NO137691B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES - Google Patents
ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES Download PDFInfo
- Publication number
- NO137691B NO137691B NO2951/73A NO295173A NO137691B NO 137691 B NO137691 B NO 137691B NO 2951/73 A NO2951/73 A NO 2951/73A NO 295173 A NO295173 A NO 295173A NO 137691 B NO137691 B NO 137691B
- Authority
- NO
- Norway
- Prior art keywords
- pyrimethamine
- ethyl
- chlorophenyl
- pyrimidine
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 13
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title abstract description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title 1
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 3
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 dipropylacetyl Chemical group 0.000 claims description 15
- 239000012458 free base Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 claims description 2
- 229960000611 pyrimethamine Drugs 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- RGEWLKLRTWXPDT-UHFFFAOYSA-N n-[5-(4-chlorophenyl)-6-ethyl-2-(2-propylpentanoylamino)pyrimidin-4-yl]-2-propylpentanamide Chemical compound CCCC(CCC)C(=O)NC1=NC(NC(=O)C(CCC)CCC)=NC(CC)=C1C1=CC=C(Cl)C=C1 RGEWLKLRTWXPDT-UHFFFAOYSA-N 0.000 description 22
- 238000012360 testing method Methods 0.000 description 21
- 230000000694 effects Effects 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 11
- 244000045947 parasite Species 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 238000007912 intraperitoneal administration Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000011081 inoculation Methods 0.000 description 8
- 231100000682 maximum tolerated dose Toxicity 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- GCLIEWSEPWRKFR-UHFFFAOYSA-N n-[4-amino-5-(4-chlorophenyl)-6-ethylpyrimidin-2-yl]-2-propylpentanamide Chemical compound CCC1=NC(NC(=O)C(CCC)CCC)=NC(N)=C1C1=CC=C(Cl)C=C1 GCLIEWSEPWRKFR-UHFFFAOYSA-N 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 241000287828 Gallus gallus Species 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 235000013330 chicken meat Nutrition 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 231100000517 death Toxicity 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000002354 daily effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 3
- GYIUDLLQLVWKPP-UHFFFAOYSA-N 2-propylpentanoyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC(=O)C(CCC)CCC GYIUDLLQLVWKPP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 108010058846 Ovalbumin Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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- FOTZBGCVSMSVBW-UHFFFAOYSA-N 3-ethylheptanoyl 3-ethylheptanoate Chemical compound C(C)C(CC(=O)OC(=O)CC(CCCC)CC)CCCC FOTZBGCVSMSVBW-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
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- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 238000001228 spectrum Methods 0.000 description 2
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
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- AMVGQNFLBRUCGF-UHFFFAOYSA-N (7-amino-2-methylphenoxazin-3-ylidene)-dimethylazanium;chloride Chemical compound [Cl-].C1=C(N)C=C2OC3=CC(=[N+](C)C)C(C)=CC3=NC2=C1 AMVGQNFLBRUCGF-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- PITHYUDHKJKJNQ-UHFFFAOYSA-N 2-propylpentanoyl chloride Chemical compound CCCC(C(Cl)=O)CCC PITHYUDHKJKJNQ-UHFFFAOYSA-N 0.000 description 1
- MCLMZMISZCYBBG-UHFFFAOYSA-N 3-ethylheptanoic acid Chemical compound CCCCC(CC)CC(O)=O MCLMZMISZCYBBG-UHFFFAOYSA-N 0.000 description 1
- YEAICDDXRUOCKJ-UHFFFAOYSA-N 4-amino-n-pyrazin-2-ylbenzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=CC=N1 YEAICDDXRUOCKJ-UHFFFAOYSA-N 0.000 description 1
- JZCLIFPQURTYFA-UHFFFAOYSA-N 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine;hydrochloride Chemical compound Cl.CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 JZCLIFPQURTYFA-UHFFFAOYSA-N 0.000 description 1
- NALREUIWICQLPS-UHFFFAOYSA-N 7-imino-n,n-dimethylphenothiazin-3-amine;hydrochloride Chemical compound [Cl-].C1=C(N)C=C2SC3=CC(=[N+](C)C)C=CC3=NC2=C1 NALREUIWICQLPS-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
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- 241000223997 Toxoplasma gondii Species 0.000 description 1
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- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000884 anti-protozoa Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
- C07D239/48—Two nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Analogifremgangsmåte for fremstilling av nye terapeutisk aktive pyrimidinderivater.Analogous process for the preparation of new therapeutically active pyrimidine derivatives.
Description
Oppfinnelsen angår analogifremgangsmåte for fremstilling av farmakologisk aktive pyrimidinderivater med den generelle formel I: The invention relates to analogue methods for the production of pharmacologically active pyrimidine derivatives with the general formula I:
og de farmasøytisk akseptable enkle (mono-) og doble (di-) syre- and the pharmaceutically acceptable single (mono-) and double (di-) acid-
addisjonssalter av disse derivater, hvor addition salts of these derivatives, where
R betyr en dipropylacetyl-, tripropylacetvl- eller R means a dipropylacetyl-, tripropylacetvl- or
2-etyl-2-butylacetylgruppe, og 2-ethyl-2-butylacetyl group, and
R-^ er hydrogen eller er identisk med R, R-^ is hydrogen or is identical to R,
karakterisert ved at 2,4-diamino-5-p-klorfenyl-6-etyl-pyrimidin med formelen: characterized in that 2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine with the formula:
oppvarmes med den passende mengde av en forbindelse med den generelle formel hvor R5 betyr en 3-heptyl-, 4-heptyl- eller 4-(4-propyl)-heptylgruppe og R& betyr et kloratom eller is heated with the appropriate amount of a compound of the general formula where R5 means a 3-heptyl-, 4-heptyl- or 4-(4-propyl)-heptyl group and R& means a chlorine atom or
hvor Rc- har den -samme betydning som i formel II, enten i fravær av et løsningsmiddel eller i nærvær av et løsningsmiddel som f.eks. pyridin og om nødvendig, i nærvær av en sterk tertiær alifatisk base som f.eks. trimetylamin eller trietylamin, for å danne det ønskede mono- eller disubstituerte derivat med formel I where Rc- has the -same meaning as in formula II, either in the absence of a solvent or in the presence of a solvent such as e.g. pyridine and, if necessary, in the presence of a strong tertiary aliphatic base such as e.g. trimethylamine or triethylamine, to form the desired mono- or disubstituted derivative of formula I
i fri baseform, som eventuelt kan omsettes med en støkiometrisk mengde av en organisk eller uorganisk syre for å danne et farmasøytisk akseptabelt enkelt eller dobbelt syreaddisjonssalt. in free base form, which may optionally be reacted with a stoichiometric amount of an organic or inorganic acid to form a pharmaceutically acceptable single or double acid addition salt.
Mengden av forbindelse II som brukes vil være slik at The amount of compound II used will be such that
1 eller 2 molekvivalenter av den reagerer med 1 molekvivalent av 2,4-diamino-5-p-klorfenyl-6-etyl-pyrimidin (som har det godkjente navnet (B.P.) pyrimetamin). Under reaksjonen dannes det en syre som kan være uorganisk (når forbindelsen med formel II er et acylklorid) eller organisk (når forbindelse med formel II er et anhydrid). Denne syre kan nøytraliseres i reaksjonsmediet ved et overskudd pyrimetamin eller ved en tertiær alifatisk base som f.eks. 1 or 2 molar equivalents of it react with 1 molar equivalent of 2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine (which has the approved name (B.P.) pyrimethamine). During the reaction, an acid is formed which can be inorganic (when the compound of formula II is an acyl chloride) or organic (when the compound of formula II is an anhydride). This acid can be neutralized in the reaction medium by an excess of pyrimethamine or by a tertiary aliphatic base such as e.g.
trimetylamin eller trietylamin. trimethylamine or triethylamine.
