METHODS FOR MANUFACTURE OF SMALL MOLECULE ACTIVATORS OF TIE-2
Disclosed herein are compounds effective for modulation of Tie-2 activity and inhibition of HPTP-beta, and methods of preparation thereof. The compounds can provide effective therapy for vascular disorders that can include, for example, retinopathies, ocular edema, and ocular neovascularization.
1 . A pharmaceutical composition comprising a mixture of a Tie-2 modulator and a second compound, wherein:
(a) each of the Tie-2 modulator and the second compound has a core structure and a nitrogen atom substituent bound to the core structure at a position on the core structure;
(b) the core structure of the Tie-2 modulator is identical to the core structure of the second compound;
(c) the position on the core structure of the Tie-2 modulator to which the nitrogen atom substituent is bound is identical to the position on the core structure of the second compound to which the nitrogen atom substituent is bound;
(d) the nitrogen atom substituent of the Tie-2 modulator is —N(H)(E), wherein E is a group that contains a sulfur atom bound to the nitrogen atom;
(e) the nitrogen atom substituent of the second compound is —NH 2 ; and
(f) the pharmaceutical composition is substantially free of solvent.
2 . The pharmaceutical composition of claim 1 , wherein the Tie-2 modulator forms at least about 99.0% (a/a) of the mixture as determined by a liquid chromatography assay, and wherein the second compound forms from about 0.001% to about 0.5% (a/a) of the mixture as determined by the liquid chromatography assay.
3 . The pharmaceutical composition of claim 1 , wherein the nitrogen atom substituent of the Tie-2 modulator is a sulfamate group.
4 . The pharmaceutical composition of claim 1 , wherein the second compound is a desulfonylation congener of the Tie-2 modulator.
5 . The pharmaceutical composition of claim 1 , wherein:
the Tie-2 modulator has a structure of Q-Z; and
the second compound has a structure of W—Z, wherein
Q is
W is H 2 N—; and
each Z is the core structure.
6 . The pharmaceutical composition of claim 5 , wherein each Z is:
wherein
Aryl 2 is an aryl group which is substituted or unsubstituted;
X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and
Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), or NHCOR g , any of which is substituted or unsubstituted, or
wherein:
L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d forms a ring that is substituted or unsubstituted;
R c is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d forms a ring that is substituted or unsubstituted;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R c forms a ring that is substituted or unsubstituted; and
R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
7 . The pharmaceutical composition of claim 6 , wherein:
Aryl 2 is substituted or unsubstituted heteroaryl; and
X is alkylene.
8 . (canceled)
9 . The pharmaceutical composition of claim 5 , wherein each Z is:
wherein:
Aryl 2 is substituted heteroaryl;
L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;
R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;
R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;
R c is H or alkyl which is substituted or unsubstituted; and
R d is H or alkyl which is substituted or unsubstituted.
10 . The pharmaceutical composition of claim 9 , wherein:
Aryl 2 is a substituted thiazole moiety;
L 2 together with the nitrogen atom to which L 2 is bound forms a carbamate linkage;
R a is alkyl, which is substituted or unsubstituted;
R b is arylalkyl, which is substituted or unsubstituted;
R c is H; and
R d is H.
11 . The pharmaceutical composition of claim 10 , wherein Aryl 2 is:
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and
R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
12 - 14 . (canceled)
15 . The pharmaceutical composition of claim 6 , wherein each Z is:
16 . (canceled)
17 . The pharmaceutical composition of claim 10 , wherein Aryl 2 is:
wherein:
R e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and
R f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
18 . The pharmaceutical composition of claim 17 , wherein:
R c is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and
R f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.
19 - 20 . (canceled)
21 . The pharmaceutical composition of claim 6 , wherein each Z is:
22 - 25 . (canceled)
26 . The pharmaceutical composition of claim 2 , wherein the Tie-2 modulator forms at least about 99.2% to about 99.5% (a/a) of the mixture as determined by the liquid chromatography assay.
27 - 29 . (canceled)
30 . The pharmaceutical composition of claim 2 , wherein the second compound forms from about 0.001% to about 0.1% (a/a) of the mixture as determined by the liquid chromatography assay.
