3 nitropyridine (6.13 g), acetonitrile (100 ml) and potassium carbonate (5.2 g) precooled to 0. The mixture is allowed slowly to warm to 20-25 and stirred rOr 16 h. The mixture i3 ~ilter-ed, the ~iltrate combined with piperazine (12.2 g) and potasaium carbonate (6 g). The resulting mixture is heated at re~lux ror 24 h and then permitted to cool to 20-25. Aqueous workup (methylene chloride,- water washed over organic layers, potass1um carbonate) and purirication by flash chromatography (allica gel) eluting with chloro-form/methanol (20:1 25:1) gi~es 2-N,N-diethylamino-3-nitro-6{1-piperazinyl)pyridine.
This material (21.8 g), ethanol (275 ml), hydrochlorlc acid (1.2 N, 27 ml) and 10% palladium on charcoal (5.25 g) is exposed to hydrogen at 50 pounds per square inch ln a Parr flask. Arter 16 h the residue is ~iltered through celite, concentrated and partitioned between trade mark 1 3''`~`7C~

~47~ 4236.1.2 chlorororm and sodlum hydroxide (5S). The organic layers are separat-ed, dried uslng potasslum carbonate, concentrated. The concentrate i9 passed through a plug Or silica gel, eluting wlth chloro~orm/methanol~-ammonium hydroxide (4/1/0.25) to give ~-amino-6-N,N-diethylamlno-2-(1-piperazlnyl)pyridine.
A solutlon Or dl t-butyl dicarbonate (11.3 g) and methylene chloride (25 ml) is added dropwise over 30 min to a mixture of 3-amino-6-N,N-diethylamino-2-(1-piperazinyl)pyridine (13.5 g), triethylamine (8.33 ml) and methylene chloride (400 ml) precooled to 0. The resulting mixture is allowed to ~lowly warm to 20-25. After 16 h using basic workup (methylene chloride, ~odium bicarbonate, potassium carbonate) the t-butyl carbonate as a solid is obtained.
The protected piperazinyl pyridine (4 g) as an aldehyde (12.8 ml), acetonitrile (80 ml) is mixed. Sodium cyanoborohydride (1.73 g) is added to the pyridine mlxture. The resultant solution is stirred ~or 48 h at 20-25. After 24 h additional sodium cyanoborohydride (500 ml) and acid aldehyde (5 ml) is added. 8asic wor~up (chlorororm/potassium carbonate1 potass1um carbonate) and purirlcatlon by rlash chromato-graphy uslng ailica gel and eluting e~th hexane ethyl acetate (5/1) glves an oil. The oil (2.36 g), ethyl acetate (50 ml), and hydro-chloric acid (3.0 N, 37.5 ml) are stirred ror 16 h at 20-25. Basic workup (chlorororm, 10S sodium hydroxlde, potassium carbonate) gi~es the title compound.
PREPARATION A-47 4-t3-(Ethylamino)-2-pyridinyl]piperazlne 2-(1-piperazinyl)-3-nitropyridine ~24.50 g), ethanol (445 ml) and hydrochloric acid (1.2 N, 44 ml) are combined and hydrogenated over night at 40 psi, refilling when necessary. The mixture i~ riltered thru celite, washed with ethanol, chloroform, ethanol and water. The organic solvents a~e removed with heat and reduced pressure. The remaining material is partitioned between methylene chloride (3 x 250 ml) and sodium bicarbonate. The organic layers are combined, drled over potassium carbonate, riltered and concentrated under reduced pressure to gi~e an oil which slo~ly solidified upon standing to give 3 amino-2-(1-plperazinyl)pyridine.
3-Amino-2-(1-piperazinyl)pyridine (19.58 g), methylene ¢hloride 600 ml), triethylamine (17.2 ml) are combined ard cooled to 60. Dl-t-butyl-dlcarbonate (24.34 g) in methylene chlorlde (50 ml) 19 added to 1 ~ n 7 -48- 4236.1.2 the pyridlne mlxture o~er 30 min and permitted to ~tand at 0 rOr 1 hr, then allowed to warm to 20 ~ 25. Arter 30 min, TLC indicates no 3tartlng material remains. The reaction mixture i3 partitioned between ~odium bicarbonate (500 ml) and methylene chloride (3 x 250 ml). The organic pha~es are combined, drled over pota~sium carbonate, flltered and concentrated under reduced pres~ure and heat to give a solid which i9 recrystallized rrom ethyl acetate to give 3-amino-2 t(4-t-bUtYldi carbonate)-1-piperazinyl~piperidine.
3~Amino~2-[(4-t-butyldicarbonate)-1-piperazinyl]piperidi~e ~2.361 g), methanol (23.6 ml) and acetaldehyde (2.1 ml) are combined at 20-25 to rorm a ~olution. Sodium cyanoborhydride (586 mg) i~ added and the mlxture stirred overnight. The organic ~ol~ent i~ removed with reduced pre~sure and heat, the remaining mixture i~ partltioned between sodium bicarbonate (50 ml) and chlorororm (3 x 50 ml). The chloroform extract~ are combined and dried over potaasium carbonate and filtered.
The filtrate i~ concentrated with heat and reduced pre~ure. The concentrate i~ column chromatographed on silica gel 60 (40 63 ~) eluting with hexane/ethyl acetate (2/1) containing triethylamine (1%).
The approprlate rraction~ are pooled and corcentrated to glve 3-ethyl~
amlno-2-t(4~t-butyldlcarbonate)-1-plperazinyl]piperldine.
3~Ethylamino-2-~(4~t-butyldicarbonate)-1-piperazlnyl~piperidine (2.47 g), ethyl acetate (67 ml~ and hydrochloric acid (3 N, 49 ml) are comblned and ~tlrred ~or 2 hr at 20 - 25. TLC indicates no ~tartin8 material. Potas~ium hydroxide t14 g) and water (80 ml) i~ added. The organic layer i8 removed ard extracted wtih chloroform (3 x 60 ml).
The organic layer3 are combined, dried o~er pota~sium carbonate, ~iltered and the riltrate concentrated to give the title compound.
PREPARATION A-48 4-[3-(Diethylamino)-2-pyridinyl]piperazine Following the general procedure of PREPARATION A-47 and making non-critlcal variation~ but reacting the protected ethylamine compound with additional acetaldehyde and again reduclng the tltle compound i~
obtained.
PREPARATION S-1 21-Bromo~17a-hydroxypregna-4,9-diene-3,20-dione See US 4,041,055 (Ex 59).
PREPARATION S-2 21-Bromo-17a-hydroxypregn-4-ene-3,11,20-trlone ~26987-70-2], see J. Chem. So¢. B., 4, 748 (1970).
PREPARATION S~3 11a~17a~2l~Trihydroxypregn-4-ene~3~2o-dione 21 1 3~ 7n7 ~ .. ..
'49- 4236.1.2 tQsylate Tosyl chloride (rre~hly recrystallized, 3.48 g) in pyrldine (10 ml) i9 added drop~ise over 15 min to a solution oS 11a,17,21-tri-hydroxypregn-4-ene-3,20~dione tBritish Patent 1,100,505, 6 g) in pyridine (90 ml) precooled to 0. The resulting mixture is stirred for 1.5 h at 0 and 1 h at 20-25. The mixture is quenched with aqueous sodium blcarbonate and ethyl acetate. Aqueous workup (chlorororm, magneslum sulrate) provides the crude tosylate. Tosylate can be purifled by rlash chromatography on silica gel elutlng with chloroform-/methanol (15/1).
PREPARATION S-4 11a,21~-Dihydroxypregn-4-ene~3,20-dlone ~600~67-9~, see US Patent 4,013,688.
PREPARATION S-5 21-Bromo-17a-hydroxypregn-4-ene-3,20adione ~20380~17-0], see US Patent 4,500,461.
PREPARATION S~6 21-Bromopregn-4-ene:3, 11 ,20~trlone t51297-00-8], 9ee US Patent 3,983,111.
PREPARATION S-7 21-Hydroxypregna-4,9(11),16-triene-3,20-dione ~24510-86-9], see Tetrahedron Lett. 25, 2581 (1984).
PREPARATION S-8 21 Iodopre8na-4,9(11)-diene-3,20-dlone ~95288-91-8~, PREPARATION 5-9 21~Bromopregn-4-ene-3,20-dlone [26987-66-6~, see J. Org. Chem., 50, 81 (1985).
PREPARATION S-10 17B-Carboxy-17~-hydroxyandrost-4-ene-3-one 17~21-Dihydroxypregna-4-ene-3,20-dione (7.41 g) in methanol (150 ml) at 0 19 added over 5 mln to a solutlon Or sodium metaperiodate (6.02 g) ln water (50 ml). The pH i8 ad~usted to about 6.3 uslng dilute aul~urlc acid. The mlxture is stirred at about 45 for 3 h.
The mlxture is then diluted with water (110 ml), stlrred ln an lce bath rOr 30 min and riltered. The solids are washed with lce cold water (200 ml) and air dried. The sollds are dlssolved in acetone (200 ml) and heated on a steam bath for 15 mln and riltered. The filtrate 19 concentrated and dissolved in water (100 ml) containlng sodium hydrox-ide (50%, 1.4 ml, pH greater than 11 ) . The mixture is washed with toluene (2 x 300 ml) and the toluene backwashed with water (100 ml).
The aqueous extract~ are comblned and riltered. The ~iltrate 19 acidified wlth acetlc acid (20%, 10 ml) to form a slurry. The slurry i~ stirred at 20-25 overnight and riltered to obtain the tltle .. . . . . .

`~ 1 3 '' " 7 0 7 -50- 4236.1.2 compound.
PREPARATION S-12 11~,17a-Dihydroxy~21-lodo-6a~methylpregna-1,4-die-ne-3,20-dlone [85847~53-6], see J. Pharm. Soc., 74, 365 (1985).
PREPARATION S-13 21-Bromo-11~,17-dihydroxypregna-1,4-diene-3,20--dlone [55706-94-0], see US Patent 3,856,956.
PREPARATION S 14 17-Hydroxy-21-lodo-16-methylpregna-1,4,9(11)--trlene-3,20-dlone t23776~76-3], ~ee US Patent 3,455,968.
P~EPARATION S-15 17,21-dlhydroxy-6a-methylpregna 1,4,9~11)-trlene--3,20-dlone t93269-35-3]. see West German DE 3,322,120.
PREPARATION S-16 17,21-Dihydroxypregna-1,4,9(11)-triene-3,20-dione 21-tosylate A mixture Or predni30lone (100 g), triethylamlne (38.8 ml), acetlc anhydride (26.3 ml), methylene chloride (1200 ml) and 4-[dimethyl~
amlno]pyrldlne is stirred under nitrogen at 20-25 ror 3 days. The rea¢tlon mlxture 19 diluted with ether and flltered through cellte 521. The solid i9 dissolved with T~F and concentrated. Additional 21-a¢etate 19 obtained from the mother llquor.
The 21-acetate (63.25 g), pyrldine (70 ml) and DMF (200 ml) i3 cooled ln an ice/acetone bath to less than 0. In a separate rlask sulrur dioxide gas 19 bubbled rOr 7 min into pyrldine (77.99 g) in an ice bath. The sulrur dloxide solution i9 poured into the sterold mixture. This mixture is stlrred at 0-5 and N-bromosucclnimide (30.93 g) 19 added slowly keeping the temperature less than 5. The reaction mixture is left at les3 than 0 for 2 h under nitrogen. The mixture is dlluted with water and partitioned with methylene chloride. The phases are separated, the organic phase ls washed with dilute aqueous hydro-ohloric acid, water dllute aqueou~ sodium bicarbonate and again with water. The organic phase is dried over sodium sulrate and concentrat-ed. The crude material is trlturated wlth ether and filtered to gl~e the ~9(11)~21-acetate. Sodium methoxlde (1.7 ml) (4.1 N ln methanol) l~ added to a stirred mlxture of the ~9(11~-21-acetate (17.03 g) ln methanol (550 ml) under nitrogen at 20~25. After about 15 mln, a preclpitate forms. The reaction is left for 3 h and then dlluted with * trade mark l3~ ,7n7 -51- 4236~1.2 cold water and flltered to glve the ~9(11 )r21-hydroxy compound which can be purl~ed by HPLC ~r desired.
The ~9(11)-21-hydroxy sterold (0.58 g) p-toluenesulfonyl chlorlde (0.42 g) and pyrldine (25 ml) are stirred under nitrogen at 20-25 ror 24 h. Arter 24 h additlonal tosyl chloride (0.42 g) i~ added. The mlxture 19 partltioned between methylene chlorlde and water, the organlc pha3e 18 separated, ~ashed with saturated aqueou~ ~odium bicarbonate, twlce wlth sallne and drled over ~odium sulrate. The mlxture 13 concentrated without heat to give the title compound.
PREPARATION S-17 17~Hydroxy-21-lodopregna-1,4-dlene~3,11,20-trione t55786-16-8], see J. Med. Chem., 28, 171 (1985).
PREPARATION S-18 21-Bromopregna-1,4-dlene-3,20-dlone t97453-07-1], 8ee Bull. Chem. Soc. Jpn. 58, ~81 (1985).
PREPARATION S-19 11a,17a,21-Trihydroxypregna-1,4'diene-3,20-dione 21-tosylate A solutlon o~ tosyl chlorlde (1.16 g) and pyrldine (3 ml) i9 added dropwise over 10 mln to a solution of 11a-17~-21-trihydroxypregna-1,4-diene-3,20-dlone (600-90-8, West German DE 2,715,854, 2.0 g) and pyridlne (30 ml) at 0. The resultlng mlxture is stlrred rOr 1.5 h at 0 and 1.5 h at 20-25. The mixture 19 quenched with ethyl acetate (8 ml) and aqueous sodium bicarbonate (20 ml). Aqueous workup (chloro-rorm, magnesium ~ul~ate) pro~ides the t~tle compound.
PREPARATION S-21 17a,21-Dihydroxypregna-1,4,9(11)-triene~3,20--dione ~10184-69-7], see West German DE 3,322,120.
PREPARATION S 22 21 Iodo-16~methylpregna~1,4,9(11)-triene-3,20--dlone A 30lutlon of 150 g (0.41 mol) o~ 21~hydroxypregna-1,4,9(11),16 tetraene-3,20-dlone 21~acetate (US Patent 2,864,834, 150 g) and 90 ml o~ 1.9 lar copper proplonate ln THF 19 cooled in an lce acetone bath. Methyl magnesium chlorlde (1.96 molar ln THF, 240 ml) 19 added dropwl~e over 30 minutes. The reaction 19 checked by TLC (1:1 ethyl acetate/hexane on slllca gel). Additlonal GriBnard rea8ent can be added ir the reaction 19 not complete. A~ter 1 h, the reactlon 19 quenched with 375 ml Or 25S concentrated hydrochloric a¢id in methanol~
. The reaction i~ partitloned between water and toluene. The organlc phase i~ wa~hed with water, ~lltered thro~gh sodlum sulrate and conce-ntrated. The resldue 19 ¢ry~talllzed rrom ether and hexane. The .

~ 3~ 7~j~
-52- 4236.1.2 crystal~ are triturated wlth ether to gl~e the de_ired (16~-met~yl) Michael addition product.
This 19 stirred in 1500 ml Or methanol and i treated wlth 5.0 ml o~ 25S sodium methoxide in methanol rOr 30 min. The mixture i9 partltloned between methylene chloride and ~odium ~icarbonate. The organlc phase ls wa~hsd with sodlum blcarbonate, riltered through sodium sulfate and concentrated. The resldue i9 crystalllzed rrOm ether to gl~e a 21-hydroxy steroid.
72.45 g Or this materlal is di~solved in 145 g of pyridine and i-~
treated wlth 86.94 g of tosyl chlorlde. Reaction temperature iQ 0.
After 15 mln, the reactlon l~ warmed to 20-25~. Arter 1 h, the reaction i~ cooled in an ice bath and 30 g Or lactic acid i~ added to destroy excess tosyl chloride. The mixture is partitioned between methylene chlorlde and aqueous sodium bicarbonate. The organic pha~e is wa~hed with bicarbonate, flltered through 30dium sul~ate and concentrated. The residue i~ chromatographed on silica gel (1:1 ethyl acetate~hexane) to gi~e a pale 30lld which is disQolved in 500 ml Or acetone. Sodium lodlde (40 g) is added and the mixture i8 stirred ror 4.25 h. The mixture is partitloned between methylene chloride and water. The organic phase is wa~hed with water, riltered through sodium sulrate and concentrated. The residue is chromatographed (1:1 ethyl acetate~hexane) to give a ~lngle spot material which is cry~tallized rrom ether to gi~e the tltle compound.
PREPARATION S 23 11a-Hydroxy-21-iodo~1~a-methylpregna-1,4-diene-3,20-dione A mixture o~ 11a-hydroxy~16ormethylprogesterone (3.44 g) and DDQ
(1.1 eq) in 250 ml or benzene is heated under rerlux ror about 20 hours. The organic layer is then wa~hed (2 x tOO ml 1 N sodium hydroxide, 2 x 100 ml water and 1 x 100 ml saline) and the aqueou~
layerQ back~ashed (2 x 100 ml ether). me extraots are dried and concentrated to give a rOam which i9 chromatographed on sllica gel (300 g), eluting with 8 l Or 10S acetone methylene chloride and 20S
acetone - methylene chloride. The appropriate ~ractions (200 ml) are pooled and concentrated to give the ~1~4-~teroid.
The ~1-4 steroid (1.7 g) in methanol (5 ml) and carbon tetrachlor' ~de (10 ml) is mixed with 0.17 ml of 10S calcium chlorlde in methanol and ~tirred for 0.25 hour~. Calcium oxide (1.73 g) is added, rollowed .. ... ., ~ . . .. ... . . ..

1 3~`"`707 -53- 4236.1.2 by ~low addltlon (4 hours) Or a guspension o~ 2.44 g Or lodine in 3.9 ml Or 10S calcium chlorlde ln methanol. She mlxture is stirred rOr an additlonal 0.5 hours, then 19 rlltered through celite (wet with ~ethanol). The flltrate ~8 concentrated to gi~re a gum. Chromatography on slllca gel (600 g) and elutlon wlth 8 l of tOS and 4 l of 20S
acetone methylene chlorlde glves the title compound as a roam which is crystallized rrom acetone:hexane, mp 153.
PREPARATION S-24 21-Iodo-16-methylpregna~1,4-diene-3,20-dione A mlxture of 16-methylprogesterone (792 mg), DDQ (575 mg) and benzene are heated at rerlux for 28 hr, after 20 hr additional DDQ
(70 mg) is added. After refluxing, the mixture is cooled to 20-25, filtered rollowed by basic workup (ether - potas~ium carbonate -magnesium ~ulrate) to give 16a-methylpregna-1,4-diene-3,20-dione.
16a-Methylpregna-1,4-diene-3,20~dione (2.26 g), carbon tetrachlor~
lde (15 ml), methanol (7.3 ml) and calcium chloride in methanol (10%, 0.24 ml) are combined and stirred rOr 15 min at 20-25. Calcium oxide (2.50 g) i9 added and the mixture stirred an additional 5 min. A
mixture Or iodine (3.54 g), calalum chloride (10S, 5.4 ml) and methanol (2.4 ml) 18 added dropwLse o~rer 1 hr to the steroid m1xture. Arter an addltlonal 30 mln the mlxture 19 diluted with methylene chlorlde (100 ml), rlltered thru celite and concentrated. The residue i~ partitioned between methylene chloride and water, the phases are separated, the organic phase i9 washed with sodium sul~lte, drled over magneslum sulfate and then concentrated to give the title compound.
25PREPARATION S-25 1 7 ~,21 -Dlhydroxy~'1 6 B-methYl-5 ~pregn-9(11)-ene--3,20-dlone ~80163-64-0~, ~ee US Patent 4,336,200.
PREPARATION ~-26 21-Bromo-3a,1~-dihydroxy-5B-pregnane-11,20-dlone t95044 38-5], 30PREPARATION S-28 11B-Hydroxypregn-5-ene-21-al 3-ethylene glycol ketal Following the general procedure o~ PREPARATION S-29 and making non-critical varlatlons but starting with 21-carboxy-11B-hydroxypregna-5,17(20)-diene 3~-ethylene glycol ketal 21-methyl ester, the tltle compound iq obtained, MS (electron impact) 374. 273 and 99;
m.p. 162-166.
PREPARATION S-29 Pregna 5,9(11)-dien-21-al 3-ethylene ~lycol ketal .

