US2008103148A1PendingUtilityA1
Cyclic pyrazinoylguanidine sodium channel blockers
Est. expiryAug 18, 2023(expired)· nominal 20-yr term from priority
Inventors:Michael R. Johnson
A61P 7/10A61P 9/12A61P 37/06A61P 43/00A61P 27/02A61P 29/00A61P 27/04A61P 3/12A61P 27/16A61P 17/16A61P 1/18A61P 1/02C07D 401/14C04B 35/632C07D 401/12A61P 11/06C07D 241/26A61P 11/08C07D 417/14C07D 405/14A61P 11/02A61P 1/04C07D 413/12A61P 11/00A61P 15/00C07D 403/12C07D 241/02
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Claims
Abstract
The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.
Claims
exact text as granted — not AI-modified1 - 178 . (canceled)
179 . A method of preventing ventilator-induced pneumonia, comprising administering to a subject an effective of 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;
each R 5 is, independently, —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,
—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m —NR 12 R 12 , —O—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m -(Z) g R 12 , —(CH 2 ) n NR 11 R 11 , O—(CH 2 ) m NR 11 R 11 , (CH 2 ) n —ND-(R 11 ) 3 , —O—(CH 2 ) m —N ⊕ —(R 11 ) 3 , —(CH 2 ) n -(Z) g —(CH 2 ) m —NR 10 R 10 , O—(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —(CH 2 ) n —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(CHOR 8 ) m —CH 2 NR 10 -(Z) g -R 10 , —(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 10 -(Z) g -R 10 , —(CH 2 ) n NR 10 —O(CH 2 ) n (CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , —O(CH 2 ) n —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —OR 8 , -(Het)-(CH 2 ) n —NR 7 R 10 , -(Het)-(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 CH 2 O) m —R 8 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , -(Het)-(CH 2 ) m —C(═O)NR 7 R 10 , -(Het)-(CH 2 ) m -(Z) g -R 7 , -(Het)-(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 ) m —CO 2 R 7 , -(Het)-(CH 2 ) m —NR 12 R 12 , -(Het)-(CH 2 ) n —NR 12 R 12 , -(Het)-(CH 2 ) m -(Z) g R 12 , -(Het)-(CH 2 ) m NR 11 R 11 , -(Het)-(CH 2 ) m —N ⊕ —(R 11 ) 3 , -(Het)-(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , -(Het)-(CH 2 ) m —(C═O)NR 12 R 12 , -(Het)-(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 ,
wherein when 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,
—(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
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 )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 —C(═O)NR 10 R 10 , Link-(CH 2 ) m —C(═O)NR 13 —(CH 2 ) m —CAP, Link-(CH 2 ) m —C(═O)NR 11 R 11 , Link-(CH 2 ) m —C(═O)NR 12 R 12 , Link-(CH 2 ) n-(Z) g -(CH 2 ) m -(Z) g -CAP, or 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, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R 13 R 13 , heteroaryl-W, —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
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 W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)NR 13 R 13 , —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each R 6 is, independently, —R 5 , —R 7 , —OR 8 , —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 ) n (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 ) n —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 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 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —(CH 2 ) m-(CHOH) n —CH 2 OH;
each Z is, independently, CHOH, C(═O) n —(CH 2 ) n —, 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 ) n —(CHOH) n —CH 2 OH, —C(═O)R 7 , or —(CH 2 ) m —(CHOH) n —CH 2 OH, —(CH 2 ) m —NR 7 R 10 ,
with the proviso that NR 13 R 13 can be joined on itself to form a group represented by one of the following:
each Het is independently, —NR 13 —S—, —SO—, —SO 2 —, —O—, —SO 2 N 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, —CR 6 R 5 —, —CR 6 R 6 —, —NR 10 , —NR 7 —, —NR 5 —, —S—, —SO— or —SO 2 —,
wherein at most three Q in a ring are —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— and/or —SO 2 —, at least one Q must be —CR 5 R 6 — or —NR 5 —, and the Q attached to the (C(R L ) 2 ) p — group is —CR 6 R 5 or N;
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 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.
180 . The method of claim 179 , wherein Y is NH 2 , X is Cl, each of R 2 , R 1 , R 3 , R L , and R 6 is H, o is 4, p is 0, and x is a single bond.
