USOO6407137B2 (12) United States Patent (10) Patent No.: US 6,407,137 B2 Shashoua (45) Date of Patent: Jun. 18, 2002

(54) DOPAMINE ANALOG AMIDE 4,097,597 A 6/1978 Horrom et al...... 424/250 (75) Inventor: Victor E. Shashoua, Brookline, MA (List continued on next page.) (US) FOREIGN PATENT DOCUMENTS (73) Assignee: Protarga, Inc., King of Prussia, PA EP O 599 576A1 1/1994 (US) JP 59-2041.75 11/1984 (*) Notice: Subject to any disclaimer, the term of this (List continued on next page.) patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS BaldeSSarini, et al., “Dopamine and Pathophysiology of (21) Appl. No.: 09/901209 Dyskinesis. ... ", Ann. Rev. Neurosci. 3:23-41 (1980). Bourat, et al., “Long Chain Esters of Pipotiazine as Long (22) Filed: Jul. 9, 2001 Acting Psychotropic Pro-Drug, Med. Chem. Proc. Int. Related U.S. Application Data Symp. 5th (1976) pp. 105-114. Dhopeshwarker, G., “Fatty Acid Transport Through the (63) Continuation of application No. 09/450,310, filed on Nov. Blood-Brain Barrier.”, Biochim. Biophys. Acta 29, 1999, now Pat. No. 6,258,836, which is a continuation 255:572-579. in-part of application No. 08/462.820, filed on Jun. 5, 1995, now Pat. No. 5,994,392, which is a continuation of appli cation No. 08/080,675, filed on Jun. 21, 1993, now aban (List continued on next page.) doned, which is a continuation of application No. 07/952, 191, filed on Sep. 28, 1992, now abandoned, which is a Primary Examiner Deborah D. Carr continuation of application No. 07/577,329, filed on Sep. 4, (74) Attorney, Agent, or Firm Wolf, Greenfield & Sacks 1990, now abandoned, which is a continuation-in-part of P.C. application No. 07/535,812, filed on Jun. 11, 1990, now abandoned, which is a continuation of application No. (57) ABSTRACT 07/315,134, filed on Feb. 24, 1989, now Pat. No. 4,933,324, which is a continuation-in-part of application No. 07/160, The invention involves the formation of a prodrug from a 667, filed on Feb. 26, 1988, now Pat. No. 4,939,174. fatty acid carrier and a neuroactive drug. The prodrug is (51) Int. Cl." ...... A61K 3/18 stable in the environment of both the stomach and the (52) U.S. Cl...... 514/437; 514/452; 514/546; bloodstream and may be delivered by ingestion. The prodrug 514/549; 514/552; 514/678; 514/688; 549/1; passes readily through the blood brain barrier. Once in the 549/23; 549/26; 554/42; 554/78; 554/85; central nervous System, the prodrug is hydrolyzed into the 554/101; 554/223; 554/234; 554/229; 568/303; fatty acid carrier and the drug to release the drug. In a 568/308; 568/335 preferred embodiment, the carrier is 4, 7, 10, 13, 16, 19 (58) Field of Search ...... 514/432, 437, docosahexa-enoic acid and the drug is dopamine. Both are 514/546, 549, 552, 678, 688; 549/1, 23, normal components of the central nervous System. The 26; 554/42, 78, 85, 101, 223, 234, 229; covalent bond between the drug and the carrier preferably is 568/303, 308,335 an amide bond, which bond may Survive the conditions in the Stomach. Thus, the prodrug may be ingested and will not (56) References Cited be hydrolyzed completely into the carrier molecule and drug molecule in the Stomach. U.S. PATENT DOCUMENTS 3,539,573 A 11/1970 Schmutz ...... 260/268 18 Claims, 2 Drawing Sheets

AM//WY

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U.S. PATENT DOCUMENTS Hesse, et al., "Uptake in brain neurophysiological activity of two lipid esters of gamma-aminobutyric acid” Neurophar 4,346,085 A 8/1982 Growdon et al...... 424/199 4,351,831 A 9/1982 Growden et al...... 424/199 macol. 27:6:637–40 (1988). 4,407,744 A 10/1983 Young ...... 260/112 R Higuchi et al., (Editors), Prodrugs as Novel Drug Delivery 4.550,109 A 10/1985 Folkers et al. . ... 514/249 Systems, Acs Symposium Series, vol. 14, ACS, Washington, 4,554.272 A 11/1985 Bocket al...... 514/219 1975, pp. 14-15. 4,558,049 A 12/1985 Bernardi et al...... 514/234 Jacob, et al., “Synthesis, brain uptake and pharmacological 4,636,494 A 1/1987 Growden et al...... 514/78 properties of a glyceryl lipid containing GABA and the 4,684,646 A 8/1987 Chang et al...... 514/221 GABA-T inhibitor, gamma-vinyl-GABA. J. Med. Chem. 4,788,063 A 11/1988 Fisher et al...... 424/449 4.902,505 A 2/1990 Pardridge et al. . ... 