WO1991011453A2 - 2,4,6-triaminopyrimidines oxygenees en position 5 - Google Patents

2,4,6-triaminopyrimidines oxygenees en position 5 Download PDF

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Publication number
WO1991011453A2
WO1991011453A2 PCT/US1991/000017 US9100017W WO9111453A2 WO 1991011453 A2 WO1991011453 A2 WO 1991011453A2 US 9100017 W US9100017 W US 9100017W WO 9111453 A2 WO9111453 A2 WO 9111453A2
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Prior art keywords
alkyl
pyrimidine
pyrrolidinyl
hydroxy
oxygenated
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PCT/US1991/000017
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English (en)
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WO1991011453A3 (fr
Inventor
John Michael Mccall
Eric Jon Jacobsen
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The Upjohn Company
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Priority to KR1019920701769A priority Critical patent/KR927003579A/ko
Publication of WO1991011453A2 publication Critical patent/WO1991011453A2/fr
Publication of WO1991011453A3 publication Critical patent/WO1991011453A3/fr

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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

Definitions

  • the 5-oxygenated-2,4,6-triaminopyrimidines are inhibitors of lipid peroxidation arid therefore are useful pharmaceutical agents.
  • Non-oxygenated compounds similar to the oxygenated pyrimidine substituted piperazine compounds of formula (X) of the present invention are known.
  • R 1 is a steroid
  • R 1 is trolox (vitamin E), see International Publication No. WO 88/08424, published November 3, 1988 based on International Publication No. PCT/US88/0I212, in particular, see the compounds of formula (III).
  • R 1 is alkyl
  • WO 88/-08424 published November 3, 1988 based on International Publication No. PCT/US88/01212, in particular, see the compounds of formula (II) and see US Patent application Serial No. 07/427,143.
  • N,N-disubstituted pyrimidines (XIII) of the present invention are known, see US Patent application Serial No. 07/427,143.
  • Q 6 is ⁇ -Q 6-1 : ⁇ -Q 6-2
  • Q 10 is ⁇ -Q 10-1 : ⁇ -Q 10-2
  • Q 7 is ⁇ -H: ⁇ -H, where one of
  • Q 6-1 and Q 6-2 is -H, and the other is -H, -F, or C 1 -C 3 alkyl
  • Q 10-2 is -CH 3
  • Q 3-4 is -H, -CO-CH 3 , -CO-C 2 H 5 , -CO-C 6 H 5 , -CO-O- CH 3 or -CO-O-C 2 H 5 ;
  • Q 5 is ⁇ -Q 5-3 : ⁇ -Q 5-4
  • Q 6 is ⁇ -Q 6-3 : ⁇ -Q 6-4
  • Q 10 is ⁇ -Q 10-3 :
  • ⁇ -Q 10-4 and Q 7 is ⁇ ;-H: ⁇ -H, where one of Q 6-3 and Q 6-4 is -H, and the other taken together with one of Q 5-3 and Q 5-4 forms a second bond between C 5 and C 6 , Q 10-4 is -CH 3 , Q 10-3 and the other of Q 5-3 and Q 5-4 taken together is -(CH 2 ) 2 -C(H)(OH)-CH 2 -;
  • Q 5 is ⁇ - Q 5-7 : ⁇ - Q 5-8
  • Q 6 is ⁇ - Q 6-7 : ⁇ - Q 6-8
  • Q 7 is ⁇ -H: ⁇ -H
  • Q 10 is ⁇ -Q 10-7 : ⁇ -Q 10-8
  • one of Q 5-7 and Q 5-8 is -H
  • Q 10-8 is -CH 3
  • one of Q 6-7 and Q 6-8 is -H and the other is -H, -F, or C 1 -C 3 alkyl
  • Q 6 is Q 6-9 :Q 6-10
  • Q 7 is Q 7-9 :-Q 7-10
  • Q 10 is ⁇ -Q 10-9 :Q 10-10