181 . The method of claim 180 , wherein R 5 is
—O—(CH 2 ) 4 —OH, —(CH 2 ) 4 —OH, —NHSO 2 CH 3 , —NH(C═O)CH 3 , —CH 2 NH 2 , —NH—CO 2 C 2 H 5 , —CH 2 NH(C═O)CH 3 , —CH 2 NHCO 2 CH 3 , —CH 2 NHSO 2 CH 3 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHCO 2 C 2 H 5 , —O(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHSO 2 CH 3 , —O—CH 2 CH 2 NH 2 , —OCH 2 CHOHCH 2 O-glucuronide, —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 -(α-CHOH) 2 CH 2 OH, —OCH 2 —(CHOH) 2 CH 2 OH, —C(═O)NH 2 , —O—CH 2 —(C═O)NHCH 2 CHOH, —O—CH 2 —(C═O)NHCH 2 CHOHCH 2 OH, —O—CH 2 (C═O)NHCH 2 (CHOH) 2 CH 2 OH, —O—CH 2 C(C═O)NHSO 2 CH 3 , —O—CH 2 (C═O)NHCO 2 CH 3 , —O—CH 2 —C(C═O)NH—C(C═O)NH 2 , —O—CH 2 —(C═O)NH—(C═O)CH 3 , —(C═NH)NH 2 , —(CH 2 ) n —NH—C(═NH)—NH 2 , —(CH 2 ) 3 —NH—C(═NH)—NH 2 , —CH 2 NH—C(═NH)—NH 2 , —(CH 2 ) n —CONHCH 2 (CHOH) n —CH 2 OH, —NH—C(═O)—CH 2 —(CHOH) n CH 2 OH, —NH—(C═O)—NH—CH 2 (CHOH) 2 CHOH, —NHC(C═O)NHCH 2 CH 2 OH, —O—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —O(CH 2 ) 3 —NH—C(═NH)—NH 2 , —O—(CH 2 ) m —CHNH 2 —CO 2 NR 7 R 10 , —OCH 2 —CHNH 2 —CO 2 NH 2 , —NHCH 2 (CHOH) 2 CH 2 OH, —O—(CH 2 ) n —NH-erythritol, —O—(CH 2 ) m —NH-sorbitol, —O—(CH 2 ) m —NH-xylitol, —O—(CH 2 ) m —NH-glycidol, —OCH 2 CO 2 H, —OCH 2 CO 2 C 2 H 5 , —O—CH 2 -dioxolane, —O—(CH 2 ) 3 —OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, —O—CH 2 —CHOH—CH 2 OH, —O—CH 2 CH 2 —O-tetrahydropyran-2-yl, —O—CH 2 CH 2 OH, —O—(CH 2 CH 2 O) 4 —CH 3 , —O—CH 2 CH 2 OCH 3 , —O—CH 2 —(CHOC(═O)CH 3 )—CH 2 —OC(═O)CH 3 , —O—(CH 2 CH 2 O) 2 —CH 3 , —OCH 2 —CHOH—CHOH—CH 2 OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, ortho —O—CH 2 —CHOH—CH 2 OH, meta —O—CH 2 —CHOH—CH 2 OH, —OCH 2 CO 2 H, —NHCH 2 (CHOH) 2 —CH 2 OH, —OCH 2 CO 2 Et, —O—CH 2 C(═O)NH 2 , —NHCO 2 Et, —OCH 2 CH 2 CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 CH 2 NHCO 2 Et, —NH—C(═NH 2 )—NH 2 OHOH, —CH 2 —CHOH—CH 2 —NHBoc, —O—CH 2 —CHOH—CH 2 —NHBoc, —OCH 2 CH 2 NHCH 2 (CHOH) 2 CH 2 OH, —OCH 2 CH 2 NH(CH 2 [(CHOH) 2 CH 2 OH)] 2 , —(CH 2 ) 4 —NHBoc, —OCH 2 CH 2 NHSO 2 CH 3 , —(CH 2 ) 3 —NHBoc, —O—CH 2 —CHOH—CH 2 —NH—C(═NH)—N(R 7 ) 2 , —O—(CH 2 ) m —N(SO 2 R 7 ) 2 , —(CH 2 ) n —CHNHBocCO 2 R 7 (α), —O—(CH 2 ) m —CHNHBocCO 2 R 7 (α) —O—(CH 2 ) 2 —N(Me) 2 , —(CH 2 ) n —CHNH 2 CO 2 R 7 (α), —O—(CH 2 ) m —CHNH 2 CO 2 R 7 (α), —C(═O)NH—(CH 2 ) m —N(R 10 ) 2 , —NHC(═O)(CH 2 ) m —N(R 10 ) 2 , —C(═O)NH—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —NH—C(═O)—(CH 2 ) m NH—C(═NH)—N(R 10 ) 2 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , or —O—CH 2 —CHOH—CH 2 -guanadine,
182 . The method of claim 179 , wherein the compound represent by formula (I) is
183 . The method of claim 179 , wherein the Q attached to the —(C(R L ) 2 ) p group is N.
184 . The method of claim 179 , wherein each Q is —CR 6 R 5 — or —CR 6 R 6 — and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 .