424/85.7 33.733-6 (1990). 4,933,324 A 6/1990 Shashoua ...... 514/17 Jacob, et al., Y-Aminobutyric Acid EsterS.1. Synthesis . . . , 4,939,174 A 7/1990 Shashoua ...... 514/549 Journal of Medicinal Chemistry, vol. 28, No. 1, pp 106-110 4.968,672 A 11/1990 Jacobson et al...... 514/46 (1985). 5,112,596 A 5/1992 Malfroy-Camine ...... 424/2 Jacob, et al., Y-Aminobutyric Acid Esters.3. Synthesis, brain 5,112,863 A 5/1992 Hashimoto et al...... 514/534 uptake and pharmacological properties of C-18 Glyceryl 5,116,624 A 5/1992 Horrobin et al...... 424/702 lipid esters of BAGA with varying degree of unsaturation, J. 5,120,760 A 6/1992 Horrobin ...... 514/458 Med. Chen. 30:1573-6. 5,169,762 A 12/1992 Grey et al...... 424/702 Jacobson, K., Adenosine analogs with covalently attached 5,169,764 A 12/1992 Shooter et al. ... 514/538 lipids have enhanced potency at A 1-adenosine receptors, 5,284.876 A 2/1994 Shashoua...... 514/549 5,516,800 A 5/1996 Horrobin ...... 514/560 FEBS Letters 225:1,2:97–102, (1987). 5,545,719 A 8/1996 Shashoua...... 530/345 Konigstorfer et al., “Biosynthesis of Ependymins from 5,604,198 A 2/1997 Poduslo et al...... 514/6 Goldfish Brain”, J. Biol. Chem., vol. 264 (23):13689–13692 5,716,614 A 2/1998 Katz et al...... 424/94.3 (1989). 5,795,909 A 8/1998 Shashoua et al. . ... 514/449 Konigstorfer et al., “Molecular Characterization Of An 5,827,819 A 10/1998 Yatvin et al...... 514/2 Ependymin Precursor from Goldfish Brain”, J. Neurochem., 5,919,815 A 7/1999 Bradley et al...... 514/449 52:310-312 (1989). 5,955.459 A 9/1999 Bradley et al...... 514/220 Lohr, et al., “Neuroleptic-Induced Movement 5,977,174 A 11/1999 Bradley et al...... 514/549 Disorders. ... ', Psychiatry, vol. 3, (1989). 5,994,392 A 11/1999 Shashoua...... 514/437 Makino, et al., Chemical Abstracts, vol. 106, No. 12,

6,005,004 A 12/1999 Katz et al...... 514/549 6,024,977 A 2/2000 Yatvin et al...... 424/450 (90177x) issued Mar. 23, 1987, “Pharmaceuticals Permeable 6,107,499 A 8/2000 Shashoua ...... 554/78 to Blood-Brain Barrier'. 6,153,653 A 11/2000 Shashoua Marder, S.R., J. Clin Psychiatry (Supp 3), Management of 6,197,764 B1 3/2001 Bradley et al. Schizophrenia 57:9-13 (1996). 6.225,444 B1 5/2001 Shashoua Nishio, et al., “Novel Water-soluble Derivatives of Docosa hexaenoic Acid Increase Diacyl-Glycerol Production Medi FOREIGN PATENT DOCUMENTS ated by Phosphatidylcholine-Specific Phospholipase C, JP 61204136 11/1984 Proc. Soc. Exp. Biol. Med. (1993) 203(2):200–208. JP 6O72868 3/1994 WO WO 85/OO520 2/1985 Schabitz, et al., “The effects of Prolonged Treatment with WO WO 89/07938 9/1989 Citicoline in Temporary Experimental Focal Ischemia', J. WO WO 92/20362 11/1992 Neurol. Sci., (1996) 138(1-2):21–25 (Abstract). WO WO 96/04001 2/1996 Shashoua, V.E., “The Role of Brain Extracellular WO WO 96/22303 7/1996 Proteins . . . . Cellular and Mol. Neurobiol., 5 WO WO 96/27380 9/1996 (1/2):183–207 (1985). WO WO 98/17325 4/1998 Shashoua, et al., Y-Aminobutyric Acid EsterS.1. WO OO/53231 * 9/2000 Synthesis . . . , J. of Med. Chem., vol. 27, pp. 659-664 ZA 96.034333 A 10/1996 (1984). OTHER PUBLICATIONS Specter, R., “Fatty Acid Transport Through the Blood-Brain Barrier.”, J. of Neurochem., 50:2:639-643 (1988). D’Orlando, et al., “Citicoline (CDP-Choline): Mechanisms Shimazaki, N., et al., “N-'-(2,2-Diphenylethyl)adenosine, of Action and Effects in Ischemic Brain Injury”, Neurol. Res. a Novel Adenosine Receptor Agonist with Antipsychotic (1995) 17:281–284. like Activity”, J. Med. Chem. 30:1709–1711 (1987). Garzon-Aburbeh, et al., “A Lymphotropic Product of L-Do Terasawa, et al., “Neurocalcin a novel calcium binding pa:Synthesis” J. Med. Chem. 29:687-691 (1986). protein from bovine brain J. Biol. Chem., 267:27 (1992), pp. Gunne, et al., “Oral Dyskinesia in Rats Following Brain 19596-19599. Lesions and Neuroleptic Drug Administration”, Psychop harmacology 77:134-139 (1982). Yamamoto et al., “The Survival of Rat Cerebral Cortical Hesse et al., “Inhibitory Effect of Neurons in the Presence of Trophic APP Peptides” J. Neu Cholesteryl-Y-Aminobutyrate”, Neurolpharmacology, vol. robiol. 25, 585–594 (1994). 24, No. 2, pp. 139–146 (1985). * cited by examiner U.S. Patent Jun. 18, 2002 Sheet 1 of 2 US 6,407,137 B2

