NZ236801A - Substituted pyrimidine derivatives and pharmaceutical compositions thereof - Google Patents

Substituted pyrimidine derivatives and pharmaceutical compositions thereof

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Publication number
NZ236801A
NZ236801A NZ236801A NZ23680191A NZ236801A NZ 236801 A NZ236801 A NZ 236801A NZ 236801 A NZ236801 A NZ 236801A NZ 23680191 A NZ23680191 A NZ 23680191A NZ 236801 A NZ236801 A NZ 236801A
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New Zealand
Prior art keywords
alkyl
pyrimidine
hydroxy
pyrrolidinyl
oxygenated
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NZ236801A
Inventor
Eric Jon Jacobsen
John Michael Mccall
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Upjohn Co
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Application filed by Upjohn Co filed Critical Upjohn Co
Priority to NZ24152991A priority Critical patent/NZ241529A/en
Publication of NZ236801A publication Critical patent/NZ236801A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £36801 _ 23 6 8 0 1 Priority I'-i.- Compter? i"\-\ cvi Ctaao: (5).^! ^ io^3>ci\?>cT; st>( cx-oouoilu^ 1.9.J&\u>. Co 1Oi+c5" 11C enouos\\ur c o c°7 H/7/01, Pub#c«ti 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 trolox (vitamin E), 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 alkyl, see International Publication No. WO 88/-08424, published November 3, 1988 based on International Patent application PCT/US/88/01212, in particular, see the compounds of formula (II) and see International Publication No. W091/06542, published May 16, 1991 based on International Patent application PCT/US90/05645.
-Hydroxypyrimidines are known, see J. Chem. Soc., 2033 (1956) and Synthesis 443 (1975).
Non-oxygenated N,N-disubstituted pyrimidines corresponding to the oxygenated N,N-disubstituted pyrimidines (XIII) of the present invention are known, see International Publication No. W091/06542.
SUMMARY OF INVENTION ^ Disclosed are the 5-oxygenated amino substituted pyrimidines of formula (X) where R( is (1) steroid substituent (steroid) where (A-I) Qs is Q;0 is <^-Qio-t•'J^-Qio-2 and Q? is or-H:J3-H, where one of Qm and Qj.; is -H, and the other is -H, -F, or Q-Cj alkyl, Q10.2 is -CH3, Q!CM and Q} taken together are -(CH,)2-C(=Q>.:.)-CH= or -CH = CH-CO-CH = , v^here Qyi is =0 or cr-H:8-OQwora-OQ,_,:A-H, where Q,_, is -H, -CO-CH3, -CO-C;H3, -CO-C4H5, -CO-O- CHj or -C0-0-C-H<; ^ *■> Q5 is a-Q5-3:1^"Q5-i' 0s is Q:o is a-Qjo-j: i 8 with one of Qj.j and Q<_, forms a second bond between Cs and C4, QI(W is -CH}, Q10.5 ** .c " F I v' 23 6 8 0 1 and the other of Qs.j and Qj^ taken together is -(CH2)2-C(H)(OH)-CH2-; (A-III) Q10 and Q, taken together are =CH-CH=C(OQ3)-CH= where Qj is -H, C,-C, alkyl, -CO-H, C2-C« alkanoyl or benzyl, Q4 is a-Q^B-Q^ where one of Qj., and Qm is -H, and the other is -H, -F, or C,-C3 alkyl and Q, is or-H:3-H; (A-IV) Qj is a-Qj.7:8-Qj.i, Qs is ocQs.7;8"Qs.i» Q7 is <*-H:8-H and Qio is c**Qio.7: 8-Qio-i, where one of Q5.7 and Qj., is -H, Q1(>7 and the other of Q5.7 and Qj., taken together are -(CH2)2-C(:=Q3.j)-CH2, where Qyi is as defined above, QJ0.» is -CH}, where one of Qj.7 and is -H and the other is -H, -F, or C,-C3 alkyl; (A-V) Q6 is Qs.9-Qs.10. »s Q-.»:Q-.io. Qio is ot-Qk^Qkmo. where one of Qs., and Qs-io is -H and the other taken together with one of Q7.9 and Q7.I0 forms a second bond between C6 and C7, and the other of Q-* and Q-.,0 is -H, QI0.10 is -CHj, Qio., and Qs taken together are -(CH2)2-C( = Qj.3)-CH = or -CH=CH-CO-CH = , where Qj.j is as defined above; (C-I) Qu is or-Qn.ffl-Q,^, where one of Q,,^ and Qu.2 is taken together with Q, to form a second bond between C, and C„ and the other of Qu l and Q,,.2 is -H; (C-II) Q, is -CI and Qn is =0 or a-H:8-Qlu where QU4 is -CI or -OH; (C-1II) Q, is -H or -F and Q,, is =0 or a-Qi,.j:B-Q1M, where one of Q,,.5 and Qlw is -H, and the other of Q,,.s and QlM is -H, -OH or C,-C12 alkoxy; (C-IV) Q, is -H or -F and Q„ is a-O-CO-Qn^rfl-H, where Q„.7 is (A) C,-C3 alkyl, (B) C|-C12 alkoxy, (D) -NQ|22Q|23, where one of Q,22 and Qm is -H, methyl or ethyl and the other is -H, C,-C4 alkyl or phenyl, (E) -Q3-Q1, where Q, is -O- or a valence bor.d, where Q, is phenyl optionally substituted with 1 through 2 -CI. -Br, C,-C3 alkoxy, -COOH, -NH2, Q-Cj alkylamino, di(C,-C3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, l-he.\amct^ylenimino-, 1-heptamethylenimino-, C2-C4 acylamino and -NH-CHO or with 1 -F or -CF3; where: (D-I) Q16 is O16.1 -Qi6-; and Q - is Qr i'Qr-:< w'here one of Q;M and Q;6: is -H or -CHj and the other taken together with one of Q^.\ and Q1?.2 forms a second bond between CI6 and C1?, and the other of QP., and Q,7.2 is -C(=Q;o)-(CH:)0-[attached to the pipera?ine of the 2.4,6-triaminopyrimidine], where Qio is =0, =CH, or Qr.9:-H where 236 8 0 1 Ql7., is -H or -CHj, where n is 0 through 6, where (D-II) Q14 is or-Qi«.}:B-Qi and the other is -(^-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q3 is -CO-, -(CH3)nl6-CO- where n,6 is 1 or 2, -(CH^- where n3 is 1-6, or 30 -C0-0-(CH:)n)j- where n,, is 2-6, Q;5 and Q;6 are -H:-H; (18-2) is 0, Q.4isQ16!:Q where one of Q!4.3 and Q1W is taken together with Qy to form a second bond between the carbon atoms to which Q16 and Q25 are attached and the other of Q^j and Q1(M is -Qr[attached to the piperazine of the 2,4,6-triarnino- pyrimidine], where Qj is as defined above, (18-3) n« is 1, and Q:4 are taken together to form a second bond between the carbon atoms to which and Q;# are attached; (3) an alkyl substituent selected from the group consisting of 5 (A) QHCHjL- where: n2 is 1-14; Qj is -H, -OH, -0-C0-(C,-C4 alkyl), -O-CO-H, -0-C0-0-(C,-C4 alkyl), (C,-C4) alkoxycarbonyl, -O-CO-aryl where arvl is optionally substitued with -OH, 10 -OCHj, -F, -CI, -Br, -CFj, -C|-C3 alkyl, and -CO-Qj where Qj is -OH, -NHj, -NHQj where Q6 is or C,-C3 alkyl, and -N(Qu)(Qij/ where Qu and Qu are the same or different and are CrC, alkyl; (B) Qj-j-O-^Hj),,!- where n, is 2 or 3 and where Qj., is -H, Q-Cj alkyl, -CO-Qj.2 where Qj.2 is -H, C,-C3 alkyl or -<£, (C) Qj.3-CO-(CH;)n9- where n, is 1 thru 3 and Qj.j is -OH, -O-Qj., where Q3_, is C,-C4 alkyl or -CH2-<£, Cl-CJ alkyl, -o optionally substituted with 1 or 2 -F, -CI, -Br, -NOj, C,-C, alkyl or -OQ^ where Q^ is C,-C3 alkyl, (D) Q3.,-0-(CH,CH;-0)nlo-CH2CH2- w here n10 is 1 or 2 and where Q^oifr < 30 as defined above, (E) Q„-CO-CH = CH-CH2- where Q3_3 is as defined above, j. ^ (F) -S02Q3.s where Q3.j is C,-C3 alkyl; (G) 'CHj-CCH^n-C'H- w here the atoms marked w ith an asterisk (') are 2368 0 1 bonded to cach other resulting in the formation of a ring and where t, is 1 thru 6; R2 and R, are the same or different and are -H, C,-C4 alky! and where R2 and R, are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-5 piperazinyl substituted in the 4- position with C,-C« alkyl with the proviso that R2 and R3 are not both -H; R7 is (1) -CO-R*, where R« is -H, C,-C4 alkyl, - optionally substituted with 1, 2 or 3 C,-C« alkyl, -OH, C|-Cj alkoxy, -F, -CI, -Br, -no2, -NOV^Rj.j) where R4., and R^ are the same or different and are -H or C,-C4 alkyl, -S-R4.J where R4.3 is -H or C,-C4 alkyl, -COORm where R44 is -H or C,-C4 alkyl, where n4 is 1-6, R*., and R4.2 are as defined -(CH^-O-CR^,) where n5 is 1-6 and R4-1 is as defined above, -(CHjX^-CHj-COOH where n7 is 1-6, -CH = CH-COOH, -(CH,)t>4-N(R4.|)(R4.,) where n4, Ri., and are as defined above, 25 -(CH^-O-lRj.,) where n5 and R4., are as defined above, -(CHj)ol-CO-N(CH3)-CHrCH2-S02-0H where n, is 1 thru 6, (2) -Rj, where Rj is C,-C3 alkyl, C4-C7 cycloalkyl, (3) -SOrOH, (4) -po(oh)2, (5) -PO(ORti)2 where R-., is C,-C4 alkyl, (6) -SO-OR71 where R7., is as defined above, (7) -[C6H1206]0|2 where n,2 is 1 thru 3, and pharmaceutical^ acceptable salts thereof. above, ~\ - / f • ' , 4 w *' I Also disclosed arc the protected 5-oxygenated pyrimidines of formula (VII) where R« is t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), CH,-CO-, <£-CO- and CHO-and where R2, R, and R? are as defined above and pharmaceutical^ acceptable salts thereof.
