# US 2013/0158071 A1 · Pharmaceutical compositions and administrations thereof

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- Number: US 2013/0158071 A1
- Document ID: US20130158071A1
- Status: Published application
- Kind: A1
- Application number: 13/657,299
- Filed: 2012-10-22
- Published: 2013-06-20
- Earliest claimed: 2010-04-22
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Fredrick F. Van Goor; Rossitza Gueorguieva Alargova; Tim Edward Alcacio; Hayley Marie Binch; Martyn Curtis Botfield; Lev Tyler Dewey Fanning; Peter Diederik Jan Grootenhuis; Dennis James Hurley; Irina Nikolaevna Kadiyala; Ritu Rohit Kaushik; Ali Keshavarz-Shokri; Mariusz Krawiec; Elaine Chungmin Lee; Brian Luisi; Ales Medek; Mehdi Numa; Urvi Jagdishbhai Sheth; Alina Silina; Marinus Jacobus Verwijs; Xiaoqing Yang; Christopher Ryan Young; Noreen Tasneem Zaman; Beili Zhang; Yuegang Zhang; Gregor Zlokarnik
- Web page: https://patentgrep.com/patent/US20130158071A1

## CPC

- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4704: 2-Quinolinones, e.g. carbostyril
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C12Q 1/34: involving hydrolase
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/20: cell-free systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with one or both of a Compound of Formula II and/or a Compound of Formula III. 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.

## Claims

### Claim 1

A pharmaceutical composition comprising:
A Compound of Formula I
or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from:
R1 is —CF3, —CN, or —C≡CCH2N(CH3)2;
R2 is hydrogen, —CH3, —CF3, —OH, or —CH2OH;
R3 is hydrogen, —CH3, —OCH3, or —CN;
provided that both R2 and R3 are not simultaneously hydrogen; and
one or both of the following:
B. A Compound of Formula II
or pharmaceutically acceptable salts thereof, wherein:
T is —CH2—, —CH2CH2—, —CF2—, —C(CH3)2—, or —C(O)—;
R1′ is H, C1-6 aliphatic, halo, CF3, CHF2, O(C1-6 aliphatic); and
RD1 or RD2 is ZDR9
wherein:
ZD is a bond, CONH, SO2NH, SO2N(C1-6 alkyl), CH2NHSO2, CH2N(CH3)SO2, CH2NHCO, COO, SO2, or CO; and
R9 is H, C1-6 aliphatic, or aryl; and/or
C. A Compound of Formula III
or pharmaceutically acceptable salts thereof, wherein:
R is H, OH, OCH3 or two R taken together form —OCH2O— or —OCF2O—;
R4 is H or alkyl;
R5 is H or F;
R6 is H or CN;
R7 is H, —CH2CH(OH)CH2OH, —CH2CH2N+(CH3)3, or —CH2CH2OH;
R8 is H, OH, —CH2CH(OH)CH2OH, —CH2OH, or R7 and R8 taken together form a five membered ring.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the Compound of Formula I is Compound 1

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the Compound of Formula II is Compound 2

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the Compound of Formula III is Compound 3

### Claim 8

A pharmaceutical composition comprising a component selected from any embodiment described in Column A of Table I in combination with one or both of the following:
a) a component selected from any embodiment described in Column B of Table I; and/or
b) a component selected from any embodiment described in Column C of Table I.
TABLE I
Column A
Column B
Column C
Embodiments
Embodiments
Embodiments
Section
Heading
Section
Heading
Section
Heading
II.A.1.
Compounds of
II.B.1.
Compounds of
II.C.1.
Compounds of
Formula I
Formula II
Formula III
II.A.2.
Compound 1
II.B.2.
Compound 2
II.C.2.
Compound 3
III.A.1.a.
Compound 1
III.B.1.a.
Compound 2
III.C.1.a.
Compound 3
Form A
Form I
Form A
III.A.2.a.
Compound 1
III.B.2.a.
Compound 2
III.C.2.a.
Compound 3
Form A-HCl
Solvate
Amorphous
Form A
Form
III.A.3.a.
Compound 1
III.B.3.a.
Compound 2
Form B-HCl
HCl Salt
Form A
III.A.4.a.
Compound 1
IV.A.1.a.
Compound 2
IV.B.1.a.
Compound 3
Form B
Form I Aqueous
Tablet
Formulation
Formulation
IV.A.2.a.
Compound 2
Form I Capsule
Formulation
IV.A.3.a.
Compound 2
Form I Tablet
Formulation

### Claim 9 (depends on 1)

A method of treating a CFTR mediated disease in a human comprising administering to the human an effective amount of a pharmaceutical composition according to claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition), Gorham's Syndrome, chloride channelopathies such as myotonia congenita (Thomson and Becker forms), Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, lysosomal storage disease, Angelman syndrome, and Primary Ciliary Dyskinesia (PCD), a term for inherited disorders of the structure and/or function of cilia, including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus and ciliary aplasia.

### Claim 11 (depends on 10)

The method of claim 10, wherein the CFTR mediated disease is cystic fibrosis, COPD, emphysema, dry-eye disease or osteoporosis.

### Claim 12 (depends on 10)

The method of claim 10, wherein the CFTR mediated disease is cystic fibrosis.

### Claim 13 (depends on 10)

The method according to claim 10, wherein the patient possesses one or more of the following mutations of human CFTR: ΔF508, R117H, and G551D.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR.

### Claim 15 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR.

### Claim 16 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on at least one allele.

### Claim 17 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the ΔF508 mutation of human CFTR on both alleles.

### Claim 18 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on at least one allele.

### Claim 19 (depends on 13)

The method according to claim 13, wherein the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on both alleles.

### Claim 20 (depends on 1)

A kit for use in measuring the activity of a CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising:
(i) a pharmaceutical composition according to claim 1;
(ii) instructions for:
a) contacting the composition with the biological sample;
b) measuring activity of said CFTR or a fragment thereof.

### Claim 21 (depends on 1, 20)

The kit of claim 20, further comprising instructions for
a) contacting an additional compound with the biological sample;
b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and
c) comparing the activity of said CFTR or fragment thereof in the presence of said additional compound with the activity of the CFTR or fragment thereof in the presence of a composition comprising a pharmaceutical composition according to claim 1.

### Claim 22 (depends on 21)

The kit of claim 21, wherein the step of comparing the activity of said CFTR or fragment thereof provides a measure of the density of said CFTR or fragment thereof.