185 . A method of restoring mucosal defense, comprising administering to a subject an effective of 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 )—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 )—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) n —R 8 , —(CH 2 CH 2 O) n —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 )_—C(═O)NR 7 R 10 , —O—(CH 2 ) n —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 )—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;
each R 5 is, independently, —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) n —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 77 —OSO 3 H, —O-glucuronide, —O-glucose,
—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m —NR 12 R 12 —O—(CH 2 ) n —NR 12 R 12 , O—(CH 2 ) m -(Z) g R 12 , —O—(CH 2 ) n NR 11 R 11 , —O—(CH 2 ) m NR 11 R 11 , —(CH 2 ) n —N ⊕ —(R 11 ) 3 , —O—(CH 2 ) m , —N ⊕ —(R 11 ) 3 , —(CH 2 ) n -(Z) g -(CH 2 ) m —NR 10 R 10 , —O—(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —(CH 2 ) n —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , (CH 2 ) n —(CHOR 8 ) m CH 2 —NR 10 -(Z) g -R 10 , —(CH 2 ) n NR 10 —O(CH 2 ) m (CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , —O(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) n —OR 8 , -(Het)-(CH 2 ) m —NR 7 R 10 , -(Het)-(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 CH 2 O) m —R 8 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , -(Het)-(CH 2 ) n —C(═O)NR 7 R 10 , -(Het)-(CH 2 ) m -(Z) g -R 7 , -(Het)-(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 ) m —CO 2 R 7 , -(Het)-(CH 2 ) m —NR 12 R 12 , -(Het)-(CH 2 ) n —NR 12 R 12 -(Het)-(CH 2 ) m -(Z) g R 12 , -(Het)-(CH 2 ) m N 11 R 11 , -(Het)-(CH 2 ) m —N ⊕ —(R 11 ) 3 , -(Het)-(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , -(Het)-(CH 2 ) m —(C═O)NR 12 R 12 —(Het)-(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 1 -(Z) g -R 10 ,
wherein when 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,
—(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
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 —C(═O)NR 10 R 10 , Link-(CH 2 ) n —C(═O)NR 13 —(CH 2 ) m —CAP, Link-(CH 2 ) n —C(═O)NR 11 R 11 , Link-(CH 2 ) m —C(═O)NR 12 R 12 , Link-(CH 2 ) n-(Z) g -(CH 2 ) m -(Z) g -CAP, or Link -Z g -(CH 2 ) m -Het-(CH 2 ) n —CAP;
each Link is, independently, —O—, —(CH 2 ) n —, —O(CH 2 ) m —, —NR 13 —C(═O)—NR 13 , —NR 1 —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, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R 13 R 13 , heteroaryl-W, —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
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 W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)NR 13 R 13 , —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each R 6 is, independently, —R 5 , —R 7 , —OR 8 , —N(R 7 ) 2 , —(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 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , —(CH 2 CH 2 O) n —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 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 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —(CH 2 ) n —(CHOH) n —CH 2 OH;
each Z is, independently, CHOH, C(═O) n —(CH 2 ) n —, 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 53 , —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, —(CH 2 ) n —NR 7 R 10 ,
with the proviso that NR 13 R 13 can be joined on itself to form a group represented by one of the following:
each Het is independently, —NR 13 —, —S—, —SO—, —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, —CR 6 R 5 —, —CR 6 R 6 —, —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— or —SO 2 —;
wherein at most three Q in a ring are —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— and/or —SO 2 —, at least one Q must be —CR 5 R 6 — or —NR 5 —, and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 or N;
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 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.
186 . The method of claim 185 , wherein Y is N 12 , X is Cl, each of R 2 , R 1 , R 3 , R L , and R 6 is H, o is 4, p is 0, and x is a single bond.
