EP0513177A1 - 5-oxygenated-2,4,6-triaminopyrimidines - Google Patents

Abstract

Amino-substituted pyrimidines of formula (X) in position 5, wherein R1 represents (1) a steroid substituent of the formula (Steroid), (2) a trolox substituent of the formula (trolox), (3) an alkyl substituent selected from the group consisting of (A) Q2-CH2n2. The invention also relates to oxygenated pyrimidines (XIII) N, N-disubstituted, all useful in the treatment of a certain number of pathological conditions, including head trauma, spinal cord injuries, etc. In addition, the invention The invention relates to useful intermediates including pyrimidines (VII) oxygenated at position 5 and pyrimidines (VIII) oxygenated at position 5. In addition, the invention relates to pyrimidines (XI) substituted by 5-hydroxy amino.

Description

5-OXYGENATED-2,4,6-TRIAMINOPYRIMIDINES

BACKGROUND OF THE INVENTION

1. Field of the Invention

The 5-oxygenated-2,4,6-triaminopyrimidines are inhibitors of lipid peroxidation arid therefore are useful pharmaceutical agents.

2. Description of the Related Art

Non-oxygenated compounds similar to the oxygenated pyrimidine substituted piperazine compounds of formula (X) of the present invention are known.

When R₁ is a steroid, see International Publication No. WO 87/01706, published March 26, 1987 based on International Publication No. PCT/US86/01797.

When R₁ is trolox (vitamin E), see International Publication No. WO 88/08424, published November 3, 1988 based on International Publication No. PCT/US88/0I212, in particular, see the compounds of formula (III).

When R₁ is alkyl, see International Publication No. WO 88/-08424, published November 3, 1988 based on International Publication No. PCT/US88/01212, in particular, see the compounds of formula (II) and see US Patent application Serial No. 07/427,143.

5-Hydroxypyrimidines are known, see J. Chem. Soc., 2033 (1956) and Synthesis 443 (1975).

Non-oxygenated N,N-disubstituted pyrimidines corresponding to the oxygenated

N,N-disubstituted pyrimidines (XIII) of the present invention are known, see US Patent application Serial No. 07/427,143.

SUMMARY OF INVENTION

Disclosed are the 5-oxygenated amino substituted pyrimidines of formula (X) where R₁ is (1) steroid substituent (steroid) where

(A-I) Q₆ is α -Q_6-1:β-Q_6-2, Q₁₀ is α-Q _10-1:β-Q_10-2 and Q₇ is α-H:β-H, where one of

Q_6-1 and Q_6-2 is -H, and the other is -H, -F, or C₁-C₃ alkyl, Q_10-2 is -CH₃, Q_10-1 and Q₅ taken together are -(CH₂)₂-C(=Q_3-3)-CH= or -CH =CH-CO-CH= , where Q_3-3 is =O or α-H:β-OQ_3-4 or α-OQ_3-4:β-H, where Q_3-4 is -H, -CO-CH₃, -CO-C₂H₅, -CO-C₆H₅, -CO-O- CH₃ or -CO-O-C₂H₅;

(A-II) Q₅ is α-Q_5-3:β-Q_5-4, Q₆ is α-Q_6-3:β-Q_6-4, Q₁₀ is α-Q_10-3:

β-Q_10-4 and Q₇ is α;-H:β-H, where one of Q_6-3 and Q_6-4 is -H, and the other taken together with one of Q_5-3 and Q_5-4 forms a second bond between C₅ and C₆, Q_10-4 is -CH₃, Q_10-3 and the other of Q_5-3 and Q_5-4 taken together is -(CH₂)₂-C(H)(OH)-CH₂-;

<A-lll) Q₁₀ and Q₅ taken together are =CH-CH=C(OQ₃₎- CH = where Q₃ is -H, C₁-C₃ alkyl, -CO-H, C₂-C₄ alkanoyl or benzyl, Q₆ is α- Q_6-5:β- Q_6-6 where one of Q_6-5 and Q_6-6 is -H, and the other is -H, -F, or C₁-C₃ alkyl and Q₇ is α-H:β-H;

(A-IV) Q₅ is α- Q_5-7 :β- Q_5-8, Q₆ is α- Q_6-7 :β- Q_6-8, Q₇ is α-H:β-H and Q₁₀ is α-Q_10-7: β-Q_10-8, where one of Q_5-7 and Q_5-8 is -H, Q_10-7 and the other of Q_5-7 and Q_5-8 taken together are -(CH₂)₂-C(=Q_3-3)-CH₂, where Q_3-3 is as defined above, Q_10-8 is -CH₃, where one of Q_6-7 and Q_6-8 is -H and the other is -H, -F, or C₁-C₃ alkyl;

(A-V) Q₆ is Q _6-9:Q_6-10, Q₇ is Q_7-9:-Q_7-10, Q₁₀ is α-Q_10-9:Q_10-10, where one of Q_6-9 and Q_6-10 is -H and the other taken together with one of Q_7-9 and Q_7-10 forms a second bond between C₆ and C₇, and the other of Q_7-9 and Q_7-10 is -H, Q_10-10 is -CH₃, Q_10-9 and Q₅ taken together are -(CH₂)₂-C(=Q_3-3)-CH= or -CH=CH-CO-CH = , where Q_3-3 is as defined above;

(C-I) Q₁₁ is α-Q_11-1:β-Q_11-2, where one of Q_11-1 and Q_11-2 is taken together with Q₉ to form a second bond between C₉ and C₁₁ and the other of Q_11-1 and Q_11-2 is -H;

(C-II) Q₉ is -Cl and Q₁₁ is =O or α-H:β-Q_11-4 where Q_11-4 is -Cl or -OH;

(C-III) Q₉ is -H or -F and Q₁₁ is =O or α-Q_11-5:β-Q_11-6, where one of Q_11-5 and Q_11-6 is -H, and the other of Q_11-5 and Q_11-6 is -H, -OH or C₁-C₁₂ alkoxy;

(C-lV) Q₉ is -H or -F and Q₁₁ is α-O-CO-Q_11-7:β-H, where Q_11-7 is

(A) C₁-C₃ alkyl,

(B) C₁- C₁₂ alkoxy,

(D) -NQ₁₂₂Q₁₂₃, where one of Q₁₂₂ and Q₁₂₃ is -H, methyl or ethyl and the other is -H, C₁-C₄ alkyl or phenyl,

(E) -Q₃-Q₁, where Q₃ is -O- or a valence bond, where Q₁ is phenyl optionally substituted with 1 through 2 -Cl, -Br, C₁-C₃ alkoxy, -COOH, -NH₂, C₁-C₃ alkylamino, di(C₁-C₃)alkylamino, where the alkyl groups are the same or different, 1- pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C₂-C₄ acylamino and -NH-CHO or with 1 -F or -CF₃;

where:

(D-I) Q₁₆ is Q_16-1:Q_16-2 and Q₁₇ is Q_17-1:Q_17-2, where one of Q_16-1 and Q_16-2 is -H or

-CH₃ and the other taken together with one of Q_17-1 and Q_17-2 forms a second bond between C₁₆ and C₁₇, and the other of Q_17-1 and Q_17-2 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q₂₀ is =O, =CH₂ or Q_17-9:-H where Q_17-9 is -H or -CH₃, where n is 0 through 6, where

(D-II) Q₁₆ is α- Q_16-3:β-Q_16-4 where one of Q_16-3 and Q_16-4 is -H and the other is -H, -F, -CH₃ or -OH, and Q₁₇ is =CH-(CH₂)_p-[attached to the piperazine of the 2,4,6- triaminopyrimidine], where p is 1 or 2;

(D-lll) Q₁₆ is α-Q_16-5:β-Q_16-6 and Q₁₇ is α - Q_17-5:β- Q_17-6, where Q_16-5 is -H, -OH, -F or -CH₃ and Q_16-6 is -H, -OH, -F, or -CH₃, with the proviso that at least one of Q_16-5 and

Q_16-6 is -H, where Q_17-5 is -H, -OH, -CH₃, -CH₂CH₃, C₂-C₇ alkahoyloxy or -O-CO-Q₁, where Q₁ is as defined above, and where Q_17-9 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triarninopyrimidine], where Q₂₀ and n are as defined above;

(D-IV) the 16,17-acetonide of a compound where Q_16-5 is -OH, Q_16-6 is -H, Q_17-5 is -OH and Q_17-6 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triamino- pyrimidine], where Q₂₀ and n are as defined above;

with the following overall provisos that:

(I) one of Q_16-1 or Q_16-2 is taken together' with one of Q_17-1 or Q_17-2 to form a second bond between C₁₆ and C₁₇, only when Q₁₀ is α -Q_10-1:β-Q_10-2, α -Q_10-3:β- Q_10-4, α-

Q_10-7:β-Q_10-8 or α-Q_10-9:β-Q_10-10,

(II) Q₁₇ is =CH-(CH₂)_p-[attached to the piperazine of the 2,4,6- triaminopyrimidine], only when Q₁₀ is α-Q_10-1: β-Q_10-2, α-Q_10-3:β-Q _10-4, α-Q_10-7:β-Q_10-8 or α-Q_10-9:β-Q_10-10,

(lll) Q₅ and Q₁₀ taken together are =CH-CH=C(OQ₃)-CH=, only when

Q₁₇ is α -Q_17-5:β-Q_17-6 or the 16,17-acetonide of a compound where Q₁₆ is α-OH:β-H and Q ₁₇ is α-OH:β-C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triamino- pyrimidine], and

(IV) Q₅ is α-Q_5-7:β-Q_5-8, only when Q₁₇ is α-Q_17-5:β-Q_17-6 or α-OH:β-C- (=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], or the 16, 17- acetonide thereof;

(2) a trolox substituent (trolox) where

W₂ is -O-, -S-, -NQ₅₄- where Q₅₄ is -H or C₁-C₃ alkyl,

n₆ is 0, 1 or 2,

Q₇ is -H or - C₁-C₄ alkyl, -CO-(C₁-C₄ alkyl), -CO-ö or -prodrug where prodrug is

-po₂-α-

-CO-CH₂-CO-NH-CH₂-SO₂-O- -CO-(C H₂)_n21- Q₅₁ where n₂₁ is 1-7 and Q₅₁ is -COO- -NQ_51-1Q_51-2 where Q_51-1 and Q_51-2 are the same or different and are -H or C₁- C₃ alkyl, -N⁺Q_51-1Q_51-2Q_{51- 3}halide where Q_51-1 Q_51-2 Q_51-3 are the same or different and are -H or C₁-C₃ alkyl, and where halide is -Cl or -Br,

-CO-CH=CH-CO-O

-CO-N^* -CH=CH-N=CH^* where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-C^*=C[(CH₂)_n22-NH₂]-CH=CH-CH=CH^* where n₂₂ is 1 or 2 and where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-C^*=CH-CH=C(-NQ₅₂)-CH=CH^* where Q₅₂ is -H or C₁-C₃ alkyl and where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-(CH₂)_n21-CO-O-[C₆H₁₂O₆ sugars],

-CO-O-CH(CH₂-O-CO-Q₅₃)₂ where the G₅₃' s are the same or different and are C₁-C₁₈,

