AU642711B2 - 5-oxygenated-2,4,6-triaminopyrimidines - Google Patents

Description

WO 91/11453 PCT/US91/00017 5-OXYGENATED-2 .4 6-TRIAMINO14PYRIMIDINES BACKGROUND OF THE INVENTION 1. Field of the Invention j The 5-oxygenated-2,4,6-triaminopyrimidines are inhibitors of lipid peroxidation therefore are useful pharmaceutical agents.

2. Description of the Related..Art Non-oxygenated compounds similar to the oxygenated pyrimidine substituted piperazine compounds of formula of the present invention are known.

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

When R, is trolox (vitamin see International Publication No. WO 88/08424, published November 3, 1988 based on International Publication No. PCT/US88/012 12-, ~1 in particular, see the compounds of formula (III).

When R, is alkyl, see International Publication No. WO 88/-08424, published November 3, 1988 based on Inter-national Publication No. PCT/US88/01212, in particular, see the compounds of formula (11) and see US Patent application Serial No.

07/427,143.

43(1975).

No ::iygnat d s,-dsu uee J Chdiem. coso din 203 (1956 andxygntei N, N-di substituted pyrimidines (XIII) of the present invention are known, see US Patent application Serial No. 07/427,143.

Dislosd re he SUMMNARY OF INVENTION Discose arthe5-oxygenated amino substituted pyrimidines of formula (X) where R, is steioid substituent (steroid) where 4

Q

6 is, c-Q- 1

B-Q&

2

Q

10 is ct-Q 0 .j:B-Q 1 0, 2 and Q 7 is where one of Q6. and Q 6 2 is and the other is or CI-C 3 alkyl, Q 1 02 is -CH 3 Q10. and taken together are -(CH 2 2

-C(=Q

3 3 )-CH or -CH =CH-CO-CH=, where Q 33 is =0 or or ai-OQ3.4: f-H, where Q31 is -CO-CH3, -CIC2H, C-C6HS, -:o (A-lI) Q5 is ca-Q 5 3 :fl-Q 54

Q

6 is C'-Q 6 3

:B-Q

6

Q

10 is a-Q 10 3 wihone Of Q,3 and Q 5 forms a second bond between C, and C 6

Q

1 04 is -CH 3 WO 91/11453 PCT/US9I /00017 and the other Of Q5. and Q51. taken together is -(CH 2 2

-C(H)(OH)-CH

2 (A-HTI) Q 1 0 and Q5 taken together are =CH-CH=C(0Q3 1 -CH =where Q3 is -H,

CX-

3 alkyl, -CO-H, C 2

-C

4 alkanoyl or benzy], Q 6 is a-_Q6 5 :B-Q64 where one of Q6- 5 and Q" is and the other is or C 1

-C

3 alkyl and Q 7 is ct-H: B-H; (A-IV) Q5 is a-Q5_ 7 :B-Q5.

8 Q6 is Ct-Q6.

7 :B-Q6.8, Q 7 is ot-H:-H and Q 1 0 is a-Q,0.7:

B-Q

1 0.s, where one Of and Q 5 is Q10. and the other Of Q5. and taken together are 3 3

)-CH

2 where Q 33 is as defined above, Q10. is -CH 3 where one of Q6. an~d Q6. is -H and the other is or C 1

-C

3 alkyl; Qj is Q6.

9 ,Q6.

1 0

Q

7 is Q 79

:Q

71 0

Q

1 0 is a-Qj0.:Qj0.

0 where one of Q 9 and Q6.1 0 is -H and the other taken together with one of Q7. and Q7.1 forms a second bond between C 6 and C 7 and the other of Q 79 and Q7.

0 is Q10.

0 is -CH 3 Q,.q and QS V taken together are -(CH 2 2 C(=Q3 2 J-CH= or -CH=CH-CO-CH=, where Q1.

3 is as defined above;

Q

1 1 is a-Qjj.

1

:B-Q

11 where one of Q1 11 arid Q 1 12 is taken toglether with Q 9 to form a second bond between C 9 and C 11 and the other of 0 1 1. and Q 1 1.

2 is -H; (C-I1) Q 9 is -Cl and Q 1 1 is =0 or ca-H:B-Q 114 where Q 1 14 is -Cl or -OH; (C-111) Q 9 is -H or -F and Q11 is =0 or cx-Q 11 5 :i3-Q 11 where one of Q1. and

Q

1 1 -6 is and the other of Q 11 5 and Q 1 16 is -OH or C 1

-C

12 alkoxy; (C-TV) Q 9 is -H or -F and Q1 1 is ce-O-CO-Q 11 7 where Q 1 1. is

C

1

-C

3 alkYl,

CI-C

1 2 alkoxy,

-NQ

1 22

Q

123 where one of Q 1 2 2 and Q 1 2 3 is methyl or ethyl and the other is alkyl or phenyl, -Q3-Q 1 where Q is or a valence bond, where Q, is phenyl optionally substituted with 1 through 2 -Br, C 1

-C

3 alkoxy, -COOH, C 1

-C

3 alkylamino, di(C I-C 3 )alkyl amino, where the alkyl groups are the same or different, 1pyrrolidinyl-, 1-piperidinyl, I -hexamethylenimino-, I -heptamethylenimino-, C2-C 4 acylamino and -NH-CHO or with 1 -F or -CF 3 where:

Q

1 6 is Q, 61

:Q

1 6.2 and Q1 7 is Q 1 7 .1:Q 1 7 where one of Q 1 6.

1 and Q 1 6 is -H or

-CH

3 and the other taken together with one Of Q 1 7.

1 and Q 1 72 forms a second bond between C 16 and C 17 and the other Of Q 1 71 and Q 1 72 is 2 o)-(CH 2 )n-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q2 0 is =CH 2 or Q 17 9 where WO 9 1/114531 PCT/US91/0001 7 WO91/11453 PCTIUS9I/0001 7 -3-

Q

1 79 is -H or -CH 3 -where n is 0 through 6, where (D-IJ) Q 1 6 is Cf-Q 1 6.

3

:B-Q

1 6 where one Of Q 1 6. and Q 1 64is -H and the other is

-CH

3 or -OH, and Q 1 7 is =CI-:(CH 2 )p~[attached to the piperazine of the 2,4,6triaminopyrimidine], where p is I or 2; '(D-III) Q 1 6 is Ot-Q 165 :i3-Q 1 6 and Q17, is aQ 1 7 5 13-Q 17 6 where Q16_5 is -OH4, -F or -CH 3 and Q16 is -OH, or -CH 3 with the proviso that at least one of Q16 5 and

Q

1 6_ is where Q 1 75 is -OH, -CH 3

-CH

2

C-H

3

C

2

-C

7 alkanoyloxy or -O-CO-Q 1 where Q, is as defined above, and where Q 1 7- is -C(=Q 20

)-(CH

2 ),,-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q 0 and n are as defined ab~ove; (D-IV) the 16,17-acetonide of a compound where Q 1 6.

5 is -OH4, Q16 6 is Q1 7 is -OH and Q 1 7 -6 is Q 20

)-(CH

2 [attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q, 0 and n are as definediabove; with the following overall provisos that: one of Q 1 61 or 2 is taken together with one Of Q 1 7 .1 or 2 to fo"m a second bond between C 1 6 and C 1 7 olwhnQ 0 icrQ 1

.:KIM

1 Ci-Q 1 3 :B-Q,04, cX-

Q

1

O.

7 :l-Q 1 ~g Or Ce-Q 1 0, 9

:B-Q

1

G

10 (11) Q 1 7 is =CH-(CH,)p-[attached to the piperazine of the 2,4,6triaminopyrimidine], only when Q 1 0 is Qe-Q 1

D.

1 :I3-Q 1 0(Q 1 0- 3

:B-Q

1 0, 0t-Qic(,:l3Q10. or (111) Q and Q1 0 taken together are CH-CH =C(0Q 3 )-CH only when

Q

1 7 is Ur-Q 1 7 .5:B-QI 7 -6 or the 16,17-acetonide of a compound where Q1 6 is c1-OH:i3-H and

Q

1 7 is -x-OH: Q 0 [attached to the piperazine of the -2,4,6-triaminopyrimidine], and (IV) Q5 is Cr-_Q 5 7

:B-Q

5 8 Only when Q 1 7~ is 0t-Q 17 5

:B-Q

17 6 or ca-OH:13-C-

(=Q

20

)-(CH

2 ),-[attached to the piperazine of the 2,4,6-triaminopyrimidine], or the 16,17acetonide thereof; a trolox substituent (trolox) where

W

2 is where Q5, is -H or C,-C 3 alkyl, n 6 is0, 1 or 2,

Q

7 is -H or -C 1

-C

4 alkNl, -CO-(C,-C 4 alkyl), -CO-6 or -prodrug where prodrug is -P0 2 -CO-CH,-CO-N -CH 2 -S0 2 WO091/11453 PI/LUS91 /00017

-CO-(CH

2 1

-Q

51 where n 21 is 1-7 and Q5 1 is -COO" -NQ 51 1

Q

51 2 where

Q

5 1.1 and 12 are the same or different and are -H or G 1

-C

3 alkyl, -N+Q .Q 1

.A

5 3 halide where Q 5

~J.

2 Q5 1 .3 are the same or different and are -H or C 1

-C

3 alkyl, and where halide is -CI or -Br, -CO-CH=CH-CO-Cr- -CO-N'-CH =GH-N =CH* where the atoms marked with an asterisk C)are bonded to each other resulting in the formation of a ring, lj-CO-C*=CG(H 2

-NH

2 ]-CH=CH-CH=CH* where n 22 is 1 or 2 and I where the atoms marked with an asterisk are bonded to each other resulting in the formation of a ring, ii-CO-C* CH-CH =C(-NQ 52 )-CH =CH* where Q5 2 is -H or C 1

-C

3 alkyl and where the atoms marked with an asterisk ()are bonded to each other resulting in the formation of a ring, ii-CO-(CH1 1

-CO--[C

6 1- 12

O

6 sugars],

-CO-O-CH(CH

2

OCOQ

3 2 where the Q 53 7 s are the same or different and are C 1

-CIS,

-CO-(CH

2 6

-CO-N(CH

3

)-CH

2

-CH

2 -SO3* cation'+ where cation'+ is sodium, potassium or trialkylarnmonium where alkyl is CI-C 3 -CH 2 -O-CO-(CH),2-NQ 1

.Q

51 2 where n 21 Q31.