Blant forbindelsene som representeres ved formel II er Among the compounds represented by formula II are
alle kloridene kjente såvel som de anhydrider hvor R,- betyr 3- heptyl og 4-heptyl. Det anhydrid hvor R5 betyr all the chlorides known as well as the anhydrides where R,- means 3-heptyl and 4-heptyl. The anhydride where R 5 means
4- (4-propyl)-heptyl kan fremstilles ved metoden beskrevet i Heiv. Chim. Acta 45 (1962), 717-737. 4-(4-propyl)-heptyl can be prepared by the method described in Heiv. Chim. Acta 45 (1962), 717-737.
I tilfelle av diacylering av pyrimetamin med et dipropyl-acetylradikal, så viser det oppnådde 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etylpyrimidin et allotropifenomen. Det har blitt observert at virkningen av dipropyleddiksyreanhydrid på pyrimetaminbasen skaffer en forbindelse som smelter ved 89°c når den krystalliseres fra pentan. Denne første allotropi-form vil heretter refereres til som "form W". Eksistensen av andre allotrope former av 2,4-bis-dipropyl-acetamido-5-p-klorfenyl-6-etyl-pyrimidin har blitt demonstrert ved hjelp av forskjellige forsøk som ga de følgende resultater: a) "form W" (sm.p. 89°c) gir når den omkrystalliseres fra isooktan, et produkt som-er kjemisk identisk med "form W", men som har et smeltepunkt på 113°C. Denne siste varietet refereres det heretter til som "form X". In the case of diacylation of pyrimethamine with a dipropylacetyl radical, the obtained 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethylpyrimidine shows an allotropy phenomenon. It has been observed that the action of dipropylacetic anhydride on the pyrimethamine base affords a compound melting at 89°C when crystallized from pentane. This first allotropy form will hereafter be referred to as "form W". The existence of other allotropic forms of 2,4-bis-dipropyl-acetamido-5-p-chlorophenyl-6-ethyl-pyrimidine has been demonstrated by various experiments which gave the following results: a) "form W" (cf. p. 89°c) gives, when recrystallized from isooctane, a product which is chemically identical to "form W", but which has a melting point of 113°C. This last variety is hereafter referred to as "form X".
b) "form W" gir "form X" når den omkrystalliseres fra heptan. b) "form W" gives "form X" when recrystallized from heptane.
c) "form W" gir "form W" når den omkrystalliseres fra pentan eller c) "form W" gives "form W" when recrystallized from pentane or
heksan. hexane.
d) "form X" gir "form W" når den omkrystalliseres fra heksan. d) "form X" gives "form W" when recrystallized from hexane.
e) "form W" eller "form X" gir en ny allotrop form som smelter ved 121°C når de progressivt oppvarmes til 140°C inntil det oppnås total smelting, og så avkjøles til 100°C og holdes i 2 timer ved denne temperatur. Denne form refereres heretter til som "form Y". f) "form X" gir "form Y" med smeltepunkt 121°c, når den oppløses til metning i White spirit, etter langsom avkjøling. g) "form W" (smp. 89°C) og "form X" (smp. 113°C) gir hver en amorf form med et glassaktig utseende med smeltepunkt 59-60 C, når de e) "form W" or "form X" gives a new allotropic form which melts at 121°C when progressively heated to 140°C until total melting is achieved, and then cooled to 100°C and held for 2 hours at this temperature. This form is referred to hereafter as "form Y". f) "form X" gives "form Y" of melting point 121°c, when dissolved to saturation in white spirit, after slow cooling. g) "form W" (m.p. 89°C) and "form X" (m.p. 113°C) each give an amorphous form with a glassy appearance with a melting point of 59-60 C, when they
smeltes ved 140°C og avkjøles raskt. Denne amorfe form vil heretter bli referert til som "form Z". melts at 140°C and cools rapidly. This amorphous form will hereafter be referred to as "form Z".
h) "form Y" (smp. 121°C) og "form Z" (smp. 59-60°C) gir "form W" h) "form Y" (m.p. 121°C) and "form Z" (m.p. 59-60°C) give "form W"
og "form X" respektive når de omkrystalliseres fra heksan eller and "form X" respectively when recrystallized from hexane or
isooktan. isooctane.
Alle disse varieteter er identiske i kjemisk sammensetning. Deres spektra når de bestemmes i oppløsninger tilsvarer hverandre nøyaktig, men når de bestemmes på forbindelsene i fast form er det forskj eller. All these varieties are identical in chemical composition. Their spectra when determined in solutions correspond exactly to each other, but when determined on the compounds in solid form there are differences.
Studium av disse forskjellige allotrope former under lagring har åpenbart det følgende: a) En langsom omdannelse av "form W" til "form X" som viser at "form W" ikke er stabil. b) Den perfekte stabiliteten av "form X" når det gjelder utseende, farve, lukt, kjemiske kontroller (smeltepunkt, spektramålinger). Study of these different allotropic forms during storage has revealed the following: a) A slow conversion of "form W" to "form X" showing that "form W" is not stable. b) The perfect stability of "form X" in terms of appearance, color, smell, chemical controls (melting point, spectra measurements).
c) Den perfekte stabiliteten for "form Y". c) The perfect stability for "shape Y".
De andre diacylerte derivater av pyrimetamin synes ikke å The other diacylated derivatives of pyrimethamine do not appear to
oppvise allotropifenomener. exhibit allotropy phenomena.
Forbindelsene fremstilt ifølge oppfinnelsen har blitt funnet å ha verdifulle farmakologiske egenskaper.. Spesielt har forbindelsene fremstilt ifølge oppfinnelsen blitt funnet å besitte en antiprotozoaktivitet, som antas å gjøre dem nyttige ved behandling av forskjellige sykdommer som f.eks. malaria, så vel som toksoplasmicide og antiallergene egenskaper. The compounds prepared according to the invention have been found to have valuable pharmacological properties. In particular, the compounds prepared according to the invention have been found to possess an antiprotozoal activity, which is believed to make them useful in the treatment of various diseases such as malaria, as well as toxoplasmicidal and antiallergenic properties.
Når det gjelder behandling av malaria, både preventiv og helbredende, er pyrimetamin det mest suksessrike og utbredt brukte middel som er kjent til dags dato. i de fleste malaria-infiserte regioner har imidlertid bruken av pyrimetamin blitt oppgitt på grunn av de uønskede bivirkninger som forårsakes av denne substans når den administreres i terapeutiske doser over et lengere tidsrom. Disse bivirkninger kan være hematologiske av karakter og f.eks. lede til slike virkninger som leukopeni, eller ta form av fordøyelses-besvær og til og med skade på nyrene. In the treatment of malaria, both preventive and curative, pyrimethamine is the most successful and widely used agent known to date. however, in most malaria-infected regions, the use of pyrimethamine has been abandoned due to the undesirable side effects caused by this substance when administered in therapeutic doses over a longer period of time. These side effects can be haematological in nature and e.g. lead to such effects as leukopenia, or take the form of indigestion and even damage to the kidneys.
