Patent EP-0106541-A3 (EP)
IPC: A61P27/02
Filed: 1983-09-16
Abstract: Compounds are disclosed of the general formula I 
  
wherein R₁ is a group of the formula II  
R₃ - X - II  
wherein R₃ is alkyl; phenyl; phenyl substituted with halogen, 
lower alkyl, hydroxy, lower alkoxy, or phenoxy; phenyl­
lower alkyl in which the phenyl group may be substituted 
with halogen, lower alkyl, hydroxy, lower alkoxy, or phe­
noxy; phenyl-lower alkenyl in which the phenyl group may 
be substituted with halogen, lower alkyl, hydroxy, lower 
alkoxy or phenoxy; and X is oxygen or sulfur; or R₁ is a 
group of the formula III 
  
wherein R₄ has the same meaning as R₃ as defined above; or 
R₄ is a group of the formula IV    
R₇ - 
 - IV  
wherein R₇ has the same meaning as R₃ as defined above; or 
R₇ is an aromatic 5- or 6-membered heterocyclic ring 
containing one or two heteroatoms selected from the group 
consisting of nitrogen, oxygen, and sulfur; and wherein R₅ 
and R₆ are the same or different and each represent 
hydrogen or have the same meaning as R₃ as defined above;  
or R₁ is a group of the formula V 
  
wherein R₅ and R₆ are as defined above and R₈ as polyhalo­
genated lower alkyl or a group of the formula VI    
R₃ - O - 
 - VI  
wherein R₃ is as defined above; or R₁ is a group of the 
formula VII 
  
wherein R₁₀ and R₁₁ together with the adjacent nitrogen 
atom form a 5- or 6-membered heterocyclic ring, which in 
addition to the nitrogen may contain one or two further 
heteroatoms selected from the group consisting of nitrogen, 
oxygen, and sulfur;  
or R₁ is as group of the formula VIII  
R₁₃ - 
 - NH -    VIII 
wherein R₁₃ is a group of the formula II, wherein R₃ and X are 
as defined above; or R₁₃ is a group of the formula VIIa 
  
wherein R₁₆ and R₁₇ are the same or different and each 
represent hydrogen or have the same meaning as R₃ as 
defined above; or R₁₃ is a group of the formula VII, wherein 
R₁₀ and R₁₁ are as defined above;  
or R₁ is a group of the formula IX  
R₁₃ - 
 - NH - 
 - NH -    IX 
wherein R₁₃ is as defined above; and R₂ is hydrogen or a 
group of the formula IV, wherein R₇ is as defined above; or 
R₂ is a group of the formula VI, wherein R₃ is as defined 
above;  
and salts thereof.  
     In the formula I, R₁ is preferably phenyl-lower alkoxy, in 
which the phenyl group is optionally substituted, such as 
benzyloxy, 2-phenylethyloxy, 4-chlorobenzyloxy, 4-­
methylbenzyloxy, and 4-tert.butylbenzyloxy, and R₂ is prefer­
ably hydrogen, acetyl, propionyl, butyryl, or benzoyl, and 
salts thereof.  
     Specially preferred compounds are such in which R₁ is 
benzyloxy, 2-phenylethyloxy, 4-chlorobenzyloxy, 4-­
tert.butylbenzyloxy, or 4-methylbenzoyloxy, and R₂ is acetyl, 
propionyl, butyryl, or benzoyl, and salts thereof.  
     Also disclosed are substantially pure salts of pilocarpic 
acid, which are prepared by hydrolyzing pilocarpine with a 
strong base, such as an alkaline metal or alkaline earth metal 
hydroxide in an aqueous medium at a temperature around 
0°C.  
     The compounds of the formula I may be prepared by 
various methods, among which a preferred method is 
reacting a salt of pilocarpic acid such as a metal salt, or a 
compound of the formula X, or a salt thereof 
  
in which R′₂ is a group R₂ as defined above or a protection 
group, with a compound of the formula XI  
R₁₄ - Z XI  
wherein R₁₄ is the same as R₃ as defined above, or R₁₄ is a 
group of the formula XII 
  
wherein R₄, R₅ and R₆ are as defined above, or R₁₄ is a group 
of the formula XIII 
  
wherein R₅, R₆, and R₈ are as defined as above, and Z is hydroxy 
or a leaving group.  
     The compounds of the formula I are prodrugs of 
pilocarpine. When administered ophthalmically to a warm-­
blooded animal such as a human, compounds of formula I, 
due to their high lipophilicity, will penetrate the cornea in an 
extent greater than pilocarpine itself, and will thereafter be 
converted into pilocarpine in a slow and controlled manner, 
thus obviating the need for frequent 
administration and the consequent side effects, such as 
induced myopia and miosis, that characterizes the use of 
pilocarpine.