US2010267757A1PendingUtilityA1
Aminothiazoles and their uses
Est. expiryMay 31, 2026(expired)· nominal 20-yr term from priority
A61P 31/00A61P 3/04A61P 31/04A61P 17/10A61P 17/02A61K 38/00C07K 5/06139C07K 5/06C07D 417/14Y02A50/30
34
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Claims
Abstract
The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases.
Claims
exact text as granted — not AI-modified1 . A compound of the formula I:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
A is selected from the group consisting of a bond, H, —(CH 2 )—, —C(alkyl) 2 -, —(CH 2 ) 1-8 —, —[C(alkyl) 2 ] 1-8 —, -(cycloalkyl)-, -(aryl)-, -(heteroaryl)-, —C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —S(O) 2 N(R 8a )—, —S(O)N(R 8a )—, —C(═NR 8 )N(R 8a )—, —C(═NR 8 )N(R 8a )C(O)—, —C(═NR 8 )—, —C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R 8a )—;
G is absent, or selected from the group consisting of H, —[C(R a )(R b )] x —, —[C(R a )(R b )] x —O—[C(R a )(R b )] y —, —[C(R a )(R b )] x —N(R 8a )—[C(R a )(R b )] y —, -(cycloalkyl)-, -(heterocycle)-, -(aryl)-, -(heteroaryl)-;
J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N + (R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle;
R a is selected from the group consisting of H, alkyl, F, CO 2 H, CO 2 -alkyl, —N(R 1 ) 2 , —OR 1 , —(CH 2 ) 0-4 -J and —R 4b ;
R b is selected from the group consisting of H, alkyl, and F;
x and y are each, independently, integers from 0-10;
R 1 is selected from —H, —C(alkyl) 2 -J, —R 4b .
R 2a is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is selected from the group consisting of absent, H and alkyl, or R 2a and R 2b may together form ═O or ═NH;
R 3 an R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -G-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H, and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
R 8 is selected from the group consisting of H, CN, NO 2 , alkyl, cycloalkyl, and SO 2 -alkyl;
R 8a is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a can also cyclize with the atom to which R 8a is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.
2 . The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
3 . The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
4 . The compound of claim 1 , wherein formula I is represented by a compound of formula II:
and pharmaceutically acceptable salts thereof.
5 . A compound of the formula III:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 12 , A, G and J have the meanings set forth for formula I;
and ring L is selected form the group consisting of cycloalkyl, heterocycle, aryl and heteroaryl, all of which may be further optionally substituted with -A-G-J.
6 . The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
7 . The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
8 . The compound of claim 5 , wherein formula III is represented by a compound of formula IV:
and pharmaceutically acceptable salts thereof
wherein
ring L, A, G and J have the meanings set forth for formula III.
9 . A compound of the formula V:
wherein A-G-J is R 1a ;
wherein R 1 , R 1a and R 2a are each, independently, selected from the group consisting of H, substituted or unsubstituted alkyl, alkyl-aryl, heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy and heterocyclylamino; all of which may be further independently substituted one or more times with Z 1 and Z 2 ; wherein Z 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl; wherein Z 1 can be independently substituted with one or more of Z 2 moieties which can be the same or different and are independently selected; wherein Z 2 is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, keto, ester or nitro; wherein each of said alkyl, alkoxy, and aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl and heteroarylalkyl;
or R 1 and R 1a may together form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different.
10 . The compound of claim 1 , wherein R 1 is H or CH 3 , and A-G-J together form H, or together form a functional group selected from the group consisting of
11 . The compound of claim 1 , wherein R 1 is H, and A-G-J together form a functional group selected from the group consisting of
wherein R 13 is selected from the group consisting of hydrogen, hydroxymethyl, and aminomethyl or from the group consisting of:
wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
12 . The compound of claim 9 , wherein R 2a is OH or OAc.
13 . The compound of claim 1 , wherein the core pyridine functionality is of the following N-oxide formula:
14 . A compound of claim 1 , wherein when J is not F, J is bonded to O or N.
15 . A compound claim 1 , wherein when R b is not F, R a is —(R 1 ) 2 .
