US2009326258A1PendingUtilityA1
Process for the preparation of substituted tetralin and substituted indane derivatives
Est. expiryApr 21, 2024(expired)· nominal 20-yr term from priority
C07C 2602/10C07C 319/28C07B 2200/07C07C 319/20C07C 211/27C07C 319/14C07C 303/08C07C 319/02C07C 323/52A61P 3/06C07C 2602/08
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Claims
Abstract
The present invention relates to novel processes for the preparation of substituted tetralin and substituted indane derivatives. The present invention is further directed to novel processes for the preparation of intermediates in the preparation of the substituted tetralin and substituted indane derivatives.
Claims
exact text as granted — not AI-modified1 . A process for the preparation of a compound of formula (L)
wherein
Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic;
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO 3 H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen;
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
reacting the compound of formula (XI), to yield the corresponding compound of formula (L).
2 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 1 and further comprising
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
3 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO 3 H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen;
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
reacting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
alternatively, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then reacting the compound of formula (VIII) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XI);
reacting the compound of formula (XI), to yield the corresponding compound of formula (L);
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
4 . The process of claim 1 wherein Q is OPg 2 , Pg 2 is t-butyl, X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)-Q group is bound at the 5-position, R 3 is hydrogen, n is 1 and R 4 is ethyl
5 . The process of claim 2 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is 0, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
6 . The process of claim 3 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is 0, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
7 . A process for the preparation of a compound of formula (L)
wherein
Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic;
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO 3 H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen;
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII);
alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII);
alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);
reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (L).
8 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 7 and further comprising
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
9 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with a suitably substituted compound of formula (V) wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (VI); and then reacting the compound of formula (VI) with ClSO 3 H, to yield the corresponding compound of formula (VII);
alternatively, reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VII) wherein R 4 is hydrogen;
reacting the compound of formula (VII) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VII), to yield a mixture of the corresponding compound of formula (VIII) and the corresponding compound of formula (IX);
de-protecting the compound of formula (VIII), isolated or in a mixture with the compound of formula (IX), to yield the corresponding compound of formula (XIII);
alternatively, de-protecting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), to yield a corresponding compound of formula (XII); and then reducing the compound of formula (XII) with a reducing agent capable of reducing the disulfide on compound of formula (XII), to yield the corresponding compound of formula (XIII);
alternatively still, reacting the compound of formula (IX), isolated or in a mixture with the compound of formula (VIII), with a reducing agent capable of reducing the disulfide on compound of formula (IX), to yield the corresponding compound of formula (VIII); and then de-protecting the compound of formula (VIII), to yield the corresponding compound of formula (XIII);
reacting the compound of (XIII) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (L);
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
10 . The process of claim 7 wherein Q is OPg 2 , Pg 2 is t-butyl, X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)-Q group is bound at the 5-position, R 3 is hydrogen, n is 1 and R 4 is ethyl
11 . The process of claim 8 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
12 . The process of claim 9 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
13 . A process for the preparation of a compound of formula (L)
wherein
Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or and aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic;
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VIIa);
reacting the compound of formula (VIIa) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa), to yield a mixture of the corresponding compound of formula (VIIIa) and the corresponding compound of formula (IXa);
de-protecting the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein W is Cl, Br or I, in the presence of a base, to yield the corresponding compound of formula (La);
alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (VIIIa); then reacting the compound of formula (VIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La);
alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (La);
reacting the compound of formula (La) with a suitably substituted compound of formula (V) wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb);
alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (La), wherein R 4b is selected from (C 1-4 straight chain alkylene)R 15 or (straight chain C 1-4 alkylene)R 16 , in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb).
14 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 13 and further comprising
reacting the compound of formula (L), to yield the corresponding compound of formula (I).
15 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4 is H or —(C 1-5 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4 has no more than 9 carbon atoms;
alternatively, R 4 is -(straight chain C 1-5 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a compound of formula (III), to yield the corresponding compound of formula (IV), wherein Pg 1 is a nitrogen protecting group which is inert to ClSO 3 H;
reacting the compound of formula (IV) with ClSO 3 H, to yield the corresponding compound of formula (VIIa);
reacting the compound of formula (VIIa) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (VIIa), to yield a mixture of the corresponding compound of formula (VIIIa) and the corresponding compound of formula (IXa);
de-protecting the compound of formula (VIIIa), isolated or in a mixture with the compound of formula (IXa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (La);
alternatively, reacting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), with a reducing agent capable of reducing the disulfide on the compound of formula (IXa), to yield the corresponding compound of formula (VIIIa); then reacting the compound of formula (VIIIa) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (XIa); and then reacting the compound of formula (XIa), to yield the corresponding compound of formula (La);
alternatively still, de-protecting the compound of formula (IXa), isolated or in a mixture with the compound of formula (VIIIa), to yield the corresponding compound of formula (XIIa); then reacting the compound of formula (XIIa) with a reducing agent capable of reducing the disulfide on the compound of formula (XIIa), to yield the corresponding compound of formula (XIIIa); and then reacting the compound of formula (XIIIa) with a suitably substituted compound of formula (X), wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and wherein W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (La);
reacting the compound of formula (La) with a suitably substituted compound of formula (V), wherein R 4a is R 4 other than hydrogen and wherein J is Br, Cl or I, to yield the corresponding compound of formula (Lb);
alternatively, reacting the compound of formula (La) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (La), wherein R 4b is selected from (C 1-4 straight chain alkylene)R 15 or (straight chain C 1-4 alkylene)R 16 , in the presence of a base, to yield the corresponding compound of formula (XVIII); and then reacting the compound of formula (XVIII) with a reducing agent capable of reducing the amide on the compound of formula (XVIII), to yield the corresponding compound of formula (Lb);
reacting the compound of formula (La) or the compound of formula (Lb), to yield the corresponding compound of formula (I).