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- W(7 US 6,407,137 B2 1 2 DOPAMINE ANALOG AMIDE “carrier molecule having an enhanced ability to croSS the blood brain barrier. The carrier-drug conjugate shares with RELTAED APPLICATIONS the carrier the ability to cross the blood brain barrier. Once This application is a Continuation of prior application Ser. in the CNS, the conjugate itself may be active. However, it No. 09/450,310, filed on Nov. 29, 1999, entitled Dopamine is believed that the ester bond between the carrier and drug Analog Amide and now U.S. Pat. No. 6,258,836 which is a is broken in the CNS to release the drug in its native form. continuation-in-part of Ser. No. 08/462,820, filed Jun. 5, This may occur due to the general presence of active, 1995 now U.S. Pat. No. 5,994,392 which is a continuation non-specific esterases throughout the CNS. of Ser. No. 08/080,675 filed Jun. 21, 1993 now abandoned which is a continuation of Ser. No. 07/952,191 filed on Sep. Appetite-SuppreSSant drugs have been Sought for many 28, 1992 now abandoned which is a continuation of Ser. No. years. Dopamine is believed to be involved in the neuro 07/577,329 filed Sep. 4, 1990 now abandoned which is a pathways responsible for appetite-Suppression. Dopamine continuation-in-part application of Ser. No. 07/535,812 filed itself is not used as an appetite-SuppreSSant because it does Jun. 11, 1990, now ABN, which is a continuation of Ser. No. not readily cross the blood brain barrier. Drugs which 07/315,134, filed Feb. 24, 1989, now patented, U.S. Pat. No. 15 closely resemble the structure of dopamine and which will 4,933,324 which is a continuation-in-part application of Ser. cross the blood brain barrier have been used with some No. 07/160,667, filed Feb. 26, 1988, now patented U.S. Pat. Success as alternatives to dopamine. No. 4,939,174. The contents of all of the above-identified The most widely used appetite-Suppressant drugs are applications are hereby incorporated by reference. generally based on derivatives of amphetamine, which Struc The contents of co-pending application Ser. Nos. 07/517, turally resembles dopamine and has Some properties which 158 and 07/517,159 both filed on May 1, 1990, now correspond to a dopamine agonist. Unlike dopamine, Suffi pending, are also expressly incorporated by reference. cient uptake of amphetamines across the blood brain barrier BACKGROUND OF THE INVENTION does occur to produce a biological effect. However, amphet 25 amines have many Serious cardiovascular and neuropsychi This invention relates in general to the fields of medicine, atric Side effects, as well as a tendency to develop tolerance, pharmacology and biochemistry, and more particularly to the increasing resistance to the usual effect of the drug over prodrugs capable of delivering a drug across the blood brain time. At Worst, tolerance to a drug renders the drug useleSS. barrier including a prodrug made of a fatty acid-dopamine At best, tolerance generally encourages the use of higher conjugate that is effective as an appetite-Suppressant. drug doses, increasing the possibility of undesirable side There are many obstacles to developing treatments which effects. In animal tests, tolerance to certain of these amphet allow the delivery of a drug to an active site in the body. amine derivatives has been shown to develop within one day Ingestion of a drug often is not possible because many drugs after one dose. Using amphetamine itself, tolerance has been will not survive the environment of the stomach. Thus, easy shown to develop within 3-15 days. and Safe Self-administration of many drugs is not available. 