FI115523B - Förfarande för framställning av antibiotiskt verkande 7-(substituerad)-9-[(substituerad glycyl)amido]-6-demetyl-6-deoxitetracykliner och mellanprodukter för användning vid förfarandet - Google Patents

Förfarande för framställning av antibiotiskt verkande 7-(substituerad)-9-[(substituerad glycyl)amido]-6-demetyl-6-deoxitetracykliner och mellanprodukter för användning vid förfarandet Download PDF

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FI115523B
FI115523B FI933565A FI933565A FI115523B FI 115523 B FI115523 B FI 115523B FI 933565 A FI933565 A FI 933565A FI 933565 A FI933565 A FI 933565A FI 115523 B FI115523 B FI 115523B
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amino
bis
dimethylamino
octahydro
methylpropyl
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Raymond Thomas Testa
Phaik-Eng Sum
Ving J Lee
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Wyeth Corp
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Claims (4)

1. Förfarande för framställning av antibiotiskt verkande 7-(substituerad)-9-[(substituerad glycyl)amido]-6-5 demetyl-6-deoxitetracykliner med formeIn (I) och farma-ceutiskt godtagbara oorganiska och organiska salter och metallkomplex därav, R N(CH3>2 W OH 0 OH 0 0 där:
10 R är halogen, som är vald ur en grupp, som utgörs av brom, klor, fluor och jod; eller R = -NR2R2, och dä R = -NR1R2 och R1 är väte, R2 = metyl, etyl, n-propyl, 1-metyletyl, n-butyl, 1-metyl-| propyl, 2-metylpropyl eller 1,1-dimetyletyl; 15 och dä R1 = metyl eller etyl, ; ·# R2 = metyl, etyl, n-propyl, 1-metyletyl, n-butyl, 1-metyl- propyl eller 2-metylpropyl; .*”* och dä R1 = n-propyl • * · ;;· ; R2 = n-propyl, 1-metyletyl, n-butyl, 1-metylpropyl eller ί 20 2-metylpropyl; » » 0 * V och dä R1 = 1-metyletyl, ' R2 = n-butyl, 1-metylpropyl eller 2-metylpropyl; och dä R1 = n-butyl, ’ R2 = n-butyl, 1-metylpropyl eller 2-metylpropyl; 25 och dä R1 = 2-metylpropyl, » R2 = 2-metylpropyl; R4 är väte eller alkyl med 1-6 kolatomer; W är amino,som är monosubstituerad med en rakkedjad eller förgrenad alkyl med 7-10 kolatomer; amino, som är mono-: 30 substituerad med cykloalkylalkyl med 4-10 kolatomer, en rakkedjad eller förgrenad alkyl, som har 1-4 kolatomer 115523 och som är substituerad med en fluoratom; amino, som är monosubstituerad med alkenyl eller alkynyl, vilka har 3 -10 kolatomer; alkylamino, som har 1-7 kolatomer och som är substituerad med hydroxi eller alkoxi med 1-7 kola-5 tomer; en 4-7-ledad heterocyklisk grupp, som innehäller en N-heteroatom och eventuellt en O-, S- eller N-atom som yt-terligare heteroatom och som eventuellt är substituerad med alkyl med 1-6 kolatomer och som är koplad till den övriga delen av molekylen via N-atomen, 10 kännetecknat därav, att en 9-[ (halogenacyl)-amido]-7-(substituerad)-6-demetyl-6-deoxitetracyklin med formeln R N(CH3>2 : 0 (m> Η Π „ I I R I 1 I oh I || y oh o oh a o 15 där R och R4 betecknar sarana som ovan, och Y är X, varvid X är halogen, som är vald ur en grupp, som utgörs av brom, · ’ klor, fluor och jod; eller ett organiskt eller oorganiskt salt eller metall * · ·,· I komplex därav omsätts med en nukleofil med formeln WH, där *·': 20 W definierat ovan, i ett polärt aprotiskt lösningsmedel 1 » · ·*; och i en inert atmosfär. . 