  • one of Q 6-9 and Q 6-10 is -H and the other taken together with one of Q 7-9 and Q 7-10 forms a second bond between C 6 and C 7
  • the other of Q 7-9 and Q 7-10 is -H
  • Q 10-10 is -CH 3
  • Q 11 is ⁇ -Q 11-1 : ⁇ -Q 11-2 , where one of Q 11-1 and Q 11-2 is taken together with Q 9 to form a second bond between C 9 and C 11 and the other of Q 11-1 and Q 11-2 is -H;
  • Q 9 is -H or -F and Q 11 is ⁇ -O-CO-Q 11-7 : ⁇ -H, where Q 11-7 is
  • Q 16 is Q 16-1 :Q 16-2 and Q 17 is Q 17-1 :Q 17-2 , where one of Q 16-1 and Q 16-2 is -H or
  • Q 16 is ⁇ -Q 16-5 : ⁇ -Q 16-6 and Q 17 is ⁇ - Q 17-5 : ⁇ - Q 17-6 , where Q 16-5 is -H, -OH, -F or -CH 3 and Q 16-6 is -H, -OH, -F, or -CH 3 , with the proviso that at least one of Q 16-5 and
  • one of Q 16-1 or Q 16-2 is taken together' with one of Q 17-1 or Q 17-2 to form a second bond between C 16 and C 17 , only when Q 10 is ⁇ -Q 10-1 : ⁇ -Q 10-2 , ⁇ -Q 10-3 : ⁇ - Q 10-4 , ⁇ -
  • W 2 is -O-, -S-, -NQ 54 - where Q 54 is -H or C 1 -C 3 alkyl,
  • n 6 0, 1 or 2
  • Q 7 is -H or - C 1 -C 4 alkyl, -CO-(C 1 -C 4 alkyl), -CO-ö or -prodrug where prodrug is
  • n 21 is 1-7 and Q 51 is -COO- -NQ 51-1 Q 51-2 where Q 51-1 and Q 51-2 are the same or different and are -H or C 1 - C 3 alkyl, -N + Q 51-1 Q 51-2 Q 51- 3 halide where Q 51-1 Q 51-2 Q 51-3 are the same or different and are -H or C 1 -C 3 alkyl, and where halide is -Cl or -Br,
  • n 21 , Q 51-1 and Q 51-2 are as defined above,
  • Q 10 is -H or -CH 3 .
  • Q 11 is -H or -CH 3 .
  • Q 12 is -H or -CH 3 .
  • Q 16 is ⁇ -Q 16-1 : ⁇ -Q 16-2 where one of Q 16-1 and Q 16-2 is -H, -CH 3 , -CH 2 CH 3 or - ⁇ and the other is -Q 3 -[attached to the piperazine of the 2,4,6-triaminopyrimidine], where Q 3 is -CO-,
  • n 16 is 1 or 2
  • n 3 is 1-6
  • Q 16 is Q 16-3 :Q 16-4 where one of Q 16-3 and Q 16-4 is taken together with Q 25 to form a second bond between the carbon atoms to which Q 16 and Q 25 are attached and the other of Q 16-3 and Q 16-4 is -Q 3 -[attached to the piperazine of the 2,4,6-triamino- pyrimidine], where Q 3 is as defined above,
  • n 6 is 1, Q 25 and Q 26 are taken together to form a second bond between the carbon atoms to which Q 25 and Q 26 are attached;
  • n 2 is 1-14;
  • Q 2 is -H, -OH, -O-CO-(C 1 -C 4 alkyl), -O-CO-H, -O-CO-O-(C 1 - C 4 alkyl), (C 1 -C 4 ) alkoxycarbonyl, -O-CO-aryl where aryl is ⁇ optionally substitued with -OH,
  • Q 14 and Q 15 are the same or different and are C 1 -C 3 alkyl;
  • Q 3-4 is C 1 - C 4 alkyl or -CH 2 - ⁇
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br,
  • R 2 and R 3 are the same or different and are -H, C 1 -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 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1- piperazinyl substituted in the 4- position with C 1 -C 4 alkyl with the proviso that R 2 and
  • R 3 are not both -H
  • R 7 is (1) -CO-R 4 , where R 4 is
  • R 4-1 and R 4-2 are the same or different and are
  • R 4-3 is -H or C 1 -C 4 alkyl
  • R 4-4 is -H or C 1 -C 4 alkyl
  • n 4 is 1-6, R 4-1 and R 4-2 are as defined above,
  • R 5 is C 1 -C 3 alkyl, C 4 -C 7 cycloalkyl
  • R 3 and R 7 are as defined above and pharmaceutically acceptable salts thereof.