1 3 7~7 54- 4236.1.2 21-Carboxypregna-5,9(11),17~20)-trlene 3-ethylene glycol ketal 21-methyl ester (4.0 g) in dry THF (60 ml) i9 added to a stlrred ~uspenslon o~ lithium aluminum hydrlde (1.58 g) in anhydrou~ ether ~50 ml) cooled in an lce/~ater bath. Arter the addltion is complete the coollng bath is removed and the mixture stirred at 20-25 rOr 18 hr.
The mlxture is cooled ln an lce/water bath and sequentially treated dropwlse with ethyl acetate (10 ml), ~ater (1.~ ml), sodium hydroxide (15S, 1.6 ml) and water (4.8 ml). Additional ether (50 ml) 19 added.
The mixture ls rlltered and the sollds washed wlth ethyl acetate. The comblned wash and flltrate i9 concentrated under reduced pres~ure to about 25 ml. This material is rlaqh chromatographed in silica gel (150 g) with hexane/ethyl acetate (1/1) as the eluent. The approprlate ~ractions are pooled and concentrated to give the title compound, m.p. 161-162; MS (electron impact) 356 and 99.
PREPARATION S-30 17a,21-Dihydroxypregn-4~ene-3,11,20-trione 21-me~y-late A mlxture Or cortisone (10 g), pyridine (100 ml) and methanesul~o-nyl chlorlde (3.2 g) i8 stlrred at 20-25 rOr one hr. The bulk Or the pyrldlne 19 removed under reduced pressure and the resldue dlssolved in methylene chlorlde ~300 ml). The mlxture is washed with cold hydro-chlorlc acld (10S, 200 ml) and drled over sodlum sul~ate. The solvent ls removed under reduced pres~ure to glve the tltle compound.
PREPARATION S-31 21-Hydroxy-20-methylpregn-4-en-3-one 21-mesylate A solution Or glaclal acetlc acid (40 ml) ls treated wlth portions Or sodium borohydrlde (0.83 g) belou 20. Artsr the rinal portlon is added, the mixture is ~tlrred at 20 ror 5 min. 3UOxo-bisnor-4-cholen-22-al (3.28 g) is added oYer a period o~ 5 min. The mixture is stlrred at 20-25 for 2 h. Excess acetic acid is removed at 45 to leave a re~idue. The residue i9 diluted with a 50~50 mixture Or water and 10%
aqueous ~odium hydroxide. This aqueous mixture is extracted wlth methylene chloride whlch is washed with 10S aqueous sodium hydroxlde followed by water and saline, then drled over sodium ~ulrate and concentrated to give 21-hydroxy 20~methylpregn~4-en~3~one.
A ~olution Or methanesulronyl chlorlde (0.37 ml) ln methylene chloride (10 ml) is added dropwi~e to an lce cold ~olution Or the 20-hydroxy steroid (1.44 g) and trlethylamine (0.7 ml) in methylene chloride (40 ml). The mixture i5 stlrred rOr 30 mln and then poured ... .... . .

"` 7 ~ 7 ` _ i -55- 4236.1.2 into lce cold dilute ~odlum bicarbonate. The layer-~ are aeparated, the organlc pha~e i~ wa~hed wlth water, drled over 30dlum 3ulfate and concentrated to gl~e the tltle compound.
PREPARATION S-32 ~1~Bl~noraldehyde A ~olution Or blsnoraldehyde tl5.5 g) ln benzene (500 ml) and DDQ
(17 g) 19 refluxed under nltrogen rOr 16 h. The mlxture ls cooled to 20-25 and the ~olid~ flltered u~lng a cellte pact runnel. The riltrate i9 concentrated to a roamlng re~ldue whlch l~ dl~solved ln chlorororm and rlash chromatographed on slllca gel elutlng with ethyl acetate-chlorororm (30/70). The appropriate fractions are pooled and concentrated to glve the tltle compound.
PREPARATION S~33 21-Hydroxypregna-1,4,9(t1),16 tetraene-3,20-dlone 21~mesylate A mixture Or 21-hydroxypregna-1,4,9(t1),16-tetraene-3,20-dione (9 g) and trlethylamlne (3.35 g) in methylene chlorlde (200 ml) at 0 under nltrogen i~ treated dropwlae wlth a mlxture of methane~ulfonyl chloride (3.5 g) in methylene chloride (50 ml) over a period of 30 mln. The mixture i~ stirred in ice for 1-1.2 h and then allowed to warm to 20-25 over Z h, Additional methane~ulfonyl chloride (1.75 g) and triethylamine ~2.3 ml) l~ added and the mixture stirred for 30 min at 20f25. The mixture is ~tored at less than O overnight. The mixture is wa~hed wlth cold dilute sodium bicarbonate, water, 2S hydro-chloric acld, saline and drLed over sodlum 3ul~ate and concentrated to glve the title compound.
PREPARATION S-34 6a-Fluoro-17a,21~dihydro%g-16B-methylpregna-4,9(11) diene-3,20-dlone 21 tosylate The 21~tosylate l~ prepared rrom the correspondlng 21-hydroxy ~teroid (US Patent 4,088,537, Preparation 3) by the procedure Or PREPA-RATION S-19.
PREPARATION S-35 21-Iodo-16a,17a-dlmethylpregna-1,4,9(11)-triene--3,20-dione A mixture Or 21~hydroxypregna-1,4,9(11),16-tetraene~3,20-dione 21-acetate (150 g) and copper propionate (1.9 M in THF, 90 ml) is cooled in an ice acetone bath. Methyl magne~lum chloride (1.96 M in THF, 240 ml) i3 added dropwise for 3~ mln. The reaction i~ monitored by TLC
(ethyl acetate/hexane, 1/1). Additional Grignard reagent i~ added lr needed. After l hr the reaotlon lo quenohed with methyl lodlde (100 g) ' ' ' ' ' -' ' ' ~ , .

-56- 4236.1.2 ln THF (200 ml). The reactlon mlxture is partioned bet~een water and toluene. The phases separated, the organlc pha3e is ~ashed ~lth ~ater, flltered thru 30dilum sulfate and concentrated. The re~idue is crysta-lllzed rrom ether and hexane. The crystals are triturated wlth ether to glve the Michael additon product with a 17o~methyl group.
This material (144.3 g) is stirred in methanol (1500 ml) and is treated with sodium methoxide (25S, 5 ml) rOr 30 min. The mixture 19 then partitionea between methylene chloride and sodium bicarbonate.
The organlc phase i-~ separated, washed wlth sodium bicarbonate, flltered thru sodium sulrate and concentrated. The residue is crystal-lized rrom ether. This material i~ dissolved in pyridine (145 G) and treated with tosyl chloride (86.94 g). The reaction temperature i9 0. After 15 min, the reaction is warmed to 20-25~. A~ter 1 hr the reaction mixture ls cooled ln an ice bath and lactic acid (30 g) is added. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic pha~e is wa3hed with bicarbon-ate, flltered thru sodlum ~ulrate and concentrated. The residue is ¢hromatographed on a ~ilica gel column, elution with ethyl acetate/hex~
ane (1/1). The approprlate ~ra¢tlon~ are pooled and concentrated to a solld, whlch 19 dl~sol~ed ln acetone (500 ml). Sodlwm iodlde (40 g) i3 added and the mlxture stlrred ~or 4.25 hr. The mixture is partitioned between methylene chloride and water. The organlc phase is washed with water, ~lltered thru sodlum sulrate and concentrated. The residue l~
chromatographed, elutlng with ethyl acetate/hexane (1/1). The appro-prlate fraction~ are pooled and concentrated to give one spot material which ls crystallized ~rom ether to glve the tltle compound.
PREPARATION S-37 21-8romo 3,17a-dlhydroxy-19~norpregna-1,3,5(10)~
trien-20-one 3~methylether See, JACS 80, 2226 (1958) ~or the 21-acetate.
PREPARATION S-38 3B-Hydroxy-21-lodo~16a-methylpregn~5-en-20~one See, Hel~ Chim Acta 42, 2043 (1959) and Re~ Romalne Chim 9, 147 ~1964).
PREPARATION S-39 3a-Hydroxy121-iodo-16~-methyl'5a-pregnan-20-one A mixture Or 3a-hydroxy-16a-methyl-5a~pregnan-20 one (21 g) methanol (80 ml), carbon tetrachloride (40 ml), THF (120 ml), cal¢ium oxlde (25 g) and cal¢ium ¢hlorlde in methanol (10S, 3 ml) i9 stirred at 25-30. A 30lution of iodine (20 g) in cal¢ium chlorlde (10S, 70 ml) .. .. . . .

~ 3`1 i7~7 ``

-57- 4236.1.2 l~ added to the ~terold mixture over 1 hr. The mixture i9 ~tirred an additional 2 hr at 30, ~lltered through a pad Or ~llter aid, and the riltrate concentrated under reduced pressure to an oll. The oil is dissolved ~n methylene chloride and rlash chromatographed over ~ilica gel (100 g) eluting wlth methylene chloride~ethyl acetate (4/1). The approprlate rractions are pooled, concentrated and the residue trltura-ted with ether to gi~e the tltle compound.
PREPARATION S-40 3a-Hydroxy-21 lodo-16a-methyl-5-pregnan 20-one Followlng the general procedure Or PREPARATION S-39 and making non-critical varlatlons but starting wlth the 3B-hYdroxY i~omer, the title compound is obtalned.
PREPARATION S~41 21~-Hydroxy-16~-methylpregna-1,4,6,9(11)-tetraene-3,20-dione Following the general procedure of Campbell and Babcock, JACS 81, 4069 (1959), a mixture Or 21-hydroxy-16-methylpregna-4,9(11)~diene-3,20-dione (21.05 g) and chloranil (15.0 g) in t-butanol (800 ml) is rerluxed ror 2 hr under nitrogen. The mixture is cooled and concentra-ted under redu¢ed pre~sure at 35, The residue 19 dl~iolved ln a minimum amount Or methylene chloride and chromatographed over neutral alumlna (32-63 ~m, 100 g) eluting with methylene chloride. The approprlate rractiOn~ are pooled and concentrated. The residue la dissolved in ethyl acetate/hexane (4/1) and ~ashed repeatedly with aqueouq sodium hydroxide (5S), then with water, dried over sodium sulrate and concentrated under reduced pre~sure to a solld. The solld is crystallized from acetone-hexane to gi~e the ~4,6~terold, mp 125.
The b4,6-steroid (3.81 g) and DDQ (2.84 g) in benzsne 19 rerluxed ror 17 hr in a nitrogen atmosphere. The mixture 19 cooled, riltered and the precipitate i8 washed with methylene chloride. me combined riltrates are concentrated under reduced pressure. The residue is dis~olved ln ethyl acetate/hexane (4/1) and washed repeatedly with aqueous sodlum hydroxide (5S), then wlth water, drled over ~odium ~ul~ate and concentrated under reduced pressure to glve the bl-steroid.
The b1'~terold (1.93 g) in methanol (20 ml) at 20-25 in a nltrogen atmo~phere l~ treated wlth a ~odium methoxlde ln methanol solution (25S, 0.75 ml) for 10 mln. The reactlon 13 then diluted with lce~cold water (60 ml) and extrected wlth methylene chlorlde. Saline is added to the aqueou~ phase and again extracted with methylene 1 3~"707 ~58~ ~236.1.2 chloride. The comblne methylene chlorlde extracts are washed ~lth ~ater, drled o~er sodlum ~ulrate, and concentrated under reduce pre~aure to glve the tltle compound.
EXAMPLE 0 2,4~Bls[dlethylaolno]~6~plperazlnopyrlmldlne (~II'1) and 2-dlethylamino~4,6~dichloropyri~idine A solution Or 2,4,6~trlchlorop~rimldine (34.0 g) in methylene chlorlde (400 Dl ) 15 stlrred at 0-. To thls solutlon 19 added drop~l~e a mlxture Or diethylamine (73 g) and trlethylamlne (50 g). The mlxture 19 warmed to 20~25 and 19 then re~luxed ~or 1 hr. The mixture is l~ partltloned between methylene chlorlde and aqueous ~odlu~ blcarbonate.
The phase~ are separated and the organlc phase 19 dried over Rodlum ~ul~ate and concentrated. The concentrate i~ chromatographed on sllica gel (400 g) elutlng ~ith 10S ethyl acetate/hexane to give the ra~ter movlng 2,4~bi~-dlethylamlno~6~chloropyrlmldine and the slower moving 2~dlethylamlno~4,6~dlchloropyrlmldlne. The dlchloro product i~
converted to the bl~diethylamlno~6~chloro pyrimidine by war~lng ln pyrldlne ~lth dlethylamlne.
A solutlon Or the 2~4~tbls~dlethylamlno]~6~chloropyrlmidlne (32.25 g) and plperazine (65 g~ ln pyrldlne (250 ml~ i3 rerluxed rOr 24 hr and then heated ln a Parr bomb at 170~ ror 20 hr. The mixture is partl~
tloned between ether and aqueous potasslum carbonate. The phases are separated and the organic pha~e is washed wlth sallne, drlea o~er ~odlum ~ulrate and concentrated. The concentrate i~ chromatographed on ~llica gel (methylene chloride to 4S methanol/methylene chloride) to give 2,4~[bi~ diethyla~lno]~6~piperazinopyrlmldine, NMR (CDCl3) 1.0~1.3, 2.75~3.0, 3.25~3.65 and 4.95 ~.
EXAMPLE 1 173~Hydroxy~21~[4~(2~pyridinyl)-1~plperazinyl]pregna~
4,9(11)~dlene~3,20~dione (I) 17~-Hydroxy~21~iodopregna~4,9(11)~dlene~3,20~dlone (4.53 g) 18 ~t$rred in acetonltrile (50 ml) with 1~(2~pyridlnyl)plperazlne (1.63 g) and pota~sium carbonate (1.34 g) at 60 ror 5 hr and at 20~25 ror 17 hr. ~he reaction i3 partltloned between ether and aqueous ~odium bicarbonate. The organic phase ls wa~hed ~lth ~allne, drled o~er sodlum ~ulrate and concentrated. The re~ldue l~ chromatographed on ~lllca gel wlth methanol/methylene chlorlde (4/96) to gl~e the tltle compound.
EXAMPLE 2 17~Hydroxy~21~t4~(2fpyrldinyl h1~plperazlnyl]pregna--1 3^~`7C7 ~59~ 4236.1.2 4,9(11)~dlene~-3,20~dlone methane~ultonate tI~
17a~ydroxy~21 ~(2~pyridinyl)~ piperazinyl]pregna~4,9(11)--dleneh3,20~dlone (Example 1) l~ dls~ol~ed in D~etbanol and treated ~lth Dethane sulronlc acld (0.224 g). The solutlon 19 concentrat-d and the resldue la crystalllzed from hot methanol and ethyl acetate to gl~re a rlrst crop Or the tltle compound. A ~econd crop Or the 3lesylate is l-~olated.
EXAMPLE 3 17a~Hydroxy~21~[~-( 2~pyridinyl)~1 ~plperazin~l]pregna~
4,9(11)~diene-3,20-dione hydrogen chlorlde salt (~
21~Bromo~17~-hydroxypregna~4,9(11)-diene~3,20~dlone (26.0 8~ i9 stlrred in acetonltrile (800 ml) ~ith 1-(2~pyrldlnyl)piperazine (13 g) and potaqsium carbonate (9 g). The reactlon i~ ~tirred at 20~25.
Arter 20 hr, another 4 g Or the amlne 19 added. After 5 hr, the reactlon l~ concentrated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated, the organic phase is dried o- er ~odlum sulrate and concentrated. The re~ldue l~ ¢hromatographed on ~lllca gel (mcthylene chlorlde to 2S
methanol/methylene chlorlde) to gl-~e a product ~hlch i~ cry~talllzed rrom hot ethyl acetate to a ~olld. The ~olid 19 dissolred in ethyl acetate and methanol and treated ~ith excess hydrochloric acld/ether.
The crystals are rlltered and then triturated ~ith hot ethyl acetate to gl~e the tltle compound.
E%AM~LE 4 21~[4~2~ Dino~6-(diethrlamino)-4~pyrimldlnyl~
plperazinyl]~ 17~h~rdroxypregna-4,9(11)~diene-3,20Ldlone (I) 2~Amino^~4~diethylamlno-6--chloropyrimldlne (1 .5~ g) and dry piperazine (3.5 g) are heated at 100 ln ethylene glycol (20 ml) ror 4 hr. The mixture is partitioned between methylene chloride and aqueous ~odlum bicarbonate, the pha~e~ are separated, the organic pha~a i~
drled ~ith ~odiuDI ~ulrate and concentrated. The re~idue i~ chromator Braphed on ~llica gel (ethyl acetate to 1S metha~ol/ethyl a¢etate to 20S methanol~1S ammonla/ethyl acetate) to yicld 1.29 g Or the pure anine product. Thi~ materlal 18 atirred at renux in aceton~trile (60 ml) ~ith 21~bromo~17~~hydroxypregna~4,9(1t)~d~ene~3,20-dlone and pota3sium aarbonate (o.8 g) ~or 7 hr then at 20~25 oYernight. The reaction mixture i~ partitioned bet~een methylene chlorlde and aqueous -qodium blcar~onate. The phase~ are separated and the organic pha~e is .. . . .