1 and Q 5 12 are as defined above,

-CO-NHC

6

H

4 -Q5 5 where Q55 is -H or C 1

-C

3 alkyl, -NO 2 -NQ 1 1

Q

51 .2 where Q 5 1_ and Q 1 are as defined albove and

Q

1 0 is -H or -Gil 3

Q

1 1 is -H or -CH 3

Q

1 2 is -H or -CH 3 (18-1) Q 1 6 is a-Q6 1 :fl-Q 1 6.2 where one of Q16.1 and Q 1 62 is -CH 3

-CH

2

C-

3 or -~and the other is -Q 3 -[attached to the piperazine of the 2,4,6-triaminopyrimidine where Q3 is -GO-,

-(CH

2 016 -CO- where n 1 6 is I or 2, where n 3 is 1-6, or

-CO-O-(CH

2 15 where n, 5 i's 2-6, Q25 and Q 2 6 are A (18-2) n 6 is 0, Q 16 is Ql 1 3

:Q

16 4 where one Of Q 163 and Q 1 64 is taken together with orma second bond between the carbon atoms to which Q 1 6 and Q2 5 are attached and the other Of Q 1 6.

3 and Q16 is -Q 3 -[attached to the piperazine of the 2,4,6-triamino- WO091/11453 PCI'/US9/OO1 7 pyrimidine], where Q3 is as defined above, (18-3) N 6 is 1, Q25 and Q 2 6 are taken together to form a second bond between the carbon atoms to which (O5 and Q 2 6 are attached; an alkyl substituent selected fromn the group consisting of Q2-(CH2).where: 14 n 2 is 1-14; Q is -OH, -O-CO-(C 1

-C

4 alkyl), -0-CO-H, -O-CO-O-(CI-C 4 alkyl), (CI-C 4 alkoxycarbonyl, -0-CO-aryl where aryl is 4) optionally substitued with -0OH,

-OCH-

3

-F,

-CI,

-Br,

-CF

3

-CI-C

3 alkyl, and -CO-Q where Q5 is -OH,

-NHQ

6 where Q 6 is or C 1

-C

3 alkyl, and

-N(Q

1 4

)(QI

5 where Q 1 4 and Q 1 5 are the same or different and are

-CO-Q

3 2 where Q3- 2 is C 1

-C

3 alkyl or-, Q3.

3

-CO-(CH

2 9 where n 9 is I thru 3 and Q 33 is

-OH,

-O-Q

34 where Q 3 4 is C 1

-C

4 alkyl or -CH 2

C

1

-C

3 alkyl, -4optionally substituted with I or 2 -CI, -Br,

-NO

2

CX-

3 or -OQ3. where Q31 is C 1

-C

3 alkyl,

Q

3 .j-O-(CHCH,-O)n 10

-CH

2

CH

2 where n 10 is I or 2 and where Q 31 is as defined above, Q3 3 -CO-CH=CH-CH,- where Q-1 is as defined above, -S0 2

Q

3 .5 where Q 3 5 is C 1

-C

3 alkyl; *CH where the atoms marked with an asterisk C)are WO 91/11453 PCT/US91/00017 -6bonded to each other resulting in~ the formation of a ring and where t, is 1 thru 6;

R

2 and R 3 are the same or different and are CI-C 4 alkyl and where R 2 and R 3 are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of I-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1piperazinyl substituted in the 4- position with CI-C 4 alkyl with the proviso that R 2 and,

R

3 are not both -H;

R

7 is where R 4 is

-H,

CX-

4 alkyl, optionally substituted with 1, 2 or 3 CI-C 4 alkyl,

-OH,

C

1

-C

3 alkoxy, -Cl, -Br,

-NO

2

-N(R

4 1

)(R

42 where R 4 4 1 and R.

2 are the same or different and are -H or C 1

-C

4 alkyl, 3 where R 4 3 is -H or CI-C 4 alkyl, -COOR.w where R 4 4 is -H or CIrC 4 alkyl,

-(CH

2 ).4-N(R 41

)(R

4 2 where n 4 is 1-6, R 4 .1 and R 4 are as defined above, -(rCH 2 4 1 where n5 is 1-6 and R4.

1 is as defined above,

(CH

2 7

-CH

2 -COOH where n 7 is 1-6, -CH =CH-COOH,

-(CH

2 4 4 2 where n 4 R4_ 1 and R, 4 2 are as defined above,

-(CH

2 4 where ns and R 4 1 are as defined above,

-(CH

2 0 1 -C0N(CH 3

)CH

2

CH

2 S0 2 0H where n, is I thru 6, -R5, where R5 is C 1

-C

3 alkyl, C-C 7 cycloalkyl, -S0 2

-OH,

-PO(OH)

2 -PO(0R 7 1 2 where R 7 1 is C,-C 4 alkyl,

-SO-OR

7 1 where R 7 4 1 is as defined above,

-[C

6

H,

2 Oj],, 2 where n 1 2 is I thru 3, and pharmaceutically acceptable salts thereof.

Also disclosed aethe protected 5-oxygenated pyrimidines of formula /00017her is -buoxcaronl (-BC),bezylxycrbn~y. CBZ, H3-O- O-O-and CHOand where R 3 and R 7 ate as defined above and pharmaceutically acceptable salts thereof.

Further disclosed are the 5-oxygenated pyrimidines of formula (VIII) where R 2

R

3 and R 7 are as defined above and pharmaceutically acceptable salts thereof.

Additionally disclosed are the 5-hydroxypyrimidines of formula (XI) where R, and R 3 are as defined above.

Additionally disclosed are the oxygenated N,N-disubstituted pyrimidines of formula (XIII) where Q, is C 1

-C

3 alkyl,

-O-CH

3

-O-CH

2

CH

3

-H

2 1

I

1 where n, is 2 or 3 and Q 1 .1 is-,C-C ly COQ.

where C 1

-C

3 alkyl or-k

-CH

2

-CH(OQ.

1

)-CH

3 where Q 11 is as defined above,

-CH

2

CH

2

-(O-CH,CH

2 1 where n 2 is I or 2 and where Q 11 is as defined above,

-(CH

2 ).3-CO-Q 1 3 where n 3 is 1 thr-u 3 and QI, 3 is

-OH,

-O-Q

1 where QJ,, is C 1

-C

4 alkyl or -CH 2 -0, Cl-C 3 alkyl, -'optionally substituted with I or 2 -Cl, -Br, -NO 2

CI-C

3 or

-O-Q

1 where Q 17 is CI-C 3 alkyl,

-CH

2 -CH=CH-CC)-Qj.3 where Q.3 is as defined above, '(7C 2 5 where N is 2 or 3 and Q 1 .5 and QI- are the same or different and are -Hl and C 1

-C

3 akyl,

Q

2 s -H,

C

1

-C

3 alkyl,

-(CH

2 ).3-O-Q 2 1 where n 5 is 2 or 3 and Q 21 is CI-C 3 alkyl, -CO-Q 2 where Q.

2 is CI-C 3 alkyl or 30-H4H02j-H hreQ4i sdfndaoe ~~-CI-1 2 CH(0 -CH 3 her 1 i sdfndaoe -C 2 H_(O-C 2 6

-O-Q

2 1 where n 6 is 1 or 2 and where Q 21 is as defined above,

-(CH

2 7

-,CO-Q

2 3 where n 7 is 1 thru 3 and Q 23 is -_Vt WO091/11453 PCU/US9I /00017 -21t WO 91/11453 PC'/US91/00017 -8-

-OH,

-O-Q

24 where Q 24 is C1-C 4 alkyl or -CH 2 -k; C -C 3 alkyl, optionally substituted with 1 or 2 -Cl, -Br,

-NO

2

C,-C

3 or -OQ2.

5 where Q-5 is C 1

-C

3 alkyl; where R 2

R

3 and R 7 are as defined above and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION The 5-oxygenated amino substituted pyrimidines the protected pyrimidines (VII) and 5-oxygenated pyrimidines (VIII) are prepared from knowncompounds by methods known to those skilled in the art.

The 5-oxygenated amino substituted pyrimidines include the ester substituted pyrimidines (II) R 7 is -CO-R 4 the ether substituted pyrimindines (J R 7 is -R 5 the sulfate substituted pyrimidines (IV) R 7 is -SO 2

-OH.

The 5-oxygenated amino substituted pyrimidines are produced by a number of known methods. One method involves oxidizing substituted pyrimidines with the appropriate reagent to form the desired ester substituted pyrimidines the ether substituted pyrimindines (Ill) or the sulfate substituted pyrimidines (IV) directly; see CHART A. Alternatively, one can start with the pyrimidine protect the piperazinyl hydrogen with an appropriate blocking group to form the protected piperazinyl pyrimidine 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 nonamine portion (IX) to form the desired 5-oxygenated amino substituted pyrimidines see CHART C. The 5-hydroxy compound (XI) can be prepared from the substituted pyrimidine by contacting the appropriate substituted pyrimidine with hydrogen peroxide, see EXAMPLE The substituted pyrimidines are known to those skilled in the art, When R, 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 Q 6 is a-H:B-H, Q 7 is Qo.2 is -CH 3 Qio., and Q 5 taken together are -CH=CH-CO-CH=. It is preferred that Q1, is a-'Qi.:B-Q.

2 where one of Q11., and Q 1 2 is taken together with Q, to form a second bond between C, and and the other of Q 1 and QI.

2 is It is also preferred that Q1g is C-Q,~ 5 6 and Qp7 is ';1E /2 WO 91/11453 PCT/US91/00017 -9a-Q7.5:B-Q-.6, where Q16. is -CH3, Qi6 is Q17.s is -H and Q17- is -C(=Q 2 0

)-(CH

2 [attached to the piperazine of the 2,4,6-triaminopyrimidine], where Qo is =0 and n is 1. When R, 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 R, is trolox, the trolox portion contains an asymmetric center and therefore the desired 5-oxygenated amino substituted pyrimidines produced when R, 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 include both the racemic from as well as both enantiomeric forms.

When R, is trolox it is preferred that Q 7 is -H and Qio, Q 1 1 and Q2 are all C, alkyl, it is also preferred that W 2 is n 6 is 1, R 25 is and R 2 6 is When R, 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 R, is alkyl it is preferred that R, is

Q

2

-(CH

2 where Q 2 is -H and n 2 is 2 thru 8 and

'CH

2

-(CH

2 where the atoms marked with an asterisk are bonded to each other resulting in the formation of a ring and where t 1 is 1 thru It is preferred that R 2 and R 3 are each C 2 alkyl and where R 2 and R 3 are taken with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl or 1piperidinyl; it is more preferred that R 2 and R 3 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 is the ester substituted pyrimidine the substituted pyrimidine 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 eir=,ion from an aqueous mixture with an organic solvent such as methylene chloride. It is preferred that the extracting solvent is the samei as the reaction mixture solvent. The organic extract is dried over an appropriate reage nt such as magnesium sulfate and concentrated. The concentrate is chromatograph; to purify the ester substituted pyrimidine. It is preferred that R 4 is -CH 3 or it is more preferred that Ra is -4.

When the desired 5-oxygenated amino substituted pyrimidine is the et er j~i (C-IV) Q 9 is -H or -F and Q 1 is a-O-CO-Q,,.