Further disclosed are the 5-oxygenated pyrimidines of formula (VIII) where R2, R3 and R7 are as defined above and pharmaceutical^ acceptable salts thereof.
Additionally disclosed are the 5-hydroxypyrimidines of formula (XI) where R2 and Rj are as defined above.
Additionally disclosed are the oxygenated N,N-disubstituted pyrimidines of 10 formula (XIIO where Q, is C,-C3 alkyl, -O-CHj, -O-CHXHj, -(CHj^-O-Q,., where n, is 2 or 3 and QM is -H, C,-Cj alkyl, -CO-Q^ where Q,.2 is -H, C,-Cj alkyl or -, -CHI-CH(OQt.l)-CHj where Qu is as defined above, 15 -CHjCHj^O-CHjCHj^-O-Q,., where n2 is 1 or 2 and where Q,., is as defined above, -(CHjXj-CO-Qm where n3 is 1 thru 3 and Q,.3 is •OH, -0-Qi_» where Q,_, is C,-C4 alkyl or -CH2-0, ^ 20 C.-C, alkyl, -0 optionally substituted with 1 or 2 -F, -CI, -Br, -N02, C,-C3 alkyl or -O-Qt.7 where Q,.7 is C,-C3 alkyl, -CHj-CI^CH-CO-Q!.} where Q^j is as defined above, -(CH2)1>4-N(Q,.3)(QlJi) where n« is 2 or 3 and Q,.j and QIJS are the same or 25 different and are -H and C,-C3 alkyl, Q: is -H, C,-C3 alkyl, -(CH2)aS-0-Q2.l where n5 is 2 or 3 and QM is -H, C,-C3 alkyl, -C0-Q2.2 where Q..2 is -H, C,-C3 alkyl or -, -CH2-CH(OQ;.,)-CH3 where Q:., is as defined above, -CH2CH;-(0-CH2CH2)n6-0-Q:.i where n^ is 1 or 2 and where Q:., is as defined above, -(CHj^-CO-Q;., where n7 is 1 thru 3 and Q2.3 is --,'{1 - I . :y 236801 -OH, -O-Qj^ where is Q-C, alkyl or -CHj-<£; C,-C, alkyl, - optionally substituted with 1 or 2 -F, -CI, -Br, 5 -NOj, C,-Cj or -OQ2.5 where Qjs is C,-C3 alkyl; where R2, R, and R7 are as defined above and the pharmaceutical^ acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION ^ The 5-oxygenated amino substituted pyrimidines (X), the protected 5-oxygenatged pyrimidines (VII) and 5-oxygenated pyrimidines (VIII) are prepared from known 10 compounds by methods known to those skilled in the art.
The 5-oxygenated amino substituted pyrimidines (X) include the ester substituted pyrimidines (II) R7 is -CO-R4, the ether substituted pyrimindines (III) R7 is -Rj, the sulfate substituted pyrimidines (IV) R7 is -SO:-OH.
The 5-oxygenated amino substituted pyrimidines (X) are produced by a number 15 of known methods. One method involves oxidizing substituted pyrimidines (I) with the appropriate reagent to form the desired ester substituted pyrimidines (II), the ether substituted pyrimindines (III) or the sulfate substituted pyrimidines (IV) directly; see CHART A. Alternatively, one can start with the pyrimidine (V), protect the piperazinyl hydrogen with an appropriate blocking group to form the protected piperazinyl 20 pyrimidine (VI), oxidize it to the protected 5-oxygenated pyrimidine (VII) and then remove the protecting group to give the desired 5-oxygenated pyrimidine (VIII); see CHART B. The 5-oxygenated pyrimidine (VIII) is then coupled with the desired non-amine portion (IX) to form the desired 5-oxygenated amino substituted pyrimidines (X); see CHART C. The 5-hydroxy compound (XI) can be prepared from the substituted 25 pyrimidine (I) by contacting the appropriate substituted pyrimidine (I) with hydrogen peroxide, see EXAMPLE 30.
The substituted pyrimidines (I) are known to those skilled in the art. When 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 30 preferred that Q6 is Q: is Q;0.2 is -CH,. Ql!M and Q5 taken together are -CH = CH-CO-CH = . It is preferred that Qu is c^-Q;11:l3-Qn.2, where one of Qu., and Q|,.2 is taken together with Q, to form a second bond between C, and Cn and the other of Qu., and Qn.2 is -H. It is also preferred that Q;6 is a-Qi6-5:8"Q;&4 and Q;7 is ^ '' J o j U 1 o-Qn-v'B-Qi7-», where Q14.j is -CH3i Q14mS is -H, Qi7.j is -H and Q17^ is -C( = Q:o)-(CH2)t-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q.0 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 Rt is trolox, the trolox portion contains an asymmetric center and therefore the desired 5-oxygenated amino substituted pyrimidines (X), 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 W way as the racemic form. It is to be understood that the 5-oxygenated amino substituted 10 pyrimidines (X) include both the racemic from as well as both enantiomeric forms.
When R, is trolox it is preferred that Q- is -H and Q;0, Qu and Q12 are all C, alkyl, it is also preferred that W2 is -0-, ns is 1, R:3 is -H:-H and R;6 is When R, is alkyl, see International Publication No. WO 88/08424, in particular, see the compounds of formula (II) and see International Publication No. W091/06542. When R, is alkyl 15 it is preferred that R, is (1) QrCCH?)^- where Q, is -H and n: is 2 thru 8 and (2) 'CH^CH^-C'H- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring and where t, is 1 thru 5.
It is preferred that R2 and R} are each C2 alkyl and where R2 and R} are taken O 20 with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl or 1-piperidinyl; it is more preferred that R: and R3 are taken together with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl.
When the desired 5-oxygenated amino substituted pyrimidine (X) is the ester substituted pyrimidine (II), the substituted pyrimidine (T) is contacted with the appropriate 25 diacyl peroxide in an appropriate solvent at about 0° for 1-10 hours. The reaction mixture is then permitted to warm to about 20-25' and stirred for about 10-100 hr. The mixture is then worked up by extraction from an aqueous mixture with an organic solvent such as methylene chloride. It is preferred that the extracting solvent is the same as the reaction mixture solvent. The organic extract is dried over an appropriate reagent 30 such as magnesium sulfate and concentrated. The concentrate is chromatographed to ' purify the ester substituted pyrimidine. It is preferred that R4 is -CH3 or -o; it is more J preferred that R< is -o. ^ y r: ' When the desired 5-oxygenated amino substituted pyrimidine (X) is the ether , r 236801 substituted pyrimidine (III), the substituted pyrimidine 0) is contacted with tert-butyl peroxybenzoate in an inert nonpolar aprotic solvent at about 0° to about 25". The reaction mixture is worked up similar to that as described for the ester substituted pyri idines (II) above. It is preferred that Rs is (claim 14) -CHj or -CjH,; it is more 5 preferred that Rs is -CHj.
When the desired 5-oxygenated amino substituted pyrimidine (X) is the sulfate substituted pyrimidine (IV), the substituted pyrimidine (I) is contacted with ammonium persulfate in a solvent such as methylene chloride at about 20-25° for 10-100 hr. The mixture is worked up as previously described for the ester substituted pyrimidines (II). 10 The second method of producing the 5-oxygenated amino substituted pyrimidines (X) is to first oxygenate the protected piperaziny pyrimidines (VI) to form the 5-oxygenated pyrimidine (VIII), CHART B, and then couple it with the appropriate non-amine portion, R, (IX), to form the desired 5-oxygenated amino substituted pyrimidine (X), see CHART C. Using this vthod the pyrimidine (V) first has the piperazinyl 15 hydrogen atom protected by an appropriate protecting group, R«. Suitable protecting groups include t-butoxycarbonyl [(CHj)jC-O-CO-, t-BOC], benzyl carbamate [<6-CH2-0-CO-, CBZ], CHj-CO-, 6-CO- and CHO-. The preferred protecting group is t-BOC and CBZ, more preferred is t-BOC. After the piperazinyl hydrogen is protected, the protected piperazinyl pyrimidine (VI) is oxygenated as described above where R, is a 20 drug such as a steroid, trolox or an alkyl group, rather than a blocking group, R« to produce the protected 5-oxygenated pyrimidine (VII). Next the protecting group is removed by methods known to those skilled in the art to give the 5-oxygenated pyrimidine (VIII).
