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||||||||III USOO5616618A United States Patent 19 11 Patent Number: 5,616,618 Takagi 45) Date of Patent: Apr ||||||||III USOO5616618A United States Patent 19 11 Patent Number: 5,616,618 Takagi 45) Date of Patent: Apr. 1, 1997 54) THREO-3-(3,4-DHYDROXYPHENYL)SERINE 56) References Cited ANALGESC COMPOSITION U.S. PATENT DOCUMENTS (75) Inventor: Hiroshi Takagi, Kyoto, Japan 4,529,603 7/1985 Mori et al. .............................. 514/565 4,647,587 3/1987 Katsube et al. ......................... 514/567 73 Assignee: Sumitomo Pharmaceuticals Company, Limited, Osaka, Japan FOREIGN PATENT DOCUMENTS 32540 9/1974 Japan. 21 Appl. No.: 495,480 125630 10/1977 Japan. 22, PCT Filed: Jan. 28, 1994 67420 4/1985 Japan. Primary Examiner-Rebecca Cook 86 PCT No.: PCT/P94/00120 Attorney, Agent, or Firm-Sughrue, Mion, Zinn, Macpeak & S371 Date: Jul. 24, 1995 Seas S 102(e) Date: Jul. 24, 1995 57 ABSTRACT 87 PCT Pub. No.: WO94/16689 Threo-3-(3,4-dihydroxyphenyl)serine exhibits an analgesic effect against acute pains and chronic or continuous pains. PCT Pub. Date: Aug. 4, 1994 Therefore, threo-3-(3,4-dihydroxyphenyl)serine is effective for the treatment of diseases with pains such as postopera (30) Foreign Application Priority Data tive pain, headache, migraine, pains accompanied by rheu Jan. 29, 1993 JP Japan .................................... 5-034366 matism, post-herpes neuralgia, cancerous pain, pains asso ciated with cervico-omo-brachial syndrome, shoulder (51] Int. Cl." ......................... AON 37/12; A61K 31/195 periarthritis, spinal distortion, and spondylosis deformans. I52 U.S. Cl. ...................................................... 54/567 58 Field of Search ............................................... 514/567 4 Claims, 5 Drawing Sheets U.S. Patent Apr. 1, 1997 Sheet 1 of 5 5,616,618 - 4 Tes r 3 r Gld 2 > 3 s s-d 2- (n-3) (ries) (n=5) (n5) O - 22,Y --'os-to-air 22 TIME AFTER DOPS D O P S C mg/kg ) ADMINISTRATION (hour) F. G. 20 G c all S 15 CN s t g 10 ar r ar k n 5 is 5 1. O H 2. 3 O 1 O W 1OO 20O 4OO TIME ARTER DOPS D O P S C ng/kg ) ADMINISTRATION (hour) U.S. Patent Apr. 1, 1997 Sheet 2 of 5 5,616,618 F G. 30 F G. 3b PHASE I PHASE I CN + (N+----OO OO OO + O > OO 2OO D O P S ( Cng/kg ) D O P S (in g/kg ) U.S. Patent Apr. 1, 1997 Sheet 3 of 5 5,616,618 F. G. 40 FIG. 4b KAON-INDUCED TAL FLICK TEST WRTHING TEST 3 P&O.O1 N.S. -N 2 a- N.S. r O E - 3. O u CN Yale-1 - O O en t CO 2 s t <- gt 5 O 5 H 2. O 9 O V V DOPS OOPS O V W DOPS OOPS - - 4. - -- W. Nix W Nix V Nx W Nix F G. 5 F G. 5b EFFECT OF EFFECT OF PHENTOLAMINE,i.c. v. PHENTOLAMINE,i.th. P.O.O. P.O.O. P.O.O. P.O.O. era. mem Y-N - Ha 2 to 2 O O 3.g d 1 e send - y < < O W V OOPS. DOPS V W DOPS OOPS r - - - - V PHT V PHT V PHT W PHT U.S. Patent Apr. 1, 1997 Sheet 4 of 5 5,616,618 -!9|Q9, ZS8AZS8 sd?0SapoA? -|909 10B-B+BBO“ECJIZVYJESNEG‘O’S (puooes) Kot al. 2 TV U.S. Patent Apr. 1, 1997 Sheet 5 of 5 5,616,618 F G. 7 2 K i O V 2OO 4OO 8OO D O P S C ng/kg P.O. ) 5,616,618 1. 2 THREO-3-(3,4-DIHYDROXYPHENYL)SERINE FIG. 4 shows the results of morphine antagonist, nalox ANALGESC COMPOSITION one, on the analgesic effect of L-threo-DOPS assessed by the tail flick method and the kaolin-induced writhing test. This application is a 371 of PCT/JP94/00120. FIG. 5 shows the results of adrenaline blocking agent, phentolamine, on the analgesic effect of L-threo-DOPS TECHNICAL FIELD assessed by the tail flick method. The present invention relates to a medical use of threo FIG. 6 shows the results of decarboxylase inhibitor, 3-(3,4-dihydroxyphenyl)serine (hereinafter abbreviated as benserazide, on the analgesic effect of L-threo-DOPS threo-DOPS). More particularly, the present invention 10 assessed by the tail flick method. relates to a medical use of threo-DOPS as an analgesic drug, FIG. 7 shows the results of the analgesic effect of L-threo especially in the treatment of acute and chronic pains or DOPS by oral administration, which was assessed by the tail continuous pains. flick method. BACKGROUND ART 5 BEST MODE FOR CARRYING OUT THE Analgesic drugs are roughly classified into a narcotic type INVENTION and a non-narcotic type. The latter type of analgesics have been widely employed for clinical use due to their safety and Threo-DOPS used in the present invention is a known easy manipulation. compound represented by the following formula: 20 In terms of clinical classification, there are two types of HO pains, i.e., acute pains and chronic or continuous pains. Acute pains are induced by specific causes such as wound ph and