3 ) J ~` 7 ~

~60~ 4236.1.2 drled wlth sodlum ~ulrate and concentrated. The resldue l~ chromato~
graphed on ~lllca gel elutlng wltb oethanol in o~thylene chloride (4/96) to glve an oll wlth an N11R consistent with the deslred product.
Tho product l~ dl~solved ln ethyl acetate and treated wlth methane sulronlc acld (325 mg). The ~olld whlch re-~ulte 1~ trlturated wlth ether to glve the tltle coopound.
EXAHPLE 5 17~11ydroxy-~21~4-hydroxy~-4~(4~trlrluoromethyl)phenyl~
1~plperldlnyl~pregna~4,9(11)Pdi~nea3,20~dione (I) 4-~Hydroxy~ 4~ 4~tritluorol~ethyl~phenyl)plperldlne (6.81 g) ls stlrred at re~lux ln acetonitrlle (200 ml) with 21^bromo~17a~hydroxy~-pregna-4,9(1t)~dlene-3,20~dione (11.39 g) and with potaseium carbonate (3.83 g) for 8 hr. Tt~ reaction is concentrated, the mixture i~
partitioned between oethylene chloride and aqueous qodium blcarbonate, the phasea are eeparated, the organic pha~e i~ dried with -Qodium sulrate and concentrated. The concentrate i3 chromatographed on silica gel eluting wlth methanol/methylene chlorlde (2/98) to give the title compound which i~ cry~talllzed rrom ho'c ethyl acetat~.
EXAMPLE 6 17~Hydroxy~2t~t4-~2-ruranylcarbonyl)-1~plperazlnyl]pre-gna-4,9(11)~dlene-3,20~ dione (I) STEP A 17~Hydroxys214t1~piperazlnyl)pregna~4~9(1l)~diene~3~2 dione A ~lxture o- 21~-bromo-17~hydroxypregnaSIl,9(i1)^diene~3,20~tdione ~40.0 g) plperazlne (16.80 g) and pota~lum carbonate (13.2 g) are heated at 70 ln acetonltrlle t800 ml) ~or 2.5 hr. The ~lxture l~
partitloned bet~een methylene chlorlde and aqueou~ ~odlum blcarbonate, the pha~es are ~eparated, the organic pha~o la dried wlth sodlu ~ulrate and concentrated. The re~idue i~ recry~talllzed from hot ethyl acetate to gl~re 17a-hydroxy~-21~ ^piperazinyl)prel5na~4,9(11)~diene~
3,20~dlone.
STU B 17 ~H~rdr oxy~ 21 ~ ~4~(2~t~uronyl¢arbonyl)~t~iplperazinyl~
pre8na~4,9(11)~diene~3,20~dione (1) 17a~Hydroxy~2l~ piperazinyl)pregna~4~9(~ dien~3~2o-dlone (Exa~ple 6A, 3.91 g) triethylamlne (1.5 g) ln dry tetrahydroruran (120 ml) 18 reacted at 0~ with 2~ ruroyl chloride (1.24 8)- J~rter the addltlon, the reactlon 19 ~tirred under nitrogen for 2 days at 20~25.
The mixt~re l~ partitioned bets~een methylene chlorlde and aqueous ~odium ~lcarbonate, the pha~e~ are separated, the organlc phase l~

1 3r''.?07 ~61h 4236.1.2 dried wit~ oodlum sulrate and conccntrated. The concentrate i3 chromatograpbed on oillca gel eluting with ~ethanol/oethylene chlorlde (3/97) to gl~e the tltle co~pound whlch i9 recry~tallized from hot ethyl acetate.
EXAMPLE 7 17~Hydroxy~21~(4~(benzo~b]thlen~2-yl)~l~plperazlnyl)-pregna~4,9(11~dlene~3,20~dlone (I) 2~Chlorobenzothiazole (5.00 g), ls heated ln alcohol (75 ml) with 3.05 g plperazlne (3.05 g) ~or 20 hr. The mixture lo partltloned between methylene chloride/ether and aqueous sodlu~ ~lcarbo~ate, the phase~ are separated, the organlc pha3e 1~ dried wlth sodium sulrate and concentrated to 8i~e 2-piperazinobenzothia20le whlch i~ rea¢ted at 70 ln acetonltrile (200 ol) wlth 21~bromo~17o~hydroxypregna~4,9(11) diene~3,20~dlone (7.45 g) and potasolu~ carbonate (2.44 g) rOr 6 hr and at 20~25 ror 3 day~. The mixture is partitioned tetween oethylene chlorlde and aqueous sodlum bicarbonate, the phases are separated, the organic phase ls dried wlth ~odluD sul~ate and concentrated. The ¢oncentrate is chromatographed on silica gel elutlng wlth Dethanol/methylene chlorlde (6/94) to glve the tltle compound whlch ls recry~talllzed rrOo ethyl acetate.
EXAMPLE 8 17a-Hydroxy~21-t4~(2~pyrimldinyl)~1~piperazlnyl]pregna~
4,9(11 )~dlene~3,20~dlone (I) A mlxture of 2~chloropyrlmldine (10.0 g) and plperazlne (16 g) in alcohol (120 ml) io stirred ror 21 hr. The mlsture io partitioned betveen methylene chloride and aqueous ~odlum bicarbonate, the phase~
are separated and t~s organlc phaoe lo drled with ~odluo sulrate and concentrated to giYe 2~pyrlmldlnyl plperazine. ~he 2-pJri-ldlnyl piperazine (4.64 g) lo -~tirred at 70 ln acetonitrile (200 ol) with 21~
bromo~17a-hydroxypregna~4,9( 11 )~dlene~3,20~dione (11.52 g~ and potas-oiu~ carbonate (3.75 g) ~or 1.5 hr and at 20~25 rOr 2 dayo. The mlxture io partitloned between mcthylene chlorlde and aqueou~ sodluo bicarbonate, the pha~e~ are -qeparated and the organlc phaoe 1~ drled with ~odiu~ sulrate and concentrated. The ¢on¢entrate l~ chromato-graph0d on ollica gel elutlng wlth 4 to 6S nethanol/nethylens chlor~de. The approprlate ~ractloD~ are pooled and concentratsd to glve the title compound which l~ crystalllzed rrOo ethyl acetate.
EXAMPLE 9 17~Hydroxy~21~[4~2~carboxybenzoyl)~1~piperazlnyl~
pregna~4,9(11~diene~3,20~dlone (I) al~o known ao 1 3r,''?(~7 ~62~ ~236.1.2 2~t~4~(17~hydrox~3,20~dioxopregna~4.9( 11 )~dlen~21~yl)~
1~plperazlnyl]acarbonyl]~benzolc aeld 17~Hydroxy~21~ piperazinyl)pregna-4, 9(11 )~dlene~3,20~dlone (Example 6~, 5.11 g) and phthalic anhydrld¢ (1.84 g) are stlrred in 5 acetonltrlle (100 ml) and methylene cnlorlde (100 l) rOr 4 hr. The mlxture l~ concentrated and the residue 18 recry3talllzed fro~ ethyl acetate and ether to ti~e the product which l~ chromatographed on ~lllca gol (4S methanol~methylene chlorlds to 8S/1s acetlc aold/Dethyl~
ene chlorlde) to give the tlSle coopound.
EXAMPLE 10 17a~Hydroxy~21~t4 ~[(3-chlorophenyl)amino~carbonyl]~
piperazlnyl]pregna~4,9(11)~diene~3,20-d~one (I) 17O-Hydroxy~21P(1~plperazinyl)pregna~4,9(11)~dlene~3,20~dione (EXAMPLE 6A, 5.00g) is treated in DMF (20 ml) with ~chlorophenyliaocy~
anate (1.84 g) for 3 days. The mixture i~ poured lnto water (200 ol~.
Arter 1 hr, the llquid i~ decanted. The ~olid i~ di~solved in methylF
ene chloride and i8 extracted wlth aqueous sodium bicarbonate. The phase~ are separated and the organlc phàse l~ drled over sodlum tulrate and ¢on¢entrated. The concentrate l~ ¢hromatographed on slll¢a gel (3S
mothanol ln methylené chlorlde to 4S) to glve the title compound which l~ cr p talllzed rrom hot ethyl acetate.
EXAMPLE 11 17n~Hydroxy~2t~t4~(2~methoxyphenyl)~1~plperazlnyl]~
pregna-4,9(11)~diene~3,20~dione (I) A mlxture Or 2~chloro-6~methoxy W rldlne (20 g) and plperazlne (32.9 g) with pota~sium carbonate (20.1 g) in water (50 ol) l~ stlrred at 100 tor 24 hr. The mixture ia partitioned between methylene chloride and aqueou~ sodium bicarbonate, the phaoe~ are ~eparated and the organic phase is dried o~er ~odlum ~ulrate and concentrated. The concentrate i~ dissol~ed ln ether. The organic phase 18 extracted ~lth hydrochloric acid (10S). The aqueo w pha~e is wa~hed ~ith ether, neutralized with sodlum hydroxlde l10S) and extra¢ted wlth methylene chloride. The organlc pha~e is drled o~er ~odium ~ulrate and concen~
trated to give 2~piperazino~6~methoxypyrldlne. Thia material 19 ~tlrred ln acetonitrlle (100 ml) with 21~bromo~17o~hydroxypregnaP
4,g~ dlene~3,20~dione ~3.01 g) and pota~lum carbonate (1.3 g) at 20~25 rOr 16 hr. The mixture is partitioned bet~een methylene chlorlde and aqueou~ ~odlum bicarbonate. The phase~ are separated and the organic pha~e 18 dried oYer ~odlum sulrate and concentrated. The 1 3~7~7 ~63~ 4236.1.2 concentrate ~ chromatographed over ~llica gel (2S methanol in methyl~
ene chloride to 4S) to gi~e the free ba~e Or the title compound whlch la 92S pure by HPLC. Thls materlal 1~ dl3sol~red ln et~lyl acetate and treated wlth ~ethane ~ulronic acld (0.606 g). The aalt l~ rlltered and recrystalllzed ~rom methanol and ethyl acetate to glve the tltle compound.
EXAMPLE 12 17a~Hydroxy~21~[4~2,6~bls(dlmethylamino)~4-~pyrlmldln~
yl]~ plperazlnyl]pregna~4,9~ dlene~3,20~dlone hydrochlorlde ~alt (I) A ~olution of dimethylaolne (16.6 g) in water (66.4 ml), triethyl~
amlne (20 g), and 1,3,5~;itrlchloropyrlmldlne (8.30 g) ln alcohol (100 ml ) l~ -~tlrred at 20~25 ror 2 hr. The mixture ls ~tored at 0 o~ernlght. Another 2 g Or dlmethyl amine ~s~lution ~25S) i~ added and the reaction mixture is stlrred at 20~25 ~or 2 hrs more. The mixture ls partltioned between methylene chloride and aqueous sodlum bicarbon4 ate. The pha~es are ~eparated, the organlc phase i~ dried o~er sodlum sulrate ant concentrated. The con¢entrate 18 chromatographed over ~llica gel wlth ethyl acetate/hexane (lOJ90) to gl~,re 2,4~bistdimethyl~
amlno]~61~,chloropyrlmldlne. Thi~ bi~ adduct la heated ~ith piperazlne (2.60 g) ln alcohol (100 Dl) rOr 1 hr. The mlxture ls partltloned bet~een methylene chloride and aqueous ~odium blcarbonate. The pbases are separated and the organlc phase is dried o~rer sodlum sulfate and concentrated. The residue is crystallized rrom ether and hexane to give the desired C21 substituent. Thi~ material (3.00 g) is atirred in acetonitrile (250 ml) ~lth 21~bromo~17~hydroxypregna-4,9( 11 )~dlene~
3,20-dione (5.97 g) and potasslum carbonate (1.98 g) ror 20 hr. The ~ixture iq partitioned between methylene chloride and aqueous sodium bicarbonate. The phasea are separated and the organic phase i9 drled over sodium sul~ate and concentrated. The concentrate l-~ chromato~
graphed oYer qillca gel (methylene chloride to 4S methanol/methylene chlorlde) to glve the correspondlng rree amine base o- the tltle compound. Thls compound is dlssol-ved in ethyl acetate and treated with exce3s hydrogen chlorlde~ether. The product ls riltered, washed with ether and triturated wlth hot ethyl acetate to gl~e the title compound.
EXAMPLE 13 17~Hydroxy~21~t4~(3,6~dimethylpyrazinyl)~ plpera-zlnyl]pregna~4,9(11)~ diene~3,20^dione monomethane-sulfonate hydrate (I) 1 3 '' ~ 7 ~

~644 4236.1.2 A solution of 3~chloro~2,5~dlmethylpyrazine (5.00 g), 1~benzylplp~
erazlne (6.20 g) and trlethylamlne (3.5 g) ln ethylene glycol (25 ml) is heated at 100 ror 10 hr. Another 3 g o~ the benzylplperazlne 19 added and the mlxture ~9 ~tlrred at 100 ror another 20 hr. The mlxture 19 partltloned between methylene chlorlde and aqueous ~odium blcarbonate. The phases are separated, the organlc phase 19 drled over sodlum sulrate and concentrated. The concentrate is chromatographed on sillca gel (10S to 30S ethyl acetate ln hexane) to gl~e t~e free base Or the 21~amlno substltuent. Thls material l~ dls~olved ln ethanol (100 ml) and methanol (2 ml) whlch l~ saturated with hydrogen chlorlde gas. Thls mlxture ls hydrogenated rOr 17 hr oYer palladlum on carOon (10S, 900 mg) at 50 psl. The mlxture i~ flltered thrcugh celite, and the solld~ are wa3hed with methanol. The organlc phase is concentrated to gl~e the 21~amlno sub~tituent. This materlal i~ reacted ln dry acetonltrlle (200 ml) wlth 21~bromo~17~hydroxypregna~4,9( 11 )-dlene~
3,20~dlone (3.60 g) and potasslum carbonate (1.18 g) at 600 ror 23 hr.
The reactlon mlxture 19 partitloned between methylene chlorlde and aqueous sodlum bicarbonate. The phase~ are separated and the organlc phase 19 dried over ~odlum sulrate and concentrated. The concentrate 19 chromatographed on slllca gel (2S methanol ln methylene chloride) to gl~e the rree base or the deslred product. Thl~ compound ls con~erted to the mono methane sulronic acld salt wlth methanesulronic acid (0.56 g) ln alcohol. The salt ls crystallized from ~ethanol/ethyl acetate to glve the title compound.
EXAMPLE 14 21h~4~[2~(Dlethylamino)~6-(l'pyrrolldlnyl)-4~pyrimidln-yl]~1~piperazinyl]~17a~hydroxypregna~4,9(11)'diene~3,20 ~dlone dlhgdrochlorlde hydrate (I) A so~utlon of 2~diethylamlno~4~plperazlno~6 chloro~pyrimldine (4.10 g) in pyrrolidlne (4.10 g) ls heated rOr 12 hr at 100~, then concentrated. The concentrate is partitloned between aqueous sodlum blcarbonate and methylene chloride. The phase~ are separated, the organic phaae is dried and concentrated to gl~e 2~dlethylamino~4~plper~
azlno~6~pyrrolidlno~pyrlmldlne. A solutlon Or this amlne (4.01 g), 21 bromo~17o~hydroxypregna~4,9(11)~diene~3,20~dlone (5.41 g), and potas~
sium carbonate (1.75 g) are stirred in acetonltrlle (200 ml) for 19 hr. The reaction mlxture i~ partltloned between methylene chlorlde and aqueous sodlum blcarbonate. The phases are ~eparated and the organic * trade mark .. . . . .. ...

1 3 i r` 7 ~65~ ~236.1.2 phase 19 dried o~er ~odluat sulrate and concentrated. The concentrate is chromatographed on slllca gel (methylene chlorlde to 4S methanol/^' methylene chloride) to glve the rree base corre~ponding to the title compound. An ethyl acetate solutlon Or this compound ls con~rerted to the hydrochloride salt wlth ether/hydrochlorlc acld to g~ve the tltle compound.
EXAMPLE t5 17~Hydroxy~21~4~[2~(diethylamlno)~6-(4~methyl~ 1~piper~
azlnyl)~4~pyrimldlnyl3~ plperazlnyl]pregna~4, 9 dlene~3,20~dlone hydrochloride hydrate (I) A solutlon o~ 2~diethrlao~lno~4~[4~ethylplperazino~6~plperazlno~
pyrlmldlne (prepared rrom 2~diethyla~ino~4,6~dlchloropyrimldine o~
EXAMPLE 0, 4.14 g), 21~bromoi~17a~hydroxypregna~4,9(11)~dlene~3,20~
dione (4.85 g) and potassium carbonate (1.58 g) in acetonitrile (200 ml) ls stirred at 20~25 rOr 24 hr. The mixture is partitloned bet~een methylene chlorlde and aqueou~ 30diu~ bicarbonate. The phases are separated and the organic phase i3 concentrated and chromatographed on silica gel (methylene chloride to 2S ~ethanol/methylene chloride) to glve the rr~e base o~ the tltle compound whlch ls converted to the hydrochloride salt.
EXAMPLE 16 17~Hydroxr~21~4~2,6~bis(diethylamino)~4~p~rrlmidinyl~
piperazinyl]pregna-4,9(11)~diene~3,20Adione dihydror ¢hloride hydrate (I) A ~olutisn ot 2,4~bi~dlethyla~ino]-6-plperazlnopyrlloidlne ~EXAMPLE 0, 6.47 g), 21'9bro~i17~hrdroxypregna~ 4,9~ diene~3,20-~
dione (11.48 g) and potassium carbonate (3.75 g) in acetonitrile (500 ~1) is stirred at 20-i25 for 24 hr. The mlxture ls partitioned bet~een methylene chloride and aqueou~ sodium bicarbonate. The phase~ are separated and the organic phase is concentrated and chro~natographed on sllica gel (methlrlene chloride to 4S methanol/methylene chloride) to gl~e the rree base corresponding to the title coDIpound ~hich la con~rerted to the hydrochlorlde salt.
EXAMPLE 17 17~Hydroxy~21~[4~[2~(diethyla~ino)~6~ piperidinyl)^~
4~pyrlmldinyl]~1~plperazinrl]pregna^4,9(11 )~d~ene~
3,20i-dlone hydrochlorlde hydrate (I) A solution o- 2-diethylamlnoL4,6~dlchloropyrlmid$ne (EXAMPLE 0, 4.00 g) ln piperid$ne (6.00 g) ls heated at 80 ror 20 min. The mlxture is stirred at 20~25 rOr 15 hr and then partltioned bet~een ~3~707 ~66~ 4Z36. 1.2 methylene chloride and aqueou~ sod~um bicarbonate. The pha~ea are separated and the organlc p~ase ~9 drled o~er ~odlum sul~ate and concentrated. The NMR l~ con~i~tent with the mono~plperldlne adduct.
The resldue and plperazine (8 g) are rerluxed ln pyrldine (100 d ) ~or 6 hr. The react~on ~lxture 19 part~tioned bet~een oethylene chlorlde and a~ueous potasalum carbonate. The pha~es are ~eparated and the organlc pha~e i~ dried over sodiu~ ~ulrate, concentrated and chrooato~
8ra~hed on sillca ~e~ ~et~ylene c~oride to 6S ~t~anol~S a~monium hydroxlde-methylene chlorlde) tO glve 2~d~ethyla~ino~4~piperidino~6~p~
perazlnopyrid dlne.
Thi~ a~ine (2.04 g) i8 treated ~ith 21 bromo~7~hydroxypregna-~
4,9(11)~dlene-3,20~dlone (2.5 g) and pota~sium carbonate (.87 g) in acetonitrile (150 ml) at 20~25 ror 67 hr. The reaction mixture i9 partitioned between methylene chloride and aqueous sodium blcarbonate.
The phases are ~eparatéd and the organlc phase i~ dried over Sodium ~ulrate, concentrated and chromatographed on ~ilica 8~1 (50/50 ethyl acetate~hexane to 82/20~ to g~ve the ~ree base correspond~ng to the product, ThlJ aompound ~9 dls~ol1~ed ln eth~ acetate and con~r~rted to the hydrochlorlde salt ~hlch 1~ triturated ~ith ether and dried to give the title compound.
EXAMPLE 18 21~t4~2,6~1s(dlethyla~ino)*4~py~1mldlnyl~ plperazln~
rlt~l7l~hrdroxr~16~methrlpregna~1~4~9(11)~tr~ene~3~2 dlone hydrochloride hydrate (I) 1 7~Hydroxr21~10do~1 6o~methylpregna^1, 4, 9(11 )~triene~3,20~d~one (2.60 g) i~ reacted with 2,4*Cbis*dlethylad no~6~piperazlnopyri~1dlne (1.39 g) and potasslum carbonate (0.75 6) ln acetonltrlle (~0 ~l) at 20~25 rOr 42 hr. The reactlon m~xture 18 partltioned bet~een methylene c~oride ~nd a~Ueou~ po~a~um car~o~ate. tne p~a3e~ are separate~ an~
the organlc pha~e ls drled o~rer aodluol ~ul~ate, concentrated and chroDatographed on ~ ca 8el ~methylene chlorlde to 2% methanol) to g~Ye the rree ba~e corresponding to the product. Thi8 compound i~
con~erted to the ~ydrochlorlde ~alt by u8e Or ethyl acetate/ether~
hydrochlorl~ acld.
EXAMPLE 19 17~Hydroxy~21~4~2,6~ (4~methyl~1~plperazlnyl)~
4~pyr~mldlnyl~ plperazlnyl~pregna~4,9(11)~dlene~3,20 dione methane~ulfonate hydrate (I) Trlchloropyrimidlne i~ added in port~on~ to an Sce cooled 801utlon . .