The 5-oxygenated pyrimidine (VIII) is then coupled with the appropriate non-25 amine portion, R,-Z (IX) to give the desired 5-oxygenated amino substituted pyrimidine (X). Z includes -CI, -Br, -I, -CHO, -CO-C1, mesylate, tosylate and carboxylic acids activated by coupling agents such as 1,1-carbonyldiimidazole (CDI), and diethyl-pyrocarbonate (DEPC). The preferred Z depends on the particular type of R| group involved.
The 5-hydroxy pyrimidines (XI) are produced by basic hydrolysis of the 5- oxygenated amino substituted p>rimid:r.es (X), the ester substituted pyrimidines (II) and the sulfate substituted pyrimidines (IV). Alternatively the 5-hydroxy pyrimidines (XI) can be produced by reaction of the substituted pyrimidines (I) with hydrogen peroxide in solvents such as acetonitrile between about 0 and about 25® and from about 1 to about 96 hr, see EXAMPLE 30.
The oxygenated N.N-disubstituted pyrimidines (XIII) are produced from the corresponding known N.N-disubstituted pyrimidines (XII) in the same way as the 5-oxygenated amino substituted pyrimidines (X) are produced from the corresponding substituted pyrimidines (I). The N.N-disubstituted pyrimidines (XII) are known, see International Publication No. WO 91/06542. With the oxygenated N,N-disubstituted pyrimidines (XIII) it is preferred that R7 is -CO-R*. It is preferred that Q, is C,-C, alkyl, -O-CHj, -(CH^-O-Q,.,, -(CH^-CO-Q,., and -CH2-CH=CH-CO-Q1.J and Q, is -H, C,-Cj alkyl and -(CH^-O-Q;.!; it is more preferred that Q, is -CH3 and Q; is -(CH^-O-Qm where n5 is 2 and Q;., is -H.
The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted 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 (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) of the present invention are amines, they readily form salts when reacted with acids of sufficient strength to produce the corresponding salts. Pharmaceutical^ acceptable salts include salts of both inorganic and organic acids. The anions of preferred pharmaceutical^ acceptable salts include acetate, benzoate, bromide, chloride, citrate, fumarate, mesylate, maleate, phosphate, nitrate, succinate, sulfate and tartrate.
In humans, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic (thromboembolic) stroke, global ischemia, resuscitation (CPR), excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced cardiac toxicity, brain tumor (neuroprotective). Parkinsonism, Alzheimer's disease, Bells Palsy, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, «kin graft reje;:ion, hepatic necrosis (e.g. from viral hepatitis, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS, inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, 23680 1 allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcers, migrane cluster headaches, complications from brain tumors, some forms of radiation damage (for example during reaiation treatment or from accidental exposure to radiation), damage 5 after MI, pre-birth infant strangulation and infant hypoxia syndrome, such opthalmic disorders as uveitis and optic neuritis, malignant hyperthermia and ischemic bowel syndrome.
In humans, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in preventing damage 10 following cardiopulmonary resuscitation, neurological or cardiovascular surgery and from cardiac infarction, occular damage after opthalmic surgery (e.g. catratic surgery).
Further, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are useful as anticancer agents.
The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-15 disubstituted pyrimidines (XIII) are useful in irrigation solutions used in eye surgery.
Generally, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are used like the glucocorticoid pharmaceuticals for the treatment of the above human conditions as well as the animal conditions listed below. While the 5-oxygenated amino substituted pyrimidines (X) and the 20 oxygenated N.N-disubstituted pyrimidines (XIII) are useful in both humans and animals in treating many of the same conditions and preventing damage from the same problems as the glucocorticoids, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are useful in treating a number of conditions and preventing damage from conditions where the glucocorticoids are not 25 useful. The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) have no glucocorticoid activity and therefore, unlike the glucocorticoids, they can be given daily for long periods of time (used chronically) without the side effects associated uith the glucocorticoids. This is a distinct advantage.
It is to be understood that each of the 5-oxygenated amino substituted pyrimidines 30 (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) is useful to a different degree for treating each of the conditions above. However, as is known to those skilled in the art, some of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are better for treating some conditions 236 8 0 1 and 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 expermentation but only routine analysis. f**) 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 y-\ 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 10 humans to prolong survival or reduce pain and/or discomfort secondary to tumor growth and the alike. Further, the arachidonic acid LDW 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. 15 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 20 in the art can readily determine which of the particular amines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury. Additionally, the cat 48 hr motor nerve degeneration model of Hall et al, Exp. Neurol., 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular 5-oxygenated 25 amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, Alzheimer's disease etc. H. Johnson in Int. Arch. Allergy Appl. Immunol., 70, 169 (1983) has described the ascarias sensitized rhesus monkey assay for anti-asthma drugs.
The standard conditions for treatment are to give the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or 1M, with a standard dose of about 0.05 to about 10 mg/kg'day IV or about 0.5 to about 50 236801 mg/kg/day, one to four times daily by mouth.
For treating spinal trauma, mild and moderate to severe head injury, damage following cardiopulmonary resuscitation, cardiac infarction, organ damage during reperfusion after transplant, hemorrhagic, traumatic and septic shock, severe burns, 5 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 10 months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury).
In treating subarachnoid hemorrhage and subsequent cerebral vasospasm or ischemic (thromboembolic) stroke the standard conditions are used and patients at risk are pre-treated orally.
In treating excess mucous secretion and asthma, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are administered orally, IV and by inhalation in the standard dose. In treating excess mucous secretions the oral dose of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) used is from about 0.5 to about 20 50 mg/kg/day. The frequency of administration is one through 4 times daily. The oral administration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) to treat excess mucous secretions may go on for months or even years. The susceptible individuals can be pre-treated a few hours before (-■, an expected problem. The IV dose is about 0.05 to about 20 mg/kg/day. The aerosol formulation contains about 0.05 to about 5.0^ of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) and is administered or used about four times daily as needed.
In treating muscular dystrophy, Parkinsonism, Alzheimer's disease and other degenerative neurological disorders (amyotrophic lateral sclerosis; multiple sclerosis) 30 amines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are administered orally using a dose of about 0.5 to about 50 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.
In addition, utility in disorders or physiological phenomena dependent on 236801 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-administer-^ ed oral heparin or systemic heparin fragments, see Science 221, 719 (1983).
In treating adriamycin-induced cardiac toxicity, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are administered orally or IV using a dose of about 0.05 to about 50 mg/kg/day, preferrably about 0.5 to about 10 mg/kg/day. The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are preferably given 10 concomitantly with IV adriamycin or the individual is pre-treated with the 5-cx/genated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted p. i nidines (XIII).
For prophylaxis prior to and preventing damage after neurological or carciovascu-lar surgery the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-15 disubstituted pyrimidines (XIII) are used according to the standard conditions. The patient can be pretreated with a single IV or IM dose just prior to surgery or orally before and after surgery.
In treating osteo- or rheumatoid arthritis and other inflammatory diseases, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted 20 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. 25 In treating drug allergic reactions, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are given in a dose of about 0.5 to 50 mg/kg/day, administered one to four times daily orally and IV. Typical treatment would be an initial IV loading dose followed by oral dosing for a few days or more.
In treating atherosclerosis and emphysema, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily for months or years. 23680 1 r>.
In treating dermatological inflammatory conditions including psoriasis, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent 5 dosage form in a concentration of about 0.05 to about 5 % as long as needed. In treating these conditions the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) can be used with steroidal agents.
For use in eye surgery, an isoosmolar solution containing about 0.001 to about 1% of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-10 disubstituted pyrimidines (XIII) is used. In treating ophthalmic disorders the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.001 to about 1% as long as needed. 15 The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as nonsteroidal anti-inflammatory compounds (NOSAC). Stress ulcers are ulcers that develop after exposure to severe conditions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. 20 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 25 pain and lesions that may lead to bleeding. The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from about 5 to about 500 mg, two to four times a day. The treatment would be either preventive, i.e., starting before ulcers have formed in patients at risk of 30 developing such lesions, or therapeutic, i.e., once the' ulcers have formed. In patients whose clir.ical condition precludes swallowing the oral dosage forms, the amines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) would be given either through a nasogastric tube, or parenterally, i.e., IV or IM. The parenteral doses would range from 236 8 0 1 about 1 to about 100 mg and be administered one to four times a day or by IV.
In dogs, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) trauma, intervertebral diseases (slipped disk), traumatic shock, flea bite and other allergies.
In horses, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis).
In cattle, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated 10 N,N-disubstituted pyrimidines (XIII) are useful in treating acute coliform mastitis, bovine mastitis, acute allergic reaction to feed lot vaccination and shipping fever.
In pigs, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) are useful in treating porcine stress syndrome and thermal stress syndrome.
The term treatment or treating as used in this patent is used broadly and includes both treatment of an existing condition as well as preventing the same condition from occurring where such is possible as is well known to those skilled in the art. For example, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) can be used to treat existing asthma conditions and to 20 prevent future ones from occurring. For example, the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) treat spinal trauma and prevent rejection of skin grafts.
The 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) can be used with other pharmaceutical agents in treat-25 ment of the conditions listed above as is known to those skilled in the art.
The exact dosage ar.d frequency of administration depends on the particular 5-oxygenated arrino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular 30 patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N.N-disubstituted pyrimidines (XIII) in the patient's blood and/or the patients response 236 8 0 1 to the particular condition being treated.