7 where Q,-7 is

C

1

-C

3 alkyl, 't C,-C, 2 alkoxy, WO 91/11453 PCT/US9 1 /00017 substituted pyrimidine (III), the substituted pyrimidine is contacted with tert-butyl peroxybenzoate in an inert nonpolar aprotic solvent at about 00 to about 250. The reaction mixture is worked up similar to that as described for the ester substituted pyri idines (II) above. It is preferred that R 5 is (claim 14) -CH 3 or -C 2 H5; it is more preferred that R 5 is -CH 3 When the desired 5-oxygenated amino substituted pyrimidine is the sulfate substituted pyrimidine the substituted pyrimidine 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 is to first oxygenate the protected piperaziny pyrimidines (VI) to form the oxygenated pyrimidine (VIII), CHART B, and then couple it with the appropriate nonamine portion, R, to form the desired '-oxygenated amino substituted pyrimidine see CiART C. Using this method the pyrimidine first has the piperazinyl hydrogen atom protected by an appropriate protecting group, R. Suitable protecting groups include t-butoxycarbonyl [(CH 3 3 C-O-CO-, t-BOC], benzyl earbamate [4-CH 2

-O-

CO-, CBZ], CH 3 6-CO- and CHO-. The preferr.d 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 R, is a drug such as a steroid, trolox or an alkyl group, rather than a blocking group, R to pro/duce the protected 5-oxygenated pyrimidine (VII). Next the protecting group is removed by methods known to those skilled in the art to give the pyrimidine (VIII).

The 5-oxygenated pyrimidine (VIII) is then coupled with the appropriate nonamine portion, R 1 -Z (IX) to give the desired 5-oxygenated amino substituted pyrimidine Z includes -Cl, -Br, -CHO, -CO-C1, mesylate, tosylate and carboxylic acr<.

activated by coupling agents such as l,l-carbonyldiimid6ole (CDij, and diethylpyrocarbonate (DEPC). The preferred Z depends on the particular type of RI group involved.

The 5-hydroxy pyrimidines (XI) are produced by basic hydrolysis of the oxygenated amino substituted pyrimidines the ester substituted pyrimidines (II) and the sulfate substituted pyrimidines Alternatively ihe 5-hydroxy pyrimidines (XI) can be produced by reaction of the substituted pyrimidines with hydrogen peroxide I) Q 7 is (CH-CH)-[attached to the piperazine of the 2,4,6-triamino- pyrimidine, only when'Qo is C-Q 1

:B-Q

2

-QI.-

3

:B-Q

1 1 tC-Q 1 0 o.

7

:-Q

1 o or

O

-Q

1 Q1o-io, WO 91/11453 PC/US91/00017 -11in solvents such as acetonitrile between about 0 and about 250 and from about 1 to about 96 hr, see EXAMPLE The oxygenated N,N-disubstituted pyrimidines (XIII) are produced from the corresponding known N,N-disubstituted pyrimidines (XII) in the same way as the oxygenated amino substituted pyrimidines are produced from the corresponding substituted pyrimidines The N,N-disubstituted 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 R 7 is -CO-R 4 It is preferred that Q, is CI-C 3 alkyl, -O-CH 3

-(CH

2 1

-(CH

2

),-CO-Q

1 3 and -CH 2

-CH=CH-CO-QI.

3 and Q 2 is

CI-C

3 alkyl and -(CH 2 1 it is more preferred that Q, is -CH 3 and Q 2 is S -(CH 2

)-O-Q

21 where n is 2 and Qz,. is -H.

The 5-oxygenated amino substituted pyrimidines and the oxygenated N,Ndisubstituted pyrimidines (XIII) of the present invention 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 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, .ruccinate, sulfate and tartrate.

In humans, the 5-oxygenated amino substituted pyrimidines 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), Parkinsonism, Alzheimer's disease, Bells Palsy, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplants, skin graft rejection, hepatic necrosis from viral hepatitis, hemorrhagic, traumaticand septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, WO91/11453 PCT/US91/00017 -12allergic 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 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 ,gery catratic surgery).

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

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

Generally, the 5-oxygenated amino substituted pyrimidines and the oxygenated N,N-disubstituted pyr ,idines (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 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 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 and the oxygenated N,Ndisubstituted 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 sidc. effects associated with the glucocorticoids. This is a distinct advantage.

It is to be understood that each of the 5-oxygenated amino substituted pyrimidines 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 and the A oxygenated N,N-disubstituted pyrimidines (XIII) are better for treating some conditions i I s WO 91/11453 PCT/US91/0001 7 -13and others are better for treating other conditions. In order to determine which compounds are better than others for a particular condition one can utilize known tests that do not require expermentatioh 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 LDs 5 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 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 amino substituted pyrimidines and the oxygenated N,N-disubstituted pyrimidines (XII) 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.

f 30 The standard conditions for treatment are to give the 5-oxygenated amino substituted pyrimidines and the oxygenated N,N-disubstituted pyrimidines (XIII) I orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, j with a standard dose of about 0.05 to about 10 mg/kg/day IV or about 0.5 to about v r; PCT/US91/00017 WO 91/11453 -14mg/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 burs,.

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 pre-vent 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 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 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 and the oxygenated N,N-disubstituted pyrimidines (XIII) and is administered or used about four times daily as needed.

In treating muscular dystrophy, Parkinsonism, Azbeimer's disease and other degenerative neurological disorders (amyotrophic lateral sclerosis; multiple sclerosis) amines and the oxygenated N,N-disubstituted pyrimidines (XIII) are administered orally using a dose of about 0.5 to about 50 mg/kg{ay, 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 CH, or -CO-O-C 2 Hs; (A-II) Qs is a-Q5.

3

:B-Q

5 Q6 is a-Q 63

:B-Q

64 Qio is a-Qo 3 B-Qi and Q 7 is a-H:B-H, where one of Q6.3 and Q6 is and the other taken together with one of Q.3 and Qs forms a second bond between C5 and C 6 Q1( is -CH 3 Q.3 i; ^j i' H 1 i: i; 1 i i WO 91/11453 PCT/L'S91/00017 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 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 (XIII) are preferably, given concomitantly with IV adriamycin or the individual is pre-treated with the amino substituted pyrimidines 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 and the oxygenated N,Ndisubstituted 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 be'ore and after surgery.

In treating osteo- or rheumatoid arthritis and other inflammatory diseases, the oxygenated amino substituted pyrimidines 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 and the oxygenated N,N-disubstituted pyrimidines (XIII) are given in a dose of about 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 and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 m_/kg/day, one to four times daily for months or years.

.I i: i- WO 91/11453 PCT/US910001-/ -16- In treating dermatological inflammatory conditions including psoriasis, the oxygenated amino substituted pyrimidines 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 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 substituted pyrimidines and the oxygenated N,Ndisubstituted pyrimidines (XIII) is used. In treating ophthalmic disorders the oxygenated amino substituted pyrimidines 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 0.001 to about 1% as long as needed.

The 5-oxygenated amino substituted pyrimidines and the oxygenated N,Ndisubstituted 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, burs, 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. NOSAC 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 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, starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, once the ulcers have formed. In patients whose clinical condition precludes swallowing the oral dosage forms, the amines and the oxygenated N,N-disubstituted pyrimidines (XIII) would be given either through a nasogastric tube, or parenterally, IV or IM. The parenteral doses would range from WO 91/11453 PCT/US91/00017 -17about .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 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 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 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 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 and the oxygenated N,Ndisubstituted pyrimidines (XIII) can be used to treat existing asthma conditions and to prevent future ones from occurring. For example, the 5-oxygenated amino substituted pyrimidines and the oxygenated N,N-disubstituted pyrimidines (XIII) treat spinal trauma and prevent rejection of skin grafts.

The 5-oxygenated amino substituted pyrimidines and the oxygenated N,Ndisubstituted 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 oxygenated amino substituted pyrimidines 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 and the oxygenated N,N-disubstituted pyrimidines (XIII) in the patient's blood and/or the patients response

-CO-O-(CH

2 )n 15 where is 2-6, Q2 5 and Q 26 are 3 (18-2) n 6 is 0, Q 1 6 is Q 1 6 3 :Qi6- where one of Qi 3 and Q6 is taken together with Q2z to form a second bond between the carbon atoms to which Qi6 and Q2 5 are attached and the other of Q 1 .3 and Q, is -Q 3 -[attached to the piperazine of the 2 ,4,6-triamino- WO 91/11453 PCT/US91/00017 -18to 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 LII, 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 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, "Z or "Ri" where 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 Z, would represent a bivalent variable if attached to the formula CH 3 Groups Ri and R, would represent monovalent variable substituents if attached to the formula CH 3

-CH

2 2 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 and Rj 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 Ci, where is the integer corresponding to the carbon atom number. For example, C 6 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 "R" lete folwdb ueia usrpfrexml,"g hr i sa inee.Teevral usiunsaeete ooaeto iaet htite WO 91/14id3 PCT/US91/00017

V

-19represents; a variable substituent (either monovalent or bivalent) at the C 6 position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms ii a linear chain. The symbol in general represents a bond between two atoms in the chain. Thus CH 3 -0-CH 2

-CH(R)-CH

3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol represents a double bond, e.g.,

CH

2

=C(R)-O-CH

3 and the symbol represents a triple bond, HC= C-CH(R)-

CH

2

-CH

3 Carbonyl groups are represented in either one of two ways: -CO- or with the former being preferred for simplicity.

Chemical formulas bf 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(CH

3 )-CH=CCI-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)-l-piperazinyl can be represented by 2

N(C

2

H,)-CH

2

-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, 2 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 which is "below" another substituent (X 2 will be identified as being in the alpha (ca) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, by the symbol or The corresponding substituent attached "above" (X 2 the other (XI) is identified as being in the beta 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 RP attached to a carbon atom as might be bivalent and be defined as oxo or keto (thus forming a carbonyl group or as two separately attached monovalent variable -PO(OR7.) where R 7 1 is C 1

-C

4 alkyl,

-SO-OR

7 where R 7 .1 is as defined above,

-[CH

2 0 6 2 where n 12 is 1 thru 3, and pharmaceutically acceptable salts thereof.

WO91/11453 PCT/US91/00017 substituents a-R, and -RAk. When a bivalent variable, is defined to consist of twc monovalent variable substituents, the convention used to define the bivalent variable is of the form "a-R:B-Ri.k" or some variant thereof. In such a case both K.j tnd are attached to the carbon atom to give For example, when the bivalent variable R 6 is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are a-R.

9 etc, giving -C(a-R.

9 etc. Likewise, for the bivalent variable two monovalent variable substituents are 2 For a ring substituent for which separate a and B orientations do not exist 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 a and B 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 -C,(R)H-C 2 (Ri)H- (C 1 and C 2 define arbitrarily a first and second carbon atom, respectively) R, and Rj may be defined to be taken together to form a second bond between C, and C 2 or a bivalent group such as oxa and the formula thereby describes an epoxide. When Ri and R) are taken together to form a more complex entity, such as the group then the orientation of the entity is such that C, in the above formula :s bonded to X and

C

2 is bonded to Y. Thus, by convention the designation R, and R are taken together to form -CH 2 -CH-O-CO- means a lactone in which the carbonyl is bonded to C 2 However, when designated R and R, are taken together to form -CO-O-CH,-CH 2 -the convention means a lactone in which the carbonyl is bonded to C,.