1 3~`~707 ~67~ 4236.1.2 Or N~meth~lplperazlne (40 g) ln alcohol (200 ml). The mlxture 19 then heated at 60 rOr 2 hr. The olxture 13 concentrated and chro~ato~
graphed on ~lllca gel wlth 2 to 5S oethanol in methylene chlorlde to gl~e 2,4-bls~4~ethylplperazino]~6-c~loropyrlmldlne. Thl~ materlal i9 5 heated at 130 ln water (30 ml) ~lth plperazlne (32 g) ln a Parr bomb ror 20 hr. The product i9 partltloned between ~ethylene chlorlde and aqueous ~odlum carbonate. The phases are separated and the organlc phase i9 drled o~er ~odlum sulrate and concentrated to gl~e 2,4~bist1~
(~methylplperazlno)]~6~plperazlnopyrlmldlne. ~hls trlamlne l~ stlrred 10 ln acetonltrlle (200 ml) with 21~bro~o~17a~hydroxrpregna~4,9(11)~dlene~
3,20~dlone (7.18 g) and pota-~slum carbonate (2 g) ~or 20 hr. The mlxture l~ partitloned between ~ethylene chlorlde and aqueou~ sodlum blcarbonate. The phases are 3eparated and the organlc pha~e ls concen~
trated and chromatographed on ~ilica gel (methylene chlorlde to 5S
l5 methanol and .5S ammonlum hydroxlde~methylene chlorlde) to gl~e the rree ba~e corre~ponding to the tltle compound. The rree ba~e ls dl~ol~ed ln ethyl acetats and treated wlth methane ~ulronlc acld (2.22 g). The product l~ trlturated wlth ether to glve the tltle compound, bubbled at 110 wlthout ob~lous decomp.
Follo~lng the general procedure Or E%AMPLES 1~6A, 7, 8, 11~19, 83 and 126 and maklng non~crltical variatlon~ but startlng with (a) tho corre pondlng 21~/22~halo ~chlorine, bromine or lodlne), 21~/22 methane~ulronate (me~ylate) or 21~/22~toluene~ulronate (to~ylate) ~terold Or the de~lred amino ~ubstltute~ ~tero~d (XI) an~
25 (b) the corre~ponding ~ree amine Or the ad no substltutent at C21/C22 of the de~ired a~ino substituted ~teroid (XI), the a~ino ~ubstituted 3terold~ (XI) Or EXAMPLES 20~27, 29, 30, 33~55, 58~101, 105, 109~111 and 113~132 are obtainea.
Followlng tho genera~ procedure ot EX~MPLE 31 ~ ester~) and 30 making non~crltlcal var~atlons, the amlno substltuted ~terold~ (XI) Or EXAMPLES 28 and 32 aro obtained.
Follo~ing the general procedure Or EXAMPLE 103 (~here n - 0) and maklng non~critlcal ~ariation~ but starting ~lth (a) the corre~ponding 17~acid Or the deslred amino ~ub~titutcd steroid (XI) and (b) the ;35 corresponding rree amine Or the amlno sub~titutent at C20 Or the deslred atolno ~ubstltuted ~tero~d (XI), the amlno substltuted Jterold~s (XI) o~ E%AMPLES 56 and 57 are obtalned.

1 3~7n7 ~68~ 4236.1.2 Follo~lng the general procedure Or EXAMPLE 104 (~ l~ not -O) and maklng non~crltlcal ~ariatlons but ~tartlng vith (a) the corresponding 21~aldehrde or equl~alent thereor Or the desired amlno 3ubstltuted ~terold (XI), and (b) the corre3pondlng rree amlne Or the amino 3ub~tltutent at C21/C22 Or the de~ired amino ~ub-~tituted steroid (XI), the aolno subatituted sterolds (XI) o~ EXAMPLES 106~108 and 112 are obtalned:
Example Amino Sub3tituted Sterold Product (XI) 17~hydroxy~21~t4~(2~pyridinyl)~1~piperazinylpregn~
4~ene-3,11,20~trione 21 11 B,17~dihYdroxY-6~-methyl~21~4~(2~Pyridinyl)~1 plperazlnyl]pregna~1,4~diene~3,20~dione 22 17a~hydroxy~21~4~(6~methoxy~2~pyridlnyl)~1 plperazln~l]pregna~4,9(11)~diene~3,20~dlone mono~ethaneaulfonate 23 11a,17o*dlhydroxy~21~[4~(2~pyridinyl)~1~plperazin~
~l]~pregn~4~eneL3,20~dlone 24 17o~hydroxy~21~tmethyl~2~(methyl~2~pyrldlnylamino)~
ethyl~amino]pregna~4,9(11)~diene~3,20~dione dihydrochlorlde 11~,17~dihydroxy~21~t4~(2~pyrldlnyl)~1~piperazin~
yl]~pregna~1,4~dlene~3,20~dlone dihydrochloride 26 11B,17o~dlhydroxy~21~[4~(4~iluorophenyl)-1 piperazlnyl]pregna~1,4~diene~3,20~dione dihydrochloride 27 11B,17o~dlhydroxy~21~[4~(4~methoxyphenyl)~1 piperazlnyl]pregna~ diene~3,20~dione dihydrochloride EXAMPLE 28 11,17~Dihydroxy~21~[4~(2~pyridinyl)-1~piperazin~l]~
pregn~4~ene*3,20~dlone 11~(3,3~di~ethyl~1~butyrate dihydrochloride Followin~ the general procedure o~ EXAMPLE 31 and making non~
critical variation~ and starting with the sterold Or E%AMPLE 23 but uslng the appropriate acid chlorlde the title compound is obtained.
Example Amino Substltuted Sterol4 Product (XI) 29 21~[4R(4~rluorophenyl)~1~plperazlnyl]~ ,17o~
dihydroxypregn~4~ene~3,20~dione dihydrochlorlde 1 3f'~f707 ~6~ 4236.1.2 11a,17o~dlhydroxy~21~ methoxyphenyl)~1~
plperazinyl]pregn~4~ene~3,20~d~one dlhydrochlorlde EXAHP~E 31 11a~17~Dlhydro%y^2l~t4~(2~pyridinyl)~l~piperazln~
yl]pregn~4~ene~3,20~dione 11~(2^~uranylcarbonyl) dlhydrochlorld~
1la~l7o~Dlhydroxy~2l~t4~(2~pyrldinyl~ p~perazin~l]pregn~4~ene~
3,20~dlone (EXAMPLE 23, 312 0g) and triethylamlne (0.144 ml) are added to a mlxture Or dlmethylamlnopyridlne (126 mg), ruroyl chlorlde (0.7 ml) and chlorororm (3.0 ml). The mlxture i9 ~tirred ror ~ix days at 20~25~. 8asic workup (chloro~or~ ~ 5S ~odlum hydroxide, potas~lum carbonate) and purirlcatlon by fla-~h chromatography on ~llica gel elutlng ~lth chlorororm~metnanol (15/1), pooling and concentrating the approprlate rractlon~ gives the title compound.
EXAMPLE 32 11 a, 17~dlhydroxy~21~t4~(4~methoxyphenyl)~1~piperazln~
lS yl~pregn~4~ene~3,20~dione 11A(3,3~dimethyl~1~butyrate) dlhydrochloride Followlng the general procedure Or EXAMPLE 31 and maklng non~crlt~
lcal ~ariatlons but startlng witn the ~teroid of EXAMPLE 30 and uslng the acid chlorlde o~ EXAMPLE 28 the tltle compound i3 obtained.
Z Examp~e Amino Substituted Steroid Product (XI) 33 11B,17ordlhydroxy~21~4~(4~methoxyphenyl)~1~pipera~
zlnyl~6~methylpregna~1,4-dlene~3,20~dione dihydrochloride 34 11~17a~dihydroxy~21~t2~(3~4-dimethoxyphenyl)eth~
yl]~amino]~6~methylpregna~1,4~diene~3,20~dlone hydrochloride 17orhydroxy~16o4methyl~2l~t4~(2~pyridinyl)~l~piper~
azlnyl]pregna~1,4,9(11)~triene~3,20~dlone 36 11a~hydroxy~21~{4~yridl~yl)~l~piperazln~1~pregn-4~ene~3,20~dione dlhydrochlorlde 37 17~hydroxy~21~tt2 (3,4~dimethcxyphenyl)ethyl]t3,~
4,5~trlmethoxyphenyl)methyl~am1no]pregna~4,9(11)~
diene-3,20~dlone hydrochlor~de 38 17o~hydroxy~21~tt2r(2~4~dlmethoxypheny~
methglethyl]amlno]~regna44,9(11~dlene~3,20~dlone hydrochlorlde 39 21~t1~(2-carboXy)piperldlnyl]~17o~hydroxypregna 1 3"~7C7 --~70~ 4236.1.2 4.9(11 )~diene~3,20-dione 21~[4~(2~pyrldinyl)~1~plperazinyl]pregn44Oene^3,20 dlone dihydrochlorlde hydrate 41 17o~hydroxy~21~t4~(2~3ethoXyphenyl)~l~piperaZinyl]~
pregn~i4~ene~3,20~dlone dlhydrschlorlde hydrate 42 17o~hydroxy~21~t4~i~3,4~dimethoxyphenyl)~ethyl]~1 piperazinylpregnaq4,9(11)~dlene~3,20~dione dihydrochloride hydrate 43 17~hydroxy~i21a~4~(2~pyrldinyl)-1~piperazinyl]~
pregn~4Jene~3,20~dione dlhydrochloride hydrate 44 17a'hydroxy~t6B~methyl~21~{4~(2~pyridinyl)hl~
piperazinyl]~5~pregn~9(11)~iene 3,20~dione dih~drochloride hydrate 21~4~(2rpyridinyl)~1~piperazinyl]pregn~4~ene~
3,11,20~trione hydrochloride hydrate 46 17o~hydroxy~6~methyl~21~i~4~(2~pyridinyl)~1~
plperazinyl]pregna~i1,4,9(11)~triene~3,204dione (E)~2~butenodioate salt 47 17a-hydrox7-6~-methyl-21-~4-[2,6-bis~l-pyrrolidinyl)--4-pyrimldinyl~-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione, ~E)-2-butenodioate 8alt -48 17~hydroxy~21~4~t~5~methyl)~4~phenyl~4H~l~2~4 triazol~3~yl]~1~piperazlnyl]pregna~i4,9(11)~dlene~
3,20~dione dlhydrochlorlde hydrate 49 21~t4~(2~pyridinyl)~ piperazlnyl~pregna'1,4,9(11)~
triene~3,20~dione hydrochloride hydrate 21~ Z,6~bis(dlethylamino)~pyri~1dinyl]~1 piperazlnyl]411~,17~dlhydroxypregn~4~ene'3,Z0 dione hydrochloride 51 17o~hydroxy~21~2~(3,4~dimethoxyphenyl)ethyl]~4 (dimethylamino)phenyl]methyl]amlno]pregna~4,9(11)~
3,20~dione hydrochloride 52 21~4~2~amino~5~ pyrrolldinyl)phenyl]~1.
piperaz~nyl]~17~hydroxypregna~i4,9(11)~d~ene-3,20~dlone hydrochlorlde 53 21~4~2,6~bia(diethylamlno)r4-pyrlmldlnyl]~1~
plperazinyl]~l7a~hYdroXypregn'4~ene~3,20~idione :~

1 3r'`~7Q7 ~71~ 4236.1.2 5~ 17a~ydroxy~21~4~(2~pyrldinylmethyl)~1^plperazin~
yl]~prs~na~4,9( 11 )~dlene~l3,20~dione (E)~2~utened~
~oate 1:1 salt 5~ t73~hydroxy~2t-~4~4~diemthylamino)phenrl~meth-yl~ p~perazlnyl~pregna~4,9(11)~diene-3,20~dione (E)~2~butenedloate 1:1 salt 56 17g~carboxr~17~hydroxyandrost~4~en~3~one 4~(2 pyridinyl)~plpera2inyl a~de 57 17g~carboxy-17~hydroxyandro~t~4-en~3*one 1~[2,6 bi~dlethylaolino)~4~pyrimidinyl~ piperazinyl~
amide 58 2l ~r4~ ~2~pyr~ dlny~ plperazinyl~pregnaA4, 9 (tl),16~triene~3,20~dione hydrochloride with trichloromethane hydrate (4:8:3:4) 59 17a~hydroxy~21~ (2~pyridinyl)~1~piperaZ~nyl3~
pregna~l,4~dlene~3,11,20~trione hydrochlor~de hydrate ~2:1:3) 77a~hydroxy~21-t4~t4,6~bll(2~propenylamlno)~1,3,5-triazin~2~yl~ piperazlnyl]pregna-4,9(t1)~diene~
3,20~dlone dlhydrochlorlde hydrate 61 ~7a'hydroxy~2~4rl3~nydroxy~2~pyrldlnyl)methyl~
piperazlnylpregna~4,9(11)~diene~3,20~dlone (E)~
2~butenedioate (1:1) salt 62 17o~hydroxy~21 t~kt6~ py~rolldinyl)~2~pyridinyl]~
~t~p~peraz~nyl~pre8na~9(~t~dlene~2o~diQne (El~
2~butenedioate (t:1) ~alt ~: ~ 63 21~[4-[2,6-bis(dlethylamino)~4~pyri~idlnyl~
piperaz~nyl~17~hydroxy-6f~met ffl lpregnaf~
~, 4, 9(11)~ttr~ene~3,20~d~ne (E)~2~butened~oate ( 1: 1 ) ~slt 64 ~hydrox~ff~2~f^~4~2,6~dl~ pyrro~d~ny~)~4~
:~ pyrlmldlnyl~ plperazinyl~pregna~l~, 9(11 )~dlene-3. 20~ d~ one (E)~2~butenedloate ( 1 ~ alt 21~4^(2~twridlnyl)~11'plperazinyl~pregna~1 ,4~dlene~
~: 35 3,20~dlone (E)~2~butenedloate (1~ alt ~: 66 11~,17~dlhydroxy~21~r~2~pyrldlny~ plperazin~
yl]~pregna~1,4~diene~3,20~dion~ (E)~2~butenedloate i,:

, 1 3"37a7 ^72~ 4236.1.2 ) salt 67 17a~hrdroxr~21~ 3~4~dlhydroxyphenyl)m~thyl]r2 (3,4~dlolethoxyphenyl)ethyl]amino]pregna4,9(11 )~dl~
ene~3,20~d~one (E)~2~ utenedloate (1:1) salt 68 21~4"~3~amino~6~(dlethylamino)~2~pyridinyl~
plperazlnyl]~l7a~hydroxypregna-4,9~ dlene~
3,20~d~one ~ydrocn~or~e 69 2t~t4n[2,6~bl~diethyla~1no~4~pyrlmldinyl]~
piperazlnyl]~tla~hydroxypregn~i4~ene~3,20~dlone df hydrochlor~ de 21~-~4~2,6~bl~(dlethylamino)~4~pyrlmldinyl~
plperazinyl~ ,17~dihydroxy~regn~4~ene~ 3,20L
dione dlhydrochlorlde 72 21J'~4~r4,6~bl ~(2~propenylam1no)~l,3,5~tr~az~n~2 ~
rl]~ plperazinyl~pregne4-ene 3,11,20~trlone dihydro~chlor~de 73 17a!~hydroxy~16a~methgls21~4~2~6~a~ pyrrolidi~
nyl~4~pyrimldlnyl]-1~plperazlnyltpregna-1,4,9~
triene-3,20~d~one (E)~-2~butenedloate (1~ alt 74 17~;~hydroxy ~21~r4~t2,6-di~ pyrrolldinyl)*4 pyrlm~dinyl~ plperazlnyl~pregna~1,4,9(11)~
trlenei~3,20*dione d~hydrochlor~de hydrate 21~4~2,6~ (diethyla~ino)~ 4~wrl~idlnl~1]~1 piperazinyl~l7~hydroxypregna~1,4,9(11)~trlene~
3,20~dione dlhydrochlorlde hydrate 7~ 21~4~4,6Abl~(dlethrlamlno)~2~wrimidlnyl~
piperazlnyl~^l7~hydroxypregna~1,4,9(11)~triene~
3,20~dione dlhydrochlorlde hydrate 77 1 6~methyl~21~4~(2-~lpyrldinyl5~1~plperazinyl~preg~
na~l,4,9(11)btriene~3,20~dlone 78 1 1 fS!~hydroxy~1 6afffl'methrl~21 ~ff4f~l 2--pyr idinyl)~
p~perazinyl]pre ~fa~l~4~dlene~3~20~dlone 79 1 6a~methyl~21 ff~t44(2~pyridinyl)f~1~piperazinyl~preg~
na~ 1, 4~dl ene~3, 20~dlone 21~i[4~[2,6~fbis(diethyla~ino)ftff4~-pyrlf~fidinyl]f~ l~
piperazinyllf~16~methylpregna~1, 4, 9 ( 1 1 )~trlene~
3,ZO~ dlone ~ ''` ' .
.

fl 1 3 . ~, 7 ~ 7 ~73~ 4236.1.2 81 21~t4~t2,6~bl~(diethylamlno)^4~pyri~idlnyl]~1 plperazlnyl~ hydroxy~16o~methylpregna~1,4 dlene~3,20-dione 82 21~[4~t2,6~bla~diethylamino)~4~wrlmldinyl]~1~
S piperazlnyl]~16~met~ylprsgna^l~4~dlene~3~2o~dlone EXAMPLE 83 16o~Methyl~21~[4~t2~6~bls(pyrrolldinO)~4~pyrlmldinyl]~1 plperazlnyl~pregna~1,4,9(11)~trlene~3,20~dlone dlmethane~sulronate A mlxture o~ 4~(2,6~dl~1~pyrrolidinyl~4~pyrlmidlngl)~1~piperazlne (PREPARATION A~22, 8.90 g), 21~lodo~16a~methylpregna~1,4,9(11)~triene~
3,20~dlone (PREPARATION S~22, 12.79 g) and 3.90 g Or dry pota~slum carbonate in 200 ml or acetonitrlle ls stirred at 60 ~or 4 h. The mlxture i~ partitioned between aqueous potas~ium carbonate and methyl~
ene chlorlde. The organlc phase ls rlltered through -Rodiu~ sulrate and 1~ concentrated. The resldue ls chromatographed on sillca gel (methylene chlorlde to 2S methanol/methylene chlorlde~ to giYe a foam. Thls roam ia crystalllzed ~rom ethyl acetate, dlssol~ed in ethyl acetate and treated wlth 5.16 g o~ methane sul~onlc acld. The ~alt ia trlturated wlth ethyl acetate to gl~e the title compound.
Example Amlno Substituted Sterold Product (XI) 84 11~hrdroxy~16o~methyl~21~[~t2~6~bis(pyrrolidl*
no)~4~pyrlmidlnyl~ plperazinyl3pregna~1,4~diene~
3,20~dlone 16~methyl~214~4~2,6~bls(pyrrolldlno)~4~pyrlmldl~
nyl~ plperazlnyl]pregna~1,4~dlene~3,20~dlone 86 16~oethyl~21~[4Ft2,6~bis(3orphollno)~4~pyrloldln~
yl~ piperazlnyl]pregna~1,4,9(11)~riene~3,20 dlone 87 11~hydroxy~16o~methyl~21~4~[2,6~bls(morphollno)~
~4~pyrlmldinyl~ plperazinyl3pregna~1,4~dlene~
3,20~dione 88 160~methyl~21~4~t2,6~bis(morpholino)~4^pyrmldn4 yl p1~piperazinyl]pre~na~1,4~dlene~3,20-dlone 89 21~t4~t2~6*bis(allylamino)~4*pyrlmldinyl]~1 piperazlnyl]~160~methylpregna~1,4,9(11)~trlene~
3,20~dione 214~44~2,6~bl~i(allylamino)~4~pyrimidnyl~b1 i 1 3~v~707 7411 4236.1.2 piperazinyl]~11a~hydroxy~16~methylpregna~1,4 diene~3,20~dlone 91 21~[4J~t2,6~bl3(allylaD~lno)~4~pyrlmldinyl]~1~
piperazlnyl]~16a~methylpregna~1,4~ dlenea3,20~dlone 92 21~(2ts(dlethyla~lno~ethyl)amlno]~9a~rluoro~
11B,17a~dlhydroxypregna~1 ,4~diene~3,20~dlone trlhydrochlorlde trihydrate 93 17~hydroxyi~21~(4~n~orphollnyl)~pregna~4,9(11)~dleh ne~3,20~dlone (E)~2~butanedioate (1~ alt 94 21~[4~2,6i~di~ pyrrolidinyl)-~4~pyrlmldlnyl]~
plperazinyl]~pregn*4-ene~3,11,20~ trione dl hydrochlorlde 21~[4*~2,6^dl~ pyrrolldlnyl)~4~ pyrlmldlnyl~
plperazlnyl]~pregna*4,9(11)~diene~3,20~dione dl hydrochlorlde 96 21 ~4~t6~(dlethylamino)~3;~(dlo~ethylam1no)~2 pyrldlnyl]~ plperazlnyl~1 7c~hydroxypregna~
4,9(11)~dlene~3,20~4ione dlhydrochlorlde 97 21 t4~2,6~dl~ pyrrolldlnyl)~4~pyr~ dlnyl]~
piperazinyl]~pregna~1, 4~diene~3, 20~dlone di~' hydrochlorlde 98 21At4~t2~pyrldin~ plperazlnyl]~ pregna~4,9(11)a dlene~3,20~dlone dihy4rochloride 99 3~,17a~dlhydroxy~21 ~4~i(2~pyrldlnyl)~1~plperazln~
yl]~-58~pregnane~11,20~dione dlhydrochlorlde hgdrate 100 21 -14~ace t yl~ 1 ~pi perazinyl)~17c~hydroxypregna~4,9 (t1)~diene~3,20~dlone tO1 17a~hydroxy-t21~(4~methyl~1~ piperazinyl)~pregna-4,9(11)~dlene~i3,20~dlone EXAMPLE 102 2,4~Bl~(diwrrolidlno)~6~piperazinopyrimldlne Followlng the procedure of Example O and nlaklng non~crltlcal ~rarlatlon~ but replaclng the diethylamine wlth wrrolldlne 2,4'-bl~(dl~
pyrrolldlno)~6~piperazinopyri~ldine i9 obtalned, NMR ~CDCl3) 1.05~1.3, 2.75~3.0, 3.25~3.6~ and 4.95 ~.
EXAMPLE tO3 17a~Hydroxy~t7B~t(2~wridinyl)methyl]a0lno]carbon andro~t~41~en~3~one (I) 1 71~tHydroxyl~17B~carboxyandro~t~4~len~3~ione in dry methylene " . .