  • n is 2 or 3 and Q 1-1 is -H, C 1 -C 3 alkyl, -CO-Q 1-2 where Q 1-2 is -H, C 1 -C 3 alkyl or - ⁇ ,
  • n 2 is 1 or 2 and where Q 1-1 is as defined above,
  • n 3 is 1 thru 3 and Q 1-3 is
  • Q 1-4 is C 1 -C 4 alkyl or -CH 2 - ⁇
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO 2 , C 1 -C 3 or -O-Q 1-7 where O 1-7 is C 1 -C 3 alkyl,
  • -CH 2 -CH CH-CO-Q 1-3
  • Q 1-3 is as defined above
  • n 4 is 2 or 3
  • Q 1-5 and Q 1-6 are the same or different and are -H and C 1 -C 3 alkyl
  • n 5 is 2 or 3 and Q 2-1 is -H, C 1 -C 3 alkyl, -CO-Q 2-2 where Q 2-2 is -H, C 1 -C 3 alkyl or - ⁇ ,
  • n 6 is 1 or 2 and where Q 2- 1 is as defined above,
  • Q 2-4 is C 1 - C 4 alkyl or -CH 2 - ⁇ ;
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br,
  • the 5-oxygenated amino substituted pyrimidines (X), the protected 5-oxygenatged pyrimidines (VII) and 5-oxygenated pyrimidines (VIII) are prepared from known compounds by methods known to those skilled in the art.
  • the 5-oxygenated amino substituted pyrimidines include the ester substituted pyrimidines (II) R 7 is -CO-R 4 , the ether substituted pyrimindines (III) R 7 is -R 5 , the sulfate substituted pyrimidines (IV) R 7 is -SO 2 -OH.
  • the 5-oxygenated amino substituted pyrimidines (X) are produced by a number of known methods.
  • One method involves oxidizing substituted pyrimidines (I) with the appropriate reagent to form the desired ester substituted pyrimidines (II), the ether substituted pyrimindines (llI) or the sulfate substituted pyrimidines (IV) directly; see CHART A.
  • the 5-oxygenated pyrimidine (VIII) is then coupled with the desired non- amine portion (IX) to form the desired 5-oxygenated amino substituted pyrimidines (X); see CHART C.
  • the 5-hydroxy compound (XI) can be prepared from the substituted pyrimidine (I) by contacting the appropriate substituted pyrimidine (I) with hydrogen peroxide, see EXAMPLE 30.
  • R 1 is a steroid
  • Q 6 is ⁇ -H: ⁇ -H
  • Q 7 is ⁇ -H: ⁇ -H
  • Q 10-2 is -CH 3
  • Q 11 is ⁇ -Q 11 -1 : ⁇ -Q 11 -2 , where one of Q 11-1 and Q 11-2 is taken together with Q 9 to form a second bond between C 9 and C 11 and the other of Q 11 -1 and Q 11-2 is -H.
  • R 1 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).
  • the trolox portion contains an asymmetric center and therefore the desired 5-oxygenated amino substituted pyrimidines (X), produced when R 1 is trolox, will be either optically active or racemic. Both enantiomers are pharmacologically active and useful in the same manner and same way as the racemic form. It is to be understood that the 5-oxygenated amino substituted pyrimidines (X) include both the racemic from as well as both enantiomeric forms.
  • R 1 When R 1 is trolox it is preferred that Q 7 is -H and Q 10 , Q 11 and Q 12 are all C 1 alkyl, it is also preferred that W 2 is -O-, n 6 is 1, R 25 is -H:-H and R 26 is -H:-H.
  • R 1 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.
  • R 1 When R 1 is alkyl it is preferred that R 1 is
  • 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 forrii a heterocyclic ring which is 1-pyrrolidinyl or 1- piperidinyl; 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.
  • the substituted pyrimidine (I) is contacted with the appropriate diacyl peroxide in an appropriate solvent at about 0° for 1-10 hours.
  • the reaction mixture is then permitted to warm to about 20-25° and stirred for about 10-100 hr.
  • the mixture is then worked up by extraction from an aqueous mixture with an organic solvent such as methylene chloride. It is preferred that the extracting solvent is the same as the reaction mixture solvent.
  • the organic extract is dried over an appropriate reagent such as magnesium sulfate and concentrated.
  • the concentrate is chromatographed to purify the ester substituted pyrimidine. It is preferred that R 4 is -CH 3 or - ⁇ ; it is more preferred that R 4 is - ⁇ .
  • the substituted pyrimidine (I) is contacted with tert-butyl peroxybenzoate in an . inert nonpolar aprotic solvent at about 0° to about 25°.
  • the reaction mixture is worked up similar to that as described for the ester substituted pyri idines (II) above. It is preferred that R 5 is (claim 14) -CH 3 or -C 2 H 5 ; it is more preferred that R 5 is -CH 3 .
  • the substituted pyrimidine (I) is contacted with ammonium persulfate in a solvent such as methylene chloride at about 20-25° for 10-100 hr.
  • a solvent such as methylene chloride
  • 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 1 (TX), to form the desired 5-oxygenated amino substituted pyrimidine (X), see CHART C.
  • the pyrimidine (V) first has the piperazinyl hydrogen atom protected by an appropriate protecting group, R 6 .