187 . The method of claim 186 , wherein R 5 is
—O—(CH 2 ) 4 —OH, —(CH 2 ) 4 —OH, —NHSO 2 CH 3 , —NH(C═O)CH 3 , —CH 2 NH 2 , —NH—CO 2 C 2 H 5 , —CH 2 NH(C═O)CH 3 , —CH 2 NHCO 2 CH 3 , —CH 2 NHSO 2 CH 3 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHCO 2 C 2 H 5 , —O(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHSO 2 CH 3 , —O—CH 2 CH 2 NH 2 , —OCH 2 CHOHCH 2 O-glucuronide, —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 — (α-CHOH) 2 CH 2 OH, —OCH 2 —(CHOH) 2 CH 2 OH, —C(═O)NH 2 , —O—CH 2 —(C═O)NHCH 2 CHOH, —O—CH 2 —(C═O)NHCH 2 CHOHCH 2 OH, —O—CH 2 (C═O)NHCH 2 (CHOH) 2 CH 2 OH, —O—CH 2 C(C═O)NHSO 2 CH 3 , —O—CH 2 (C═O)NHCO 2 CH 3 , —O—CH 2 —C(C═O)NH—C(C═O)NH 2 , —O—CH 2 —(C═O)NH—(C═O)CH 3 , —(C═NH)NH 2 , —(CH 2 ) n —NH—C(═NH)—NH 2 , —(CH 2 ) 3 —NH—C(═NH)—NH 2 , —CH 2 NH—C(═NH)—NH 2 , —(CH 2 ) n —CONHCH 2 (CHOH) n —CH 2 OH, —NH—C(═O)—CH 2 —(CHOH) n CH 2 OH, —NH—(C═O)—NH—CH 2 (CHOH) 2 CHOH, —NHC(C═O)NHCH 2 CH 2 OH, —O—(CH 2 ) n —NH—C(═NH)—N(R 7 ) 2 , —O(CH 2 ) 3 —NE-C(═NH)—NH 2 , —O—(CH 2 ) m —CHNH 2 —CO 2 NR 7 R 10 , —OCH 2 —CHNH 2 —CO 2 NH 2 , —NHCH 2 (CHOH) 2 CH 2 OH, —O—(CH 2 ) m —NH-erythritol, —O—(CH 2 ) m —NH-sorbitol, —O—(CH 2 ) m —NH-xylitol, —O—(CH 2 ) m —NH-glycidol, —OCH 2 CO 2 H, —OCH 2 CO 2 C 2 H 5 , —O—CH 2 -dioxolane, —O—(CH 2 ) 3 —OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, —O—CH 2 —CHOH—CH 2 OH, —O—CH 2 CH 2 —O-tetrahydropyran-2-yl, —O—CH 2 CH 2 OH, —O—(CH 2 CH 2 O) 4 —CH 3 , —O—CH 2 CH 2 OCH 3 , —O—CH 2 —(CHOC(═O)CH 3 )—CH 2 —OC(═O)CH 3 , —O—(CH 2 CH 2 O) 2 —CH 3 , —OCH 2 —CHOH—CHOH—CH 2 OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, ortho —O—CH 2 —CHOH—CH 2 OH, meta —O—CH 2 —CHOH—CH 2 OH, —OCH 2 CO 2 H, —NHCH 2 (CHOH) 2 —CH 2 OH, —OCH 2 CO 2 Et, —O—CH 2 C(═O)NH 2 , —NHCO 2 Et, —OCH 2 CH 2 CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 CH 2 NHCO 2 Et, —NH—C(═NNH 2 )—NH 2 OHOH, —CH 2 —CHOH—CH 2 —NHBoc, —O—CH 2 —CHOH—CH 2 —NHBoc, —OCH 2 CH 2 NHCH 2 (CHOH) 2 CH 2 OH, —OCH 2 CH 2 NH(CH 2 [(CHOH) 2 CH 2 OH)] 2 , —(CH 2 ) 4 —NHBoc, —OCH 2 CH 2 NHSO 2 CH 3 , —(CH 2 ) 3 —NHBoc, —O—CH 2 —CHOH—CH 2 —NH—C(═NH)—N(R 7 ) 2 , —O—(CH 2 ) m —N(SO 2 R 7 ) 2 , —(CH 2 ) n —CHNHBocCO 2 R 7 (O), —O—(CH 2 ) m —CHNHBocCO 2 R 7 (<) —O—(CH 2 ) 2 —N(Me) 2 , —(CH 2 ) n —CHNH 2 CO 2 R 7 (α), —O—(CH 2 ) m —CHNH 2 CO 2 R 7 (α), —C(═O)NH—(CH 2 ) m —N(R 10 ) 2 , —NHC(═O)(CH 2 ) m —N(R 10 ) 2 , —C(═O)NH—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —NH—C(═O)—(CH 2 ) m NH—C(═NH)—N(R 10 ) 2 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , or —O—CH 2 —CHOH—CH 2 -guanadine,
188 . The method of claim 185 , wherein the compound represent by formula (I) is
189 . The method of claim 185 , wherein the Q attached to the —(C(R L ) 2 ) p group is N.
190 . The method of claim 185 , wherein each Q is —CR 6 R 5 — or —CR 6 R 6 — and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 .