~ .

1 3"`~J707 ~75~ ~236.1.2 chlorlde i9 reacted wlth DCC and HO~T at 20~25 ror 48 hr. ~Z~Pyridin~
yl)methylamine i~ added and the ml~ture stlrred at 20~25 for 8 hr.
The mlxture l~ washed with sodlum blcar~onate, water and saline, dried and concentrated. The con¢entrate ls rla3h chromatographod on silica gel eluting with ethyl acetate. The appropriate ~ractions are pooled and concentrated to gi~e the title compound, hlgh resolution mass spectroscopy 422.2585.
EXAMPLE 104 2i~4~(2,6~Di~ pyrrolidinyl)~4~pyri~idinyl)~1~piperaz~
inyl]pregna~4,9(11)~dlen~3~one hydrochloride (I) A mixture Or pregna~5,9(t1)~dien-21qal 3~ethylene glycol ketal (PREPARATION S~29, 0.6 g), 4~(2,6-di~1~pyrrolidinyl~4~pyrimidlnyl~
piperazlne (PREPARATION A~22, 0.5 g) and methanol (50 ml) are ~tirred at 20~25 for 1 hr. Sodium cyanoborohydride (0.12 g) ls added to the mixture and the resulting ~ixture is stirred at 20~25 ~or 18 hr. The methanol i~ remo~ed under reduced pressure and the ~ollds are washed twice wlth cold water and air drled. This materlal 19 triturated ~ith ether to gl~e a ~olld. Thl~ solld is stlrred wlth acetone (20 ml) and hydrochlorlc acld (6 N, 2 ml) for 1 hr at 20~25. The acetone is remo~ed under reduced pre~sure and the residue ls distributed b~tween chloro~orm (50 ml) and w dium hydroxide ~10S, 50 ml). The pha~e~ are ~eparated and the aqueou3 phase is extracted wlth chlorororm (50 d ).
The organic pha~es are comblned and dried o~er ~odlum aulrate and the organlc ~ol~ent remo~ed under reduced pres~ure to giYe an oil. The oil is flashed chromatographed on ~ilica gel (100 g) eluting with chlorofo~
rm/ ethyl acetate (3/23, the approprlate rractiOn~ are pooled and concentrated to gl~e the free base o~ the tltle compound. The ~ree base is reacted with ethereal hydrochloric acid, the solids are collected, triturated with ether twice and dried under a stream Or nltrogen to gi~e the title compound.
E%AMPLE 105 21~4~(2,6hDi~(4~morpholinyl)~4~pyrialdinyl)~1~plperazi-nyl~17o~hydroxypregna~4,9(11)~diene~3,20~dlone dihydro-chloride, hydrate (I) Followlng the general procedure of EXAMPLES 1~6A, 7, 8, 9~11 and 83 and making non*critical ~arlatlons but starting with the amlne Or PREPARATION A~23 and the ~terold of PREPARATION S~1, the title compound is o~tained.

~ 3 n o~ 7 o 7 ~76- 4236.1.2 EXAMPLE 106 ll~-Hydroxy-2l-l4-(2-pyridilly})-l-piper-azlnyl ] pregn-4-en-3-o~e dihydrochloride ( I ) Followlng the general procedure o~ EXAMPLE 104 and maklng nonacrl~
tlcal ~rarlatlon~ but starting wlth the amlne o~ PREPARATION A-6 and the ~terold o~ PREPARATION S~28, the title compound 19 obtained.
Exampl e Amino Substltuted Sterold Product (XI) 107 21-~4~(2,6~Di~ pyrrolidinyl~4~pyrlsldinyl)~1 piperazinyl~pregna~i4~1ene~3~one hydrochlorlde 108 20~Methyl~21~4~(2~pyridlnyl)a1~piperazlnyl]pregn~
~4~en;-3~one 109 16~Methyl421~4~2,6~bis(pyrrolidino)~4~pyri0idi--nyl~ piperazinyl3pregna~1,4,9(t1 )~triene~l3,20 dione~oonomethane3ulf`0nate ~onohydrate 110 21~-~4~(2,6~Di;~ wrrolid$nyl)~4~pyrimidlnyl) plperazlnyl~1a'~cyano~pregna~,g(11)~dien~31-one~
trlhydrochlorlde, hydrate 111 21~4~(2,64Dl-~ pyrrolidinyl)~4~pyrimidinyl~
plperazinyl]pregna~1,4,9(11)~trlene~3,204dlone dlhydrochlorlde 112 21~4~(2,6~Di~ pyrrolidlnyl)~4~pyrimldinyl)~1~
plperazinyl ]~20~methylpregna~ 1,4~dlen~-3~one ~ethanesulronate, hydrate 113 21~4~(2,6~Di~ pyrrolldlnyl)~4~pyrimldinyl)~
plperazlnyl3pre~naa1,4,9(11),16~tetraene~3,20-dione methanesul~onate, hydrate 114 21~t4~1(4,6~Di~ wrrolldin~ 1,3,5~triazin~2i~yl)~
~11 plperazinyl~--16~ethylpregna~1,4, 9(1'1 )~trlene-3,20~dlone dlhydrochloride 115 21~4~t2~4~t2~6~dl~ wrrolldinyl)ll4~pyrlmidln~
yl3~ plperazlnyl3ethyl]~1-piperazlnyl3~17~hydro~
xypregna~ 4,9(11)~dlene-~3,20~dione hydrochloride 1 6 21~ ~4~2,6~dl~(4~oorphollno)~4bpyrlmldlnyl]~1 plperazinyl]pregna~1,4~diene~3,20gdlone dlhydro~
chloride 117 21~4~2,6~bis(diethylamlno)~4~pyrimldlnyl]~1 L~J~ plperazlnyl]~6a~rlUoro~17a-hydroxy^16B~methyl~

1 3~7~

~-77~ 4236.1.2 pregna~i4,9(~ dlene~3,20~-dlone dlhydrochloride 118 6~-Fluoro-~l7~hydroxy/^16B~methyl~21^[4~t2,S~bl~
pyrrolldlnyl)~4~pyriD~1dlnyl~ `plperazinyl~
pregna~4,9(11)~dlene~3,2~dlone dihydrochlorlde 119 6~r~Fluoro~17~hydroxy~16~ethyl~21~4~(2~pyrldln~
yl)~ plperazlnyl]pregna~4,9(11)~dlene~3,20-dlone dlhydrochlorlde 120 21-[4-[5,6-Bis(diethylamino)-2-pyridinyl~-1-piperazinyl]-pregna-l ,4-dien~-3,20-dione dihydrochloride 121 16~methyl~21~4~2,6~ bis(l~pyrrolidlnyl)~4 pyrlmllnyl~ piperazlnyl]pregna~l,4-diene~3,20 dlone dihydrochloride 122 21-[4-~5,6-Bis(diethylamino)-2-pyridinyl]-1-piperazinyl]-16~-methylpregna-1,4,9(11)-triene-3,20-dlone hydrochloride 123 21~-~4~(2,6~dl*t1~ pyrrolldlnyl)~4~pyr~olldlnyl)~
plperazlnyl~l6a,17a~dlmethylpregna~1,4,9(11)~
trlene~3,20~dione hydrochloride ~f ~ ~ 124 21-L4-[5,6-Bl~(diethylamino)-2-pyridinyl]-1-piperazin;yl]-16a,17-dimeth~lpregna-1,4,9(11)-triene-3,20-dione hydrochlor~de , , _, . .. .
125 3,17~DihydroxyJ 21~t4~2,6~bls(1~pyrrolldinyl)~4~
pyrl~ldinyl~ plperazinyl~lg~ norpregna~1,3,5tlO)-trlen~20 one 3~methyl ether (E)~2.~butenedloate 1:1 ~alt EXAMPLE 126 3B~HYdro~Y~16~methylb21-~4~2,6~ bi3(1bpyrrolldinyl)1^4 pyrlmidinyl]~ piperazinyl]pregn~5~en-~20-~one 3B~HYdroxY~2l~$odo~l6~methylpregn~5~en~2o~one (10 g~ 1 added all ~ ~ at once to 4~{2,6~bls(1~pyrrolldinyl)~4;~pyrl~1dlnyl~plperazlne tl6 g) .~ ~ in DMF t400 ml) at 65 and then concentrated to 50 D~l under reduced pres~ure. The concentrate i5 added to sodium dihydrogen phosphate (0.3 M, 400 ml) and ethyl acetate (500 ~1). The pH i9 adJu~ted to 4.5 ~ith 35 0.3 M phosphoric acld. The ethyl acetate layer i~ 9eparated and ~ extracted ~lth sodiu~ dihydrogen pho~phate (0.3 M, 2 x 200 ml). The - ~ ethyl acetate extract 19 then wa~hed with pho~phoric acld (0.3 M, 400 . ' ~ 3 , ~ 7 0 7 ~78~ 4236.1.2 ml). The acld extract 19 stlrred and the ph 13 ad~u~ted to 3.5 wlth sodium hydroxlde (10S). The resulting percipltate 13 riltered, ~ashed with water ~200 ml) and drled to glYe the tltle compound.
Example ~mlno Substltuted Sterold Product (XI) -127 21~[4~6~(Ethylamlno)~2~pyrldlnyl]plperazlnyl]~16 methylpregna~1, 4,9(11 )~trlene~3,20~dlone hydrochlo~
ride 128 -- 21~[4~[6~(Dlethylamlno)~2~pyridlnyl]piperazinyl]~
16O~methylpregna~1,4,9(11)~trlene~3,20~dlone hydrochlorlde 129 3,17~Dlhydroxy~21~4~t2,6~bls(1~pyrrolldlnyl)~4 pyrlmldinyl]~1~plperazinyl]~19~norpregna~1,3,5(10)~
trlen~20~one (E)~2~butenedioate 1:1 3alt 130 3B~Hydroxy^16o~methyl~21~[4~t2,6~bl~
pyrrolldlnyl)~4~pyrlmidlnyl]~1~plperazinyl]~5a~
pregnan~20~one 131 3~*~ydroxy~16o~methyl421~4~2,6~bl~
pyrrolldlnyl)4~pyrlmldlnyl]al4piperazlnyl]~5a~
pregnan~20~one 132 16~Methyl~21h~4^~2,6~bls~(1hpyrrolldlnrl)~4 pyrlmldlnyl]~1~piperazinyl]pregna~1,4,6,9(11)~
tetraene~3,20~dione EXAMPLE A Con~ugated Dlene Formatlon A3say The rormation Or con~ugated dienes as assayed by 3raughler, J.
25Neurochem., 44, 1282 (1985), Bucher, Fund. Applied Tox., 3, 222 (1983) and Teln, Arch. 8lochem. 8iophy., 216, 142 (1982) 19 a standard pharma~
cological laboratory procedure userul for identirylng compounds ~hich lnhiblt llpld peroxldatlon. Slnce llpid peroxidation l~ lnYolYed in the pathophysiology Or central nerYou~ sy~tem trauma, compounds which 30lnhiblt conJugated dlene rormatlon are userul ln treating the condlti~
ons listed below.
In~lbltion Or con~ugated diene formatlon as measured by any Or the abo~e procedures or the modlfled procedure below demonstrates useruln~
ess ln treatlng spinal trauma, mild and/or moderate to seYere head 35ln~ury, subarachnold hemorrhage and subsequent cerebral ~aso~pasm, ischemlc (thromboembolic) ~troke, muscular dYstrophy, adrlamycln cardlac toxlclty, Parklnsoni3m, Alzheimer's dlsease, other degeneratiYe j, 13 `707 ~79~ ~236.1.2 neurologlcal dl30rder~, multlple scleroais, organ dama8e during reprefu~lon arter tran~plant, ~kln grart reJectlon, hemorrhaglc, traumatlc, or ~ept~c ~hock, ~e~ere burns, ARDS, allerglc reactlons, emphysema and post burn pulmonary compllcatlon. Further, an lnhlbltlon S o~ conJugated dlene rormation al~o demon~trates userulness ln prevent~
ing da~age rollowlng cardlopulmonary resuscltatlon, neurologlcal or cardlo~a~cular surgery and cardla¢ lnfarctlon.
Whlle not necessary to demon~trate conJugated dlene lnhibltion, the above as~ays haYe been modlrled as rOllow9 rat brain sy~aptosomes are prepared accordlng to the procedure de~crlbed ln J. Neurochem. 44, 1282 (1985). Synaptosomal suspension (10 ~1) Is added to 1 ml o~
physiological (normal) sallne containlng 1 S Lubrol P% (Slg~a Chemlcal Co. St. Loul~, Mo.), 100 ~M hydrogen peroxide and 100 ~M (or les~) Or the drug to be tested prepared in elther absolute ethanol or water dependlng upon solubllltr. The reactlon is ~tarted by the rapid addition Or 200 ~M rerrous ammonlum sulrate prepared in argon~purged water, The ~ample 1~ rapldly mlxed and the change ln absorbance at 232nm ~9 followed in a Gilford Response Spectrophotometer equipped with a rapld sa~pler. Due to the rapidity o~ the reactlon, rapid additlon Or the iron, rapld mixlng and sampling are obligatory to the accuracy Or the a~say. For best results absorbance readings of one/sec should be started ~lthin 5 sec rollowlng the addition Or lron. The initial linear rate o~ absorbance change during the rirst 30 sec Or reaction are compared ~ith the rate Or a reaction containing all reagents except synaptosomes. The dirrerence ln rates 19 the rate Or conJugated diene rormation. Rates with drug are compared to rates obtalned in the absence of drug and the S inhlbition is calculated. A compound that inhibits conJu~ated diene rormation by 50S or more i9 considered to be "actlve" .
The compounds Or Examples 2, 4, 5, 6B~8, 10~22, 24428, 30~34, 36~41, 43~45, 47, 50~54, 58~76, 83, 84, 86, 93~99, 103~107, 111, 112 and 11 4b122 demonstrate such actlvity by inhibltion Or conJugated dienes.
The above ln vitro te~t/assay is a ~tandard pharmacological laboratory procedure ror demonstrating compounds ~hich are u~eful ln treatinB the condltions llsted abo~e. Followlng the in vlvo mouse head in~ury procedure Or Hall, J, Neurosurg., 62, 882 (19B5) compounds ~hlch * trade mark 1 3~'-'7~

~80~ 4236.1.Z
~tatistlcally slgniricantly (p < 0.05) lncrea-~e the 1 hr neurological reco~ery rollowing head ln~ury are considered preferred compounds for treatlng the above condition~, the~e are:
S Increase ln 1 hr Post-InJury 5Crlp Test Score~ A~ter 3 m~/kg CODPOUnd Or Example 200.8 127 199.7 69 184.4 109 148.3 7 134.5 83 112.6 18 EXAMPLE B Arachldonic Acid Antagonlsm Assay (AAAA) The Arachidonlc Acld Antagonism Assay (AAAA) as set forth ln Thrombosls Re~., 9, 67 t1976) i9 a ~tandard laboratory procedure rOr demonstratlng antagonism Or the efrects Or arachidonic acid metabo~
lltes. Slnce these metabollte~ contrlbute to the pathologlcal problems as~oclated ~lth stroke, ~plnal trauma and head inJury, compound~ which antagonlze arachldonlc acld are u~eful in treatlng stroke, splnal trauma and head lnJury. Compounds whlch slgnlrlcantly ele~ate the LD50 Or arachidonlc acid in amlmals are consldered to be u-~erul rOr the traatment Or these csndltlons.
Whlle not neces~ary to determine arachldonlc acid antagoni~m, the abo~e assay has been modlried as rollows: Charle~ Ri~er male CFb1 mice welghing 18~22g are treated IY wlth the test compound dls~ol~ed in 1.0S
Tween~80 and 0.1% h~drochloric acld ln distilled water, 0.2 ml total volume. Flrteen minutes later ~odium arachidonate (90S pure) in physiological (normal) saline i~ in~ected into the tail vein. The LD50 i-~ measured using the Spearman~Karber method with a log dose interval Or 0.05 (N~6). Compound~ whlch ele~ate the LDso out91de Or the 95S
eonridence inter~al o~ the control LDso are considered to be "actiYen.
The compound~ or Examples 2, 4, 11~17, 19, 21, 22, 24, 25, 29, 41, 45, 47, 51, 53, 54, 57, 60, 62, 74, 75, 93 and 99-101 demonstrate arachldonic acid antagonism.
The ~ollowing are test re~ult~ in the Arachidonic Acid Antagoni~m A~say ror the compounds ldentified:
S or Control LD50 ~OOmg~k~ Compound or Example ~o.

. .