The 5-hydroxy pyrimidines (XI) are very potent inhibitors of lipid peroxidation and therefore are useful in the treatment of the above conditions, there usefulness being limited by the very short half-life. Because of their potency they are also useful as stan-5 dards 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 (X) with the 10 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 15 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 "R," where Mi" is an integer. These variable substituents are either monovalent or bivalent, that is, they 20 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}-C(=Z,)H. Groups Rj and Rj would represent monovalent variable substituents if attached to the formula CHj-CH2-C(RJ(R,)H2. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the 25 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 Rf are bonded to the preceding carbon atom. Also, for any molecule with an established system 30 of carbon atom numbering, such as steroids, these carbon atoms are designated as C,, tthere "i" is the integer corresponding to the carbon atom number. For example, Q 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 "IV 236801 rcpresents a variable substituent (either monovalent or bivalent) at the C4 position.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbolin general represents a bond between two atoms in the chain. Thus CHj-0-CH2-CH(R^-CHj represents a 2-substituted-l-methoxypropane 5 compound. In a similar fashion, the symbol " = " represents a double bond, e.g., CH2=C(RJ-0-CHj, and the symbol" a" represents a triple bond, e.g., HCsC-CH(R,)-CH2-CH,. Carbonyl groups are represented in either one of two ways: -CO- or -C(=0)-, with the former being preferred for simplicity.
Chemical formulas of cyclic (ring) compounds or molecular fragments can be 10 represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N*=C(CH,)-CH=CC1-CH=C'H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-l -piperazinyl can be represented by -N'^CH^-15 NtCjHjKHj-CH,.
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, -CQQPQ- the two substituents may 20 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 25 (X,) which is "below" another substituent (X,) will be identified as being in the alpha (or) configuration and is identified by a broken, dashed or dotted line attachment lo the carbon atom, i.e., by the symbol"—" orThe corresponding substituent attached "above" (Xj) the other (X,) is identified as being in the beta (8) 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 R, attached to a carbon atom as -C( = RJ- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable 236801 substituents ar-R^ and B-R,*. When a bivalent variable, R,, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "or-R^rB-R^" or some variant thereof. In such a case both a-R^ and B-R„t are attached to the carbon atom to give -C(a-R1>)(8-Rvt)-. For example, when the 5 bivalent variable R«, -C( = RJ- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are a-R^B-R^i, ... a-R«.»:8-R«.io. etc, giving -C(ar-R4.,)(B-R«,2)- -C(a-R«.9)(B-R«.,q)-, etc. Likewise, for the bivalent variable RM, -C(=R,,)-, two monovalent variable substituents are a-Rn.^fl-R,,.^ For a ring substituent for which separate a and fl orientations do not exist (e.g. due to the 10 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 15 together to form a bivalent variable. For example, in the formula -C,(RJH-C2(R,)H- (C, and C2 define arbitrarily a first and second carbon atom, respectively) Rj and R, may be defined to be taken together to form (1) a second bond between C, and C2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When R, and R, are taken together to form a more complex entity, such as the group -X-Y-, 20 then the orientation of the entity is such that C, in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation "... Rj and Rj are taken together to form -CHj-CHj-O-CO- ..." means a lactone in which the carbonyl is bonded to C2. However, when designated "... RJ and R, are taken together to form -C0-0-CH2-CH2-the convention means a lactone in which the carbonyl is bonded to C,. 25 The carbon atom content of variable substituents is indicated in one of two ways.
The first method uses a prefix to the entire name of the variable such as "C,-C4", where both T and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C,-C4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric 30 forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3-(CH2)n-0-CO- where n is zero, one or two. By the second method the carbon atom content of only each w' portion of the definition is indicated separately by enclosing the "C,-C," designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C,-C,)alkoxycarbonyl has the same meaning as Q-C, alkoxycarbonyl because the "C|-Cj" refers only to the carbon atom content of the alkoxy group. Similarly while both Cj-C( alkoxyalkyl and (C,-C))alkoxy(Ci-C])alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
II. DEFINITIONS All temperatures are in degrees Centigrade.
TLC refers to thin-layer chromatography.
Saline refers to an aqueous saturated sodium chloride solution.
IR refers to infrared spectroscopy.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (5) downfield from tetramethylsilane. i and 6 both refer to phenyl (C4H5).
MS refers to mass spectrometry expressed as m/e or mass/charge unit. [M + H]* refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
Ether refers to diethyl ether.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
EXAMPLES 236 8 0! rs 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 5 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 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a- methylpregna-1,4,9( 11 )-trien-3,20-dione-21 -yl]-piperazine 5-10 benzoate (II) Benzoyl peroxide (0.950 g) is added to a solution of 16a-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-l,4,9(l l)-triene-3,20-dionemethane-sulfonate monohydrate (I, International Publication No. WO 87/01706 Example 109, 2.22 g) and dichloromethane (4.10 ml) at 0°. The resultant solution is stirred at 0° for 15 4 hours and is then allowed to warm to 20-25®. After 72 hours, aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2952, 2924, 2856, 1744, 1666, 1555, 1468, 1447, 1375, 1345, 1245, 1175, 1053,1023 and 714 cm1; NMR (300 MHz, CDClj) 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 20 5; MS (EI m/e) exact mass calcd for C4jHS6N404 (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-l-benz-opyran-2-yl)methyl]-l-piperazinyl]-5-hydroxy-2,6-di-(l-pyr-25 rolidinyl)-4-pyrimidinyl 5-benzoate (II) Benzoyl peroxide (0.257 g) is added to a solution of 2-[[4-(2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl)-l-pipe razinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-l-benzopyran-6-ol (I, International Publication No. WO 88/08424 Example 21, 0.500 g) and methylene chloride (1.10 ml) at 0°. The resultant solution is allowed to stir for 4 hours at 0° and 30 48 hours at 20-25°. Basic workup (methylene chloride, sodium dicarbonate, magnesium sulfate) and purification by flash chromatography (1/1, hexane/ethyl aceta'e)provides the title compound, IR (nujol) 3524, 2925, 2856, 1744, 1556, 1448, 1345, 1246, 1090 and 713 cm"1; NMR (300 MHz, CDC13) 8.15, 7.62, 7.49, 3.2-3.7, 2.14, 2.08, 1.98 and 1.18 236 8 0 ; MS (HI m/e) 535, 435, 379, 122 and 105, exact mass calcd for C,7HuNt04 (640.3737), found 640.3753.
The hydrochloride salt of the title compound is prepared in ether, mp 152-156'. EXAMPLE 3 l-[5-(Hydroxy)-2,6-di-(l-pyrroIidinyl)-4-pyrimidinyl]-4-(16o-5 methylpregna-l,4,9(ll)-trien-3,20-dione-21-yl]-piperazine 5-acetate (II) A solution of diacetyl peroxide (75/25 dimethyl phthalate/isobutyl isobutylrate, 0.65 ml) is added to a solution of 16ar-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-l ,4,9(1 l)-triene-3,20-dione methanesulfonate 10 monohydrate (I, 0.80 g) and methylene chloride (1.5 ml) at 0°. The solution is allowed to stir for 6 hours at 0° and 42 hours at 20-25*. Aqueous workup (methylene chloride/magnesium sulfate) and purification by flash chromatography (1/3, hexane/ethyl acetate) provides the title compound, IR (nujol) 2954, 2916, 2855, 1760, 1666, 1557, 1446, 1375, 1345, 1207, 1012 and 887 cm1; NMR (300 MHz, CDC1,)7.17, 6.28, 6.08, 15 5.51, 3.47, 3.12, 2.18, 1.40, 0.95 and 0.67 5; MS (EI m/e) 639, 373, 359, 317, 291 and 246, exact mass calcd for C4()HMN404 (682.4206), found 682.4189.
The hydrochloride salt of the title compound is prepared in ether, mp dec 215°. EXAMPLE 4 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-methylpregna-l,4,9(ll)-trien-3,20-dione-21-yl]-piperazine 5-(o-20 chlorobenzoate) (II) Di-o-chlorobenzoyl peroxide (479 mg) is added to a solution of 16ar-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-l,4,9(ll)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. The resultant solution is stirred for 4 hours at 0° and 48 hours at 20-25°. Aqueous workup 25 (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1 -0/100, hexane/ethyl acetate) provides the title compound, IR (nujol) 2937, 2856, 1665, 1557, 1448, 1377, 1345, 1239 and 750 cm1; NMR (300 MHz, CDC13) 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 5; MS (FAB m/e) 639, 260 and 139, exact mass calculated for C45H56N604C1 (779.4051), found 779.4030. 30 The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 155°.
EXAMPLE 5 1-[5-(Hydroxy)-?, 6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-( 16a- methylpregna-1,4,9( 1 l)-trien-3,20-dione-2l-yl]-piperazine 5-(p- 236 8 0 1 methoxybenzoate) (II) Di-p-methoxybenzoyl peroxide (466 mg) is added to a solution of 16a-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinylJ-pregna-l,4,9(U)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.5 ml) at 0°. 5 The solution is stirred for 4 hours at 0° and 44 hours at 20-25#. Aqueous workup (methylene chloride, magnesium sulfate), flash chromatography (3/1, ethyl ace-tate/hexane) and acidic workup (ethyl acetate, methylene chloride, magnesium sulfate) to remove unreacted peroxide gives the title compound, IR (nujol) 2954, 2926, 2856, 1736, 1666, 1606, 1555, 1446, 1253 and 1164 cm1; NMR (300 MHz, CDC1,) 8.10, 10 7.17, 6.97, 6.28, 6.07, 5.48, 3.89, 3.3-3.7,3.02, 1.39, 0.90 and 0.62 5; MS (FAB m/e) 639, 135, exact mass calcd for C^HjjNjOj (775.4547), found 775.4578.