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 where both and are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C-C 4 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 C 2

-C

4 alkoxycarbonyl describes a group CHI-(CH2),-O-CO- where n is zero, one or two. By the second method the carbon atom content of only each i defined above,

-(CH

2 7

-CO-Q

2 3 where n 7 is 1 thru 3 and Q 23 is 1 m I 1 WO 91/11453 PCT/US91/00017 -21portion of the definition is indicated separately by enclosing the designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C,-C 3 )alkoxycarbonyl has the same meaning as C^-C 4 alkoxycarbonyl'because' the "C,-C 3 refers only to the carbon atom content of the alkoxy group. Similarly while both C 2

-C

6 alkoxyalkyl and

C

3 )alkoxy(Ci-C 3 )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 g-oups 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 for'iula of that particular substituent.

II. DEFINITIONS All temperatures are in degrees Centigradt.

TLC refers to thi,-layer chromatography.

Saline refers to an aqueous saturated sodium chloride solution.

IR refers to infrared spectroscopy.

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

6 refers to phenyl (C 6

H

3 MS refers to mass spectrometry expressed as m/e or mass/charg; unit. [M M, refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.

Ether refers to diethy' ether.

Pharmaceuticdlly acceptable refers to those properties and/or substances which are acteptable to the patient from a pharmacological/toxicological point of view and to t, 'inufacturing pharmaceutical chemist from a physical/chemical point of view regarding corrmposition, formulation, stability, patient acceptance and bioavailability, When solvent pairs are used, the ratios of solvents used ar. volume/volume 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

1 1 I ee~ h~c lsn;rr*rrrrrrmr~llllli I WO 91/11453 PC/US9]/00017 -22- 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-[16amethylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine benzoate (II) Benzoyl peroxide (0.950 g) is added to a solution of 16a-methyl-21-[4-[2,6-di-(lpyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9( 11)-triene-3,20-dionemethanesulfonate monohydrate International Publication No. WO 87/01706 Example 109, 2.22 g) and dichloromethane (4.10 ml) at The resultant solution is stirred at 00 for 4 hours and is then allowed to warm to 20-250. 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 NMR (300 MHz, CDC 3 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 5; MS (El m/e) exact mass calcd for C 45 H5 6

N

6 0 4 (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-benzopyran-2-yl)methyl]- I -piperazinyl]-5-hydroxy-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl 5-benzoate (II) Benzoyl peroxide (0.257 g) is added to a solution of 2-[[4-(2,6-di-(1-pyrrolidinyl)- 4 pyrimidinyl)- lpiperazinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H- -benzopyran-6ol International Publication No. WO 88/08424 Example 21, 0.500 g) and methylene chloride (1.10 ml) at 00. The resultant solution is allowed to stir for 4 hours at 00 and 48 hours at 20-250. Basic workup (methylene chloride, sodium dicarbonate, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) provides the title compound, IR (nujol) 3524, 2925, 2856, 1744, 1556, 1448, 1345, 1246, 1090 and 713 cm'; NM (300 MHz, CDC13) 815, 7.62, 7.49, 3.2-3.7, 2.14, 2.08, 1.98 and 1.18 <1 i -8 N i WO091/11453 PcT/US9I /00017 -23- 6; MS (El m/e) 535, 435, 379, 122 and 105, exact mass calcd for C 37

H

4 8N.0 4 (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-[ 16crmethylpregna-1 ,4,9(1 1)-trien-3,20-diune,-2 1-yl]-piperazine A solution of diacetyl peroxide (75/25 dimethyl phthalate/isobutyl isobutyirate, 0.65) ml) is added to a solution of 16cr-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)-4pyr-imidinyl]-l1-pipe-razinyl]-pregna- 1,4,9(1 1)-triene-3 ,20-dione methanesul fonate monohydrate 0.80 g) and mnethylene chloride (1.5 ml) at 00. The solution is allowed to stir for 6 hours at 00 and 42 hours at 20-25'. Aqueous workup (methylene chloride/magnesium sulfate) and purifi,%,ation by flash rThromatography hexane/ethyl acetate) provides the title compound, IR (nujol) 2954, 2916, 2855, 1760, 1666, 1557, 1446, 1375, 1345, 1207, 1012 and 887 NMR(300 MHz, CDCl 3 7.17, 6.28, 6.08, 5.51, 3.47, 3.12P 2.18, 1.40, 0.95 and 0.67 a; MS (El m/e) 639, 373, 359, 317, 291 and 246, exact mass calcd for C 4 0H_,N 6 0 4 (682.4206), found 682.4189.

The hydrochloride salt of the title compound is prepared in ether, mp dec 2115'.

EXAMPLE 4 1 -[5-(Hydroxy)-2 ,6-di-(1-pyrrolidinyl)-4-pyrimiidinyl]-4-[ 1 6 aemethylpregna- 1,4,9(11 )-trien-3 ,20-dione-2 1-yl]-pin", clilorobenzoate) (II) Di-o-chlorobenzoyi peroxide (4'79 mg) is added to a solution of 1 6ce-methyl-2 1.44-' [2,6-di-(1 -pyrrolidinyl)-4-pyri mid inyl]- I -piperazinyl]-pregna- 1,4,9(11 )-triene-3 iJmethanesulfonate monohydrate 1,800 mg) and methylene chloride (1.50 ml) at 00. The resultant solution is stirred for 4 hours at 0* and 48 hours at 20-250. Aqueous workupK (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1 0/100, hexanei/ethyl a,.,etate) provides the title compound, IR (nujol) 2937, 2856, 1665, 1557, 1448, 1377, 1345, 1239 and 750 NMR (300 MHz, CDCI 3 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 a; MS (FAB m/e) 639, 260 and 139, exact mass calculated for C 45 H3 6

N

6 0 4 C1 (779.4051), found 779.4030. j The hydrochloride salt of the tidt compound is prepared in ether/ethyl acetate, mp dec 1550.

EXAMPLE 5 1-[5-(Hydroxy)-2,6-di-(-pyrrolidinyl)-4-pyrimidinyl]-4-[1 6cmethyipregna- 1,4,9(11 )-trien-3 ,20-dione-2 1-yi]-piperazine W09/14S .PkTF/ 1S391/0001 7 the sul!fate substituted pyiimidines Alternatively the 5-hydroxy pyrimidines (XI) can be produced by reaction of the substituted pyrimidin .es with hydrogen peroxide WO091/11453 PCT/US91/00017 -24methoxybenzoate) (11) Di-p-methoxybenzoyl peroxide (466 mg)-is added to a solution of l6cf-methyl-2 I1- I -pyrrolidinyl) 4-pyrimidinyl]-l1-piperazinyl]-pregna-1 ,4 ,9(I 11)-triene-3 I dione methanesulfonate monohydrate 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 ethyl acetate/hexane) and acidic workup (ethyl acetate, methylene chloride, magnesium sulfate) to remove unreacted peroxide gives the title compound, IR (nujol) 2954, 2926, 28,56, .1736, 1666, 1606, 1555, 1446, 1253 and 1164 cm- 1 NMR (300 MHz, CDCI 3 8. 7.17, 6.97, 6.28, 6.07, 5.42, 3.89, 3.3-3.7, 3.02, 1.39, 0.90 and 0.62 6; MIS (FAH0- We) 639, 135, exact mass calcd for C,,H 5 9

N

6

O

5 (775.4547), found 775.4578.

Tnhe hydrochloride salt of the title compound is prepared in ether/ethyl acetate, .4kmp d'ec 150-152'.

7EXAMPLE 6 14[5-(Hydroxy)-2 ,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-4-[l 6 a- V 15 methylpregna-1 ,4,9(1 l)Itrien-3 ,20-dione-2 1-yl]-piperazine chlorobenzoate) (11) Di-p-chlorobenzoyl peroxide (439 mg) is added to a solution of 16ce-methyl-2l-[4- [2,6-di-(1 -pyrrolidinyl)-4-pyrimidinyl]- 1-piperazinyl]-pregna- 1,4,9(11 )-triene-3 11 methanesulfonate monohydrate 800 mg) and methylene chloride (1.50 ml) at 00. The solution is stiffed for 6 hr at 0* and 26 hr at 20-250. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography ethyl acetate/hexane) provides benzoate, IR (nujol) 2953, 2914, 2856, 1743, 16566, 1557, 1468, 1448, 1376, 1345, 1252, 1091, 1014 and 756 cm-1; NMR (300 MHz, CDCI 3 8.09, 7.48, 7.18, 6.30, 6.07, 5.49, 3.2-3.7, 3.02, 1.39, 0.91 and 0.6286; MIS (FAB m/e) 639, 469 and 260, exact mass calcd for C 4 5H 56

N

6 0 4 C1 (779."-051), found 779.4015, The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 151.1550.

EXAMPLE 7 1 (H-yd roxv)-2 ,6-di-(1 -pyrr-olidinyl)-4-py'ri mid inyll-4-[ 6crmethyipregna- 1,4,9(1 1)-trien-3,20-dione-2 i-yl]-piperazine myristoate (11) Dimyristoyl peroxide (641 ma) is added toa solution of 16c-methyl-2l.[4-[2,6-di- (1 -pyrrolidinyl)-4-pyrimidinyl]-1 -piperazinyll-pregna-1I,4,9(1 I )-triene-3,20-dione methanesulfonate monohydrate 800 mg) and methylene chloride (1.50 ml) at An epanuc necrosis 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, 1 I- :_r Ir I i (i PCT/US91/00017 WO 91/11453 additional 1.0 ml.of methylene chloride is added to the mixture which is stirred for 3 hr at 00 and 21 hr at 20-250. Aqueous workup (methylene chloride, magnesium sulfate and purification by flash chromatography ethyl acetate/hexane) provides the title compound, IR (neat) 2927, 2855, 1763, 1719, 1667, 1557, 1447 and 1345 cm'; NMR (300 MHz, CDCl 3 7.17, 6.29, 6.08, 5.51, 3.47, 3.14, 1.40, 1.26, 0.95, 0.88 and 0.67 6; MS (FAB m/e) 639, 541 and 260, exact mass calcd for C 52

H

7 9

N

6 0 4 (851.6162), found 851.6129.

The hydrochloride salt of the title compound is prepared in etheriethyl acetate, mp dec 1190.