-CO-(CH₂)₆-CO-N(CH₃)-CH₂-CH₂-SO₃-cation⁺ where cation⁺ is sodium, potassium or trialkylammonium where alkyl is C₁-C₃,

-CH₂-O-CO-(CH₂)_n21-NQ_51-1Q_51-2 where n₂₁, Q_51-1 and Q_51-2 are as defined above,

-CO-NH-C₆ H₄-Q₅₅ where Q₅₅ is -H or C₁-C₃ alkyl, -NO₂, -NQ_51-1Q_51-2 where Q_51-1 and Q_51-2 are as defined above and

Q₁₀ is -H or -CH₃,

Q₁₁ is -H or -CH₃,

Q₁₂ is -H or -CH₃,

(18-1) Q₁₆ is α-Q_16-1 :β-Q_16-2 where one of Q_16-1 and Q_16-2 is -H, -CH₃, -CH₂CH₃ or -Φ and the other is -Q₃-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q₃ is -CO-,

-(CH₂)_n16-CO- where n₁₆ is 1 or 2, -(CH₂)_n3- where n₃ is 1-6, or

-CO-O-(CH₂)_n15- where n₁₅ is 2-6, Q₂₅ and Q₂₆ are -H:-H;

(18-2) n₆ is 0, Q₁₆ is Q_16-3:Q_16-4 where one of Q_16-3 and Q_16-4 is taken together with Q₂₅ to form a second bond between the carbon atoms to which Q₁₆ and Q₂₅ are attached and the other of Q_16-3 and Q_16-4 is -Q₃-[attached to the piperazine of the 2,4,6-triamino- pyrimidine], where Q₃ is as defined above,

(18-3) n₆ is 1, Q₂₅ and Q₂₆ are taken together to form a second bond between the carbon atoms to which Q₂₅ and Q₂₆ are attached;

(3) an alkyl substituent selected from the group consisting of

(A) Q₂-(CH₂)_n2- where:

n₂ is 1-14;

Q₂ is -H, -OH, -O-CO-(C₁-C₄ alkyl), -O-CO-H, -O-CO-O-(C₁- C₄ alkyl), (C₁-C₄) alkoxycarbonyl, -O-CO-aryl where aryl is Φ optionally substitued with -OH,

-OCH₃,

-F,

-Cl,

-Br,

-CF₃,

-C₁- C₃ alkyl, and

-CO-Q₅ where Q₅ is -OH,

-NH₂,

-NHQ₆ where Q₆ is Φ or C₁-C₃ alkyl, and

-N(Q₁₄)(Q₁₅) where Q₁₄ and Q₁₅ are the same or different and are C₁-C₃ alkyl;

(B) Q_3-1- O-(CH₂)_n8- where n₈ is 2 or 3 and where Q_3-1 is -H, C₁-C₃ alkyl, -CO-Q_3-2 where Q_3-2 is -H, C₁-C₃ alkyl or -Φ,

(C) Q_3-3-CO-(CH₂)_n9- where n₉ is 1 thru 3 and Q_3-3 is

-OH,

-O-Q_3-4 where Q_3-4 is C₁- C₄ alkyl or -CH₂-Φ,

C₁-C₃ alkyl,

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br,

-NO₂, C₁-C₃ or -OQ_3-6 where Q_3-6 is C₁-C₃ alkyl,

(D) Q_3-1-O-(CE₂CH₂-O)_{n 10}-CH₂CH₂- where n₁₀ is 1 or 2 and where Q_3-1 is as defined above,

(E) Q_3-3-CO-CH=CH-CH₂- where Q_3-3 is as defined above,

(F) -SO₂Q_3-5 where Q_3-5 is C₁-C₃ alkyl;

(G) ^*CH₂-(CH₂)_t1-C^*H- where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring and where t, is 1 thru 6;

R₂ and R₃ are the same or different and are -H, C₁-C₄ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and

R₃ are not both -H;

R₇ is (1) -CO-R₄, where R₄ is

-H,

C₁-C₄ alkyl,

-Φ optionally substituted with 1, 2 or 3 C₁-C₃ alkyl,

-OH,

C₁-C₃ alkoxy,

-F, -Cl, -Br,

-NO₂,

-N(R_4-1 )(R_4-2) where R_4-1 and R_4-2 are the same or different and are

-H or C₁-C₄ alkyl,

-S-R_4-3 where R_4-3 is -H or C₁-C₄ alkyl,

-COOR_4-4 where R_4-4 is -H or C₁-C₄ alkyl,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄ is 1-6, R_4-1 and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_4-1) where n₅ is 1-6 and R_4-1 is as defined above, -(CH₂)_n7-CH₂-COOH where n₇ is 1-6,

-CH=CH-COOH,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄, R_4-1 and R_4-2 are as defined above, -(CH₂)_n5-O-(R_4-1) where n₅ and R_4-1 are as defined above,

-(CH₂)_n1- CO-N(CH₃)-CH₂-CH₂-SO₂-OH where n, is 1 thru 6,

(2) -R₅, where R₅ is C₁-C₃ alkyl, C₄-C₇ cycloalkyl,

(3) -SO₂-OH,

(4) -PO(OH)₂,

(5) -PO(OR_7-1)₂ where R_7-1 is C₁-C₄ alkyl,

(6) -SO-OR_7-1 where R_7-1 is as defined above,

(7) -[C₆H₁₂O₆]_n12 where n₁₂ is 1 thru 3, and pharmaceutically acceptable salts thereof. Also disclosed are the protected 5-oxygenated pyrimidines of formula (VII) where R₆ is t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), CH₃-CO-, Φ-CO- and CHO- and where R₂, R₃ and R₇ are as defined above and pharmaceutically acceptable salts thereof.

Further disclosed are the 5-oxygenated pyrimidines of formula (VIII) where R₂,

R₃ and R₇ are as defined above and pharmaceutically acceptable salts thereof.

Additionally disclosed are the 5-hydroxypyrimidines of formula (XI) where R₂ and R₃ are as defined above.

Additionally disclosed are the oxygenated N,N-disubstituted pyrimidines of formula (XIII) where Q₁ is C₁-C₃ alkyl,

-O-CH₃, -O-CH₂CH₃,

-(CH₂)_n1 -O-Q_1-1 where n, is 2 or 3 and Q_1-1 is -H, C₁-C₃ alkyl, -CO-Q_1-2 where Q_1-2 is -H, C₁-C₃ alkyl or -Φ,

-CH₂-CH(OQ_1-1)-CH₃ where Q _1-1 is as defined above,

-CH₂CH₂-(O-CH₂C H₂)_n2-O-Q_1-1 where n₂ is 1 or 2 and where Q_1-1 is as defined above,

-(CH₂)_n3-CO-Q_{1- 3} where n₃ is 1 thru 3 and Q_1-3 is

-OH,

-O-Q _1-4 where Q_1-4 is C₁-C₄ alkyl or -CH₂-Φ,

C₁-C₃ alkyl, .

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO₂, C₁-C₃ or -O-Q_1-7 where O_1-7 is C₁-C₃ alkyl,

-CH₂-CH=CH-CO-Q_1-3 where Q_1-3 is as defined above, -(CH₂)_n4-N(Q_1-5)(Q_1-6) where n₄ is 2 or 3 and Q_1-5 and Q_1-6 are the same or different and are -H and C₁-C₃ alkyl,

Q₂ is -H,

C₁-C₃ alkyl,

-(CH₂)_n5-O-Q_2-1 where n₅ is 2 or 3 and Q_2-1 is -H, C₁-C₃ alkyl, -CO-Q_2-2 where Q_2-2 is -H, C₁-C₃ alkyl or -Φ,

-CH₂-CH(OQ_2-1)-CH₃ where Q_2-1 is as defined above,

-CH₂CH₂-(O-CH₂CH₂)_n6-O-Q_2-1 where n₆ is 1 or 2 and where Q_2-1 is as defined above,

-(CH₂)_n7-CO-Q_2-3 where n₇ is 1 thru 3 and Q_2-3 is -OH,

-O-Q_2-4 where Q_2-4 is C₁- C₄ alkyl or -CH₂-Φ;

C₁- C₃ alkyl,

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br,

-NO₂, C₁- C₄ or -OQ_2-5 where Q_2-5 is C₁-C₃ alkyl; where R₂, R₃ and R₇ are as defined above and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The 5-oxygenated amino substituted pyrimidines (X), the protected 5-oxygenatged pyrimidines (VII) and 5-oxygenated pyrimidines (VIII) are prepared from known compounds by methods known to those skilled in the art.

The 5-oxygenated amino substituted pyrimidines (X) include the ester substituted pyrimidines (II) R₇ is -CO-R₄ , the ether substituted pyrimindines (III) R₇ is -R₅, the sulfate substituted pyrimidines (IV) R₇ is -SO₂-OH.

The 5-oxygenated amino substituted pyrimidines (X) are produced by a number of known methods. One method involves oxidizing substituted pyrimidines (I) with the appropriate reagent to form the desired ester substituted pyrimidines (II), the ether substituted pyrimindines (llI) or the sulfate substituted pyrimidines (IV) directly; see CHART A. Alternatively, one can start with the pyrimidine (V)., protect the piperazinyl hydrogen with an appropriate blocking group to form the protected piperazinyl pyrimidine (VI), oxidize it to the protected 5-oxygenated pyrimidine (VII) and then remove the protecting group to give the desired 5-oxygenated pyrimidine (VIII); see CHART B. The 5-oxygenated pyrimidine (VIII) is then coupled with the desired non- amine portion (IX) to form the desired 5-oxygenated amino substituted pyrimidines (X); see CHART C. The 5-hydroxy compound (XI) can be prepared from the substituted pyrimidine (I) by contacting the appropriate substituted pyrimidine (I) with hydrogen peroxide, see EXAMPLE 30.

The substituted pyrimidines (I) are known to those skilled in the art. When R₁ is a steroid, see International Publication No. WO 87/01706, published March 26, 1987 based on International Patent application PCT/US86/01797. When R, is a steroid, it is preferred that Q₆ is α-H:β-H, Q₇ is α-H:β-H, Q_10-2 is -CH₃, Q_10-1 and Q₅ taken together are -CH=CH-CO-CH=. It is preferred that Q₁₁ is α-Q_{11 -1}:β-Q_{11 -2}, where one of Q_11-1 and Q_11-2 is taken together with Q₉ to form a second bond between C₉ and C₁₁ and the other of Q_{11 -1} and Q_11-2 is -H. It is also preferred that Q₁₆ is α -Q_16-5:β-Q_16-6 and Q₁₇ is α-Q_17-5:β- Q_17-6, where Q_16-5 is -CH₃, Q_16-6 is -H, Q_17-5 is -H and Q_17-6 is -C(=Q₂₀)-(CH₂)_n- [attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q₂₀ is =O and n is 1. When R₁ is trolox, see International Publication No. WO 88/08424, published November 3, 1988 based on International Patent application PCT/US88/01212, in particular, see the compounds of formula (III). When R₁ is trolox, the trolox portion contains an asymmetric center and therefore the desired 5-oxygenated amino substituted pyrimidines (X), produced when R₁ is trolox, will be either optically active or racemic. Both enantiomers are pharmacologically active and useful in the same manner and same way as the racemic form. It is to be understood that the 5-oxygenated amino substituted pyrimidines (X) include both the racemic from as well as both enantiomeric forms. When R₁ is trolox it is preferred that Q₇ is -H and Q₁₀, Q₁₁ and Q₁₂ are all C₁ alkyl, it is also preferred that W₂ is -O-, n₆ is 1, R₂₅ is -H:-H and R₂₆ is -H:-H. When R₁ is alkyl, see International Publication No. WO 88/08424, in particular, see the compounds of formula (II) and see US Patent application Serial No. 07/427,143. When R₁ is alkyl it is preferred that R₁ is

(1) Q₂-(CH₂) _n2- where Q₂ is -H and n₂ is 2 thru 8 and

(2) ^*CH₂-(CH₂)_t1-C^*H- where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring and Where t₁ is 1 thru 5.