Resultatene av de forskjellige tester som utførtes méd forbindelsene fremstilt ifølge oppfinnelsen indikerer at de sistnevnte ikke har disse ulempene, mens de på samme tid utøver en terapeutisk effekt som er minst ekvivalent med pyrimetamins. The results of the various tests carried out with the compounds produced according to the invention indicate that the latter do not have these disadvantages, while at the same time they exert a therapeutic effect which is at least equivalent to pyrimethamines.
Tester på akutt toksisitet ble utført på forbindelser fremstilt ifølge oppfinnelsen ifølge teknikken til Litchfield og Wilcoxon (J. Pharmacol., 1949, 95, 99). Testene ble utført på mus av den sveitsiske stammen som veide mellom 20 og 30 g. Dyrene ble delt i grupper på 50 og den undersøkte forbindelse ble administrert enten intraperitonealt eller oral, til suksessive grupper på en slik måte at hver gruppe fikk en høyere dose enn den foregående gruppe. Formålet med testen var å fastslå LD^0 eller minimums-dosen for å drepe 50% av forsøksdyrene. Den valgte referenssubstans var pyrimetamin. Acute toxicity tests were performed on compounds prepared according to the invention according to the technique of Litchfield and Wilcoxon (J. Pharmacol., 1949, 95, 99). The tests were carried out on mice of the Swiss strain weighing between 20 and 30 g. The animals were divided into groups of 50 and the test compound was administered either intraperitoneally or orally, to successive groups in such a way that each group received a higher dose than the previous group. The purpose of the test was to determine the LD^0 or minimum dose to kill 50% of the test animals. The chosen reference substance was pyrimethamine.
Det ble imidlertid funnet at mens LD,.,- kunne bestemmes for du However, it was found that while LD,.,- could be determined for du
pyrimetamin, manglet forbindelsene fremstilt ifølge oppfinnelsen toksisitet slik at det ikke i det hele tatt kunne fastslås noen letal dose. For forbindelsene fremstilt ifølge oppfinnelsen var den begrensende faktor den mengde av produktet som dyrene var fysisk istand til å absorbere enten intraperitonealt eller oralt. Denne sistnevnte dose som ikke drepte noen av dyrene, blir heretter referert til som den maksimalt tolererte dose (MTD), dvs. den maksimale mengde av produktet som dyrene var fysisk istand til å motta. Denne dose kan også refereres til som LDQ, dvs. den høyeste dose dyrene kan motta uten at det opptrer noen døde. pyrimethamine, the compounds prepared according to the invention lacked toxicity so that no lethal dose could be determined at all. For the compounds prepared according to the invention, the limiting factor was the amount of the product which the animals were physically able to absorb either intraperitoneally or orally. This latter dose, which did not kill any of the animals, is hereafter referred to as the maximum tolerated dose (MTD), i.e. the maximum amount of the product that the animals were physically able to receive. This dose can also be referred to as the LDQ, i.e. the highest dose the animals can receive without any deaths occurring.
I nærværende søknad vil imidlertid forkortelsen MTD blir brukt. In the present application, however, the abbreviation MTD will be used.
Under disse omstendigheter ble de følgende resultater registrert: For pyrimetamin var LD^Q ved intraperitoneal administrasjon gjennomsnitlig 74 mg/kg og ved oral administrasjon 128 mg/kg. Under these circumstances, the following results were recorded: For pyrimethamine, the LD^Q for intraperitoneal administration was on average 74 mg/kg and for oral administration 128 mg/kg.
Med de to foretrukne forbindelser fremstilt ifølge oppfinnelsen, nemlig: 2-dipropylacetamido-4-amino-5-p-klorfenyl-6-etyl-pyrimidin (heretter referert til som B 8270) og With the two preferred compounds produced according to the invention, namely: 2-dipropylacetamido-4-amino-5-p-chlorophenyl-6-ethyl-pyrimidine (hereinafter referred to as B 8270) and
2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine
(heretter referert til som B 8370) (hereafter referred to as B 8370)
ble det funnet at MTD ved intraperitoneal administrasjon for både B 8270 og B 8370 oversteg 1500 mgAg mens MTD ved oral administrasjon for disse to forbindelser oversteg 3000 mg/kg. it was found that the MTD by intraperitoneal administration for both B 8270 and B 8370 exceeded 1500 mgAg, while the MTD by oral administration for these two compounds exceeded 3000 mg/kg.
Samme MTD ble registrert for både B 8270 og B 8370 i toksisitetstester på kyllinger ved intraperitoneal administrasjon, mens en intraperitoneal dose på 75 mg/kg pyrimetamin drepte 60% The same MTD was recorded for both B 8270 and B 8370 in toxicity tests on chickens by intraperitoneal administration, while an intraperitoneal dose of 75 mg/kg pyrimethamine killed 60%
av kyllingene. of the chickens.
Når det gjelder antiprotozo-aktivitet ble tester først utført på mus for å bestemme aktiviteten mot plasmodium Berghei. Dyrene ble kunstig infisert ved intraperitoneal administrasjon As regards antiprotozoal activity, tests were first carried out on mice to determine the activity against Plasmodium Berghei. The animals were artificially infected by intraperitoneal administration
ved hjelp av en suspensjon i en isotonisk oppløsning av natriumklorid av 5 x 10 parasittbærende røde celler tatt fra dyr som var infisert 5 dager tidligere. by means of a suspension in an isotonic solution of sodium chloride of 5 x 10 parasite-bearing red cells taken from animals infected 5 days previously.
Sykdommen som var frembragt slik utviklet seg som følger når den ikke ble behandlet: The disease thus produced developed as follows when left untreated:
1. Prehematologisk fase 1. Prehematological phase
Parasitter viste seg i blodet 48 timer etter inokulering med den parasitt-bærende suspensjon av røde celler. Under denne prehematologiske fase øket ribonukleaseaktiviteten for plasma og parasittene virket selektivt på retikulocytene som så ble omdannet til acidofile erytrocyter. Det ble derfor et fall i antall retikulocyter sammenlignet med det opprinnelige nivå. Parasites appeared in the blood 48 hours after inoculation with the parasite-bearing suspension of red cells. During this prehaematological phase, the ribonuclease activity of the plasma increased and the parasites acted selectively on the reticulocytes, which were then converted into acidophilic erythrocytes. There was therefore a drop in the number of reticulocytes compared to the original level.
2. Hematologisk fase 2. Hematological phase
Under denne fase kunne parasittene lett oppdages ved utgnidninger på en glassplate farvet med "May Grunwald Giemsa Stain" During this phase, the parasites could be easily detected by smears on a glass plate stained with "May Grunwald Giemsa Stain"
(en oppløsning av metylenblått-eosinat i metylalkohol) eller brilliant kresyl-purpur (dibenzoparaoksazin) eller en blanding derav. (a solution of methylene blue eosinate in methyl alcohol) or brilliant cresyl purple (dibenzoparaoxazine) or a mixture thereof.
Parasittantallet i blodet øket inntil dyrene døde. På dette punkt ble det observert at anemien var gått så langt som til et erytrocyt-tall på 1,5 x 10^. The number of parasites in the blood increased until the animals died. At this point it was observed that the anemia had progressed to an erythrocyte count of 1.5 x 10^.
3. Fase for full utvikling av sykdommen 3. Phase for full development of the disease
Denne fase begynte på den sjette dag etter inokulering. This phase began on the sixth day after inoculation.
Det var økende tap av vekt, fulgt av apati, mens hårene sto rett opp og ørene og øynene ble misfarvet. There was increasing loss of weight, followed by apathy, while the hair stood on end and the ears and eyes became discolored.