EXAMPLE 8 1-[5-(Hydroxy)-2,6-di-(1 -pyrrolidinyl)-4-pyrimidinyl]-4-[16amethylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine toluoate (II) A solution of di-o-toluoyl peroxide (381 mg) and methylene chloride (0.50 mi) is added to a solution of 16a-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-lpiperazinyll-piegna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate 800 mg) and methylene chloride (1.25 ml) at 00. The resultant solution is stirred for 4 hr at 00 and 23 hr at 20-250. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography ethyl etate/hexane) gives the title compound, IR (nujl) 2954, 2914, 2856, '716, 1664, 1625, 1569, 1455, 1416, 1378, 1338, 1236 and 743 NMR (300 MHz, CDCI3) 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 8.

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-[16amethylpregna-1,4,9(11)-trien-3,20-dione-21-yl]-piperazine (1) W mi) is added to a mixture of 16cr-methyl-21-[4-[2,6-di-(1-pyrrolidinyl)- 4-pyrimidinyl]-1 -piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate 1.14 ammonium persulfate (623 mg) and methylene chloride ml). The mixture is stirred for 3 days at 20-250. Aqueous workup (methylene chloride, magnesium sulfate) and trituration of the residue with ethyl acetate several times gives the title compound, mp. effr 2230; IR (nujol) 2929, 2870, 2855, 1665, 1626, 1555, 1454, 1377 and 1043 cm*; NMR (300 MHz, CDCI 3 7.15-7.25, 6.2-6.35, 6.06, 5.50, WO91/11453 PCT/US91/00017 -26- 1.39, 0.95 and 0.66 5; MS (FAB m/e) 721, 641 and 247.

EXAMPLE 10 4-[4-(t-Butoxycarbonyl)piperazin-1-yl]- 2 ,6-di-(1-pyrrolid pyrimidine (VI) A solution of r:-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-(l-pyrrolidinyl)pyrimidine International Publication No. WO 87/01706 PREPARATION A- 22, 6.00 triethylamine. (3.10 nil), 4-dimethylaminopyridine (20 mg) and methylene chloride (20.0 ml) at The solution is allowed to stir at 0" for 1 hr and 16 hrs at 250. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) provides the carbamate as a solid. An analyti al 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, J142 and 788 cm'; NMR (300 MHz, CDCI 3 4.85, 3.3-3.6, 1.8-2.0 and 1.47 MS (El m/e) 402, 301 and 246.

EXAMPLE 11 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1-yl]-2,6-di-(1pyrrolidinyl)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 The resultant slution is stirred for 6.5 hr at 0° and 72 hr at 20-25°. Basic workup (m e thylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) provides the title compound, IR (nujol) 2952, 292,4, 2856, 1747, 1698, 1559, 1468, 1345, 1247, 1172 and 712 NMR (300 MHz,

CDCI

3 8.16, 7.64, 7.51, 3.2-3.7, 1.7-2.0 and 1.42 5; MS 417 and 361, exact mass calcd for C 28

H

38

N

6 0 4 (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 pyrimidine (VII, EXAMPLE 11, 286 mg) and methylene chloride (2.1 ml) at 00. After stirring for 30 minutes at 00 the solution is concentrated. Basic workup (methylene chloride, potassium carbonate, magnesium sulfate) provides the title compound, NMR (300 MHz, CDCI 3 8.15, 7.62, 7.49, 3.3-3.7, 1.7-2.9 and 1.7-2.1 The hydrochloride salt of the title compound is formed in ether, mp 78-820; IR i (nujol) 3396, 2955, 2921, 2856, 1734, 1711, 1631, 1573, 1452, 1414, 1326 and 719 ~Cr~m7-rr WO 91/11453 PCT/US91/00017 -27- MS 317, 246 and 105, exact mass calcd for C2 1 h 3 oN 6 0 2 (422.2430), found 422.2432.

EXAMPLE 13 5-Hydroxy-4-(4-methyl-l-piperazinyl)-2,6-di-(l-pyrrolidinyl)pyrimidine 5-benzoate (X) Formaldehyde (0.30 ml, 37% aqueous) is added to a solution of 5-hydroxy-4- (piperazinyl)-2, -di-(1-pyrrolidinyl)pyrimidine 5-benzoate (VIII, 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, i449, 1347, 1306, 1242, 1052 and 709 NMR (300 MHz, CDCl 3 8.16, 7.64, 7.51, 3.3-3.7, 2.2-2.5, 2.21 and 1.6-2.0 6; MS 366 and 331, exact mass calculated for

C

24

H

32

N

6 0 2 (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 (VIII, EXAMPLE 12, 0.74 propionaldehyde (0.16 ni!) and methanol (7.0 ml). After minutes acetic K id (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 NMR (300 MHz, CDCI 3 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 6; MS 359, 274, 260 and 247, exact mass calcd for C 2 6

H

3 6

N

6 0, (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]-l-piperazinyl]-5-hydroxy-2,6-di-(1-pyrrolidinyl)-4- 5I8IhLLI4J I V1 Ua U IVLJU times a day. The treatment may go on for years.

In addition, utility in disorders or physiological phenomena dependent on Nor- _W 11 WO 91/11453 PC~r/US91 /00017 -28pyrimidine 5-benzoate (X) 1,1-Carbonyldifimida-zole (0.454 g) is added to a solution of pyrrolidinyl)-4-pyrimidinyl)-lI-piperazinyl]carbonyl]-3 ,4-dihydro-2 ,5,7 8-tetramethyl-2H- 1-benzopyran-6-ol 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 hydroxy-4-(piperazinyl)-2 1-pyrrolidinyl)pyrimidine 5-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 ethyl acetate/hexane) provides the title compound, mp. 214-217'; IR (nujol) 3404, 2926, 2856, 1745, 1625, 1556, 145 1, 1345, 1244, 1089 and 714 cn- 1 NMIR (300 MHz, CDCI 3 8.14, 7.64, 7.51, 25, 3.3-3.6, 2.4-2.8, 2.08, 2.04 and 1.55 b; MS 549, 385, 371 and 205, exact mass calcd for

C

3 7H46N 6

O

3 (654.3529), found 654.3519.

EXAMPLE 16 5-Hydr-oxy-4-[4-(t-butoxycarbonyl)piperazin- 1-yl]-2 ,6-di-(l pyrrol idinyl)pyri mid ine 5-acetate (VII) A solution of diacetyl peroxide (0.81 ml, 25%) is added to a solution of butoxycarbonyl)piperazin- 1-yl]-2 ,6-d 1- pyrrol idinyl)pyrimidine (VI, EXAMPLE 0, 0.40 g) and methylene chloride (1.0 ml) at The solution is stirred for 3.5 hours at 0 0 C and 24 hours at 20-25". Acidic workup (ether, chloroform, cold 3% hydrochloric acid, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) provides the title compound, IR (nujol) 2925, 2855, 1691, 1564, 1443, 1264, 1243, 1210, 1194 ar.x' 1180 cm"; NMNR (300 MHz, CDCl 3 3.3-3.7, 2.20, 1.75-2.05 and 1.4736; MS 417, 361 and 246, exact mass calcd for C23HmN 6

O

4 (460.2798), found 460.2803.

EXAMPLE 17 5-Hydroxy-4-piperazinyl-2 1-di-(1 -pyrrolidinyl)pyrimidine acetate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4 -[4-(t-butoxycarbonyl)piperazin-1I-yl]-2 Ipyrrolidinyl)pyr-.midine 5-acetate (VII, EXAMPLE 16) the title compound is obtained, EXAMPLE 18 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l -yl]-2 ,6-di-(I pyrrolidinyl)pyrimidine 5-o-chlordbenzoate (VII) Di-o-chlorobenzoyl peroxide (0.179 g) is added to a solution of 4-[4-(t-butoxv- F.j11iics tA) aria ie oxygenated N,N-disubstituted py-imidines (XIII) are given orally in a dose of about 0.5 to about 50 m.F/kg/day, one to four times daily for months or years.

WO 91/11453 PCT/US9I /00017 -29carbonyl)piperazin- Il-yl]-2 1 -pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0. 200 g) and methylene chloride (0.50 ml) at 00. The solution is allowed to stir at 0' for 2 hours and at 20-250 for 12 hours. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) gives the title.

compound, IR (nujol) 2954, 2926, 1757, 1698, 1558, 1449, 1345, 1246, 1167, 1026 and 747 NMR (300 MHz, CDCI 3 8.10, 7.45-7.6, 7.3-7.4, 3.3-3.6, 1.7-2.0 and 1.44 8; MS (rn/c) mass calcd for C 28

H

37

N

6 0 4 (556.2565), found 556.2554.

EXAMPLE 19 5-Hydroxy-4-pi perazinyl-2 I1-di-( 1 -pyrrol id iny)l pyri mid ine chlorobenzoate(VIII) Following the -general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1I-yl]-2 ,6-di-(I pyrrolidinyl)pyrimidine 5-o-chlorobenzoate (VII, EXAMPLE 18) the title compound is obtained.

EXAMPLE 20 5-Hydro-Ay-4-[4-t-butoxycarbonyl)piperazin-1-yl]-2 ,6-di- 1- (pyr-rolidinyl)pyrimidine 5-p-methoxybenzoate (VII) Di-p-methoxybenzoyl peroxide (188 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)piperazin- 1-yl]-2 1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at The resultant solution is stirred for 2 hours at 00 and 72 hours at 20-250. Aqueous workup (methylene chloride, magnesium sulfate) :and purification by flash chromatography 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, CDC1 3 8.11, 6.98, 3.90, 3.1-3.6, 1.6-2.0 and 1.42 8; MS (rn/c) calcd for C 29

H

4

ON

6

O

3 (552.3060), found 552.3047.

EXAMPLE 21 5-Hydroxy-4 -piperazinyl-2 ,6-di-(I -pyrrolidinyl)pyri midine methoxyberizoate (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-(lIpyrrolidinyl)pyrirnidine 5-p-methoxybenzoate (VII, EXAMPLE 20) the title compound is obtained.

EXAMPLE 22 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-lI-yl]]-2,6-di-( Ipyrrolidinyl)pyrimidine 5-p-chlorobenzoate (VII) Di-p-chlorobenzoyl peroxide (193 mg) is added to a solution of* 4-[4-(t-butoxycarbonyl)piperazin- 1 -yl] -2 ,6-d i-(1 -pyrrol id inyl)pyri mid ine (VI, EXAMPLE 10, 0.200 g) WO091/11453 PCT/US9/0001"7 and methylene chloride (0.50 ml) at 00. The solution. is stirred for 3 hours at 00 and hours at 20-25". Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) gives the title compound, mp.