It is preferred that R₂ and R₃ are each C₂ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to forrii a heterocyclic ring which is 1-pyrrolidinyl or 1- piperidinyl; it is more preferred that R₂ and R₃ are taken together with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl.

When the desired 5-oxygenated amino substituted pyrimidine (X) is the ester substituted pyrimidine (II), the substituted pyrimidine (I) is contacted with the appropriate diacyl peroxide in an appropriate solvent at about 0° for 1-10 hours. The reaction mixture is then permitted to warm to about 20-25° and stirred for about 10-100 hr. The mixture is then worked up by extraction from an aqueous mixture with an organic solvent such as methylene chloride. It is preferred that the extracting solvent is the same as the reaction mixture solvent. The organic extract is dried over an appropriate reagent such as magnesium sulfate and concentrated. The concentrate is chromatographed to purify the ester substituted pyrimidine. It is preferred that R₄ is -CH₃ or -Φ; it is more preferred that R₄ is -Φ.

When the desired 5-oxygenated amino substituted pyrimidine (X) is the ether substituted pyrimidine (III), the substituted pyrimidine (I) is contacted with tert-butyl peroxybenzoate in an . inert nonpolar aprotic solvent at about 0° to about 25°. The reaction mixture is worked up similar to that as described for the ester substituted pyri idines (II) above. It is preferred that R₅ is (claim 14) -CH₃ or -C₂H₅; it is more preferred that R₅ is -CH₃.

When the desired 5-oxygenated amino substituted pyrimidine (X) is the sulfate substituted pyrimidine (lV), the substituted pyrimidine (I) is contacted with ammonium persulfate in a solvent such as methylene chloride at about 20-25° for 10-100 hr. The mixture is worked up as previously described for the ester substituted pyrimidines (II).

The second method of producing the 5-oxygenated amino substituted pyrimidines

(X) is to first oxygenate the protected piperaziny pyrimidines (VI) to form the 5- oxygenated pyrimidine (VIII), CHART B, and then couple it with the appropriate non- amine portion, R₁ (TX), to form the desired 5-oxygenated amino substituted pyrimidine (X), see CHART C. Using this method the pyrimidine (V) first has the piperazinyl hydrogen atom protected by an appropriate protecting group, R₆. Suitable protecting groups include t-butoxycarbonyl [(CH₃)₃C-O-CO-, t-BOC], benzyl carbamate [Φ-CH₂-O- CO-, CBZ], CH₃-CO-, ö-CO- and CHO-. The preferred protecting group is t-BOC and CBZ, more preferred is t-BOC. After the piperazinyl hydrogen is protected, the protected piperazinyl pyrimidine (VI) is oxygenated as described above where R₁ is a drug such as a steroid, trolox or an alkyl group, rather than a blocking group, R₆ to produce the protected 5-oxygenated pyrimidine (VII). Next the protecting group is removed by methods known to those skilled in the art to give the 5-oxygenated pyrimidine (VIII).

The 5-oxygenated pyrimidine (VIII) is then coupled with the appropriate non- amine portion, R₁- Z (IX) to give the desired 5-oxygenated amino substituted pyrimidine (X). Z includes -Cl, -Br, -I, -CHO, -CO-Cl, mesylate, tosylate and carboxylic acids activated by coupling agents such as 1,1-carbonyldiimidazole (CDI), and diethylpyrocarbonate (DEPC). The preferred Z depends on the particular type of R₁ group involved.

The 5-hydroxy pyrimidines (XI) are produced by basic hydrolysis of the 5- oxygenated amino substituted pyrimidines (X), the ester substituted pyrimidines (II) and the sulfate substituted pyrimidines (IV). Alternatively the 5-hydroxy pyrimidines (XI) can be produced by reaction of the substituted pyrimidines (I) with hydrogen peroxide in solvents such as acetonitrile between about 0 and about 25° and from about 1 to about 96 hr, see EXAMPLE 30.

The oxygenated N,N-disubstituted pyrimidines (XIII) are produced from the corresponding known N,N-disubstituted pyrimidines (XII) in the same way as the 5- oxygenated amino substituted pyrimidines (X) are produced from the corresponding substituted pyrimidines (I). The N,N-dιsubstituted pyrimidines (XII) are known, see US Patent application Serial No. 07/427,143. With the oxygenated N,N-disubstituted pyrimidines (XIII) it is preferred that R₇ is -CO-R₄. It is preferred that Q₁ is C₁- C₃ alkyl, -O-CH₃, -(CH₂)_n1-O-Q_1-1, -(CH₂)_n3-CO-Q_1-3 and -CH₂-CH=CH-CO-Q_1-3 and Q₂ is -H, C₁- C₃ alkyl and -(CH₂)_n5-O-Q_2-1 ; it is more preferred that Q₁ is -CH₃ and Q₂ is -(CH₂)_n5-O-Q_2-1 where n₅ is 2 and Q_2-1 is -H.

The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) of the present indention are useful pharmaceutical agents in treating a number of different medical conditions in humans and useful warm blooded animals.

Since the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) of the present invention are amines, they readily form salts when reacted with acids of sufficient strength to produce the corresponding salts. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The anions of preferred pharmaceutically acceptable salts include acetate, benzoate, bromide, chloride, citrate, fumarate, mesylate, maleate, phosphate, nitrate, succinate, sulfate and tartrate.

In humans, the 5-oxygenated amino substituted, pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic (thromboembolic) stroke, global ischemia, resuscitation (CPR), excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced cardiac toxicity, brain tumor (neuroprotective), Parkin- sonism, Alzheimer's disease, Bells Palsy, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hepatic necrosis (e.g. from viral hepatitis, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcers, migrane cluster headaches, complications from brain tumors, some forms of radiation damage (for example during reaiation treatment or from accidental exposure to radiation), damage after MI, pre-birth infant strangulation and infant hypoxia syndrome, such opthalmic disorders as uveitis and optic neuritis, malignant hyperthermia and ischemic bowel syndrome.

In humans, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and from cardiac infarction, occular damage after opthalmic surgery (e.g. catratic surgery).

Further, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful as anticancer agents.

The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are useful in irrigation solutions used in eye surgery.

Generally, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are used like the glucocorticoid pharmaceuticals for the treatment of the above human conditions as well as the animal conditions listed below. While the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in treating a number of conditions and preventing damage from conditions where the glucocorticoids are not useful. The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines,, (XIII) have no 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) is useful to a different degree for treating each of the conditions above. However, as is known to those skilled in the art, some of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are better for treating some conditions and others are better for treating other cpnditions. In order to determine which compounds are better than others for a particular condition one can utilize known tests that do not require expermentation but only routine analysis.

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 prostaglandin 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 particular 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 of the particular amines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury. Additionally, the cat 48 hr motor nerve degeneration 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (Xlll ) 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a standard dose of about 0.05 to about 10 mg/kg/day IV or about 0.5 to about 50 mg/kg/day, one to four times daily by mouth.

For treating spinal trauma, mild and moderate to severe head injury, damage following cardiopulmonary resuscitation, cardiac infarction, organ damage during reperfusion after transplant, hemorrhagic, traumatic and septic shock, severe burns, ARDS, and nephrotic syndrome and preventing skin graft rejection, the standard conditions are used. Typical treatment will involve an initial loading dose, e.g. an IV dose of 0.01 mg to 2 mg/kg followed by maintenance dosing e.g. IV infusion for a day to a week depending on the particular condition of the patient and the 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are administered orally, IV and by inhalation in the standard dose. In treating excess mucous secretions the oral dose of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) used is from about 0.5 to about 50 mg/kg/day. The frequency of administration is one through 4 times daily. The oral administration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) 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 20 mg/kg/day. The aerosol formulation contains about 0.05 to about 5.0% of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) and is administered or used about four times daily as needed.

In treating muscular dystrophy, Parkinsonism, Alzheimer's disease and other degenerative neurological disorders (amyotrophic lateral sclerosis; multiple sclerosis) amines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are administered orally using a dose of about 0.5 to about 50 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.

In addition, utility in disorders or physiological phenomena dependent on angiogenesis or neovascularization such as embryo implantation (antifertility), arthritis, and atherosclerosis is exhibited with the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) with or without co-administered oral heparin or systemic heparin fragments, see Science 221, 719 (1983).

In treating adriamycin-induced cardiac toxicity, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are administered orally or IV using a dose of about 0.05 to about 50 mg/kg/day, preferrably about 0.5 to about 10 mg/kg/day. The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIll) are preferably, given concomitantly with IV adriamycin or the individual is pre-treated with the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII).

For prophylaxis prior to and preventing damage after neurological or cardiovascular surgery the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are used according to the standard conditions. 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 inflammatory diseases, the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally or IM in doses of about 0.5 to about 50 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 or nonsteroidal antiinflammatory 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-arterial administration may be employed.

In treating drug allergic reactions, the 5-oxygenated amino substituted pyrimidines

(X) and the oxygenated N,N-disubstituted pyrimidines (Xlll) are given in a dose of about 0.5 to 50 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 or more.

In treating atherosclerosis and emphysema, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily for months or years. In treating dermatological inflammatory conditions including psoriasis, the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 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 conditions the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) can be used with steroidal agents.

For use in eye surgery, an isoosmolar solution containing about 0.001 to about 1 % of the 5-oxygenated amino substitu yrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) is used. In treating ophthalmic disorders the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIll) are given orally in a dose of about 0.5 to about 50 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 0.001 to about 1% as long as needed.

The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) 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 by these compounds. NOS AC includes drugs such as ibuprofen, 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from about 5 to about 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 amines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) would be given either through 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) trauma, intervertebral diseases (slipped disk), traumatic shock, flea bite and other allergies.

In horses, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated

N,N-disubstituted pyrimidines (XIII) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis).

In cattle, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in treating acute coliform mastitis, bovine mastitis, acute allergic reaction to feed lot vaccination and shipping fever.

In pigs, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) 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 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIll) can be used to treat existing asthma conditions and to prevent future ones from occurring. For example, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) treat spinal trauma and prevent rejection of skin grafts.

The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) can be used with other pharmaceutical agents in treatment of the conditions listed above as is known to those skilled in the art.

