WO1987007895A1 - Androstane-type and cortical aminoesters - Google Patents

Abstract

Androstane-type aminoesters (IV) and cortical aminoesters (VIII), more particularly 17-aminoesters (I), 11,17-diaminoesters (II), 3,17-diaminoesters (III), 21-aminoesters (V), 11-aminoesters (VI), and 3-aminoesters (VII) which are useful as pharmaceutical agents for treating a number of conditions, more particularly mild to severe head injury and spinal trauma.

Description

ANDROSTANE-TYPE AND CORTICAL AMINOESTERS BACKGROUND OF THE INVENTION Various amino (substituted) steroids are known with the amine substitution on either the steroidal ring system or on the side chain of the D-ring at C₁₇.

U.S. Patent 4,456,602 (ANDERSON) discloses steroidal 21-esters in which there is an amino function in the non-steroidal portion of the ester. ANDERSON links a secondary amine to a corticosteroid at C₂₁ with an ester linkage to form a prodrug which produces as the active pharmacological agent the parent corticosteroid. The prodrug contains additional functional groups between the ester and the amine. With the present invention, the amine function is attached to the carbonyl carbon atom of the ester linkage only by a -CH₂ - (acetyl) or -C(CH₃)H- propionyl. With the present invention the amine function is part of the active compound, not just part of a prodrug.

In the 3α-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 is cyclized. These patents also disclose reduced A-ring steroids as well as steroids with a hydrogen atom at C₁₇ and two hydrogen atoms at C_lt.

20-Amino steroids are known in the Δ⁴-3-keto series with no substitution at C_χι 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.-Biol. Interact., 46, 1 (1983); J. Steroid Biochem. , 20, 1095 (1984); Inorg. Chim. Acta, 91, 257 (1984), with substitution at C_lχ, see Steroids 35, 265 (1980) and Biochim. Biophys. Acta, 623, 280 (1980) as well as with substitution at both C_X1 and C₁₇, see Steroids, supra. 20-Amino steroids are known in the Δ^lιA-3-keto series with an 11/9-hydroxyl substitution, see Steroids, supra, as well as with ll£,17α-dihydroxy substitution, see Protides Biol. Fluids, 29, 393 (1982); J. Clin. Chem. Clin. Biochem., 22, 209 (1984); Eur. J. Biochem., 108, 47 (1980); J. Steroid Biochem. , 14, 697 (1981), Nature (London) 279, 158 (1979) and Eur. J. Biochem., 131, 333 (1983) and with ll ,17α-dihydroxy substitution, see J. Clin. Chem. Clin. Biochem., 21, 69 (1983). US Patent 4,191,759 discloses 20-amino- Δ^{1, 4}-3-keto steroids without any substitution at the 11 position where the amine substituent is morpholine or piperazine.

21-Amino steroids are known in the Δ⁴-3-keto series with no sub¬ stitution at C_{ll t} see J. Org. Chem., 45, 3084 (1980); J. Org. Chem., 26, 1223 and 5052 (1961); J. Chem. Soc, Perkin Trans. 1, 502 (1972); Great Britain Patent 954,146; Austrian Patent 249,883; Arch. Biochem. Biophys., 182, 197 (1977) and Khim.-Farm. 2, 26 (1968). In addition 21-amino steroids are known in the Δ^{1, 4}-3-keto series substituted with lLS-hydroxyl, .see Arch. Biochem. Biophys., 182, 197 (1977); Int. Conf. Chem. Biotechnol. Biol. 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); Hungarian Patent 150,350 and J. Org. Chem., 45, 3084 (1980). For example Hungarian Patent 150,350 discloses dipersolone, 1 9,17α-dihydroxy-21-(4-methyl-l-piperazinyl)- pregna-l,4-diene-3,20-dione. Further, U.S. Patent 3,705,150 dis- closes 21-N-(N' -methyl)piper zinyl prednisolone.

In the 20-amino 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 combinations and substituents. These amines include 4- [hydroxyethyl] -1-piperidine, 4- [hydroxyethyl] -1-ρi- perazine, 4-methylpiperazine, 4-acetylpiperazine and 4-formyl- piperazine.

Japanese patent J8 5043068 discloses azepino-(1,2,3-lh)-/3-car- boline derivatives which inhibit lipid peroxidation and are useful in inhibiting the aging of living bodies.

A number of 20-amino steroids are known where the 20-amino group is of the general type -NH-(CH₂)_χ-N(R₁) (R₂) where x is 2 or 3 and R_χ and R₂ are methyl or ethyl. See, for example, Arch. Farmacol. Toxicol. 4, 265 (1978), Lipids 2, 5 (1967), J. Med. Chem. 15, 1129 (1972), ibid 15, 1284 (1972), French Patent 90805, Lipids 11, 616 (1976), US Patent 3,558,608, Chem. Abst. 62, 14784a, ibid 64, 14573e, ibid 65, 2334d, ibid 56, 15583a, b, and i, ibid 57, 12574d, ibid 57, 6225d. Many 20-amino and 21-amino steroids are known where the amine function is substituted with simple alkyl 0,-0₃), ^si^mple aralkyl (benzyl), substituents containing hetero atoms (sulfur), esters, acids, amino substituted alkyl, alcohols, ethynyl groups, etc. Other 20-amino steroids are known where the amino group is a simple amine including very simple cyclic and heterocyclic amines, see US Patents 3,523,942 and 4,191,759. Also known are 21-amino substituted steroids where the amine is a simple (substituted) cyclic amine such as 4-(2-hydroxyethyl)-l-piperazinyl [CA 65;20189g]; 4-(2-hydroxy- ethyl)-l-piperidinyl [83544-11-0]; 4,4-dimethyl-l-piperazinyl, 3- hydroxyethyl-1-piperidinyl, 4-hydroxy-l-piperidinyl, 4-carboxy-l- piperidinyl, 3-hydroxy-l-piperidinyl, 3-carboxy-l-piperidinyl, piperazinyl, bis(hydroxyethyl)amino, 4-acetyl-l-piperazinyl, 4- carboxaldehyde-1-piperazinyl, 1-piperadinyl, [Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. [Proc] 1st. Vol. 2, p. 135, 1981]; 4-methyl-l-piperazinyl [Great Britin Patent 2,136,293]; 3,6-dihydro- 2,6-dioxo-l(2H)-pyrimidinyl, 5-fluoro-3,6-dihydro-2,6-dioxo-l(2H)- pyrimidinyl, 5-fluoro-3,4-dihydro-2,4-dioxo-l(2H)-pyrimidinyl, 3,4- dihydro-2,4-dioxo-l(2H)-pyrimidinyl, 3,4-dihydro-5-methyl-2,4-dioxo- 1(2H)-pyrimidinyl [J. Steroid Biochem. 9, 1155 (1978)]; and 4- morpholinyl [J. Chem. Soc. Perkin Trans I, 502 (1972)].

The amino steroids of the prior art above, with the exception of ANDERSON do not have an ester group between the amine function and the steroid. Further, in the amino steroids of the prior art above the steroids were generally of the corticoid type whereas the steroids of the present invention are of the androstane (17 -hydroxy) type.

SUMMARY OF THE INVENTION Disclosed ia an androstane-type aminoester of formula (IV) where:

(A-I) R₁₀ is α-R₁₀₁:/3-R₁₀₂, where R₁₀₂ is -CH₃ , ^R10 1 and ₅ taken together are -CH₂-CH₂-C0-CH-, R_g is o-H:_/9-H,

(A-II) R₁₀ is α-R₁₀₃ :^-R₁₀₄ , where R_χ0 is -CH₃ , ^R10 3 and ^R3 taken together are -CH-CH-C0-CH-, R_g is α-H: -H,

(A-III) R₅ is a-R_{5 5} : β-R_{5 6} , R_g is α-R^ : β-R_{6 6} , R₁₀ is a ^{" R}10 5 :β- R₁₀₆, where R₁₀₆ is -CH₃ , where one of R₆₅ and R_gg is ! -H and the other taken together with one of R₅₅ and R₅₆ forms a second bond between C₅ and C₆ and R₁₀₅ and the other of R₅₅ and ^ taken together are

-CH₂-CH₂-C(R₃)-CH₂- where R₃ is α-H: -AE or α-AE:j9-H, where AE is -O-CO-C(X₅)H-NR₂₁R₂₁₀ where

(A) X₅ is -H or -CH₃ , (B) R₂₁ is

(1) -(CH₂)_[n-NR₂₁₁-X₂ , where m is 2, 3 or 4, where R₂₁₁ is -H or C_j^C-_j alkyl, where X₂ is:

(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted on a ring carbon atom thereof by 1 or 2 R₂₁₂, being the same or different, where R₂₁₂ is

(i) -F, (ϋ) -Cl, (ϋi) -Br, (iv) C-.-C_J alkyl,

(v) -CH₂-CH-CH₂,

(vi) -X_χ , where X_χ is phenyl optionally substituted with 1 through 2 -Cl, -Br, C₁-C₃ alkoxy, -COOH, -NH₂ , C_j^-C₈ alkylamino, di(C_χ-C₃)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl- , 1-piperidinyl, 1-hexamethyl- enimino-, 1-hep amethylenimino-, C₂-C₄ acylamino and -NH-CHO or with 1 -F or -CF₃ ,

(vii) -R₂i_{3 2}i₃ where the R₂i₃'^{s are} the same or different and are -H, C_χ-C₃ alkyl or -CH₂-CH=-CH₂ , (viii ) -^*CH₂-(CH₂) -CE^-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 7,

(vii S) -^*CH₂-CH₂-(CH₂)₀ -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 -0-, -S- or- NHR_21ή , where R₂₁₄ is -H, C_j^ alkyl, or X_χ as defined above, where c and d are each 0 through 2 with the provisos that _the total number of ring carbon atoms is 4, 5 or 6, (F-l)

(ix) 3-pyrrolin-l-yl, (F-2) (x) pyrrol-1-yl optionally substituted with -C₈ alkyl, (F-3)

(xi) piperidin-1-yl optionally substituted with 1 or 2 C_χ-C₃ alkyl, (F-4)

(xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-5) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-6)

(xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C_j-C.- alkyl being the same or different, (F-7) (xv) -CF₃, (xvi) -CC1₃, (xvii) -OH, (xviii) C_χ-C₃ alkoxy, (xix) -NR₂₁₇-(CH₂)_β-Q where Q is 2-pyridinyl where R₂₁₇ is -H or C_χ -C₃ alkyl and e Is 0 through 3, (F-8)

(b) l,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with R₂₁₂ as is defined above, (F-9) (c) pyrimidin-4-yl or the N-oxide thereof optionally optionally substituted at the 2- and/or 6- position with R₂₁₂ as is defined above, (F-10)

(d) pyrimidin-2-yl optionally substituted with 1 or 2 R₂₁₂ as is defined above, (F-ll) (e) pyrazin-2-yl optionally substituted with 1 or

2 R₂₁₂ as is defined above, (F-12)

(f) imidazol-2-yl optionally substitututed in the 1 position with C_χ-C₃ alkyl or -X_χ , as defined above, and further optionally substituted with 1 or 2 R₂₁₂ as defined above, (F-13) (g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C-^C_j alkyl or -X_χ , as defined above, and further optionally substituted with ₂₁₂ ^as defined above, (F-14)

(h) imidazol-4- or 5-yl optionally substituted in the 1 position with C_χ-C₃ aikyl or -X_χ , where X_χ is as defined above, and further optionally substituted with 1 or 2 R_j^ are as defined above, (F-15)

(i) benzo[b]thien-2-yl, (F-16)

(j) indol-2-yl, (F-17)

(fc) benzo[b]thiazol-2-yl, (F-18) (1) benzimidazol-2-yl, (F-19)

(m) 4-[2-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimi- dinyl] -1-piperazinyl]ethyl]piperazinyl, (F-20)

(2) (1-piperazinyl)-(C₂-C_A)alkyl optionally sub¬ stituted in the 4- position with -X_χ or -X₂ as defined above, (F-21) (3) -X₂ , as defined above,

(4) -(CH₂)_m-X₄ where m is as defined above and where is

(a) -0-CH₂CH₂-Y, where Y is C^C_g alkylamino, di(C_χ-C₃)alkylamino where the alkyl groups are the same or different, C₃-C₆ alkylenei ino, optionally substituted with 1 or 2 C_χ-C₃ alkyl,

(b) -NR₂₂₀CH₂CH₂-Y, where R^_Q is -H or C_χ-C₃ alkyl and Y is as defined above, (c) -(CH₂)_g.-N(R₂₂₀)-X₂, where g is 2, 3 or 4, and where R₂₂₀ and X₂ are as defined above,

(5) -(CH₂)_m-NR₂₂₂R2_{23 I} where R₂₂₂ is -H or

C_χ-C₃ alkyl and g^ is -X_χ or -X₂ as defined above, or R₂₂₂ ^and ₂₂₃ ^{are ta}^^en together with the attached nitrogen atom to form a saturated mono-nitrogen C₃-C₆ heterocyclic ring and where is as defined above,

