US2009018144A1PendingUtilityA1
Capped pyrazinoylguanidine sodium channel blockers
Est. expiryAug 18, 2023(expired)· nominal 20-yr term from priority
A61P 9/12A61P 43/00A61P 7/10A61P 27/02A61P 27/16A61P 17/00A61P 11/12A61P 15/00A61P 1/00A61P 1/02A61P 1/10A61P 11/00A61P 11/06A61P 17/16C07D 241/26C07D 403/12C07D 241/32C07D 473/00C07D 473/16A61K 31/4965A61K 31/497C07D 413/12C07D 417/12C07D 241/34C07D 401/12
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Claims
Abstract
The present invention relates to compounds represented by formula (I): where the structural variables are as defined herein. The compounds are useful for promoting hydration of mucosal surfaces.
Claims
exact text as granted — not AI-modified1 - 114 . (canceled)
115 . A compound represented by formula (I):
wherein
X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl;
Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R 2 ) 2 ;
R 1 is hydrogen or lower alkyl;
each R 2 is, independently, —R 7 , —(CH 2 ) m —OR 8 , —(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —(CH 2 ) n -Z g -R 7 , —(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , or
R 3 and R 4 are each, independently, hydrogen, a group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso that at least one of R 3 and R 4 is a group represented by formula (A):
wherein
each R L is, independently, —R 7 , —(CH 2 ) n —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n -(Z) g -R 7 , —O—(CH 2 ) m -(Z) g -R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose,
each o is, independently, an integer from 0 to 10;
each p is an integer from 0 to 10;
with the proviso that the sum of o and p in each contiguous chain is from 1 to 10;
each x is, independently, O, NR 10 , C(═O), CHOH, C(═N—R 10 ), CHNR 7 R 10 , or represents a single bond;
wherein each R 5 is, independently, Link-(CH 2 ) n —CAP, Link-(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CAP, Link-(CH 2 CH 2 O) m —CH 2 —CAP, Link-(CH 2 CH 2 O) m —CH 2 CH 2 —CAP, Link-(CH 2 ) n -(Z) g -CAP, Link-(CH 2 ) n (Z) g -(CH 2 ) m —CAP, Link-(CH 2 ) n —NR 13 —CH 2 (CHOR 8 )(CHOR 8 ) n —CAP, Link-(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 13 -(Z) g -CAP, Link-(CH 2 ) n NR 13 —(CH 2 ) m (CHOR 8 ) n CH 2 NR 13 -(Z) g -CAP, Link-(CH 2 ) m -(Z) g -(CH 2 ) m —CAP, Link-NH—C(═O)—NH—(CH 2 ) m —CAP, Link-(CH 2 ) m —C(═O)NR 13 —(CH 2 ) m —CAP, Link-(CH 2 ) n -(Z) g -(CH 2 ) m -(Z) g -CAP, Link-(Z) g -(CH 2 ) m -Het-(CH 2 ) m —CAP;
each Link is, independently, —O—, —(CH 2 ) n —, —O(CH 2 ) m —, —NR 13 —C(═O)—NR 13 , —NR 13 —C(═O)—(CH 2 ) m —, —C(═O)NR 13 —(CH 2 ) m , —(CH 2 ) n -(Z) g -(CH 2 ) n , —S—, —SO—, —SO 2 —, —SO 2 NR 7 —, —SO 2 NR 10 —, or -Het-;
each CAP is, independently, —CR 10 ((Z) g R 13 )((Z) g R 13 );
each Ar is, independently, phenyl, substituted phenyl, wherein the substituents of the substituted phenyl are 1-3 substituents independently selected from the group consisting of OH, OCH 3 , NR 13 R 13 , Cl, F, and CH 3 , or heteroaryl;
each R 6 is, independently, —R 7 , —OR 7 , —OR 11 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) m —NR 7 R 10 , —(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) m —R 8 , —O—(CH 2 CH 2 O) m —R 8 —(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , —(CH 2 ) n —C(═O)NR 7 R 10 , —O—(CH 2 ) m —C(═O)NR 7 R 10 , —(CH 2 ) n (Z) g -R 7 , —O—(CH 2 ) m -(Z) g -R 7 , —(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 ) n —CO 2 R 7 , —O—(CH 2 ) m —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose,
wherein when two R 6 are —OR 11 and are located adjacent to each other on a phenyl ring, the alkyl moieties of the two R 6 may be bonded together to form a methylenedioxy group;
each R 7 is, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl;