191 . A method of increasing hydration in a mucosal surface of a subject, comprising topically administering to a mucosal surface of a subject an effective amount of 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;
each R 5 is, independently, —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 ) n —CO 2 R 7 , —OSO 3 H, —O-glucuronide, —O-glucose,
—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m —NR 12 R 12 , —O—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m -(Z) g R 12 , —(CH 2 ) n NR 11 R 11 , —O—(CH 2 ) m NR 11 R 11 , —(CH 2 ) n —N ⊕ —(R 11 ) 3 , —O—(CH 2 ) m , —N ⊕ —(R 11 ) 3 , —(CH 2 ) n -(Z) g —(CH 2 ) m —NR 10 R 10 , —O—(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , —(CH 2 CH 2 O) n —CH 2 CH 2 NR 12 R 12 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —(CH 2 ) n —(C═O)NR 12 R 12 , —O—(CH 2 ) m (C═O)NR 12 R 12 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) n -R 10 , —(CH 2 ) n —(CHOR 8 ) m CH 2 -(Z) g -R 10 , —(CH 2 ) n NR 10 —O(CH 2 ) m (CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , —O(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —OR 8 , -(Het)-(CH 2 ) m —NR 7 R 10 , -(Het)-(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 CH 2 O) m —R 8 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , -(Het)-(CH 2 ) m —C(═O)NR 7 R 10 , -(Het)-(CH 2 ) m -(Z) g -R 7 , -(Het)-(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 ) m —CO 2 R 7 , -(Het)-(CH 2 ) m —NR 12 R 12 , -(Het)-(CH 2 ) n —NR 12 R 12 , -(Het)-(CH 2 ) m -(Z) g R 12 , -(Het)-(CH 2 ) n NR 11 R 11 , -(Het)-(CH 2 ) m —N ⊕ —R 11 ) 3 , -(Het)-(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , -(Het)-(CH 2 ) m —(C═O)NR 12 R 12 , -(Het)-(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 ,
wherein when 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,
—(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
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) n —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 —C(═O)NR 10 R 10 , Link-(CH 2 ) n —C(═O)NR 13 —(CH 2 ) m —CAP, Link-(CH 2 ) m —C(═O)NR 11 R 11 , Link-(CH 2 ) n —C(═O)NR 12 R 12 Link-(CH 2 ) n -(Z) g -(CH 2 ) m -(Z) g -CAP, or 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, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R 13 R 13 , heteroaryl-W, —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )— (Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
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 W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)NR 13 R 13 —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each R 6 is, independently, —R 5 , —R 7 , —OR 8 , —N(R 7 ) 2 , —(CH 2 ) m —OR 8 , —O—(CH 2 ) n —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 77 —OSO 3 H, —O-glucuronide, —O-glucose,
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 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —(CH 2 ) m-(CHOH) n —CH 2 OH;
each Z is, independently, CHOH, C(═O) n —(CH 2 ) n —, 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, —(CH 2 ) m —NR 7 R 10 ,
with the proviso that NR 13 R 13 can be joined on itself to form a group represented by one of the following:
each Het is independently, —NR 13 —, —S—, —SO—, —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, —CR 6 R 5 —, —CR 6 R 6 —, —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— or —SO 2 —,