The exact dosage and frequency of administration depends on the particular 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition 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 concentration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) in the patient's blood and/or the patients response to the particular condition being treated.

The 5-hydroxy pyrimidines (XI) are very potent inhibitors of lipid peroxidation and therefore are useful in the treatment of the above conditions, there usefulness being limited by the very short half-life. Because of their potency they are also useful as standards in the malonyldialdehyde (MDA) formation assay, see Buege, and Aust, Methods in Enzymology, Fleisher and Packer Editors, Academic Press, 1978, New York, Vol Lll, p 302-310 and Kohn and Liversedge, J. Pharmacol. Txpl Ther. 82, 292 (1944). The 5-hydroxy pyrimidines (XI) are also useful as intermediates in the preparation of the ester substituted pyrimidines (II) by acylation of the 5-hydroxy pyrimidines (X) with the appropriate acid halide.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecular 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, "Z₁" or "R_i" where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z₁ would represent a bivalent variable if attached to the formula C_H3-C(=Z₁)H. Groups R_i and R_j would represent monovalent variable substituents if attached to the formula CH₃-CH₂-C(R_i)(R_j)H₂. When 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_i and R_j are bonded to the preceding 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, C₆ 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 rnonovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general represents a bond between two atoms in the chain. Thus CH₃-O-CH₂-CH(R_i)-CH₃ represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol " =" represents a double bond, e.g. , CH₂=C(R_i)-O-CH₃, and the symbol "≡" represents a triple bond, e.g., HC≡C-CH(R_i)- CH₂-CH₃. Carbonyl groups are represented in either one of two ways: -CO- or -C(=O)-, with the former being preferred for simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments 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=CCl-CH=C^*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N^*-(CH₂)₂- N(C₂H₅)-CH₂-C^*H ₂-

A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(X₁)(X₂)- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X₁) which is "below" another substituent (X₂) will be identified as being in the alpha (α) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "--- " or "...". The corresponding substituent attached "above" (X₂) the other (X₁) is identified as being in the beta (β) configuration and is indicated by an unbroken line attachment to the carbon atom.

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 R₁ attached to a carbon atom as -C(=R_i)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R_i-j and β-R_i-k. When a bivalent variable, R_i, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α -R_i-j:β-R_i-k" or some variant thereof. In such a case both α-R_i-j and β-R_i-k are attached to the carbon atom to give -C(α-R_i-j)(β-R_i-k)-. For example, when the bivalent variable R₆, -C(=R₆)- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R_6-1:β-R_6-2, .... α-R_6-9:β-R_{6- 10}, etc, giving -C(α -R_6-1)(β-R_6-2)-. .... -C(α -R_6-9)(β-R_6-10)-, etc. Likewise, for the bivalentvariable R ₁₁, -C(=R₁₁)-, two monovalent variable substituents are α-R_{11- 1}:β-R_{11- 2}. For a ring substituent for which separate a and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the α and β designations are omitted.

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 -C₁(R_i)H-C₂(R_j) H- (C₁ and C₂ define arbitrarily a first and second carbon atom, respectively) R_i and R_j may be defined to be taken together to form (1) a second bond between C₁ and C₂ or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide. When R_i and R_j are taken together to form a more complex entity, such as the group -X-Y-, then the orientation of the entity is such that C₁ in the above formula is bonded to X and C₂ is bonded to Y. Thus, by convention the designation "... R_i and R_j are taken together to form -CH₂-CH₂-O-CO- ... " means a lactone in which the carbonyl is bonded to C₂. However, when designated "... R_j and R_i are taken together to form -CO-O-CH₂-CH₂-the convention means a lactone in which the carbonyl is bonded to C₁ .

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 "C₁- C₄", 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, "C₁-C₄ 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 defined. Thus C₂-C₄ alkoxycarbonyl describes a group CH₃-(CH₂)_n-0-CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C_i-C_j" designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C₁- C₃)alkoxycarbonyl has the same meaning as C₂-C₄ alkoxycarbonyl because the "C₁- C₃" refers only to the carbon atom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyl and (C₁- C₃)alkoxy(C₁-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 fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) 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.

IR refers to infrared spectroscopy.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane.

6 refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e or mass/charge unit. [M + H]⁺ refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. Cl refers to chemical ionization. FAB refers to fast atom bombardment.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those- properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/ volume (wt/v).

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.

EXAMPLE 1 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5- benzoate (II)

Benzoyl peroxide (0.950 g) is added to a solution of 16α-methyl-21-[4-[2,6-di-(1- pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dionemethane- sulfonate monohydrate (I, International Publication No. WO 87/01706 Example 109, 2.22 g) and dichloromethane (4.10 ml) at 0°. The resultant solution is stirred at 0° for 4 hours and is then allowed to warm to 20-25°. After 72 hours, aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2952, 2924, 2856, 1744, 1666, 1555, 1468, 1447, 1375, 1345, 1245, 1175, 1053, 1023 and 714 cm^-1; NMR (300 MHz, CDCl₃) 8.15, 7.63, 7.50, 7.16, 6.28, 6.07, 5.48, 3.50, 3.01, 1.39, 0.90 and 0.62 δ; MS (El m/e) exact mass calcd for C₄₅H₅₆N₆O₄ (744.4363), found 744.4393.

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 146-148°.

EXAMPLE 2 4-[4-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benz- opyran-2-yl)methyl]-1-piperazinyl]-5-hydroxy-2,6-di-(1-pyr- rolidinyl)-4-pyrimidinyl 5-benzoate (ll)

Benzoyl peroxide (0.257 g) is added to a solution of 2-[[4-(2,6-di-(1-pyrrolidinyl)- 4-pyrimidinyl)-1-piperazinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6- ol (I, International Publication No. WO 88/08424 Example 21, 0.500 g) and methylene chloride (1.10 ml) at 0°. The resultant solution is allowed to stir for 4 hours at 0° and 48 hours at 20-25°. Basic workup (methylene chloride, sodium dicarbonate, magnesium sulfate) and purification by flash chromatography (1/1; hexane/ethyl acetate) provides the title compound, IR (nujol) 3524, 2925, 2856, 1744, 1556, 1448, 1345, 1246, 1090 and713 cm^-1; NMR (300 MHz, CDCl₃) 8.15, 7.62, 7.49, 3.2-3.7, 2.14, 2.08, 1.98 and 1.18 δ; MS (El m/e) 535, 435, 379, 122 and 105, exact mass calcd for C₃₇H₄₈N₆O₄ (640.3737), found 640.3753.

The hydrochloride salt of the title compound is prepared in ether, mp 152-156°.

EXAMPLE 3 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- memylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-acetate

(ll)

A solution of diacetyl peroxide (75/25 dimethyl phthalate/isobutyl isobutylrate,

0.65 ml) is added to a solution of 16α-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)-4- pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 0.80 g) and methylene chloride (1.5 ml) at 0°. The solution is allowed to stir for 6 hours at 0° and 42 hours at 20-25°. Aqueous workup (methylene chloride/magnesium sulfate) and purification by flash chromatography (1/3, hexane/ethyl acetate) provides the title compound, IR (nujol) 2954, 2916, 2855, 1760, 1666, 1557,

1446, 1375, 1345, 1207, 1012 and 887 cm^-1; NMR (300 MHz, CDCl₃) 7.17, 6.28, 6.08, 5.51, 3.47, 3.12, 2.18, 1.40, 0.95 and 0.67 δ; MS (El m/e) 639, 373, 359, 317, 291 and 246, exact mass calcd for C₄₀H₅₄N₆O₄ (682.4206), found 682.4189.

The hydrochloride salt of the title compound is prepared in ether, mp dec 215°. EXAMPLE 4 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-(o- chlorobenzoate) (II)

Di-o-chlorobenzoyl peroxide (479 mg) is added to a solution of 16α-methyl-21-[4- [2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 m g) and methylene chloride (1.50 ml) at 0°. The resultant solution is stirred for 4 hours at 0° and 48 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1 - 0/100, hexane/ethyl acetate) provides the title compound, IR (nujol) 2937, 2856, 1665, 1557, 1448, 1377, 1345, 1239 and 750 cm^-1; NMR (300 MHz, CDCl₃) 8.09, 7.1-7.6, 7.17, 6.29, 6.08, 5.4-5.6, 3.3-3.7, 1.39, 0.91 and 0.63 δ; MS (FAB m/e) 639, 260 and 139, exact mass calculated for C₄₅H₅₆N₆O₄Cl (779.4051), found 779.4030.

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 155°.

EXAMPLE 5 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1 ,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-(p- methoxybenzoate) (II)

Di-p-methoxybenzoyl peroxide (466 mg) is added to a solution of 16α-methyl-21- [4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20- dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.5 ml) at 0°. The solution is stirred for 4 hours at 0° and 44 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate), flash chromatography (3/1, ethyl ace- tate/hexane) and acidic workup (ethyl acetate, methylene chloride, magnesium sulfate) to remove unreacted peroxide gives the title compound, IR (nujol) 2954, 2926, 2856, 1736, 1666, 1606, 1555, 1446, 1253 and 1164 cm^-1; NMR (300 MHz, CDCl₃) 8.10, 7.17, 6.97, 6.28, 6.07, 5.48, 3.89, 3.3-3.7, 3.02, 1.39, 0.90 and 0.62 δ; MS (FAB m/e) 639, 135, exact mass calcd for C^H^N-A (775.4547), found 775.4578.

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 150-152°.

EXAMPLE 6 1-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1 ,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-(p- chlorobenzoate) (II)

Di-p-chlorobenzoyl peroxide (439 mg) is added to a solution of 16α-methyl-21-[4- [2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. The solution is stirred for 6 hr at 0° and 26 hr at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (2/1, ethyl acetate/hexane) provides benzoate, IR (nujol) 2953, 2914, 2856, 1743, 1666, 1557, 1468, 1448, 1376, 1345, 1252, 1091, 1014 and 756 cm^-1; NMR (300 MHz, CDCl₃) 8.09, 7.48, 7.18, 6.30, 6.07, 5.49, 3.2-3.7, 3.02, 1.39, 0.91 and 0.62 δ; MS (FAB m/e) 639, 469 and 260, exact mass calcd for C₄₅H₅₆N₆O₄Cl (779.4051), found 779.4015

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 151-155°.

EXAMPLE 7 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1 ,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5- myristoate (II)

Dimyristoyl peroxide (641 mg) is added to a solution of 16α-methyl-21-[4-[2,6-di- (1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1 ,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. An additional 1.0 ml. of methylene chloride is added to the mixture which is stirred for 3 hr at 0° and 21 hr at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate, and purification by flash chromatography (2/1, ethyl acetate/hexane) provides the title compound, IR (neat) 2927, 2855, 1763, 1719, 1667, 1557, 1447 and 1345 cm^-1; NMR (300 MHz, CDCl₃) 7.17, 6.29, 6.08, 5.51, 3.47, 3.14, 1.40, 1.26, 0.95, 0.88 and 0.67 δ; MS (FAB m/e) 639, 541 and 260, exact mass calcd for C₅₂H₇₉N₆O₄ (851.6162), found 851.6129.

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 119°.