  • Suitable protecting groups include t-butoxycarbonyl [(CH 3 ) 3 C-O-CO-, t-BOC], benzyl carbamate [ ⁇ -CH 2 -O- CO-, CBZ], CH 3 -CO-, ö-CO- and CHO-.
  • the preferred protecting group is t-BOC and CBZ, more preferred is t-BOC.
  • the protected piperazinyl pyrimidine (VI) is oxygenated as described above where R 1 is a drug such as a steroid, trolox or an alkyl group, rather than a blocking group, R 6 to produce the protected 5-oxygenated pyrimidine (VII).
  • R 1 is a drug such as a steroid, trolox or an alkyl group, rather than a blocking group
  • R 6 to produce the protected 5-oxygenated pyrimidine (VII).
  • the protecting group is removed by methods known to those skilled in the art to give the 5-oxygenated pyrimidine (VIII).
  • the 5-oxygenated pyrimidine (VIII) is then coupled with the appropriate non- amine portion, R 1 - Z (IX) to give the desired 5-oxygenated amino substituted pyrimidine (X).
  • Z includes -Cl, -Br, -I, -CHO, -CO-Cl, mesylate, tosylate and carboxylic acids activated by coupling agents such as 1,1-carbonyldiimidazole (CDI), and diethylpyrocarbonate (DEPC).
  • CDI 1,1-carbonyldiimidazole
  • DEPC diethylpyrocarbonate
  • the preferred Z depends on the particular type of R 1 group involved.
  • the 5-hydroxy pyrimidines (XI) are produced by basic hydrolysis of the 5- oxygenated amino substituted pyrimidines (X), the ester substituted pyrimidines (II) and the sulfate substituted pyrimidines (IV).
  • 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-d ⁇ substituted 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 .
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) of the present indention are useful pharmaceutical agents in treating a number of different medical conditions in humans and useful warm blooded animals.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) of the present invention are amines, they readily form salts when reacted with acids of sufficient strength to produce the corresponding salts.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the anions of preferred pharmaceutically acceptable salts include acetate, benzoate, bromide, chloride, citrate, fumarate, mesylate, maleate, phosphate, nitrate, succinate, sulfate and tartrate.
  • the 5-oxygenated amino substituted, pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) of the present invention are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic (thromboembolic) stroke, global ischemia, resuscitation (CPR), excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced cardiac toxicity, brain tumor (neuroprotective), Parkin- sonism, Alzheimer's disease, Bells Palsy, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hepatic necrosis (e.g.
  • inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcers, migrane cluster headaches, complications from brain tumors, some forms of radiation damage (for example during reaiation treatment or from accidental exposure to radiation), damage after MI, pre-birth infant strangulation and infant hypoxia syndrome, such opthalmic disorders as uveitis and optic neuritis, malignant hyperthermia and ischemic bowel syndrome.
  • inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcer
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and from cardiac infarction, occular damage after opthalmic surgery (e.g. catratic surgery).
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful as anticancer agents.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are useful in irrigation solutions used in eye surgery.
  • 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.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in both humans and animals in treating many of the same conditions and preventing damage from the same problems as the glucocorticoids
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in treating a number of conditions and preventing damage from conditions where the glucocorticoids are not useful.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines,, (XIII) have no glucocorticoid activity and therefore, unlike the glucocorticoids, they can be given daily for long periods of time (used chronically) without the side effects associated with the glucocorticoids. This is a distinct advantage.
  • each of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) is useful to a different degree for treating each of the conditions above.
  • some of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are better for treating some conditions and others are better for treating other cpnditions.
  • the fertile egg or chick embryo assay of Folkman 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.
  • Another method useful for determining which particular compounds inhibit lipid peroxidation and which are therefore useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc is described by Pryor in Methods of Enzymology 105, 293 (1984). Further, the mouse head injury assay of Hall, J.
  • Neurosurg., 62, 882 (1980) discloses an assay from which one skilled in the art can readily determine which of the particular amines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury. Additionally, the cat 48 hr motor nerve degeneration model of Hall et al, Exp.
  • Neurol., 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (Xlll ) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, Alzheimer's disease etc. H. Johnson in Int. ,Arch. Allergy Appl. Immunol., 70, 169 (1983) has described the ascarias sensitized rhesus monkey assay for anti-asthma drugs.
  • X 5-oxygenated amino substituted pyrimidines
  • Xlll oxygenated N,N-disubstituted pyrimidines
  • the standard conditions for treatment are to give the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a standard dose of about 0.05 to about 10 mg/kg/day IV or about 0.5 to about 50 mg/kg/day, one to four times daily by mouth.