wherein at most three Q in a ring are —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— and/or —SO 2 —, at least one Q must be —CR 5 R 6 — or —NR 5 —, and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 or N;
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 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.
192 . The method of claim 191 , wherein Y is NH 2 , X is Cl, each of R 2 , R 1 , R 3 , R L , and R 6 is H, o is 4, p is 0, and x is a single bond.
193 . The method of claim 192 , wherein R 5 is
—O—(CH 2 ) 4 —OH, —(CH 2 ) 4 —OH, —NHSO 2 CH 3 , —NH(C═O)CH 3 , —CH 2 NH 2 , —NH—CO 2 C 2 H 5 , —CH 2 NH(C═O)CH 3 , —CH 2 NHCO 2 CH 3 , —CH 2 NHSO 2 CH 3 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHCO 2 C 2 H 5 , —O(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHSO 2 CH 3 , —O—CH 2 CH 2 NH 2 , —OCH 2 CHOHCH 2 O-glucuronide, —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 -(α-CHOH) 2 CH 2 OH, —OCH 2 —(CHOH) 2 CH 2 OH, —C(═O)NH 2 , —O—CH 2 —(C═O)NHCH 2 CHOH, —O—CH 2 —(C═O)NHCH 2 CHOHCH 2 OH, —O—CH 2 (C═O)NHCH 2 (CHOH) 2 CH 2 OH, —O—CH 2 C(C═O)NHSO 2 CH 3 , —O—CH 2 (C═O)NHCO 2 CH 3 , —O—CH 2 —C(C═O)NH—C(C═O)NH 2 , —O—CH 2 —(C═O)NH—(C═O)CH 3 , —(C═NH)NH 2 , —(CH 2 ) n —NH—C(═NH)—NH 2 , —(CH 2 ) 3 —NH—C(═NH)—NH 2 , —CH 2 NH—C(═NH)—NH 2 , —(CH 2 ) n —CONHCH 2 (CHOH) m —CH 2 OH, —NH—C(═O)—CH 2 —(CHOH) n CH 2 OH, —NH—(C═O)—NH—CH 2 (CHOH) 2 CHOH, —NHC(C═O)NHCH 2 CH 2 OH, —O—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —O(CH 2 ) 3 —NH—C(═NH)—NH 2 , —O—(CH 2 ) m —CHNH 2 —CO 2 NR 7 R 10 , —OCH 2 —CHNH 2 —CO 2 NH 2 , —NHCH 2 (CHOH) 2 CH 2 OH, —O—(CH 2 ) m —NH-erythritol, —O—(CH 2 ) m —NH-sorbitol, —O—(CH 2 ) m —NH-xylitol, —O—(CH 2 ) m —NH-glycidol, —OCH 2 CO 2 H, —OCH 2 CO 2 C 2 H 5 , —O—CH 2 -dioxolane, —O—(CH 2 ) 3 —OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, —O—CH 2 —CHOH—CH 2 OH, —O—CH 2 CH 2 —O-tetrahydropyran-2-yl, —O—CH 2 CH 2 OH, —O—(CH 2 CH 2 O) 4 —CH 3 , —O—CH 2 CH 2 OCH 3 , —O—CH 2 —(CHOC(═O)CH 3 )—CH 2 —OC(═O)CH 3 , —O—(CH 2 CH 2 O) 2 —CH 3 , —OCH 2 —CHOH—CHOH—CH 2 OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, ortho —O—CH 2 —CHOH—CH 2 OH, meta —O—CH 2 —CHOH—CH 2 OH, —OCH 2 CO 2 H, —NHCH 2 (CHOH) 2 —CH 2 OH, —OCH 2 CO 2 Et, —O—CH 2 C(═O)NH 2 , —NHCO 2 Et, —OCH 2 CH 2 CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 CH 2 NHCO 2 Et, —NH—C(—NH 2 )—NH 2 OHOH, —CH 2 —CHOH—CH 2 —NHBoc, —O—CH 2 —CHOH—CH 2 —NHBoc, —OCH 2 CH 2 NHCH 2 (CHOH) 2 CH 2 OH, —OCH 2 CH 2 NH(CH 2 [(CHOH) 2 CH 2 OH)] 2 , —(CH 2 ) 4 —NHBoc, —OCH 2 CH 2 NHSO 2 CH 3 , —(CH 2 ) 3 —NHBoc, —O—CH 2 —CHOH—CH 2 —NH—C(═NH)—N(R 7 ) 2 , —O—(CH 2 ) m —N(SO 2 R 7 ) 2 , —(CH 2 ) n —CHNHBocCO 2 R 7 (α), —O—(CH 2 ) m —CHNHBocCO 2 R 7 (α) —O—(CH 2 ) 2 —N(Me) 2 , (CH 2 ) n —CHNH 2 CO 2 R 7 (α), —O—(CH 2 ) m —CHNH 2 CO 2 R 7 (α), —C(═O)NH—(CH 2 ) m —N(R 10 ) 2 , —NHC(═O)(CH 2 ) m —N(R 10 ) 2 , —C(═O)NH—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —NH—C(═O)—(CH 2 ) m NH—C(═NH)—N(R 10 ) 2 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , or —O—CH 2 —CHOH—CH 2 -guanadine,
194 . The method of claim 191 , wherein the compound represent by formula (I) is
195 . The method of claim 191 , wherein the Q attached to the —(C(R L ) 2 ) p group is N.
196 . The method of claim 191 , wherein each Q is —CR 6 R 5 — or —CR 6 R 6 — and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 .