(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 R₂₂ is phenyl optionally substituted with 1 through 3 -OH, C_χ-C₃ alkoxy,- ^NR _{225 226} ^wh^ere K-₂₂₅ ^an(* ₂₂₆ being ^fche same or different and are -H, C_χ -C₃ alkyl or are taken together with the attached nitrogen atom to form a saturated mononitrogen C₄_C₇ heterocyclic ring,

(7) -(CH₂)_i-X₂, where i is 1 through 4 and X₂ is as defined above, (8) (1-piperazinyl)acetyl substituted in the 4- position by X_j where X₂ is as defined above, (F-22)

(9) (l-piperazinyl)carbonylmethyl substituted in the 4-position by -X_g where ^ is as defined above, and (F-23)

(C) R_2χo is (1) -H,

(2) C₅-C₇ cycloalkyl,

(3) -(CH₂)_m-N ₂₁₁-X₂ , where m, R^_j^ and ^ are as defined above, ^"

(4) (l-piperazinyl)-(C₂-C_A )alkyl optionally sub- stituted in the 4- position with -X_χ or -X_j as defined above, (F-21)

(5) -X₂ , as defined above,

(6) -(CH₂)_m-X₄, where m and X₄ are as defined above,

(7) -(CH₂)_m-NR₂₂₂R₂₂₃, where m, R^ and ^ _{2 3} are as defined above, (8) -(CHCH₃)_b-(CH₂)_f-R2₂₄, where b, f and R₂₂₄ are as defined above,

(9) -(CH₂ i-X2, where i and X_j are as defined above,

(10) (l-piperazinyl)acetyl substituted in the 4-

position by -X₂ as defined above, (F-22)

(11) (l-piperazinyl)carbonylmethyl substituted In the

4- position by -X₂ as defined above, or (F-23)

(D) R₂₁ and R_2X0 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of

(1) 2-(carboxy)-l-pyrrolidinyl optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-24)

(2) 2-(carboxy)-l-piperidinyl optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-25)

(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-26)

(4) 2-(carboxy)-1-heptamethyleneimino optionally as the C_x-C₃ alkyl ester or as a pharmaceutically acceptable salt,(F-27) (5)' 1-piperazinyl substituted in the 4- position with

R₂₂₈-C0-(CH₂)_j - where ^_g is -X_χ , -NR_22gX_χ and 2-furanyl, where R_22g is -H or C_χ-C₃ alkyl, where j is 0 through 3 and X_χ is as defined above, with the proviso that R₂₂₈ is X_χ substituted with a carboxyl group, only when j is not 0, (F-28) (6) 1-piperazinyl substituted in the 4- position with

X₂-(CH₂)_j-, where _j and j are as defined above, (F-29)

(7) 1-piperazinyl substituted in the 4- position with X_χ-(CH₂)_j-, where X_χ and j are as defined above, (F-30)

(8) 4-hydroxy-l-piperidinyl substituted in the 4- position with X_χ as defined above, (F-31)

(9) 1-piperazinyl substituted in the 4- position with X₂-NR_22g-C0-(CH₂)_i-, where K^ , R_22g and i are as defined above, (F-32)

(10) l-(4-methyl)-piperazinyl, (F-33)

(11) l-(4-acetyl)-piperazinyl, (F-34) (12) l-(4-hydroxy)-piρeridinyl (F-35)

(13) 1-piperidinyl optionally substituted with

2-hydroxyethyl, (F-36)

(14) 4-morpholinyl; (F-37) (A-IV) R₅ is α-R₅₇.-jfl-Rjg and R_χ0 is α-R_χo7 •'_/S-Rio_{β •} ^{wlιere or}*e of R₅₇ and R₅₈ is -H, R₁₀₇ and the other of R₅₇ and ₅₈ taken together are -CH₂ -CH₂-C(^«R₃ )-CH₂- , where R₃ is as defined above, R₁₀₈ is -CH₃ , _g is α-H: -H; where:

(C-I) R_lχ is α-R_χχχ :j8-R₁₁₂ , where one of R_X11 and R_1X2 is taken together with R_g to form a second bond between C_g and C_χx and the other of R_χxι and R_lχ2 is -H,

(C-II) R_xx is -0 and R_g is -H,

(C-III) R_X1 is -H:3-H and R_g is -H, (C-IV) R_χχ is α-AE:/3-H where AE is as defined above and R_g is -H; where:

(D-I) AE is as defined above, and pharmaceutically acceptable salts thereof; and hydrates thereof; with the following overall provisos that

(1) R_xx is α-AE:,8-H only when R_χo is c.-R₁₀ι ^{: _R}io₂ ^{or α}"^Ri₀₃ ^:

^^"R104 '

(2) R_X05 and the other of R₅₅ and R₅₆ taken together are -CH₂-CH₂-C(-R₃)-CH₂- only when R_X1 is α-R_llχ :j9-R_χx2 , -0 or α-H:/3-H and

(3) R₁₀₇ and the other of R₅₇ and R₅₈ taken together are -CH₂-CH₂-C(-R₃)-CH₂- only when R_χχ is et-R_lχl :/3-R_χx2. =0 or c.-H:j9-H.

Further disclosed is an androstane-type aminoester where R_χox and R₅ taken together are -CH₂-CH₂-C0-CH- or R_χo3 and R₅ taken together are -CH-CH-CO-CH- and R_χχ is a-R_lu:_l9-R₁₁₂₁ =-0 or α-H: -H; which is the 17-aminoester of formula (I) where .... is a single or double bond, X_χχ is -0, α-H: -H or α-X_χχχ '.β-X_χi2 , X_g is -H or taken together with one of X_χxx and X_χX2 to form a second bond between C_g and C_χχ and the other of X_XX1 and X₁₁₂ is -H.

Also disclosed is an androstane-type aminoester where R₁₀₁ and R₅ taken together are -CH₂-CH₂-C0-CH= or R_χo3 and R₅ taken together are -CH=CH-C0-CH- and R_χχ is α-AE:j9-H; which is the 11-aminoester of formula (II) where .... is a single or double bond. Additionally disclosed is an androstane-type aminoester where R₁₀₅ and one of R₅₅ and R₅₆ or R_χo7 and one of R₅₇ and R₅₈ taken together are -CH₂-CH₂-C^)-CH₂- and R_χχ is α-R_lxl : -R_χι2 , -0 or - H: -H; which is the 3-aminoester of formula (III) where - indicates the AE group is in either the α or β configuration, .... is a single or double bond, X_χχ is -0, -H:/3-H or c.-X_χχχ : -X_χχ2 , X_g is -H or taken together with one of X_χxx and X_X12 to form a second bond between C_g and C_χχ and the other of X_X1X and X_X12 is -H.

Disclosed is a cortical aminoester of formula (VIII) where: (A-I) R_xo is α-R_xox:_/9-R₁₀₂, where R₁₀₂ is -CH₃ , R_χ01 and R₅ taken together are -CH₂ -CH₂ -C0-CH-, R_g is α-R_gχ: -H where R_gX is -H, -F and -CH₃ ,

(A-II) R_χo is α-R_χ03:0-R₁₀₄ , where R_χot is -CH₃ , R_χ03 and R₅ taken together are -CH-CH-C0-CH-, R_g is α-R_g3 :^-H where R_g3 is -H, -F and -CH₃ ,

(A-III) R₅ is α-R_5S:0-R_sβ, R₆ is α-R_g5:0-Rg₆, R₁₀ is a-R_10S:β- R_χ06, where R_χ06 is -CH₃ , where one of R_g5 and R₆₆ is -H and the other taken together .with one of R₅₅ and R₅₆ forms a second bond between C₅ and C₆ and R_χ05 and the other of R₅₅ and R₅₆ taken together are -CH₂ -CH₂ -C(R₃ ) -CH₂ - where R₃ is a-E:β-AE or α-AE:/3-H, where AE is -0-C0-C(X₅ )H-NR_2χR_2χo where

(A) X₅ is -H or -CH₃ ,

(B) R_2X is (1) -(CH₂)_m-NR_2χχ-X₂ , where is 2, 3 or 4, where R_2χχ is -H or C_χ-C₃ alkyl, where X₂ is:

(a) pyridin-2-, 3- or 4-yl or the N-oxide thereof optionally substituted on a ring carbon atom thereof by 1 or 2 R₂₁₂, being the same or different, where R_2χ2 is (i) -F,

(ϋ) -Cl, (iϋ) -Br, (iv) C_χ-C₅ alkyl, (v) -CH₂-CH-CH₂, (vi) -X_χ , where X_χ is phenyl optionally substituted with 1 through 2 -Cl, -Br, C_χ-C₃ alkoxy, -C00H, -NH₂ , C_χ-C₃ alkylamino, di(C_χ-C₃)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl- , 1-piperidinyl, 1-hexamethyl- enimino-, 1-heptamethylenimino- , C₂-C acylamino and -NH-CHO or with 1 -F or -CF₃ ,

(vii) -NR_2X3R_2X3 where the R₂₁₃'s are the same or different and are -H, C_χ-C₃ alkyl or -CH₂-CH-CH₂,

(viiiα) -^*CH₂-(CH₂)_q-CH₂-N^*- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring, where q is 1 through 7,

(viiiø) -^*CH₂-CH₂-(CH₂)₀-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 -0-, -S- or -NHR_2X4, where R_2X4 is -H, C_χ -C₃ alkyl, or X_χ as defined above, where c and d are each 0 through 2 with the provisos that _the total number of ring carbon atoms is 4, 5 or 6, (F-l)

(ix) 3-pyrrolin-l-yl, (F-2) (x) pyrrol-1-yl optionally substituted with

C_χ-C₃ alkyl, (F-3)

(xi) piperidin-1-yl optionally substituted with 1 or 2 C_χ-C₃ alkyl, (F-4)

(xii) 1,2,3,6-tetrahydropyridin-l-yl, (F-5) (xiii) 1-hexamethyleneimino containing a 3- or 4- double bond or 3- and 5- double bonds, (F-6)

(xiv) 1,4-dihydro-l-pyridinyl substituted in the 4 position by two C_χ-C₃ alkyl being the same or different, (F-7)

(xv) -CF₃, (xvi) -CC1₃ ,

(xvii) -OH,

(xviii) C_χ-C₃ alkoxy,

(xix) -NR_2χ7-(CH₂)_β-Q where Q is 2-pyridinyl where R_2χ7 is -H or C_χ-C₃ alkyl and e is 0 through 3, (F-8) (b) l,3,5-triazin-4-yl or the N-oxide thereof optionally substituted at the 2- and/or 6- position with _2X2 as is defined above, (F-9)

(c) pyrimidin-4-yl or the N-oxide thereof optionally optionally substituted at the 2- and/or 6- position with ^R ₂i₂ ^as -^s defined above, (F-10)

(d) pyrimidin-2-yl optionally substituted with 1 or 2 R₂₁₂ ^as is defined above, (F-ll)

(e) pyrazin-2-yl optionally substituted with 1 or 2 R₂₁₂ ^as I^s defined above, (F-12) (f) imidazol-2-yl optionally substitututed in the

1 position with C_χ-C₃ alkyl or -X_χ , as defined above, and further optionally substituted with 1 or 2 R_2X2 as defined above, (F-13)

(g) l,3,4-triazol-2-yl optionally substituted in the 1 position with C_χ-C₃ alkyl or -X_χ , as defined above, and further optionally substituted with R₂₁₂ as defined above, (F-14)

(h) imidazol-4- or 5-yl optionally substituted in the 1 position with C_χ-C₃ alkyl or -X_χ , where X_χ is as defined above, and further optionally substituted with 1 or 2 R₂₁₂ are as defined above, (F-15)

(i) benzo[b]thien-2-yl, (F-16)

(j) indol-2-yl, (F-17)

(k) benzo[b]thiazol-2-yl, (F-18) (1) benzimidazol-2-yl, (F-19)

(m) 4-[2-[4-[2,6-bis(l-ρyrrolidinyl)-4-pyrimidin- yl] -1-piperazinyl]ethyl]piperazinyl, (F-20)

(2) (1-piperazinyl)-(C₂-C )alkyl optionally sub¬ stituted in the 4- position with -X_χ or -X₂ as defined above, (F-21) (3) -X₂ , as defined above,

(4) -(CH₂)_m-X where m is as defined above and where X_A is

(a) -0-CH₂CH₂-Y, where Y is C_χ-C₃ alkylamino, di(C_χ -C₃ )alkylamino where the alkyl groups are the same or different, C₃ -C₆ alkyleneimino, optionally substituted with 1 or 2 C_χ-C₃ alkyl,

(b) -NR₂₂₀CH₂CH₂-Y, where R₂₂₀ is -H or C_χ-C₃ alkyl and Y is as defined above,

(c) -(CH₂)_g-N(R₂₂₀)-X₂ , where g Is 2, 3 or 4, and where ^-. and X₂ are as defined above, (5) -(CH₂)_m-NR₂₂₂R_{223 >} where R„₂ is -H or