16 . A compound of the formula VI:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
R is -(heteroaryl)-A-G-Q-J;
A is a bond or is selected from the group consisting of —C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —S(O) 2 N(R 8a )—, —S(O)N(R 8a )—, —C(═NR 8 )N(R 8a )—, —C(═NR 8 )N(R 8a )C(O)—, —C(═NR 8 )—, —C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R 8a )—;
G is absent, selected from the group consisting of —[C(R a )(R b )] x —, —[C(R a )(R b )] x —C(R a )═C(R a )—[C(R a )(R b )] y —, —[C(R a )(R b )] x —O—[C(R a )(R b )] y —, and —[C(R a )(R b )] x —N(R 8a )—[C(R a )(R b )] y —, or is selected from the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-, and -(heteroaryl)- each of which has 0-4 substituents;
Q is absent, selected from the group consisting of —C(O)—[C(R a )(R b )] x —, —C(O)—[C(R a )(R b )] x —C(R a )═C(R a )—[C(R a )(R b )] y —, —C(O)—[C(R a )(R b )] x —O—[C(R a )(R b )] y —, and —C(O)—{N(R 8a )—[C(R a )(R b )] y } p —, or is selected from the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-, -(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-, —C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4 substituents;
J is selected from the group consisting of H, C 1-4 alkyl, halogen, C 1-4 alkoxy, hydroxy, amino, mono- and di-C 1-4 alkylamino, triC 1-4 alkylammonium, N(R 8a )C(O)C 1-4 alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CH 2 CO 2 H, CH 2 C(═O)N(R 8a ) 2 , CO 2 —C 1-4 alkyl, C(O)C 1-4 alkyl, P(O)(OH) 2 , P(O)(O—C 1-4 alkyl) 2 , C 0-4 alkylene-(cycloalkyl) and C 0-4 alkylene-(heterocycle), which heterocycle may be substituted 0-4 times;
R a is selected from the group consisting of H, alkyl, F, CO 2 H, CO 2 -alkyl, —N(R 1 ) 2 , —OR 1 , —(CH 2 ) 0-4 -J and —R 4b ;
R b is selected from the group consisting of H, alkyl, and F;
p is 0, 1, 2, or 3;
x and y are each, independently selected at each occurrence from integers from 0-10;
R 2 is hydrogen, C 1-6 -alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 0-6 alkyl, C 3-7 cycloalkylC 0-4 alkyl, arylC 0-4 alkyl, or a residue of the formula:
R 2a is selected from the group consisting of H, C 1-6 alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is H or C 1-6 alkyl, or R 2a and R 2b taken in combination form an oxo or imino group;
R 3 and R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -G-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
R 8 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, and SO 2 —C 1-6 alkyl;
R 8a is absent, or selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl substituted with J, and R 4b , or two R 8a residues, taken in combination may form a saturated, unsaturated or aromatic ring having 3 to 7 ring atoms, which ring may be substituted 0-4 times; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.
17 . The compound of claim 16 , wherein R 2 is a residue of the formula:
R 2a is selected from the group consisting of H, C 1-6 alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ; and
R 2b is H or C 1-6 alkyl, or R 2a and R 2b taken in combination form an oxo or imino group.
18 . The compound of claim 16 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
19 . The compound of claim 16 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
20 - 21 . (canceled)
22 . The compound of claim 16 , wherein R 2a is OH or OAc and R 2b is H.
23 . The compound of claim 16 , wherein A is C(O), C(O)O, or C(O)NH;
G is C 4-7 cycloalkyl; Q is absent; and J is CO 2 H or CO 2 C 1-4 alkyl.
24 . The compound of claim 16 , wherein formula VI is represented by a compound of formula VII:
and pharmaceutically acceptable salts thereof.
25 . A compound of the formula VIII:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
is a 4-7 membered heteroaryl ring having 0-2 additional ring heteroatoms which is substituted with a -A-G-Q-J residue and 0-4 additional substituents;
A is a bond or is selected from the group consisting of —C(O)—, —C(O)C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —S(O) 2 N(R 8a )—, —S(O)N(R 8a )—, —C(═NR 8 )N(R 8a )—, —C(═NR 8 )N(R 8a )C(O)—, —C(═NR 8 )—, —C═C—C(O)—, —C═C—C(O)O—, —C═C—C(O)N(R 8a )—;
G is absent, selected from the group consisting of —[C(R a )(R b )] x —, —[C(R a )(R b )] x —C(R a )═C(R a )—[C(R a )(R b )] y —, —[C(R a )(R b )] x —O—[C(R a )(R b )] y —, and —[C(R a )(R b )] x —N(R 8a )—[C(R a )(R b )] y —, or is selected from the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-, and -(heteroaryl)- each of which has 0-4 substituents;
Q is absent, selected from the group consisting of —C(O)—[C(R a )(R b )] x —, —C(O)—[C(R a )(R b )] x —C(R a )═C(R a )—[C(R a )(R b )] y —, —C(O)—[C(R a )(R b )] x —O—[C(R a )(R b )] y —, and —C(O)—{N(R 8a )—[C(R a )(R b )] y } p —, or is selected from the group consisting of -(cycloalkyl)-, -(heterocycle)-, -(aryl)-, -(heteroaryl)-, —C(O)-(cycloalkyl)-, —C(O)-(heterocycle)-, —C(O)-(aryl)-, and —C(O)-(heteroaryl)-, each of which has 0-4 substituents;
J is selected from the group consisting of H, C 1-4 alkyl, halogen, C 1-4 alkoxy, hydroxy, amino, mono- and di-C 1-4 alkylamino, triC 1-4 alkylammonium, N(R 8a )C(O)C 1-4 alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CH 2 CO 2 H, CH 2 C(═O)N(R 8a ) 2 , CO 2 —C 1-4 alkyl, C(O)C 1-4 alkyl, P(O)(OH) 2 , P(O)(O—C 1-4 alkyl) 2 , C 0-4 alkylene-(cycloalkyl) and C 0-4 alkylene-(heterocycle), which heterocycle may be substituted 0-4 times;