197 . A method comprising topically administering to a mucosal surface of a subject 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;
each R 5 is, independently, —O—(CH 2 ) m —OR 8 , —(CH 2 ) n —NR 7 R 10 , —O—(CH 2 ) n —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,
—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m —NR 12 R 12 , —O—(CH 2 ) n —NR 12 R 12 , —O—(CH 2 ) m -(Z) g R 12 , —(CH 2 ) n NR 11 R 11 , —O—(CH 2 ) m NR 11 R 11 , —(CH 2 ) n —N ⊕ —(R 11 ) 3 , —O—(CH 2 ) m —N ⊕ —(R 1 ) 3 , —(CH 2 ) n -(Z) g —(CH 2 ) m —NR 10 R 10 , —O—(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , —(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —O—(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , —(CH 2 ) n —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(C═O)NR 12 R 12 , —O—(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , —(CH 2 ) n —(CHOR 8 ) m CH 2 —NR 10 -(Z) g -R 10 , —(CH 2 ) n NR 10 —O(CH 2 ) m (CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , —O(CH 2 ) m —NR 10 —(CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —OR 8 , -(Het)-(CH 2 ) m —NR 7 R 10 , -(Het)-(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 CH 2 O) m —R 8 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 7 R 10 , -(Het)-(CH 2 ) m —C(═O)NR 7 R 10 , (Het)-(CH 2 ) m -(Z) g -R 7 , -(Het)-(CH 2 ) m —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , -(Het)-(CH 2 ) m —CO 2 R 7 , -(Het)-(CH 2 ) m —NR 12 R 12 , -(Het)-(CH 2 ) n —NR 12 R 12 , -(Het)-(CH 2 ) m -(Z) g R 12 , -(Het)-(CH 2 ) m NR 11 R 11 , -(Het)-(CH 2 ) m —N ⊕ —(R 11 ) 3 , -(Het)-(CH 2 ) m -(Z) g -(CH 2 ) m —NR 10 R 10 , -(Het)-(CH 2 CH 2 O) m —CH 2 CH 2 NR 12 R 12 , -(Het)-(CH 2 ) m —(C═O)NR 12 R 12 , -(Het)-(CH 2 ) m —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , -(Het)-(CH 2 ) m —NR 10 (CH 2 ) m —(CHOR 8 ) n CH 2 NR 10 -(Z) g -R 10 ,
wherein when 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,
—(CH 2 ) n (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) m (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
—O—(CH 2 ) n —NR 10 —CH 2 (CHOR 8 )(CHOR 8 ) n —CH 2 OR 8 , with the proviso that at least two —CH 2 OR 8 are located adjacent to each other and the R 8 groups are joined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,
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 —C(═O)NR 10 R 10 , Link-(CH 2 ) m —C(═O)NR 13 —(CH 2 ) m —CAP, Link-(CH 2 ) m —C(═O)NR 11 R 11 , Link-(CH 2 ) m —C(═O)NR 12 R 12 , Link-(CH 2 ) n-(Z) g -(CH 2 ) m -(Z) g -CAP, or 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, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R 13 R 13 , heteroaryl-W, —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , —SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
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 W is independently, thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)NR 13 R 13 —CN, —O—C(═S)NR 13 R 13 , -Z g R 13 , —CR 10 (Z g R 13 )(Z g R 13 ) n —C(═O)OAr, —C(═O)NR 13 Ar, imidazoline, tetrazole, tetrazole amide, —SO 2 NHR 13 , SO 2 NH—C(R 13 R 13 )-(Z) g -R 13 , a cyclic sugar or oligosaccharide, a cyclic amino sugar or oligosaccharide,
each R 6 is, independently, —R 5 , —R 7 , —OR 8 , —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,
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 7 , —C(═O)NR 7 R 9 , —C(═O)R 7 , or —(CH 2 ) m-(CHOH) n —CH 2 OH;
each Z is, independently, CHOH, C(═O) n —(CH 2 ) n —, 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 ) n-(CHOH) n —CH 2 OH, —C(═O)R 7 , or —(CH 2 ) n —(CHOH) n —CH 2 OH, —(CH 2 ) n —NR 7 R 10 ,
with the proviso that NR 13 R 13 can be joined on itself to form a group represented by one of the following:
each Het is independently, —NR 13 —, —S—, —SO—, —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, —CR 6 R 5 —, —CR 6 R 6 —, —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— or —SO 2 —;
wherein at most three Q in a ring are —NR 10 —, —NR 7 —, —NR 5 —, —S—, —SO— and/or —SO 2 —, wherein at least one Q must be —CR 5 R 6 — or —NR 5 —, and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 or N;
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 1 , or (R 1 ) 2 ;
with the proviso that, when 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,
whereby hydration of the mucosal surface is increased.
198 . The method of claim 197 , wherein Y is NH 2 , X is Cl, each of R 2 , R 1 , R 3 , R L , and R 6 is H, o is 4, p is 0, and x is a single bond.