each R 8 is, independently, hydrogen, lower alkyl, —C(═O)—R 11 , glucuronide, 2-tetrahydropyranyl, or
each R 9 is, independently, —CO 2 R 13 , —CON(R 13 ) 2 , —SO 2 CH 2 R 13 , or —C(═O)R 13 ;
each R 10 is, independently, —H, —SO 2 CH 3 , —CO 2 R 13 , —C(═O)NR 13 R 13 , —C(═O)R 13 , or —(CH 2 ) m —(CHOH) n —CH 2 OH;
each Z is, independently, CHOH, C(═O), CHNR 13 R 13 , C═NR 13 , or NR 13
each R 11 is, independently, lower alkyl;
each R 12 is independently, —SO 2 CH 3 , —CO 2 R 13 , —C(═O)NR 13 R 13 , —C(═O)R 13 , or —CH 2 —(CHOH) n —CH 2 OH;
each R 13 is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl, —SO 2 CH 3 , —CO 2 R 7 , —C(═O)NR 7 R 7 , —C(═O)NR 7 SO 2 CH 3 , —C(═O)NR 7 —CO 2 R 7 , —C(═O)NR 7 —C(═O)NR 7 R 7 —C(═O)NR 7 —C(═O)R 7 , —C(═O)NR 7 —(CH 2 ) m-(CHOH) n —CH 2 OH; —C(═O)R 7 , or —(CH 2 ) m-(CHOH) n —CH 2 OH;
each Het is independently, —NR 13 , —S—, —SO—, or —SO 2 —; —O—, —SO 2 NR 13 —, —NHSO 2 —, —NR 13 CO—, or —CONR 13 —;
each g is, independently, an integer from 1 to 6;
each m is, independently, an integer from 1 to 7;
each n is, independently, an integer from 0 to 7;
each Q is, independently, C—R 5 , C—R 6 or a nitrogen atom, wherein one Q in a ring is a nitrogen atom;
each V is, independently,
with the proviso that when V is attached directly to a nitrogen atom, then V can also be, independently, R 7 , R 10 , or (R 11 ) 2 ;
with the proviso that, when any two —CH 2 OR 8 groups are located 1, 2 or 1,3- with respect to each other, the R 8 groups may be joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;
or a pharmaceutically acceptable salt thereof; and
inclusive of all enantiomers, diastereomers, and racemic mixtures thereof.
116 . The compound of claim 115 , wherein Y is —NH 2 .
117 . The compound of claim 116 , wherein R 2 is hydrogen.
118 . The compound of claim 117 , wherein R 1 is hydrogen.
119 . The compound of claim 118 , wherein X is chlorine.
120 . The compound of claim 119 , wherein R 3 is hydrogen.
121 . The compound of claim 120 , wherein each R L is hydrogen.
122 . The compound of claim 121 , wherein o is 4.
123 . The compound of claim 122 , wherein p is 0.
124 . The compound of claim 123 , wherein x represents a single bond.
125 . The compound of claim 124 , wherein each R 6 is hydrogen.
126 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CAP.
127 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 CH 2 O) m —CH 2 —CAP.
128 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 CH 2 O) m —CH 2 CH 2 —CAP,
129 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n -(Z) g -CAP.
130 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n (Z) g -(CH 2 ) m —CAP.
131 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CAP.
132 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 10 -(Z) g -CAP.
133 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n NR 10 —(CH 2 ) m (CHOR 8 ) n CH 2 NR 10 -(Z) g -CAP.
134 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) m -(Z) g -(CH 2 ) m —CAP.
135 . The compound of claim 125 , wherein R 5 is represented by the formula Link-NH—C(═O)—NH—(CH 2 ) m , —CAP.
136 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) m —C(═O)NR 10 —(CH 2 ) m —CAP.
137 . The compound of claim 125 , wherein R 5 is represented by the formula Link-(CH 2 ) n -(Z) g -(CH 2 ) m -(Z) g -CAP.
138 . The compound of claim 125 , wherein R 5 is represented by the formula Link-Z g -(CH 2 ) m -Het-(CH 2 ) m —CAP.
139 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n —CAP.
140 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CAP.
141 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 CH 2 O) m —CH 2 —CAP.
142 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 CH 2 O) m —CH 2 CH 2 —CAP.
143 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n -(Z) g -CAP.