217-218"; IR (nujol) 2954, 2925, 1740, 1696, 1559, 1457, 1446, 1264, 1255, 1245, 1180, 1169, 1091 and 757 NMR (300 MHz, CDC 3 8.09, 7.49, 3.2-3.7, 1.7-2.0 and 1.43 56; MS 417 and 361,'exact mass calcd for C 2 gH 37

N

6

O

4 CI (556.2565), found 556.2573.

EXAMPLE 23 5-Hydroxy-4 -pipera.zinyl-2 ,6-1 1 .pyrrolid inyl)pyri midine chlorobenzoate (VINI) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1I-yl]-2 1pyrrolidinyl)pyrimidine 5-p-chlorobenzoate (VII, EXAMPLE 22) the title compound is obtained, EXAMPLE 24 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin- 1-yl]-2 1pyrrolidinyl)pyrimidine 5-myristoate (VII) Dimyristoyl peroxide (282 mg) is added to a solution of 4-[4-(t-butoxycarbony])piperazin- 1 -yl] -2 ,6-d i-(i -pyrrolid inyl)pyri mid ine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (00ml) at 00. Additional methylene chloride (0.50 ml) is added workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (/,hexane/ethyl acetate) gives the title compound, mp 58-62*; IR (nujol) 2924, 2854, 1757, 1695, 1565, 1452, 1346, 1247, 1175 and 1162 NMR (300 MHz,

CDCI

3 3.67, 3.2-3.6, 2.45, 2.31, 1.5-2.0, 1.47, 1.26 and 0.88 6; MS (in/c) 417 and 361, exact mass calcd for- C 3 5ii6JN' 6 4 (628.4676), found 628.4668.

EXAMPLE 25 5-Hydroxy-4-piperazinyl-2 ,6-1 -di-(l -pyrrolidinyl)-pyri midine rnyristoate (VIII) Following, the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1I-yl] -2 1pyrrolidinyl)pyrimidine 5.-myristoate (VII, EXAMPLE 24) the titlea compound is obtained.

EXAMPLE 26 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1I-yl]-2 ,6-di-(I1 pyrrolidinyl)pyrimidilne 5-o-toluoate (VII) Di-o-toluoyl peroxide (168 mg) is added to a solution of 4 -[4-(t-butoxycarbonyl)- I .A A W091/1453PCT/US91 /00017 -31piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine EXAMPLE 10, 200 mg) and methylene chloride (0.50 ml) at The resultant solution is stirred for 2 hours at 0' and 16 hours at 20-25*. Aqu~eous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography hexane/ethyl acetate) gives the title comnpound, mp. 147-150*; IR (nujol) 2965, 2926, 2859, 1744, 1687, 1552, 1470, 1451, 1422, 1262, 1251, 1236, 117.1, 1030 and 742 cm"; NMR (300jMHz, CDC1 3 8.13, 7.48, 7.2-7.4, 3.2-3.6, 2.64, 1.7-2.0 and 1.43 6; MS 417 and 361, exact mass calcd for

C

29 H4ON 6 0 4 (536.3111), found 536. 3102.

EXAMPLE 27 5-Hydroxy-4-piperazinyl-2 1 1 -pyrrolidinyl)pyri mid ine toluoate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin- l-yl]-2 1pyrrolidinyl)pyrimidine 5-o-toluoate (VII, EXAMPLE 26) the title compound is obtained.

EXAMPLE 28 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin- l-yl]-2 ,6-di-(1pyrrolidi nyl)pyri mid ine 5-0-sulfate (VII) Water (2.0 ml) is added to a mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]- 2 1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 200 mg), ammonium persul fate (170 mg) and methylene chloride (2.0 ml). The mixture is stirred 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, !563, 1456, 1414, 1327, 1265, 1168 and 986 NMR (300 MHz, CDCl 3 3.4-4.4, 1.7-2.3 and 1.46 6.

EXAMPLE 29 5 -Hyd rox y-4-piperazi nyl-2 1 -d 1 -pyrrol id inyl)pyri mid ine sulfate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations (including an aqueous workup) and s'aring with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-1I -yl]-2 I -pyrrolid inyl)pyri midine5-sul fate (VII, EXAMPLE.)8), the title compound is obtained.

EXAMPLE 30 1- -(Hydroxy)-2 ,6-di-(l -pyrro,di nyl)-4-pyri mid! nyl]-4- [6cemethylpregna- 1,4,9(11 )-trien-3 ,210"-dione-2 I -yl]-piperazine (XI) Hydrogen peroxide (307c, 71pl) is added to a solution of 16a-methyl-21-[4-[2,6di-(l-pyrrolidinyl)-4-pyrimidinyl]-1 -piperazinyl]-pregna-1 ,4 ,9(1 1)-triene-3 methanesulfonate monohydrate 100 mc,) and acetonitrile (50 ml) at The mixture I I: u WO 91/11453 PCT/US91/00017 -32is stirred for 3 hr at 0° and for 3 hr at 20-250. 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 chloroform/methanol/ammonia (375/25/5). The appropriate fractions are pooled and concentrated to give the title compound., IR (nujol) 2954, 2925, 2856, 1664, 1606, 1574 and 1456 cm'.

EXAMPLE 31 5-Hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-( -pyrrolidinyl)pyrimidine 5-acetate (XIII) Following the general procedure of EXAMPLE 3 but starting with 4-(2-(hydroxyethyl)methylamino)-2,6-di-(l-pyrrolidinyl)pyrimidine (XII, 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)pyrmidine (XII, US Patent application Serial No. 07/427,143), the title compound is obtained.

WO 91/11453 PCT/LIS91/.0001'/ .33- CHART A N

-R

N

NR

3 Rl-N N N

N-R

3 NR3 (ii)

RINN/

R

4 -CO-0

N-R

3 N

R

N I N R 1 -N N (III)

N-R

3 N R 2 R3

(IV)

N-R

3 .j&u%,iji1cu. inus U 2

-U

4 alkoxylcarbonyl describes a group CH 3

-(CH

2 where n is zero, one or two. By the second method the carbon atom content. of only each PCT/US9I/OOO1 7 WO 91/11453 -34- CHART B H_ N N -R 3 I'l R2

R

6 -N N

(VI)

N-R3

I

K2

R

6 -NN N (VII)

R

7 0 N -R 3 H-N N N

R

7 0 N-R 3

(VITII)

I~ 4 r WO 91/11453 PCT/US9I /00017

CHARTIC

N% 'R 1 3 -I N N (Vill) R 70 N-R 3

R

1

.Z

N \R 3 RjNN

N

(IX)

N-R3

I

r, 2 twe compound, 1K (nujol) 3524, 2925, 2856, 1744, 1556, 1448, 1345, 1246, 1090 and 713 cm; NMR (300 MI-z, CDC1 3 8.15, 7.62, 7.49, 3.2-3.7, 2.14, 2.08, 1.98 and 1. 18 PCI1/US9/OO1 7 WO 91/i11453 -36- CHART 1) Rl-N N N -R 3 N IzR2 N R 1)

N-R

3

III

I

iiI, "IR2

N

N

R

I Y2 N -R (XI 1) I.R2

N

N

R

3

Q

1 -N-j

R

7 0 N 13 (XI:i) EXAMPLE 5 1 -[5-(Hydroxy)-2 ,6-di-(l -pyrrolidinyl)-4-pyrimidinyJ]-4-[ I6crmethylpreg~na- 1,4,9(11 )-trien'-3 ,20-dione-21-yI]-piperazine

I

K!

WO 91/11453 PCF,/US9I /00017 -37- CHART E (stsroic (trolox)

Claims (11)

1. A 5-oxygenated amino substituted pyrimidine of formula (X) N Q Q 16 N R 2 N ~R 3 N N -R 3 a 2 where Q 6 is ct-Q(, 1 :B-Q& 2 Q1 0 is cr-QIO-I:B-QIc. 2 and Q7 is ce-H:13-H, where one of Q6. 1 and Q6- 2 is and the other is or C 1 -C 3 alkyl, Q, 0 is -CR 3 Q 1 cl and Q, 215 taken together are Q-, 3 )-CH or -CH =CH-CO-CH where Q 3 is 0 or a-H:B-O-Q3, or ce-O-Q3,:B-H, where Q34 is -CO-CH 3 -CO-CHS, -CO-C 6 H 5 -CO- 0-CH 3 or -CO-O-C 2 (A-11) Q5 is Ce-Q5 3 :B-Q5, Q 6 is U-Q6. 3 :I-Q64, Q 1 0 is Ce-Q 1 O- 3 :1-Qjw and Q 7 is a-H:B-H, where one of Q6_ 3 and Q64is and the other taken together with one of Q5.3 and Q_,4 forms a second bond between C 5 and C 6 Qw is -CR 3 Q 103 and the other of and Q;4 taken together is -(CH 2 2 -C(H)(OH)-CH 2 (A-Ill) Q10 and Q5 taken together are =CH-CH=C(OQ3)-CH= where Q3 is -H, C 1 -C 3 alkyl, -CO-H, C 2 -C 4 alkanoyl or benzyl, Q 6 is cr-Q 6 5 B-Q64where one of Q6_ magnesium sulfate) and trituration of the residue with ethyl acetate several times gives the title compound, mp. effr 22.30; JR (nujol) 292.9, 2870, 2855, 1665, 1626, 1555, 1454, 1377 and 1043 cm'1; NMR (300 MHz, C.DCI 3