1 3"3707 ~81~ 4236.1.2 EX~PLE C Malonyldialdehyde (MDA) Formatlon A3say The MDA as~aya Or Buege and Aust, Methods In Enzymology, Flelsher and Packer Edltors, Academlc Pre~s, 1978, New York, Yol LII, p 302~310 and Kohn and LlYersedge, J. Pharmacol. Exp. Ther. 82, 292 (1944) are standard pharmacological laboratory procedures ror demonstrating the occurrence or lipid peroxidatlon by the rormation Or MDA. Since lipid peroxfdatlon 19 fn~ol~ed fn the pathophy~folo~y or central ner~ous system trau~a, compound3 ~hlch inhibit MDA formation are userul in treatlng the condit~ona li~ted below.
MDA rormation a3 mea3ured by any o~ the above procedure-~ or the modi~ied procedure ~elow demonstrate3 u3e~ulnes~ in treating spinal trauma, mild and/or moderate to se~ere head lnJurr, ~ubarachnold hemorrhage and ~ub~equent cerebral ~asospasm, 1sche0ic (thromboembollc) ~troke, muscular dy~trophy, adrlamycln cardiac toxlclty, Parklnsonlsm, Alzhel~er'a tiseaae, other degenerative neurological di~order~, mult~ple ~clero ls, or~an damage during reprerw 10n arter tran~plant, skin Brart reJection, hemorrhagic, traumatic and septic shock, se~ere burn~, ~RDS, allergic reactions, emphy~ema and po~t burn pul~onary eo~plicatlon. Further, M~A rormatiOn also demon~trates u~e~ulne3~ in pre~enting damage rollowing cardiopulmonary rea w cltation, neurologlcal or card~ovascular ~urgery an~ card~ac inrarction, Whlle not nece-~aary to determlne HDA rOr~at$on, the abo~e as~ays ha~e been modlrled a~ rollow~: rat brain ~napto~ome-~ are prepared as descriOed ~n the Example about the con~ugated diene a~say, except that the r~nal waah or the aynaptoao~e~ and r~na~ suapenaion are in physio~
logical (normal) ~aline in which the pH haa been adJu3ted to 7Ø The synaptosome~ are incubated rOr 10 miQ at 37 1n physlological (normal) sal~ne pH 7.0 (total t~olume ~ 100 ul~ conta~n~n~; 10 ul synaptosomal 3u~penslon, 10S DMSO plus or mlnu~ drug, 150 uM Fe~ and 50 uM Fe~.
Tne lncubation ia atarted by the rapid addltion o~ iron to the other~
~ 35 wiae complete reactlon. The iron aolutlon~ are prepared rresn a~
err~c chlorlde and ferrou~ ammonium ~ulrate ln argon~purged water.
Following the 10 s1n lncubàtion, the reaction is stopped by the - .

~ 3 '` ' ;~ " 7 82~ 4236.1.2 addltion Or 500 ul lce~cold 12S trichloroacetic acld prepared ln 0.5 N
hydrochoric acld. Water (300 ul) 19 ~hen added along wlth 100 ul Or treshly prepared thlobarbituric acld (3.3S in 0.5N ~odlum hydroxide) and 10 ul Or 5mM de~rerrioxamlne. The ~ample l~ then heated ln a bolllng ~ater bath rOr 20 olnutes. The sample~ are cooled and centrl~
5ruged ror 15 minutes at 1500 xg and the absorbance Or the ~upernatant tractlon ia read at 532 nm. The S lnhlbltion o~ MDA rormation l~
calculated b~ dl~lding the absorbance Or aample containing drug by the abaorbance Or ~ample3 lncubated without drug. Reaction blanks are sample~ lncubated ln the abaence Or iron. A compound that lnhibits MDA
lOtormation by 50S or more at a concentratlon Or 200yM or le~ is consldered "actlve".
The compounds of Examples 17, 47, 49~52, 62, 67~71, 73~75, 83, 86, 95-g7, 104, 107, 110, 111~113, 118, 120, 121, 125, 127 and 129 demon~t~
rate such acti~lty by inhlbitlon of MDA tormation.
15The aboYe in ~itro test/a~ay l~ a ~tandard pharmacological laboratory procedure for demonstrating compounds which are userul ln treatlng the condltion~ llsted abo~e. Followlng the in vlvo mouse head ~nJury procedure or Hall, J. Neurosurg., 62, 882 (1985) compounds ~hich ~tatistically slgnlrlcantly (p < 0.05) lncreaae the 1 hr neurologlcal 20reco~ery rollowing head lnJury are con~idered prererred compound3 tor treatlng the abo~e condit~on~, these are:
S Increa~e ln 1 hr Post~In~ury Grlp Te~t Scores Arter 3 mg/kg Compound Or Example 200.8 127 199.7 69 184.4 109 148.3 70 134.5 83 il2.6 18 30 E%AMPLE D AcylCoA:Chole~terol Acyltransrera~e (ACAT) Inhlbltlon Assay ACAT esteriries arterlal cholesterol whlch la a key reactlon in the developoent o~ atheroaclerosis. The procedure Or Bell, Can. J.
Biochem. 60, 967 (1982~ provide~ a ~tandard procedure ror demon~trating which compound~ inhiblt ACAT and theretore lnhlbit rormatlon ot esteriried arterlal chole~terol thereby preventln~ atherosclerosia. In " ;: 1 3~`707 ~

~83~ 4236.l.2 the ACAT a~say lt 1~ prererred to use Fu5AH cells, ~ee Llpid~ 9, 526 (1974). Accordlng to thls procedure, compounds whlch lnhlblt ACAT
actl~lty equal to, or greater than, that o~ chlorpromazlne are consl~
dered "actl~e".
The compounds or Examples 3, 17 and 18 are actlve in lnhlb~tlng ACAT-The followlng are test results ln the ACAT assay ~or the compounds ldentlrled:
S Inhlbltlon Or ACAT
(5 wg/ml) _ Compound Or Example 63.9 48.4 18 32.2 17 EXAMPLE E Antlatherosclerosls Soreen ln Susceptable to Experlmen~
tal Atherosclerosls (SEA) Japanese Quall Demonstratlon Or antlatherosclerotic act$~1ty o~ a compound ln SEA
Japanese Quall la done by showlng that the compound reduces the ~erum and arterial chole3terol ln quall red an atherogenic dlet. Thls -~tandard laboratory procedure rOr demon~trating a reductlon ln arterlal and serum cholesterol ln SEA Japanese quall has been descrlbed by Stevens ln Artherosclerosis 56, 313 (1985). ~hlle not neceqsary, some mlnor modlricatlon~ rOr extraction Or cholesterol rrom the artery ha~e been made. These are as rollows: frozen arterle~ are homogenlzed ln hexane/lsopropanol (3/2) and She ~olume adJusted wlth Trlton 100 ~olutlon (1.5S ln hexane/l~opropanol) to 7 ml. After standlng 12 hr at 20~25, the supernatant, obtained by low speed centrafugatlon ls e~aported until dry and then the resldue 19 suspended ln 0.5 ml of 5$
Triton 100 in lsopropanol. This su~pension ls lncubated ror 10 min at 45 to dlssol~e the material. Thls solutlon a~ well as the diluted serum sample~ are analyzed ror cholesterol by ~tandard cllnical 3~ chemlstry analyzer methods. Accordlng to the abo~e procedure compounds which decrease serum or arterial cholesterol > 30 S are considered to be ~actlven.
Compounds whlch reduce serum and arterial cholesterol and are u~eful in treatlng artherosclerosl~ and its complicatlons; rOr example, reduction Or serum cholesterol by dru~9 reducea the incidence Or coronary heart disease, JAMA 251, 351 (1984) and JAMA 251, 365 (1984).

* trade mark , 1 3~'`7n7 ~84~ 4236.1.2 The compound o~ Example 3 de~onstrate~ reductlon Or ~erum and arterial chole~terol.
EXAMPLE F In~ibltion Or Interleukln~1 The lnhibltion Or interleukln~1 lnduced T cell prollferation asaay, Proc. Nat. Acad. Scl. USA, 78, 1133 (1981) l-~ a ~tandary laboratory procedure ror demonstrating lnhlbltlon Or interleukln*1 bloactl~ltle~. Slnce people wlth arthrltis make exce~ lnterleukin 1, compound3 ~hich lnhiblt the activlty Or lnterleukin 1 are userul ln the treatment Or arthritl~. Accordlng to thl~ procedu~e compounds which lnhlbit the actl~lty Or lnterleukin 1 greater that 30S at 10~6 M are consldered to be "actl~en.
The compounds Or Examples 21, 37, 47, 83, 84, 86, 94, 96, 97, 101, 105 and 120 demonstrate inhlbition Or interleukln 1.
S Inhlbitlon at 10~6 MCompound of Example 56 t20 EXAMPLE G Inhlbitlon Or Mucou~ Secretlon The lnhSbitlon Or mucou~ ~ecretlon assay or John~on Int. Arch. o~
Allergy and Applled I~munology 75, 97 (1984) i3 a standard pharma~
cological laboratory procedure for de~onstrating inhlbit~on ot mucous ~ecretlons and thererore u~erulne~s in pre~enting and/or treating ~UOOU9 3ecretlons, asthma, ln~lammatory lung diseases, bronchltis, allergic reactlon~ and ARDS. According to this procedure comp~unds which lnhlbit or block enhancement or lnduced ~ucou~ secretions ~hen te ted are considered to be ~acti~en.
The compounds Or Examples 2, 4, 16, 18, 83 and 105 demonstrate such actl~lty.
The te~t result~ dl~clo~e that the compound~ ot Example3 2, 83 and 105 are the prererred mucous inhlbitors, EXAMPLE H Asthma Test in O~albumln Sensltized ~ulnea Pigs The o~albumln ~en~ltlzed gulnea pig test, Brlt. J. Pharm. 78, 67 (1983) l~ a standard laboratory procedure rOr demonstratlng lnhlbitlon Or bronchoconstrlctlon and thererore use in treating~pre~entlng asthma.
Whlle not necessary the abo~e test ha~ been modlrled a~ rollows. ~ale 1 3r'~?~
.. ~ , ~85~ ~236.1.2 gulnea plg~ (500~700 g at thc tlme Or antlgen challenge) are en~ltlzed by IH lnJectlon Or ovalbumln (5S, 0.35 ml) lnto each hlnd llob and repeated 6 days later. Fl~e weeks arter the lnltial lnJectlon Or o~albumln, the anlmal~ are anestheslzed wlth urethane (1.5 g/kg lntra~
perltoneally), the trachea cannulated and the lung~ ~entllated at constant ~olume uslng a Har~ard Apparatuq Rodent Resplrator. Tracheal pressure 19 measured rro~ a slde~arm of the tracbeal cannula ~ia a Statham P23AC pres-~ure transducer Or a furnes~ control mlcromanometer.
The chest ls opened along the mld~llne. Bronchoconstrlction ls mea~ured as the absolute lncrease in transpulmonary pre~ure in cm water with respect to the atmoaphere. Blood presqure i9 recorded uslng a Statham P23Db pres~ure transdu3er vial a catheter lnserted lnto a carotld artery. Heart rate i3 derl~ed Srom the blood pre~sure slgnal uslng a Craqs 7P4F tachograph. A Jugular veln is catheterlzed rOr lnJectlon o~ drugs and antlgen. The amlmals are pretreated wlth the rollowlng: lndomethacln (10 ~g/kg, 15 mln prlor to antlgen), pyril~
amine maleate (2 mg/kg, 10/11 mln berore antigen), and propranolol (0.25 mg/kg, 5 ~ln prlor to antigen). Antigen challenge consl3ts of o~albumin (0.3 mg/kg) gl~en IV.
The compound3 to ~e tested are admlnlstered by either IY (compound Z precede~ the antlgen challenge by rour mlnutes), orally (fasted anlmals are dosed at elther 2 or 4 hr prlor to challenge) or by areosol (the compound is nebullzed thru the HarYard resplrator and dlrectly lnto the tracheal cannula 180 sec four mln prior to the IV antigen challenge).
Vehlcles include IV (~aline), oral (emulphor or 0.1S Tween 80) or ror aerosol (DMS0).
The antlgen proYocatlon produce3 a slowly deYeloplng bronchocon~
~trlction ~hlch la~ts at least 15 min. The percent lnhibltlon at varlous tlmes points arter antlgen challenge compares the test compound to control animals (Yehicle only). ~ccordlng to thls procedure compound3 which gl~e 50S or greater inhlbitlon at 10 mg/kg are consl~
dered to be "acti~e".
EXAMPLE I Inhlbitlon Or Tumor Crowth The rertlle egg or chlck embryo assay Or Folkman, Sclence 221, 719 (1983) is the standard pharmacological laboratory procedurs rOr demon~
3trating lnhlbltion Or angiogenesi~, and therefore or tumor growth ~Folkman, ln Ad~ances in Cancer Research, C. Klein and S. ~elnhouse, * trad~ mark . .

j .l 1 3r ,7(~7 . .

~86~ 4236.1.2 ed., 43, 175 (1985)]. Accordlng to thi~ procedure compound~ which are con~ldered to be "actlve" (l.e. antlanglogenlc) 8l~e an ava~cular zone Or 4 om or greater ln ~ome embryos ~hen te3ted at 50 pg~l O ~1 ln the presence Or 50 ~g~10 ~ Or heparin.
The compound3 Or Example~ 2~5, 6B, 8~10, 12~18, 20, 21, 24, 26~30, 532, 33, 34, 36, 37, 39~41, ~3~48, 51~55, 63, 64, 83, 86, 97, 99, 104 and 105 demonstrate lnhibltion Or anglogene~
The rollowlng are test result3 ln the Folkman a~say ror the compounds identi r led:
S Or E~bryo9 ~lth 4 mm or Creater A~ascular Zone Coopound Or Example No.
91 21, 16 EXAMPLE J A~plrln Induced Ulcer Te~t The a~pirln/cold lnduced ulcer as~ay Or Rain~rord, Agents and 20Actlon~ 5, 553 (1975) ls a standard pharmacologlcal laboratory proced~
ure ror demonstratlng antl~ulcer activity. ~ccordlng to this procedure compounds ~hlch glYe a 50S or more reduction Or ulcer index are considered to be "actlYe~.
The co~pound Or Example 16 demon-qtrate~ anti~ulcer acti~ity.

* trade mark - . , -- ` 1 3 r' 3 7 ~ 7 -8j~- 4236. 1 . 2 CIIA RT A

(C112)n-~ ~ 21 = 210 . ~ Rl 75( Ia ) ~ ~ ~;. RRl 665 R33 ~

(CH2)n-N \R

Rll~^R165 (Ib) , ~~ Rl 66 H~J

~CH2)n~N \
-Z

Rl l ~ ~ ~'Rl 6s ( I I) ... . . . .. . . ., .. . . . , . .. , . . . . . ~ ,_. ... . . . . . .

I ~

1 3~,?G7 88 -~8- 4236. 1 . 2 C~ART B
(C~2) ~ Zl . _z Rl 1 ~ ~ R161 ( lIIa) (CH2) -N ~ 2 ¦= R21 0 R ( IIIb) 11 q~ R

H~

(CHz) -N ~ 2 =~
(IV) Rl l ~ R165 :: ~ 35 1~ ~-~
: ~ ~ R

~67 R68 ~::
' ' '-' ' , ~: ' .

`^` 13~?~,7 "
-89- 4236.1 . 2 CHA RT C
/ R
( CH2 ) -J~
Cl~

~ 63 (Va~

R

(CH2~p-N/ 2t C~
Rl 1 ~63 ~J 164 (Vb ) H~
HO H

~J

~ , ,. .. ` E17 El~J~ E16 ~v;

5~

: ::

` . .

, ~ 3~i `7C7 90 4236.1.2 CHART D

Formula Name Che~ical Structure No.

l-piperazlnyl-(C r C4) -(C2-C4 alkyl)-N~___/N-(Xl or X2)o l tB~
optionally substituted in the 4-po~ltion ~
l-piperazinylacetyl -acetyl-N N-%2 tl,]
substituted in the 4-position ~~~~\
1-piperazinylcarbonylmethyl-carbonylmethyl- V _X2 tM]
substituted in the 4-posltion -N ~
2-(carboxy)-1-pyrrolidinyl ~ tC-l]

COOH

~
2-(carboxy)-1-piperidinyl - ~ tC-2]

COOH

2-(cart~cJ) l he,l~ethyl~nel~lAo -n~ ~C-3J
tOOH

~; 35 2~(carboxy)-1-heptamethylenelmino -N ) tC-4 COOH

.. . .. .. . . .... . .. .. .. .. . ..

~, , . ' 1 3 ,~ 7-91- 4236.1.2 CHART D - contlnued Formula Name Chemlcal StructureNo.

l-plperazinyl sùbstltuted ln -N~ N-(CH2)r-CO-R228 tD~
the 4-posltlon ~
l-piperazinyl -~ub~tituted in -N~ N-~C~2)f-x2 tE]
the 4-po~ition l-piperazinyl ~ub~tituted in /---\N-(CH2)f-Xl tF~
the 4-posltion ~ / OH
4-hydroxy~1-piperidlnyl - ~ tC]
sub~tltuted ln the 4-po~itlon 1-plperazinyl substituSed in -N~ N-(CH2~-CO-NR229-X2 tN~
the 4-position .. _ , .. ...... . .. . ... . .
~, , 1 3 r ~`7 0 7-92- 4236.1.2 CHART E

Formula Name Chemlcal Structure N .

~ iz-(c~l2)~-c-(cN2)d-~Nz-N -~CN2-~CH2) _ ~ ~b~
3-pyrrolin-l-yl ~

pyrrol-1-yl optlonally -N ~ Cl-C3 alkyt ~c]
substituted ~,~ Cl -C3 a 1 kyl piperldin-1-yl optlonally ~ ~d~
~ubst~tuted Cl -C3 a I kyl 1,Z,3,6-tetrahydropyrldlr.-1-y~ ~ [~

l-hexamethylenelmino containlng a 3- or 4- -N ~ tr, double bond or 3- and 5- double bond~

~--~ /a number of 1,4-dlbydro-1-pyrld~nyl -N ~ tif~erent groups ~g~
sub~tituted ~n the 4-posltion a number of ::

,, ~ , .. . . . .. ... ... . . . . . . ...... . . . . . .. . . ..
:

j !

93_ 4236.1.2 CHART F

Formula Name Chemical Structure No.
-~ (R212 )0-2 ~4~
pyridinr2-, / ~ (1 () 0-1 212)0-2 N (2) (o) 0-1 ~ R212)0-2 or 4-yl optlonally substituted ~ -()0-1 (3) optlonally as the N-oxlde : 1,3,5-triazln-4-yl or the (~212)0-N-oxide thereof optionally t~ ~
~ubstituted at the 2- and~or ~ ~ N-()o-l (4) 6- position (R

pyrimidin-4-yl or the N-oxlde N (R212)0-thereof optionally substituted ~ ~ ~ K-(0) at the 2- and/or 6-position ~ 0-1 (R21 2)0-1 ;~'~' ' ' ' ' ' '' ' .

~ ~ `
1 3~7~7 4236.1.2 C~ART F - contlnued Formula N _ Chemlcal Structure No.

N R212 )0-2 _<~ X> (6) pyrimidln-2-yl optlonally N J
~ubstituted ~ N ~ R212)0-2 pyrazin-2-yl optlonally ~ N
sub~tltuted ~ / ~ R212)0-2 imldazol-2-yl optlonally N (8) ~ub8tltuted Cl-C3alkYl or -X

N- N
1,3,4-trlazol-2-yl optionally ~ ~ ~ ( 212)0-1 sub~tltuted N (9) Cl-C3 alkyl or -X

lmldazol-4- or 5-yl optionally ~ R212)0-2 (~0 substituted N
\tl-C3 alkyl or -X

benzo[b~th~en-Z-yl ~

.. . . ... . . .. .. .

.