C_χ-C₃ alkyl and R₂₂₃ is -X_χ or -X₂ as defined above, or R₂₂₂ ^{an( R} ₂₂₃ ^{are ta}^en together with the attached nitrogen atom to form a saturated mono-nitrogen C₃-C₈ heterocyclic ring and where m is as defined above, (6) -(CHCH₃)_b-(CH₂)_f-R_22A , where b is 0 and f is 1 through 3 or b is one and f is 0 through 3, where R_22A is phenyl optionally substituted with 1 through 3 -OH, C_χ-C₃ alkoxy,

where R₂₂₅ and R₂₂₆ being the same or different and are -H, C_χ-C₃ alkyl or are taken together with the attached nitrogen atom to form a saturated mononitrogen C_A_C₇ heterocyclic ring,

(7) -(CH₂)_i-X₂, where i is 1 through 4 and X_j is as defined above,

(8) (l-piperazinyl)acetyl substituted in the 4- position by X₂ where X₂ is as defined above, (F-22) (9) (l-piperazinyl)carbonylmethyl substituted in the

4-position by ^ where X₂ is as defined above, and (F-23)

(C) R^ is (1) -H, (2) C₅-C₇ cycloalkyl,

(3) -(CH₂)_m-NR₂₁₁-X₂ , where m, R_2lχ and ^ are as defined above,

(4) (1-piperazinyl) -(C₂-C )alkyl optionally sub- stituted in the 4- position with -X_χ or -^ as defined above, (F-21)

(5) -X₂ , as defined above,

(6) -(CH₂)_m-X_A, where m and X_A are as defined above,

(7) -(CH₂)_m-NR₂₂₂R₂₂₃, where m, R₂₂₂ and R^_g are as defined above, (8) -(CHCH₃)_b-(CH₂)_f-R_22A , where b, f and R_22A are as defined above,

(9) - CH₂)i-X₂, where i and X₂ are as defined above,

(10) (1-piperazinyl)acetyl substituted in the 4- position by -X₂ as defined above, (F-22) (11) (l-piperazinyl)carbonylmethyl substituted in the

4- position by -^ as defined above, (F-23)

(D) 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)-l-pyrrolidinyl optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-24)

(2) 2-(carboxy)-l-piperidinyl optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-25)

/(3) 2-(carboxy)-1-hexamethyleneimino optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt, (F-26)

(4) 2-(carboxy)-l-he tamethyleneimino optionally as the C_χ-C₃ alkyl ester or as a pharmaceutically acceptable salt,(F-27)

(5) 1-piperazinyl substituted in the 4- position with R₂₂₈-C0-(CH₂)_j - where R^_g is -X_χ , -NR_22gX_χ and 2-furanyl, where R_22g is -H or C_χ-C₃ alkyl, where j is 0 through 3 and X_χ is as defined above, with the proviso that R₂₂₈ is X_χ substituted with a carboxyl group, only when j is not 0, (F-28)

(6) 1-piperazinyl substituted in the 4- position with X₂- CH₂)_j-, where X₂ and j are as defined above, (F-29) (7) 1-piperazinyl substituted in the 4- position with

X_x-(CH₂)_j-, where X_χ and j are as defined above, (F-30)

(8) 4-hydroxy-l-piperidinyl substituted in the 4- position with X_χ as defined above, (F-31) (9) 1-piperazinyl substituted in the 4- position with X₂-NR_22g-C0-(CH₂)_i-, where X₂ , R^_g and i are as defined above, (F-32)

(10) l-(4-methyl)-piperazinyl, (F-33)

(11) l-(4-acetyl)-piperazinyl, (F-34) (12) l-(4-hydroxy)-piperidinyl (F-35)

(13) 1-piperidinyl optionally substituted with

2-hydroxyethyl, (F-36)

(14) 4-morpholinyl; (F-37) R₈ is a-R_{S 5} :β-H where R₆₅ is -H, -F and -CH₃ ; (A-IV) R₅ is -R₅₇:^-R₅₈ and R_χo is α-R_χ07 :0-R_χ08 , where one of R₅₇ and R₅₈ is -H, R₁₀₇ and the other of R₅₇ and R₅₈ taken together are -CH₂ -CH₂ -C(R₃ )-CH₂- , where R₃ is as defined above, R_X08 is -CH₃ , R₆ is α-R₅₇:^3-H where R₆₇ is -H, -F and -CH₃ ,

(A-V) R_χ0 is c.-R₁₀₉: -_X0X0, where R_X010 is -CH₃ , R_χ09 taken together with R₅ are -CH₂-CH₂ -C(R₃ )-CH-, where R₃ is α-H:^-AE or α-AE:9-H, where AE is as defined above, where:

(C-I) R_χχ is ot-R_xll :j9-R_XX2 , where one of R_χxl and R₁₁₂ is taken together with R_g to form a second bond between C_g and C_χχ and the other of R_11X and R_χl2 is -H,

(C-II) R_χχ is -0 and R_g is -H, (C-III) R_χχ is a- :β-H and R_g is -H,

(C-IV) R_χχ is -AE:^-H where AE is as defined above and R_g is -H; where:

(D-I) R_χ6 is .-R_16X :_/S-R_x62 where one of R_χgl and R_X62 is -H and the other is -H or CH₃ ;

(D-II) R_χ7 is c--R_X71 :/3-R_χ72, where R_χ7χ is -H, -OH, -0-C0-R_X73 where R_χ73 is -H or C_χ-C₅ alkyl, where R_χ72 is (A) -CO-CH₂-0-CO-C(X₅)H-NR₂₁R_2χo , where X₅ , R_2χ and R_2χo are as defined above,

(B) -CO-CH₂-NR₂₁R_2χo , where R₂₁ and R_2χo are as defined above,

(C) -C0-CH₃ ; and pharmaceutically acceptable salts thereof; and hydrates thereof; with the following overall provisos that: (1) R_χχ is α-AE: -H only when R_χo is α-R_χoχ : -R_X02 or α-R₁₀₃:0-R_χ0A and

(2) R₅ and R_x0 are -CH₂-CH₂ -C(R₃ )-CH₂- only when R_X1 is α-R_χxl: -R₁₁₂. -0 ^or α-H:0-H.

Also disclosed is a cortical aminoester where R_χ01 and R₅ taken together are -CH₂-CH₂-CO-CH- or R_χ03 and R₅ taken together are -CH-CH-C0-CH-, R_χx is α- _lu:Hπ₂. ^{=0 or α}-H:/8-H and R_χ72 is -C0-CH₂-0-C0-C(X₅)H-NR_2XR_2XO which is the 21-aminoester of formula (V) where .... is a single or double bond, X_χχ is =0, -H:3-H or α-X_χχx : -X_xl2 , X₉ is -H or taken together with one of X_χxx and X_1X2 to form a second bond between C_g and C_χχ and the other of X_χιx and X_χl2 is -H.

Further disclosed is a cortical aminoester where R_χox and R₃ taken together are -CH₂-CH₂-CO-CH- or R_χ03 and R₅ taken together are -CH-CH-CO-CH-, R_χχ is α-AE:y3-H; which is the 11-aminoester of formula (VI) where .... is a single or double bond, where X^ is -AE, -H and -NR_2χR₂₁₀.

Additionally disclosed is a cortical aminoester where R₁₀₅ and one of R₅₅ and R_5g or R_χ07 and one of R₅₇ and R₅₈ taken together are -CH₂-CH₂-C(=R₃ )-CH₂- or R₁₀₉ and one of R₅₉ and R₅₁₀ taken together are -CH₂-CH₂-C(=R₃)-CH-, R_χι is α-R_χχχ : -R_χχ2 , =0 or α-H:/3-H; which is the 3-aminoester of formula (VII) where - indicates the AE group is in either the a or β configuration, .... is a single or double bond, X_χχ is -0, a-H.-β-H or α:-X_χχχ :j8-X_χι2 , X₉ is -H or taken together with one of X_χxx and X_χx2 to form a second bond between C₉ and C_χχ and the other of X_χxι and X_XX2 is -H, X^ is -AE, -NR_2χR_2;L0 and -H.

DETAILED DESCRIPTION OF THE INVENTION The androstane-type aminoesters (IV) encompass the 17-aminoester (I), the 11,17-diaminoester (II) and the 3,17-diaminoester (III). The cortical aminoesters (VIII) encompass the 21-aminoester (V) , the 11,21-diaminoester (VI) and the 3,21-diaminoester (VII).

The androstane-type aminoesters (IV) and cortical aminoesters (VIII) are produced from steroids well known to those skilled in the art by methods well known to those skilled in the art. The andros- tane-type aminoesters (IV) and cortical aminoesters (VIII) are prepared from known steroids containing one or two acylable hydroxyl groups (la, Ila, Ilia, Va, Via and Vila, respectively) by reaction with with an acylating agent (IXA or IXB) . It is preferred that the acylating agent (IX) be an α-halo acid halide (IXA) or an α-halo acid anhydride (IXB) . Suitable acylating agents include α-chloroacetyl chloride, chloroacetic acid anhydride, bromoacetylbromide and 2- chloropropionyl chloride, preferred is α-chloroacetyl chloride. A solution of the steroid with the acylable hydroxyl group (la, Ila, Ilia, Va, Via or Vila) in a basic organic solvent such as pyridine is cooled to about 0" to about 20° and the acylating agent (IX) is added slowly. The reaction is quenched in the usual manner, with ice and water, and the α-halo ester (lb, lib, Illb, Vb, VIb or Vllb, respectively) is isolated by extraction and purified by means well known to those skilled in the art such as chromatography and/or crystallization. Alternatively, the acylable steroid (la, Ila, Ilia, Va, Via or Vila) may be dissolved in an inert solvent such as methylene chloride or chloroform, cooled to about 0^β to about -70* and treated with the acylating agent (IX) after addition of a hindered amine base (such as diisopropylethylamine) .

The α-halo ester (lb, lib, Illb, Vb, VIb or Vllb) is then reacted with the appropriate amine in an aprotic solvent containing a base, as is well known to those skilled in the art, to produce the desired androstane-type aminoester (IV) or cortical aminoester (VIII) respectively.

In either step above, it must be recognized that if the acylable steroid contains two acylable hydroxyl groups (Ila, Ilia, Via and Vila) then twice as much acylating agent (IX) will have to be added. Like wise in the second step when the amine is added to the Inter¬ mediate (lib, Illb, VIb or Vllb) twice as much amine Is necessary as for the intermediate with only one acylable hydroxyl group (lb or Vb).

It is preferred that the steroid A-ring be Δ*-3-keto. With regard to the C-ring, it is preferred that R₉ be -H or with R_χχ be A^{9 i l l )} , more preferably Δ^{9 l l l )} . With regard to the aminoester (AE) it is preferred that X₅ be -H. It is also preferred that R_2χ and R_2X0 be taken together with the attached nitrogen atom to form 1- piperazinyl substituted in the 4- position with X₂(CH₂)_j- and X₁(CH₂)_j-. It is preferred that j is 0. It is preferred that X₂ be selected from the group consisting of l,3,5-triazin-4-yl substituted in the 2- and 6- position with -CH₂-CH-CH₂, pyrimidin-4-yl sub¬ stituted in the 2- and 6- position with 1-pyrrolidinyl, pyrimidin-4- yl substituted in the 2- and 6- position with 4-morpholinyl, 1,3,5- triazin-4-yl substituted in the 2- and 6- position with 1-pyr- rolidinyl and pyridinyl substituted in the 3- position with -NR_2χ3R_2X3 where one of ^^ is -H and the other is C₂ alkyl with the cortical aminoesters (VIII). For the D-ring it is preferred that the substitution at C_χ5 be methyl and it is preferred that it be in the α configuration. It is preferred that the substituent at the C_χ7α position (R_17X) be -H. It is preferred that the substituent at the C_{1 7 β} position (R_χ72) he -C0-CH₂-0-C0-C(X₅)H-NR_2XR_2X0. It is prefer- red that X₅ be -H.

The androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are reacted with acids to form amine salts as is well known to those skilled in the art to prepare compounds which are much more water soluble and therefore preferable to use when an aqueous formulation is desired such as a solution for IV use. Generally the androstane-type aminoesters (IV) and cortical aminoesters (VIII) possess one or more basic nitrogen atoms to be converted to an acid addition salt. The pharmaceutically acceptable salt forms of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are generally preferred over the free base form since the salts have greater water solubility and form crystals more suitable for pharmaceutical purposes. An acid addition salt of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be converted to the free base, which can be converted to any desired pharmaceutically acceptable acid addition salt by methods well known to those skilled in the art. It is preferred that the acid addition salt be prepared by reacting the free base of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) with a stoichiomet- ric amount of an acid, such as hydrochloric, hydrobromic, hydrogen iodidic, sulfuric, phosphoric, acetic, lactic, citric, succinic, benzole, salicyclic, pamoic, cyclohexanesulfamic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, oxalic acid and the like. It is preferred that the acid be selected from the group consisting of hydrochloric, maleic, methanesulfonic and fumaric acids.

The androstane-type aminoesters (IV) and cortical aminoesters (VIII) and acid addition salts can be isolated as hydrates or solvates, and such forms are regarded as equivalent to the cor- responding androstane-type aminoesters (IV) and cortical aminoesters (VIII) not containing water or solvent.

The androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are useful pharmaceutical agents in treating a number of different medical conditions in humans and useful warm blooded animals.