2. Förfarande enligt patentkrav 1, känne tecknat därav, att man framställer [4S— (4a, 12aa) ]—9—[[[ (cyklopropylmetyl) amino]acetyl]amino]-4, -25 7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a-oktahydro-3,10,-12,12a-tetrahydroxi-l,ll-dioxo-2-naftacenkarboxamiddihyd-' : roklorid; [4S- (4a, 12aa) ]-9-[[[ (2,2-dietoxietyl) amino]acetyl]amino]-4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a-oktahydro-3,10, 12,-30 12a-tetrahydroxi-l,ll-dioxo-2-naftacenkarboxamiddihydro-klorid; 115523 [4S- (4α, 12aa) ]-4,7-bis (dimetylamino) -1,4,4a, 5,5a, 6, 11,12a-oktahydro-3,10,12,12a-tetrahydroxi-9-[[[ (2-metoxietyl) ami-no]acetyl]amino]-l,ll-dioxo-2-naftacenkarboxamiddihydroklorid; 5 [4S- (4a, 12aa) ]-4,7-bis (dimetylamino) -1,4,4a, 5,5a, 6,11,12a- oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[ (2-prop-enylamino) ]acetyl]amino]-2-naf tacenkarboxamiddihydroklorid; [4S - (4a, 12aa) ]-4,7-bis (dimetylamino) -1,4, 4a, 5, 5a, 6, 11,12a-oktahydro-3,10,12,12a-tetrahydroxi-9-[[[ (3-metoxpropyl) ami-I 10 no]acetyl]amino]-l, ll-dioxo-2-naftacenkarboxamiddihydroklo- rid; [7S-(7a,10aa)]-N-[9-(aminokarbonyl)-4,7-bis(dimetylamino)-5,5a,6,6a,7,10,10a,12-oktahydro-l,8,10a,11-tetrahydroxi- 10.12- dioxo-2-naftacenyl]-4-tiomorfolinacetamiddihydroklo-15 rid; [7S —(7a, 10aa) ]—N—[9—(aminokarbonyl)-4,7-bis(dimetylamino)-5,5a,6,6a,7,10,10a,12-oktahydro-l,8,10a,11-tetrahydroxi- 10.12- di oxo-2-naf tacenyl]-4-metyl-l-piperidinacetamiddi- i hydroklorid; 20 [7S-(7a,10aa) ]-N-[9-(aminokarbonyl)-4,7-bis(dimetylamino)- 5,5a,6,6a,7,10,10a,12-oktahydro-l,8,10a,11-tetrahydroxi-10, 12-dioxo-2-naftacenyl]-4-metyl-l-piperazinacetamiddi- » ,· hydroklorid; [4S- ( 4a, 12aa) ]-4 , 7-bis (dimetylamino) -9-[[ (heptylamino) ]acet- : v. 25 yl]amino-l,4,4a,5,5a,6,11,12a-oktahydro-3, 10,12,12a-tetra-♦ · hydroxi-l, ll-dioxo-2-naftacenkarboxamiddihydroklorid; [4S-(4a, 12aa)]-4,7-bis (dimetylamino) -1,4,4a, 5, 5a, 6,11,12a- * » » ·’ * oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[ (undekyl- amino) ]acetyl]amino-2-naftacenkarboxamiddihydroklorid; 30 [4S-(4a, 12aa) ]-4,7-bis(dimetylamino)-1,4,4a,5,5a, 6,11,12a- oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[[ (pyri-dinylmetyl) amino) ]acetyl]amido]-2-naftacenkarboxamiddihyd-roklorid; [4S-(4a,12aa)]-4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a-.· 35 oktahydro-3,10,12,12a-tetrahydroxi-9-[[[ (2-hydroxietyl) ami- 115523 I 44 ! no) ]acetyl]amino]-l, ll-dioxo-2-naftacenkarboxamidmonohydro- j klorid; [4S- (4a, 12aa)]-4,7-bis (dimetylamino) -1,4,4a,5,5a,6,11,12a-oktahydro-3, 10,12, 12a-tetrahydroxi-9-[[[ (2-hydroxietyl) met-5 ylamino) ]acetyl]ainino]-l, ll-dioxo-2-naftacenkarboxamid; [4S- (4a,12aa) ]-4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a-oktahydro-3,10,12, 12a-tetrahydroxi-9-[[[ (4-hydroxibutyl) -amino]acetyl]amino]-l, ll-dioxo-2-naftacenkarboxamid; [4S - (4a,12aa) ]-4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a-10 oktahydro-3, 10,12,12a-tetrahydroxi-9-[[[ (2,2,2-trif luoret-yl) amino]acetyl]amino]-l, ll-dioxo-2-naftacenkarboxamid; [4S — (4a, 12aa)]-4,7-bis (dimetylamino) — 9—[[[ (2-fluoretyl) ami-no]acetyl]amino]-l,4,4a,5,5a,6,11,12a-oktahydro-3,10,12,-12a-tetrahydroxi-l,ll-dioxo-2-naftacenkarboxamid; 15 [4S— ( 4a,12aa) ]-4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12a- I oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[[2- (1- piperidinyl) etyl) amino]acetyl]amino]-2-naftacenkarboxamid; [4S-(4a,12aa)]-4,7-bis(dimetylamino) -1,4,4a,5,5a,6,11,12a-oktahydro-3,10,12,12a-tetrahydroxi-9-[[[metyl-2-propynyl-2 0 amino]acetyl]amino]-2-naf tacenkarboxamid ; [4S—(4a,12aa) ]—4,7-bis(dimetylamino)-1,4,4a,5,5a,6,11,12 a-j : : oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[ (1-pipe- : ridinylamino) acetyl]amin]-2-naftacenkarboxamid; eller [4S-(4a, 12aa) ] — 4,7-bis (dimetylamino)-1, 4,4a, 5,5a, 6, 11,12a-25 oktahydro-3,10,12,12a-tetrahydroxi-l, ll-dioxo-9-[[[ (9-fen-ylmetoxi) amino]acetyl]amino]-2-naftacenkarboxamid. * I