4. Sluttfase 4. Final phase
Denne fase begynte på den åttende dag etter inokulering. Musene var fullstendig misfarvet, hodene hang ned mellom forlabbene mens bakbena sto ut. De avslo all mat og drikke og deres bak-parter var paralysert. Åndenød oppsto sammen med krampetrekninger og ekstremt lav temperatur (hypotermi) fulgt av døden. This phase began on the eighth day after inoculation. The mice were completely discolored, their heads hung down between their forepaws while their hind legs stuck out. They refused all food and drink and their hindquarters were paralyzed. Shortness of breath occurred along with convulsions and extremely low temperature (hypothermia) followed by death.
Ved slutten av 15 dager var alle dyrene døde. At the end of 15 days, all the animals were dead.
I den utførte test ble de to foretrukne forbindelser fremstilt ifølge oppfinnelsen sammenlignet med pyrimetamin. In the test carried out, the two preferred compounds prepared according to the invention were compared with pyrimethamine.
De følgende forsøksbetingelser ble fulgt: The following experimental conditions were followed:
Musene ble delt i grupper på 10. The mice were divided into groups of 10.
Kontrolldyrene ble inokulert med den parasittbærende suspensjon, men fikk ingen behandling. The control animals were inoculated with the parasite-carrying suspension but received no treatment.
Ved preventiv behandling ble forsøksforbindelsen gitt In preventive treatment, the test compound was given
24 timer etter inokulering. 24 hours after inoculation.
Ved helbredende behandling ble forsøksforbindelsen gitt In curative treatment, the test compound was given
4 dager etter inokulering. 4 days after inoculation.
Utviklingen av sykdommen ble studert ved hjelp av farvede utgnidninger utført dagen etter inokuleringen og så i gjennomsnitt hver annen dag i en uke og deretter en gang i uken i minst en måned. The development of the disease was studied using stained smears performed the day after inoculation and then on average every other day for a week and then once a week for at least a month.
Forsøksforbindelsene ble administrert i 6 påfølgende dager. The test compounds were administered for 6 consecutive days.
Musene ble ansett å være fri for parasittene når 50 etter-følgende mikroskopiske undersøkelser av utgnidningene hadde gitt negative resultater og når inokulering med deres blod ikke overførte sykdommen til nye mus. The mice were considered free of the parasites when 50 subsequent microscopic examinations of the smears had given negative results and when inoculation with their blood did not transmit the disease to new mice.
De undersøkte produkter ble ansett for å være aktive når de forlenget overlevelsen for halvparten av de behandlede dyrene med minst 15 dager etter at det siste kontrolldyret var død. Dosen som oppnådde dette resultat refereres heretter til som den effektive dose 50 eller EDr„. Dosering av de tre forbindelsene som ble brukt The investigated products were considered active when they prolonged the survival of half of the treated animals by at least 15 days after the death of the last control animal. The dose that achieved this result is hereafter referred to as the effective dose 50 or EDr„. Dosage of the three compounds used
ou ouch
i testen ble beregnet slik at de skulle inneholde en ekvimolekylær mengde av pyrimetaminbase. in the test were calculated so that they should contain an equimolecular amount of pyrimethamine base.
Resultatene oppnådd i disse testene er gjengitt i de følgende tabeller I, II, III og IV. The results obtained in these tests are reproduced in the following tables I, II, III and IV.
Fra de resultater som således oppnåddes kan aktivitetsindeksen for hver forbindelse bestemmes. Aktivitetsindeksen beregnes ved å dividere LD^q (eller i tilfelle av forbindelsene fremstilt ifølge oppfinnelsen, MTD siden forbindelsene er for lite toksiske til at en LDC(~ lar seg bestemme) med EDrr. eller From the results thus obtained, the activity index for each compound can be determined. The activity index is calculated by dividing the LD^q (or in the case of the compounds prepared according to the invention, the MTD since the compounds are too little toxic for an LDC(~ to be determined) by the EDrr. or
DU 5U YOU 5U
effektive dose 50, dvs. effective dose 50, i.e.
De sammenlignbare resultater ifølge denne beregning er som følger: The comparable results according to this calculation are as follows:
Disse tallene viser at EDC_ for de tre forbindelsene som These figures show that the EDC_ for the three compounds which
DO DIE
er nevnt er sammenlignbare med hverandre med en svak fordel i favør av B 8370. Aktivitetsindeksene er markert i favør av B 8270 og B 8370 på grunn av den eksepsjonelt lave giftigheten for disse sistnevnte forbindelser. are mentioned are comparable to each other with a slight advantage in favor of B 8370. The activity indices are marked in favor of B 8270 and B 8370 due to the exceptionally low toxicity of these latter compounds.
En ytterligere serie antiprotozo-tester bLe utført for A further series of antiprotozoan tests were carried out for
å bestemme aktiviteten for forbindelsene fremstilt ifølge oppfinnelsen mot plasmodium gallineacum. to determine the activity of the compounds produced according to the invention against plasmodium gallineacum.
I disse tester ble den eksperimentelle sykdommen provosert i 15 dager gamle kyllinger ved en intramuskulær injeksjon av blod tatt fra en kylling med toppinfeksjon (tiende dag). In these tests, the experimental disease was provoked in 15-day-old chicks by an intramuscular injection of blood taken from a chick with peak infection (tenth day).
Fra den tiende/tolvte dagen etter injeksjonen dør 40 til 50% av kyllingene hvoretter parasitt-nivået hos de overlevende synker. Mellom den tjue-femte og trettiførste dagen er det et nytt fatalt angrep. Tilslutt overlever ca. 30% av de parasitterte kyllinger. From the tenth/twelfth day after the injection, 40 to 50% of the chickens die, after which the parasite level in the survivors drops. Between the twenty-fifth and thirty-first day there is another fatal attack. In the end, approx. 30% of the parasitized chickens.
■Behandling ble gitt intraperitonealt over et tidsrom på ■Treatment was given intraperitoneally over a period of
8 påfølgende dager. 8 consecutive days.
Som i de tidligere forsøk ble dyrene delt i grupper på As in the previous experiments, the animals were divided into groups of
10 og pyrimetamin ble brukt som referanseprodukt. Resultatet ble vurdert fra parasitt-nivået i blodet og antallet døde. 10 and pyrimethamine was used as the reference product. The result was assessed from the parasite level in the blood and the number of dead.
I preventivtestene ble forsøksforbindelsen eller pyrimetaminet injisert 2 dager etter administrasjon av den infiserende dose. In the prevention tests, the test compound or pyrimethamine was injected 2 days after administration of the infective dose.
I helbredelsestestene ble injeksjonene gitt 7 dager etter administrasjon av den infiserende dose. I denne sistnevnte test ble alle behandlede kyllinger og de overlevende kontrolldyr reinfisert med en ny intramuskulær injeksjon av plasmodium på den tjue-sjuende dag og resultatene ble igjen vurdert, denne gang på den ellevte dag, uttrykt som parasitt-nivå i blodet og ved antallet døde. In the cure tests, the injections were given 7 days after administration of the infective dose. In this latter test, all treated chickens and the surviving control animals were reinfected with a new intramuscular injection of plasmodium on the twenty-seventh day and the results were again assessed, this time on the eleventh day, expressed as parasite level in the blood and by the number of dead .