35 A drug, of course, may be injected directly into the blood Dopamine is also known to play a crucial role in Several Stream of a patient. However, because Some drugs do not neurologically related disorders. For example, Parkinsonism Survive for very long in the bloodstream, frequent injections is a striatal dopamine deficiency. Because dopamine (and at great inconvenience to a patient may be necessary. The related catacholamines) essentially does not cross the blood brain barrier Parkinsonism is treated with L-Dopa, a pre inability of a drug to survive in the bloodstream may be 40 overcome in certain instances by increasing the dosage or by cursor to Dopamine. This treatment, however, is at the increasing the frequency of administration. However, expense of a wide variety of undesireable Side effects, increasing the dosage can result in undesirable side effects including hallucination. Dopamine agonists which are used and increasing the frequency of administration only adds in the treatment of hyperprolactinemia associated with pitu inconvenience. 45 itary adenomas or amenorrhea also induce undesireable side The delivery of a neuroactive drug to the central nervous effects. Thus, there is a Serious need for delivering dopamine system (CNS) via the bloodstream involves an extraordinary itself or dopaminergic agents directly to the brain. obstacle; the drug must be capable of crossing the blood brain barrier. The blood brain barrier may loosely be SUMMARY OF THE INVENTION regarded as a biological eXclusion barrier involving both 50 The invention involves the formation of a prodrug from a passive and active transport, which barrier controls the fatty acid carrier and a drug. The prodrug is believed to be eXchange of materials between the plasma and the central stable in the environment of both the stomach and the nervous System. Many drug Substances are unable to pass bloodstream and may be delivered by ingestion. The prodrug through this barrier in efficacious amounts or at all. Thus, passes readily through the blood brain barrier. The prodrug there is a Serious need for a mechanism for introducing a 55 has a brain penetration index of at least two times the brain drug across the blood brain barrier and into the CNS. penetration indeX of the drug alone. Once in the central Efforts have been taken to enhance the ability of certain nervous System, the prodrug, which preferably is inactive, is drugs to pass through the blood brain barrier. Investigators hydrolyzed into the fatty acid carrier and the drug. The have attempted to mask the polar groups of a drug to carrier preferably is a normal component of the central produce more lipophilic derivatives, as lipophilic com 60 pounds are believed to cross the blood brain barrier more nervous System and is inactive and harmless. The drug, once readily than hydrophilic compounds. For example, diacetyl released from the fatty acid carrier, is active. and triacetyl esters of dopamine and norepinephrine have Preferably, the fatty acid carrier is a partially-Saturated been made to mask the hydroxyl groups of these compounds Straight chain molecule having between about 16 and 26 and produce more lipophilic derivatives. This investigator 65 carbon atoms, and more preferably 20 and 24 carbon atoms. has formed an ester bond between Y-aminobutyric acid, a Most preferably, the carrier is 4, 7, 10, 13, 16, 19 drug which is unable to croSS the blood brain barrier, and a docosahexa-enoic acid. US 6,407,137 B2 4 Another object of the invention is to provide pharmaceu O tical preparations containing preselected doses of the pro CH-CH-CH=CH-CH-CH-C-OH drugs of the invention. An object of the invention to provide an appetite SuppreSSant drug that will not induce tolerance and will not The covalent bond between the drug and the carrier prefer ably is an amide bond, which bond may survive the condi cause harmful side effects. tions in the Stomach. Thus, the prodrug may be ingested and Another object of the invention is to provide an amide will not be hydrolyzed completely into the carrier molecule derivative of dopamine with biological activity useful in the and drug molecule in the Stomach. regulation of appetite. The prodrugs of the invention preferably are formed of fatty acids conjugated to neurotransmitters, anti-aids Yet a further object of the invention is to provide a method Substances, anti-cancer Substances, antibiotics, peptides, for treating neurological disorders in general, and Specifi anti-viral Substances, anti-addiction Substances, anti cally for introducing dopamine