Patent EP-0106541-A2 (EP)
Inventor: BUNDGAARD HANS
IPC: A61P27/02
Filed: 1983-09-16
Abstract: Compounds are disclosed of the general formula Iwherein R, is a group of the formula IIwherein R<sub>3</sub> 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 phenoxy; 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 R, is a group of the formula IIIwherein R<sub>4</sub> has the same meaning as R<sub>3</sub> as defined above; or R<sub>4</sub> is a group of the formula IVwherein R<sub>7</sub> has the same meaning as R<sub>3</sub> as defined above; or R<sub>7</sub> 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 R<sub>5</sub> and R<sub>6</sub> are the same or different and each represent hydrogen or have the same meaning as R<sub>3</sub> as defined above;or R, is a group of the formula Vwherein R<sub>5</sub> and R<sub>6</sub> are as defined above and R<sub>s</sub> is polyhalogenated lower alkyl or a group of the formula VIwherein R<sub>3</sub> is as defined above; or R, is a group of the formula VIIwherein R<sub>10</sub> and R<sub>11</sub> 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 R, is a group of the formula VIIIwherein R<sub>13</sub> is a group of the formula II, wherein R<sub>3</sub> and X are as defined above; or R<sub>13</sub> is a group of the formula VIIawherein R<sub>16</sub> and R<sub>17</sub> are the same or different and each represent hydrogen or have the same meaning as R<sub>3</sub> as defined above; or R,<sub>3</sub> is a group of the formula VII, wherein R<sub>10</sub> and R<sub>11</sub> are as defined above; or R, is a group of the formula IXwherein R<sub>13</sub> is as defined above; and R<sub>2</sub> is hydrogen or a group of the formula IV, wherein R<sub>7</sub> is as defined above; or R<sub>2</sub> is a group of the formula VI, wherein R<sub>3</sub> is as defined above; and salts thereof.In the formula I, R, 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 R<sub>2</sub> is preferably hydrogen, acetyl, propionyl, butyryl, or benzoyl, and salts thereof.Specially preferred compounds are such in which R, is benzyloxy, 2-phenylethyloxy, 4-chlorobenzyloxy, 4-tert butylbenzyloxy, or 4-methylbenzyloxy, and R<sub>2</sub> 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 thereofin which R'<sub>2</sub> is a group R<sub>2</sub> as defined above or a protection group, with a compound of the formula XIwherein R<sub>14</sub> is the same as R<sub>3</sub> as defined above, or R<sub>14</sub> is a group of the formula XIIwherein R<sub>4</sub>, R<sub>s</sub>, and R<sub>6</sub> are as defined above, or R<sub>14</sub> is a group of the formula XIIIwherein R<sub>5</sub>, R<sub>6</sub>, and R<sub>8</sub> are as defined above, and Z is hydroxy or a leaving group.The compounds of the formula I are prodrugs of pilocarpine. When administered ophthatmically 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 (Figures 3 and 4), thus obviating the need for frequent administration and the consequent side effects, such as induced myopia and miosis, that characterizes the use of pilocarpine.