US2015299131A1PendingUtilityA1
Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
Est. expiryAug 21, 2032(~6.1 yrs left)· nominal 20-yr term from priority
Inventors:Noah BellChristopher CarrerasDominique CharmotTao ChenMichael R. LeadbetterJeffrey W. JacobsJason G. Lewis
A61P 7/10A61P 31/12A61P 43/00A61P 9/04A61P 9/12A61P 13/12A61P 1/00A61P 1/04A61P 1/10A61K 47/55A61K 31/4725A61K 31/496C07D 217/18C07D 401/14A61K 47/32A61K 47/38C07D 217/14A61K 31/5377A61K 47/60A61K 45/06A61K 47/36C07D 217/04Y02A50/30
51
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Claims
Abstract
The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the structure of Formula (I):
or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein:
(a) NHE is a NHE-inhibiting small molecule moiety having the following structure of Formula (A):
wherein:
each R 1 , R 2 , R 3 , R 5 and R 9 are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7 and R 8 are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L;
R 4 is selected from H, C 1 -C 7 alkyl, or a bond linking the NHE-inhibiting small molecule to L;
R 6 is absent or selected from H and C 1 -C 7 alkyl; and
Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring;
(b) Core is a Core moiety having the following structure of Formula (B):
wherein:
X is selected from C(X 1 ), N and N(C 1-6 alkyl);
X 1 is selected from hydrogen, optionally substituted alkyl, —NX a N b , —NO 2 , —NX c —C(═O)—NX c —X a , —C(═O)NX c —X a , —NX c —C(═O)—X a , —NX c —SO 2 —X a , —C(═O)—X a and —OX a ,
each X a and X b are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;
Y is C 1-6 alkylene;
Z is selected from —NZ a —C(═O)—NZ a —, —C(═O)NZ a —, —NZ a —C(═O)— and heteroaryl when X is CX 1 ;
Z is selected from —NZ a —C(═O)—NZ a —, —NZ a —C(═O)— and heteroaryl when X is N or N(C 1-6 alkyl); and
each X, and Z a is independently selected from hydrogen and C 1-6 alkyl; and
(c) L is a bond or linker connecting the Core moiety to the NHE-inhibiting small molecule moieties.
2 . A compound of claim 1 wherein the NHE-inhibiting small molecule moiety has the following structure:
wherein:
each R 1 , R 2 and R 3 are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7 and R 8 are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L.
3 . A compound of claim 2 wherein the NHE-inhibiting small molecule moiety has one of the following structures:
4 . A compound of any of claims 1 - 3 wherein L is a polyalkylene glycol linker.
5 . A compound of any of claims 1 - 4 wherein L is a polyethylene glycol linker.
6 . A compound of any of claims 1 - 5 wherein X is C(X 1 ).
7 . A compound of claim 6 wherein each X, is hydrogen.
8 . A compound of any of claims 1 - 5 wherein X is N.
9 . A compound of any of claims 1 - 8 wherein each Z a is hydrogen.
10 . A compound having the structure of Formula (II):
or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein:
(a) NHE is a NHE-inhibiting small molecule moiety having the structure of Formula (A):
wherein:
each R 1 , R 2 , R 3 , R 5 and R 9 are independently selected from H, halogen,
—NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7 and R 8 are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L;
R 4 is selected from H, C 1 -C 7 alkyl, or a bond linking the NHE-inhibiting small molecule to L;
R 6 is absent or selected from H and C 1 -C 7 alkyl; and
Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring;
(b) Core is a Core moiety having the following structure of Formula (C):
wherein:
W is selected from alkylene, polyalkylene glycol, —C(═O)—NH-(alkylene)-NH—C(═O)—, —C(═O)—NH-(polyalkylene glycol)-NH—C(═O)—, —C(═O)-(alkylene)-C(═O)—, —C(═O)-(polyalkylene glycol)-C(═O)— and cycloalkyl,
X is N;
Y is C 1-6 alkylene;
Z is selected from —NZ a —C(═O)—NZ a —, —C(═O)NZ a —, —NZ a —C(═O)— and heteroaryl;
each Z a is independently selected from hydrogen and C 1-6 alkyl; and
(c) L is a bond or linker connecting the Core moiety to the NHE-inhibiting small molecules.
11 . A compound of claim 10 wherein the NHE-inhibiting small molecule moiety has the following structure:
wherein:
each R 1 , R 2 and R 3 are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7 and R 8 are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L.
12 . A compound of claim 11 wherein the NHE-inhibiting small molecule moiety has one of the following structures:
13 . A compound of any of claims 10 - 12 wherein L is a polyalkylene glycol linker.
14 . A compound of any of claims 10 - 13 wherein L is a polyethylene glycol linker.
15 . A pharmaceutical composition comprising a compound of any of claims 1 - 14 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
16 . A pharmaceutical composition of claim 15 , further comprising a fluid-absorbing polymer.
17 . A pharmaceutical composition of claim 16 wherein the fluid-absorbing polymer is delivered directly to the colon.