EXAMPLE 8 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-o- toluoate (II)

A solution of di-o-toluoyl peroxide (381 mg) and methylene chloride (0.50 ml) is added to a solution of 16α-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1- piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.25 ml) at 0°. The resultant solution is stirred for 4 hr at 0° and 23 hr at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (2/1, ethyl acetate/hexane) gives the title compound, IR (nujol) 2954, 2914, 2856, 1716, 1664, 1625, 1569, 1455, 1416, 1378, 1338, 1236 and 743 cm^-1; NMR (300 MHz, CDCl3) 8.11, 8.01, 7.2-7.5, 6.29, 6.08, 5.49, 3.3-3.7, 3.03, 2.64, 1.38, 0.89 and 0.61 δ.

The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 146-149°.

EXAMPLE 9 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-sulfate

(II)

Water (8.5 ml) is added to a mixture of 16α-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)- 4-pyrimidinyl]-1-piperazinyl]-pregna-1 ,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 1.14 g), ammonium persulfate (623 mg) and methylene chloride (8.5 ml). The mixture is stirred for 3 days at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and trituration of the residue with ethyl acetate several times gives the title compound, mp. effr 223°; IR (nujol) 2929, 2870, 2855, 1665, 1626, 1555, 1454, 1377 and 1043 cm^-1; NMR (300 MHz, CDCl₃) 7.15-7.25, 6.2-6.35, 6.06, 5.50, 1.39, 0.95 and 0.66 δ; MS (FAB m/e) 721, 641 and 247.

EXAMPLE 10 4-[4-(t-Butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)- pyrimidine (VI)

A solution of di-tert-butyl dicarbonate (4.76 g) and methylene chloride (10.0 ml) is added dropwise over 10 minutes to a solution of 4-(1-piperazinyl)-2,6-di-(1-pyrrol- idinyl)pyrimidine (V, International Publication No. WO 87/01706 PREPARATION A- 22, 6.00 g), triethylamine (3.10 ml), 4-dimethylaminopyridine (20 mg) and methylenechloride (20.0 ml) at 0°. The solution is allowed to stir at 0° for 1 hr and 16 hrs at 20- 25°. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (2/1, hexane/ethyl acetate) provides the carbamate as a solid. An analytical sample is prepared by recrystallization from hot ethyl acetate to provide the title compound, mp 169-169.5°; IR (nujol) 2925, 2854, 1701, 1570, 1556, 1435, 1242 and 788 cm^-1; NMR (300 MHz, CDCl₃) 4.85, 3.3-3.6, 1.8-2.0 and 1.47 δ; MS (El m/e) 402, 301 and 246.

EXAMPLE 11 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-benzoate (VII)

Benzoyl peroxide (1.49 g) is added to a solution of the protected piperazinyl pyrimidine (VI, EXAMPLE 10, 2.26 g) and methylene chloride (5.60 ml) at 0°. The resultant solution is stirred for 6.5 hr at 0° and 72 hr at 20-25°. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2952, 2924, 2856, 1747, 1698, 1559, 1468, 1345, 1247, 1172 and 712 cm^-1; NMR (300 MHz, CDCl₃) 8.16, 7.64, 7.51, 3.2-3.7, 1.7-2.0 and 1.42 δ; MS (m/e) 417 and 361, exact mass calcd for C₂₈H₃₈N₆O₄ (522.2954), found 522.2977.

EXAMPLE 12 5-Hydroxy-4-(piperazinyl)-2,6-di-(1-pyrrolidinyl)

pyrimidine 5-benzoate (VIII)

Trifluoroacetic acid (2.1 ml) is added to a solution of the protected 5-oxygenated pyrimidine (VII, EXAMPLE 11, 286 mg) and methylene chloride (2.1 ml) at 0°. After stirring for 30 minutes at 0° the solution is concentrated. Basic workup (methylene chloride, potassium carbonate, magnesium sulfate) provides, the title compound, NMR

(300 MHz, CDCl₃) 8.15, 7.62, 7.49, 3.3-3.7, 2.7-2.9 and 1.7-2.1 δ.

The hydrochloride salt of the title compound is formed in ether, mp 78-82°; IR (nujol) 3396, 2955, 2921, 2856, 1734, 1711, 1631 , 1573, 1452, 1414, 1326 and 719 cm^-1; MS (m/e) 317, 246 and 105, exact mass calcd for C₂₃H₃₀N₆O₂ (422.2430), found 422.2432.

EXAMPLE 13 5-Hydroxy-4-(4-methyl-1-piperazinyl)-2,6-di-(1-pyrrolidinyl)- pyrimidine 5-benzoate (X)

Formaldehyde (0.30 ml, 37% aqueous) is added to a solution of 5-hydroxy-4-

(piperazinyl)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-benzoate (Vlll, EXAMPLE 12, 0.72 g) and methanol (7.0 ml). Sodium cyanoborohydride (0.14 g) is added to the mixture followed by 1 drop of acetic acid 20 minutes later. After 1 hour, a solution is formed, which after 2 hours turns into a thick slurry. The mixture is stirred overnight and is then concentrated. Basic workup (chloroform, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (ethyl acetate→ 15/1 ethyl acetate/methanol) provides the title compound, IR (nujol) 2949, 2921, 2855, 1740, 1561, 1449, 1347, 1306, 1242, 1052 and 709 cm^-1; NMR (300 MHz, CDCl₃) 8.16, 7.64, 7.51, 3.3-3.7, 2.2-2.5, 2.21 and 1.6-2.0 δ; MS (m/e) 366 and 331, exact mass calculated for C₂₄H₃₂N₆O₂ (436.2587), found 436.2573. The hydrochloride salt of the title compound is formed in ether/ ethyl acetate, mp 106-109°.

EXAMPLE 14 5-Hydroxy-4-(4-propyl-1-piperazinyl)-2,6-di-(1-pyrrolidinyl)- pyrimidine 5-benzoate (X)

Sodium cyanoborohydride (0.14 g) is added to a solution of 5-hydroxy-4-(piperazinyl)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-benzoate

(Vlll, EXAMPLE 12, 0.74 g), propionaldehyde (0.16 ml) and methanol (7.0 ml). After 20 minutes acetic acid (1 drop) is added and the solution stirred overnight. Methylene chloride (2.0 ml) is added to the mixture and the resultant solution stirred for an additional 3 hrs. Concentration, basic workup (chloroform, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (ethyl acetate) provides the title compound, IR (nujol) 2953, 2925, 1745, 1559, 1446, 1343, 1246, 1162, 1057 and 709 cm^-1; NMR (300 MHz, CDCl₃) 8.16, 7.63, 7.51 , 3.3-3.7, 2.34, 2.22, 1.6-2.0, 1.35- 1.55 and 0.84 δ; MS (m/e) 359, 274, 260 and 247, exact mass calcd for C₂₆H₃₆N₆O₂ (464.2900), found 464.2918.

The hydrochloride salt of the title compound is formed in ether/ ethyl acetate, mp

99-101°.

EXAMPLE 15 4-[[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyan-

2-yl)carbonyl]-1-piperazinyl]-5-hydroxy-2,6-di-(1-pyrrolidinyl)-4- pyrimidine 5-benzoate (X)

1,1' -Carbonyldiimidazole (0.454 g) is added to a solution of 2-[[4-(2,6-di-(1- pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]carbonyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-

1-benzopyran-6-ol (I, International Publication No. WO 88/08424, 0.701 g) and tetrahydrofuran (7.0 ml). After stirring for 40 minutes at 20-25°, a solution of 5- hydroxy-4-(piperazinyl)-2,6-di-(1-pyrrolidinyl)pyrimidine5-benzoate(VIII, EXAMPLE

12, 2.54 mmol) and tetrahydrofuran (7.0 ml) are added. The reaction is allowed to stir for 16 hours at 20-25°. Basic workup (chloroform, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (1/2, ethyl acetate/hexane) provides the title compound, mp. 214-217°; IR (nujol) 3404, 2926, 2856, 1745, 1625, 1556, 1451,

1345, 1244, 1089 and 714 cm^-1; NMR (300 MHz, CDCl₃) 8.14, 7.64, 7.51, 25, 3.3-3.6,

2.4-2.8, 2.08, 2.04 and 1.55 δ; MS (m/e) 549, 385, 371 and 205, exact mass calcd for

C₃₇H₄₆N₆O₅

(654.3529), found 654.3519.

EXAMPLE 16 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-acetate (VII)

A solution of diacetyl peroxide (0.81 ml, 25%) is added to a solution of 4-[4-(t- butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.40 g) and methylene chloride (1.0 ml) at 0°. The solution is stirred for 3.5 hours at 0°C and 24 hours at 20-25°. Acidic workup (ether, chloroform, cold 3% hydrochloric acid, magnesium sulfate) and purification by flash chromatography (4/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2925, 2855, 1691, 1564, 1443, 1264, 1243, 1210, 1194 and 1180 cm^-1; NMR (300 MHz, CDCl₃) 3.3-3.7, 2.20, 1.75-2.05 and 1.47 δ; MS (m/e) 417, 361 and 246, exact mass calcd for C₂₃H₃₆N₆O₄ (460.2798), found 460.2803.

EXAMPLE 17 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidinyl)pyrimidine 5- acetate (VIII)

Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-acetate (VII, EXAMPLE 16) the title compound is obtained, EXAMPLE 18 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-o-chlorobenzoate (VII)

Di-o-chlorobenzoyl peroxide (0.179 g) is added to a solution of 4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyr rolidinyl)pyrimidine(VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. The solution is allowed to stir at 0° for 2 hours and at 20-25° for 72 hours. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, IR (nujol) 2954, 2926, 1757, 1698, 1558, 1449, 1345, 1246, 1167, 1026 and 747 cm^-1; NMR (300 MHz, CDCl₃) 8.10, 7.45-7.6, 7.3-7.4, 3.3-3.6, 1.7-2.0 and 1.44 δ; MS (m/e) mass calcd for C₂₈H₃₇N₆O₄ (556.2565), found 556.2554.

EXAMPLE 19 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidiny)lpyrimidine 5-o- chlorobenzoate(VIII)

Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-o-chlorobenzoate (VII, EXAMPLE 18) the title compound is obtained.

EXAMPLE 20 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-1- (pyrrolidinyl)pyrimidine 5-p-methoxybenzoate (VII)

Di-p-methoxybenzoyl peroxide (188 mg) is added to a solution of 4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine(VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. The resultant solution is stirred for 2 hours at 0° and 72 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) provides the title compound, mp. 215-217°; IR (nujol) 2925, 2856, 1730, 1681, 1607, 1560, 1446, 1255 and 1164 cm^-1; NMR (300,MHz, CDCl₃) 8.11, 6.98, 3.90, 3.1-3.6, 1.6-2.0 and 1.42 δ; MS (m/e) calcd for C₂₉H₄₀N₆O₅ (552.3060), found 552.3047.

EXAMPLE 21 5-Hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine 5-p- methoxybenzoatb (VIII)

Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-p-methoxybenzoate (VII, EXAMPLE 20) the title compound is obtained.