199 . The method of claim 198 , wherein R 1 is
—O—(CH 2 ) 4 —OH, —(CH 2 ) 4 —OH, —NHSO 2 CH 3 , —NH(C═O)CH 3 , —CH 2 NH 2 , —NH—CO 2 C 2 H 5 , —CH 2 NH(C═O)CH 3 , —CH 2 NHCO 2 CH 3 , —CH 2 NHSO 2 CH 3 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHCO 2 C 2 H 5 , —O(CH 2 ) 3 —NH 2 , —OCH 2 CH 2 NHSO 2 CH 3 , —O—CH 2 CH 2 NH 2 , —OCH 2 CHOHCH 2 O-glucuronide, —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 -(α-CHOH) 2 CH 2 OH, —OCH 2 —(CHOH) 2 CH 2 OH, —C(═O)NH 2 , —O—CH 2 —(C═O)NHCH 2 CHOH, —O—CH 2 —(C═O)NHCH 2 CHOHCH 2 OH, —O—CH 2 (C═O)NHCH 2 (CHOH) 2 CH 2 OH, —O—CH 2 C(C═O)NHSO 2 CH 3 , —O—CH 2 (C═O)NHCO 2 CH 3 , —O—CH 2 —C(C═O)NH—C(C═O)NH 2 , —O—CH 2 —(C═O)NH—(C═O)CH 3 , —(C═NH)NH 2 , —(CH 2 ) n —NH—C(NH)—NH 2 , —(CH 2 ) 3 —NH—C(═NH)—NH 2 , —CH 2 NH—C(═NH)—NH 2 , —(CH 2 ) n —CONHCH 2 (CHOH) n —CH 2 OH, —NH—C(═O)—CH 2 —(CHOH) n CH 2 OH, —NH—(C═O)—NH—CH 2 (CHOH) 2 CHOH, —NHC(C═O)NHCH 2 CH 2 OH, —O—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —O(CH 2 ) 3 —NH—C(═NH)—NH 2 , —O—(CH 2 ) m —CHNH 2 —CO 2 NR 7 R 10 , —OCH 2 —CHNH 2 —CO 2 NH 2 , —NHCH 2 (CHOH) 2 CH 2 OH, —O—(CH 2 ) n —NH-erythritol, —O—(CH 2 ) m —NH-sorbitol, —O—(CH 2 ) m —NH-xylitol, —O—(CH 2 ) m —NH-glycidol, —OCH 2 CO 2 H, —OCH 2 CO 2 C 2 H 5 , —O—CH 2 -dioxolane, —O—(CH 2 ) 3 —OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, —O—CH 2 —CHOH—CH 2 OH, —O—CH 2 CH 2 —O-tetrahydropyran-2-yl, —O—CH 2 CH 2 OH, —O—(CH 2 CH 2 O) 4 —CH 3 , —O—CH 2 CH 2 OCH 3 , —O—CH 2 —(CHOC(═O)CH 3 )—CH 2 —OC(═O)CH 3 , —O—(CH 2 CH 2 O) 2 —CH 3 , —OCH 2 —CHOH—CHOH—CH 2 OH, —O—CH 2 —(CHOH) 2 —CH 2 OH, ortho —O—CH 2 —CHOH—CH 2 OH, meta —O—CH 2 —CHOH—CH 2 OH, —OCH 2 CO 2 H, —NHCH 2 (CHOH) 2 —CH 2 OH, —OCH 2 CO 2 Et, —O—CH 2 C(═O)NH 2 , —NHCO 2 Et, —OCH 2 CH 2 CH 2 CH 2 OH, —CH 2 NHSO 2 CH 3 , —OCH 2 CH 2 CHOHCH 2 OH, —OCH 2 CH 2 NHCO 2 Et, —NH—C(═NH 2 )—NH 2 OHOH, —CH 2 —CHOH—CH 2 —NHBoc, —O—CH 2 —CHOH—CH 2 —NHBoc, —OCH 2 CH 2 NHCH 2 (CHOH) 2 CH 2 OH, —OCH 2 CH 2 NH(CH 2 [(CHOH) 2 CH 2 OH)] 2 , —(CH 2 ) 4 —NHBoc, —OCH 2 CH 2 NHSO 2 CH 3 , —(CH 2 ) 3 —NHBoc, —O—CH 2 —CHOH—CH 2 —NH—C(═NH)—N(R 7 ) 2 , —O—(CH 2 ) m —N(SO 2 R 7 ) 2 , —(CH 2 ) n —CHNHBocCO 2 R 7 (α), —O—(CH 2 ) m —CHNHBocCO 2 R 7 (α) —O—(CH 2 ) 2 —N(Me) 2 , —(CH 2 ) n —CHNH 2 CO 2 R 7 (α), —O—(CH 2 ) m —CHNH 2 CO 2 R 7 (α), —C(═O)NH—(CH 2 ) n —N(R 10 ) 2 , —NHC(═O)(CH 2 ) m —N(R 10 ) 2 , —C(═O)NH—(CH 2 ) m —NH—C(═NH)—N(R 7 ) 2 , —NH—C(═O)—(CH 2 ) m NH—C(═NH)—N(R 10 ) 2 , —O—(CH 2 ) n —(CHOR 8 ) m CH 2 NR 10 -(Z) g -R 10 , or —O—CH 2 —CHOH—CH 2 -guanadine,
200 . The method of claim 197 , wherein the compound represent by formula (I) is
201 . The method of claim 197 , wherein the Q attached to the —(C(R L ) 2 ) p group is N.
202 . The method of claim 197 , wherein each Q is —CR 6 R 5 — or —CR 6 R 6 — and the Q attached to the —(C(R L ) 2 ) p — group is —CR 6 R 5 .Join the waitlist — get patent alerts
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