In humans, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarach- noid hemorrhage and subsequent cerebral vasospasm, ischemic (throm- boembolic) stroke excess, mucous secretion, asthma, muscular dystro¬ phy, adriamycin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumat¬ oid arthritis, nephrotic syndrome (immunological) , systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example, dermatological, inflammatory and psoriasis conditions), emphysema, cancer (limit metastasis, limit tumor growth) and (stress induced) ulcers.

In humans, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in preventing damage following car- diopulmonary resuscitation, neurological or cardiovascular surgery and cardiac infarction.

Generally, androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in the same way as glucocorticoid pharmaceuticals ^' for the treatment of above human conditions as well as the animal conditions listed below. While the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in both humans and animals in treating many . of the same conditions and preventing damage from the same problems as .the glucocorticoids, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating a number of conditions and preventing damage from conditions where the glucocorticoids are not useful. The androstane- type aminoesters (IV) and cortical aminoesters (VIII) have diminished glucocorticoid activity and therefore, unlike the glucocorticoids, they can be given daily for long periods of time (used chronically) without the side effects associated with the glucocorticoids. This is a distinct advantage.

It is to be understood that each of the androstane-type amino¬ esters (IV) and cortical aminoesters (VIII) is useful for a number of the above conditions but not each and every compound is useful for each and every condition. It is well within the ability of those skilled in the art to easily determine which particular androstane- type aminoesters (IV) and cortical aminoesters (VIII) are useful 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), discloses an assay to determine antiangiogenic activity which is indicative of inhibition of tumor growth and anti-cancer utility. Because of the ability of the compounds which are active in the Folkman embryo test to inhibit tumor growth, they are useful in the treatment of various diseases and conditions, especially various forms of cancer. Accordingly, they are administered to animals and humans to prolong survival or reduce pain and/or discomfort secondary to tumor growth and the alike. Further, the arachidonic acid LD₅₀ test of Kohler, Thrombosis Res., 9, 67 (1976), identifies compounds which are antioxidants, which inhibit lipid peroxidation, and/or which inhibit the pros- taglandin cascade and are useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc. Another method useful for determining which par- ticular compounds inhibit lipid peroxidation and which are therefore useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc is described by Pryor in Methods of Enzymology 105, 293 (1984). Further, the mouse head injury assay of Hall, J. Neurosurg. , 62, 882 (1980) discloses an assay from which one skilled in the art can readily determine which particular androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury. Additionaly, the cat 48 hr motor nerve degerneration model of Hall et al, Exp. Neurol., 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular androstane-type aminoesters (IV) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, Alzheimer™s disease etc. H. Johnson in Int. Arch. Allergy Appl. Immunol., 70, 169 (1983) has described the ascarias sensitized rhesus monkey assay for anti-asthma drugs.

The standard conditions for treatment are to give the andros- tane-type aminoesters (IV) and cortical aminoesters (VIII) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a dose of about 0.05 to about 100 mg/kg/day, one to four times daily for oral or IM administration and continuously for IV infusion.

For treating spinal trauma, mild and moderate to severe head injury, damage following cardiopulmonary resuscitation, or cardiac infarction, organ damage during reperfusion after transplant, hemor¬ rhagic, traumatic and septic shock, severe burns, ARDS, nephrotic syndrome and preventing skin graft rejection, the standard conditions are used. Typical treatment will involve an initial IV loading dose of 0.01 to 1 mg/kg followed by IV infusion for a day to a week depending on the particular condition of the patient and particular compound used. This may be supplemented with IM or oral dosing for days, weeks or months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury). In treating subarachnoid hemorrhage and subsequent cerebral vasospasm or ischemic (thromboembolic) stroke the standard conditions are used and patients at risk are pre-treated orally.

In treating excess mucous secretion and asthma the androstane- type aminoesters (IV) and cortical aminoesters (VIII) are adminis- tered orally, IV, and by inhalation in the standard dose. The frequency of administration is according to the standard conditions. The oral administration of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) to treat excess mucous secretions may go on for months or even years. The susceptible individuals can be pre- treated a few hours before an expected problem. The IV dose is about 0.05 to about 50 mg/kg/day. The aerosol formulation contains about 0.05 to about 1.0% of the androstane-type aminoesters (IV) and cortical aminoesters (VIII) and is administered or used about three times daily. In treating cancer, muscular dystrophy, Parkinsonism, Alzheimer's disease and other degenerative neurological disorders (amyotrophic lateral sclerosis; multiple sclerosis,) the androstane- type aminoesters (IV) and cortical aminoesters (VIII) are adminl- stered orally using a dose of about 0.05 to about 100 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.

In addition, utility in cancer as well as other disorders or physiological phenomena dependent on angiogenesis or neovasculariza- tion such as embryo implantation (antifertility) , arthritis, and atherosclerosis is exhibited with the androstane-type aminoesters (IV) and cortical aminoesters (VIII) with or without co- dministered oral heparin or systemic heparin fragments, see Science 221, 719 (1983).

In treating adriamycin-induced cardiac toxicity the androstane- type aminoesters (IV) and cortical aminoesters (VIII) are adminis¬ tered orally or IV using a dose of about 0.05 to about 100 mg/kg/day (orally) or (IV). The androstane-type aminoesters "(IV) and cortical aminoesters (VIII) are preferably given concomitantly with IV adriamycin or the individual is pre-treated with the androstane-type aminoesters (IV) and cortical aminoesters (VIII) .

For prophylaxis prior to and preventing damage after neurologi¬ cal or cardiovascular surgery the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are used in the standard way. The patient can be pretreated with a single IV or IM dose just prior to surgery or orally before and after surgery.

In treating osteo- or rheumatoid arthritis and other inflam¬ matory diseases the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are given orally or IM in doses of about 0.05 to about 100 mg/kg/day, one to four times daily. Orally the drug will be given over a period of months or years alone or with other steroidal agents. The initial dose with some severe rheumatoid patients may be given IV and followed with an IV drip for up to 24 hr or more. In addition, intra-articular administration may be employ¬ ed.

In treating drug allergic reactions the androstane- ype amino¬ esters (IV) and cortical aminoesters (VIII) are given orally or IV in a dose of about 0.05 to 100 mg/kg/day, administered one to four times daily (orally) and (IV) . Typical treatment would be an initial IV loading dose followed by oral dosing for a few days.

In treating atherosclerosis and emphysema the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are given orally in a dose of about 0.05 to about 100 mg/kg/day, one to four times daily for months or years.

In treating dermatological inflammatory conditions including psoriasis the androstane-type aminoesters (IV) and cortical amino- esters (VIII) are given orally in a dose of about 0.05 to about 100 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.05 to about 5% as long as needed. In treating these condi¬ tions the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be used with other steroidal agents.

In promoting burn healing and wound healing the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are given orally or IV in a dose of about 0.05 to about 100 mg/kg/day administered one to four times daily orally and IV. Typical treatment would be an initial IV loading dose of 0.01 to 1 mg/kg followed by oral dosing for a few days.

The androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as nonsteroidal anti- inflammatory compounds (NOSAC) . Stress ulcers are ulcers that develop after exposure to severe conditions 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 include lesions that can lead to upper gastrointestinal bleeding; such bleeding is likely to be prevented or stopped by these compounds. NOSAC includes drugs such as aspirin, indomethacin, naproxen, piroxicam and 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 androstane-type aminoesters (IV) and cortical amino¬ esters (VIII) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from 5 to 500 mg, two to four times a day. The treatment would be either preventive, i.e., starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ulcers have formed. In patients whose clinical condition precludes swallowing the oral dosage forms, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) would be given either thru a nasogastric tube, or parenterally, i.e., IV or IM. The parenteral doses would range from about 1 to about 100 mg and be administered one to four times a day or by IV.

In dogs, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating head and spinal trauma, intervertebral diseases (slipped disk) , traumatic shock, flea bite and other allergies.

In horses, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis) .

In cattle, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating acute coliform mastitis, bovine mastitis and acute allergic reaction to feed lot vaccination. In pigs, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) are useful in treating porcine stress syndrome and thermal stress syndrome.

The term treatment or treating as used in this patent is used broadly and includes both treatment of an existing condition as well as preventing the same condition from occurring where such is possible as is well known to those skilled in the art. For example, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) can be used to treat existing asthma conditions and to prevent future ones from occurring. Also, the androstane-type aminoesters (IV) and cortical aminoesters (VIII) treat spinal trauma and prevent rejection of skin grafts.

The exact dosage and frequency of administration depends on the particular androstane-type aminoesters (IV) and cortical aminoesters (VIII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condi¬ tion of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentra¬ tion of the androstane-type aminoester (IV) and cortical aminoesters (VIII) in the patient's blood and/or the patients response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout the entire patent application including both the speci¬ fication and the claims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecu- lar fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z" or "R_χ " where "i" is an integer. These variable substituents are either monovalent or bivalent, that is represent a group attached to the formula by one or two chemical bonds. For example, a group Z would represent a bivalent variable if attached to the formula CH₃-C(-Z)H. Groups R_χ and R_j would represent monovalent variable substituents If attached to the formula CH₃-CH₂-C(R_i)(R_j )H₂. hen chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R_L and R^ are bonded to the preced¬ ing carbon atom. Also, for any molecule with an established system / of carbon atom numbering, such as steroids, these carbon atoms are designated as C_i , where "i" is the integer corresponding to the carbon atom number. For example, C_g represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term "R₆ " represents a variable substituent (either monovalent or biva- lent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general repre¬ sents a bond between two atoms in the chain, more specifically it represents a carbon-carbon bond. Thus CH₃ -0-CH₂-C^ )H-CH₃ represents a 2-subsituted-l-methoxypropane compound. In a similar fashion, the symbol "-" represents a double bond, e.g., CH₂-C(R_i)-0- CH₃ , and the symbol "}" represents a triple bond, e.g., HCΞC-CH(R_χ)- CH₂-CH₃. Carbonyl groups are represented in either one of two ways: -C0- or -C(-O)-, with the former being preferred for simplicity.

Chemical forumlas of cyclic (ring) compounds or molecular frag¬ ments can be represented in a linear fashion. Thus, the compound 4- chloro-2-methylpyridine can be represented in linear fashion by N*-C(CH₃)-CH-CC1-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(C₂H₅ )-CH₂- C^*H₂. A cyclic (ring) structure for any compound herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the cyclic compound. In formulas depicting such compounds, a substituent attached to a carbon atom below the plane of the ring is identified as being in the alpha (α) configuration and is indicated by a broken line attachment to the carbon atom, i.e., by the symbol "- - -". The corresponding sub¬ stituent attached above the plane of the ring is identified as being in the beta (β) configuration. When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R attached to a carbon atom as -C(-R_±)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monvalent variable substituents ct- _j. and jS-R_ik . When a bivalent variable, R_A , is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R^ : -R_ik.. or some variant thereof. In such a case both α- _j. and -R_ik are attached to the carbon atom to yield -C(α-R_χ^ ) (f3-R_ik)- . For example, when the bivalent variable R_g , -C(-R_g)-, is defined to consist of two monovalent variable sub- stituents, two monovalent variable substituents are α-R_gχ :jS-R_g2 , .... α-R_gg:^-R_gχo, etc, yielding -C(α-R_gχ) G8- _g2)- -C(α-R₆₉) (_/3-

R_6X0)-, etc. Likewise, for the bivalent variable R_χχ, -C(=R_χχ)-, two monovalent variable substituents are α- m: ₁₁₂-

Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -C_χ (R_i)H-C₂ R^ )H- (C_χ and C₂ define arbitrarily a first and second carbon atom, respectively) R_χ and R. may be defined to be taken together to form (1) a second bond between C_χ and C₂ or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When R_t and R_j are taken together to form a more complex entity, such as the group -A_x -A^ - , then the orientation of the entity is such that C_χ in the above formula is bonded to A_χ and C₂ is bonded to A^ . Thus, by convention the designation "... R_x and R, are taken together to form -CH₂-CH₂-0- CO- ..." means a lactone in which the carbonyl is bonded to C₂. However, when designated "... ^ and R_χ are taken together to form- CH₂-CH₂ -O-CO- the the convention means a lactone in which the carbonyl is bonded to C_χ .

The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C_χ-C ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C_χ-C_A alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given) . Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defin¬ ed. Thus C2-C4 alkoxycarbonyl describes a group CH₃ -(CH₂)_n-0-CO- where n is zero, one or 2. By the second method the carbon atom content of only each portion of the definition is Indicated separate¬ ly by enclosing the "Ci-Cj" designation in parentheses and placing it immediately (no intervening space) before the portion of the defini¬ tion being defined. By this optional convention (C1-C3)alkoxycar¬ bonyl has the same meaning as C2-C4 alkoxycarbonyl because the "Cl- C3"refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (Cl-C3)alkoxy(Cl-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms. When the claims contain a (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be the notation (F-##) , formula-number, which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.

II. DEFINITIONS All temperatures are in degrees Centigrade. TLC refers to thin-layer chromatography. Saline refers to an aqueous saturated sodium chloride solution. Ether refers to diethyl ether.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (5) downfield from tetramethyl- silane. dec refers to decomposition.

The steroids of the Examples were chromatographed on 63-200 micron silica gel by gravity chromatography. Alcohol refers to ethyl alcohol. Allyl refers to 2-propen-l-yl. ARDS refers to acute/adult respiratory distress syndrome.