EXAMPLE 22 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-p-chlorobenzoate (VII)

Di-p-chlorobenzoyl peroxide (193 mg) is added to a solution of 4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimid ine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. The solution is stirred for 3 hours at 0° and 20 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the tide compound, mp. 217-218°; IR (nujol) 2954, 2925, 1740, 1696, 1559, 1457, 1446, 1264, 1255, 1245, 1180, 1169, 1091 and 757 cm^-1; NMR (300 MHz, CDCl₃) 8.09, 7.49, 3.2-3.7, 1.7-2.0 and 1.43. δ; MS (m/e) 417 and 361, exact mass calcd for C₂₈H₃₇N₆O₄Cl (556.2565), found 556.2573.

EXAMPLE 23 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidinyl)pyrimidine 5-p- chlorobenzoate (VIII)

Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-p-chlorobenzoate (VII, EXAMPLE 22) the title compound is obtained.

EXAMPLE 24 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-myristoate (VII)

Dimyristoyl peroxide (282 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)- piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. Additional methylene chloride (0.50 ml) is added to the mixture which is stirred for 2 hours at 0° and 20 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, mp 58-62°; IR (nujol) 2924, 2854, 1757, 1695, 1565, 1452, 1346, 1247, 1175 and 1162 cm^-1; NMR (300 MHz, CDCl₃) 3.67, 3.2-3.6, 2.45, 2.31, 1.5-2.0, 1.47, 1.26 and 0.88 δ; MS (m/e) 417 and 361, exact mass calcd for C₂₅H₆₀N₆ O₄ (628.4676), found 628.4668.

EXAMPLE 25 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidinyl)-pyrimidine 5- m yristoate (VIII)

Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-myristoate (VII, EXAMPLE 24) the title compound is ob- tained.

EXAMPLE 26 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine 5-o-toluoate (VII)

Di-o-toluoyl peroxide (168 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)- piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 200 mg) and methylene chloride (0.50 ml) at 0°. The resultant solution is stirred for 2 hours at 0° and 16 hours at 20-25°. Aqueous work up (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, mp. 147-150°; IR (nujol) 2965, 2926, 2859, 1744, 1687, 1552, 1470, 1451,

1422, 1262, 1251, 1236, 1171, 1030 and 742 cm^-1; NMR (300 MHz, CDCl₃) 8.13, 7.48,

7.2-7.4, 3.2-3.6, 2.64, 1.7-2.0 and 1.43 δ; MS (m/e) 417 and 361, exact mass calcd for C₂₉H₄₀N₆O₄ (536.3111), found 536,3102.

EXAMPLE 27 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidinyl)pyrimidine 5-o- toluoate (VIII)

Following the general proc sedure of EXAMPLE 12 and making non-critical variations but starting with 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine5-o-toluoate (Vll, EXAMPLE 26) the title compound is obtained.

EXAMPLE 28 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrr olidinyl)pyrimidine 5-O-sulfate (VII)

Water (2.0 ml) is added to a mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-

2,6-di-(1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 200 mg), ammonium persulfate

(170 mg) and methylene chloride (2.0 ml). The mixture is stured for 4 days at 20-25°.

Aqueous workup (methylene chloride, magnesium sulfate) provides a foam which is triturated with ether several times to provide the title compound, IR (nujol) 2954, 2926,

2855, 1696, 1629, 1563, 1456, 1414, 1327, 1265, 1168 and 986 cm^-1; NMR (300 MHz,

CDCl₃) 3.4-4.4, 1.7-2.3 and 1.46 δ.

EXAMPLE 29 5-Hydroxy-4-piperazinyl-2,6-1-di-(1-pyrrolidinyl)pyrimidine 5-O- sulfate (Vlll)

Following the general procedure of EXAMPLE 12 and making non-critical variations (including an aqueous workup) and starting with 5-hydroxy-4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine5-sulfate(VII,EXAMPLE28), the title compound is obtained.

EXAMPLE 30 1-[5-(Hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α- methylpregna-1,4,9(1l)-trien-3,20-dione-21-yl]-piperazine (XI)

Hydrogen peroxide (30% , 71μl) is added to a solution of 16α-methyl-21-[4-[2,6- di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1 ,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 100 mg) and acetonitrile (50 ml) at 0°. The mixture is stirred for 3 hr at 0° and for 3 hr at 20-25°. Methyl sulfide (0.20 ml) is added and the reaction stirred for an additional 30 min. The mixture is concentrated, triturated with ether several times and purified by rapid flash chromatography, eluting with chloro- form/methanol/ammonia (375/25/5). The appropriate fractions are pooled and con- centrated to give the title compound., IR (nujol) 2954, 2925, 2856, 1664, 1606, 1574 and 1456 cm^-1.

EXAMPLE 31 5-Hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-acetate (XIII)

Following the general procedure of EXAMPLE 3 but starting with 4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine (Xll, US Patent application Serial No. 07/427,143), the title compound is obtained.

EXAMPLE 32 5-Hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-benzoate (XIII)

Following the general procedure of EXAMPLE 1 but starting with 4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine (XII, US Patent application Serial No. 07/427,143), the title compound is obtained.

Claims

1. A 5-oxygenated amino substituted pyrimidine of formula (X)

where R₁ is (1) steroid substituent of the formula

where

(A-I) Q₆ is α -Q_6-1:β-Q_6-2, Q₁₀ is α-Q_10-1:β-Q_10-2 and Q₇ is α-H:β-H, where one of

Q_6-1 and Q_6-2 is -H, and the other is -H, -F, or C₁-C₃ alkyl, Q_10-2 is -CH₃, Q_10-1 and Q₅ taken together are -(CH₂)₂-C(=Q_3-3)-CH= or -CH=CH-CO-CH=, where Q_3-3 is =O or α-H:β-O-Q_3-4 or α-O-Q_3-4:β-H, where Q_3-4 is -H, -CO-CH₃, -CO-C₂H₅, -CO-C₆H₅, -CO-

O-CH₃ or -CO-O-C₂H₅;

(A-II) Q₅ is α-Q_5-3:β-Q_5-4, Q₆ is α-Q_6-3:β-Q_6-4, Q₁₀ is α -Q_10-3:β-Q_10-4 and Q₇ is α-H:β-H, where one of Q_6-3 and Q_6-4 is -H, and the other taken together with one of Q_5-3 and Q_5-4 forms a second bond between C₅ and C₆, Q_10-4 is -CH₃, Q_10-3 and the other of Q_5-3 and Q_5-4 taken together is -(CH₂)₂-C(H)(OH)-CH₂-;.

(A-III) Q₁₀ and Q₅ taken together are =CH-CH=C(OQ₃₎-CH= where Q₃ is -H, C₁-C₃ alkyl, -CO-H, C₂-C₄ alkanoyl or benzyl, Q₆ is α-Q_6-5: β-Q_6-6 where one of Q_6-5 and Q_6-6 is -H, and the other is -H, -F, or C₁-C₃ alkyl and Q₇ is α-H:βΗ;

(A-IV) Q₅ is α-Q_5-7 :β-Q_4-8, Q₆ is α-Q_{6- 7}:β-Q_6-8, Q₇ is α-H:β-H and Q₁₀ is α-Q_10-7: β-Q_10-8, where one of Q_5-7 and Q_5-8 is -H, Q_10-7 and the other of Q_5-7 and Q_5-8 taken together are -(CH₂)₂-C(=Q_3-3)-CH₂, where Q_3-3 is as defined above, Q_10-8 is -CH₃, where one of Q_6-7 and Q_6-8 is -H and the other is -H, -F, or C₁-C₃ alkyl;

(A-V) Q₆ is Q_6-9:Q_6-10, Q₇ is Q _7-9:Q_7-10, Q₁₀ is α-Q_10-9 :Q_10-10, where one of Q_6-9 and

Q_{6- 10} is -H and the other taken together with one of Q_7-9 and Q_7-10 forms a second bond between C₆ and C₇, and the other of Q_7-9 and Q_7-10 is -H, Q_10-10 is -CH₃, Q_10-9 and Q₅ taken together are -(CH₂)₂-C(=Q_3-3)-C H= or -CH=CH-CO-CH=, where Q_3-3 is as defined above;

(C-I) Q₁₁ is α-Q_11-1 :β-Q_11-2, where one of Q_{11 -1} and Q_11-2 is taken together with Q₉ to form a second bond between C₉ and C ₁₁ and the other of Q _11-1 and Q_{11 -2} is -H;

(C-II) Q₉ is -Cl and Q₁₁ is =O or α -H:β-Q_11-4 where Q_{1 1-4} is -Cl or -OH;

(C-III) Q₉ is -H or -F and Q₁₁ is =O or α -Q_{11 -5}:β-Q_11-6, where one of Q_{11 -5} and Q_11-6 is -H, and the other of Q_{11 -5} and Q_11-6 is -H, -OH or C₁-C₁₂ alkoxy;

(C-IV) Q₉ is -H or -F and Q₁₁ is α-O-CO-Q_11-7:β-H, where Q_{11 -7} is

(A) C₁-C₃ alkyl,

(B) C₁-C₁₂ alkoxy,

(D) -NQ₁₂₂Q₁₂₃, where one of Q₁₂₂ and Q₁₂₃ is -H, methyl or ethyl and the other is -H, C₁-C₄ alkyl or phenyl,

(E) -Q₃-Q₁, where Q₃ is -O- or a valence bond, where Q, is phenyl optionally substituted with 1 through 2 -Cl, -Br, C₁- C₃ alkoxy, -COOH, -NH₂, C₁-C₃ alkyl- amino, di(C₁-C₃)alkylamino, where the alkyl groups are the same or different, 1- pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C₂-C₄ acylamino and -NH-CHO or with 1 -F or -CF₃;

where:

(D-I) Q₁₆ is Q_{16- 1}:Q_16-2 and Q₁₇ is Q_17-1:Q_17-2, where one of Q_16-1 and Q_16-2 is -H or -CH₃ and the other taken together with one of Q_17-1 and Q_17-2 forms a second bond between C₁₆ and C₁₇, and the other of Q_17-1 and Q_17-2 is -C(=Q₂₀)-(CH₂)_n- [attached to the piperazine of the 2,4,6-triarninopyrimidine], where Q₂₀ is =O, =CH₂ or Q_17-9:-H where Q_17-9 is -H or -CH₃, where n is 0 through 6, where

(D-II) Q₁₆ is α -Q_16-3:β-Q_16-4 where one of Q_16-3 and Q_16-4 is -H and the other is -H, -F, -CH₃ or -OH, and Q₁₇ is = CH-(CH ₂)_p-[attached to the piperazine of the 2,4,6-tri- aminopyrimidine], where p is 1 or 2;

(D-lll) Q₁₆ is α-Q_16-5:β-Q_{1 6-6} and Q₁₇ is α-Q_17-5 :β-Q_{17 -6}, where Q_16-5 is -H, -OH, -F or -CH₃ and Q_16-6 is -H, -OH, -F, or -CH₃, with the proviso that at least one of Q_16-5 and Q_16-6 is -H, where Q_17-5 is -H, -OH, -CH₃, -CH₂CH₃, C₂-C₇ alkanoyloxy or -O-CO-Q₁, where Q₁ is as defined above, and where Q_17-6 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q₂₀ and n are as defined above;