18 . A pharmaceutical composition of claim 16 or 17 wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 5 kPa.
19 . A pharmaceutical composition of any of claims 16 - 18 wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 10 kPa.
20 . A pharmaceutical composition of any of claims 16 - 19 wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 10 g/g.
21 . A pharmaceutical composition of any of claims 16 - 20 wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 15 g/g.
22 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is superabsorbent.
23 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a crosslinked, partially neutralized polyelectrolyte hydrogel.
24 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a crosslinked polyacrylate.
25 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a polyelectrolyte.
26 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is calcium Carbophil.
27 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is prepared by a high internal phase emulsion process.
28 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a foam.
29 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is prepared by a aqueous free radical polymerization of acrylamide or a derivative thereof, a crosslinker and a free radical initiator redox system in water.
30 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a hydrogel.
31 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is an N-alkyl acrylamide.
32 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a superporous gel.
33 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is naturally occurring.
34 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is selected from the group consisting of xanthan, guar, wellan, hemicelluloses, alkyl-cellulose hydro-alkyl-cellulose, carboxy-alkyl-cellulose, carrageenan, dextran, hyaluronic acid and agarose.
35 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is psyllium.
36 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a polysaccharide that includes xylose and arabinose.
37 . A pharmaceutical composition of any of claims 16 - 21 wherein the fluid-absorbing polymer is a polysaccharide that includes xylose and arabinose, wherein the ratio of xylose to arabinose is at least about 3:1, by weight.
38 . A pharmaceutical composition of any of claims 16 - 37 , further comprising another pharmaceutically active agent or compound.
39 . A pharmaceutical composition of claim 38 wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, aldosterone antagonist, aldosterone synthase inhibitor, renin inhibitor, calcium channel blocker, beta blocker, alpha blocker, central alpha agonist, vasodilator, blood thinner, anti-platelet agent, lipid-lowering agent, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agent.
40 . A pharmaceutical composition of claim 39 wherein the diuretic is selected from the group consisting of a high ceiling loop diuretic, a benzothiadiazide diuretic, a potassium sparing diuretic, and a osmotic diuretic.
41 . A pharmaceutical composition of claim 38 wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of an analgesic peptide or agent.
42 . A pharmaceutical composition of claim 41 wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of a laxative agent selected from a bulk-producing agent (e.g. psyllium husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, stool softeners/surfactant (e.g., docusate, Colace, Diocto), a hydrating or osmotic agent (e.g., dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt), monobasic sodium phosphate, sodium biphosphate), a hyperosmotic agent (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)).
43 . A method for inhibiting NHE-mediated antiport of sodium and hydrogen ions, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of claims 1 - 42 .
44 . A method for treating a disorder associated with fluid retention or salt overload, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of claims 1 - 42 .
45 . A method for treating a disorder selected from the group consisting of heart failure, chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of claims 1 - 42 .
46 . The method of claim 45 wherein the heart failure is congestive heart failure.
47 . A method for treating hypertension, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of claims 1 - 42 .
48 . A method of any of claims 44 - 47 wherein the method comprises administering a pharmaceutically effective amount of the compound to the mammal in order to increase the mammal's daily fecal output of sodium and/or fluid.
49 . A method of any of claims 44 - 48 wherein the method comprises administering a pharmaceutically effective amount of the compound to the mammal in order to increase the mammal's daily fecal output of sodium by at least about 30 mmol, and/or fluid by at least about 200 ml.
50 . A method of any of claims 44 - 49 wherein the mammal's fecal output of sodium and/or fluid is increased without introducing another type of cation in a stoichiometric or near stoichiometric fashion via an ion exchange process.
51 . A method of any of claims 44 - 50 , further comprising administering to the mammal a fluid-absorbing polymer to absorb fecal fluid resulting from the use of the compound that is substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein.
52 . A method of any of claims 44 - 51 wherein the compound or composition is administered to treat hypertension.
53 . A method of any of claims 44 - 52 wherein the compound or composition is administered to treat hypertension associated with dietary salt intake.
54 . A method of any of claims 44 - 51 wherein administration of the compound or composition allows the mammal to intake a more palatable diet.
55 . A method of any of claims 44 - 51 wherein the compound or composition is administered to treat fluid overload.
56 . A method of claim 55 wherein the fluid overload is associated with congestive heart failure.
57 . A method of claim 55 wherein the fluid overload is associated with end stage renal disease.
58 . A method of claim 55 wherein the fluid overload is associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy.
59 . A method of any of claims 44 - 51 wherein the compound or composition is administered to treat sodium overload.
60 . A method of any of claim 44 - 51 wherein the compound or composition is administered to reduce interdialytic weight gain in ESRD patients.
61 . A method of any of claims 44 - 51 wherein the compound or composition is administered to treat edema.
62 . A method of claim 61 wherein the edema is caused by chemotherapy, pre-menstrual fluid overload or preeclampsia.
63 . A method of any of claims 44 - 62 wherein the compound or composition is administered orally, by rectal suppository, or enema.