IV refers to intravenous, including injection, infusion and continuous drip.

IM refers to intramuscular.

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacologi- cal/toxicological point of view including bioavailability and patient acceptance or to the manufacturing chemist from a physical-chemical point of view regarding composition, formulation, stability and isolatability. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) .

[NNNNNN-NN-NJ refers to Chemical Abstracts Service (CAS) registry numbers where each N is an integer from 0 thru 9, but deleting leading zeros in the 6-digit portion of the number. Registry numbers are assigned to a particular chemical compound by CAS only when there is sufficient proof according to CAS criteria that the compound has been found to exist and it has been charac¬ terized in some way. Compounds published from approximately 1967 to the present are registered publicly and the registry numbers is the key to finding references in the CAS data base for such a registered compound. The CAS database is publicly available from several database vendors such as STN International, System Development Corporation (SDC) , Orbit Search Service, Lockheed Dialog, Bibliogra- phic Retrieval Systems, Questel, etc. CAS registry numbers are included in the EXAMPLES for some of the compounds which have been registered.

Aldrich item refers to an item listed for sale by Aldrich Chemical Co., P.O. Box 355, Milwaukee, Wisconsin, 53201, USA in their

1984-1985 catalog.

AE is (aminoester) -0-C0-C (X₅ ) H-NR_{2 χ}R_{2 χ o} .

Q_χ is -Cl or -Br .

Q₂ is -Cl or -Br . X_χχ is -0, α-H:/3-H or α-X_lχι :^-X_χχ2 , X₉ is -H or taken together with one of X_χxl and X₁₁₂ to form a second bond between C_g and C_χχ and the other of X_lxl and X_X12 is -H.

- indicates that the attached group can be in either the α or β configuration. .... is a single or double bond.

EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize

* appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

PREPARATION A-6 4-(2-Pyridinyl)piperazine [34803-66-2], see

French Patent 7253 M. PREPARATION A-14 4-[4,6-Bis(2-propenylamino)-1,3,5-triazin-2-yl] - piperazine A solution of 2-chloro-4,6-bis(2-propenylamino)-1,3,5-triazine (10.44 g) and 15.95 g of piperazine in 150 ml of DMF is heated under reflux for about 18 hours. The reaction mixture is cooled and stored at 5° and crystals are deposited. The soluble fraction is con¬ centrated and the residue is extracted with ethyl acetate. The extracts are washed with aqueous potassium carbonate, 50% saline and saline and dried over magnesium sulfate and concentrated to give a gum. Chromatography on silica gel (400 g) and elution (200 ml fractions) with 20% acetone-methylene chloride gives the formamide. The formamide (9.2 g) in 200 ml of methanol is heated to reflux, then cooled under nitrogen and mixed with 4 ml of 45% potassium hydroxide solution. The mixture is heated under reflux for about 20 hours, then cooled and concentrated. The residue is partitioned between ethyl acetate and water. The organic extracts are washed with water and saline, dried over magnesium sulfate and concentrated to give a gum. Crystallization from 50 ml of carbon tetrachloride gives the title compound, mp 93-94.5°. PREPARATION A-22 .4- [2 , 6-Bis(1-pyrrolidinyl)-4-pyrimidinyl]pipera- zine

A solution of pyrrolidine (80 g) in THF (500 ml) is chilled in an ice water bath and stirred mechanically under nitrogen. With a syringe pump of 2,4,6-trichloropyrimidine (50 g) is added over 35 minutes. The reaction is 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 mixture stirred at 20-25° overnight. The reaction is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is concentrated and the residue chromatographed on silica gel (10% ethyl acetate/hexane) to yield 51 g of crystalline 2,4-bis[pyrrolidino] - -6-chloropyrimidine. Immediately after the initial addition of reagents, two spots are seen with 25% ethyl acetate on a silica gel plate. These are the 2- and the 4- adducts. The bis product forms over time. It moves between these first two spots. The 51 g of product is reacted with piperazine (40 g) in 100 ml of dry pyridine at 100° for 50 h. The reaction is concentrated. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and concentrated. The residue is chromatographed on silica gel eluting with methylene chloride to 10% methanol/1% ammonia/methylene chloride to give the title com¬ pound. PREPARATION A-23 _A -[2,6-Bis(morpholino)-4-pyrimidinyl]piperazine

A solution of 160 g of morpholine in 1000 ml of methylene chloride is treated dropwise with 100 g of 2,4,6-trichloropyrimidine. The reaction is immersed in an Ice water bath. After 1 h, 300 ml of pyridine is added. The reaction is stirred for two days and con¬ centrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The residue is chromatographed on silica gel (10% ethyl acetate/hexane to 25% to methylene chloride) to give 2,4- [bis-morpholino] -6-chloropyrimidine. A solution of 40 g of 2,4- [bis-morpholino]-6-chloropyrimidine and 34 g of piperazine in 60 g of pyridine is heated at 100° for 24 h. The mixture is partitioned between methylene chloride and aqueous potassium carbonate. The organic phase is filtered through sodium sulfate and concentrated. The residue is chromatographed (methylene chloride to 4% methanol/1% ammonium hydroxide/methylene chloride) to give the title compound. PREPARATION A-47 4- [3-(Ethylamino) -2-pyridinyl]piperazine 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 is filtered thru celite, washed with ethanol, chloroform, ethanol and water. The organic solvents are removed with heat and reduced pressure. The remaining material is partitioned betweened methylene chloride (3 x 250 ml) and sodium bicarbonate. The organic layers are combined, dried over potassium carbonate, filtered and concentrated under reduced pressure to give an oil which slowly solidified upon standing to give 3-amino-2-(l-piperazinyl)pyrldine. 3-Amino-2-(l-piperazinyl)pyridine (19.58 g) , methylene chloride 600 ml), triethylamine (17.2 ml) are combined and cooled to 6°. Di- t-butyl-dicarbonate (24.34 g) in methylene chloride (50 ml) is added to the pyridine mixture over 30 min and permitted to stand at 0° for 1 hr, then allowed to warm to 20 - 25°. After 30 min, TLC indicates no starting material remains. The reaction mixture is partitioned between sodium bicarbonate (500 ml) and methylene chloride (3 x 250 ml) . The organic phases are combined, dried over potassium car¬ bonate, filtered and concentrated under reduced pressure and heat to give a solid which is recrystallized from ethyl acetate to give 3- amino-2- [(4-t-butyldicarbonate)-l-piperazinyl]piperidine.

3 -Amino-2- [ (4-t-butyldicarbonate) -l-piperazinyl]piperidine (2.361 g) , methanol (23.6 ml) and acetaldehyde (2.1 ml) are combined at 20 - 25° to form a solution. Sodium cyanoborhydride (586 mg) is added and the mixture stirred overnight. The organic solvent is removed with reduced pressure and heat, the remaining mixture is partitioned between sodium bicarbonate (50 ml) and chloroform (3 x 50 ml) . The chloroform extracts are combined and dried over potassium carbonate and filtered. The filtrate is concentrated with heat and reduced pressure. The concentrate is column chromatographed on silica gel 60 (40 63 μ) eluting with hexane/ethyl acetate (2/1) containing triethylamine (1%). The appropriate fractions are pooled and concentrated to give 3-ethylamino-2- [(4-t-butyldicarbonate)-1- piperazinyl]piperidine.

3-Ethylamino-2- [ (4-t-butyldicarbonate)-1-piperazinyl]piperidine (2.47 g) , ethyl acetate (67 ml) and hydrochloric acid (3 N, 49 ml) are combined and stirred for 2 hr at 20 - 25°. TLC indicates no starting material. Potassium hydroxide (14 g) and water (80 ml) is added. The organic layer is removed and extracted wtih chloroform (3 x 60 ml) . The orgnic layers are combined, dried over potassium carbonate, filtered and the filtrate 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-critical variations but reacting the protected ethylamine compound with additional acetaldehyde and again reducing the title compound is obtained. PREPARATION S-22 21-Hydroxy-16α-methylpregna-l,4,9(11)-triene-3,20 dione

A solution of 150 g (0.41 mol) of 21-hydroxypregna-l,4,9(11) ,16- tetraene-3,20-dione 21-acetate (US Patent 2,864,834, 150 g) and 90 ml of 1.9 molar copper propionate in THF is cooled in an ice acetone bath. Methyl magnesium chloride (1.96 molar in THF, 240 ml) is added dropwise over 30 minutes. The reaction is checked by TLC (1:1 ethyl acetate/hexane on silica gel) . Additional Grignard reagent can be added if the reaction is not complete. After 1 h, the reaction is quenched with 375 ml of 25% concentrated hydrochloric acid in methan- ol. The reaction is partitioned between water and toluene. The organic phase is washed with water, filtered through sodium sulfate and concentrated. The residue is crystallized from ether and hexane. The crystals are triturated with ether to give the desired (16α- methyl) Michael addition product.

This is stirred in 1500 ml of methanol and is treated with 5.0 ml of 25% sodium methoxide in methanol for 30 min. The mixture is partitioned between methylene chloride and sodium bicarbonate. The organic phase is washed with sodium bicarbonate, filtered through sodium sulfate and concentrated. The residue is crystallized from ether to give the title compound.

PREPARATION S-23 llα-Hydroxy-21-iodo-16α-methylpregna-l,4-diene-

3,20-dione A mixture of llα-hydroxy-16α-methylprogesterone (3.44 g) and DDQ (1.1 eq) in 250 ml of benzene is heated under reflux for about 20 hours. The organic layer is then washed (2 x 100 ml 1 N sodium hydroxide, 2 x 100 ml water and 1 x 100 ml saline) and the aqueous layers backwashed (2 x 100 ml ether). The extracts are dried and concentrated to give a foam which is chromatographed on silica gel (300 g) , eluting with 8 1 of 10% acetone - methylene chloride and 20% acetone - methylene chloride. The appropriate fractions (200 ml) are pooled and concentrated to give the Δ¹•* -steroid.

The Δ¹ • * -steroid (1.7 g) in methanol (5 ml) and carbon tetra- chloride (10 ml) is mixed with 0.17 ml of 10% calcium chloride in methanol and stirred for 0.25 hours. Calcium oxide (1.73 g) is added, followed by slow addition (4 hours) of a suspension of 2.44 g of iodine in 3.9 ml of 10% calcium chloride in methanol. The mixture is stirred for an additional 0.5 hours, then is filtered through celite (wet with methanol) . The filtrate is concentrated to give a gum. Chromatography on silica gel (600 g) and elution with 8 1 of 10% and 4 1 of 20% acetone-methylene chloride gives the title compound as a foam which is crystallized from acetone-hexane, mp 153°. EXAMPLE 1 17;9-Hydroxyandrost-4-en-3-one 17-bromoacetate A mixture of bromoacetylbromide (0.9 ml) and methylene chloride (10 ml) is added slowly to a solution of testosterone (2.88 g) and diisopropylethylamine (1.9 ml) in methylene chloride (25 ml) at -14 to -5°. The mixture Is slowly permitted to warm to 20-25° over a period of 2 hours and then is washed with hydrochloric acid (0.1 N) and potassium bicarbonate (1 N) . The extract is filtered through sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (200 g) and eluted with acetone/methylene chloride (5/95). The appropriate fractions are pooled and concentrated. The concentrate is crystallized from acetone-hexane. These crystals are rechromatographed on silica gel eluting with acetone/methylene chloride (2/98) . The appropriate fractions are pooled, concentrated and crystallized from acetone/hexane to give the title compound, mp 140.5-144.5°; NMR (CDC1₃) 0.9, 1.2, 3.85, 4.72 and 5.79 ό\ EXAMPLE 2 17 -Hydroxyandrost-4-en-3-one 17- [4- (2-pyridinyl) -1- piperazinyl]acetate dihydrochloride

(A) A mixture of 17£-hydroxyandrost-4-en-3-one 17-bromoacetate (EXAMPLE 1, 1.38 g) and 4-(2-pyridinyl)piperazine (PREPARATION A-6, 0.6 ml) and acetonitrile (14 ml) is allowed to stand at 20-25° for 1.5 hours and is then heated at reflux for 1 hour. The mixture is concentrated and the residue partitioned between methylene chloride and aqueous potassium bicarbonate. The layers are separated, the organic phase is washed with saline, filtered through sodium sulfate and concentrated to a solid which is chromatographed on silica gel (180 g) . Elution is performed with acetone/methylene chloride (10/90 - 20/80) . The appropriate fractions are pooled and concentrated to give a solid which is crystallized from acetone. The crystals are rechromatographed on silica gel using the same elution system. The appropriate fractions are pooled and concentrated to give the free amine of the title compound, NMR (CDC1₃ ) 0.83, 1.20, 2.7, 3.3, 3.64, 4.75, 5.78, 6.68, 6.76, 7.55 and 8.34 5.