(D-IV) the 16, 17-acetonide of a compound where Q_16-5 is -OH, Q_16-6 is -H, Q_17-5 is -OH and Q_17-6 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triam- inopyrimidine], where Q₂₀ and n are as defined above;

with the following overall provisos that:

(I) one of Q_16-1 or Q_16-2 is taken together with one of Q_17-1 or Q_17-2 to form a second bond between C₁₆ and C₁₇ , only when Q₁₀ is α -Q_10-1:β-Q_10-2, α-Q_10-3:β-Q_10-4, α- Q_10-7:β-Q_10-8 or α-Q_10-9:β-Q_10-10,

(II) Q₁₇ is =CH-(CH₂)_p-[attached to the piperazine of the 2,4,6-triamino- pyrimidine], only when Q₁₀ is α-Q_10-1:β-Q_10-2, α-Q_10-3 :β-Q_10-4, α-Q_10-7 :β-Q_10-8 or α-Q_10-9:β-

Q_10-10,

(III) Q₅ and Q₁₀ taken together are =CH-CH=C(OQ₃)-CH=, only when Q₁₇ is α -Q_17-5:β-Q_17-6 or the 16,17-acetonide of a compound where Q₁₆ is α-OH:β-H and Q₁₇ is α-OH:β-C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], and

(lV) Q₅ is α-Q_5-7:β-Q_5-8, only when Q₁₇ is α-Q_17-5:β-Q_17-6 or α-OH:β-C- (=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], or the 16,17- acetonide thereof;

(2) trolox substituent of the formula

where

W₂ is -O-, -S-, -NQ₅₄- where Q₅₄ is -H or C₁-C₃ alkyl,

n₆ is 0, 1 or 2,

Q₇ is -H or -C₁-C₄ alkyl, -CO-(C₁- C₄ alkyl), -CO-Φ or -prodrug where prodrug is

-PO₂-O-

-CO-CH₂-CO-NH-CH₂-SO₂-O

-CO-(CH₂)_n21 -Q₅₁ where n₂₁ is 1-7 and Q₅₁is -COO -NQ_51-1Q_51-2 where Q₅₁- ₁ and Q_51-2 are the same or different and are -H or C₁-C₃ alkyl, -N⁺Q_51-1Q_51-2Q_51-3halide where Q_51-1Q_51-2Q_51-3 are the same or different and are -H or C₁-C₃ alkyl, and where halide is -Cl or -Br,

-CO-CH=CH-CO-O

-CO-N^*-CH= CH-N=CH^* where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-C^*=C[(CH₂)_n22-NH₂] -CH= CH-CH=CH^* where n₂₂ is 1 or 2 and where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-C^*=CH-CH=C(-NQ₅₂)-CH=CH^* where Q₅₂ is -H or C₁-C₃ alkyl and where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring,

-CO-(CH₂)_n21-CO-O-[C₆H₁₂O₆ sugars],

-CO-O-CH(CH₂-O-CO-Q₅₃)₂ where the Q₅₃'s are the same or different and are C₁-C₁₈,

-CO-(CH₂)₆-CO-N(CH₃)-CH₂-CH₂-SO₃-cation⁺ where cation⁺ is sodium, potassium or trialkylammonium where alkyl is C₁-C₃ ,

-CH₂-O-CO -(CH₂)_n21-NQ_51-1Q_51-2 where n₂₁, Q_51-1 and Q_51-2 are as defined above,

-CO-NH-C₆H₄-Q₅₅ where Q₅₅ is -H or C₁-C₃ alkyl, -NO₂, -NQ_51-1Q_51-2 where Q_51-1 and Q_51-2 are as defined above and

Q₁₀ is -H or -CH₃,

Q₁₁ is -H or -CH₃,

Q₁₂ is -H or -CH₃,

(18-1) Q₁₆ is α-Q_16-1 :β-Q_16-2 where one of Q_16-1 and Q_16-2 is -H, -CH₃, -CH₂CH₃ or -Φ and the other is -Q₃-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q₃ is -CO-,

-(CH₂)_n16-CO- where n₁₆ is 1 or 2, -(CH₂)_n3 - where n₃ is 1-6, or -CO-O-(CH₂)_n15- where n₁₅ is 2-6, Q₂₅ and Q₂₆ are -H:-H; (18-2) n₆ is 0, Q₁₆ is Q_16-3: Q_{16- 4} where one of Q_16-3 and Q_16-4 is taken together with Q₂₅ to form a second bond between the carbon atoms to which Q₁₆ and Q₂₅ are attached and the other of Q_16-3 and Q_16-4 is -O₃-[attached to the piperazine of the 2,4,6-triamino- pyrimidine], where Q₃ is as defined above,

(18-3) n₆ is 1, Q₂₅ and Q₂₆ are taken together to form a second bond between the carbon atoms to which Q₂₅ and Q₂₆ are attached;

(3) an alkyl substituent selected from the group consisting of (A)Q₂-(CH₂)_n2- where:

n₂ is 1-14;

Q₂ is -H, -OH, -O-CO-(C₁- C₄ alkyl), -O-CO-H, -O-CO-O-(C₁- C₄ alkyl), (C₁- C₄) alkoxycarbonyl, -O-CO-aryl where aryl is δ optionally substitued with -OH,

-OCH₃,

-F,

-Cl,

-Br,

-CF₃,

-C₁-C₃ alkyl, and

-CO-Q₅ where Q₅ is -OH,

-NH₂,

-NHQ₆ where Q₆ is Φ or C₁- C₃ alkyl, and

-N(Q₁₄)(Q₁₅) where Q₁₄ and Q₁₅ are the same or different and are C₁-C₃ alkyl;

(B) Q_3-1-O-(CH₂)_n8- where n₈ is 2 or 3 and where Q_3-1 is -H, C₁-C₃ alkyl, -CO-Q_3-2 where Q_3-2 is -H, C₁-C₃ alkyl or -Φ,

(C) Q_3-3-CO-(CH₂)_n9- where n₉ is 1 thru 3 and Q_3-3 is

-OH,

-O-Q_3-4 where Q_3-4 is C₁-C₄ alkyl or -CH₂-Φ,

C₁-C₃ alkyl,

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO₂, C₁-C₃ or -OQ_3-6 where Q_3-6 is C₁- C₃ alkyl,

(D) Q_3-1- O-(CH₂CH₂-O)_n10-CH₂CH₂- where n₁₀ is 1 or 2 and where Q_3-1 is as defined above,

(E) Q_3-3-CO-CH=CH-CH₂- where Q_3-3 is as defined above, (F) -SO₂Q_3-5 where Q_3-5 is C₁- C₃ alkyl;

(G) ^*CH₂-(CH₂)_t1-C^*H- where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring and where t₁ is 1 thru 6;

R₂ and R₃ are the same or different and are -H, C₁-C₄ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and

R₃ are not both -H;

R₇ is (1) -CO-R₄, where R₄ is

-H,

C₁- C₄ alkyl,

-Φ optionally substituted with 1, 2 or 3 C₁-C₄ alkyl,

-OH,

C₁-C₃ alkoxy,

-F, -Cl, -Br,

-NO₂,

-N(R_4-1)(R_4-2) where R_4-1 and R_4-2 are the same or different and are -H or C₁-C₄ alkyl,

-S-R_4-3 where R_{4- 3} is -H or C₁-C₄ alkyl,

-COOR_4-4 where R_4-4 is -H or C_1-C4 alkyl,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄ is 1-6, R_4-1 and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_4-1 ) where n₅ is 1-6 and R_4-1 is as defined above, -(CH₂)_n7-CH₂-COOH where n₇ is 1-6,

-CH=CH-COOH,

-(CH₂)_n4-N(R_4-1) (R_4-2 ) where n₄, R_4-1 and R_4-2 are as defined above, -(CH₂)_n5-O-(R_4-1) where n_s and R_4-1 are as defined above, -(CH₂)_n1-CO-N(CH₃)-CH₂-CH₂-SO₂- OH where n₁ is 1 thru 6, (2) -R₅, where R₅ is C₁-C₃ alkyl, C₄-C₇ cycloalkyl,

(3) -SO₂-OH,

(4) -PO(OH)₂,

(5) -PO(OR_7-1)₂ where R_7-l is C₁- C₄ alkyl,

(6) -SO-OR_7-1 where R_7-1 is as defined above, (7) -[C₆H₁₂O₆] _n12 where n₁₂ is 1 thru 3, and pharmaceutically acceptable salts thereof.

2. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₁ is a steroid.

3. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where Q₆ is α -H:β-H, Q₇ is α-H:β-H, Q_10-2 is -CH₃, Q_10-1 and Q₅ taken together are -CH=CH-CO-CH=.

4. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where Q₁₁ is α-Q_11-1:β-Q_11-2, where one of Q_11-1 and Q_11-2 is taken together with Q₉ to form a second bond between C₉ and C₁₁ and the other of Q_11-1 and Q_11-2 is -H.

5. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 2 where Q₁₆ is α-Q_16-5:β-Q_16-6 and Q₁₇ is o-Q_17-5:β-Q_17-6, where Q_16-5 is -CH₃, Q_16-6 is -H, Q_17-5 is -H and Q_17-6 is -C(=Q₂₀)-(CH₂)_n-[attached to the piperazine of the 2,4,6- triaminopyrimidine], where Q₂₀ is =O and n is 1.

6. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₁ is trolox.

7. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 6 where Q₇ is -H and Q₁₀, Q₁₁ and Q₁₂ are all C₁ alkyl.

8. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 6 where W₂ is -O-, n₆ is 1, R₂₅ is -H:-H and R₂₆ is -H:-H.

9. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₁ is an alkyl group.

10. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₁ is (1) Q₂-(CH₂)_n2- where Q₂ is -H and n₂ is 2 thru 8 and

(2) ^*CH₂-(CH₂)_t1-C^*H- where the atoms marked with an asterisk (^*) are bonded to each other resulting in the formation of a ring and where t₁ is 1 thru 5.

11. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₇ is -CO-R₄.

12. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 8 where R₄ is -Φ or -CH₃.

13. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₇ is -R₅.

14. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 10 where R₅ is -CH₃ or -C₂H₅.

15. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₇ is -SC₂- OH.

16. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R₂ and R₃ are each C₂ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl or 1-piperidinyl.

17. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 which is

1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α-methylpregna- 1 ,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine 5-benzoate,

4-[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramemyl-2H-1-berizopyιan-2-yl)memyl]-1- piperazmyl]-5-hydroxy-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl5-benzoate,

1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α-methylpregna-

1 ,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-acetate,

1 -[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16αmethylpregna- 1,4,9(11)-trien-3,20-dione-21-yl]-piperazine5-(o-chlorobenzoate), 1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α -methylpregna- 1 ,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-(p-methoxybenzoate),

1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α -methylpregna- 1,4,9(11)-trien-3,20-dione-21-yl]-piperazine5-(p-chlorobenzoate),

1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α-methylpregna-

1 ,4,9(11)-trien-3,20-dione-2 l-yl]-piperazine 5-myristoate,

1-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-methylpregna- 1,4,9(11)-trien-3,20-dione-21-yl]-piperazine 5-o-toluoate,

1-[5-(hydroxy)-2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α-methylpregna- 1,4,9(1l)-trien-3,20-dione-21-yl]-piperazine 5-sulfate,

5-hydroxy-4-(4-memyl-1-piperazinyl)-2,6-di-(1-pyrrolidinyl)pyrimidine5-benzo- ate,

5-hydroxy-4-(4-propyl-1-piperazinyl)-2,6-di-(1-pyιrolidinyl)pyrimidine 5-benzoate, 4-[[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyan-2-yl) carbonyl]-1-piperazinyl]-2,6-di-(1-pyrrondinyl)-4-primidine5-benzoate.