The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 150-152".
EXAMPLE 6 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16o- methylpregna-l,4,9(ll)-trien-3,20-dione-21-yl]-piperazine 5-(p- chlorobenzoate) (II) Di-p-chlorobenzoyl peroxide (439 mg) is added to a solution of 16a-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-l,4,9(ll)-triene-3,20-dione methanesulfonate monohydrate (1, 800 mg) and methylene chloride (1.50 ml) at 0°. The 20 solution is stirred for 6 hr at 0° and 26 hr at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (2/1, ethyl acetate/hexane) provides benzoate, IR (nujol) 2953 , 2914 , 2856, 1743, 1666, 155 7, 1468, 1448, 1376, 1345, 1252, 1091, 1014 and 756 cm1; NMR (300 MHz, CDC1}) 8.09, 7.48,7.18, 6.30, 6.07, 5.49, 3.2-3.7, 3.02, 1.39,0.91 and 0.62 5; MS (TA 3 m/e) 25 639, 469 and 260, exact mass calcd for C4sH54N404Cl (779.4051), found 779.4015 The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 151-155°.
EXAMPLE 7 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a- methylpregna-1,4,9( 1 l)-trien-3,20-dione-21 -yl]-piperazine 5-30 myristoate (II) Dimyristoyl peroxide (641 mg) is added to a solution of 16a-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l -piperazi nyl]-pregna-1,4,9(1 l)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. An 236801 additional 1.0 ml of methylene chloride is added to the mixture which is stirred for 3 hr at O4 and 21 hr at 20-25®. Aqueous workup (methylene chloride, magnesium sulfate, and purification by flash chromatography (2/1, ethyl acetate/hexane) provides the title compound, IR (neat) 2927, 2855, 1763, 1719, 1667, 1557, 1447 and 1345 cm1; NMR 5 (300 MHz, CDClj) 7.17, 6.29, 6.08, 5.51, 3.47, 3.14, 1.40, 1.26, 0.95, 0.88 and 0.67 3; MS (FAB m/e) 639,541 and 260, exact mass caJcd for CjjHt^NjO, (851.6162), found 851.6129.
The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 119*.
EXAMPLE 8 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a- methylpregna-1,4,9( 11 )-trien-3,20-dione-2 l-yl]-piperazine 5-o-toluoate (II) A solution of di-o-toluoyl peroxide (381 mg) and methylene chloride (0.50 ml) is added to a solution of 16or-methyl-21-[4-[2,6-di-(l-pyrrolidiny])-4-pyrimidinyl]-l-15 piperazinyl]-pregna-l,4,9(ll)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.25 ml) at 0°. The resultant solution is stirred for 4 hr at 0° and 23 hr at 20-25®. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (2/1, ethyl acetate/hexane) gives the title compound, IR (nujol) 2954, 2914, 2856, 1716, 1664, 1625, 1569,1455, 1416, 1378, 1338, 20 1236 and 743 cnr1; NMR (300 MHz, CDC13) 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 5.
The hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 146-149°.
EXAMPLE 9 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-25 methylpregna-l,4,9(ll)-trien-3,20-dione-21-yl]-piperazine 5-sulfate (II) Water (8.5 ml) is added to a mixture of l6a-methyl-21-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-1,4,9(1 l)-triene-3,20-dione methanesulfonate monohydrate (I, 1.14 g), ammonium persulfate (623 mg) and methylene chloride (8.5 30 ml). The mixture is stirred for 3 days at 20-25®. Aqueous workup (methylene chloride, magnesium sulfate) and trituration of the residue with ethyl acetatc several times gives the title compound, mp. effr 223°; IR (nujol) 2929, 2870, 2855, 1665, 1626, 1555, 1454, 1377 and 1043 cm1; NMR (300 MHz, CDC13) 7.15-7.25, 6.2-6.35, 6.06, 5.50, 236801 1.39, 0.95 and 0.66 6; MS (FAB m/e) 721, 641 and 247.
EXAMPLE 10 4-[4-(t-Butoxycarbonyl)piperazin- l-yl]-2,6-di-( 1 -pyrrolidinyl)-pyrimidine (VI) A solution of di-tert-butyl dicarbonate (4.76 g) and methylene chloride (10.0 ml) 5 is added dropwise over 10 minutes to a solution of 4-(l-piperazinyl)-2,6-di-(l-pyrrol-idinyl)pyrimidine (V, International Publication No. WO 87/01706 PREPARATION A-22, 6.00 g), triethylamine (3.10 ml), 4-dimethylaminopyridine (20 mg) and methylene chloride (20.0 ml) at 0°. The solution is allowed to stir at 0# for 1 hr and 16 hrs at 20-25®. Basic workup (methylene chloride, sodium bicarbonate, magnesium sulfate) and 10 purification by flash chromatography (2/1, hexane/ethyl acetate) provides the carbamate as a solid. An analytical sample is prepared by recrystallization from hot ethyl acetate to provide the title compound, mp 169-169.5°; IR (nujol) 2925, 2854, 1701, 1570, 1556, 1435, 1242 and 788 cm1; NMR (300 MHz, CDC13) 4.85, 3.3-3.6, 1.8-2.0 and 1.47 5; MS (EI m/e) 402, 301 and 246.
EXAMPLE 11 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l- pyrrolidinyl)pyrimidine 5-benzoate (VII) Benzoyl peroxide (1.49 g) is added to a solution of the protected piperazinyl pyrimidine (VI, EXAMPLE 10, 2.26 g) and methylene chloride (5.60 ml) at 0°. The resultant solution is stirred for 6.5 hr at 0° and 72 hr at 20-25°. Basic workup 20 (methylene chloride, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2952, 2924, 2856, 1747, 1698, 1559, 1468, 1345, 1247, 1172 and 712 cm '; NMR (300 MHz, CDClj) 8.16, 7.64, 7.51, 3.2-3.7, 1.7-2.0 and 1.42 5; MS (m/e) 417 and 361, exact mass calcd for C3H3,N604 (522.2954), found 522.2977.
EXAMPLE 12 5-Hydroxy-4-(piperazinyl)-2,6-di-(l-pyrrolidinyl) pyrimidine 5-benzoate (VIII) Trifluoroacetic acid (2.1 ml) is added to a solution of the protected 5-oxygenated pyrimidine (VII, EXAMPLE 11, 286 mg) and methylene chloride (2.1 ml) at 0°. After stirring for 30 minutes at 0° the solution is concentrated. Basic workup (methylene 30 chloride, potassium carbonate, magnesium sulfate) provides the title compound, NMR (300 MHz, CDClj) 8.15, 7.62, 7.49, 3.3-3.7, 2.7-2.9 and 1.7-2.15.
The hydrochloride salt of the title compound is formed in ether, mp 78-82°; IR (nujol) 3396, 2955, 2921, 2856, 1734, 1711, 1631, 1573, 1452, 1414, 1326 and 719 2368 0 1 cm l; MS (m/c) 317, 246 and 105, exact mass calcd for C^HjoNjO, (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- (piperaziny!)-2,6-di-(l-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 10 then concentrated. Basic workup (chloroform, sodium bicarbonate, magnesium sulfate) and purification by flash chromatography (ethyl acetate —► 15/1 ethyl acetate/methanol) provides the title compound, IR (nujol) 2949, 2921, 2855, 1740, 1561, 1449, 1347, 1306, 1242, 1052 and 709 cm1; NMR (300 MHz, CDClj) 8.16, 7.64, 7.51, 3.3-3.7, 2.2-2.5, 2.21 and 1.6-2.0 5; MS (m/e) 366 and 331, exact mass calculated for 15 CJ4H„N602 (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- l-piperazinyl)-2,6-di-(l-pyrrolidinyl)-pyrimidine 5-benzoate (X) Sodium cyanoborohydride (0.14 g) is added to a solution of 5-hydroxy-4-(piper-20 azinyl)-2,6-di-(l-pyrrolidinyl)pyrimidine 5-benzoate (VIII, EXAMPLE 12, 0.74 g), propionaldehyde (0.16 ml) and methanol (7.0 ml). After 20 minutes acetic acid (1 drop) is added and the solution stirred overnight. Methylene chloride (2.0 ml) is added to the mixture and the resultant solution stirred for an additional 3 hrs. Concentration, basic workup (chloroform, sodium bicarbonate, 25 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 cnr'; NMR (300 MHz, CDClj) 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 5; MS (m/e) 359, 274, 260 and 247, exact mass calcd for C26H36N602 (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-l-benzopyan-2-yl)carbonyl]-l-piperazinyl]-5-hydroxy-2,6-di-(l-pyrrolidinyl)-4- 236 8 0 1 r> pyrimidine 5-benzoate (X) l.T-Carbonyldiimidazole (0.454 g) is added to a solution of 2-{[4-(2,6-di-(l-pyrToIidinyl)-4-pyrimidinyl)-l-piperazinyl]carbonyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (I, International Publication No. WO 88/08424, 0.701 g) and 5 tetrahydrofuran (7.0 ml). After stirring for 40 minutes at 20-25", a solution of 5-hydroxy-4-(piperazinyl)-2,6-di-(l-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 (1/2, ethyl acetate/hexane) provides the 10 title compound, mp. 214-217°; IR (nujol) 3404, 2926, 2856, 1745, 1625, 1556, 1451, 1345, 1244, 1089 and 714 cmNMR (300 MHz, CDClj) 8.14, 7.64, 7.51, 25, 3.3-3.6, 2.4-2.8, 2.08, 2.04 and 1.55 5; MS (m/e) 549, 385, 371 and 205, exact mass calcd for Cj;HwN4OJ (654.3529), found 654.3519.