7.15-7.25, 6.2-6.35, 6.06, 5.50. W0 91/11453 PCT/LJS9I/00017 -39- and Qm is and the other is or C,-C 3 alkyl and Q 7 is a-H:B-H; (A-IV) Q5 is a-Q 57 Q 6 is Uc- 7 :8-Q6. 8 Q 7 is a-H:B-H and Q 1 0 is. a-Q 1 0. 7 B-Qlog, where one Of Q3. 7 and Q 58 is Q 1 0. 7 and the other Of Q. and taken together are -(CH 2 2 -C(=Q3. 3 )-CH 2 whe're Q 33 ig as defined above, Q10, is -CH 3 where one Of Q 67 and Q6. is -H and the other is or C 1 -C 3 alkyl; Q 6 is Q 69 :Q6. 1 0 Q 7 is Q 79 :Q 71 0 Q 1 0 S is aQM~ 9 :Q 1 1 0 where one of Q 69 and Q6. 0 is -H and tlve other taken together with one of Q7. and Q1 for-,~ :-cond bond between C 6 and C 7 and the other of Q 79 and Q7. 0 is Q1. 1 0 is -C"14, Q~g and Q taken together are -(CH 2 2 -C(=Q3. 3 or -CH=CH-CO-CH- iere Q 33 is as defined above; Q 1 1 is Cf-Q 11 1 :il-Q 11 where one ofl C 111 and Q11_2 is taken together with Q 9 to form a second bond between C 9 and C 1 1 and thie other of Q 1 11 and Q 1 12 is -H; (C-Il) Q 9 is and Q 11 is =0 or c*-H:B-Q 1 4 where Q 1 ,1 is -Cl or -OH; (C-Ill) Qq is -H or -F and Q 11 is =0 or a-Q 1 1 5 :8-Q 11 where one of Q1 15 and Q11_ is and the other Of Q 1 15 and Q11. is -OH or C 1 -C 12 alkoxy; (C-IV) Q 9 is -H or -F and Q 1 1 is U-O-CO-Q 11 7 where Q11- is C 1 -C 3 alkyl, C 1 -C 12 alkoxy, -NQ 12 2 Q 1 23 where one Of Q 1 2 2 and Q 1 2 3 is methyl or ethyl and the other is CX- 4 alkyl or phenyl, -Q 3 -Q 1 where Q3 is or a valence bond, where Q, is phenyl option- ally substituted with 1 through 2 -Cl, -Br, CX- 3 alkoxy, -COOH, -NH 2 C 1 -C 3 alkyl- amino,, di(C 1 -C 3 )alkylamino, where the alk-yl groups are the same or different, I- pyrrolidinyl-, 1-piperidinyl, I -hexamethiylenimino-, 1 -heptamethyleni mino-, C 2 -C 4 acylamino and -NN- CHO or with 1 -F or -CF 3 where: Q 16 is Q 1 1 :QI6- 2 and Q 1 7 is Q 1 71 :Q 172 where one of Q 1 61 and Q 1 6 2 is -H or -CH 3 and the other taken together with one Of Q 171 and Q 172 forms a second bond be- tween C 1 6 and C 17 and the other Of Q 1 71 and Q 1 72 is -C(=Q 2 0)-(CH 2 ),-[attached to the' piperazine of the 2,4,6-triami nopyri mid ine], where Q2 0 is =CH 2 or Q 17 9 where Q 179 is -H or -CH 3 where, ,j ;s 0 through 6, where (D-II) Q 1 6 is a-Q, 6 3 :B-Q 1 64 where one of Q 1 6- 3 and Qj&4is -H and the other is -H, CH~or na s 2 )p-[attached to the piperazine of the 2,4,6-tni- aminopyrimidine], where p is 1 or 2; (D-III) Q 1 6 is ce-Qj6 3 and Q 1 7 is ar-Ql',.S:B-Q 17 where Q 1 5 is -OH, -F or -CH 3 and Q16 is -OH, or -CH 3 with the proviso that at least one of Q16. and Q 1 64 is where Ql-. is -OH, -CH 3 -CHCH 3 C,-C 7 alkanoyloxy or -O-CO-Ql, where Q, is as defined above, and where Q 1 7 -6 is -C(=Q 20 )-(CH 2 ).-[attached to the piperazine of the '2,4,6-triarninopyrimnidine], where Q2 0 and n are as defined above-, (D-IV) the 16,171-acetonide of a compound where Qj&5 is -OH, Q" is is -OH and Q 7 -6 is -C Q 20 -(CH,),,-[attached to the piperazine of the 2,4,6-triam- inopyrirnidine], where and n are as defined above; with the following overall provisos that: one of Q,6, or Q16. is taken together with one o'f Q 71 or Q 17 to form a second bond between C 16 and only when Q1 0 is ce-Q 1 1 :B-Q 1 0.2, ca-Q 10 3 :I-Q 1 Ce- QjcLB-Q 1 g or ce-Qj 0 9 :B-Qj~ 0 .0 (II) Q 1 7 is =CH-(CH 2 )p-[attached to the piperazine of the 2",4,6-triamino- pyrimidine], only when Q 1 0 is 2 U-Q 1 O. 3 :B-Q 1 L -QIO. 7 :Bl-Q 1 -9 Or a".Qic. 9 :l 3 -t (III) Q.3 and Q 20 taken togethier are =CH-CH=C(0Q,)-CH=, only when Q 1 7 is a-Ql-,. 5 :B-Q 1 Or the 16, i7-acct.inide of a compound where Q 1 6 is ce-OH:13-H and Q 17 is a-OH:B-C(=Q 20 )-(CH,),-[attached to the piperazine of the 2,4,6-triaminopyrim- idine], and (MV Q is a-QS. 7 only when Q 17 is a-QI7, 5 :B-Q 1 7 -6 Or a-OH:B-C- (=Q 20 )-(CH 2 [attached to the piperazine of the 2,4,6-triaminopyrimiciine], or the 16,17- acetonide thereof; J~ST~TUT~T 41 R 2 and R 3 are the same or different and are C 1 -C 4 al-kyl and where R 2 and R 3 are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyi, 1-morpi y,1-ieaiy and 1- piperazinyl substituted in the 4- position with alkyl with the proviso that R, and R 3 are not both -H; R 7 is -CO-R 4 where PR, is -H, C 1 -C 4 alkylI, -doptionally substituted with 1, 2 or 3 C 1 -C 4 alkyl, 0 -OH, C 1 -C 3 alkoxy, -Cl, -Br, I whereR and R1 2 are the same or different and are -H or C 1 -C 4 alkyl, -S-R,3 where R13 is -H or C1-C 4 alkyl, -COOR, where R,4 is -H or Cj 1 c alkyl, -(CH 2 4 where n, is 1-6, R 4 1 and R1 2 are as defined above, -(CH 2 1 where ns is 1-6 and R4. is as defined above,T -(CH 2 7 -CH 2 -COOH where n 7 is 1-6, -CH =CH-COOH, -(CH N(R 41 where n 4 R 4 1 and R4- 2 are as defined above, 41 where n5 and R1 are as defined above, -(CH2L,-CO-N(CH )-CH 2 -CH 2 -SO 2 -OH where n, is 1 thru 6, (2 Rwhere R 5 is C 1 -C 3 alkyl, C 4 -C27 cycloalkyl, -S0 2 -OH, H -PO(OH) 2 -PO(OR-,L) 2 where R 7 .1 is CX- 4 alkyl, -SO-OR 7 1 where RM. is as defined above, 42 C 6 H 1 2 o 6 1 2 where nI 1 2 is 1 to 3, and pharmaceutically-acceptable salts thereof. 2. A compound according to claim. 1, where Q 6 is Q 7 is H:H, Q 1 2 iLs CH 3 and Q 10 1 and Q 5 taken together are -CH=CH-CO-CH=. 3. A compound according to claim or claim 2, where Q 1 1, is -Q 1 1 1 1 2 oe o Q 1 1 and Q, is taken together with Q 9 to form a second bond between C 9 and C 11 and the other off Q 11 1 and Q11. 2 is H. 4. A compound according to any preceding claim, where Q1 is a-CH 3 :8-H and Q 1 7 is a-Hi:B-CO-CH 2 A compound according to any preceding claim, where R 7 is -CO-R 4 6. A compound according to claim 5, where R, is phenyl or CH,.. 7. A compound according to any of claims 1 to 4, where R 7 is R,. S. A compound according tocam7 hr 5 is CH 3 or

9. A compound according to any of claims 1 to 4, where R7 is -S0 2 -OF. 1. Ac,..mpound according to any preceding claim, where either R 2 and R 3 are each ethyl or NR 2 R 3 Is 1-pyrro!ldinyl or 1-piperidinyl.

11. A compound according to claim 1,which is the 5-acetate, 5-(o-chlorobenzoate) methoxybenzoate) 5-(p-chlorobenzoatLe), 5-myri stoate or 5-sulphate of l--5-hvdroxy-2,6-di(1- Pyrrolidinyl)-4-pyrir.idinyl-4-16a-methvblpregna-1,4,9(11) tr-iene-3,20-dion-21-vl)piperazine. pyrroaaclnyl)pyn midine 5-p-chlorobenzoate (VII) Di-p-chlorobenzoyl peroxide (193 mg) is added to a solution of. 4-[4-(t-butoxy- carbonyl)piperazin- l-yl]-2 ,6-di-(1 -pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.200 g U m~4 INOMM- MWWW W 0 I

12. A compound of the f ormula Q2 6 N-R 3 Q2 where W 2 is -NH- or -N(C,-C 3 alkyl) is 0, 1 or 2, Q 7 is H, C 1 -C 4 alkyl, -CO-('C 1 -C 4 alkyl), prodrug where tnrodrug -CO0-~ or r C.; EXAMPLE 26 5-Hydroxy-4-[4-(t-butoxycarbony)piperazin- l-yl]-2 I- pyrrol id inyl)pyrimidine 5 -o-toluoate (VII) Di-o-toluoyl peroxide (168 mg) is added to a solution of 4 4 -(t-butoxycarbony])- '44 is -Po 2 -cr. -CO-CH 2 -CO-NH-CH,-SQ-Cr_ -CO-(CHD,)2j-Q 1 j where n 21 is 1-7 and Q 5 1 is -COO-' -NQ 511 0 1 where Q 1. 1and Q51. are the same or different and are -H or C 1 -C 3 alkYl, -N'Q 5 1 IQ 1 2 5 13 ha~de' where Q- 5 1 Q 5 l. 2 QS 13 are the same or different and are -orC- 3 alkyl, and where halide is -CI or -Br, -CO-C CH-CO-0', -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[(CH-),-N~H]-CH=CH-CH=CH where nn. is I 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(-NQO-CH=CH'where QS 2 is -H or C 1 -C 3 alkyl and where the atoms marked with an asterisk C)are bonded to each other resulting in the formation. of a ring, 1 -COO[C 6 H 2 O 6 sugars], -CO-O-CH(CH 2 -O-CO-Q 53 2 where the Q 's are the same or different a;. are C,-Ci, -CO-(CH 2 6 -CO-N(CH 3 )-CH 2 -CH 2 -SO 3 cation+ where cation' is sodium, potassium or t-ialkylammonium where alkyl is C 1 -C 3 -CH 2 -0-CO-(CH~a-NQ 5 .Q 5 j. 2 where n 2 l, Q51. and Q-51 2 are as defined a0bove, -CO NH-CAH-Q5 3 where Q55 is -H or C,-C 3 alkyl, -NO 2 -NQ5. 1 Q 512 where Q.5. 1 and Q51. 2 are as defined above and Q 1 0 is -H or -CH 3 Q1 1 is -H or -CH 3 ,A Q 1 2 is -H or -CH 3 (18-1) Q 1 6 is a-Q 1 1 :B-OI& 2 where one of Q 1 6_ 1 .and Q1. 2 is -CH3, -CH 2 CH 3 or -4and the other is -Q 3 -fattached to the piperazine of the 2,4,6-triaminopyrimidine], where Q3 is -CO-, -(CH2 16 -CO- where n, 6 is 1 or 2, where n 3 is 1-6, or '1-CQ-O-(CH 5 where nij is 2-6, Q23 and %6 are -H:-HI; 2 r ~,I Hydrogen peroxide 7 IlI) is added to a solution of l6cr-methvl-2l-[4-[2,6- f di-(I-pyrrolidinyl)-4-pyrimidinyl]-1 -piperazinyl]-pregna-1 ,4 ,9(1 1)-triene-3,20-dione I methanesulfonate monohydrate 100 and acetonitrile (50 ml) at 0. The mixture (18-2) n 6 is 0 and Q 1 6 is Q 16 3 :Q 16 4 where one of Q 16 3 and Q 16-, is taken together with Q 25 to form a second bond between the carbon atoms to which Q 16 and Q 2 5 are attached and the other of Q 1 6 3 and Q, 6 -4 is -Q 3 -fattached to the pioerazine of the 2,4,6-triamino-pyrimidine], where Q 3 is as defined above, or (18-3) n 6 is 1 and Q 25 and Q 26 together form a second bond between the carbon atoms to which they are attached; and R 2 R 3 and R 7 are as defined in claim 1, and preferably as in any of claims 5 to 10, and pharmaceutically- acceptable salts thereof. 2.2. A compound according to claim 12, where W 7 is H and Ql, Qj_ and Q 12 are all CH 3 and/or where W 2 is n 6 is 1, I R 25 is H:H and R 26 is H-:H.