18. A protected 5-oxygenated pyrimidine of formula (VII)

where R₂ and R₃ are the same or different and are -H, C₁-C₄ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and R₃ are not both -H;

R₆ is t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), CH₃-CO-, Φ-CO- and CHO-; R₇ is (1) -CO-R₄, where R₄ is

-H,

C₁-C₄ alkyl,

-Φ optionally substituted with 1, 2 or 3 C₁-C₄ alkyl,

-OH,

C₁-C₃ alkoxy,

-F, -Cl, -Br,

-NO₂,

-N(R_4-1)(R_4-2) where R_{4- 1} and R_4-2 are the same or different and are -H or C₁- C₄ alkyl,

-S-R_4-3 where R_4-3 is -H or C₁-C₄ alkyl,

-COOR_4-4 where R_4-4 is -H or C_1-C4 alkyl,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n ₄ is 1-6, R_{4- 1} and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_{4- 1}) where n₅ is 1-6 and R_4-1 is as defined above,

-(CH₂)_n7-CH₂-COOH where n₇ is 1-6,

-CH=CH-COOH,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄, R_{4- 1} and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_{4- 1}) where n₅ and R_4-1 are as defined above, -(CH₂)_n1-CO-N(CH₃)-CH₂-CH₂-SO₂-OH where n₁ is 1 thru 6,

(2) -R₅, where R₅ is C₁- C₃ alkyl, C₄-C₇ cycloalkyl,

(3) -SO₂-OH,

(4) -PO(OH)₂,

(5) -PCKOR_7-1)₂ where R_7-1 is C₁- C₄ alkyl,

(6) -SO-OR_7-1 where R_7-1 is as defined above,

(7) -[C₆H₁₂O₆]_n12 where n₁₂ is 1 thru 3, and pharmaceutically acceptable salts thereof.

19. A protected 5-oxygenated pyrimidine (Vll) according to claim 18 where R₆ is t-BOC or CBZ.

20. A protected 5-oxygenated pyrimidine (VII) according to claim 18 where R₇ is -CO- R₄.

21. A protected 5-oxygenated pyrimidine (VII) according to claim 18 where R₂ and R₃ are each C₂ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring which is l-pyrrolidinyl or 1-piperidinyl.

22. A protected 5-oxygenated pyrimidine (VII) according to claim 18 which is

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-benzoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-acetate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine

5-o-chlorobenzoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-p-methoxybenzoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-p-chlorobenzoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-myristoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine 5-o-toluoate,

5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine

5-sulfate.

23. A 5-oxygenated pyrimidine of formula (Vlll)

where R₂ and R₃ are the same or different and are -H, C₁-C₄ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and R₃ are not both -H;

R₇ is (1) -CO-R₄, where R₄ is

-H,

C₁-C₄ alkyl,

-Φ optionally substituted with 1, 2 or 3 C₁-C₄ alkyl,

-OH,.

C₁-C₃ alkoxy,

-F, -Cl, -Br,

-NO₂,

-N(R_4-1 )(R_4-2) where R_{4- 1} and R_4-2 are the same or different and are -H or C₁-C₄ alkyl,

-S-R_4-3 where R_4-3 is -H or C₁-C₄ alkyl,

-COOR_4-4 where R_4-4 is -H or C_1-C4 alkyl,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄ is 1-6, R_4-1 and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_4-1) where n₅ is 1-6 and R_4-1 is as defined above, -(CH₂)_n7-CH₂- COOH where n₇ is 1-6,

-CH=CH-COOH,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄, R_4-1 and R_4-2 are as defined above, -(CH₂)_n5-O-(R_4-1) where n₅ and R_4-1 are as defined above, -(CH₂)_n1-CO-N(CH₃)-CH₂- CH₂-SO₂-OH where n₁ is 1 thru 6, (2) -R₅, where R₅ is C₁-C₃ alkyl, C₄-C₇ cycloalkyl,

(3) -SO₂-OH,

(4) -PO(OH)₂,

(5) -TO(OR_7-1)₂ where R_7-1 is C₁-C₄ alkyl,

(6) -SO-OR_7-1 where R_7-1 is as defined above,

(7) -[C₆H₁₂ O₂] _n12 where n₁₂ is 1 thru 3, and pharmaceutically acceptable salts thereof.

24. A 5-oxygenated pyrimidine (Vlll) according to claim 23 where R₂ and R₃ are each C₂ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a hetero- cyclic ring which is 1-pyrrolidinyl or 1-piperidinyl.

25. A 5-oxygenated pyrimidine (Vlll) according to claim 23 which is

5-hydroxy-4-(piperazinyl)-2,6-di-(1-pyrrolidinyl)pyrimidine5-benzoate,

5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine 5-acetate,

5-hydroxy-4-piperazmyl-2,6-di-(1-pyrrolidinyl)pyrimidine5-o-chlorobenzoate, 5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine5-p-methoxybenzoate, 5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine 5-p-chlorobenzoate, 5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine 5-myristoate,

5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine5-o-toluoate,

5-hydroxy-4-piperazinyl-2,6-di-(1-pyrrolidinyl)pyrimidine 5-O-sulfate.

26. A 5-hydroxy pyrimidine of formula (XI)

where R₂ and R₃ are the same or different and are -H, C₁-C₄ alkyl and where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and R₃ are not both -H, and where R₁ is as defined in claim 1.

27. A 5-hydroxy pyrimidine (XI) according to claim 26 which is 1-[5-(hydroxy)-2,6-di- (1-pyrrolidinyl)-4-pyrimidinyl]-4-[16α-methylpregna-1,4,9(1l)-trien-3,20-dione-21-yl]- piperazine.

28. An oxygenated N,N-disubstituted pyrimidine of formula (Xlll)

where R₂ and R₃ are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1- piperazinyl and 1-piperazinyl substituted in the 4- position with C₁-C₄ alkyl with the proviso that R₂ and R₃ are not both -H;

R₇ is (1) -CO-R₄, where R₄ is

-H,

C₁-C₄ alkyl,

-Φ optionally substituted with 1, 2 or 3 C₁-C₄ alkyl,

-OH,

C₁-C₃ alkoxy,

-F, -Cl, -Br,

-NO₂,

-N(R_4-1)(R_4-2) where R_4-1 and R_4-2 are the same or different and are -H or C₁-C₄ alkyl,

-S-R_4-3 where R_4-3 is -H or C₁-C₄ alkyl,

-COOR_4-4 where R_4-4 is -H or C_{1 -c4} alkyl,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄ is 1-6, R_4-1 and R_4-2 are as defined above,

-(CH₂)_n5-O-(R_4-1) where n₅ is 1-6 and R_4-1 is as defined above,

-(CH₂)_n7- CH₂-COOH where n₇ is 1-6,

-CH=CH-COOH,

-(CH₂)_n4-N(R_4-1)(R_4-2) where n₄, R_4-1 and R_4-2 are as defined above, -(CH₂)_n5-O-(R_4-1) where n₅ and R_4-1 are as defined above, -(CH₂)_n1-CO-N(CH₃)-CH₂-CH₂-SO₂-OH where n₁ is 1 thru 6,

(2) -R₅, where R₅ is C₁-C₃ alkyl, C₄-C₇ cycloalkyl,

(3) -SO₂-OH,

(4) -PO(OH)₂, (5) -PO(OR_7-1)₂ where R_7-1 is C₁-C₄ alkyl,

(6) -SO-OR_7-1 where R_7-1 is as defined above,

(7) -[C₆H₁₂O ₆]_n12 where n₁₂ is 1 thru 3;

Q₁ is C₁-C₃ alkyl,

-O-CH₃, -O-CH₂CH₃,

-(CH₂)_n1-O-Q_{1- 1} where n₁ is 2 or 3 and Q_1-1 is -H, C₁-C₃ alkyl, -CO- Q_1-2 where Q_1-2 is -H, C₁- C₃ alkyl or -ö,

-CH₂-CH(OQ_1-1)-CH₃ where Q_1-1 is as defined above,

-CH₂CH₂-(O-CH₂CH₂)_n2-O-Q_1-1 where n₂ is 1 or 2 and where Q_1-1 is as defined above,

-(CH₂)_n3-CO-Q_1-3 where n₃ is 1 thru 3 and Q_1-3 is

-OH,

-O-Q_1-4 where Q_1-4 is C₁-C₄ alkyl or -CH₂-Φ,

C₁-C₃ alkyl,

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br,

-NO₂, C₁-C₃ or -OQ_1-7 where Q_1-7 is C₁-C₃ alkyl,

-CH₂-CH=CH-CO-Q_1-3 where Q_1-3 is as defined above, -(CH₂)_n4-N(Q_1-5)(Q_1-6) where n₄ is 2 or 3 and Q_1-5 and Q_1-6 are the same or different and are -H and C₁-C₃ alkyl,

Q₂ is -H,

C₁-C₃ alkyl,

-(CH₂)_n5-O-Q_2-1 where n₅ is 2 or 3 and Q_2-1 is -H, C₁-C₃ alkyl, -CO- Q_2-2 where Q_2-2 is -H, C₁-C₃ alkyl or -Φ,

-CH₂-CH(OQ_2-1 )-C H₃ where Q_2-1 is as defined above,

-CH₂CH₂-(O-CH₂CH₂)_n6-O-Q_2-1 where n₆ is 1 or 2 and where Q_2-1 is as defined above,

-(CH₂)_n7-CO-Q_2-3 where n₇ is 1 thru 3 and Q_2-3 is

-OH,

-O-Q_2-4 where Q_2-4 is C₁-C₄ alkyl or -CH₂-Φ;

C₁-C₃ alkyl,

-Φ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO₂, C₁-C₃ or -O-Q_2-5 where Q_2-5 is C₁-C₃ alkyl and pharmaceutically acceptable salts thereof.

29. An oxygenated N,N-disubstituted pyrimidine (XIII) according to claim 28 where R₇ is -CO-R₄.

30. An oxygenated N,N-disubstituted pyrimidine (Xlll) according to claim 28 where Q₁ is C₁-C₃ alkyl, -O-CH₃, -(CH₂)_n1-O-Q_1-1, -(CH₂)_n3-CO-Q_1-3 and -CH₂-CH=CH-CO-Q_1-3 and Q₂ is -H, C₁-C₃ alkyl and -(CH₂)_n5-Q-Q_2-1.

31. An oxygenated N,N-disubstituted pyrimidine (Xlll) according to claim 28 which is

5-hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-acetate,

5-hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(1-pyrrolidinyl)pyrimidine 5-benzoate.