3. Mellanprodukt för användning vid förfarandet ' ’ enligt patentkrav 1, vilken mellanprodukt har formeln (III) : r n<ch3)2 o (IXI> h II I I R I I oh I I Y 0H 0 0H 0 0 : 30 115523 där: Y är X, X är halogen, soin är vald ur en grupp, som utgörs av brom, klor, fluor och jod;
5 R är halogen, som är vald ur en grupp, som utgörs av brom, klor, fluor och jod; eller R = -NR1R2, och dä R = -NR1R2 och R1 är väte, R2 = metyl, etyl, n-propyl, 1-metyletyl, n-butyl, 1-metyl-propyl, 2-metylpropyl eller 1,1-dimetyletyl; 10 och da R1 = metyl eller etyl, R2 = metyl, etyl, n-propyl, 1-metyletyl, n-butyl, 1-metyl-propyl eller 2-metylpropyl; och dä R1 = n-propyl R2 = n-propyl, 1-metyletyl, n-butyl, 1-metylpropyl eller 15 2-metylpropyl; och dä R1 = 1-metyletyl, R2 = n-butyl, 1-metylpropyl eller 2-metylpropyl; och dä R1 = n-butyl, R2 = n-butyl, 1-metylpropyl eller 2-metylpropyl; 20 och dä R1 = 1-metylpropyl, R2 = 2-metylpropyl; ; ,·. R4 är väte eller Ci-6-alkyl, som är vald ur en grupp, som ’·* utgörs av metyl, etyl, propyl, isopropyl, butyl, isobutyl, pentyl och hexyl; * * * V 25 dä R4 är annat än väte, kan den asymmetriska kolatomens # · : ·* stereokemi vara antingen racemat (DL) eller en enskild • enantiomer (L eller D) ; · och ett organiskt eller oorganiskt sait eller metallkom-plex därav. : ; 30 4. Förening enligt patentkrav 3, där: : Y är X, X är halogen, som är vald ur en grupp, som utgörs av brom, i ; klor, fluor och jod; * R är halogen, som är vald ur en grupp, som utgörs av brom, 35 klor, fluor och jod; eller R = -NR1R2, och dä R = -NR1R2 och R1 är metyl eller etyl, 115523 R2 = metyl eller etyl; R4 är vald ur en grupp, som utgörs av väte och Ci-2-alkyl·, som är vald ur en grupp, som utgörs av metyl och etyl; da R4 är annat än väte, kan den asymmetriska kolatomens 5 stereokemi vara antingen racemat (DL) eller en enskild enantiomer (L eller D); och ett organiskt eller oorganiskt sait eller metallkom-plex därav. » · » · * · I I » » · » • · » » t * · * I « » > I · I » • * > »
FI933565A 1992-08-13 1993-08-12 Förfarande för framställning av antibiotiskt verkande 7-(substituerad)-9-[(substituerad glycyl)amido]-6-demetyl-6-deoxitetracykliner och mellanprodukter för användning vid förfarandet FI115523B (sv)

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US07/928,589 US5328902A (en) 1992-08-13 1992-08-13 7-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines
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Publication number Priority date Publication date Assignee Title
USRE40183E1 (en) 1991-10-04 2008-03-25 Wyeth Holdings Corporation 7-Substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5494903A (en) * 1991-10-04 1996-02-27 American Cyanamid Company 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US5442059A (en) * 1992-08-13 1995-08-15 American Cyanamid Company 9-[(substituted glycyl)amido)]-6-demethyl-6-deoxytetracyclines
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US5380888A (en) 1995-01-10
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