and dopaminergic agents psychotic Substances and anti-inflammatory Substances. The into the brain to treat dopamine related disorders. prodrugs of the invention further may be provided in com 15 bination with pharmaceutically-acceptable carriers to form BRIEF DESCRIPTION OF THE DRAWINGS pharmaceutical preparations. Tablets and capsules are par ticularly preferred preparations. FIG. 1 is a graph showing the effect of the produrg of the In one preferred embodiment, the drug is dopamine, also preferred embodiment on motor activity and food intake of a normal component of the central nervous System and the prodrug is mice; FIG. 2 is a graph comparing the effect on motor activity O in mice of varying the mode of delivery of the prodrug of the preferred embodiment; 25 FIG. 3 is a graph showing the effect on motor activity in arrier(compound 8739) OrOH mice of long term administration of the prodrug of the preferred embodiment; and Compound 8739 may be expressed alternatively as FIG. 4 is a graph comparing the effect on food intake in mice of long term administration of the prodrug of the OH perferred embodiment with amphetamine.

DETAILED DESCRIPTION OF THE N Sn Sn OH 35 PREFERRED EMBODIMENTS AND OF THE DRAWINGS This compound has been found to be useful as an appetite SuppreSSant. It also is believed to have anti-psychotic prop The most preferred embodiment of the invention is

O | OH CH-CH-CH=CH-CH-CH-C-NH-CH-CH

OH erties. It has a brain penetration index of 33, a value eight This compound has extraordinary and unexpected proper times that of dopamine. It is inactive until it crosses the ties. This compound, hereinafter called compound 8739, is blood brain barrier and hydrolyzes to release dopamine into inactive until it crosses the blood brain barrier to release the central nervous System. The drug Suppresses appetite 50 dopamine into the central nervous system (CNS). Unlike without harmful Side effects and without inducing tolerance. dopamine, compound 8739 survives sufficiently in the envi The prodrug also appears to be capable of delivering the ronment of the stomach and the bloodstream and therefore dopamine preferentially into the Synaptosomal membranes, can be administered orally. the location of the drug action. Compound 8739 has an enhanced ability to cross the An object of the invention is to provide a carrier molecule 55 blood brain barrier, with a brain penetration index (BPI) of capable of being combined with a drug to form a prodrug about 33, as compared to about 4 for dopamine. It is inactive that will readily cross the blood brain barrier and allow as a prodrug in that it does not bind to either D-1 or D-2 release of the drug into the central nervous System. dopamine receptorS. Rather, once in the central nervous Another object of the invention is to provide a prodrug System, dopamine is released as an active fragment of that is stable in the environment of the stomach and in the 60 compound 8739. In addition, compound 8739 is taken up bloodstream. into the Synaptosomal membranes preferentially, the Synap Another object of the invention is to provide pharmalogi toSomal membranes being the Site of activity for the dopam cal compositions comprising amides of the carriers of the ine. This property may contribute to the compound's desir invention combined with drugs, including dopamine. able properties. Another object of the invention is to provide a method for 65 Once dopamine is released as an active fragment, it delivering a neuroactive drug, including dopamine, to the produces effects on food intake and on general locomotor central nervous System. activity in mice in a dose-dependent manner. Food intake US 6,407,137 B2 S 6 decreased by as much as 50% at the higher doses. Open field and Stirring was continued for an additional 30 min to activity also decreased by about 50%, indicating that, unlike completely hydrolyze any remaining unreacted anhydride. amphetimine, compound 8739 has a tranquilizing effect The liquid phase was isolated and evaporated to dryneSS to rather than an activity-enhancing effect. yield a brown viscous solid. This was then dissolved in 70% Many of the undesirable