16 . The process of claim 13 wherein Q is OPg 2 , Pg 2 is t-butyl, X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)-Q group is bound at the 5-position, R 3 is hydrogen, n is 1 and R 4 is ethyl.
17 . The process of claim 14 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
18 . The process of claim 15 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
19 . A process for the preparation of a compound of formula (Lc)
wherein
Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic;
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
reacting the compound of formula (XIV) with ClSO 3 H, to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII):
reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb);
alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
20 . A process for the preparation of a compound of formula (Ic)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 19 and further comprising
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
21 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
reacting the compound of formula (XIV) with ClSO 3 H, to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group on the compound of formula (XV), to yield a mixture of the corresponding compound of formula (XVI) and the corresponding compound of formula (XVII);
reacting the compound of formula (XVI), isolated or in a mixture with the compound of formula (XVII), with a reducing agent capable of reducing the amide on the compound of formula (XVI), to yield the corresponding compound of formula (XIIIb);
alternatively, reacting the compound of formula (XVII), isolated or in a mixture with the compound of formula (XVI), with a reducing agent capable of reducing the amide and the disulfide on the compound of formula (XVII), to yield the corresponding compound of formula (XIIIb);
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (Lc);
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
22 . The process of claim 19 wherein Q is OPg 2 , Pg 2 is t-butyl, X is S, R 1 is methyl, R 2 is methyl, wherein the —X—C(R 1 R 2 )—C(O)Q group is bound at the 5-position, R 3 is hydrogen, n is 1 and R 4 is ethyl
23 . The process of claim 20 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
24 . The process of claim 21 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
25 . A process for the preparation of a compound of formula (Lc)
wherein
Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic;
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
reacting the compound of formula (XIV) with ClSO 3 H, to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein W is Br, Cl or I, in the presence of a base, to yield the corresponding compound of formula (Lc).
26 . A process for the preparation of a compound of formula (IC)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising the process of claim 25 and further comprising
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
27 . A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof,
wherein
each of R 1 and R 2 is independently H, C 1-6 alkyl, (CH 2 ) m NR a R b , (CH 2 ) m OR 8 , (CH 2 ) m NH(CO)R 8 or (CH 2 ) m CO 2 R 8 ;
wherein each of R a , R b , and R 8 is independently H or C 1-6 alkyl; and m is an integer from 1 to 6;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl;
n is an integer from 1 to 2;
X is S;
provided that when n is 1, X is bound at the 5 or 6 position; and when n is 2, X is bound at the 6 or 7 position; provided further that when n is 2 and X is bound at the 6 position, then R 3 is other than hydrogen and bound at the 7 position;
R 3 is H, C 1-3 alkoxy, C 1-3 alkylthio, halo, C 1-6 alkyl, NR 9 R 10 , NHCOR 10 , CONHR 10 or COOR 10 ; and R 3 is ortho or meta to X; provided that R 3 is other than CF 3 ;
each R 9 and R 10 is independently C 1-6 alkyl;
R 4b is —(C 1-4 straight chain alkylene)R 15 ; wherein R 15 is H, C 1-7 alkyl, [di(C 1-2 alkyl)amino](C 1-6 alkylene)-, (C 1-3 alkoxyacyl)(C 1-6 alkylene)-, C 1-6 alkoxy, C 3-7 alkenyl or C 3-8 alkynyl;
wherein R 4b has no more than 8 carbon atoms;
alternatively, R 4b is -(straight chain C 1-4 alkylene)R 16 ; wherein R 16 is C 3-6 cycloalkyl or a 5-6 membered non-aromatic heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
c is an integer from 0 to 1;
each of R 5 and R 7 is independently selected from H, C 1-6 alkyl, halo, cyano, nitro, COR 11 , COOR 11 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 11 R 12 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
R 6 is selected from C 1-6 alkyl, halo, cyano, nitro, COR 13 , COOR 13 , C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, phenyl, NR 13 R 14 or a 5-6 membered heterocyclyl with between 1 and 2 heteroatoms selected from N, O, and S;
alternatively, R 5 and R 6 or R 6 and R 7 may be taken together to be a bivalent moiety, saturated or unsaturated, selected from C 3-4 alkylene, C 3-4 alkenylene or (CH 1-2 ) p N(CH 1-2 ) q ;
p is an integer from 0 to 2 and q is an integer from 1 to 3; wherein the sum (p+q) is at least 2;
each R 11 , R 12 , R 13 and R 14 is independently H or C 1-6 alkyl;
