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P99 annulated heterocycles from canrenone
Posters / European Journal of Pharmaceutical Sciences 2 (1994) 117-194 Pg"/SYNTHESIS OF 4-~-ACETYI.AMINOETHYL DERIVATNES OF 1,2,4-TRIAZOLIN E-S-THIONE M. Dobosz, A. Pachuta-Stec Departmentof Org. Chem.,,Schoolel Medidne,20-081Lublin,Poland
%he compe~a~ obtained in the reaction of the salte of amidrazones with etho~.ycarbor~,ir.mthylisothiocyanate have bean used as the startin~ materials to the synthesis of 4-~acetyl~l~noethyl derivstives of 1,2,&-triazoline-5-thione The reactions were performed according to the scheme: R ~-NH-R"
-c. - r ~
-NH,C1
NCS
m~ ÷1
ff~O00C
"
~ )rg
A
~'-N'-R" x
I"I't,.R"-
1
.~
C=5
~.
~gs Ia,b
IIs,b-IVa,b
a:
Vs,b,.-VIIa, b
VIIIa, b-,"~, b
R--c~ R'~:~ b: a:c~ a'=% R-'=%%%-,c~%-, C ~ -
4-Ethoxycarbonylmethyl-l,2,4-triazoline.5-thionederivatives were undergone to the reaction with primary amines (propylamine, benzylanine, aniline) in anhydrou[ ethanol. The obtained amides were reduced with LiAIH4 in ether medium to corresF~nnding ~mines. These products with acetic anhydride were transformed into 4-[~-acetyl~ninoethyl derivatives of 1,2,&-triazoline-5-~hione. 5~ne of these compounds were tested on the experimental animals. These products characterized by relatively low toxicity and have shown analgesic action. 'the structures of new obtain~ compounds were confirmed by elemental analysis as well as by IR spectra snd -H ~ R spectra.
Pgg ANNULATED HETEROCYCLES FROM CANRENONE K. G~iditzerl, P. Moormannt, K. Pol/o~, M. Sehaffraffl2 1 Inst.for Pharm.Chem.der TU, 38106Braunschweig,Germany, 2 K/inikurnderJohannesGutenberg.Univ.,55131Ma.;nz,Germany
143
Pgll THE RRIIT AND GENERAL SYNTHESIS OF PHOSPHONIC DERNA'nVES OF 4-OXO-4H-1. AND 2H-1-BENZOPYRANS wrrH PHARMACOLOGICAL ACTIVITY K. Kos%kal,R. Modrenkal, A. Szadowska2,J. Greczyk2, D. Orezulak2 f Instituteof Chemistry,2 Departmentof Pharmacology,fried.Univ.,9@151LCJ~,Poland
P h o s p h o r ~ t e compounds a n d c h r ~ m n e and ehromene d e r i v a t i v e s a r e o f i n ~ e r e s ~ b e c a u s e o f t h e i r b i o l o g i c a l activity. ~ Extensive study o f transformation o f title compounds and their derivatives with phosphites has been carried out. New groups o f compom~ds o f i n t e r e s t i n g p h a r m a c o l o g i c a l a n d c h e m i c a l p r o p e r ~ i e s h a v e b e e n o b t a i n e d . Transformations o f beruno-~'--l~rran and its 2 and 3 substituted derivatives (CHO, COO1) as well as 4,iu
V.I.Yudelevieh, E.V.Koma~ov, B.l.lonin, Khim.Farm.~., 1___99, 668 ( 1 9 0 5 ) ; M.Gabor, The Pharmacology of Benmopyrone De1~ivatives and Related Oompotmds, Akademiai I(iad6, Budapest, 19~8.
2.
K.Kostka, R.)lodranka, Phosphorus, Sulfur, and Silicon, 5_..7_7. 279 ( 1 9 9 1 ) ; 70, 29 ( 1 9 9 2 ) ; 8 3 , 209 ( 1 9 9 3 ) .