Resultatene oppnådd med pyrimetamin og B 8370 er gjengitt i de følgende tabeller: The results obtained with pyrimethamine and B 8370 are reproduced in the following tables:
Preventiv behandling Preventive treatment
Helbredende behandling Healing treatment
Helbredende behandlingReinfeksjon Curative treatment Reinfection
Den samme konklusjon kan trekkes som i tilfellet med testen på mus beskrevet ovenfor. B 8370 er med en dose på 5 mg/kg i den helbredende behandling mer aktiv enn pyrimetaminbasen i en ekvimolar dose. På den tjue-sjuende dagen viste ingen kyllinger noen parasittemi, mens med pyrimetaminbase hadde alle kyllingene blitt reinfisert. Om relative toksisitetsverdier tas i betraktning er overlegenheten for B 8370 enda mer markert. The same conclusion can be drawn as in the case of the mouse test described above. B 8370 with a dose of 5 mg/kg in the curative treatment is more active than the pyrimethamine base in an equimolar dose. On the twenty-seventh day, no chickens showed any parasitemia, whereas with pyrimethamine base all the chickens had been reinfected. If relative toxicity values are taken into account, the superiority of B 8370 is even more marked.
Antitoksoplasmisk aktivitet Antitoxoplasmic activity
De medisiner som normalt anvendes for behandling av toksoplasmose er pyrimetamin, som er et meget aktivt middel ved denne indikasjon, og visse fulfonamider, som f.eks. sulfapyrazin. Som angitt ovenfor innebærer forlenget bruk av pyrimetamin risken med uønskede bivirkninger. Bruken av sulfonamidene kan også følges av bivirkninger som kan gå så langt som til nyreskader. The medicines normally used to treat toxoplasmosis are pyrimethamine, which is a very active agent for this indication, and certain fulfonamides, such as e.g. sulfapyrazine. As indicated above, prolonged use of pyrimethamine entails the risk of unwanted side effects. The use of the sulfonamides can also be followed by side effects that can go as far as kidney damage.
Det er derfor mest ønskelig at andre midler kan utvikles, som ikke oppviser ulempene ved å frembringe uønskede bivirkninger ved langtidsbehandling, mens de har verdifulle antitoksoplasmisk aktivitet. It is therefore most desirable that other agents can be developed, which do not exhibit the disadvantages of producing unwanted side effects during long-term treatment, while they have valuable antitoxoplasmic activity.
Forbindelsene fremstilt ifølge oppfinnelsen vil antagelig være slike ønskelige erstatningsmidler, siden det har blitt observert at de er i besittelse av markerte antitoksoplasmiske egenskaper. The compounds prepared according to the invention will presumably be such desirable substitutes, since they have been observed to possess marked antitoxoplasmic properties.
Denne antitoksoplasmiske aktivitet ble fastslått i This antitoxoplasmic activity was established in
tester på mus som var infisert med toksoplasma Gondii (Sabin tests on mice infected with Toxoplasma Gondii (Sabin
Rh stamme). Friske mus ble inokulert intraperitonealt med 0,25 ml av en suspensjon av asciter tatt fra en mus som var inokulert tre dager tidligere. Rh strain). Healthy mice were inoculated intraperitoneally with 0.25 ml of a suspension of ascites taken from a mouse inoculated three days earlier.
Uten behandling utvikler sykdommen seg som følger: Without treatment, the disease develops as follows:
Enten: Either:
a) Dyret mister raskt vekt (25%), dets pels blir matt, hårene står rett opp, dyret er kraftløst og utmattet. Det tar a) The animal rapidly loses weight (25%), its fur becomes dull, the hairs stand straight up, the animal is weak and exhausted. It takes
ikke lenger til seg mat eller drikke. Døden inntrer vanligvis på den femte dag under en tilstand av fullstendig utmattelse. no longer eat or drink. Death usually occurs on the fifth day in a state of complete exhaustion.
Eller_ : Or_ :
b) Dyret gjenvinner sitt normale utseende, dog med en b) The animal regains its normal appearance, albeit with one
svak kraftløshet, og på dagen etter injeksjonen utvikles enorme weak powerlessness, and on the day after the injection develop enormous
asciter rike på toksoplasma. På den femte dagen begynner åndingen å bli vanskelig, men det er ingen markert avmagring. Mot den sjette dagen blir pelsen matt og dyret tar ikke til seg mer næring. Døden inntrer mellom den sjette og syvende dag. ascites rich in toxoplasma. On the fifth day, breathing begins to become difficult, but there is no marked emaciation. Towards the sixth day, the fur becomes dull and the animal does not take in any more nutrition. Death occurs between the sixth and seventh day.
Som i de foregående forsøk ble forbindelsene fremstilt ifølge oppfinnelsen sammenlignet med pyrimetaminbase som referanseprodukt. Alle produktene ble gitt oralt to dager før inokuleringen med parasitten og så hver dag inntil slutten av forsøket (førti-femte dag). Dosene som bruktes var en femtedel av LD,-0 for pyrimetaminbasen og en sjettedel av MTD for forbindelsene fremstilt ifølge oppfinnelsen. Disse dosene ble valgt fordi lavere doser ble funnet å være inaktive under de anvendte forsøks-betingelsene. Musene var av den sveitsiske stammen og ble delt i grupper på 25. As in the previous experiments, the compounds prepared according to the invention were compared with pyrimethamine base as a reference product. All products were given orally two days before the inoculation with the parasite and then every day until the end of the experiment (forty-fifth day). The doses used were one-fifth of the LD,-0 for the pyrimethamine base and one-sixth of the MTD for the compounds prepared according to the invention. These doses were chosen because lower doses were found to be inactive under the experimental conditions used. The mice were of the Swiss strain and were divided into groups of 25.
Den følgende tabell gjengir resultatene oppnådd med pyrimetamin og B 8370. The following table reproduces the results obtained with pyrimethamine and B 8370.
Resultatene viser at mens alle kontrolldyrene var døde den sjette dagen og 60% av de pyrimetamin-behandlede dyrene var døde ved slutten av forsøket, overlevde alle dyr behandlet med B 8370. The results show that while all the control animals were dead by the sixth day and 60% of the pyrimethamine-treated animals were dead by the end of the experiment, all animals treated with B 8370 survived.
Antiallergenisk aktivitet Antiallergenic activity
Den antiallergeniske aktiviteten for forbindelsene fremstilt ifølge oppfinnelsen ble sammenlignet med pyrimetaminets ved den klassiske testen på lungeødem frembragt av ovalbumin hos marsvin. The antiallergenic activity of the compounds produced according to the invention was compared with that of pyrimethamine in the classical test on pulmonary edema produced by ovalbumin in guinea pigs.
Fire grupper på hver 8 hanmarsvin (albino) som veide Four groups of 8 male guinea pigs (albino) weighed
ca. 300 g ble brukt og den følgende fremgangsmåte ble fulgt: Gruppe nr. 1: Dette var kontrollgruppene Hvert dyr fikk en daglig intraperitoneal dose på 6,2-ml av en isotonisk oppløsning av natriumklorid i en periode på 15 dager for å plassere dem i samme "fysiologiske" about. 300 g was used and the following procedure was followed: Group No. 1: These were the control groups Each animal received a daily intraperitoneal dose of 6.2 ml of an isotonic solution of sodium chloride for a period of 15 days to place them in the same "physiological"
tilstand som de behandlede dyrene. condition as the treated animals.
Gruppe nr. 2: Hvert dyr i denne gruppen fikk en daglig intraperitoneal dose på 0,5 mg/kg av pyrimetaminbase i et tidsrom av 15 dager. Group No. 2: Each animal in this group received a daily intraperitoneal dose of 0.5 mg/kg of pyrimethamine base for a period of 15 days.