1 3C~707 4236.1.2 CHART F - contlnued Formula Na~e Chemlcal Structure No.

lndol-2-yl ~ (12b) benzotb~thlazol-2-yl ~ 5 ~ (12c~

benzimldazol-2-yl N ~ (t2d) 4-t2-t4-~2,6-bls-(~-pyrrolldlnyl)-4-pyrlmldlnyl~ CH CH -N N~
plperazlnyl~ethyl~- 2 2 ~ N - ~
plperazLnyl ~ (13) . .: ,:
' ~ I''' .

--1 3 r~ ~v~ 7 0 7 ~
-96- 4236. 1 . 2 CHART G

~--\
-N~ N-C~3 ~)1 -N30H .)3 ~--~CH2CH20H
-N~ J4 :

-N O .)5 ~ ' ' ~
~` ~

. . . . . .. .. ... . .. . ........................ ..

i !

1 3 ~, ` 7 11 7 _97_ 4236.1.2 CHA RT H
Compound of Exampls Physical Data m.p. MS tM ~ H]+
'0 See ~pecif ication 1 None 3 189-194 dec 4 170-174 dec 577 6A 172-174~
63 ' 195-197 8 209-211 491 .
9 108-110 561-, 174-'75-5 566, 568 12 240-245 568, 570 14 1 g5-2000 631 17 154-i 59 645 24 187 dec 491 , . , ... .. , ........ ., .. .. ,~ . .

13",707 .
~9~~ 423~.1.2 CHART H - ¢ontinued 233 dec 37 68~

39 273-275 dec 201 dec 41 210 dec 535 42 219 dec 563 43 219 dec 492 44 204 dec 202 dec 47 193-196 dec 641 48 243-2500 dec 49 197-208 dec 53 218 de¢ 635 ~ : 58 1690 ded : 59 181 dec 184 dec 61 142 dec : ~ 64 156-i58 ; , . . . . .

j !

,` 7 ~1 7 -99- 4236.1.2 CHART H - continued 69 ~ 634 71 185 dec 73 220-230 dec 74 215 dec 165-175 dec 76 . 160-t65 84 215 dec 86 127 dec 657 92 220-225 dec 94 221 dec 217 dec 96 1820 dec 97 217 dec 98 173 dec 99 195 dec 100 i52-155 102 See 3pecification 103 ~ See specirlcation 104 212-214 dec 599 105 205-208 dec 661 106 243-245 dec 479 . 108 . 476 109 181-185 dec 110 74,388E 19129-FJ~D-22 111 210 dec ~; ~ 35 113 609 1t4 219 dec 115 215-222 dec 741 (M~) ~:
-- .. .

, :, .

~` 1 3~Jni707 ~

-lO0- 4236.1.2 CHART H - contlnued 116 644 (M~) 117 664 (M ' ) 118 660 (M~) 119 522 (M~ ~
120 615 (M') 121 626 (M~) 122 627 (M~ ) 125 164 dec 629 (M~) 127 194 dec 129 179-185 dec 2~

:

: 35

Claims (27)

1. An amino substituted steroid of formula XI

(XI) where:
(A-I) R6 is .alpha.-R6l:.beta.-R62, R10 is .alpha.-R101:.beta.-R102 and R7 is .alpha.-H:.beta.-H, where one of R61 and R62 is -H, and the other is -H, -F, or C1-C3 alkyl, R102 is -CH3, R10l and R5 taken together are -(CH2)2-C(-R33)-CH-or CH-CH-CO-CH-, where R33 is -O or .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5;
(A-II) R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64, R10 is .alpha.-R103:.beta.-R104 and R7 is .alpha.-H:.beta.-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 are -(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 .alpha.-R65:.beta.-R66 where one of R65 and R66 is -H, and the other is -H, -F, or C1-C3 alkyl and R7 is .alpha.-H:.beta.-H;
(A-IV) R5 is .alpha.-R57:.beta.-R58, R6 is .alpha.-R67:.beta.-R68, R7 is .alpha.-H:.beta.-H and -102- 4236.1.2 R10 is .alpha.-R107:.beta.-R108, where one of R57 and R57 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 .alpha.-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;
where:
(C-I) R11 is .alpha.-R111:.beta.-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 .alpha.-H:.beta.-R114 where R114 is -Cl or -OH;
(C-III) R9 is -H or -F and R11 is -O or .alpha.-R115:.beta.-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 .alpha.-O-CO-R117:.beta.-H, where R117 is (A) C1-C3 alkyl, (B) C1-C12 alkoxy, (C) furanyl, (D) -NR122R123, 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 acylamino and -NH-CHO
or with 1 -F or -CF3;
where:
(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 18 -C(=Z)-(CH2)n-NR21R210, where Z is =O, =CH2 or R179:-H where R179 is -H or -CH3, where n is 0, 1 or 2, where (A) R21 is -103- 4236.1.2 (1) -(CH2)m-NR211-X2, where m is 2, 3 or 4, where R211 is -H or C1-C3 alkyl, where X2 is: [A]
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R212, being the same or different, where R212 is (i) -F, (ii) -Cl, (iii) -Br, (iv) C1-C5 alkyl, (v) -CH2-CH=CH2, (vi) -X1, where X1 is as defined above, (vii) -NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CH2-CH=CH2, (viii.alpha.) *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, (viii.beta.) *CH2-CH2-(CH2)c-C-(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 C 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, (xii) -NR217-(CH2)e-Q where Q is 2-pyridinyl where R217 is -H or C1-C3 alkyl and e is 0 through 3, (1) (b) 1,3,5-triazin-4-yl or the N-oxide thereof -104- 4236.1.2 optionally substituted at the 2- and/or 6- position with R212 is as defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereof optional-ly substituted at the 2- and/or 6- position with R212 is as defined above, (5) (d) pyrimidin-2-yl optionally substituted at 4-and/or 6- position with 1 or 2 R212 as is defined above, (6) (e) pyrazin-2-yl optionally substituted with 1 or 2 R212 as is defined above, (7) (f) imidazol-2-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (8) (g) 1,3,4-triazol-2-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with R212 as defined above, (9) (h) imidazol-4- or 5-yl optionally substituted in the 1 position with C1-C3 alkyl or -X1, where X1 is as defined above, and further optionally substituted with 1 or 2 R212 as defined above, (10) (i) benzo[b]thien-2-yl, (12a) (j) indol-2-yl, (12b) (k) benzo[b]thiazol-2-yl, (12c) (l) benzimidazol-2-yl, (12d) (m) 4-[2-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]ethyl]piperazinyl, (13) (2) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B]
(3) -X2, as defined above, [O]
(4) -(CH2)m-X4 where m is as defined above and where X4 is (a) -O-CH2CH2-Y, where Y is C1-C3 alkylamino, di(C1-C3)alkylamino where the alkyl groups are the same or different, C3-C6 alkyleneimino, optionally substituted with 1 or 2 C1-C3 alkyl, (b) -NR220CH2CH2-Y, where R220 is -H or C1-C3 alkyl and Y is as defined above, (c) -(CH2)g-N(R220)-X2, where g is 2, 3 or 4, and -105- 4236.l.2 where R220 and X2 are as defined above, [H]
(5) -(CH2)m-NR222R223, where R222 is -H or C1-C3 alkyl and R223 is -X1 or -X2 as defined above, or R222 and R223 are taken together with the attached nitrogen atom to form a saturated mono-nitrogen C3-C6 heterocyclic rlng and where m is as defined above, [I]
(6) (CHCH3)b-(CH2)f-R224, where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R224 is phenyl substituted with 1 through 3 -OH, C1-C3 alkoxy, -NR225R226 where R225 and R226 are the same or different and are -H, C1-C3 alkyl or are taken together with the attached nitrogen atom to form a C4-C7 cyclicamino ring,[J]
(7) -(CH2)i-X2, where i is 1 through 4 and X2 is as defined above, [K]
(8) (1-piperazinyl)acetyl substituted in the 4- position by X2 where X2 is as defined above, [L]
(9) (1-piperazinyl)carbonylmethyl substituted in the 4- position by -X2 where X2 is as defined above, and [M]
(B) R210 is (1) -H, (2) C1-C3 alkyl, (3) C5-C7 cycloalkyl, (4) -(CH2)m-NR211-X2, where m, R211 and X2 are as defined above, [A]
(5) (1-piperazinyl)-(C2-C4)alkyl optionally substituted in the 4- position with -X1 or -X2 as defined above, [B]
(6) -(CH2)m-X4, where m and X4 are as defined above, [H]
(7) -(CH2)m-NR222R223, where m, R222 and R223 are as defined above, [I]
(8) -(CHCH3)b-(CH2)f-R224, where b, f and R224 are as defined above, [J]
(C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (1) 2-(carboxy)-1- pyrrolidinyl optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-1]
(2) 2-(carboxy)-1-piperidinyl optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-2]

-106- 4236.1.2 (3) 2-(carboxy)-1-hexamethyleneimino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-3]
(4) 2-(carboxy)-1-heptamethyleneimino optionally as the C1-C3 alkyl ester or as a pharmaceutically acceptable salt, [C-4]
(5) 1-piperazinyl substituted in the 4- position with R228-CO-(CH2)j- where R228 is -X1, -NR229X1 and 2-furanyl, where R229 is -H or C1-C3 alkyl, where j is 0 through 3 and X; is as defined above, [D]
(6) 1-piperazinyl substituted in the 4- position with X2-(CH2)j-, where X2 and j are as defined above, [E]
(7) 1-piperazinyl substituted in the 4- position with X1-(CH2)j-, where X1 and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4-position with X1 as defined above, [G]
(9) 1-piperazinyl substituted in the 4- position with X2-NR229-CO-(CH2)i-, where X2, R229 and i are as defined above; [N]
(D-II) R16 is .alpha.-R163:.beta.-R164 where one of R163 and R164 is -H and the other is -H, -F, -CH3 or -OH, and R17 is =CH-(CH2)p-NR21R210, where p is 1 or 2, where R21 and R210 are as defined above;
(D-III) R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-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, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, where X1 is as defined above, and where R176 is -C(=Z)-(CH2)n-NR21R210, 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-NR21R210, where Z, n, R21 and R210 are as defined above;
and pharmaceutically acceptable salts thereof, if desired, and hydrates and solvates thereof, if desired;
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 .alpha.-R10l:.beta.-R102, .alpha.-R103:.beta.-R104, .alpha.-R107:.beta.-R108 or .alpha.-R109:B-R1010, (II) R17 is =CH-(CH2)p-NR21R210, only when R10 is .alpha.-R101:
.beta.-R102, .alpha.-R103:.beta.-R104, .alpha.-R107:.beta.-R108 or .alpha.-R109:.beta.-R1010, (III) R5 and R10 taken together are =CH-CH=C(OR3)-CH=, only -107- 4236.1.2 when R17 is .alpha.-R175:.beta.-R176 or the 16,17-acetonide of a compound where R16 is .alpha.-OH:.beta.-H and R17 is .alpha.-OH:.beta.-C(-Z)-(CH2)n-NR21R210, and (IV) R5 is .alpha.-R57:.beta.-R58, only when R17 is .alpha.-R175:.beta.-R176 or .alpha.-OH:.beta.-C-(-Z)-(CH2)n-NR21R210, or the 16,17-acetonide thereof.

2. An amino substituted steroid according to claim 1 where:
(A-I) R6 is .alpha.-R61:.beta.-R62, R10 is .alpha.-R101:.beta.-R102 and R7 is .alpha.-H:.beta.-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 .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5;
(A-II) R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64, R10 is .alpha.-R103:.beta.-R104 and R7 is .alpha.-H:.beta.-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 are -(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 .alpha.-R65:.beta.-R66 where one of R65 and R66 is -H, and the other is -H, -F, or C1-C3 alkyl and R7 is .alpha.-H:.beta.-H;
(A-IV) R5 is .alpha.-R57:.beta.-R58, R6 is .alpha.-R67:.beta.-R68, R7 is .alpha.-H:.beta.-H and R10 is .alpha.-R107:.beta.-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 .alpha.-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;
where:
(C-I) R11 is .alpha.-R111:.beta.-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 .alpha.-H:.beta.-R114 where R114 is -Cl or -108- 4236.1.2 -OH;
(C-III) R9 is -H or -F and R11 is =O or .alpha.-R115:.beta.-R116- where one Or 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 .alpha.-O-CO-R117:.beta.-H, where R117 is (A) C1-C3 alkyl, (B) C1-C12 alkoxy, (C) furanyl, (D) -NR122R123, 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, C1-C3 alkoxy, -NH2- C1-C3 alkylamino, di(C1-C3)alkylamino, where the alkyl groups are the same or different, 1- pyrrolidinyl-, 1-piperidinyl, C2-C4 acylamino and -NH-CHO;
where:
(D-III) R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-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, -CH2CH3, C2-C7 alkanoyloxy or -C-CO-X1, where X1 is as defined above, and where R116 is -C(-Z)-(CH2)n-NR21R210, where Z is =O, -CH2 or R179:-H- where R179 is -H or -CH3, where n is 1, where (C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (6) 1-piperazinyl substituted in the 4- position with X2-(CH2)j-, where j is 0 and where X2 is:
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereor optionally substituted by 1 or 2 R212, being the same or different, where R212 is (iv) C1-C3 alkyl, (v) -CH2-CH-CH2, (vi) -X1, where X1 is as defined above, (vii) -NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CH2-CH-CH2-, (viii.alpha.) *CH2-(CH2)q-CH2-N*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the -109- 4236.1.2 formation of a ring, where q is 1 through 3, (viii.beta.) *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 or a ring, where C 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 or 5, [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]
(xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C1-C3 alkyl being the same or different, [g]
(xvi) C1-C3 alkoxy, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 is as defined above, (4) (c) pyrimidin-4-yl or the N-oxide thereof optional-ly substituted at the 2- and/or 6- position with R212 is as defined above, (5) (d) pyrimidin-2-yl optionally substituted at 4 and/or 6- position with 1 or 2 R212 as is defined above, (6)[E]
(7) 1-piperazinyl substituted in the 4- position with X1-(CH2)j-, where X1 and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4-position with X1 as defined above, [G]
and pharmaceutically acceptable salts thereof, desired, and hydrates and solvates thereof, if desired.

3. An amino substituted steroid according to claim 2 where:
[A-I) R6 is .alpha.-R61:.beta.-R62, R10 is .alpha.-R101:.beta.-R102 and R7 is .alpha.-H:.beta.-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-.

-110- 4236.1.2 or -CH=CH-CO-CH=, where R33 is =O;
where:
(C-I) R11 is .alpha.-R111:.beta.-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-III) R9 is -H and R11 is .alpha.-R115:.beta.-R116, where both R115 and R116 are -H;
where:
(D-III) R16 is .alpha.-R165:.beta.-R166 and R17 13 .alpha.-R175:.beta.-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, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, where X1 is as defined above, and where R176 is -C(=Z)-(CH2)n-NR21R210, where Z is =O, -CH2 or R179:-H, where R179 is -H or -CH3, where n is 1, where (C) R21 and R210 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of (6) 1-piperazinyl substituted in the 4- position with X2-(CH2)j-, where j is O and where X2 is:
(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted by 1 or 2 R212, being the same or different, where R212 is (iv) C1-C3 alkyl, (v) -CH2-CH-CH2, (vi) -X1, where X1 is as defined above, (vii) NR213R213 where the R213's are the same or different and are -H, C1-C3 alkyl or -CH2-CH=CH2, (viii.alpha.) *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 3, (viii.beta.) *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 or 5, [a]
(ix) 3-pyrrolin-1-yl, [b]

-111- 4236.1.2 (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]
(xiv) 1,4-dihydro-1-pyridinyl substituted in the 4 position by two C1-C3 alkyl being the same or different, [g]
(xvi) C1-C3 alkoxy, (b) 1,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R212 is as defined above, (4) (c) pyrimidin-4-yl or the N oxide thereof optional-ly substituted at the 2- and/or 6- position with R212 is as defined above, (5) (d) pyrimidin-2-yl optionally substituted at 4-and/or 6- position with 1 or 2 R212 as is defined above, (6)[E]
(7) 1-piperazinyl substituted in the 4- position with X1-(CH2)j-, where X1 and j are as defined above, [F]
(8) 4-hydroxy-1-piperidinyl substituted in the 4-position with X1 as defined above, [G]
and pharmaceutically acceptable salts thereof, if desired, and hydrates and solvates thereof, if desired.

4. An amino substituted steroid according to claim 1 where R6 is .alpha.-R61:.beta.-R62 and R10 is .alpha.-R101:.beta.-R102, 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 .alpha.-H:.beta.-OR34 or C-OR34:B-H, where R34 is -H, -CO-CH3, -CO-C2H5-, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5 or R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64 and R10 is .alpha.-R103:.beta.-R104 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 are -CH2)2-C(H)(OH)-CH2-, R7 is .alpha.-H:.beta.-H and R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-R176, where R165 is -H, -OH, -F or -CH3 and R166 1s -H, -OH, -F, or -CH3, with the proviso that at least one of R165 and R166 must -112- 4236.1.2 be -H, where R175 is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, and where R176 is -C(-Z)-(CH2)n-NR21R210; which is the amino sterold of formula Ia or Ib (Ia) (Ib) .... is a single or double bond and ~ indicates that there are 2 possible orientations for the attached group, (1) .alpha. or .beta. when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond.

5.. An amino substituted steroid according to claim 4 where R101 and R5 taken together are -(CH2)2-C(-R33)-CH- or -CH-CH-CO-CH-, where R33 is -O.