(B) A solution of the free base in ether/methylene chloride (1/1) is mixed with ethereal hydrochloric acid (1 ml) . The mixture is concentrated and the residue dried under reduced pressure over potassium hydroxide to give the title compound, mp 195° . EXAMPLE 3 llα,17 -Dihydroxyandrost-4-en-3-one ll,17-bis(chloro- acetate) A mixture of chloroacetylchloride (2.4 ml) and methylene chloride (60 ml) is added slowly to a stirred suspension of llα- hydroxytestosterone (3.04 g) and diisopropylethylamine (5.2 ml) in methylene chloride (50 ml) at -4 to -8°. The reaction mixture is stirred at -5° .for 3.5 hours and then is washed with cold hydro¬ chloric acid (1 N) and potassium bicarbonate (1 N) . The organic phase is separated, dried and concentrated to give a solid which is chromatographed on silica gel (500 g) . Elution is performed with acetone/methylene chloride (2/98 - 6/94). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDC1₃) 0.94, 1.30, 3.95-4.25, 4.78, 5.33 and 5.8 S . EXAMPLE 4 llα,17j8-Dihydroxyandrost-4-en-3-one ll,17-bis[4-(2- pyridinyl)-1-piperazinyl]acetate tetrahydrochloride A mixture of llα,17^-dihydroxyandrost-4-en-3-one ll,17-di(chlo- roacetate) (EXAMPLE 3, 0.9 g) and 4-(2-pyridinyl)piperazine (PREPARA- TION A-6, 0.64 ml) in acetonitrile (16 ml) is heated under reflux for about 18 hours. The reaction mixture is concentrated and the residue partitioned between methylene chloride and aqueous potassium bi¬ carbonate. The phases are separated, the organic phase is con- centrated. The concentrate is chromatographed on silica gel (120 g) eluting with acetone/methylene chloride (20/80 - 30/70). The ap¬ propriate fractions (50 ml) are pooled and concentrated to obtain the free amine of the title compound.

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 184° dec.

EXAMPLE 5 llα,17^-Dihydroxyandrost-4-en-3-one 11,17-bis[4-[4,6- bis(2-propenylamino)-1,3,5-triazin-2-yl] -1-piperazin¬ yl]acetate tetrahydrochloride A mixture of llα,17/3-dihydroxyandrost-4-en-3-one ll,17-di(chlo- roacetate) (EXAMPLE 3, 0.69 g) and l-(4,6-bispropenylamino-l,3,5- triazin-2-yl)piperazine (PREPARATION A-14, 1.65 g) in acetonitrile (30 ml) is heated under reflux for 6.5 hours. The crude product is chromatographed on silica gel (120 g) eluting with acetone/methylene chloride (0.5 liters 20/80 and 4 liters 30/70 - 60/40). The ap¬ propriate fractions (50 ml) are pooled and concentrated to give the free amine of the title compound, NMR (CDC1₃) 2.58, 3.16, 3.24, 3.7- 4.2, 4.75, 5.0-5.5, 5.8 and 5.7-6.3 6 .

Following the general procedure of EXAMPLE 2(B.) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 186° .

EXAMPLE 6 llα,17α,21-Trihydroxypregn-4-ene-3,20-dione 11,17- di(chloroacetate) Following the general procedure of EXAMPLE 3 and making non- critical vaiations but starting with llα,17α,21-trihydroxypregn-4- ene-3,20-dione the title compound is obtained.

EXAMPLE 7 llα,17α,21-Trihydroxypregn-4-ene-3,20-dione 11,21- bis[4- [4,6-bis(2-propenylamino)-l,3,5-triazin-2-yl] -1- piperazinyl]acetate tetrahydrochloride A mixture of llα,17α,21-trihydroxypregn-4-ene-3,20-dione 11,17- di(chloroacetate) (EXAMPLE 6, 0.37 g) , 1- [4,6-bis(2-propenylamino)-

1,3,5-triazin-2-yl)]piperazine (PREPARATION A-14, 0.78 g) and potassium carbonate (0.138 g) in acetonitrile (14 ml) is heated under reflux for 3 hours. The reaction mixture is worked up as in Examples 2, 4 and 5 to give a solid which is chromatographed on silica gel (100 g) . The column is eluted with acetone/methylene chloride (30/70 - 50/50, 3.5 1). The appropriate fractions (50 ml) are pooled and concentrated to give the free amine of the title compound, NMR (CDC1₃) 0.77, 1.24, 2.60, 3.14, 3.35, 3.8-4.1, 4.8-5.5, 5.8 and 5.8- 6.3 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 183° .

EXAMPLE 8 llα,17α,21-Trihydroxypregn-4-ene-3,20-dione 11,21- bis[4-(2-pyridinyl)-1-piperazinyl]acetate tetrahydro¬ chloride Following the general procedure of EXAMPLE 7 and 2(B) and making non-critical variations but starting with 4-(2-pyridinyl)piperazine (PREPARATION A-6) the title compound is obtained, mp 185° dec. EXAMPLE 9 llα-Hydroxy-16α-methylprogesterone 11-chloroacetate

A mixture of chloroacetyl chloride (0.6 ml) in methylene chloride (15 ml) is added slowly to a mixture of llα-hydroxy-16α- methylprogesterone (1.72 g) and diisopropylethylamine (1.3 ml) in methylene chloride (25 ml) at -10°. The reaction mixture is allowed to stand at -10° for 2 hours and then worked up as described above to give a solid. The solid is chromatographed on silica gel (200 g) and eluted with acetone/methylene chloride (1/99-10/90, 3 liters). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDC1₃) 0.77, 0.98, 1.28, 2.13, 4.05, 5.34, 5.83 δ . EXAMPLE 10 llα-Hydroxy-16α-methylprogesterone 11-[4-(2-pyrid- ihyl)-1-piperazinyl]acetate dihydrochloride A mixture of llα-hydroxy-16α-methylprogesterone 11-chloroacetate (EXAMPLE 9, 1.17 g) and 4-(2-pyridinyl)piperazine (PREPARATION A-6, 1 ml) in acetonitrile (15 ml) is heated under reflux for 6 hours. The crude product is chromatographed on silica gel (200 g) . Elution is performed with acetone/methylene chloride (10/90 - 40/60, 4 liters). The appropriate fractions (50 ml) are pooled and concentrated to give the free amine of the title compound, NMR (CDC1₃) 0.77, 0.98, 1.29, 2.13, 2.7, 3.23, 3.64, 5.37, 5.82, 6.68, 7.55 and 8.25 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 172° dec.

EXAMPLE 11 llα-Hydroxy-16α-methylprogesterone 11- [4- [2,6-bis(mor- pholino)-4-pyrimidinyl] -1-piperazinyl]acetate dihydro- chloride Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of llα-hydroxy-16α- methylprogesterone 11-chloroacetate (EXAMPLE 9, 0.43 g) , and 4- [2,6- bis(morpholino)-4-pyrimidinyl]piperazine (PREPARATION A-23, 0.56 g) the free amine of the title compound is obtained, NMR (CDC1₃) 0.76, 0.97, 1.25, 2.1, 2.65, 3.18, 3.4-3.7, 3.75, 5.12, 5.35 and 5.8 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 200° dec. EXAMPLE 12 llα-Hydroxy-16α-methylprogesterone 11- [4- [2,6-bis(l- pyrrolidinyl) -4-pyrimidinyl] -l-ρiperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of llα-hydroxy-16α- methylprogesterone 11-chloroacetate (EXAMPLE 9, 0.43 g) , and 4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine (PREPARATION A- 22, 0.5 g) the free amine of the title compound is obtained, NMR (CDC1₃) 0.75, 0.96, 1.27, 2.12, 2.62, 3.18, 3.2-3.75, 4.88, 5.35 and 5.8 δ .

Following the general procedure of EXAMPLE 2(B) and making ndn- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 202° dec. EXAMPLE 13 21-Hydroxypregn-4-ene-3,20-dione 21-chloroacetate

A mixture of 21-hydroxypregn-4-ene-3,20-dione (1.65 g) and diisopropylethylamine (1.5 ml) in methylene chloride (12 ml) is cooled to -70° and chloroacetic anhydride (1.28 g) added. The mixture is stirred briefly and then sored at -15° overnight. The mixture is worked up with ice water, aqueous potassium bicarbonate, dried, concentrated and chromatographed over silica gel eluting with acetone/methylene chloride (10/90) . The appropriate fractions are pooled and concentrated to give the title compound, mp 123-123.5°; NMR (CDCL_g) 0.72, 1.22, 4.22, 4.75 and 5.78 δ .

EXAMPLE 14 21-Hydroxypregn-4-ene-3,20-dione 21-[4- [2,6-bis(l-pyr^ rolidinyl) -4-pyrimidinyl ] -1-piperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of 21-hydroxypregn-4- ene-3,20 dione 21-chloroacetate (EXAMPLE 13, 0.4 g) , and 4- [2,6- 5 bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine (PREPARATION A-22, 0.45 g) the free amine of the title compound is obtained, NMR (CDC1₃) 0.72, 1.20, 2.65, 3.35-3.8, 4.73, 4.88 and 5.8 S .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title 0 compound (salt) is obtained, mp 157° dec.

EXAMPLE 15 21-Hydroxypregn-4-ene-3,20-dione 21- [4- [4,6-bis(2- propenylamino) -1,3,5-triazin-2-yl] -1-piperazinyl]- acetate dihydrochloride Following the general procedure of EXAMPLE 2(A) and making non- 5 critical variations but starting with a mixture of 21-hydroxypregn-4- ene-3,20 dione 21-chloroacetate (EXAMPLE 13, 0.4 g) , and 4-(4,6 -bis(2-propenylamino)-l,3,5-triazin-2-yl)]piperazine (PREPARATION A- 14, 0.3 g) the free amine of the title compound is obtained, NMR (CDC1₃) 0.72, 1.20, 3.62, 3.4, 3.7-4.2, 4.73, 4.9-5.4, 5.78 and 5.8- 0 6.25 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 164° .

EXAMPLE 16 llα-Hydroxy-21-iodo-16α-methylpregna-l,4-diene-3,20- 5 dione 11-chloroacetate

Following the general procedure of EXAMPLE 13 and making non- critical variations but starting with llα-Hydroxy-21-iodo-16α-methyl- pregna-l,4-diene-3,20-dione (PREPARATION S-23) the title compound is obtained, NMR (CDC1₃) 0.8, 1.0, 1.3, 3.76, 4.08, 5.35, 6.16, 6.28 and 0 6.85 δ .

EXAMPLE 17 llα-Hydroxy-21- [4- [2,6-bis(l-pyrrolidinyl)-4-pyrimi¬ dinyl] -1-piperazinyl] -16α-methylpregna-l,4-diene-3,20- dione 11-[4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl] 1-piperazinyl]acetate tetrahydrochloride 5 Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of llα-hydroxy-21- iodo-16α-methylpregna-l,4pdiene-3,20 dione 11-chloroacetate (EXAMPLE 16, 0.3 g) , and 4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]piperazine f i

I

I (PREPARATION A-22, 0.45 g) the free amine of the title compound is obtained, NMR (CDC1₃ ) 0.78, 0.95, 1.28, 3.12, 3.21, 4.88, 5.3, 6.12, 6.2 and 6.9 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 215° dec.

EXAMPLE 18 3/9,17α-Dihydroxy-6α-methylpregn-4-en-20-one 17-acetate 3- [4-(2-pyridinyl)-l-piperazinyl]acetate dihydrochlo- ride Following the general procedure of EXAMPLES 1, 3, 6, 9, 13, and 16 and making non-critical variations but starting with 3 ,17α- dihydroxy-6α-methylpregn-4-en-20-one 17-acetate (J. Med. Chem. 7, 355 (1964) *3.89 g) , 3/3,17α-dihydroxy-6α-methylpregn-4-en-20-one 17- acetate 3-chloroacetate is obtained. Following the general procedure of EXAMPLE 2(A) and making non- critical variations but starting with a mixture of 3y3,17α-dihydroxy- 6α-methylpregn-4-en-20-one 17-acetate 3-chloroacetate (above) and 1- (2-pyridinyl)piperazine (PREPARATION A-6, 1.0 ml), the free amine of the title compound is obtained, NMR (CDC1₃ ) 0.65, 1.0, 1.08, 2.04, 2.11, 2.72 3.3, 3.63, 5.2-5.6, 6.64, 6.75, 7.55 and 8.25 δ .

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 164° dec.

EXAMPLE 19 3/3-Hydroxy-16α-methylpregn-5-en-20-one 3- [4-(2- pyridinyl) -l-piperazinyl]acetate hydrochloride

Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with 3 -hydroxy-16α-methylpregn-5- en-20-one (Swiss .Patent 368,490, *1.65 g) and 4-(2-pyridinyl) ipera¬ zine (PREPARATION A-6), the title compound is obtained. NMR (CDCL_g) of the free amine of the title compound 0.68, 0.95, 1.03, 2.13, 2.7, 3.28, 3.62, 4.75, 5.4, 6.67, 7.6 and 8.4 ό^*.

EXAMPLE 20 21-Hydroxy-16α-methylpregna-l,4,9(11)-triene-3,20-- dione 21- [4- [2,6-bis(morpholino) -4-pyrimidinyl] -1-pi¬ perazinyl] -acetate dihydrochloride Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with a mixture of 21-hydroxy-16α- methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22, reference*), and 4- [2,6-bis(morpholino)-4-pyrimidinyl]piperazine (PREPARATION A-23, 0.56 g) the free amine of the title compound is obtained

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 161° dec.

