Methods for manufacture of small molecule activators of tie-2
AssigneeEyePoint Pharmaceuticals, Inc.
InventorsJohn JANUSZ, Jared RANDALL, James COPP
Life of this patent
Estimating the term…
Abstract
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.
Claims47
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 —NH2;
- and
- (f) the pharmaceutical composition is substantially free of solvent.
(canceled)
12-14. (canceled)
(canceled)
19-20. (canceled)
22-25. (canceled)
27-29. (canceled)
31-34. (canceled)
36-37. (canceled)
(canceled)
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)
78-112. (canceled)
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)
125-145. (canceled)
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:
- Aryl1 is an aryl group which is substituted or unsubstituted;
- Aryl2 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;
- L2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L2 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 Ra, Rb, Rc, and Rd forms a ring that is substituted or unsubstituted;
- Ra is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L2, Rb, Rc, and Rd forms a ring that is substituted or unsubstituted;
- Rb is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L2, Ra, Rc, and Rd forms a ring that is substituted or unsubstituted;
- Rc is H or alkyl which is substituted or unsubstituted, or together with any of L2, RaRb, and Rd forms a ring that is substituted or unsubstituted;
- Rd is H or alkyl which is substituted or unsubstituted, or together with any of L2, RaRb, and Rc forms a ring that is substituted or unsubstituted;
- and
- Rg 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)
166-174. (canceled)
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)
185-190. (canceled)
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)
A compound of formula (G-2):
Dependencies are inferred from the claim text.