P100 PIRITREXIM-ANALOGU ES: UPOPHlUC INHIBITORS OF MAMMALIAN DIHYDROFOLATEREDUCTASE M. Zink, T. Dennstedt, R. Trosch0tz J r ~ for Phatmazieu. I . ~ m i e , Univ.Erl~N0mherg, 91052Erlmgen, Germany
Spironoiactone (Aldacrone~) shows aldostcrone blocking activity Searching for aides!crone antagonists without side effects several A-ring hctcrocyclic annulatcd spirolactons were synthesized starting from canrenone. Treatment ofcanrenone with methyl formiate and sodium methanolate gave 2-hydroxymcthylcne canrenone I and the 2,21-bis-hydroxymethylcne
Increasing resistances of tumor ceils against Methotrexate (MTX) by changing the uptake system afford the search for new relate.antagonists. Unlike MTX, Piritrexim (PTX) does not depend on uptake-systems to enter cancer ceils. Additionally tumor cells can become resistant to MTX via alterations in the target enzyme. Fortunatety this term of resistance can be overcome by using lipephilic antitolates. Pidtrexim is now in phase II clinical studies as a lipid-soluble substitvte Ior the antineoplasttc drug MTX.
cm'npound as by-product 1 was converted with hydroxylan'tine to the isoxazole 2 and with
OMe
CH= NH=
hydrazines to the pyrazoles 3, 4 and 5 The pyrimidine 6 was formed by Bredcrcck-(;omppcr reaction heating 1 in tbrmanfidc. Attempts to prepare the pyrimidincs 7 and 8 directly by ONe
cyclisation of I with amidines failed Therefore it was necessary to transform I at first into the
Pidtrexlm(PTX)
isobutylcnolether The compounds
1-5 were tested in receptor (androgen,
estrogen, glucocorticoid
mineralocorticoid, progesterone) binding studies. None of the compounds showed any activities
3R=H O H .., 0
~
4 R = t-butyl 5 R = pheny/
N
~
~
t
Within the scope of the synthesis of new folate-anlagonists we report on fimt variations of the structure of Pidtrexim. Two dilferent syntheses to substituted 5-benzylpyridoI2,3-d}pyrimidine-2,4.diaminaswere applied: 1. Anellation of a banzylpyridine-ring to 2,4,6-triaminopyrimidine by means of benzyl-C-3-building-blocks such as malondialdehyde-derivatives, trimethinium-salts and acrolein-ds rivatives. 2. Synthesis of a suitable substituted 2-aminonicotinoniVile and following reaction with guanidina to yield a pyddo[2,3-d]pyrimidine-2,4-diamine-dedvative.
NH2 OMe
0
I~=/i
OMe
NH=
0 NH2 @Me
N R
]
Iq
7 R = methyl $ R = phenyl
CN
lGuanldin OMe
OMe
CN
/BuOH I &
%he compe~a~ obtained in the reaction of the salte of amidrazones with etho~.ycarbor~,ir.mthylisothiocyanate have bean used as the startin~ materials to the synthesis of 4-~acetyl~l~noethyl derivstives of 1,2,&-triazoline-5-thione The reactions were performed according to the scheme: R ~-NH-R"
-c. - r ~
-NH,C1
NCS
m~ ÷1
ff~O00C
"
~ )rg
A
~'-N'-R" x
I"I't,.R"-
1
.~
C=5
~.
~gs Ia,b
IIs,b-IVa,b
a:
Vs,b,.-VIIa, b
VIIIa, b-,"~, b
R--c~ R'~:~ b: a:c~ a'=% R-'=%%%-,c~%-, C ~ -
4-Ethoxycarbonylmethyl-l,2,4-triazoline.5-thionederivatives were undergone to the reaction with primary amines (propylamine, benzylanine, aniline) in anhydrou[ ethanol. The obtained amides were reduced with LiAIH4 in ether medium to corresF~nnding ~mines. These products with acetic anhydride were transformed into 4-[~-acetyl~ninoethyl derivatives of 1,2,&-triazoline-5-~hione. 5~ne of these compounds were tested on the experimental animals. These products characterized by relatively low toxicity and have shown analgesic action. 'the structures of new obtain~ compounds were confirmed by elemental analysis as well as by IR spectra snd -H ~ R spectra.
