Ocular protein stimulants

#This invention relates to lacrimal secretion stimulants. It represents an improvement over the invention of our earlier U.S. Pat. No. 4,820,737, issued Apr. 11, 1989.

#Tear film disturbances account for eye symptoms in millions of Americans. At the present time, treatment primarily consists of replacing a defective tear film with artificial tear substitutes which are sold over-the-counter. The major limitation of these products is their short retention time in the eye. Patients must apply drops as often as every hour to obtain comfort from these products. Recent accomplishments have focused on developing aqueous solutions containing components which will stabilize the tear film or replace specific deficiencies.

#A normal tear film is the product of: (1) aqueous secretion by the lacrimal gland and accessory lacrimal glands; (2) secretion of mucous primarily by the goblet cells of the conjunctiva; and (3) lipids secreted by the meibomian gland and the glands of Zeis and Moll in the lids. Mucin, the innermost layer (0.035 .mu.m), wets the lipophilic epithelial surface of the cornea with the middle aqueous layer. The aqueous layer (7 .mu.m) contains dissolved proteins, carbohydrates, glycoproteins, oxygen, and inorganic salts. The outer lipid layer (0.1 .mu.m) retards evaporation of the aqueous component.

#The following examples are offered to illustrate but not limit the invention.

#The general synthetic procedure for one prototype molecule (.+-.)-N,N-dimethyl-trans-2-phenylcyclopropylamine hydrochloride and its isomers (.+-.)-N,N-dimethyl-trans-2-phenylcyclopropylamine hydrochloride and (-)-N,N-dimethyl-trans-2-phenylcyclopropylamine hydrochloride involves preparation of trans-2-phenylcyclopropylamine as mixture of (+) and (-) isomers by the literature method ›Burger, A. B.; Yost, A., J. Am. Chem. Soc., 1948, 70 2198!, resolution of the (+)-trans-2-phenylcyclopropylamine and (-)-trans-2-phenylcyclopropylamine by the literature method ›Kaiser, C.; Lester, B. M.; Zirkle, C. L.; Burger, A. B.; Davis, C. S.; Delia, T. J.; Zimgibl, L. J. Med. Chem. 1962, 5, 1243!, and N,N-dimethylation Borch reductive alkylation ›Borch, R. F.; Hassid, A. I. J. Org. Chem 1972, 37, 1673-4! to (+)-trans-N,N-dimethyl-2-phenylcyclopropylamine and (-)-trans-N,N-dimethyl-2-phenylcyclopropylamine. These literature references disclose conventional preparation techniques, but not the uses of the invention. They are incorporated by reference.

#Protein Secretion Rate Assay for (.+-.)-N,N-dimethyl-trans-2-phenylcyclopropylamine hydrochloride in rabbits