Process of making somatostatin modulators
AssigneeCrinetics Pharmaceuticals, Inc.
InventorsJayachandra P. REDDY, Mahmoud MIRMEHRABI, Madhukar KOTA, Uttam DASH, Jian ZHAO, Yunfei ZHU
Life of this patent
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Abstract
Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.
Claims66
3-[4-(4-Amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof, having the following structure:
Crystalline 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof.
A method of making crystalline 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof, comprising the steps of:
- (a) slurrying 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride in 5 volumes of isopropanol:water (1:1) mixture;
- (i) heating the slurry of (a) to about 45° C.;
- (ii) adding about 0.5 to about 1.2 equivalents of ammonium hydroxide solution, sodium bicarbonate solution, or sodium hydroxide solution to the heated slurry of step (a)(i) to achieve a pH of about 4.0-6.0;
- (iii) adding water over about 2 hours to the mixture of step (a)(ii);
- and
- (iv) filtering the slurry of step (a)(iii) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof;
- or
- (b) adding a suitable solvent to 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile;
- (i) adding about 1 equivalent of hydrochloric acid to the mixture of solvent and 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile of (b);
- and
- (ii) filtering the solids resulting from step (b)(ii) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof;
- or
- (c) stirring 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride in about 20 volumes to about 50 volumes of water;
- and
- (i) filtering the solids of step (c) to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride, or solvate thereof.
A process for the synthesis of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride:
- comprising the step of treating Compound A-VI:
- with hydrochloric acid in a suitable solvent.
A process for the synthesis of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride:
- comprising the steps of:
- (1) treating Compound A-VI:
- with hydrochloric acid in a suitable solvent to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride;
- and
- (2) treating 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile dihydrochloride with aqueous ammonia to provide 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxy-benzonitrile monohydrochloride.
A process for the preparation of Compound A-VI:
- comprising the steps of:
- (1) reacting Compound A-IV:
- with Compound 1:
- wherein,
- B is a boronic acid, bononate ester, or trifluoroborate;
- in the presence of a coupling catalyst, a suitable base, and in a suitable solvent, to provide Compound A-V:
- and
- (2) reacting Compound A-V with 3,5-difluorophenylboronic acid:
- in the presence of a coupling catalyst, a suitable base, and in a suitable solvent, to provide Compound A-VI.
A process for the preparation of Compound A-IV:
- comprising the steps of:
- (1) chlorinating Compound A-I
- with a suitable chlorinating agent in a suitable solvent to provide Compound A-II
- (2) brominating Compound A-II with a suitable brominating agent in a suitable solvent to provide Compound A-III:
- and
- (3) coupling 4-(N-Boc amino)piperidine with Compound A-III in the presence of a suitable base and in a suitable solvent to provide Compound A-IV;
- or
- (i) coupling 4-(N-Boc amino)piperidine with 6-bromo-4-chloro-quinoline in the presence of a suitable base and in a suitable solvent to provide Compound 4;
- and
- (ii) chlorinating Compound 4 with a suitable chlorinating agent in a suitable solvent to provide Compound A-IV.
A process for the preparation of Compound 1:
- wherein,
- B is a boronic acid or boronate ester;
- comprising the steps of:
- (1) protecting the hydroxyl group of Compound 2:
- with a suitable protecting group (PG′) to provide compound 2a:
- (2) reacting Compound 2a with a borylation agent under suitable reaction conditions;
- and
- (3) removal of the protecting group (PG′) to provide Compound 1.
A compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or enantiomer thereof:
- wherein:
- Ra is F, Cl, or —CH3;
- Rb is hydrogen, F, Cl, —CH3, —CN, —OH, or —OCH3;
- RB is an unsubstituted or substituted phenyl or an unsubstituted or substituted pyridinyl, wherein if RB is substituted then RB is substituted with Rc and Rd;
- Rc is hydrogen, F, Cl, Br, —CH3, —CN, —OH, —OCH3, —C(═NOCH3)H, or —C(═NOH)H;
- Rd is —OH, or —NH2;
- and
- each Rf is hydrogen or F.
The compound 3-[4-(4-aminopiperidin-1-yl)-5-fluoro-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-hydroxybenzonitrile:
- or a pharmaceutically acceptable salt thereof.
The compound 3-[4-(4-aminopiperidin-1-yl)-7-fluoro-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-hydroxybenzonitrile:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.