EXAMPLE 21 21-Hydroxy-16α-methylpregna-l,4,9(11)-triene-3,20-- dione 21- [4- [2,6-bis(l-pyrrolidinyl) -4-pyrimidinyl] -1- piperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with a mixture of 21-hydroxy-16α- methylpregna-1,4,9(11)-triene-3,20-dione and 4- [2,6-bis(l-pyrrolid- Inyl)-4-pyrimidinyl]piperazine (PREPARATION A-22), the free amine of the title compound is obtained

Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 161° dec.

EXAMPLE 22 21-Hydroxy-16α-methylpregna-l, ,9(11)-triene-3,20-- dione 21-[4- [4,6-bis(2-propenylamino)-l,3,5-triazin-2- yl] -1-piperazinyl]acetate dihydrochloride Following the general procedure of EXAMPLE 18 and making non- critical variations but starting with a mixture of 21-hydroxy-16α- methylpregna-1,4,9(11)-triene-3,20-dione and 4- [(4,6-bis(2-propenyl- amino)-l,3,5-triazin-2-yl)]piperazine (PREPARATION A-14), the free amine of the title compound is obtained Following the general procedure of EXAMPLE 2(B) and making non- critical variations but starting with free amine above, the title compound (salt) is obtained, mp 159°. EXAMPLE A Conjugated Diene Formation Assay

The formation of conjugated dienes as assayed by Braughler, J. Neurochem. , 44, 1282 (1985), Bucher, Fund. Applied Tox. , 3, 222 (1983) and Tein, Arch. Biochem. Biophy. , 216, 142 (1982) is a standard pharmacological laboratory procedure useful for identifying compounds which inhibit lipid peroxidation. Since lipid peroxidation is involved in the pathophysiology of central nervous system trauma, compounds which inhibit conjugated diene formation are useful in treating the conditions listed below.

Inhibition of conjugated diene formation as measured by any of the above procedures or the modified procedure below demonstrates usefulness in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vaso- spasm, ischemic (thromboembolic) stroke, muscular dystrophy, adriamy¬ cin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reprefusion after transplant, skin graft rejection, hemor¬ rhagic, traumatic, or septic shock, severe burns, ARDS, allergic reactions, emphysema and post burn pulmonary complication. Further, an inhibition of conjugated diene formation also demonstrates usefulness in preventing damage following cardiopulmonary resuscita¬ tion, neurological or cardiovascular surgery and cardiac infarction.

While not necessary to demonstrate conjugated diene inhibition, the above assays have been modified as follows: rat brain synap- tosomes are prepared according to the procedure described in J. Neurochem. 44, 1282 (1985). Synaptosomal suspension (10 μl) is added to 1 ml of physiological (normal) saline containing 1 % Lubrol PX (Sigma Chemical Co. St. Louis, Mo.), 100 μM hydrogen peroxide and 100 μM (or less) of the drug to be tested prepared in either absolute ethanol or water depending upon solubility. The reaction is started by the rapid addition of 200 μM ferrous ammonium sulfate prepared in argon-purged water. The sample is rapidly mixed and the change in absorbance at 232nm is followed in a Gilford Response Spectrophoto- eter equipped with a rapid sampler. Due to the rapidity of the reaction, rapid addition of the iron, rapid mixing and sampling are obligatory to the accuracy of the assay. For best results absorbance readings of one/sec should be started within 5 sec following the addition of iron. The initial linear rate of absorbance change during the first 30 sec of reaction are compared with the rate of a reaction containing all reagents except synaptosomes. The difference in rates is the rate of conjugated diene formation. Rates with drug are compared to rates obtained in the absence of drug and the % inhibition is calculated. A compound that inhibits conjugated diene formation by 50% or more is considered to be "active".

The compounds of Examples 2, 4 and 5 demonstrate such activity by inhibition of conjugated dienes.

The above in vitro test/assay is a standard pharmacological laboratory procedure for demonstrating compounds which are useful in treating the conditions listed above. Following the in vivo mouse head injury procedure of Hall, J. Neurosurg. , 62, 882 (1985) com¬ pounds which statistically significantly (p < 0.05) increase the 1 hr neurological recovery following head injury are considered preferred compounds for treating the above conditions. EXAMPLE B Arachidonic Acid Antagonism Assay (AAAA)

The Arachidonic Acid Antagonism Assay (AAAA) as set forth in Thrombosis Res., 9, 67 (1976) is a standard laboratory procedure for demonstrating antagonism of the effects of arachidonic acid metabol¬ ites. Since these metabolites contribute to the pathological problems associated with stroke, spinal trauma and head injury, compounds which antagonize arachidonic acid are useful in treating stroke, spinal trauma and head injury. Compounds which significantly elevate the LD₅₀ of arachidonic acid in amimals _are considered to be useful for the traatment of these conditions. While not necessary to determine arachidonic acid antagonism, the above assay has been modified as follows: Charles River male CF-1 mice weighing 18-22g are treated IV with the test compound dissolved in 1.0% Tween-80 and 0.1% hydrochloric acid in distilled water, 0.2 ml total volume. Fifteen minutes later sodium arachidonate (90% pure) in physiological (normal) saline is injected into the tail vein. The LD₅₀ is measured using the Spearman-Karber method with a log dose interval of 0.05 (N-6) . Compounds which elevate the LD₅₀ outside of the 95% eonfidence interval of the control LD₅₀ are considered to be "active". The compounds of Example 4 demonstrates arachidonic acid antagonism. EXAMPLE C Malonyldialdehyde (MDA) Formation Assay

The MDA assays of Buege and Aust, Methods in Enzymology, Fleisher and Packer Editors, Academic Press, 1978, New York, Vol LII, p 302-310 and Kohn and Liversedge, J. Pharmacol. Exp. Ther. 82, 292 (1944) are standard pharmacological laboratory procedures for demonstrating the occurrence of lipid peroxidation by the formation of MDA. Since lipid peroxidation is involved in the pathophysiology of central nervous system trauma, compounds which inhibit MDA formation are useful in treating the conditions listed below.

MDA formation as measured by any of the above procedures or the modified procedure below demonstrates usefulness in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospas , ischemic (thrombo- embolic) stroke, muscular dystrophy, adriamycin cardiac toxicity, Parkinsonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reprefusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, severe burns, ARDS, allergic reactions, emphysema and post burn pulmonary complication. Further, MDA formation also demon¬ strates usefulness in preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and cardiac infarction.

While not necessary to determine MDA formation, the above assays have been modified as follows: rat brain synaptosomes are prepared as described in the Example about the conjugated diene assay, except that the final wash of the synaptosomes and final suspension are in physiological (normal) saline in which the pH has been adjusted to 7.0. The synaptosomes are incubated for 10 min at 37° in physiologi¬ cal (normal) saline pH 7.0 (total volume - 100 ul) containing; 10 ul synaptosomal suspension, 10% DMSO plus or minus drug, 150 uM Fe⁺⁺⁺ and 50 uM Fe++. The incubation is started by the rapid addition of iron to the otherwise complete reaction. The iron solutions are prepared fresh as ferric chloride and ferrous ammonium sulfate in argon-purged water. Following the 10 min incubation, the reaction is stopped by the addition of 500 ul ice-cold 12% trichloroacetic acid prepared in 0.5 N hydrochoric acid. Water (300 ul) is then added along with 100 ul of freshly prepared thiobarbituric acid (3.3% in 0.5N sodium hydroxide) and 10 ul of 5mM desferrioxamine. The sample is then heated in a boiling water bath for 20 minutes. The samples are cooled and centrifuged for 15 minutes at 1500 xg and the absor¬ bance of the supernatant fraction is read at 532 nm. The % inhibi- tion of MDA formation is calculated by dividing the absorbance of sample containing drug by the absorbance of samples incubated without drug. Reaction blanks are samples incubated in the absence of iron. A compound that inhibits MDA formation by 50% or more at a concentra¬ tion of 200μM or less is considered "active". The compounds of Example 5 demonstrates such activity by inhibition of MDA formation.

The above in vitro test/assay is a standard pharmacological laboratory procedure for demonstrating compounds which are useful In treating the conditions listed above. Following the in vivo mouse head injury procedure of Hall, J. Neurosurg. , 62, 882 (1985) com¬ pounds which statistically significantly (p < 0.05) increase the 1 hr neurological recovery following head injury are considered preferred compounds for treating the above conditions.

EXAMPLE D AcylCoA:Cholesterol Acyltransferase (ACAT) Inhibition Assay ACAT esterifies arterial cholesterol which is a key reaction in the development of atherosclerosis. The procedure of Bell, Can. J. Biochem. 60, 967 (1982) provides a standard procedure for demonstrat¬ ing which compounds inhibit ACAT and therefore inhibit formation of esterified arterial cholesterol thereby preventing atherosclerosis. In the ACAT assay it is preferred to use Fu5AH cells, see Lipids 9, 526 (1974). According to this procedure, compounds which inhibit ACAT activity equal to, or greater than, that of chlorpromazine are considered "active".

EXAMPLE E Antiatherosclerosis Screen in Susceptable to

Experimental Atherosclerosis (SEA) Japanese Quail

Demonstration of antiatherosclerotic activity of a compound in SEA Japanese Quail is done by showing that the compound reduces the serum and arterial cholesterol in quail fed an atherogenic diet.

This standard laboratory procedure for demonstrating a reduction in arterial and serum cholesterol in SEA Japanese quail has been described by Stevens in Artherosclerosis 56, 313 (1985.).. While not necessary, some minor modifications for extraction of cholesterol from the artery have been made. These are as follows: frozen arteries are homogenized in hexane/isopropanol (3/2) and the volume adjusted with Triton 100 solution (1.5% in hexane/isopropanol) to 7 ml. After standing 12 hr at 20-25°, the supernatant, obtained by low speed centrafugation is evaported until dry and then the residue is suspended in 0.5 ml of 5% Triton 100 in isopropanol. This suspension is incubated for 10 min at 45° to dissolve the material. This solution as well as the diluted serum samples are analyzed for cholesterol by standard clinical chemistry analyzer methods. According to the above procedure compounds which decrease serum or arterial cholesterol > 30 % are considered to be "active" .

Compounds which reduce serum and arterial cholesterol and are useful in treating artherosclerosis and its complications; for example, reduction of serum cholesterol by drugs reduces the incidence of coronary heart disease, JAMA 251, 351 (1984) and JAMA 251, 365 (1984).

EXAMPLE F Inhibition of Interleukin-1 The inhibition of interleukin-1 induced T cell proliferation assay, Proc. Nat. Acad. Sci. USA, 78, 1133 (1981) is a standary laboratory procedure for demonstrating inhibition of interleukin-1 bioactivities. Since people with arthritis make excess interleukin 1, compounds which inhibit the activity of interleukin 1 are useful in the treatment of arthritis. According to this procedure com¬ pounds which inhibit the activity of interleukin 1 greater that 30% at 10^{" s} M are considered to be "active". EXAMPLE G Inhibition of Mucous Secretion

The inhibition of mucous secretion assay of Johnson Int. Arch.- of Allergy and Applied Immunology 75, 97 (1984) is a standard pharmacological laboratory procedure for demonstrating inhibition of mucous secretions and therefore usefulness in preventing and/or treating mucous secretions, asthma, inflammatory .lung diseases, bronchitis, allergic reactions and ARDS. According to this procedure compounds which inhibit or block enhancement of induced mucous secretions when tested are considered to be "active". EXAMPLE H Asthma Test in Ovalbumin Sensitized Guinea Pigs

The ovalbumin sensitized guinea pig test, Brit. J. Pharm. 78, 67 (1983) is a standard laboratory procedure for demonstrating inhibi- tion of bronchoconstriction and therefore use in treating/preventing asthma. While not necessary the above test has been modified as follows. Male guinea pigs (500-700 g at the time of antigen chal¬ lenge) are sensitized by IM injection of ovalbumin (5%, 0.35 ml) into each hind limb and repeated 6 days later. Five weeks after the initial injection of ovalbumin, the animals are anesthesized with urethane (1.5 g/kg intraperitoneally) , the trachea cannulated and the lungs ventilated at constant volume using a Harvard Apparatus Rodent Respirator. Tracheal pressure is measured from a side-arm of the tracheal cannula via a Statham P23AC pressure transducer of a furness control micromanometer. The chest is opened along the mid-line. Bronchoconstriction is measured as the absolute increase in transpul- monary pressure in cm water with respect to the atmosphere. Blood pressure is recorded using a Statham P23Db pressure transducer vial a catheter inserted into a carotid artery. Heart rate is derived from the blood pressure signal using a Grass 7P4F tachograph. A jugular vein is catheterized for injection of drugs and antigen. The amimals are pretreated with the following: indomethacin (10 mg/kg, 15 min prior to antigen), pyrilamine maleate (2 mg/kg, 10/11 min before antigen), and propranolol (0.25 mg/kg, 5 min prior to antigen). Antigen challenge consists of ovalbumin (0.3 mg/kg) given IV.