144 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n (Z) g -(CH 2 ) n —CAP.
145 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CAP.
146 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 10 -(Z) g -CAP.
147 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n NR 10 —(CH 2 ) m (CHOR 8 ) n CH 2 NR 10 -(Z) g -CAP.
148 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) m -(Z) g -(CH 2 ) m —CAP.
149 . The compound of claim 115 , wherein R 5 is represented by the formula Link-NH—C(═O)—NH—(CH 2 ) m —CAP.
150 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) m —C(═O)NR 10 —(CH 2 ) m —CAP.
151 . The compound of claim 115 , wherein R 5 is represented by the formula Link-(CH 2 ) n -(Z) g -(CH 2 ) m -(Z) g -CAP.
152 . The compound of claim 115 , wherein R 5 is represented by the formula Link-Z g -(CH 2 ) m -Het-(CH 2 ) m —CAP.
153 . The compound of claim 115 , wherein x is a single bond.
154 . The compound of claim 115 , which is in the form of a pharmaceutically acceptable salt.
155 . A composition, comprising:
the compound of claim 115 ; and a P2Y2 receptor agonist.
156 . A composition, comprising:
the compound of claim 115 ; and a bronchodilator.
157 . A pharmaceutical composition, comprising the compound of claim 115 and a pharmaceutically acceptable carrier.
158 . A method of promoting hydration of mucosal surfaces, comprising:
administering an effective amount of the compound of claim 115 to a mucosal surface of a subject.
159 . A method of blocking sodium channels, comprising:
contacting sodium channels with an effective amount of the compound of claim 115 .
160 . A method of treating chronic bronchitis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
161 . A method of treating cystic fibrosis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
162 . A method of treating sinusitis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
163 . A method of treating vaginal dryness, comprising:
administering an effective amount of the compound of claim 115 to the vaginal tract of a subject in need thereof.
164 . A method of treating dry eye, comprising:
administering an effective amount of the compound of claim 115 to the eye of a subject in need thereof.
165 . A method of promoting ocular hydration, comprising:
administering an effective amount of the compound of claim 115 to the eye of a subject.
166 . A method of promoting corneal hydration, comprising:
administering an effective amount of the compound of claim 115 to the eye of a subject.
167 . A method of promoting mucus clearance in mucosal surfaces, comprising:
administering an effective amount of the compound of claim 115 to a mucosal surface of a subject.
168 . A method of treating Sjogren's disease, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
169 . A method of treating distal intestinal obstruction syndrome, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
170 . A method of treating dry skin, comprising:
administering an effective amount of the compound of claim 115 to the skin of a subject in need thereof.
171 . A method of treating esophagitis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
172 . A method of treating dry mouth (xerostomia), comprising:
administering an effective amount of the compound of claim 115 to the mouth of a subject in need thereof.
173 . A method of treating nasal dehydration, comprising:
administering an effective amount of the compound of claim 115 to the nasal passages of a subject in need thereof.
174 . The method of claim 173 , wherein the nasal dehydration is brought on by administering dry oxygen to the subject.
175 . A method of treating ventilator-induced pneumonia, comprising:
administering an effective amount of the compound of claim 115 to a subject on a ventilator.
176 . A method of treating asthma, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
177 . A method of treating primary ciliary dyskinesia, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
178 . A method of treating otitis media, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
179 . A method of inducing sputum for diagnostic purposes, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
180 . A method of treating chronic obstructive pulmonary disease, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
181 . A method of treating emphysema, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
182 . A method of treating pneumonia, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
183 . A method of treating constipation, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
184 . The method of claim 183 , wherein the compound is administered orally or via a suppository or enema.
185 . A method of treating chronic diverticulitis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
186 . A method of treating rhinosinusitis, comprising:
administering an effective amount of the compound of claim 115 to a subject in need thereof.
187 . A method of treating hypertension, comprising administering the compound of claim 115 to a subject in need thereof.
188 . A method of reducing blood pressure, comprising administering the compound of claim 115 to a subject in need thereof.
189 . A method of treating edema, comprising administering the compound of claim 115 to a subject in need thereof.
190 . A method of promoting diuresis, comprising administering the compound of claim 115 to a subject in need thereof.
191 . A method of promoting natriuresis, comprising administering the compound of claim 115 to a subject in need thereof.
192 . A method of promoting saluresis, comprising administering the compound of claim 115 to a subject in need thereof.Join the waitlist — get patent alerts
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