  • Typical treatment will involve an initial loading dose, e.g. an IV dose of 0.01 mg to 2 mg/kg followed by maintenance dosing e.g. IV infusion for a day to a week depending on the particular condition of the patient and the particular compound used. This may be supplemented with IM or oral dosing for days, weeks or months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury).
  • 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.
  • the oral dose of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) used is from about 0.5 to about 50 mg/kg/day.
  • the frequency of administration is one through 4 times daily.
  • the oral administration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) to treat excess mucous secretions may go on for months or even years.
  • the susceptible individuals can be pre-treated a few hours before an expected problem.
  • the IV dose is about 0.05 to about 20 mg/kg/day.
  • the aerosol formulation contains about 0.05 to about 5.0% of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) and is administered or used about four times daily as needed.
  • 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.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are administered orally or IV using a dose of about 0.05 to about 50 mg/kg/day, preferrably about 0.5 to about 10 mg/kg/day.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIll) are preferably, given concomitantly with IV adriamycin or the individual is pre-treated with the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII).
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are used according to the standard conditions.
  • the patient can be pretreated with a single IV or IM dose just prior to surgery or orally before and after surgery.
  • the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally or IM in doses of about 0.5 to about 50 mg/kg/day, one to four times daily. Orally the drug- will be given over a period of months or years alone or with other steroidal or nonsteroidal antiinflammatory agents.
  • the initial dose with some severe rheumatoid patients may be given IV and followed with an IV drip for up to 24 hr or more.
  • intra-arterial administration may be employed.
  • X and the oxygenated N,N-disubstituted pyrimidines (Xlll) are given in a dose of about 0.5 to 50 mg/kg/day, administered one to four times daily orally and IV. Typical treatment would be an initial IV loading dose followed by oral dosing for a few days or more.
  • 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.
  • the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.05 to about 5 % as long as needed.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) can be used with steroidal agents.
  • an isoosmolar solution containing about 0.001 to about 1 % of the 5-oxygenated amino substitu yrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) is used.
  • the 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIll) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.001 to about 1% as long as needed.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as nonsteroidal anti-inflammatory compounds (NOSAC).
  • Stress ulcers are ulcers that develop after exposure to severe conditions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. Patients in intensive care units are particularly prone to develop stress ulcers. Stress ulcers also include lesions that can lead to upper gastrointestinal bleeding; such bleeding is likely to be prevented by these compounds.
  • NOS AC includes drugs such as ibuprofen, aspirin, indomethacin, naproxen, piroxicam and the like that are usually taken for analgesia, and that are often associated with gastrointestinal intolerance characterized by pain and lesions that may lead to bleeding.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from about 5 to about 500 mg, two to four times a day.
  • the treatment would be either preventive, i.e., starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ulcers have formed.
  • the amines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) would be given either through a nasogastric tube, or parenterally , i . e. , IV or IM.
  • the parenteral doses would range from about 1 to about 100 mg and be administered one to four times a day or by IV.
  • N,N-disubstituted pyrimidines are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis).
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) are useful in treating acute coliform mastitis, bovine mastitis, acute allergic reaction to feed lot vaccination and shipping fever.
  • 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.
  • 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.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIll) can be used to treat existing asthma conditions and to prevent future ones from occurring.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) treat spinal trauma and prevent rejection of skin grafts.
  • the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N- disubstituted pyrimidines (XIII) can be used with other pharmaceutical agents in treatment of the conditions listed above as is known to those skilled in the art.
  • the exact dosage and frequency of administration depends on the particular 5- oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 5-oxygenated amino substituted pyrimidines (X) and the oxygenated N,N-disubstituted pyrimidines (XIII) in the patient's blood and/or the patients response to the particular condition being treated.
  • the 5-hydroxy pyrimidines (XI) are very potent inhibitors of lipid peroxidation and therefore are useful in the treatment of the above conditions, there usefulness being limited by the very short half-life. Because of their potency they are also useful as standards in the malonyldialdehyde (MDA) formation assay, see Buege, and Aust, Methods in Enzymology, Fleisher and Packer Editors, Academic Press, 1978, New York, Vol Lll, p 302-310 and Kohn and Liversedge, J. Pharmacol. Txpl Ther. 82, 292 (1944).
  • MDA malonyldialdehyde
  • the 5-hydroxy pyrimidines (XI) are also useful as intermediates in the preparation of the ester substituted pyrimidines (II) by acylation of the 5-hydroxy pyrimidines (X) with the appropriate acid halide.
  • R i and R j would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(R i )(R j )H 2 .