Gruppe nr. 3: Hvert dyr fikk en daglig intraperitoneal dose Group No. 3: Each animal received a daily intraperitoneal dose
på 0,75 mgAg av B 8270 i et tidsrom av 15 dager. Gruppe nr. 4: Hvert dyr fikk en daglig intraperitoneal dose på of 0.75 mgAg of B 8270 over a period of 15 days. Group No. 4: Each animal received a daily intraperitoneal dose of
1 mg/kg av B 8370 i et tidsrom av 15 dager. 1 mg/kg of B 8370 for a period of 15 days.
På den første og andre dag etter administrasjonen av de ovenfor angitte doser ble hver gruppe sensitivert ved hjelp av en intraperitoneal injeksjon av 0,2 ml av en 2%ig vandig oppløsning av ovalbumin pr. 300 g legemsvekt. On the first and second day after the administration of the above-mentioned doses, each group was sensitized by means of an intraperitoneal injection of 0.2 ml of a 2% aqueous solution of ovalbumin per 300 g body weight.
Sjokket ble avbremset på den femtende dagen med en intra-kardial injeksjon på 0,1 mg av den samme ovalbuminoppløsningen pr. 300 g kroppsvekt. The shock was stopped on the fifteenth day with an intra-cardiac injection of 0.1 mg of the same ovalbumin solution per 300 g body weight.
Resultatene som ble oppnådd er gjengitt i den følgende tabell: The results obtained are reproduced in the following table:
Disse tallene viser at forbindelsene fremstilt ifølge oppfinnelsen har en høyere grad av antiallergenisk aktivitet enn pyrimetamin. These figures show that the compounds produced according to the invention have a higher degree of antiallergenic activity than pyrimethamine.
Det skal forstås at for terapeutisk anvendelse vil normalt forbindelsene fremstilt ifølge oppfinnelsen administreres i form av et farmasøytisk eller veterinærpreparat, som kan være i en doseringsenhetform som passer for den ønskede administrasjonsmåte, eksempelvis en belagt eller ubelagt tablett, et pulver, en kapsel eller en sirup inneholdende fra 100 til 500 mg aktiv substans for oral administrasjon eller et suppositorium for rektal administrasj on. It should be understood that for therapeutic use the compounds produced according to the invention will normally be administered in the form of a pharmaceutical or veterinary preparation, which may be in a dosage unit form suitable for the desired administration method, for example a coated or uncoated tablet, a powder, a capsule or a syrup containing from 100 to 500 mg of active substance for oral administration or a suppository for rectal administration.
Uberoende av preparatets form vil det farmasøytiske eller veterinærpreparatet normalt omfatte minst en av forbindelsene fremstilt ifølge oppfinnelsen med formel I eller et farmasøytisk akseptabelt salt av den, i forbindelse med en farmasøytisk bærer. Bæreren kan være et fast eller flytende fortynningsmiddel eller bindemiddel av det slag som vanligvis anvendes ved fremstilling av medikamenter ferdig til bruk, som f.eks. minst en av de følgende substanser: talk, magnesiumstearat, melkesukker, sakkarose, karboksymetyl-cellulose, stivelser, kaolin, levulitt eller kakaosmør. Regardless of the form of the preparation, the pharmaceutical or veterinary preparation will normally comprise at least one of the compounds prepared according to the invention with formula I or a pharmaceutically acceptable salt thereof, in connection with a pharmaceutical carrier. The carrier can be a solid or liquid diluent or binder of the kind that is usually used in the production of drugs ready for use, such as e.g. at least one of the following substances: talc, magnesium stearate, milk sugar, sucrose, carboxymethyl cellulose, starches, kaolin, levulite or cocoa butter.
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1 Example 1
Fremstilling av 2-dipropylacetamido-4-amino-5-p-klorfenyl-6-etyl-pyrimidin Preparation of 2-dipropylacetamido-4-amino-5-p-chlorophenyl-6-ethyl-pyrimidine
I en 1-liters kolbe tilførtes 149 g pyrimetamin og 500 g pyridin. Blandingen ble oppvarmet til 95°C, da det oppnåddes en homogen oppløsning, og ved samme temperatur tilsattes 40,5 g d ipropy1acetylklorid. 149 g of pyrimethamine and 500 g of pyridine were added to a 1-liter flask. The mixture was heated to 95°C, when a homogeneous solution was obtained, and at the same temperature 40.5 g of dipropylacetyl chloride were added.
Tilsetningen varte i ca. 45 minutter hvoretter reaksjonsmediet ble holdt på 95°C i 1 time. Den således oppnådde blanding ble avkjølt til 20°C og den resulterende feining av pyrimetamin-hydroklorid ble avfiltrert. Filtratene ble oppsamlet og oppvarmet til 60°C under 25 mm Hg for å oppnå et oljeprodukt. Denne olje ble under tilbakeløp opptatt i 200 g etanol og den således oppnådde oppløsning ble innført i en blanding av 200 g etanol og 250 g avmineralisert vann. Oppløsningen fikk stå ved 0°C i 12 timer og bunnfallet som ble dannet ble vasket først med 250 g 10%ig eddiksyreløsning og så med avmineralisert vann til nøytralitet. Bunnfallet ble tørket under vakuum i en tørke-ovn ved 70°C til konstant vekt (ca. 12 timer). På denne måten oppnåddes 43,5 g råprodukt, som er et utbytte på 46,5% når det beregnes på pyrimetamin. Dette råproduktet ble oppløst under omrøring og tilbakeløp i en blanding av 280 g heptan og 40 g toluen i nærvær av 4,5 g aktivert trekull. Blandingen ble holdt på tilbakeløp i 30 minutter og så ble trekullet fjernet ved filtrering. The addition lasted approx. 45 minutes after which the reaction medium was kept at 95°C for 1 hour. The mixture thus obtained was cooled to 20°C and the resulting precipitate of pyrimethamine hydrochloride was filtered off. The filtrates were collected and heated to 60°C under 25 mm Hg to obtain an oil product. This oil was refluxed in 200 g of ethanol and the solution thus obtained was introduced into a mixture of 200 g of ethanol and 250 g of demineralized water. The solution was allowed to stand at 0°C for 12 hours and the precipitate that formed was washed first with 250 g of 10% acetic acid solution and then with demineralized water to neutrality. The precipitate was dried under vacuum in a drying oven at 70°C to constant weight (approx. 12 hours). In this way, 43.5 g of crude product was obtained, which is a yield of 46.5% when calculated on pyrimethamine. This crude product was dissolved under stirring and reflux in a mixture of 280 g of heptane and 40 g of toluene in the presence of 4.5 g of activated charcoal. The mixture was refluxed for 30 minutes and then the charcoal was removed by filtration.
Filtratet ble avkjø lt til -10°c i 4 timer og bunnfallet som oppsto ble så filtrert på glassfilter og tørket under vakuum i en tørkeovn ved 60°C til konstant vekt. Etter denne første rensing oppnåddes 34 g av det ønskede produkt, som ble opptatt under tilbakeløp i 240 g etanol i nærvær av 1,5 g aktivert trekull. Trekullet ble avfiltrert og filtratet konsentrert under vakuum til ca. 100 ml og avkjølt til 0°C i 12 timer. Det således oppnådde bunnfall ble avfiltrert, skylt med 10 g iskjølt etanol og så tørket under vakuum i en tørkeovn ved 60°C til konstant vekt. Ved denne fremgangsmåte ble det oppnådd 31,5 g 2-dipropylacetamido-4-amino-5-p-klorfenyl-6-etylpyrimidin, smp. 172 C i et utbytte av 73%. The filtrate was cooled to -10°C for 4 hours and the resulting precipitate was then filtered on a glass filter and dried under vacuum in a drying oven at 60°C to constant weight. After this first purification, 34 g of the desired product was obtained, which was taken up under reflux in 240 g of ethanol in the presence of 1.5 g of activated charcoal. The charcoal was filtered off and the filtrate concentrated under vacuum to approx. 100 ml and cooled to 0°C for 12 hours. The precipitate thus obtained was filtered off, rinsed with 10 g of ice-cooled ethanol and then dried under vacuum in a drying oven at 60°C to constant weight. By this method, 31.5 g of 2-dipropylacetamido-4-amino-5-p-chlorophenyl-6-ethylpyrimidine were obtained, m.p. 172 C in a yield of 73%.