Pgg ANNULATED HETEROCYCLES FROM CANRENONE K. G~iditzerl, P. Moormannt, K. Pol/o~, M. Sehaffraffl2 1 Inst.for Pharm.Chem.der TU, 38106Braunschweig,Germany, 2 K/inikurnderJohannesGutenberg.Univ.,55131Ma.;nz,Germany
143
Pgll THE RRIIT AND GENERAL SYNTHESIS OF PHOSPHONIC DERNA'nVES OF 4-OXO-4H-1. AND 2H-1-BENZOPYRANS wrrH PHARMACOLOGICAL ACTIVITY K. Kos%kal,R. Modrenkal, A. Szadowska2,J. Greczyk2, D. Orezulak2 f Instituteof Chemistry,2 Departmentof Pharmacology,fried.Univ.,9@151LCJ~,Poland
P h o s p h o r ~ t e compounds a n d c h r ~ m n e and ehromene d e r i v a t i v e s a r e o f i n ~ e r e s ~ b e c a u s e o f t h e i r b i o l o g i c a l activity. ~ Extensive study o f transformation o f title compounds and their derivatives with phosphites has been carried out. New groups o f compom~ds o f i n t e r e s t i n g p h a r m a c o l o g i c a l a n d c h e m i c a l p r o p e r ~ i e s h a v e b e e n o b t a i n e d . Transformations o f beruno-~'--l~rran and its 2 and 3 substituted derivatives (CHO, COO1) as well as 4,iu
V.I.Yudelevieh, E.V.Koma~ov, B.l.lonin, Khim.Farm.~., 1___99, 668 ( 1 9 0 5 ) ; M.Gabor, The Pharmacology of Benmopyrone De1~ivatives and Related Oompotmds, Akademiai I(iad6, Budapest, 19~8.
2.
K.Kostka, R.)lodranka, Phosphorus, Sulfur, and Silicon, 5_..7_7. 279 ( 1 9 9 1 ) ; 70, 29 ( 1 9 9 2 ) ; 8 3 , 209 ( 1 9 9 3 ) .
P100 PIRITREXIM-ANALOGU ES: UPOPHlUC INHIBITORS OF MAMMALIAN DIHYDROFOLATEREDUCTASE M. Zink, T. Dennstedt, R. Trosch0tz J r ~ for Phatmazieu. I . ~ m i e , Univ.Erl~N0mherg, 91052Erlmgen, Germany
Spironoiactone (Aldacrone~) shows aldostcrone blocking activity Searching for aides!crone antagonists without side effects several A-ring hctcrocyclic annulatcd spirolactons were synthesized starting from canrenone. Treatment ofcanrenone with methyl formiate and sodium methanolate gave 2-hydroxymcthylcne canrenone I and the 2,21-bis-hydroxymethylcne
Increasing resistances of tumor ceils against Methotrexate (MTX) by changing the uptake system afford the search for new relate.antagonists. Unlike MTX, Piritrexim (PTX) does not depend on uptake-systems to enter cancer ceils. Additionally tumor cells can become resistant to MTX via alterations in the target enzyme. Fortunatety this term of resistance can be overcome by using lipephilic antitolates. Pidtrexim is now in phase II clinical studies as a lipid-soluble substitvte Ior the antineoplasttc drug MTX.
cm'npound as by-product 1 was converted with hydroxylan'tine to the isoxazole 2 and with
OMe
CH= NH=
hydrazines to the pyrazoles 3, 4 and 5 The pyrimidine 6 was formed by Bredcrcck-(;omppcr reaction heating 1 in tbrmanfidc. Attempts to prepare the pyrimidincs 7 and 8 directly by ONe
cyclisation of I with amidines failed Therefore it was necessary to transform I at first into the
Pidtrexlm(PTX)
isobutylcnolether The compounds
1-5 were tested in receptor (androgen,
estrogen, glucocorticoid
mineralocorticoid, progesterone) binding studies. None of the compounds showed any activities
3R=H O H .., 0
~
4 R = t-butyl 5 R = pheny/
N
~
~
t
Within the scope of the synthesis of new folate-anlagonists we report on fimt variations of the structure of Pidtrexim. Two dilferent syntheses to substituted 5-benzylpyridoI2,3-d}pyrimidine-2,4.diaminaswere applied: 1. Anellation of a banzylpyridine-ring to 2,4,6-triaminopyrimidine by means of benzyl-C-3-building-blocks such as malondialdehyde-derivatives, trimethinium-salts and acrolein-ds rivatives. 2. Synthesis of a suitable substituted 2-aminonicotinoniVile and following reaction with guanidina to yield a pyddo[2,3-d]pyrimidine-2,4-diamine-dedvative.
NH2 OMe
0
I~=/i
OMe
NH=
0 NH2 @Me
N R
]
Iq
7 R = methyl $ R = phenyl
CN
lGuanldin OMe
OMe
CN
/BuOH I &