Certain (2s)-n-[(1s)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides for treating anca associated vasculitides

Patent metadata

Field	Value
Publication number	US-2021186984-A1
Application number	US-202117157216-A
Country	US
Kind code	A1
Filing date	Jan 25, 2021
Priority date	Feb 7, 2018
Publication date	Jun 24, 2021
Grant date	—

Abstract

The present disclosure relates to methods for treating an ANCA associated vasculitis, for example, granulomatosis with polyangiitis (GPA), with compositions comprising an effective amount of certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds of Formula (I), including pharmaceutically acceptable salts thereof,that inhibit dipeptidyl peptidase 1 (DPP1) activity. In one embodiment, the compound of Formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)phenyl]ethyl}-1,4-oxazepane-2-carboxamide (INS1007).

First claim

1 . A method for treating an antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis in a patient in need of treatment, comprising, administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein,
R 1 is

R 2 is hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl;
R 3 is hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2 or SO 2 NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or
R 6 is C 1-3 alkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran;
R 7 is hydrogen, F, Cl or CH 3 ;
X is O, S or CF 2 ;
Y is O or S; and
Q is CH or N.

2 .- 173 . (canceled)

174 . The method of claim 1 , wherein
R 1 is

175 . The method of claim 1 , wherein,

R 1 is
X is selected from O, S or CF 2 ;
Y is selected from O or S;
R 6 is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran;
R 7 is selected from hydrogen, F, Cl or CH 3 ;
or a pharmaceutically-acceptable salt thereof.

176 . The method of claim 1 , wherein R 1 is

177 . The method of claim 1 , wherein,
R 1 is

X is O, S or CF 2 ;
R 6 is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and
R 7 is hydrogen, F, Cl or CH 3 .

178 . The method of claim 177 , wherein X is O and R 7 is hydrogen.

179 . The method of claim 178 , wherein R 6 is methyl or ethyl.

180 . The method of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

181 . The method of claim 1 , wherein the administering comprises oral adminsitration.

182 . The method of claim 1 , wherein the ANCA associated vasculitis is granulomatosis with polyangiitis (GPA).

183 . The method of claim 1 , wherein the ANCA associated vasculitis is microscopic polyangiitis (MPA).

184 . The method of claim 1 , wherein the treating comprises decreasing the patient's antineutrophil cytoplasmic autoantibodies (ANCA) blood concentration, as compared to the patient's ANCA blood concentration, prior to treatment.

185 . The method of claim 1 , wherein the decreasing the ANCA blood concentration of the patient is by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or at least about 80%.

186 . The method of claim 185 , wherein the ANCA blood concentration is measured in the patient's blood plasma, blood serum or a combination thereof.

187 . The method of claim 182 , wherein the patient has a Birmingham Vasculitis Activity Score specific for Wegener's granulomatosis (BVAS/WG)>0 at the onset of the treating, and the treating comprises decreasing the BVAS/WG score for the patient, as compared to the BVAS/WG score of the patient prior to the treatment.

188 . The method of claim 182 , wherein the patient is in GPA remission at the onset of treatment.

189 . The method of claim 187 , wherein the treating comprises decreasing the BVAS/WG score for the patient by 1 point or more.

190 . The method of claim 187 , wherein the treating comprises inhibiting a GPA flare, wherein a flare is defined as an increase in the BVAS/WG score of one point or more.

191 . The method of claim 1 , wherein the treating comprises improving the short form health survey questionnaire (SF-36) score for the patient, as compared to the SF-36 score of the patient prior to the treatment.

192 . The method of claim 1 , wherein the treating comprises decreasing the number of CD19+ B-cells in the patient, as compared to the number of CD19+ B-cells in the patient prior to the treatment.

Assignees

• Insmed Inc

Inventors

• Dipetrillo Keith
• Fernandez Carlos
• Zhang Jimin

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/56

  Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids · CPC title