Pharmaceutical Compositions and Administrations Thereof

Patent metadata

Field	Value
Publication number	US-2016022665-A2
Application number	US-201514630778-A
Country	US
Kind code	A2
Filing date	Feb 25, 2015
Priority date	Apr 22, 2010
Publication date	Jan 28, 2016
Grant date	—

Abstract

The present invention relates to pharmaceutical compositions comprising a compound of Formulas I and II, optionally in combination with a Compound of Formula III and/or a Compound of Formula IV. The invention also relates to solid forms and to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis.

First claim

What is claimed is:

1 . A pharmaceutical composition comprising:
A. A Compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
Each of WR W2 and WR W4 is independently selected from CN, CF 3 , halo, C 2-6 straight or branched alkyl, C 3-12 membered cycloaliphatic, phenyl, a 5-10 membered heteroaryl or 3-7 membered heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S, or N, wherein said WR W2 and WR W4 is independently and optionally substituted with up to three substituents selected from —OR′, —CF 3 , —OCF 3 , SR′, S(O)R′, SO 2 R′, —SCF 3 , halo, CN, —COOR′, —COR′, —O(CH 2 ) 2 N(R′) 2 , —O(CH 2 )N(R′) 2 , —CON(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 )OR′, —CH 2 CN, optionally substituted phenyl or phenoxy, —N(R′) 2 , —NR′C(O)OR′, —NR′C(O)R′, —(CH 2 ) 2 N(R′) 2 , or —(CH 2 )N(R′) 2 ;
WR W5 is selected from hydrogen, —OCF 3 , —CF 3 , —OH, —OCH 3 , —NH 2 , —CN, —CHF 2 , —NHR′, —N(R′) 2 , —NHC(O)R′, —NHC(O)OR′, —NHSO 2 R′, —CH 2 OH, —CH 2 N(R′) 2 , —C(O)OR′, —SO 2 NHR′, —SO 2 N(R′) 2 , or —CH 2 NHC(O)OR′; and
Each R′ is independently selected from an optionally substituted group selected from a C 1-8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
provided that:
iii) WR W2 and WR W4 are not both —Cl;
 WR W2 , WR W4 and WR W5 are not —OCH 2 CH 2 Ph, —OCH 2 CH 2 (2-trifluoromethyl-phenyl), —OCH 2 CH 2 -(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), or substituted 1H-pyrazol-3-yl;
and
B. A Compound of Formula II

or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from:

R 1 is —CF 3 , —CN, or —C≡CCH 2 N(CH 3 ) 2 ;
R 2 is hydrogen, —CH 3 , —CF 3 , —OH, or —CH 2 OH;
R 3 is hydrogen, —CH 3 , —OCH 3 , or —CN;

provided that both R 2 and R 3 are not simultaneously hydrogen;

optionally in combination with one or both of:
C. A Compound of Formula III

or pharmaceutically acceptable salts thereof, wherein:
T is —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —C(CH 3 ) 2 —, or —C(O)—;
R 1 ′ is H, C 1-6 aliphatic, halo, CF 3 , CHF 2 , O(C 1-6 aliphatic); and
R D1 or R D2 is Z D R 9
wherein:
Z D is a bond, CONH, SO 2 NH, SO 2 N(C 1-6 alkyl), CH 2 NHSO 2 , CH 2 N(CH 3 )SO 2 , CH 2 NHCO, COO, SO 2 , or CO; and
R 9 is H, C 1-6 aliphatic, or aryl; and/or

D. A Compound of Formula IV

or pharmaceutically acceptable salts thereof, wherein:
R is H, OH, OCH 3 or two R taken together form —OCH 2 O— or —OCF 2 O—;
R 4 is H or alkyl;
R 5 is H or F;
R 6 is H or CN;
R 7 is H, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 N + (CH 3 ) 3 , or —CH 2 CH 2 OH;
R 8 is H, OH, —CH 2 CH(OH)CH 2 OH, —CH 2 OH, or R 7 and R 8 taken together form a five membered ring.

2 . The pharmaceutical composition of claim 1 , comprising a Compound of Formula I and Compound of Formula II.

3 . The pharmaceutical composition of any one of claims 1 - 2 , comprising Compound 1 and Compound 2.

4 . The pharmaceutical composition of any one of claims 1 - 3 , further comprising one or both of Compound 3 and/or Compound 4.

5 . The pharmaceutical composition of claim 4 , comprising Compound 1, Compound 2, and Compound 3.

6 . The pharmaceutical composition of claim 1 , comprising Compound 1, Compound 2, and Compound 4.

7 . The pharmaceutical composition of claim 4 , comprising Compound 1, Compound 2, Compound 3 and Compound 4.

8 . A pharmaceutical composition comprising at least one component from Column A of Table I, at least one component from Column B of Table 1, and optionally an additional component from one or both of Column C and/or Column D

TABLE I

Column A
Column B
Column C
Column D

Embodiments
Embodiments
Embodiments
Embodiments

Section
Heading
Section
Heading
Section
Heading
Section
Heading

II.A.1.
Compounds
II.B.1.
Compounds
II.C.1.
Compounds
II.D.1.
Compounds

of Formula I

of Formula

of Formula

of Formula

II

III

IV

II.A.2.
Compound 1
II.B.2.
Compound 2
II.C.2.
Compound 3
II.D.2.
Compound 4

III.A.1.a.
Compound 1
III.B.1.a.
Compound 2
III.C.1.a.
Compound 3
III.D.1.a.
Compound 4

Form C

Form A

Form I

Form A

IV.A.1.a.
Compound 1
III.B.2.a.
Compound 2
III.C.2.a.
Compound 3
III.D.2.a.
Compound 4

First

Assignees

• Vertex Pharma

Inventors

• Van Goor Fredrick F
• Alargova Rossitza Gueorguieva
• Alcacio Tim Edward
• Arekar Sneha G
• Binch Hayley Marie
• Botfield Martyn Curtis
• Fanning Lev Tyler Dewey
• Grootenhuis Peter Diederik Jan
• Hurley Dennis James
• Johnston Steven C
• Kadiyala Irina Nikolaevna
• Kaushik Ritu Rohit
• Keshavarz-Shokri Ali
• Krawiec Mariusz
• Lee Elaine Chungmin
• Luisi Brian
• Medek Ales
• Mudunuri Praveen
• Numa Mehdi
• Sheth Urvi Jagdishbhai
• Silina Alina
• Sullivan Mark Jeffrey
• Verwijs Marinus Jacobus
• Yang Xiaoqing
• Young Christopher Ryan
• Zaman Noreen Tasneem
• Zhang Beili
• Zhang Yuegang
• Zlokarnik Gregor

Classifications

• G01N2333/4703

  Regulators; Modulating activity · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K31/4709 Primary

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• G01N33/6872

  Intracellular protein regulatory factors and their receptors, e.g. including ion channels · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title