Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-04-25
2004-04-27
Lewis, Patrick (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S043000, C514S049000, C536S022100, C536S028100, C536S028400, C536S028530, C536S055300
Reexamination Certificate
active
06727232
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds of AA-896 which exhibit antibacterial activity.
BACKGROUND OF THE INVENTION
Natural products, Liposidomycins A, B and C, have been isolated and reported to have antibacterial activity(Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K.; Izaki, K.; Nelson, C. C.; McCloskey, J. A.,
J.Antibiotics,
1985, 38, 1617-1621. Ubukata, M.; Isono, K.; Kimura, K.; Nelson, C. C.; McCloskey, J. A.
J.Am.Chem.Soc.,
1988,110, 4416-4417. Kimura, K.; Miyata, N.; Kawanishi, G.; Kamino, Y.; Izaki, K.; Isono, K.
Agric.Biol.Chem.,
1989, 53,1811-1815.). Isolated Liposidomycins A-(I), A-(II), A-(III) and A-(IV) are also reported to have antibacterial activity (Kimura, K.; Ikeda, Y.; Kagami, S.; Yoshihara, M.,
J. Antibiotics,
1998, 51, 1099-1104. and other references herein). The detailed structural analysis of Liposidomycins A, B and C using their chemical degradation products has been reported (Ubukata, M.; Kimura, K.; Isono, K.; Nelson, C. C.; Gregson, J. M.; McClosky, J. A.,
J.Org.Chem.,
1992, 57, 6392-6403). Liposidomycin class compounds are further reported (JPO05078385) and are derivatives of 2-methylamino-3-(5-aminomethyl-4-hydroxy-3-hydroxy-tetrahydro-fura-2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl)tetrahydro-2-furanyl]propanoic acid or the degraded products of 2-methylamino-3-(5-aminomethyl-4-hydroxy-3-hydroxy-tetrahydro-fura-2-yloxy)-3-[3,4-dihyoxy-5-(2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl)tetrahydro-2-furanyl]-propanoic acid.
This invention is concerned with a new series of nucleoside peptide antibiotics of AA-896.
SUMMARY OF THE INVENTION
This invention is concerned with novel nucleoside peptide antibiotics of AA-896 which have antibacterial activity; with methods of treating infectious disease in mammals employing these novel nucleoside peptide antibiotics; with pharmaceutical compositions containing these novel nucleoside peptide antibiotics and processes for the production of novel nucleoside peptide antibiotics of the invention. Compounds according to the invention comprise compounds of the formula
wherein:
R
1
is H, aryl, alkyl (C
1
-C
20
), —CH
2
-aryl, —C(O)alkyl(C
1
-C
20
), C(O)NHalkyl(C
1
-C
20
), or —C(O)NHaryl;
R
2
is H, alkyl (C
1
-C
20
), —CH
2
aryl, or —C(O)alkyl(C
1
-C
20
);
R
3
is —OH;
R
2
and R
3
may optionally be taken together to form a moiety
R
4
is alkyl (C
1
-C
20
), or aryl;
provided R
1
and R
2
are not H when R
3
is —OH
or a pharmaceutically acceptable salt thereof.
Among the preferred groups of compounds of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein other variables are as defined above:
a) R
2
and R
3
are taken together to form a moiety
b) R
2
is H, alkyl (C
1
-C
12
), or —CH
2
aryl; and
c) R
1
is H, —C(O)alkyl(C
1
-C
16
), or —C(O)aryl when
R
2
and R
3
are taken together to form a moiety
d) R
4
is alkyl(C
1
-C
16
), or aryl.
Specifically preferred compounds of the invention are the following compounds or a pharmaceutically acceptable salt thereof:
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-(4-fluorophenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-2,4-dioxo-3-pentyl-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{((2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-hexyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-3-dodecyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-15-benzyl-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-15-dodecyl-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-15-[12-(4-morpholinyl)dodecyl]-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
16-((R)-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-15-pentyl-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid,
4-[13-((2R)-2-{[(3R,4S,5R)-5-(Aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}-1-carboxy-2-{(2S,3S,4R,5R)-5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}ethyl)-26-carboxy-19-(1-hydroxy-2-methylpropyl)-22-(2-iminohexahydro-4-pyrimidinyl)-27-methyl-18,21,24-trioxo-13,17,20,23,25-pentaazaoctacos-1-yl]-4-methylmorpholin-4-ium,
14-[5-((R)-{(2S,3S,4R,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(3R,4S,5R)-4-hydroxy-3-methoxy-5-({[(octylamino)carbonyl]amino}methyl)tetrahydro-2-furanyl]oxy}methyl)-3-octyl-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(5R)-4-hydroxy-3-methoxy-5-({[(4-fluoroanilino)carbonyl]amino}methyl)tetrahydro-2-furanyl]oxy}methyl)-3-(4-fluorophenyl)-2,4-dioxo-1-imidazolidinyl]-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11-tetraazatetradecan-1-oic acid,
14-[5-((R)-{(2S,5R)-5-[2,4-Dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}{[(
Francisco Gerardo DelaCruz
Li Zhong
Lin Yang-I
McDonald Leonard Alexander
Lewis Patrick
Moran Daniel B.
Wyeth Holdings Corporation
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