64 . A method of any one of claims 44 - 63 , wherein the method comprises administering a pharmaceutically effective amount of the compound or composition in combination with one or more additional pharmaceutically active compounds or agents.
65 . A method of claim 64 wherein the one or more additional pharmaceutically active compounds or agents is selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, aldosterone antagonist, aldosterone synthase inhibitor, renin inhibitor, calcium channel blocker, beta blocker, alpha blocker, central alpha agonist, vasodilator, blood thinner, anti-platelet agent, lipid-lowering agent, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agent.
66 . A method of claim 65 wherein the diuretic is selected from the group consisting of a high ceiling loop diuretic, a benzothiadiazide diuretic, a potassium sparing diuretic, and a osmotic diuretic.
67 . A method of any of claims 64 - 66 wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as part of a single pharmaceutical preparation.
68 . A method of any of claims 64 - 66 wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as individual pharmaceutical preparations.
69 . A method of claim 68 wherein the individual pharmaceutical preparation are administered sequentially.
70 . A method of claim 69 wherein the individual pharmaceutical preparation are administered simultaneously.
71 . A method for treating a gastrointestinal tract disorder, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of claims 1 - 42 .
72 . A method of claim 71 wherein the gastrointestinal tract disorder is a gastrointestinal motility disorder.
73 . A method of claim 71 wherein the gastrointestinal tract disorder is irritable bowel syndrome.
74 . A method of claim 71 wherein the gastrointestinal tract disorder is chronic constipation.
75 . A method of claim 71 wherein the gastrointestinal tract disorder is chronic idiopathic constipation.
76 . A method of claim 71 wherein the gastrointestinal tract disorder is chronic constipation occurring in cystic fibrosis patients.
77 . A method of claim 71 wherein the gastrointestinal tract disorder is opioid-induced constipation.
78 . A method of claim 71 wherein the gastrointestinal tract disorder is a functional gastrointestinal tract disorder.
79 . A method of claim 71 wherein the gastrointestinal tract disorder is selected from the group consisting of chronic intestinal pseudo-obstruction and colonic pseudo-obstruction.
80 . A method of claim 71 wherein the gastrointestinal tract disorder is Crohn's disease.
81 . A method of claim 71 wherein the gastrointestinal tract disorder is ulcerative colitis.
82 . A method of claim 71 wherein the gastrointestinal tract disorder is a disease referred to as inflammatory bowel disease.
83 . A method of claim 71 wherein the gastrointestinal tract disorder is associated with chronic kidney disease (stage 4 or 5).
84 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation induced by calcium supplement.
85 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with the use of a therapeutic agent.
86 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with a neuropathic disorder.
87 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is post-surgical constipation (postoperative ileus).
88 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is idiopathic (functional constipation or slow transit constipation).
89 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with neuropathic, metabolic or an endocrine disorder (e.g., diabetes mellitus, renal failure, hypothyroidism, hyperthyroidism, hypocalcaemia, Multiple Sclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis, autonomic neuropathy, Chagas disease, Hirschsprung's disease or cystic fibrosis, and the like).
90 . A method of claim 71 wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is due the use of drugs selected from analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.
91 . A method for treating irritable bowel syndrome, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or a pharmaceutical composition of any of claims 1 - 42 .
92 . A method of any of claims 71 - 91 wherein the compound or composition is administered to treat or reduce pain associated with a gastrointestinal tract disorder.
93 . A method of any of claims 71 - 91 wherein the compound or composition is administered to treat or reduce visceral hypersensitivity associated with a gastrointestinal tract disorder.
94 . A method of any of claims 71 - 91 wherein the compound or composition is administered to treat or reduce inflammation of the gastrointestinal tract.
95 . A method of any of claims 71 - 91 wherein the compound or composition is administered to reduce gastrointestinal transit time.
96 . A method of any of claims 71 - 95 wherein the compound or composition is administered either orally or by rectal suppository.
97 . A method of any of claims 71 - 96 wherein the method comprises administering a pharmaceutically effective amount of the compound or composition, in combination with one or more additional pharmaceutically active compounds or agents.
98 . A method of claim 97 wherein the one or more additional pharmaceutically active agents or compounds are an analgesic peptide or agent.
99 . A method of claim 97 wherein the one or more additional pharmaceutically active agents or compounds are selected from the group consisting of a laxative agent selected from a bulk-producing agent (e.g. psyllium husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, stool softeners/surfactant (e.g., docusate, Colace, Diocto), a hydrating or osmotic agent (e.g., dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt), monobasic sodium phosphate, sodium biphosphate), and a hyperosmotic agent (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)).
100 . A method of any of claims 97 - 99 wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as part of a single pharmaceutical preparation.
101 . A method of any of claims 97 - 99 wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as individual pharmaceutical preparations.
102 . A method of claim 101 wherein the individual pharmaceutical preparation are administered sequentially.
103 . A method of claim 101 wherein the individual pharmaceutical preparation are administered simultaneously.Join the waitlist — get patent alerts
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