EXAMPLE 16 5-Hydroxy-4-[4-(t-butoxycarbonyI)piperazin-l-yl]-2,6-di-(l- pyrrolidinyDpyrimidine 5-acetate (VII) A solution of diacetyl peroxide (0.81 ml, 25%) is added to a solution of 4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l- pyrroIidinyl)pyrimidine (VI, EXAMPLE 10, 0.40 g) and methylene chloride (1.0 ml) at 0°. The solution is stirred for 3.5 hours at 20 0°C and 24 hours at 20-25°. Acidic workup (ether, chloroform, cold 3% hydrochloric acid, magnesium sulfate) and purification by flash chromatography (4/1, hexane/ethyl acetate) provides the title compound, IR (nujol) 2925, 2855, 1691, 1564, 1443, 1264, 1243, 1210, 1194 and 1180cm1; NMR (300 MHz, CDC1}) 3.3-3.7,2.20, 1.75-2.05 and 1.47 5; MS (m/e) 417, 361 and 246, exact mass calcd for C^H^N^ (460.2798), found 25 460.2803.
EXAMPLE 17 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidinyl)pyrimidine 5-acetate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-30 pyrrolidinyl)pyrimidine 5-acetate (VII, EXAMPLE 16) the title compound is obtained. EXAMPLE 18 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-( 1-pyrrolidinyl)pyrimidine 5-o-chlorobenzoate (VII) Di-o-chlorobenzoyl peroxide (0.179 g) is added to a solution of 4-[4-(t-butoxy- 236 8 0 1 r> carbonyl)piperazin-l-yI]-2,6-di-(l-pyrrolidinyl)pyrimidine(VI, EXAMPLE 10,0.200g) and methylene chloride (0.50 ml) at 0®. The solution is allowed to stir at 0° for 2 hours and at 20-25° for 72 hours. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title 5 compound, IR (nujol) 2954, 2926, 1757, 1698, 1558, 1449, 1345,1246, 1167, 1026 and 747 cm '; NMR (300 MHz, CDClj) 8.10, 7.45-7.6, 7.3-7.4, 3.3-3.6, 1.7-2.0 and 1.44 5; MS (m/e) mass calcd for C^H^N^ (556.2565), found 556.2554.
EXAMPLE 19 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidiny)lpyrimidine 5-o- chlorobenzoate(VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyOpyrimidine 5-o-chlorobenzoate (VII, EXAMPLE 18) the title compound is obtained.
EXAMPLE 20 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-l-15 (pyrrolidinyl)pyrimidine 5-p-methoxybenzoate (VII) Di-p-methoxybenzoyl peroxide (188 mg) is added to a solution of 4-[4-(t-butoxy-carbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine(VI, EXAMPLE 10, 0.200g) and methylene chloride (0.50 ml) at 0°. The resultant solution is stirred for 2 hours at 0° and 72 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) 20 and purification by flash chromatography (3/1, hexane/ethyl acetate) provides the title compound, mp. 215-217°; IR (nujol) 2925, 2856, 1730, 1681, 1607, 1560, 1446, 1255 and 1164 cm1; NMR (300 MHz, CDC1,) 8.11, 6.98, 3.90, 3.1-3.6, 1.6-2.0 and 1.42 3; MS (m/e) calcd for (VWO, (552.3060), found 552.3047.
EXAMPLE 21 5-Hydroxy-4-pipera2inyl-2,6-di-(l-pyrrolidinyl)pyrimidine 5-p-25 methoxybenzoate (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]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-p-methoxybenzoate (VII, EXAMPLE 20) the title compound is obtained.
EXAMPLE 22 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l- pyrrolidinyI)pyrimidine 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-(l-pyrrolidinyl)pyrimidine(VI, EXAMPLE 10,0.200 g) 236801 and methylene chloride (0.50 ml) at 0°. The solution is stirred for 3 hours at 0° and 20 hours at 20-25*. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, mp. 217-218°; IR (nujol) 2954, 2925, 1740, 1696, 1559, 1457, 1446, 1264, 1255, 1245, 5 1180, 1169, 1091 and 757 cm'; NMR (300 MHz, CDC1,) 8.09, 7.49, 3.2-3.7, 1.7-2.0 and 1.43 5; MS (m/e) 417 and 361, exact mass calcd for C2»H37N404C1 (556.2565), found 556.2573.
EXAMPLE 23 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidinyl)pyrimidine 5-p-chlorobenzoate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyOpyrimidine 5-p-chlorobenzoate (VII, EXAMPLE 22) the title compound is obtained.
EXAMPLE 24 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-( 1-15 pyrroIidinyl)pyrimidine 5-myristoate (VII) Dimyristoyl peroxide (282 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)-piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. Additional methylene chloride (0.50 ml) is added to the mixture which is stirred for 2 hours at 0° and 20 hours at 20-25°. Aqueous 20 workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, mp 58-62°; IR (nujol) 2924, 2854, 1757, 1695, 1565, 1452, 1346, 1247, 1175 and 1162 cm"'; NMR (300 MHz, CDClj) 3.67, 3.2-3.6, 2.45, 2.31, 1.5-2.0, 1.47, 1.26 and 0.88 5; MS (m/e) 417 and 361, exact mass calcd for CjjH^oN^ (628.4676), found 628.4668.
EXAMPLE 25 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidinyl)-pyrimidine 5- myristoate (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]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-myristoate (VII, EXAMPLE 24) the title compound is ob-30 tained.
EXAMPLE 26 5-Hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-o-toluoate (VII) Di-o-toluoyl peroxide (168 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)- 236 8 0 1 pipcrazin-l-yI]-2,6-di-(l-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 200 mg) and methylene chloride (0.50 ml) at 0s. The resultant solution is stirred for 2 hours at 0° and 16 hours at 20-25°. Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) gives the title compound, mp. 147-150°; IR (nujol) 2965, 2926, 2859, 1744, 1687, 1552, 1470, 1451, 1422, 1262, 1251, 1236, 1171, 1030 and 742 cm'; NMR (300 MHz, CDC1}) 8.13, 7.48, 7.2-7.4, 3.2-3.6, 2.64, 1.7-2.0 and 1.43 5; MS (m/e) 417 and 361, exact mass calcd for C^H^A (536.3111), found 536.3102.
EXAMPLE 27 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidinyl)pyriinidine 5-o-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]-2,6-di-(l-pyrrolidinyOpyrimidine 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-(l-pyrrolidinyOpyrimidine 5-O-sulfate (VII) Water (2.0 ml) is added to a mixture of 4-[4-(t-butoxycarbonyI)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 200 mg), ammonium persulfate (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, 1563, 1456, 1414, 1327, 1265, 1168 and 986 cm"'; NMR (300 MHz, CDClj) 3.4-4.4, 1.7-2.3 and 1.46 5.
EXAMPLE 29 5-Hydroxy-4-piperazinyl-2,6-l-di-(l-pyrrolidinyl)pyrimidine5-0-sulfate (VIII) Following the general procedure of EXAMPLE 12 and making non-critical variations (including an aqueous workup) and starting with 5-hydroxy-4-[4-(t-butoxy-carbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine5-sulfate(VII,EXAMPLE28), the title compound is obtained.
EXAMPLE 30 l-[5-(Hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-methylpregna-1,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine (XI) Hydrogen peroxide (30°^, 71^1) is added to a solution of 16a-methyl-2l-[4-[2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-l-piperazinyl]-pregna-l,4,9(l l)-triene-3,20-dione methanesulfonate monohydrate (I, 100 mg) and acetonitrile (50 ml) at 0°. The mixture ? 3 6 BO 1 is stirred for 3 hr at 0# and for 3 hr at 20-25°. Methyl sulfide (0.20 ml) is added and the reaction stirred for an additional 30 min. The mixture is concentrated, triturated with ether several times and purified by rapid flash chromatography, eluting with chloroform/methanol/ammonia (375/25/5). The appropriate fractions are pooled and con-5 centrated to give the title compound., IR (nujol) 2954, 2925, 2856, 1664, 1606, 1574 and 1456 cm'1.
EXAMPLE 31 5-Hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(l-pyrroli-dinyl)pyrimidine 5-acetate (XIII) Following the general procedure of EXAMPLE 3 but starting with 4-(2-(hy-10 droxyethyl)methylamino)-2,6-di-(l-pyrrolidinyl)pyrimidine (XII, International Publication No. W091/06542), the title compound is obtained.
EXAMPLE 32 5-Hydroxy-4-(2-(hydroxyethyl)methylamino)-2,6-di-(l-pyrroli-dinyl)pyrimidine 5-benzoate (XIII) Following the general procedure of EXAMPLE 1 but starting with 4-(2-(hyd-15 roxyethyl)methylamino)-2,6-di-(l-pyrrolidinyl)pyrimidine (XII, International Publication No. w091/06542), the title compound is obtained.