-113- 4236.1.2

6. An amino steroid (Ia and Ib) according to claim 4 which is selected from the group consisting of 17.alpha.-hydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-4,9( 11)-diene-3,20-dione, 21-[4-[2-amino-6(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-hydroxy-4-(4-trifluoromethyl)phenyl-1-piperidinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-(2-furanylcarbonyl)-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-(4-(benzo[b]thien-2-yl)-1-piperazinyl)pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-(2-pyrimidinyl)-1-piperazinyl]pregna-4,9(11) diene-3,20 dione, 17.alpha.-hydroxy-21-[4-[[(3-chlorophenyl)amino]carbonyl]-1-piperazinyl]pregna-4,9(11)-diene 3,20-dione, 17.alpha.-hydroxy-21-[4-(2-methoxyphenyl)-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2,6-bis(dimethylamino)-4-pyrimindinyl]-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-(3,6-dimethylpyrazinyl)-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 21-[4-[2-(diethylamino)-6-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2-(diethylamino)-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-t2-(diethylamino)-6-(1-piperidinyl)-4-pyrimidiyl]1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxy-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2,6-bis(4-methyl-1-piperazinyl)-4-pyrimidinyl]-1-piperazinyl]pregna4,9(11)-diene-3,20-dione, 17.alpha.-hydrox-21-[4-(2-pyridinyl)-1-piperazinylpregn-4-ene-3,11,20-trione, -114- 4236.1.2 ll.beta.,l7.alpha.-dihydroxy-6.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]
pregna-1,4-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-(6-methoxy-2-pyridinyl)-1-piperazinyl]pregna 4,9(11)-diene-3,20-dione, 11.alpha.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene 3,20-dione, 17.alpha.-hydroxy-21-[methyl[2-(methyl-2 pyridinylamino)ethyl]amino]-pregna-4,9(11)-diene-3,20-dione, 11.beta.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 11.beta.,17.alpha.-dihydroxy-21-[4-(4-fluorophenyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 11.beta.,17.alpha.-dihydroxy-21-[4-(4-methoxyphenyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 11.alpha.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,20-dione 11-(3,3-dimethyl-1-butyrate), 21-[4-(4-fluorophenyl)-1-piperazinyl] 1l.alpha.-17.alpha.-dihydroxypregn-4 ene-3,20-dione, 11.alpha.,17.alpha.-dihydroxy-21-[4-(4-methoxyphenyl)-1-piperazinyl]pregn-4 ene-3,20-dione dihydrochloride, 11.alpha.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,20-dione 11-(2-furanylcarbonyl), 1l.alpha.,17.alpha.-dihydroxy-21-[4-(4-methoxyphenyl)-1-piperazinyl]pregn-4 ene-3,20-dione 11-(3,3-dimethyl-l-butyrate), 11.beta.,17.alpha.-dihydroxy-21-[4-(4-methoxyphenyl)-1-piperazinyl]-6.alpha.-methylpregna-1,4-diene-3,20-dione, 11.beta.,17.alpha.-dihydroxy-21-[[2-(3-4-dimethoxyphenyl)ethyl]amino]-6.alpha.
methylpregna-1,4-diene-3,20-dione, 17.alpha.-hydroxy-16.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4,9(11 )-triene-3,20-dione, 11.alpha.-hydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,20-dione, 17.alpha.-hydroxy-21-[[2-(3,4-dimethoxyphenyl)ethyl][3,4,5-trimethoxy-phenyl)methyl]amino]pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[[2-(2,4-dimethoxyphenyl)-1-methylethyl]amino]-pregna-4,9(11)-diene-3,20-dione, 21-[l-(2-carboxy)piperidinyl]-17.alpha.-hydroxypregna-4,9(11) diene--115- 4236.1.2 3,20-dione, 21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,20-dione, 17.alpha.-hydroxy-21-[4-(2-methoxyphenyl)-1-piperazinyl]pregn-4-ene-3,20-dione, 17.alpha.-hydroxy-21-[4-[3,4-dimethoxyphenyl)methyl]-1-piperazinyl-pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,20-dione, 21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-ene-3,11,20-trione, 17.alpha.-hydroxy-6.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 17.alpha.-hydroxy-6.alpha.-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 17.alpha.-hydroxy-21-[4-(5-methYl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-11.alpha.,17.alpha.-dihydroxypregn-4-ene-3,20-dione, 17.alpha.-hydroxy-21-[[2-(3,4-dimethoxyphenyl)ethyl]-4-[dimethylamino)-phenyl]methyl]amino]pregna-4,9(11)-3,20-dione, 21-[4-[2-amino-5-(1-pyrrolidinyl)phenyl]-1-piperazinyl]-17.alpha.-hydroxy-pregna-4,9(11)-diene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxypregn-4-ene-3,20-dione, 17.alpha.-hydroxy-21-[4-(2-pyridinylmethyl)-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-{[4-(diemthylamino)phenyl]methyl}-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 17.beta.-carboxy-17.alpha.-hydroxyandrost-4-en-3-one-4-(2-pyridinyl)-1-piperazinyl amide, 17.beta.-carboxy-17.alpha.-hydroxyandrost[-4-en-3-one 1-[2,6-bis(diethyl-amino)-4-pyrimidinyl]-1-piperazinyl] amide, 17.alpha.-hydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4-diene-3,11,20-trione, 17.alpha.-hydroxy-21-[4-[4,6-bis(2-propenylamino)-1,3,5 triazin-2-yl]-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, -116- 4236.1.2 17.alpha.-hydroxy-21-[4-[(3-hydroxy-2-pyridinyl)methyl]-1-piperazin pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-21-[4-[6-(1-pyrrolidinyl)-2-pyridinyl]-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 21-4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxy-6.alpha.-methylpregna-1,4,9(11) triene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-4,9(11)-diene-3,20-dione, 21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 11.alpha.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4-diene-3,20-dione, 17.alpha.-hydroxy-21-[[(3,4-dihydroxyphenyl)methyl][2-(3,4-dimethoxy-phenyl)-ethyl]amino]pregna-4,9(11)-diene-3,20-dione, 21-[4-[3-amino-6-(diethylamino)-2-pyridinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-4,9(11)-diene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-11.alpha.-hydroxypregn-4-ene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-11.alpha.,17.alpha.-dihydroxypregn-4-ene-3,20-dione, 21-[4-[4,6-bis(2-propenylamino)-1,3,5-triazin-2-yl]-1-piperazinyl]-pregn-4-ene-3,11,20-trione, 17.alpha.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 17.alpha.-hydroxy-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione, 21-[4-[4,6-bis(diethylamino)-2-pyrimidinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-l,4,9(11)-triene-3,20-dione, 16.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione, 11.alpha.-hydroxy-16.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregna 1,4-diene-3,20-dione, 16.alpha.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregna-1,4 diene3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidiny1]-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, -117- 4236.1.2 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-11.alpha.
hydroxy-16.alpha.-methylpregna-1,4-diene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-16.alpha.
methylpregna-1,4-diene-3,20-dione, 16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione, 11.alpha.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-piperazinyl]pregna-1,4-diene-3,20-dione, 16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4-ene-3,20-dione, 16.alpha.-methyl-21-[4-[2,6-bis(morpholino)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione, 11.alpha.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis(morpholino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4-diene-3,20-dione, 16.alpha.-methyl-21-[4-[2,6-bis(morpholino)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4-ene-3,20-dione, 21-[4-[2,6-bis(allylamino)-4-pyrimidinyl]-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, 21-[4-[2,6-bis(allylamino)-4-pyrimidinyl]-1-piperazinyl}-11.alpha.-hydroxy-16.alpha.-methylpregna-1,4-ene-3,20-dione, 21-[4-[2,6-bis(allylamino)-4-pyrimidinyl]-1-piperazinyl]-16.alpha.-methylpregna-1,4-ene-3,20-dione, 21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregn-4-ene-3,11,20-trione, 21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-4,9(11 )-diene-3,20-dione, 21-[4-[6-(diethylamino)-3-(dimethylamino)-2-pyridinyl]-1-piperazinyl]-17.alpha.-hydroxypregna-4,9(11)-diene-3,20-dione, 21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4-diene-3,20-dione, 21-[4-[2-pyridinyl)-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 17.alpha.-hydroxy-17.alpha.-[[[(2-pyridinyl)methyl]amino]carbonyl]androst-4-en-3-one, 21-[4-(2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 21-[4-(2,6-di-(4-morpholinyl)-4-pyrimidinyl)-1-piperazinyl]-17.alpha.--118- 4236.1,2 hydroxypregna-4,9(11)-diene-3,20-dione, 11.beta.-hydroxy-21-[4-(2-pyridinyl)-1-piperazinylpregn-4-en-3-one, 21-[4-(2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-pregna-4-ene-3-one, 20-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]pregn-4-en-3-one, 21-[4-(2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione, 21-[4-(2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-20-methylpregna-1,4-dien-3-one, 21-[4-(4,6-di-(1-pyrrolidinyl)-1,3,5-triazin-2-yl)-1-piperazinyl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, 21-[4-[2-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperaziny]-ethyl]-1-piperazinyl]-17.alpha.-hydroxypregna-4,9(11)-diene-3,20-dione, 21-[4-[2,6-di-(4-morpholino)-4-pyrimidinyl]-l-piperazinyl]pregna-1,4-diene-3,20-dione, 21-[4-[2,6-bis(diethylamino)-4-pyrimidinyl]-1-piperazinyl]-6.alpha.-fluoro-17.alpha.-hydroxy-16.beta.-methyl-pregna-4,9(11)-diene-3,20-dione, 6.alpha.-fluoro-17.alpha.-hydroxy-16.beta.-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 6.alpha.-fluoro-17.alpha.-hydroxy-16.beta.-methyl-21-[4-(2-pyridinyl)-1-piperazinyl]-pregna-4,9(11)-diene-3,20-dione, 21-[4-[5,6-bis-(diethylamino)-2-pyridinyl]-1-piperazinyl]pregna-1,4-diene-3,20-dione, 16.alpha.-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyriminyl]-1-piperazinyl]pregna-1,4-diene-3,20-dione, 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-piperazin-yl]-16.alpha.-methylpregna-1,4,9(11)-triene-3,20-dione, 21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-16.alpha.,17.alpha.-dimethylpregna-1,4,9(11)-triene-3,20-dione, 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1-piperazinyl]-16.alpha.,17.alpha.-dimethylpregna-1,4,9(11)-triene-3,20-dione, 3.beta.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregn-5-en-20-one, 21-[4-[3-(ethylamino)-2-pyridinyl]piperazinyl]-16.alpha.-methyl-pregna-1,4,9(11)-triene-3,20-dione, 21-[4-[3-(diethylamino)-2-pyridinyl]piperazinyl]-16.alpha.-methylpregna--119- 4236.1.2 1,4,9(11)-trlene-3,20-dione, and 16.alpha.-methyl-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrlmidinyl]-1-piperazinyl]pregna-1,4,6,9(11)-tetraene-3,20-dione.

7. An amino steroid accordlng to claim 6 which is 16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-pilperazinyl]pregna-1,4,9(11)-triene-3,20-dione.

8. An amino steroid according to claim 7 which is 16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesufonate, 16.alpha.-methyl-21-[4-[2,6-bis-(pyrrolidino)-4-pyrimidinyl]-1-plperazinyl]pregna-1,4,9(11)-triene-3,20-dione bismethanesulfonate and 16.alpha.-methyl-21-[4-[2,6-bis-(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione hydrochloride.

9. An amino steroid according to claim 8 which is 16.alpha.-methyl-21-[4-[2,6-bis(pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate.

10. An amino substituted steroid according to claim 1 where 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 .alpha.-R65:.beta.-R66 where one of R65 and R66 is -H, and the other is -H, -F or C1-C3 alkyl, R7 is .alpha.-H:.beta.-H and R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-R176, where R165 is -H, -OH, F or -CH3 and R166 is -H, -OH, -F, -CH3, with the proviso that at least one of R165 and R166 must be -H, where R175 is -H, -OH, CH3, -CH2CH3-, C2-C7 alkanoyloxy or -O-CO-X1, and where R176 is -C(-Z)-(CH2)n-NR21R210; which is the aromatic steroid of formula II, -120- 4236.1.2 (II)

11 An aromatic steroid (II) accordng to claim 10 which is selected from the group consisting of 3,17.alpha.-dihydroxy-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazlnyl]-19-norpregna-1,3,5(10)-trlen-20-one 3-methyl ether and 3,17.alpha.-dihydroxy-21-[4-[2,6-bis(1-pyrrolidinyl)?4-pyrimidinyl]-1-piperazingl]-19-norpregna-1,3,5(10)-trien-20-one.

12. An amino substituted steroid according to claim l uhere R6 19 .alpha.-R61:.beta.-R62 and R10 is .alpha.-R101:.beta.-R102, where one of R61 or R62 is -H, and the other is -H, -OH, -F, C1-C3 alkyl or phenyl, R102 19 -CH3, R101 and Rs taken together are -(CH2)2-C(-R33)-CH- or -CH-CH-CO-CH-, where R33 is -O or .alpha.-H:.beta.-OR34 or .alpha.-OR34:B-H, where R34 is -H, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5 or R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64 and R10 is .alpha.?R103:B-R104 where one of R63 and R64 is -H, and the other taken together ulth one of Rs3 and Rs4 forms a second bond between C5 and C6, R104 is -CH3, R103 and the other of R53 and R54 taken together are -(CH2)2-C(H)(OH)-CH2-, R7 is .alpha.-H:B-H and 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 -121- 4236.1.2 C(-Z) (CH2)n-NR21R210; which is the .DELTA.16 steroid of formula IIIa or IIIb (IIIa) (lIlb) ... is a single or double bond and where ~ indicates that there are 2 possible orientations for the attached group, (1) .alpha. or .beta. when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond.

13 A .DELTA.16 steroid (IIIa and IIIb) according to claim 12 which is selected from the group consisting of 21-[4-(2-pyridinyl)-l-piperazinrl]pregna-4,9(11),16-triene-3,20-dione,and -122- 4236.1.2 21-[4-(2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-l-piperazinyl]-pregna-1,4, 9(11 ),16-tetraene-3,20-dione-

14. An amino substituted steroid according to claim 1 where R5 is .alpha.-57:.beta.-R58, R6 is .alpha.?R67:.beta.-R68 and R10 is .alpha.-R107:.beta.-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 -O or .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -CO-CH3, -CO-C2Hs, -CO-C6Hs, -CO-O-CH3 or -CO-O-C2H5, R108 is -CH3, where one of R67 and R68 is -H and the other ia -H, -F or C1-C3 alkyl, R7 is .alpha.-H:.beta.-H and R16 is .alpha.-R165:.beta.-R166 and R17 is .alpha.-R175:.beta.-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 must be -H, where R175 is -H, -OH, -CH3, -CH2CH3, C2-C7 alkanoyloxy or -O-CO-X1, and where R176 is -C(-Z)-(CH2)n-NR21R210; which is the reduced A-ring steroid of formula IV

(lV) -123- 4236.1.2 is a single or double bond and where ~ indicates that there are 2 possible orientations for the attached group, (1) .alpha. or .beta. when attached to the steroid ring and (2) cis or trans when attached to a carbon atom of a double bond.

15. A reduced A-ring steroid (IV) according to claim 14 which is selected from the group consisting of 17.alpha.-hydroxy-16.beta.-methrl-21-[4-(2-pyridinyl)-1-piperazinyl]-5.alpha.-pregn-9( 11 )-ene-3,20-dione, 3.alpha.,17.alpha.-dihydroxy-21-[4-(2-pyridinyl)-1-piperazinyl]-5.beta.-pregnane11,20-dione, 3.beta.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-5.alpha.-pregnan-20-one, and 3.alpha.-hydroxy-16.alpha.-methyl-21-[4-[2,6-bis-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-5.alpha.-pregnan-20-one.

16 An amino substltuted 3terold accordlng to claim l where R6 19 .alpha.-R61:.beta.-R62 and R10 is .alpha.-R101:.beta.-R102, where one of R61 and R62 is -H, and the other is-H, -F or Cl-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 .alpha.-H:.beta.-OR34 or .alpha.-OR34:.beta.-H, where R34 is -H, -CO-CH3, -CO-C2H5, -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5 or R5 is .alpha.-R53:.beta.-R54, R6 is .alpha.-R63:.beta.-R64 and R10 is .alpha.-R103:B-R104 where one of R63 and R64 is -H, and the other taken together with one ot R53 and R54 forms a second bond between C5 and C6, R104 is -CH3, R103 and the other of Rs3 and Rs4 taken together are -(CH2)2-C(H)(OH)-CH2-. R7 is .alpha.-H:.beta.-H and R16 is .alpha.-R163:.beta.-R164 where one of R163 and R164 is -H and the other is -H, -OH, F or -CH3, and R17 is -CH-(CH2)p-NR21R210, where p is 1 or 2 which is the .DELTA.17 steroid of formula Va or Vb -124- 4236.1.2 (Ya) (Vb) where .... is a single or double bond and where ~indicates that there are 2 possible orientations for the attached group, (1) .alpha. or .beta. when attached to the steroid ring and (2) cis or trans when attached to a carbon atom or a double bond.

17, An amino substituted steroid according to claim l where R11 is .alpha.-R111:.beta.-R112. where one of R111 and R112 is taken together with Rg to form a second bond between C9 and C11 and the other of R111 and R112 is -H.

-125- 4236.1.2

18. An amino substituted steroid according to claim l where is -H.

19 . An amino substituted steroid according to claim 1 where Z is -O..

20. An amino substituted steroid according to claim l where n is 1.

21. An amino substituted steroid according to claim l where R21 and R210 are taken together with the attached nitrogen atom from 1-piperazinyl substituted in the 4- position with X2-(CH2)j-.

22. An amino substituted steroid according to claim 21 where j is 0.

23 An amino substituted steroid according to claim 21 where R21 and R210 are taken together with the attached nitrogen atom form a cyclic amine substitutent selected from the group consisting of . 4-(2-pyridinyl)-1-piperazinyl, 4-[4,6-bis(2-propenylamino)-1,3,5-triazin-2-yl]-1-piperazinyl, 4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl, 4-[2,6-bis(morpholino)-4-pyrimidinyl]-1-piperazinyl, 4-t4,6-bls(diethylamino)-2-pyrimidinyl]-1-piperazinyl, 4-[4,6-bis(1-pyrrolidinyl)-1,3,5-triazin-2-yl]-1-piperazinyl, 4-[3,6-bis(diethylamino)-2-pyridinyl]-1-piperazinyl and 4-[3-(ethylamino)-2-pyridinyl]-l-piperazinyl.

24 . An amino substituted steroid according to claim 1 where R21 and -126- 4236.1.2 R210 are taken together with the attached nitrogen atom forms 1-piperazinyl substituted in the 4- position with Xl-(CH2)j-.

25. An amino substituted steroid according to claim l where the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromlde, hydrogen iodlde, sulfate, phosphate, acetate, lactate, citrate, succinate, benzoate, saiicyclate, pamoate, cyclohexanesulfamate, methanesulfonate, naphthalenesulfonate, p-toluenesulfonate, maleate, fumarate and oxalate.

26. A .DELTA.9(11)-steroid of the formula (VI) where:
(A-I) E6 is .alpha.-E61:.beta.-E62 and E10 is .alpha.-E10l:.beta.-E102, where one of E61 and E62 is -H, and the other is -H, -F, -Cl, -Br or C1-C3 alkyl, E101 and E5 taken together are -(CH2)2-C(-E33)-CH- or -CH-CH-CO-CH-, where E33 is -O or .alpha.?H:.beta.-OE34 or .alpha.-OE34:.beta.-H, where E34 is -H, -CO-CH3, -CO-C2H5- -CO-C6H5, -CO-O-CH3 or -CO-O-C2H5, where E102 is -CH3;
(A-II) E5 is .alpha.-E53:.beta.-E54; E6 is .alpha.-E63:.beta.-E64 and E10 is .alpha.-E103:

-127- 4236.1.2 B-E104, where one of E63 and E64 is -H, and the other taken together with one of E53 and E54 forms a second bond between C5 and C6, E104 is -CH3, E103 and the other of E53 and E54 taken together are -(CH2)2-C(H)(OH)-CH2-;
(A-IV) E5 is .alpha.-E57:.beta.-E58, E6 is .alpha.-E67:.beta.-E68 and E10 is .alpha.-E107:
.beta.-E108, where one of E57 and E58 is -H, E107 and the other of E57 and E58 taken together are -(CH2)2-C(-E33)-CH2, where E33 is as defined above, E108 is -CH3, where one of E67 and E68 is -H and the other is -H, -F or C1-C3 alkyl;
where:

(D-I) E16 is .alpha.-E161;.beta.-E162, where one of E161 and E162 is -H and the other is-H, -F, -CH3 or ?OH;
(D-II) E17 is -H, -CH3, -C 2H5, -OH or -O-CO-E171, where E171 is C1-C6 alkyl or X1, where Xl is phenyl optionally substituted with 1 through 2 -Cl, -Br, Cl-C3 alkoxy, -COOH, -NH2, Cl-C3 alkylamino, di(C1-C3)alkylamino, where the alkyl groups are the same or different, 1?pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylen-imino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3;
(D-III) Z is -O, -CH2, E20:-H where E20 is -H or -CH3;
(D-IV) J is 1-(4-methyl)-plperazinyl, [J-1]
1-(4-acetyl)-piperazinyl, [J-2]
1-(4-hydroxy)-piperidinyl [J-3]
1-piperidinyl optionally substituted with 2-hydroxyethyl, [J-4]
4-morpholinyl [J-5]
and the 16,17-acetonide thereof when E161 and E17 are both -OH;
and pharmaceutically acceptable salts thereof if desired and hydrates and solvates thereof if desired.

27. A .DELTA.9(11)-steroid according to claim 26 which is selected from the group consisting of 17.alpha.-hydroxy-21-(4-morpholinyl)-pregna-4,9(11)-dlene-3,20-dione, 21-(4-acetyl-1-piperazinyl)-17.alpha.-hydroxypregna-4,9(11)-diene-3,20.
dione, and 17.alpha.-hydroxy-21-(4-methyl-1-piperazinyl)-pregna-4,9(11-diene-3,20-4236.1.2 4236. 1.2 dione.
3~

.

'