side effects of amphetamines ethanol in water (25 ml), and the Solution was then passed were absent. Compound 8739 failed to induce “stereotypy”, through a mixed-bed ion exchange resin containing a Strong failed to produce an effect on “circling behavior” of striatal acidic resin based on polystyrene Sulfonic acid and a Strong lesioned rats, and failed to demonstrate any diverse effects basic resin based on quanternary amonium Substituents Such on motor function or motivation in test animals. as tetramethyl amonimum hydroxide (RG501, Fisher Remarkably, there was no indication of tolerance. Failure to Scientific, Cambridge, Mass.) using 90% ethanol in water as induce tolerance was unexpected. the eluent. This resin removes from the mixture unreacted Another favorable property of compound 8739 was unex dopamine, dimethylaminopyridine, as well as the liberated pected. Previous reports have demonstrated that fatty acids, DHA molecule. The effluent from the column (a pale yellow including the fatty acid of compound 8739, induce Swelling Solution) was then evaporated in a rotary evaporator to give of the brain. Chan, P. H., Fishman, R. A., SCIENCE, Vol. 20, 15 a Solid. The product was recrystallized from aqueous ethanol 358-360 (1978). Compound 8739 (and another prodrug (yield=75%). compound made from a Straight chain fatty acid having 20 The structure of compound 8739 (III) was established by carbon atoms and 4 double bonds), however, did not induce mass spectrometry. The major peak (95% of the compound) any Swelling. consisted of a product with a mass of 550. Fragment analysis Experimental Data by mass spectrometry and carbon, hydrogen, infrared, and Synthesis of the Compound 8739 NMR spectra confirmed the structure of compound 8739. Compound 8730 is synthesized as follows: A trimethyl silyl derivative (compound IV) of the two hydroxyl groups of dopamine was also Synthesized to fur O ther confirm the structure of compound 8739. This deriva 25 tive was shown to have the correct mass of 608. CH-CH-CH=CH-CH-CH-C- (DHA) (CH)CH) SiOSi NH-C-CH-CH2-(CH=CH-CH-)-CH ()----O) (CH3)SiO CH-CH-CH=CH-CH-CH-CO Compound IV O Compound 8739 was stored as a solution in ethanol (12 35 mg/ml) in the cold. Aliquots of this were evaported to CH-CH-CH=CH-CH-CH-CO dryness and dissolved in 15% propylene glycol in 0.1 M NaHCO for use in biological activity tests. (DHA ANHYDRIDE) Brain Uptake Studies OH A brain penetration index (BPI) determination was used dimethyl as a criterion for measuring the capacity of a compound to DHAANHYDRIDE - NH2 --aminopyridine cross the blood brain barrier. Shashoua, V. E., Jacob, J. N., OH Ridge, R., Campbell, A. and Baldessarini, R. J., J. Med. (DOPAMINE) Chem. 27, 659 (1984). The BPI is a measure of the uptake 45 of a compound by the brain relative to its uptake by the liver. Compound 8739 The liver is chosen as a reference Since it is an organ which has no barrier to diffusable molecules present in the blood. DHA is first converted to DHA anhydride in the presence Moreover, even if Subcutaneous injections are used, the of dicyclohexyl carbodiimide. This is then reacted with injected material tends to remain largely at the Site of the dopamine in the presence of 4-dimethylaminopyridine as the 50 injection and slowly diffuse into the circulation. Therefore, acid acceptor in tetrahydrofuran. In a typical experiment 300 the amount of material in the liver will reflect the amount mg of DHA (0.009 M) was dissolved in a mixture of 3 ml available rather than the initial dose injected. hexane and 4 ml benzene and Stirred under nitrogen. Next, Measurements of the quantity of the drug present in the a solution of 0.00615 M of dicyclohexyl carbodiimide in 4 brain and liver were measured at five minutes after a ml benzene (0.1267 g) was stirred together with the DHA for 55 Subcutaneous injection and were used to calculate the BPI, 3 hr at room temperature. A white precipitate of dicyclo the equation being: hexyl urea formed as the reaction proceeded. The dicyclo hexyl urea was filtered off to give a clear Solution of the BPI-brain/liverx100 anhydride in benzene. This was concentrated down to 