IP Library › Patent Application 14179845

Patent Application

App. No. 14/179,845

NOVEL ANTIBACTERIAL COMPOUNDS, METHODS OF MAKING THEM, AND USES THEREOF

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Patent No.: US None
App. No.: 14/179,845

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Abstract

The present invention relates to novel therapeutics with antibacterial activity, processes for their preparation, and pharmaceutical, veterinary and nutritional compositions containing them as active ingredients. The present invention also relates to uses of the novel therapeutics, for example, as medicants or food additives in the treatment of bacterial infections or to aid body mass gain in a subject.

Claims (336)

1 . A method for making a product compound having the formula:

said method comprising:

fermenting a culture medium comprising Streptomyces strain AMRI-7957 (ATCC Accession No. PTA-11098) under conditions effective to produce a fermentation broth comprising the product compound, and

isolating the product compound.

2 . The method according to claim 1 , wherein fermenting comprises:

culturing Streptomyces strain AMRI-7957 (ATCC Accession No. PTA-11098), and

inoculating the culture into a fermentor.

3 . The method according to claim 1 , wherein isolating comprises:

separating the fermentation broth into a biomass fraction and a supernatant fraction.

4 . The method according to claim 3 , wherein isolating comprises:

extracting the product compound from the biomass fraction.

5 . The method according to claim 3 , wherein isolating comprises:

extracting the product compound from the supernatant fraction.

6 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , —OR 12 , or —NR 12 R 13 ;

R 2 is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 3 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;

R 4 is selected from the group consisting of H, halogen, —OR 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , phenyl, benzyl, ═NOR 14 , ═NR 14 , a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;

R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 6 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

or R 5 and R 6 can combine to form a heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and optionally substituted 1 to 3 times with halogen, oxo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 7 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;

R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —OR 12 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

R 10 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , —(CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , —(CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, C 1 -C 4 alkoxy, an amino acid group, or [NR 11 C(O)(CH 2 ) n ] m NR 16 R 17 , which is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy, aryl alkyl, wherein the C 1 -C 4 alkyl and the aryl alkyl substituents are optionally substituted 1 to 3 times with halogen, alkyl, OH, NH 2 , —CO 2 H, —C(O)NH 2 , —NHC(O)NH 2 , —NHC(NH)NH 2 , imidazole, pyrolidine, SMe, SH, or SeH;

or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

R 14 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —S(O) q R 12 , —(CH 2 ) n NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —(CH 2 ) n NR 11 C(O)OR 12 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —(CH 2 ) n NR 11 C(O)OR 12 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , —OR 12 , —NR 12 R 13 , or an amino acid group;

R 15 is H, C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, or phenyl, wherein each of C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, and phenyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 16 and R 17 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , —C(O)OR 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;

or R 16 and R 17 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate compound having the structure

under conditions effective to form the product compound.

7 . The method according to claim 6 , wherein treating comprises reacting the first intermediate with R 1 Z 1 , wherein Z 1 is a halide.

8 . A method of making a product compound of formula I

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate compound having the structure:

under conditions effective to form the product compound.

9 . The method according to claim 8 , wherein treating comprises reacting the first intermediate with R 2 Z 2 , wherein Z 2 is a halide or H.

10 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

R 2 is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate compound having the structure:

under conditions effective to form the product compound.

11 . The method according to claim 10 , wherein treating comprises reacting the first intermediate compound with N—R 3 -succinimide.

12 . The method according to claim 10 , wherein R 3 is NO 2 and treating comprises reacting the first intermediate with a nitration agent.

13 . The method according to claim 12 , wherein the nitration agent is zirconyl(IV) nitrate hydrate.

14 . The method according to claim 12 further comprising:

reacting the product compound with a reducing agent.

15 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

R 4 is selected from the group consisting of H, halogen, —OR 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , (CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , phenyl, benzyl, ═NOR 14 , ═NR 14 , a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

16 . The method according to claim 15 , wherein R 4 is ═NR 14 and treating comprises reacting the first intermediate with NH 2 R 14 .

17 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

18 . The method according to claim 17 , wherein treating comprises reacting the first intermediate compound with R 5 Z 1 , wherein Z 1 is a halide.

19 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

R 2 is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of (CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 6 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , —N 12 R 13 , (CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;

R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —OR 12 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , (CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

20 . The method according to claim 19 , wherein X is N and treating comprises reacting the first intermediate with NH 2 R 6 .

21 . The method according to claim 19 further comprising:

reacting the product compound with a coupling agent such that R 5 and R 6 combine to form a heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and optionally substituted 1 to 3 times with halogen, oxo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy.

22 . The method according to claim 21 , wherein the coupling agent is carbonyldiimidazole.

23 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure

under conditions effective to form the product compound.

24 . The method according to claim 23 , wherein treating comprises reacting the first intermediate compound with N—R 7 -succinimide.

25 . The method according to claim 23 , wherein R 7 is —NO 2 and treating comprises reacting the first intermediate with a nitration agent.

26 . The method according to claim 25 , wherein the nitration agent is zirconyl(IV) nitrate hydrate.

27 . The method according to claim 25 further comprising:

reacting the product compound with a reducing agent.

28 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

29 . The method according to claim 28 , wherein treating comprises reacting the first intermediate with R 8 -M-L, wherein M is a metal and L is a halide.

30 . The method according to claim 28 , wherein treating comprises reacting the first intermediate with R 9 -M-L, wherein M is a metal and L is a halide.

31 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

32 . The method according to claim 31 , wherein Y is N and treating comprises reacting the first intermediate with NH 2 R 10 .

33 . A method of making a product compound of formula I:

wherein:

the carbohydrate anomeric carbon designated * is in the R or S configuration;

or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;

X is O or N;

Y is O or N;

m is 0, 1, 2, or 3;

n is 0 to 5;

q is 0, 1, or 2; and

represents an optional double bond;

said method comprising:

treating a first intermediate having the structure:

under conditions effective to form the product compound.

34 . The method according to claim 33 , wherein treating comprises reacting the first intermediate with an imidate having a formula:

35 . The method according to claim 34 , wherein the imidate is

Assignments (3)

CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 7541537 PREVIOUSLY RECORDED AT REEL: 034045 FRAME: 0951. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 14, 2018

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 046796/0352 →

RELEASE OF SECURITY INTEREST Recorded Aug 31, 2017

From: BARCLAYS BANK PLC, AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC; AMRI SSCI, LLC; EUTICALS INC.

Reel/Frame 043742/0085 →

SECURITY INTEREST Recorded Oct 24, 2014

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 034045/0951 →