IE/, o\ JAkJ992 ' 236 8 0 1 CHART A / \ M I w \= (I) (ii) (III) N, n 0 tl t» 1 | *3 ho-so2 i2 (IV) CHART B * N W \ d . n-r, I r2 23 6 8 0 1 (v) (VI) / \ I ! w \= r70 n —r» I *2 ,/R2 \ R7O S —Rj (vii) (VIII) r2 CHART r 236 8 0 1 -N ,r^ n w N r;0 n-r3 (viii) R^Z (ix) (X) 236 8 0 CHART n /R2 N w" n-r, I *2 (xi) (xii) /R2 n N / NR3 | \ / (XIII) Q2 >=< *7° n-r, I r2

Claims (27)

*5 -37- CHART E 2 3 ff 8 Q ^ I—Ql6 (steroid) (trolox) 23 6 8 0 1 -38- 7 -CLAIMS-
1. A 5-oxygenated amino substituted pyrimidine of formula (X) ,*2 N, Rl-f N W W r7o n-r3 I *2 10 (X) where R, is 0) steroid substituent of the formula 15 20 (Steroid) where (A-I) Q« is a*Qn:®-Q6.:. Qio is a-Qiai:B-QI0.j and Q7 is ar-H:fl-H, where one of Qu and is -H, and the other is -H, -F, or C,-Cj alkyl, Ql0.2 is -CH3, Ql(M and Q$ 25 taken together are -(CH,)2-C( = Qj.j)-CH = or -CH=CH-CO-CH = , where Q33 is =Oor a-H.B-O-Q^ or a-O-Q^iB-H, where Qj_, is -H, -CO-CH3, -CO-CjHs, -CO-C6Hj, -CO-O-CHj or -CO-O-CjHj; (A-II) Qs is c*"Qj.j'13-Q.5_4i Q(i is Qio's ^'Qio^B'Qiw ^d Q7 is where one of and Qw is -H. and the other taken together with one of Q}3 30 and Qu forms a second bond between C5 and C6, Q1CU is -CH3 ' Ql>3 and the other of QSi and Qu taken together is -(CH,):-C(H)(OH)-CHr; (A-I1I) Q,0 and Q5 taken together are =CH-CH = C(OQ3,-CH= where Q3 is -H, C,-Cj alkyl, -CO-H, C2-C4 alkanoyl or benzyl, Q6 is or-Qvj: B-Qs.« where one of Q6j 236 8 0 1 * -39- and is -H, and the other is -H, -F, or C,-Cj alkyl and Q, is (A-IV) Q, is ar-Qj.7:fl-Qj.i. Q4 is a-Q^fl-Qs.,, Q7 is a-H:fl-H and Q,„ is ar-QI0.7: 8-Qio-i. where one of Qj.7 and Qj.| is -H, Q1(V7 and the other of Q5.7 and Q,., taken together are -(CH2)2-C(=Qj.))-CH2, where Qj.j is as defined above, Q10., is -CHj, where 5 one of and QM is -H and the other is -H, -F, or C,-Cj alkyl; (A-V) Q4 is QuiQs-io. Q? >s Q^Qno. Qio is ot-QIs -H, and the other of Q,,.s and Q,M is -H, -OH or C,-C,2 alkoxy; (C-IV) Q, is -H or -F and Q,, is a-0-C0-Q11?:fl-H, where QM.7 is (A) C,-Cj alkyl, (B) C,-Cl2 alkoxy, (D) -NQ122Qi2j, where one of Qm and Q12J is -H, methyl or ethyl and the 20 other is -H, C,-C« alkyl or phenyl, (E) -Qj-Qi, where Qj is -O- or a valence bond, where Q, is phenyl optionally substituted with 1 through 2 -CI, -Br, C,-Cj alkoxy, -COOH, -NH2, C,-Cj alkylamino, di(C,-C3)alkylamino, where the alkyl groups are the same or different, 1-pyrrolidinyl-, 1-piperidinyl, 1-hexamethylenimino-, 1-heptamethylenimino-, C2-C4 25 acylamino and -NH-CHO or with 1 -F or -CF3; where: (D*I) Ql6 is Ql6-1 :Qi6-2 and Q17 is Qi7.j:Qi7.2, where one of Q16_, and Q16.2 is -H or -CHj and the other taken together with one of Q17., and Q17.2 forms a second bond between CI6 and C17, and the ether of Qr, and Q17.2 is -C(=Q;0)-(CH:)o-[attached to the 30 piperazine of the 2,4,6-triaminopuiniidine], where Q;0 is =0, = CH2 or Qi7.<>:-H where Q17., is -H or -CHj, where n is 0 through 6, where (D-II) Q16 is a-Qie-j.'B-Qiw where one of Qi6.j and Q1M is -H and the other is -H, -F, -CHj or -OH, and Q,7 is =CH-(CH2)p-[attached to the piperazine of the 2,4,6-tri- 236801 -40- 10 aminopyrimidine], where p is 1 or 2; (D-III) Q,t is or-Qi6.5;®*Qiw Q17 is 0f-Qi7.s:®'Qi7.«» where Qi».j is -H, -OH, -F or -CH, and Qtv« is -H, -OH, -F, or -CH}, with the proviso that at least one of Qt4., and Q1M is -H, where Q17.s is -H, -OH, -CH,, -CH2CHj, C2-C7 alkanoyloxy or -O-CO-Q,, where Q, is as defined above, and where Q,M is -C^QmHCHO.-fattached to the piperazine of the 2,4,6-triaminopyrimidine], where Q& and n are as defined above; (D-IV) the 16,17-acetonide of a compound where Ql4.5 is -OH, Q,w is -H, Q,7.5 is -OH and Q,™ is -C(=QM)-(CH2),-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Qs and n are as defined above; with the following overall provisos that: (I) one of Q16.! or Q!6.2 is taken together with one of Q17., or Q17.2 to form a second bond between C,4 and Cl7, only when Q10 is or-Qi or C,-C, alkyl, and -N(Qm)(Q13) where Q14 and Q1S are the same or different and are C.-C, alkyl; (B) Qm-0-(CH2).i- where n, is 2 or 3 and where is -H, C,-Cj alkyl, -CO-Q„ where Q^2 is -H, C,-C, alkyl or -, (C) Cb.,-CO-(CH2)rf- where n, is 1 thru 3 and Qj.j is -OH, -0-Qj-« where Qm is Ct-C4 alkyl or -CHj-^, C.-C, alkyl, -4> optionally substituted with J or 2 -F, -CI, -Br, -NOj, C,-C, alkyl -OQm where is C,-C, alkyl, (D) Q,.,-O-(CH2CH2-O).10-CH2CH2- where n,0 is 1 or 2 and where Q^ is as defined above, (E) Qj.,-CO-CH=CH-CH2- where Qj.j is as defined above, ,c- 1 OCi \ 236 8 0 -43- (F) -SOjQj.5 where Qj.5 is C,-C, alkyl; (G) 'CHj^CHjVC'H- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring and where t, is 1 thru 6; R2 and R, are the same or different and are -H, C,-C4 alkyl and where R2 and R, 5 are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-piperazinyl substituted in the 4- position with C,-C4 alkyl with the proviso that R2 and R) are not both -H; R7 is (1) -CO-R*, where R, is 10 -H, C,-C4 alkyl, optionally substituted with I, 2 or 3 C,-C4 alkyl, -OH, C,-Cj alkoxy, 15 -F, -CI, -Br, -NO,, -N(R*.00*4.2) where R*., and R^ are the same or different and are -H or C,-C« alkyl, -S-R4.J where R^j is -H or C,-C4 alkyl, O 20 -COOR44 where R^ is -H or C1
2. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 5 where R( is a steroid.
3. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where Q6 is cr-H:B-H, Q, is cr-H:B-H, Q10.2 is -CH3, Ql0., and Qj taken together are -CH =CH-CO-CH =. 10
4. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where Qn is cr-Qu.j:B-Qi,.2, where one of Qu., and Qu.2 is taken together with Q, to form a second bond between C, and C„ and the other of Q,M and Q„.2 is -H. 15
5. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 2 where Q16 is cr-Q16.j:B-Q1(W and Qn is ar-Q,73:B-Qi74, where Q1#.j is -CH3, Q1W is -H, Q,7.j is -H and Q17^ is -C(=Q2o)-(CH2)1-[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Qx is =0 and n is 1. 20
6. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R, is trolox.
7. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 6 where Q? is -H and Q,* Qn and Q12 are all C, alkyl. 25
8. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 6 where W2 is -0-, n« is 1, Rjj is -H:-H and RM is -H:-H.
9. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 30 where Rt is an alkyl group.
10. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R( is 236801 -45- 0) QrfCHj)^- where Q2 is -H and n2 is 2 thru 8 and (2) ,CH1-(CH2)u-C*H- where the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring and where t( is 1 thru 5.
11. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R7 is -COR,.
12. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 8 where R, is or -CH,.
13. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R7 is -R5.
14. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 10 where R, is -CH, or -CjH,.
15. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R7 is -S
16. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 where R} and R, are each C} alkyl and where R2 and R, are taken with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl or 1-piperidinyl.