14. A compound according to claim 12, which is 4-f [4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramnethyl-2H-l- benzooyran-2-yl) methyljpiperazin-l-yl] -5-hydroxy-2, 6-diL(I- pyrroidn) pyrimidine 5-benzoate, or 4-f f4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-., benzonyran-2-yl) carbonyl ]piperazin-l-yl )-5-hydro>xy-2 6- di(l-ovrr-olidiny1) -4-pyrimtidine A compound of formula X 2 5 N I 'R RI-NN N (X) R 7 0 N-R3 R 2 where R 1 is an alkyl substituent selected from Q 2 (CH 2 )1 2 where 46 n, is 1-14; is -OH, -O-CO-(Cl-C 4 alkYl), -0-CO-H, -O-CO-O-(C-C 4 alkyl), 4 aikoxycarbonyl, -0-CO-aryl where arvi is 6 optionally substitued with -OH, -OCH 3 -F, -Cl, -Br, I0 -CF 3 -C 1 -C 3 alkyl, andI -CO-Q 5 where 05 is -OH, -NHQ 6 where Q 6 is 4) or CI-C 3 alkyl, and -N(QM4)(Qs) where Q1 4 and Q15 are the same or different and are Cl-C 3 alkyl; Q3- 1 -O-(CH 2 where ng is 2 or 3 and where Q3. is CI-C3 alkyl, -CO-Q.. 2 where Q3- 2 is C,-C 3 alkyl or Q 33 -CO-(CH 2 X 9 g- where n 9 is I thru 3 and Q1. 3 is -OH, -O-Q3- where Q,4 is Cl-C 4 alkYl or -CH 2 Cl-C 3 alkyl, -0 optionally substituted with or 2 -Cl, -Br, -NO 2 C 1 -C 3 or -OQ,6 where Q34 is C 1 alkyl, Q3j0(HC2-)j7HC2 where njo is 1 or 2 and where Q3-, is as defined above, Q3. 3 -CO&CH=CH-CH 2 where Q3.3 is as defined above, A 47 -S0,Q 3 -5 where Q3-. 5 is C -C 3 alkyl; or *CH 2 -(CH 2 where the atoms marked with an asterisk are bonded to each other resulting in the formation of a ring and where t 1 is 1 to 6; and R 2 R 3 and R7 are as defined in claim 1, and preferably as in any of claims 5 to and pharmaceutically-acceptable salts thereof.

16. A compound according to claim 15, where R, is 2 where n 2 is 2 to 8, or *CH 2 -(CH 2 where the atoms marked with an asterisk are bonded to each other resulting in the formation of a ring and where ti is 1 to

17. A compound according to claim 15, which is 5-hydroxy-4-(4-methyl-1-piperazinyl)-2,6-di(l- pyrrolidinyl)pyrimidine 5-benzoate, or 5-hydroxy-4-(4-propyl-l-p iperaz1inyl)-2,6-di(l- pyrrolidinyl)pyrimidine 5-benzoate. o

18. A ptcted 5-oxygenated pyrimidine of formula (VII) It 3( 252 R703 N3 12 where R 2 R 3 and R, are as defined in claim 1; and R 6 is t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), CH3-CO-, p-CO- or CHO-; and pharmaceutically-acceptable salts thereof.

19. A compound according to claim 18, where R 6 is t-BOC. or CBZ. A compound according to claim 18, where R 7 is -CO-R 4 i R- sZ P~ INTERNATIONAL SEARCH REPORT international Application No PCT/US 91/00017 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC C 07 J 43/00, C 07 D 405/14, C 07 D 239/50, C 07 D 403/14 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbo's C 07 J; C 07 D Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in Fields Searched 8 III. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category I Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 X WO, A2, 8701706 (THE UPJOHN COMPANY) 1-5,16- 26 March 1987, 17,23- see the whole document 25,28- 31 X WO, Al, 8808424 (THE UPJOHN COMPANY) 1,6-8, 3 November 1988, 16-17, see the whole document 23-25,

28-31 A WO, Al, 8707895 (THE UPJOHN COMPANY) 1-5,16- December 1987, 17,23- see the claims 25,28- 31 Special categories of cited dscuints: 10 'T later document publishd afterI th erntiona flng date A' docu nt definngthe eneral state of the art which Is not r prirty date and not ple I r the apndrlying t ut c e to udetandy underlying the E earlier document but published on or after the international filing date document of particular ralennce, the claimed Invention cannot be considered novel or cannot be considered to L" document which may throw doubts pn priority clalm(s) or nvolve an Inventive step h cn hs cited to Estan as alin the p' 0"o 1ae ao. an oer witation or other seabih the pu(licaion e ond) nY document of particular rlevance, the claimed Invention citation or othercannot be co sidered to involve an Inventive step when the S mereferring to n oral diclosure, use, exhibtion or ocumen om d wth on or mo other such docu Sdocument rating to n orl dlou ue exhibitiontssuch combi nation being obvious to a person skilled other means In the art P' document ublisheon pror tol the nt emational filing date but document member of the same patent family later than he priority t lgclaimed document member of the me patent family IV, CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 6th September 1991 0 3. 10, 91 International Search.ig Authority Signature thorized Ofi r EUROPEAN PATELT OFFICE Mme Damar FRAN Form PCTIISA/210 (econd sheet) (January t195) OMPINNP- 0 1 -low; International Applicatiov; No. PCT/USI 91/00C117 FURTHER INFORf.IATION CONTINUED FROM THE SECOND V. [I OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEAARCHABLE This international search. rpprt has not been established in respect of certain claims under Article 17(2) for the following reasons'. 1, 0 Claim numbers.....because they relate to subject iniatter not required to be searched by this Authority, namely. claim numbers because they relate to Par. of the International application that do not comply with the prescribed requirernen is to such !ni extent that no meaningi international search can be carried out, specifically; SClam numers. because they ami dependeat claims and are not drafted in accordance with the second and ihird sen- tenzas f PCT fltle G:W~a). VI. EJ OBSERVATIONS WHERE UNIT'Y 00 INVENTION IS LACKING2 This lnternatioiial Se-rching Authority found rcowple Inventions In tnils internatinal appi Ion as follows: See next sheet 1 lAs all required additlonat search fees were timely paid by the applicant, this international search report covers all searchable claims of the inter-nattonal appllcalion. 2. As onl so of the required additional search fees we%'p tImelV paid by. the applicantl, thiq international gearch report covers onytoecaims of the international application for which lees wefv paid, specifically claims: 1)claims 1-5,11-17; 2) claims 1,4, 6-8,11-17; 3) claims 23-25; 4) clai.ms 28-31 3, 0i Nor trsddltoa ferl ees rare timely Fl byteapicn.Cn lieritty, this International search report Is restrict- ad h 4ieninfirst mentioned n the the c a Ma. It is covered by claim sititm~r: F As111sehable claims could bq searched without effort justifying an additional fee, the 'international Searching Authority 4.-E did not Initayment of any additonal fee. Remarkt on Protest The additional search fees were accompanied by applicant protest. No protest accompanied the payment of additional iteach fets, Form PCT/ISA/Z,10 (Suppleeintal shet (JwYJei'y 19~85) I <ii I FURTH~ER INfORMATION CON~TINUED from PCT/I SA/210 (suppI. sheet The compounds X as defined in claims 1-17 are so different from each other that no technical relatlonship. or inter- action can be appreciated to be Present so as; to form a single general inventive concept. Claims 18-31 define 4 different intermediales. The inter~- medines are not closely interconnected with the end pro- ducts. Therefore the relationship intermediates/c-nd products is lacki'ng.- The in ;ehtions are listed below 1) 5-oxygena-ted amino substituted pyrimidine when 91is a -*,steroid dlaims :L-5 ,ll-17 2) 5-oxygenated arniho substituted pyrimidine when R1is a trolox claimrnj,4,6-8,l17 3) 5-oxygenated amino- substituted pyrimidine when R 1 it a n tunsubstituted or iubstituted ell .yl, claims 1,4,01-17 4) A protected 5-oxygenated pyrimidine of formula VII claims 18-22 A S-oxygenated pyrimidine of formula VIII, claims 23-25 6) A 5-hydroxy pyrimidine of formula YX, cl aims~ 26-27 <17) An oxygenated N,.N-disubstituteri 1?yrimidinf. of formula XIII,claims 28-31 h I7 J- Form PCTIISA International Applic&~ion No. PCT/US 91/00017 Jill. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND Caegor Citation ot Document, with indication, where appropriate, of the relevant passages I Relevant to Claim No EP, Al, 0389370 (ROUSSEL-UCLAF) 26 September 1990, see the claims EP, Al, 0389369 (ROUSSEL-UCLAF) see the claims EP, Al, 0389368 (ROUSSEL-UCLAF) see the claims 26 September 1990, 26 September 1990, 1-5, 11- 17,23- 25,28- 31 1-5,11- 17,23- 25,28- 31 1-5,11- 17,23- 25,28- 31 For. PCT/ISA/21O (extra shoot) (January 1985) ~TTr- -T. r ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/US 91/00017 SA 44465 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 31/07/91 The European Patent office is in no way liable for theseparticulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date WO-A2- 8701706 26/03/87 EP-A- 0263213 13/04/88 AU-B- 593284 08/02/90 AU-D- 4080689 07/12/89 AU-D- 6335686 07/04/87 EP-A- 0238545 30/09/87 JP-T- 63500868 31/03/88 WO-A1- 8808424 03/11/88 AU-D- 1709888 02/12/88 EP-A- 0293078 30/11/88 EP-A- 0358676 21/03/90 JP-T- 2503198 04/10/90 WO-Al- 8707895 30/12/87 AU-D- 7580187 12/01/88 EP-A1- 0389370 26/09/90 FR-A- 2644789 28/09/90 JP-A- 2273693 08/11/90 EP-Al- 0389369 26/09/90 FR-A- 2644788 28/09/90 JP-A- 2268195 01/11/90 EP-Al- 0389368 26/09/90 FR-A- 2644787 28/09/90 JP-A- 2273660 08/11/90 For more details about this annex: see Official Journal of the European patent Office, No. 12182 EPO FORM P0479