The compounds to be tested are administered by either IV (compound precedes the antigen challenge by four minutes) , orally (fasted animals are dosed at either 2 or 4 hr prior to challenge) or by areosol (the compound is nebulized thru the Harvard respirator and directly into the tracheal cannula 180 sec four min prior to the IV antigen challenge) . Vehicles include IV (saline) , oral (emulphor or 0.1% Tween 80) or for aerosol (DMSO) . The antigen provocation produces a slowly developing broncho¬ constriction which lasts at least 15 min. The percent inhibition at various times points after antigen challenge compares the test compound to control animals (vehicle only) . According to this procedure compounds which give 50% or greater inhibition at 10 mg/kg are considered to be "active".

EXAMPLE I Inhibition of Tumor Growth

The fertile egg or chick embryo assay of Folkman, Science 221, 719 (1983) is the standard pharmacological laboratory procedure for demonstrating inhibition of angiogenesis, and therefore of tumor growth [Folkman, in Advances in Cancer Research, G. Klein and S. Weinhouse, ed. , 43, 175 (1985)]. According to this procedure compounds which are considered to be "active" (i.e. antiangiogenic) give an avascular zone of 4 mm or greater in some embryos when tested at 50 μg/10 μl in the presence of 50 μg/10 μ of heparin. EXAMPLE J Aspirin Induced Ulcer Test

The aspirin/cold induced ulcer assay of Rainsford, Agents and Actions 5, 553 (1975) is a standard pharmacological laboratory procedure for demonstrating anti-ulcer activity. According to this procedure compounds which give a 50% or more reduction of ulcer index are considered to be "active" . CHART A

25

CHART B

35 CHART C

15

CHART D

CHART E

Formula

Name Chemical Structure No.

-*CH₂-(CH₂)_c-G-(CH₂)_d CH₂-N -

3-pyrrolin-l-yl

(F-2)

pyrrol-1-yl optionally C_rC₃ alkyl )_Q__{1 (F}.₃₎ substituted <³r piperidin-1-yl optionally Vl (F-4) substituted

alkyl )_Q_₁

1,2, 3 ,6-tetrahydropyridin-l-yl

1-hexamethyleneimino containing a 3- or 4- double bond or

3- and 5- double bonds

1,4-dihydro-1-pyridinyl substituted in the

(F-7) 4-position different groups CHART E - Continued

Formula

Name Chemical Structure No.

pyridin-2- , (F-8)

or 4-yl optionally substituted optionally as the N-oxide

1,3,5-triazin-4-yl or the

N_χ -oxide thereof optionally (F-9) substituted at the 2- and/or 6- position

pyrimidin-4-yl or the N_χ -oxide thereof optionally substituted (F-10) at the 2- and/or 6-position

CHART E - Continued

Formula

Name Chemical Structure No.

pyrimidin-2-yl optionally (_F- ₎ substituted

pyrazin-2-yl optionally substituted <r ( 212 ^0-2

(F-12)

imidazol-2-yl optionally substituted in

l,3,4-triazol-2-yl optionally (F-14) substituted

(c_rc. alkyl or -X l) 0-1

imidazol-4- or 5-yl optionally substituted

benzo[b]thien-2-yl

indol-2-yl

CHART E - Continued

Formula

Name Chemical Structure No .

benzo [b] thiazol-2-yl (F-18)

benzimidazol-2-yl (F-19)

(1-piperazinyl)-(C₂-C^ ) optionally substituted

^■(C₂-Cϋ al yl)-N N-(Xι or X2) (F-21) in the 4-position

(1-piperazinyl)acetyl substituted in the 4-position

(1-piperazinyl)carbonyl■ methyl substituted in the 4-position

CHART E - Continued

Formula

Name Chemical Structure No.

- (carboxy) -1-pyrrolidinyl (F-2U)

- (carboxy) -1-piperidinyl (F-25)

2-(carboxy) -1-hexamethyleneimino (F-26)

2- (carboxy) -1-heptamethyleneimino (F-27)

1-piperazinyl substituted in

-N I-(CH₂)j-CO-R228 (F-28) the 4-position

/ \

1-piperazinyl substituted in -N N-(CH₂)j-χ₂ (F-29) the 4-position

1-piperazinyl substituted in (F-30) the 4-position

CHART E - Continued

Formula

Name Chemical Structure No.

4-hydroxy-l-piperidinyl ⁽F-31⁾ substituted in the 4-position

1-piperazinyl substituted in ~N N-(CH₂)_χ-C0-NR₂₂9-X (F-32) the 4-position

l-(4-methyl)piperazinyl -N N-CH (F~33)

l-(4-acetyl)piperazinyl -N N-C0-CH (F-3*)

l-(4-hydroxy)piperidinyl -N VoH (F-35)

1-piperidinyl optionally (F~36) substituted with 2 -hydroxyethyl

4-morpholinyl -N 0 (F-37) ^ ^f

CHART F

Q_χ-CO-C(X₅)H-Q₂ (IXA)

0-[C0-C(X₅)H-Q₂]₂ (IXB)

Claims

oorriiggiinnaall ccllaaiimmss 1100--2200 rreeppllaacceedd bbyy aimended claims 10-20 (5 pages)J bond between Cg and Oχ and the other of Xχ_χ and X χ2 ^s "^H-

7. An androstane-type aminoester according to claim 1 where R o is -R Ql^: "^Rl02> where ^Rχo2 ^s " H3, ^Rχoi ^an<* ^R5 taken together are -CH2-CH2-CO-CH-, Rg is α-H:0-H.

8. An androstane-type aminoester according to claim 1 where R2 and ^R210 ^are taken together with the attached nitrogen atom to form 1- piperazinyl substituted in the 4- position with X2-(CH2 4-.

9. An androstane-type aminoester according to claim 1 where R2 and ^R210 ^are taken together with the attached nitrogen atom form 1- piperazinyl substituted in the 4- position with X -(CH2 -.

10. A cortical aminoester of formula VIII

where:

(A-I) Rχ₀ is

where R ₀₂ is -CH3, R₁₀i and R5 taken together are -CH2-CH2-CO-CH-, Rg is α-Rg :/3-H where R is -H, -F and -CH_3>

(A-II) R₁₀ is α-R₁₀3: -Rχo4. where R₁₀ is -CH3, R₁₀₃ and R₅ taken together are -CH-CH-CO-CH-, Rg is α-Rg₃:jS-H where Rg₃ is -H, -F and -CH3,

(A-III) R₅ is α-R₅₅:j3-R5g, Rg is α-Rg₅:j9-R₆g, R₁₀ is a-R₁₀₅ β- ^R106» where Rχ₀₆ ^is -CH3, where one of Rg₅ and Rgg is -H and the other taken together with one of R55 and R₅g forms a second bond between C5 and Cg and R Q₅ and the other of R55 and R₅g taken together are -CH₂-CH2-C(R3)-CH₂- where R3 is α-H: -AE or α-AE:y3-H, are -CH2-CH2-C( 3)-CH2- , where R₃ is as defined above, o8 ^is "^CH3. Rg is α-Rg₇:0-H where Rg₇ is -H_r -F and -CH₃,

(A-V) R₁₀ is

where χoiθ ^is -^CH3« ^R109 ^taken together with R₅ are -CH2-CH2-C(R₃ -CH-, where R₃ is α-H: -AE or α-AE:0-H, where AE is as defined above, where:

(C-I) R ι is α-^Rlll'-^- ll2> where one of Rχχι and R 2 ^is taken together with Rg to form a second bond between Cg and Oχχ and the other of Rχιχ and Rχχ2 -^s "**»

(C-II) R is -0 and Rg is -H, (C-III) Rxx is α-H:0-H and Rg is -H,

(C-IV) R is α-AE:j9-H where AE is as defined above and Rg is -H; where:

(D-I) R g is α-^Rιgχ'. -^Rl62 where one of R and Rχg2 is "^H and the other is -H or CH3; (D-II) Rχ7 is α-^Rχ7χ:/S-^Rl72_> where Rχ₇χ is -H, -OH, -0-CO-R 73 where Rχ₇ is -H or Cχ-Cg alkyl, where R ₇2 i

(A) -CO-CH2-O-CO-C( ₅)H-NR2 2X0» where X₅, R₂χ and R₂χo are as defined above,

(B) -CO-CH2- R2 R2χo» where R2 and R210 ^{are as} defined above,

(C) -CO-CH3; and pharmaceutically acceptable salts thereof; and hydrates thereof; with the following overall provisos that: (1) R is α-AE: -H only when R o is α-R :/3-RχQ2 or c.-R ₀3:

0-^R104 ^and

(2) R₅ and Rχ₀ are -CH2-CH2-C(R3)-CH₂- only when R is ^α"^Rlll^: "^RU2' "° ^or a-H:/3-H.

11. A cortical aminoester according to claim 10 where Rχoχ ^a d R5 taken together are -CH2-CH2-CO-CH- or Rχø3 and R5 taken together are -CH-CH-CO-CH-, R is

"° or α-H: -H and Rχ₇₂ is -C0- CH2-0-CO-C(X5)H-NR2 R2χo which is the 21-aminoester of formula V

where is a single or double bond, is -0, α-H: -H or ^α"^xlll^: "^x112' ^x9 ^is "^{H or} taken together with one of X and X 2 to form a second bond between Cg and 0χ and the other of x and X₁₁₂ is -H.

12. A cortical aminoester according to claim 11 which^' is

21-hydroxypregn-4-ene-3,20-dione 21-[4-[2,6-bis(l-pyrrolidinyl)- 4-pyrimidinyl]-1-piperazinyl]acetate,

21-hydroxypregn-4-ene-3,20-dione 21-[4-[4,6-bis(2-propenyl- amino)-l,3,5-triazin-2-yl]-1-piperazinyl]acetate,

21-hydroxy-16α-methylpregna-l, ,9(11)-triene-3,20-dione 21- [4-[2,6-bis(morpholino)-4-pyrimidinyl]-1-piperazinyl]-acetate, 21-hydroxy-16α-methylpregna-l,4,9(11)-triene-3,20-dione 21- [4-[2,6-bis(l-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]acetate and

21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-[4- [4,6-bis(2-propenylamino)-1,3,5- riazin-2-yl]-1-piperazinyl]acetate.

13. A cortical aminoester according to claim 10 where Rχoχ and R5 taken together are -CH2-CH2-CO-CH- or θ3 an R5 taken together are -CH-CH-CO-CH-, R ι is α-AE:/3-H; which is the 11-aminoester of formula VI

where is a single or double bond, where X2 is -AE, -H and

14 A cortical aminoester according to claim 13 which is llα-hydroxy-16α-methylprogesterone 11-[4-(2-pyridinyl)-1- piperazinyl]acetate, llα,17α,21-trihydroxypregn-4-ene-3,20-dione ll,21-bis[4- [4,6- bis(2-propenylamino)-1,3,5-triazin-2-yl]-1-piperazinyl]acetate, llα,17α,21-trihydroxypregn-4-ene-3,20-dione 11,21-bis[4-(2- pyridinyl)-1-piperazinyl]acetate, llα-hydroxy-21-[4-[2,6-bis(l-pyrrolidino)-4-pyrimidinyl] -1- piperazinyl]-16α-methylpregna-1,4-diene-3,20-dione 11-[4-[2,6-bis(1- pyrrolidino)-4-pyrimidinyl]-1-piperazinyl]acetate,. llα-hydroxy-16α-methylprogesterone 11-[4-[2,6-bis(morpholino)-4- pyri idinyl]-1-piperazinyl]ace ate and llα-hydroxy-16α-methylprogesterone 11-[4-[2,6-bis(l-pyrrolidin- yl) -pyrimidinylJ-1-piperazinyl]acetate.

15. A cortical aminoester according to claim 10 where R _Q5 and one of R55 and R5 or o7 and one of R57 and R58 taken together are -CH2-CH2-C(-R3)-CH2- or R øg and one of R₅9 and R5 0 taken together are -CH2-CH2-C(-R₃ -CH-, R is α- χχi: -^Rll2_> ~° ^or <*-H:/9-H; which is the 3-aminoester of formula VII

where - indicates the AE group is in either the α or β configuration, .... is a single or double bond, X is -0, α-H:)9-H or «-Xχχχ:^-Xχχ2_> Xg is -H or taken together with one of xx and χχ2 to form a second bond between Cg and 0χ and the other of Xχχι and X 2 is -H, 2 is

16. A cortical aminoester according to claim 15 which Is 3?,17α-dihydroxy-6α-methylpregn-4-en-20-one 17-acetate 3-[4-(2- pyridinyl)-1-piperazinyl]acetate and

3j8-Hydroxy-16α-methylpregn-5-en-20-one 3-[4-(2-pyridinyl)-1- piperazinyl]acetate.

17. A cortical aminoester according to claim 10 where Rx x is -CH3.

18. A cortical aminoester according to claim 10 where R2 and 210 are taken together with the attached nitrogen atom to form 1-piperaz¬ inyl substituted in the 4- position with 2*(CH2)j-.

19. A cortical aminoester according to claim 18 where j Is 0.

20. A cortical aminoester according to claim 10 where R2 and ^R2χo are taken together with the attached nitrogen atom form 1-piperazinyl substituted in the 4- position with Xχ-(CH2)j-«