17. A 5-oxygenated amino substituted pyrimidine of formula (X) according to claim 1 which is l-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16or-methylpregna-1,4,9(1 l)-trien-3,20-dione-21 -yl]-piperazine 5-benzoate, 4-[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl)methyl]-l-piperazinyl]-5-hydroxy-2,6-di-(l-pyrrolidinyl)-4-pypmidinyl 5-benzoate, 1 -[5-(hydroxy)-2,6-di-( 1 -pyrrolidinyl)-4-pyrimidinyl]-4-[ 16a-methylpregna-1,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine 5-acetate, l-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16amethylpregna-1,4,9( 1 l)-trien-3,20-dione-21 -yl]-piperazine 5-(o-chlorobenzoate), 2368 0 1 -46- l-[5-(hydroxy)-2,6-di-(l-pyrroIidinyl)-4-pyrimidinyl]-4-[16a-methylpregna-1,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine 5-(p-methoxybenzoate), 1 -[5-(hydroxy)-2,6-di-( 1 -pyrrolidinyl)-4-pyrimidinyll-4-[ 16a-methylpregna-1,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine 5-(p-chlorobenzoate), l-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-methylpregna-1,4,9(11 )-trien-3,20-dione-21 -yl]-piperazine 5-myristoate, l-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16or-methylpregna-1,4,9(11 )-trien-3,20-dione-21 -yl]-piperazine 5-o-toluoate, l-[5-(hydroxy)-2,6-di-(l-pyrrolidinyl)-4-pyrimidinyl]-4-[16a-methylpregna-1,4,9(1 l)-trien-3,20-dione-21-yl]-piperazine 5-sulfate, 5-hydroxy-4-(4-methyl-l-pipera2inyl)-2,6-di-(l-pyrrolidinyl)pyrimidine5-b€nzo- ate, 5-hydroxy-4-(4-propyl-1 -piperazinyl)-2,6-di-( 1 -pyrrolidinyOpyrinridinc 5-benzoate, 4-[[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyan-2-yl) carbonyl]-1-piperazinyl]-2,6-di-( 1-pyrrolidinyl)-4-pyrimidinc 5-benzoate.
18. A protected 5-oxygenated pyrimidine of formula (VII) where R2 and R, are the same or different and are -H, C,-C4 alkyl and where R2 and Rj are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-piperazinyl substituted in the 4- position with C,-C4 alkyl with the proviso that R2 and R, are not both -H; R« is t-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), CH,-CO-, £-CO- and CHO-; h ^*2 236801 -47- R7 is (1) -CO-R*, where R, is -H, C,-C4 alkyl, optionally substituted with 1, 2 or 3 C,-C4 alkyl, -OH, C,-Cj alkoxy, -F, -CI, -Br, -NO,, -NCR^JCR^j) where R*., and are the same or different and are -H or C,-C4 alkyl, -S-R^., where R*., is -H or C,-C4 alkyl, -COOR^ where R^ is -H or Cl-C4 alkyl, -(CH^-NO^OCR^-i) where is 1-6, R*., and R^ are as defined above, -(CH^-O-OW where ns is 1-6 and R*., is as defined above, -(CH^-CHrCOOH where n7 is 1-6, -CH=CH-COOH, -(CHj^-NO^OO^J where 1%, R^, and R^j are as defined above, -(CH^-O-O^,) where n5 and R*., are as defined above, -(CH1),1-CO-N(CH^-CH2-CH1-SO,-OH where n, is 1 thru 6, (2) -Rj, where Rs is C,-Cj alkyl, C4-C, cycloalkyl, (3) -SOrOH, (4) -PCKOH)2, (5) -PCKOR,.,), where R7., is C,-C4 alkyl, (6) -SO-OR7., where R7., is as defined above, (7) -[CtHuOtLu where nl2 is 1 thru 3, and pharmaceutical^ acceptable salts thereof.
19. A protected 5-oxygenated pyrimidine (VII) according to claim 18 where R« is t-BOC or CBZ.
20. A protected 5-oxygenated pyrimidine (VII) according to claim 18 where R7 is -CO- R«. 236 8 0 1 -48-
21. A protected 5-oxygenated pyrimidine (VII) according to claim 18 where R2 and R, are each C? alkyl and where R2 and R, are taken with the attached nitrogen atom to form a heterocyclic ring which is 1-pyrrolidinyl or 1-piperidinyl.
22. a protected 5-oxygenated pyrimidine (VII) according to claim 18 which is 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimiduie 5-benzoate, 5-hydroxy-4-[4-(t-butoxycarbonyi)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-acetate, 5-hydroxy-4-[4-(t-butoxycarbonyi)piperazin-l-yl]-2,6-dHl-pynolidinyl)pyrimidine 5-o-chlorobenzoate, 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pym>lidinyl)pyrimidine 5-p-methoxybenzoate, 5-hydroxy-4-[4-(t-butoxycarbon>1)piperazin-l-yl]-2,6-di-(l-pynolidinyl)pyrimidine 5-p-chlorobenzoate, 5-hydroxy-4-[4-(t-butoxycarbon>l)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-myristoate, 5-hydroxy-4-[4-(t-butoxycarbonyi)piperazin-l-yl]-2,6-di-(l-pyrrolidinyl)pyrimidine 5-o-toluoate, 5-hydroxy-4-[4-(t-butoxycarbonyl)piperazin-l-yl]-2,6-di-(l-pyTTolidinyl)pyrimidine 5-sulfate.
23. A 5-oxygenated pyrimidine of formula (VIII) n (VIII) r70 n-rj *2 ' where R2 and R, are the same or different and are -H, C,-C4 alkyl and where R2 and Rj are taken with the attached nitrogen atom to form a heterocyclic ring selected from the 23680 1 0 -49- group consisting of l-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-piperazinyl substituted in the 4- position with C,-C4 alkyl with the proviso that R2 and R} are not both -H; R7 is (1) -CO-R,, where R, is 5 -H, C,-C4 alkyl, •4> optionally substituted with 1, 2 or 3 C,-C4 alkyl, -OH, C,-Cj alkoxy, 10 -F, -CI, -Br, -NOj, -NCR^JCR^j) where R^ and R<.j are the same or different and are -H or C,-C4 alkyl, -S-R4.J where R4.J is -H or C,-C4 alkyl, 15 -COOR44 where R^ is -H or C,^ alkyl, -(CHjXtNOWO^j) where n< is 1-6, R*., and R^ are as defined above, -(CH^-O-O^,) where n, is 1-6 and R*, is as defined above, -(CHJ,7-CH2-COOH where n7 is 1-6, 20 -CH=CH-COOH, -(CH^4-N(R4.1)(R4.I) where r^, R*., and R^j are as defined above, -(CH^-O-fR*.,) where n3 and R*., are as defined above, -(CH^-CO-N(CHjJ-CHj-CHj-SCVOH where n4 is 1 thru 6, (2) -R5, where Rj is C,-C3 alkyl, C4-C7 cycloalkyl, 25 (3) -SOj-OH, (4) -PO(OH)2, (5) -PO(OR7.,)2 where R7., is C,-C4 alkyl, (6) -SO-OR7., where R7., is as defined above, (7) -[CjHjjOsJbu where n,2 is 1 thru 3, and pharmaceutical^ acceptable 30 salts thereof.
24. A 5-oxygenated pyrimidine (VIII) according to claim 23 where R2 and Rj are each Cj alkyl and where R2 and R} are taken with the attached nitrogen atom to form a hetero- 236801 -50- cyclic ring which is l-pyrrolidinyl or 1-piperidinyl.
25. A 5-oxygenated pyrimidine (VHI) according to claim 23 which is 5-hydroxy-4-(piperazinyl)-2,6-di-( 1-pyrrolidinyl)pyrimidine 5-benzoate, 5 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine 5-acetate, 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine5-o-chlorobenzoate, 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine5-p-niethoxybenzoate, 5-hydroxy-4-piperazinyl-2,6-di-( 1-pyrrolidinyl)pyrimidine 5-p-chlorobenzoate, 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine 5-myristoate, 10 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine 5-o-toluoate, 5-hydroxy-4-piperazinyl-2,6-di-(l-pyrrolidinyl)pyrimidine5-0-sulfate.
26. A 5-hydroxy pyrimidine of formula (XI) 15 20 (XI) where R2 and R} are the same or different and are -H, C,-C4 alkyl and where R2 and R3 are taken with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of l-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-25 piperazinyl substituted in the 4- position with C|-C« alkyl with the proviso that R2 and R, are not both -H, and where R, is as defined in claim 1.
27. A 5-hydroxy pyrimidine (XI) according to claim 26 which is l-[5-(hydroxy)-2,6-di-(1 -pyrrolid iny l)-4-pyri midinyl] -4-[ 16a-methylpregt\a-1,4,9(1 l)-trien-3,20-dione-21 -yl]- 30 piperazint' 10 c>2.
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CA1338012C (en) * 1987-04-27 1996-01-30 John Michael Mccall Pharmaceutically active amines
FR2644787B1 (en) * 1989-03-22 1995-02-03 Roussel Uclaf NOVEL AMINOSUBSTITUTED STEROIDS 21, THEIR PREPARATION PROCESS AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR2644789B1 (en) * 1989-03-22 1995-02-03 Roussel Uclaf NOVEL 19-NOR, 3-CETO STEROIDS COMPRISING AN AMINOSUBSTITUTED 17-CHAIN, THEIR PREPARATION METHOD AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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CA2071000A1 (en) 1991-07-27
EP0513177A1 (en) 1992-11-19
KR927003579A (en) 1992-12-18
WO1991011453A2 (en) 1991-08-08
JPH05503705A (en) 1993-06-17
WO1991011453A3 (en) 1991-11-14
AU642711B2 (en) 1993-10-28
AU7243891A (en) 1991-08-21

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