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R i and R j are bonded to the preceding carbon atom.
  • C i represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either rnonovalent or bivalent) at the C 6 position.
  • the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N * -(CH 2 ) 2 - N(C 2 H 5 )-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.
  • the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.
  • 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.
  • a substituent (X 1 ) which is "below” another substituent (X 2 ) will be identified as being in the alpha ( ⁇ ) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "--- " or "!.
  • the corresponding substituent attached “above” (X 2 ) the other (X 1 ) is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
  • variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
  • R i is defined to consist of two monovalent variable substituents
  • the convention used to define the bivalent variable is of the form " ⁇ -R i-j : ⁇ -R i-k " or some variant thereof.
  • both ⁇ -R i-j and ⁇ -R i-k are attached to the carbon atom to give -C( ⁇ -R i-j )( ⁇ -R i-k )-.
  • the two monovalent variable substituents are ⁇ -R 6-1 : ⁇ -R 6-2 , .... ⁇ -R 6-9 : ⁇ -R 6- 10 , etc, giving -C( ⁇ -R 6-1 )( ⁇ -R 6-2 )-.
  • 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.
  • R i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
  • variable substituents 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 1 - C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -0-CO- where n is zero, one or two.
  • C 2 -C 6 alkoxyalkyl and (C 1 - C 3 )alkoxy(C 1 -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 groups to 3 carbon atoms.
  • TLC refers to thin-layer chromatography
  • Saline refers to an aqueous saturated sodium chloride solution.
  • IR refers to infrared spectroscopy.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • MS refers to mass spectrometry expressed as m/e or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • Cl refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • Ether refers to diethyl ether.
  • Pharmaceutically acceptable refers to those- properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • the ratios of solvents used are volume/volume (v/v).
  • the ratio of the solid to the solvent is weight/ volume (wt/v).
  • Benzoyl peroxide (0.950 g) is added to a solution of 16 ⁇ -methyl-21-[4-[2,6-di-(1- pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dionemethane- sulfonate monohydrate (I, International Publication No. WO 87/01706 Example 109, 2.22 g) and dichloromethane (4.10 ml) at 0°. The resultant solution is stirred at 0° for 4 hours and is then allowed to warm to 20-25°.
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 146-148°.
  • Benzoyl peroxide (0.257 g) is added to a solution of 2-[[4-(2,6-di-(1-pyrrolidinyl)- 4-pyrimidinyl)-1-piperazinyl]methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6- ol (I, International Publication No. WO 88/08424 Example 21, 0.500 g) and methylene chloride (1.10 ml) at 0°. The resultant solution is allowed to stir for 4 hours at 0° and 48 hours at 20-25°.
  • the hydrochloride salt of the title compound is prepared in ether, mp 152-156°.
  • Di-o-chlorobenzoyl peroxide (479 mg) is added to a solution of 16 ⁇ -methyl-21-[4- [2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 m g) and methylene chloride (1.50 ml) at 0°.
  • the resultant solution is stirred for 4 hours at 0° and 48 hours at 20-25°.
  • Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (1/1 - 0/100, hexane/ethyl acetate) provides the title compound, IR (nujol) 2937, 2856, 1665, 1557, 1448, 1377, 1345, 1239 and 750 cm -1 ; NMR (300 MHz, CDCl 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 ⁇ ; MS (FAB m/e) 639, 260 and 139, exact mass calculated for C 45 H 56 N 6 O 4 Cl (779.4051), found 779.4030.
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 155°.
  • Di-p-methoxybenzoyl peroxide (466 mg) is added to a solution of 16 ⁇ -methyl-21- [4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20- dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.5 ml) at 0°.
  • the solution is stirred for 4 hours at 0° and 44 hours at 20-25°.
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 150-152°.
  • Di-p-chlorobenzoyl peroxide (439 mg) is added to a solution of 16 ⁇ -methyl-21-[4- [2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. The solution is stirred for 6 hr at 0° and 26 hr at 20-25°.
  • Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (2/1, ethyl acetate/hexane) provides benzoate, IR (nujol) 2953, 2914, 2856, 1743, 1666, 1557, 1468, 1448, 1376, 1345, 1252, 1091, 1014 and 756 cm -1 ; NMR (300 MHz, CDCl 3 ) 8.09, 7.48, 7.18, 6.30, 6.07, 5.49, 3.2-3.7, 3.02, 1.39, 0.91 and 0.62 ⁇ ; MS (FAB m/e) 639, 469 and 260, exact mass calcd for C 45 H 56 N 6 O 4 Cl (779.4051), found 779.4015
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 151-155°.
