Corneal perception recovery drug containing amide compound
View Patent ↗The amide compound of the formula (I) [each symbol is as defined in the description] has a promoting action on neuritogenesis of trigeminal nerve cells, and the compound is useful as a corneal neuritogenesis promoter, an agent for recovering corneal sensitivity by promotion of corneal neuritogenesis, and an agent for treating dry eye.
1. A method of recovering corneal sensitivity after corneal surgery, which comprises administering after corneal surgery and topically to the eye of a patient in need thereof an effective amount of an amide compound represented by the formula (I):
wherein
Ra is a formula:
wherein
in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, each optionally having substituent(s) on the ring, or a formula:
wherein
R 6 is hydrogen, alkyl or a formula: —NR 8 R 9 wherein R 8 and R 9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, and
R 7 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano,
or R 6 and R 7 in combination form a heterocyclic group further optionally containing, in the ring, an oxygen atom, a sulfur atom, or a nitrogen atom optionally having a substituent,
R 1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, each optionally having substituent(s) on the ring,
or R and R 1 in combination form, together with the adjacent nitrogen atom, a heterocyclic group further optionally containing, in the ring, an oxygen atom, a sulfur atom, or a nitrogen atom optionally having a substituent,
R 2 is hydrogen or alkyl,
R 3 and R 4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl or azido, and
A is a formula:
wherein
R 10 and R 11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R 10 and R 11 in combination form cycloalkyl, and
l, m, n are each 0 or an integer of 1-3, and
in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or di-alkylaminoalkyl, tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino, or a formula:
wherein
B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, α-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q 1 is hydrogen, halogen, a hydroxyl group, aralkyloxy or thienylmethyl,
W is alkylene,
Q 2 is hydrogen, halogen, a hydroxyl group or aralkyloxy,
X is alkylene,
Q 3 is hydrogen, halogen, a hydroxyl group, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl, and
Y is a single bond, alkylene or alkenylene,
a bond shown by a broken line and a solid line in the formula (c) is a single bond or a double bond, and
R 5 is hydrogen, a hydroxyl group, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy,
Rb is hydrogen, alkyl, aralkyl, aminoalkyl or mono- or di-alkylaminoalkyl, and
Rc is a nitrogen-containing heterocycle optionally having substituent(s), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
2. The method of claim 1 , wherein Ra is a formula:
wherein each symbol is as defined in claim 1 .
3. The method claim 1 , wherein the amide compound, an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof is (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide hydrochloride.