Eksempel 2 Example 2
Fremstilling av 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin Preparation of 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine
Form x Form x
I en 250 ml tohalskolbe med kjøler og mekanisk omrører ble innført 47,6 g (0,19 mol) pyrimetamin og 121,6 g (0,45 mol) dipropyleddiksyreanhydrid. Blandingen ble oppvarmet med kraftig omrøring ved 150°c i tre dg en halv time. Den dannede dipropyl-eddiksyre såvel som overskudd dipropyleddiksyreanhydrid ble avdestillert under vakuum (0,2 mm Hg). På denne måte oppnåddes 58 g av en blanding som destillerte ved 90-94°C under 0,2 mm Hg. 47.6 g (0.19 mol) of pyrimethamine and 121.6 g (0.45 mol) of dipropylacetic anhydride were introduced into a 250 ml two-necked flask with a cooler and mechanical stirrer. The mixture was heated with vigorous stirring at 150°C for three days and half an hour. The formed dipropylacetic acid as well as excess dipropylacetic anhydride were distilled off under vacuum (0.2 mm Hg). In this way, 58 g of a mixture which distilled at 90-94°C under 0.2 mm Hg was obtained.
Den varme resten ble tatt opp i 200 ml heptan. Oppløsningen ble The hot residue was taken up in 200 ml of heptane. The resolution was
så plassert i ca. 10 timer i et kjøleskap og de således oppnådde krystaller ble sentrifugert ut og vasket to ganger med isavkjølt heptan. Etter tørking ble det oppnådd 82,6 g rent 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etylpyrimidin (form X), then placed in approx. 10 hours in a refrigerator and the crystals thus obtained were centrifuged out and washed twice with ice-cooled heptane. After drying, 82.6 g of pure 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethylpyrimidine (form X) were obtained,
smp. 113-114°C, som var et utbytte på 87%. m.p. 113-114°C, which was a yield of 87%.
Den frie basen ble omdannet til hydrokloridet, oksalatet The free base was converted to the hydrochloride, the oxalate
og dimetansulfonatet som nedenfor beskrevet. and the dimethanesulfonate as described below.
Monohydroklorid Monohydrochloride
Til en eterløsning av 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin (form X) ble tilsatt en oppløsning av saltsyre i eter (1 mol fri base til 1 mol saltsyre). 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin (form X)-monohydrokloridet som ble dannet på denne måten hadde et smp. på 119-121°C ved krystallisasjon fra isopropyleter. To an ether solution of 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form X) was added a solution of hydrochloric acid in ether (1 mol free base to 1 mol hydrochloric acid). The 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form X) monohydrochloride thus formed had a m.p. of 119-121°C by crystallization from isopropyl ether.
Monooksalat Monooxalate
Til en eterløsning av den tidligere oppnådde frie base To an ether solution of the previously obtained free base
ble tilsatt en oppløsning av oksalsyre i eter (1 mol fri base til 1 mol oksalsyre). 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin(form X)-monooksalatet som ble dannet slik ble så krystallisert fra isopropanol. was added a solution of oxalic acid in ether (1 mol free base to 1 mol oxalic acid). The 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form X) monooxalate thus formed was then crystallized from isopropanol.
Dimetansulfonat Dimethanesulfonate
Til en eteroppløsning av den tidligere oppnådde frie base To an ether solution of the previously obtained free base
ble tilsatt metansulfonsyre. 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin(form X)-dimetansulfonatet som ble methanesulfonic acid was added. The 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form X) dimethanesulfonate which was
dannet slik hadde et smp. på 84,5°C når det ble krystallisert fra isopropyleter. formed thus had a m.p. of 84.5°C when crystallized from isopropyl ether.
Form W. Shape W.
2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etylpyrimidin (form W) ble fremstilt ved den samme fremgangsmåte som beskrevet for "form X", med med pentan istedenfor heptan som løsningsmiddel. Produktet hadde et smp. på 89°c. 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethylpyrimidine (form W) was prepared by the same procedure as described for "form X", using pentane instead of heptane as solvent. The product had a m.p. at 89°C.
Form Y Form Y
5 g 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin (form W eller X) ble gradvis oppvarmet til 140°C i 5 ml white spirit. Ved langsom avkjøling oppnåddes 2 g 2,4-bis-dipropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin (form Y), 5 g of 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form W or X) was gradually heated to 140°C in 5 ml of white spirit. On slow cooling, 2 g of 2,4-bis-dipropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine (form Y) were obtained,
sm.p. 121°C, som betyr et utbytte på 40%. sm.p. 121°C, which means a yield of 40%.
Eksempel 3 Example 3
Fremstilling av 2,4-bis-(2-etyl-2-butyl-acetamido)-5-p-klorfenyl-6- etyl- pyrimidin- dimetansulfonat Preparation of 2,4-bis-(2-ethyl-2-butyl-acetamido)-5-p-chlorophenyl-6-ethyl-pyrimidine- dimethanesulfonate
I en 100 ml tohalskolbe utstyrt med kjøler og mekanisk omrører ble innført 12,5 g (0,05 mol) pyrimetamin og 29,7 g (0,11 mol) 2-etylheksankarboksylsyreanhydrid. Blandingen ble oppvarmet i tre og en halv time ved 150°C hvoretter den 2-etylheksan-karboksylsyre som var dannet og overskudd 2-etylheksankarboksylsyreanhydrid ble avdestillert under vakuum. Oljeresten ble opp-løst i 100 ml heksan og oppløsningen ble så plassert i et kjøleskap. De dannede krystaller som var nesten rene, ble så sentrifugert ut, vasket og tørket. På denne måten oppnåddes 18 g (utbytte: 72%) 12.5 g (0.05 mol) of pyrimethamine and 29.7 g (0.11 mol) of 2-ethylhexanecarboxylic anhydride were introduced into a 100 ml two-necked flask equipped with a condenser and mechanical stirrer. The mixture was heated for three and a half hours at 150°C, after which the 2-ethylhexanecarboxylic acid which had formed and excess 2-ethylhexanecarboxylic anhydride were distilled off under vacuum. The oil residue was dissolved in 100 ml of hexane and the solution was then placed in a refrigerator. The formed crystals, which were almost pure, were then centrifuged out, washed and dried. In this way, 18 g were obtained (yield: 72%)
av det ønskede produkt. Produktet ble så omkrystallisert fra 70 ml pentan og så fra 30 ml heksan. of the desired product. The product was then recrystallized from 70 ml of pentane and then from 30 ml of hexane.
Ved denne fremgangsmåte oppnåddes 8,5 g rent 2,4-bis-(2-etyl-2-butyl-acetamido)-5-p-klorfenyl-6-etyl-pyrimidin i fri baseform, som representerte et utbytte på 34% etter rensing. By this method, 8.5 g of pure 2,4-bis-(2-ethyl-2-butyl-acetamido)-5-p-chlorophenyl-6-ethyl-pyrimidine were obtained in free base form, which represented a yield of 34% after cleansing.