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydro 60 For these measurements, compound 8739 was synthe furan (dry). The freshly prepared anhydride was then added sized from "C-labeled dopamine. Thirty uCi of dopamine to a solution of dopamine hydrobromide (0.1053 g) (or labeled hydrochloride was mixed with 0.1 mg of unlabeled 0.005 M) in the presence of 0.009 M of dopamine hydrobromide and reacted with a two-fold exceSS 4-diethylaminopyridine (0.098 g). The initially cloudy mix of DHA anhydride. The reaction was run overnight; the ture after Stirring for 30 min at room temperature gave a 65 product was then evaporated to dryneSS and dissolved in mixture of a clear liquid and a brown precipitate. At the end ethanol. The compound was identified as 8739 by its migra of the reaction, 0.2 ml of water was added to the mixture, tion properties on thin-layer chromatography using chloro US 6,407,137 B2 7 8 form: methanol as one Solvent and dimethylformamide an average of 2.3 than in the P1 fraction (nuclear and cell (DMF) as the other. The migration properties were equiva membrane fraction). This Suggests that there is a preferential lent to those of the unlabeled product. concentration of the compound into the Synaptic fraction P2, "C-labeled 8739 was dissolved in 15% propylene glycol indicating that 8739 is more highly associated with nerve in 0.1 M NaHCO and then injected subcutaneously (s.c.) endings, as would be expected from the natural distribution into male balb C mice (20+2 g). After 5 minutes the animals were sacrificed by cervical fracture and the brain and liver of DHA in lipid glycerides in such membranes. were dissected out, weighed and homogenized in 8 and 10 Pharmacological Properties ml of Brain Protein Solvent (BPS) buffer, respectively Open-field motor activity measurement BPS=2% sodium dodecyl sulfate in 0.03 M Tris, 6 Murea, The effect of compound 8739 on general motor activity pH 7.6, 0.01 M EDTA and 0.14N NaCl). Aliquots were then was determined. The general motor activity of balb-c mice counted for 'C content in 10 ml of a liquid scintillation was measured in a Stoelting electronic activity monitor fluid, Liquiscent (National Diagnostic Company, apparatus during a 90-min period following an intraperito Somerville, N.J.) using a Beckman liquid Scintillation neal injection of the compound as a Solution in 15% pro counter. The ''C counts were then used to calculate the total pylene glycol in 0.1 M NaHCO. A detailed description of quantity of compound 8739 present in the brain per gram of 15 the apparatus is reported in Stewart R. J., Campbell A., tissue as compared to that in the liver. The ratio of the amount in the brain as a percent of that present in liver was Spark G. and Balessarini R. J. Psychopharmacol. 60, 281 determined. (1979). Results The test group (six mice) received an i.p. injection of the drug in a vehicle (15% propylene glycol in 0.1 M NaHCO, TABLE I a total volume of between about 1-0.3 ml.). The six control mice received the same Volume of vehicle, but no drug. The Compound Brain (cpm/g) Liver (cpm/g) BPI Value (%) results (Shown in FIG. 1.) are expressed as the percent 8739 1305 43OO 3O decrease in open field activity for the test group versus the 8739 1297 3931 33 control group. The results indicate that compound 8739 Dopamine 4 25 depresses the activity of the mice by as much as 50%, D-glucose 33 demonstrating that compound 8739 is biologically active following its uptake into the brain. The response was dose The results indicate that the brain uptake of compound 8739 dependant with higher doses of compound 8739 resulting in is over eight-fold higher than the brain uptake for dopamine. a greater decrease in general motor activity. Compound 8739 also compares favorably with glucose Food Consumption Measurements which is reported in the literature to have a BPI index of 33. The effect of compound 8739 on food consumption was Studies of the Pattern of Distribution of 8739 in Membranes determined for balb-c mice that were food deprived for 24 of the Central Nervous System hr, with water freely available. The Six test mice were given The utility of a drug may be determined by its ability