  • Dimyristoyl peroxide (641 mg) is added to a solution of 16 ⁇ -methyl-21-[4-[2,6-di- (1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1 ,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.50 ml) at 0°. An additional 1.0 ml. of methylene chloride is added to the mixture which is stirred for 3 hr at 0° and 21 hr at 20-25°.
  • Aqueous workup (methylene chloride, magnesium sulfate, and purification by flash chromatography (2/1, ethyl acetate/hexane) provides the title compound, IR (neat) 2927, 2855, 1763, 1719, 1667, 1557, 1447 and 1345 cm -1 ; NMR (300 MHz, 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 ⁇ ; MS (FAB m/e) 639, 541 and 260, exact mass calcd for C 52 H 79 N 6 O 4 (851.6162), found 851.6129.
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp dec 119°.
  • a solution of di-o-toluoyl peroxide (381 mg) and methylene chloride (0.50 ml) is added to a solution of 16 ⁇ -methyl-21-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl]-1- piperazinyl]-pregna-1,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 800 mg) and methylene chloride (1.25 ml) at 0°.
  • the resultant solution is stirred for 4 hr at 0° and 23 hr at 20-25°.
  • the hydrochloride salt of the title compound is prepared in ether/ethyl acetate, mp 146-149°.
  • 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°.
  • Trifluoroacetic acid (2.1 ml) is added to a solution of the protected 5-oxygenated pyrimidine (VII, EXAMPLE 11, 286 mg) and methylene chloride (2.1 ml) at 0°. After stirring for 30 minutes at 0° the solution is concentrated. Basic workup (methylene chloride, potassium carbonate, magnesium sulfate) provides, the title compound, NMR
  • the hydrochloride salt of the title compound is formed in ether, mp 78-82°; IR (nujol) 3396, 2955, 2921, 2856, 1734, 1711, 1631 , 1573, 1452, 1414, 1326 and 719 cm -1 ; MS (m/e) 317, 246 and 105, exact mass calcd for C 23 H 30 N 6 O 2 (422.2430), found 422.2432.
  • Formaldehyde (0.30 ml, 37% aqueous) is added to a solution of 5-hydroxy-4-
  • 1,1' -Carbonyldiimidazole (0.454 g) is added to a solution of 2-[[4-(2,6-di-(1- pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]carbonyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-
  • a solution of diacetyl peroxide (0.81 ml, 25%) is added to a solution of 4-[4-(t- butoxycarbonyl)piperazin-1-yl]-2,6-di-(1- pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.40 g) and methylene chloride (1.0 ml) at 0°.
  • the solution is stirred for 3.5 hours at 0°C and 24 hours at 20-25°.
  • Di-o-chlorobenzoyl peroxide (0.179 g) is added to a solution of 4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyr rolidinyl)pyrimidine(VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. The solution is allowed to stir at 0° for 2 hours and at 20-25° for 72 hours.
  • Di-p-methoxybenzoyl peroxide (188 mg) is added to a solution of 4-[4-(t-butoxy- carbonyl)piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine(VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°.
  • the resultant solution is stirred for 2 hours at 0° and 72 hours at 20-25°.
  • Aqueous workup (methylene chloride, magnesium sulfate) and purification by flash chromatography (3/1, hexane/ethyl acetate) provides the title compound, mp.
  • Dimyristoyl peroxide (282 mg) is added to a solution of 4-[4-(t-butoxycarbonyl)- piperazin-1-yl]-2,6-di-(1-pyrrolidinyl)pyrimidine (VI, EXAMPLE 10, 0.200 g) and methylene chloride (0.50 ml) at 0°. Additional methylene chloride (0.50 ml) is added to the mixture which is stirred for 2 hours at 0° and 20 hours at 20-25°.
  • Aqueous workup (methylene chloride, magnesium sulfate) provides a foam which is triturated with ether several times to provide the title compound, IR (nujol) 2954, 2926,
  • Hydrogen peroxide (30% , 71 ⁇ l) is added to a solution of 16 ⁇ -methyl-21-[4-[2,6- di-(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]-pregna-1 ,4,9(11)-triene-3,20-dione methanesulfonate monohydrate (I, 100 mg) and acetonitrile (50 ml) at 0°. The mixture is stirred for 3 hr at 0° and for 3 hr at 20-25°. Methyl sulfide (0.20 ml) is added and the reaction stirred for an additional 30 min.