Produktet hadde et smeltepunkt på 48,4°C. The product had a melting point of 48.4°C.
250 mg av den oppnådde frie base ble oppløst i 1 ml heksan. 250 mg of the free base obtained was dissolved in 1 ml of hexane.
Denne oppløsning ble tilsatt til 120 mg metansulfonsyre oppløst i 1 ml eter. Den således oppnådde olje ble tatt opp flere ganger i This solution was added to 120 mg of methanesulfonic acid dissolved in 1 ml of ether. The oil thus obtained was taken up several times in
heksan. 10 ml eter ble så tilsatt til oppløsningen og det falt ut krystaller som ble avsentrifugert og tørket. hexane. 10 ml of ether was then added to the solution and crystals precipitated which were centrifuged off and dried.
Ved denne metode oppnåddes 300 mg 2,4-bis-(2-etyl-2-butyl-acetamido)-5-p-klorfenyl-6-etyl-pyrimidin-dimetansulfonat, By this method, 300 mg of 2,4-bis-(2-ethyl-2-butyl-acetamido)-5-p-chlorophenyl-6-ethyl-pyrimidine-dimethanesulfonate was obtained,
smp. 73,3°C. m.p. 73.3°C.
i in
Eksempel 4 Example 4
Fremstilling av 2,4-bis-tripropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin Preparation of 2,4-bis-tripropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine
I en 50 ml tohalskolbe utstyrt med en kjøler og en mekanisk omrører ble innført 2,25 g (0,009 mol) pyrimetamin og 7,25 g (0,0204 mol) tripropyleddiksyreanhydrid. Blandingen ble så oppvarmet ved 170°C i 24 timer. Etter avkjøling ble den oppnådde olje kromatografert på en aluminiumoksydkolonne og eluert to ganger med 250 ml eter inneholdende 2% kloroform. Løsningsmidlene ble destillert av under vakuum det oppnåddes en brunaktig olje som krystalliserte langsomt fra pentan. De dannede krystaller ble avsentrifugert og omkrystallisert fra 15 ml heksan. Ved denne fremgangsmåte oppnåddes 1,10 g rent 2,4-bis-tripropylacetamido-5-p-klorfenyl-6-etyl-pyrimidin, som representerte et utbytte på 21%. Produktet hadde et smeltepunkt på 117,4°C. Into a 50 ml two-necked flask equipped with a condenser and a mechanical stirrer were introduced 2.25 g (0.009 mol) of pyrimethamine and 7.25 g (0.0204 mol) of tripropylacetic anhydride. The mixture was then heated at 170°C for 24 hours. After cooling, the oil obtained was chromatographed on an alumina column and eluted twice with 250 ml of ether containing 2% chloroform. The solvents were distilled off under vacuum to give a brownish oil which crystallized slowly from pentane. The formed crystals were centrifuged off and recrystallized from 15 ml of hexane. By this method, 1.10 g of pure 2,4-bis-tripropylacetamido-5-p-chlorophenyl-6-ethyl-pyrimidine were obtained, which represented a yield of 21%. The product had a melting point of 117.4°C.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB3437872A GB1384150A (en) | 1972-07-21 | 1972-07-21 | Pyrimidine derivatives and process for preparing the same |
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NO137691B true NO137691B (en) | 1977-12-27 |
NO137691C NO137691C (en) | 1978-04-05 |
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NO2951/73A NO137691C (en) | 1972-07-21 | 1973-07-20 | ANALOGICAL PROCEDURE FOR PREPARING NEW THERAPEUTICALLY ACTIVE PYRIMIDINE DERIVATIVES |
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JP (1) | JPS4980082A (en) |
AR (1) | AR197241A1 (en) |
AT (1) | AT326671B (en) |
AU (1) | AU470607B2 (en) |
BE (1) | BE802451A (en) |
CA (1) | CA986518A (en) |
CH (1) | CH579552A5 (en) |
DE (1) | DE2336678A1 (en) |
DK (1) | DK131626C (en) |
ES (1) | ES417142A1 (en) |
FR (1) | FR2193604B1 (en) |
GB (1) | GB1384150A (en) |
HU (1) | HU167313B (en) |
IE (1) | IE38033B1 (en) |
NL (1) | NL7309988A (en) |
NO (1) | NO137691C (en) |
OA (1) | OA04539A (en) |
SE (1) | SE399556B (en) |
SU (1) | SU468422A3 (en) |
YU (1) | YU180673A (en) |
ZA (1) | ZA734406B (en) |
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1972
- 1972-07-21 GB GB3437872A patent/GB1384150A/en not_active Expired
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1973
- 1973-06-28 ZA ZA734406A patent/ZA734406B/en unknown
- 1973-06-29 IE IE1093/73A patent/IE38033B1/en unknown
- 1973-06-29 AR AR248838A patent/AR197241A1/en active
- 1973-07-02 YU YU01806/73A patent/YU180673A/en unknown
- 1973-07-04 AU AU57699/73A patent/AU470607B2/en not_active Expired
- 1973-07-05 AT AT591673A patent/AT326671B/en not_active IP Right Cessation
- 1973-07-17 BE BE133575A patent/BE802451A/en unknown
- 1973-07-18 NL NL7309988A patent/NL7309988A/xx unknown
- 1973-07-19 DE DE19732336678 patent/DE2336678A1/en active Pending
- 1973-07-19 SE SE7310102A patent/SE399556B/en unknown
- 1973-07-20 HU HULA829A patent/HU167313B/hu unknown
- 1973-07-20 FR FR7326645A patent/FR2193604B1/fr not_active Expired
- 1973-07-20 CA CA176990A patent/CA986518A/en not_active Expired
- 1973-07-20 OA OA54970A patent/OA04539A/en unknown
- 1973-07-20 SU SU1939807A patent/SU468422A3/en active
- 1973-07-20 NO NO2951/73A patent/NO137691C/en unknown
- 1973-07-20 CH CH1066673A patent/CH579552A5/xx not_active IP Right Cessation
- 1973-07-20 DK DK404273A patent/DK131626C/en active
- 1973-07-21 JP JP48082371A patent/JPS4980082A/ja active Pending
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NL7309988A (en) | 1974-01-23 |
SE399556B (en) | 1978-02-20 |
YU180673A (en) | 1980-04-30 |
HU167313B (en) | 1975-09-27 |
DE2336678A1 (en) | 1974-01-31 |
FR2193604A1 (en) | 1974-02-22 |
CH579552A5 (en) | 1976-09-15 |
JPS4980082A (en) | 1974-08-02 |
NO137691C (en) | 1978-04-05 |
ATA591673A (en) | 1975-03-15 |
AR197241A1 (en) | 1974-03-22 |
DK131626C (en) | 1976-01-19 |
CA986518A (en) | 1976-03-30 |
ES417142A1 (en) | 1976-03-01 |
IE38033B1 (en) | 1977-12-07 |
ZA734406B (en) | 1974-06-26 |
IE38033L (en) | 1974-01-21 |
AT326671B (en) | 1975-12-29 |
OA04539A (en) | 1980-03-30 |
AU470607B2 (en) | 1976-03-25 |
SU468422A3 (en) | 1975-04-25 |
AU5769973A (en) | 1975-01-09 |
BE802451A (en) | 1974-01-17 |
FR2193604B1 (en) | 1977-01-28 |
DK131626B (en) | 1975-08-11 |
GB1384150A (en) | 1975-02-19 |
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