inflammation. Conventional analgesics have all been HO CH- CHCOOH developed and clinically used for acute pains. On the other hand, chronic pains involve continuous pains over more than 25 NH2 6 months to a few years even after wounds causing acute pains have been healed. For such chronic pains, conven This compound may be prepared according to known meth tional analgesics are not always effective. A variety of drugs ods as reported in Japanese Patent Application KOKOKU Such as antidepressants and antispasmodics are applied to No. 1-49 139 and U.S. Pat. No. 4480,109. Threo-DOPS has relieve chronic pains but there has been no decisive drug so 30 optically active L- and D-forms and racemic DL-form. far Hiroshi Takagi, "Kyuseitsu-oyobi-Manseitsuno-Yakuri Among them, L-threo-DOPS is preferred for the purpose of the present invention. Since 1989, L-Threo-DOPS has been (Pharmacology of acute and chronic pains)', Nihon Ishikai clinically applied to improve freezing gait observed in Zasshi, Vol. 104, No. 1, pages 37-41, 1990). Parkinson's disease. Therefore, an object of the present invention is to provide 35 In the present invention, threo-DOPS may be employed an analgesic drug which is different from known analgesics also in the form of pharmaceutically acceptable acid addi in the action mechanism and is effective not only for acute tion salts thereof. To form the acid addition salts, there may pains but also for chronic pains. be used inorganic acids such as hydrochloric acid, hydro bronic acid and Sulfonic acid; and organic acids such as DISCLOSURE OF INVENTION 40 fumaric acid, citric acid, tartaric acid and succinic acid. The present inventors have made extensive studies to According to the present invention, threo-DOPS or its achieve the foregoing object. As a result, it has been dis pharmaceutically acceptable acid addition salts may also be covered that a pharmaceutical composition comprising used in combination with a decarboxylase inhibitor. Pre threo-DOPS as an effective ingredient exhibits an analgesic ferred examples of such a decarboxylase inhibitor include activity to relieve chronic or continuous pain as well as acute 45 benserazide and carbidopa. pain. The present invention has thus been accomplished. It is known that, after administration, threo-DOPS is That is, the present invention relates to an analgesic transported to a brain that is a site on which threo-DOPS composition comprising as an effective ingredient threo acts, and then decarboxylated therein into a corresponding DOPS or a pharmaceutically acceptable acid addition salt noradrenaline by decarboxylase to exhibit an activity for the 50 treatment of Parkinson's disease (U.S. Pat. No. 4,497.826). thereof. It is also known that, where threo-DOPS is administered in The present invention also relates to a method for the combination with the decarboxylase inhibitor, decarboxyla treatment of diseases with pains which comprises adminis tion of threo-DOPS by decarboxylase in the peripheral tissue tering to human an effective dose of threo-DOPS or a can be prevented, resulting in that the transportation of pharmaceutically acceptable acid addition salt thereof. 55 threo-DOPS into a brain can be accelerated. As a result, a The present invention further relates to use of threo dose of threo-DOPS to be administered as a drug for treating DOPS or a pharmaceutically acceptable acid addition salt Parkinson's disease may be reduced, and side effects of thereof in the production of an analgesic composition. threo-DOPS in the peripheral tissue may be reduced (J. Pharm. Pharmacol., 1981, 33,772-777). BRIEF DESCRIPTION OF DRAWINGS 60 As will be noted from test examples described hereinafter, threo-DOPS in the present invention is also considered to be FIG. 1 shows the results of the analgesic effect of L-threo transported into a brain and converted therein into norad DOPS assessed by the tail flick method. renaline to exhibit an analgesic effect. It is thus expected in FIG. 2 shows the results of the analgesic effect of L-threo the present invention that the combination of threo-DOPS DOPS assessed by the kaolin-induced writhing test. 65 with decarboxylase inhibitors will reduce a dose of threo FIG.3 shows the results of the analgesic effect of L-threo DOPS as an analgesic, and will therefore prevent side effects DOPS assessed by the formalin-induced encroachment test. in the peripheral tissue. 5,616,618 3 4 Threo-DOPS or its pharmaceutically acceptable acid chronic pain is used Pain, 51, 195-198 (1992)).
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