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Abstract

Pyrimidines de la formule (X) à substitution amino oxygénées en position 5, dans laquelle R1 représente (1) un substituant de stéroïde de la formule (Stéroïde), (2) un substituant de trolox de la formule (trolox), (3) un substituant d'alkyle choisi dans le groupe composé de (A)Q2-CH2n2. L'invention concerne également des pyrimidines (XIII) N,N-disubstituées oxygénées, toutes utiles dans le traitement d'un certain nombre d'états pathologiques parmi lesquels le traumatisme crânien, des lésions de la moelle épinière etc.. De plus, l'invention concerne des intermédiaires utiles parmi lesquelles les pyrimidines (VII) oxygénées en position 5 et les pyrimidines (VIII) oxygénées en position 5. En outre, l'invention concerne des pyrimidines (XI) à substitution 5-hydroxy amino.
PCT/US1991/000017 1990-01-26 1991-01-08 2,4,6-triaminopyrimidines oxygenees en position 5 WO1991011453A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025539A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux derives de piperazinil-bis(alkylamino)pyrimidine et procede pour leur preparation
WO1993025570A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux steroides a squelette pregnane, compositions pharmaceutiques les contenant et procede pour leur preparation
LT3118B (en) 1992-06-09 1994-12-27 Richter Gedeon Vegyeszet Novel, biologically active eburnamenine derivatives and a process for preparing the same
US5831104A (en) * 1993-09-10 1998-11-03 Jenapharm Gmbh Steroid intermediate products and method of their production
US5914325A (en) * 1993-11-10 1999-06-22 Jenapharm Gmbh Steroids with radical-attracting aromatic substituents, process for the production thereof and pharmaceutical compounds containing the said substances
US6172056B1 (en) 1993-11-10 2001-01-09 Jenapharm Gmbh & Co. Kg Pharmaceutical compositions and method for prophylaxis and therapy of radical-mediated cell damage

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987001706A2 (fr) * 1985-09-12 1987-03-26 The Upjohn Company Amino-steroides c20 a c26
WO1987007895A1 (fr) * 1986-06-23 1987-12-30 The Upjohn Company Aminoesters corticaux et du type androstane
WO1988008424A1 (fr) * 1987-04-27 1988-11-03 The Upjohn Company Amines pharmaceutiquement actives
EP0389368A1 (fr) * 1989-03-22 1990-09-26 Roussel Uclaf Nouveaux dérivés de la 6-(1-pipérazinyl) 2,5-pyridine diamine N,N,N',N'-substituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
EP0389370A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 19-Nor 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé,leur application comme médicaments et les compositions pharmaceutiques les contenant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987001706A2 (fr) * 1985-09-12 1987-03-26 The Upjohn Company Amino-steroides c20 a c26
WO1987007895A1 (fr) * 1986-06-23 1987-12-30 The Upjohn Company Aminoesters corticaux et du type androstane
WO1988008424A1 (fr) * 1987-04-27 1988-11-03 The Upjohn Company Amines pharmaceutiquement actives
EP0389368A1 (fr) * 1989-03-22 1990-09-26 Roussel Uclaf Nouveaux dérivés de la 6-(1-pipérazinyl) 2,5-pyridine diamine N,N,N',N'-substituée, leur procédé de préparation et les intermédiaires de ce procédé, leur application comme médicaments et les compositions pharmaceutiques les renfermant
EP0389370A1 (fr) * 1989-03-22 1990-09-26 Roussel-Uclaf Nouveaux stéroides 19-Nor 3-céto comportant une chaîne en 17 aminosubstituée, leur procédé de préparation et les intermédiaires de ce procédé,leur application comme médicaments et les compositions pharmaceutiques les contenant

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025539A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux derives de piperazinil-bis(alkylamino)pyrimidine et procede pour leur preparation
WO1993025570A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux steroides a squelette pregnane, compositions pharmaceutiques les contenant et procede pour leur preparation
LT3118B (en) 1992-06-09 1994-12-27 Richter Gedeon Vegyeszet Novel, biologically active eburnamenine derivatives and a process for preparing the same
US5547949A (en) * 1992-06-09 1996-08-20 Richter Gedeon Vegyeszeti Gyar Rt. Steroids with pregnane skeleton, pharmaceutical compositions containing them
US5831104A (en) * 1993-09-10 1998-11-03 Jenapharm Gmbh Steroid intermediate products and method of their production
US5914325A (en) * 1993-11-10 1999-06-22 Jenapharm Gmbh Steroids with radical-attracting aromatic substituents, process for the production thereof and pharmaceutical compounds containing the said substances
US6172056B1 (en) 1993-11-10 2001-01-09 Jenapharm Gmbh & Co. Kg Pharmaceutical compositions and method for prophylaxis and therapy of radical-mediated cell damage

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

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