31 - 34 . (canceled)
35 . The pharmaceutical composition of claim 1 , wherein the composition comprises no more than about 100 ppm of a third compound as determined by HPLC, wherein the third compound comprises an azoxy moiety.
36 - 37 . (canceled)
38 . The pharmaceutical composition of claim 5 , wherein the composition comprises no more than about 100 ppm of a third compound as determined by HPLC, wherein the third compound has a structure of Z-J-Z, wherein J is
39 . (canceled)
40 . A process for preparing a composition, the process comprising:
(i) contacting an initial quantity of an amine with a sulfur trioxide source in a solvent to afford a first mixture, wherein the first mixture comprises a quantity of a first ion pair that is a sulfamate anion and an organic cation; and
(ii) contacting the first ion pair with a sodium cation source to provide a second mixture, wherein the second mixture comprises a second ion pair and the amine, wherein the second ion pair is a sodium cation and the sulfamate anion,
wherein the initial quantity of the amine is at least 1 kg, and a ratio of the sulfamate anion to the amine in the second mixture is at least 99:1 (a/a) as determined by a liquid chromatography assay.
41 - 76 . (canceled)
77 . The process of claim 40 , wherein:
i) the sulfamate anion is of formula (Ia5):
and
ii) the amine is of formula (IIa5):
78 - 112 . (canceled)
113 . A process comprising reducing a nitro compound in presence of a solvent to provide a reaction mixture comprising an amino compound, wherein the amino compound is a desulfonylation congener of a Tie-2 modulator, and a solubility of the solvent in water is less than about 20 grams of the solvent per 100 grams of water at 20° C.
114 - 123 . (canceled)
124 . The process of claim 113 , wherein:
i) the nitro compound is of formula (IVa1):
and
ii) the amine is of formula (IIa1):
125 - 145 . (canceled)
146 . A process comprising contacting an acid of formula (V):
with an amine compound of formula (VI):
or a salt thereof,
in presence of an amide coupling reagent and a solvent to provide a reaction mixture, the reaction mixture comprising an amide of formula (VII):
wherein:
Aryl 1 is an aryl group which is substituted or unsubstituted;
Aryl 2 is an aryl group which is substituted or unsubstituted;
X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond;
L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d forms a ring that is substituted or unsubstituted;
R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d forms a ring that is substituted or unsubstituted;
R c is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a R b , and R d forms a ring that is substituted or unsubstituted;
R d is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a R b , and R c forms a ring that is substituted or unsubstituted; and
R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, wherein a solubility of the solvent in water is less than about 20 grams of the solvent per 100 grams of water at 20° C.
147 - 164 . (canceled)
165 . The process of claim 146 , wherein:
i) the acid is of formula (Va1):
ii) the amine is of formula (VIc1):
and
iii) the amide is of formula (VIIc1):
166 - 174 . (canceled)
175 . A process comprising contacting a quantity of L-phenylalanine with a quantity of methyl chloroformate in presence of a base and a solvent to form a reaction mixture, wherein the reaction mixture comprises a quantity of a compound of formula (Va1):
and a quantity of a side-product of formula (VIII):
and
wherein an area/area ratio of the quantity of the compound of formula (Va1) to the quantity of the side-product of formula (VIII) is at least about 95:5 as determined by a liquid chromatography assay, wherein the assay is performed on a sample of the reaction mixture that is obtained at least about 1 hour after initiation of the contacting, and wherein the quantity of methyl chloroformate is at least 1 kg.
176 - 183 . (canceled)
184 . The process of claim 175 , wherein the contacting comprises:
(i) dissolving the quantity of L-phenylalanine and the base in the solvent to provide a basic solution; and
(ii) adding the quantity of the methyl chloroformate to the basic solution to form the reaction mixture.
185 - 190 . (canceled)
191 . A composition comprising:
a) a compound of formula (Ia6):
and
b) a compound of formula (IIa6):
in a mixture, wherein the compound of formula (Ia6) forms at least about 99.0% (a/a) of the composition as determined by UPLC, and wherein the compound of formula (IIa6) forms from about 0.001% to about 0.5% (a/a) of the composition as determined by UPLC, wherein the composition is substantially free of solvent.
192 - 198 . (canceled)
199 . The composition of claim 191 , comprising no more than 100 ppm of a compound of formula (G-2):
200 . A compound of formula (G-2):