R a is selected from the group consisting of H, alkyl, F, CO 2 H, CO 2 -alkyl, —N(R 1 ) 2 , —OR 1 , —(CH 2 ) 0-4 -J and —R 4b ;
R b is selected from the group consisting of H, alkyl, and F;
p is 0, 1, 2, or 3;
x and y are each, independently selected at each occurrence from integers from 0-10;
R 1 is independently selected at each occurrence from —H, alkyl substituted with J, and —R 4b ;
R 2 is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 0-6 alkyl, C 3-7 cycloalkylC 0-4 alkyl, arylC 0-4 alkyl, or a residue of the formula:
R 2a is selected from the group consisting of H, C 1-6 alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is H or C 1-6 alkyl, or R 2a and R 2b taken in combination form an oxo or imino group;
R 3 and R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -G-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
R 8 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, and SO 2 —C 1-6 alkyl;
R 8a is absent, or selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl substituted with J, and R 4b , or two R 8a residues, taken in combination may form a saturated, unsaturated or aromatic ring having 3 to 7 ring atoms, which ring may be substituted 0-4 times; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.
26 . The compound of claim 25 , wherein R 2 is a residue of the formula:
R 2a is selected from the group consisting of H, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ; and
R 2b is H or C 1-6 alkyl, or R 2a and R 2b taken in combination form an oxo or imino group.
27 . The compound of claim 25 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
28 . The compound of claim 25 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
29 . The compound of claim 25 , wherein
is an imidazolyl ring; and A-G-Q-J together form H, or together form a functional group selected from the group consisting of
30 . The compound of claim 25 , wherein
is an imidazolyl ring; and A-G-Q-J together form a functional group selected from the group consisting of
wherein R 13 is selected from the group consisting of hydrogen, hydroxymethyl, and aminomethyl or from the group consisting of:
n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
31 . The compound of claim 25 , wherein R 2a is OH or OAc and R 2b is H.
32 . (canceled)
33 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of claim 1 such that the bacterial infection is treated.
34 . (canceled)
35 . A method of treating, inhibiting or preventing the activity of EF-Tu in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 1 .
36 . The method of claim 35 , wherein a bacterial infection is treated in a subject in need thereof.
37 - 39 . (canceled)
40 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound claim 1 in combination with a pharmaceutically effective amount of an additional therapeutic agent, such that the bacterial infection is treated.
41 . The method of claim 40 wherein the compound of claim 1 and the other pharmaceutical agent are administered as part of the same pharmaceutical composition.
42 . The method of claim 40 wherein the compound of claim 1 and the other therapeutic agent are administered as separate pharmaceutical compositions, and the compound is administered prior to, at the same time as, or following administration of the other agent.
43 . (canceled)
44 . A method of treating acne in subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 1 .
45 . A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier or diluent.
46 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of claim 16 such that the bacterial infection is treated.
47 . A method of treating, inhibiting or preventing the activity of EF-Tu in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 16 .
48 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of claim 16 in combination with a pharmaceutically effective amount of an additional therapeutic agent, such that the bacterial infection is treated.
49 . The method of claim 40 wherein the compound of claim 16 and the other pharmaceutical agent are administered as part of the same pharmaceutical composition.
50 . The method of claim 40 wherein the compound of claim 16 and the other therapeutic agent are administered as separate pharmaceutical compositions, and the compound is administered prior to, at the same time as, or following administration of the other agent.
51 . A method of treating acne in subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 16 .
52 . A pharmaceutical composition comprising a compound of claim 16 and at least one pharmaceutically acceptable carrier or diluent.
53 . The compound of claim 5 wherein R 1 is H, and A-G-J together form a functional group selected from the group consisting of
wherein R 13 is selected from the group consisting of hydrogen, hydroxymethyl, and aminomethyl or from the group consisting of:
wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.
54 . The compound of claim 9 wherein R 1 is H, and A-G-J together form a functional group selected from the group consisting of
wherein R 13 is selected from the group consisting of hydrogen, hydroxymethyl, and aminomethyl or from the group consisting of:
wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000.Cited by (0)
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