wherein each of the above hydrocarbyl and heterocarbyl moieties may be optionally substituted with between 1 and 3 substituents independently selected from F, Cl, Br, I, amino, methyl, ethyl, hydroxy or methoxy;
comprising
reacting a suitably substituted compound of formula (III) with a suitably substituted acylating agent capable of attaching an —C(O)—R 4b group onto the nitrogen of the compound of formula (III), in the presence of a base, to yield the corresponding compound of formula (XIV);
reacting the compound of formula (XIV) with ClSO 3 H, to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with a reducing agent capable of reducing the chlorosulfonyl group and the amide group on the compound of formula (XV), to yield the corresponding compound of formula (XIIIb);
reacting the compound of formula (XIIIb) with a suitably substituted compound of formula (X) wherein Q is selected from the group consisting of OH, OPg 2 , NH 2 and N(Pg 3 Pg 4 ); wherein Pg 2 is a carboxylic acid protecting group; and wherein Pg 3 and Pg 4 are each independently selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl or aryl; or Pg 3 and Pg 4 are taken together with the nitrogen atom to which they are bound to form C 3-10 heteroaryl or C 3-10 non-aromatic heterocyclic; and W is Br, Cl or I; in the presence of a base, to yield the corresponding compound of formula (Lc);
reacting the compound of formula (Lc), to yield the corresponding compound of formula (Ic).
28 . The process of claim 25 wherein Q is OPg 2 , Pg 2 is t-butyl, X is S, R 1 is methyl, R 2 is methyl, wherein the —X—C(R 1 R 2 )—C(O)Q group is bound at the 5-position, R 3 is hydrogen, n is 1 and R 4 is ethyl
29 . The process of claim 26 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
30 . The process of claim 27 wherein X is S, R 1 is methyl, R 2 is methyl, the —X—C(R 1 R 2 )—C(O)—OH group is bound at the 5-position, R 3 is hydrogen, n is 1, R 4 is ethyl, c is O, R 5 is hydrogen, R 6 is trifluoromethoxy and R 7 is hydrogen.
31 . A process for the preparation of a compound of formula (Le)
wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising
(a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (R,S) diastereomeric salt, the compound of formula (XX);
(b) reacting the (R,S) diastereomeric salt, the compound of formula (XX), with an inorganic base, to yield the corresponding compound of formula (Le).
32 . The process of claim 31 wherein Q b is t-butoxy.
33 . A process for the preparation of a compound of formula (Le)
wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising
(a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C.; or in THF at about room temperature; to yield the corresponding (R,R) diastereomeric salt, the compound of formula (XXI);
(b) reacting the (R,R) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Le).
34 . The process of claim 33 wherein Q b is t-butoxy.
35 . A process for the preparation of the compound of formula (Lf)
wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising
(a) reacting a compound of formula (Ld) with (S)-2-(4-hydroxyphenoxy)propionic acid, in acetone, at a temperature greater than about 35° C.; or in THF at about room temperature; to yield the corresponding (S,S) diastereomeric salt, the compound of formula (XXII);
(b) reacting the (S,S) diastereomeric salt, the compound of formula (XXI) with an inorganic base, to yield the corresponding compound of formula (Lf).
36 . A process for the preparation of the compound of formula (Lf)
wherein Q b is selected from the group consisting of C 1-6 alkoxy, wherein the C 1-6 alkoxy is not substituted with amino; comprising
(a) reacting a compound of formula (Ld) with (R)-2-(4-hydroxyphenoxy)propionic acid, in an alcohol; or in acetone, at a temperature in the range of from about 35° C. to about 0° C.; to yield the corresponding (S,R) diastereomeric salt, the compound of formula (XXIII);
(b) reacting the (S,R) diastereomeric salt, the compound of formula (XXIII) with an inorganic base, to yield the corresponding compound of formula (Lf).
37 . A crystalline N,N′-dibenzylethylenediamine salt of a compound of formula (IIa)
38 . The crystalline salt as in claim 37 wherein the ratio of the compound of formula (IIa) to the N,N′-dibenzylethylenediamine is 1:1.
39 - 42 . (canceled)
43 . A compound of formula (IIa) comprising the structure:
or a pharmaceutically acceptable salt, C 1-6 ester or C 1-6 amide thereof.
44 . The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 90%.
45 . The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 96%.
46 . The compound of claim 43 wherein said compound has an enantiomeric excess of at least about 99%.
47 . A compound comprising the structure:
48 . The compound of claim 47 wherein said compound has an enantiomeric excess of at least about 90%.
49 . The compound of claim 47 wherein said compound has an enantiomeric excess of at least about 96%.
50 . The compound of claim 47 wherein said compound has an enantiomeric excess of at least about 99%.
51 . A pharmaceutical composition comprising the compound of claim 43 .
52 . A pharmaceutical composition comprising the compound of claim 47Cited by (0)
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