to an i.p. injection of compound 8739 as a solution in 15% be taken up Selectively by the particular regions of the brain 35 propylene glycol in 0.1 M NaHCO, a total volume of upon which the drug acts. A Study was made to determine the between about 0.1-0.3 ml. The six control mice received the pattern of distribution of compound 8739 in the various membranes in the central nervous System. Approximately Same Volume of vehicle, but no drug. The quantity of 2x10 counts of "C-labeled 8739 in 0.3 ml of 15% propy “mouse chow' eaten during the 60-min period following the lene glycol in 0.1 M NaHCO was injected subcutaneously injections was determined. The results, also shown in FIG. into test mice (20+2 g). After 30 minutes the animals were 40 1, are expressed as the percent decrease in food consumption Sacrificed by cervical fracture; the brain was then removed for the test group versus the control group. The results and homogenized in 4 ml of isotonic medium (0.14N NaCl, indicate that compound 8739 is an appetite SuppreSSant 0.03 M Tris pH 7.4 containing 1.5 rpm calcium acetate) (40-50% decrease in food intake). The decrease was dose according to the method of Whittaker (Whitaker V. P. dependent, with higher doses of compound 8739 causing Biochem J., 72 694–706 (1959). The fraction P1 containing 45 greater decrease in food intake. The same experiment was nuclear and cell membrane components was Sedimented for conducted using oral administration of compound 8739. The 5 min at 2,500 rpm at 0°C. The Supernatant containing the results were the same. crude Synaptosomal fraction was next centrifuged at 13,000 Determination of the Effect of Mode of Delivery of Com rpm for 30 min to yield a pellet containing the crude pound 8739 on Open Field Activity synaptosomal fraction (P2). P1 and P2 were then dissolved 50 The effects of the mode of delivery of Compound 8739 in BPS, and the amount of label and protein in each fraction (oral VS. i.p.) on the general open-field activity of mice (n=6) was determined. was assessed. AS shown in FIG. 2, the drug was as active Results when ingested as when injected. A 40-50% decrease in activity occurred when either delivery method was TABLE II 55 employed. No Significant changes in open-field activity occurred when either the carrier molecule (T) or dopamine CPM/mg Protein after 30 min of Uptake (DA) is administered at the same dose. Expt. No. P, P, P/P, Evaluation of Circling Behavior Dopamine agonists Such as apomorphine and amphet (Nuclear and (Crude Synapto Cell Membrane somal Fraction) 60 amine cause circling behavior in animals with nigrostriatal Fraction) lesions. Compound 8739 releases dopamine following pro 1. 2.7 5.2 1.9 teolysis by central nervous System enzymes. It was expected 2 2.7 5.6 2.1 that compound 8739 would cause circling behavior in ani 3 4.19 12.5 2.9 mals with nigrostriatal lesions in a manner Similar to that of 65 dopamine agonists. As shown in Table II, the uptake of compound 8739 into the Unilateral nigrostriatal lesions in rats were produced by crude Synaptosomal fraction (P2) was greater by a factor of administering unilateral injections of 6-OH dopamine into US 6,407,137 B2 9 10 the nigrostriatum pathway. Seven days later, these animals Then, the test mice were given i.p. injections of the drug in were i.p. injected with the test drugs and circling behavior a vehicle and the control mice were given i.p. injections of was recorded as rotations per minute during a 30-min period the vehicle only. This regimen was carried out for a 21 day in the test apparatus, Ungerstedt U. and Arbathnott G. W., test period. At the end of the 21 days, the vehicle alone was Brain Res. 24, 485–493 (1970). given daily to both test and control mice and open field activity and food consumption was monitored for an addi TABLE III tional Six dayS. FIG. 3 plots the percent decrease in open field activity of AVERAGE ROTATION SCORES the test mice (n=6) as compared to the controls (n=6). AS DOSE Rotations/minutes shown in FIG. 3, the level of activity prior to injections was COMPOUND (mg/kg) Ipsilateral Contralateral the same for both groups. Upon initation of injections, there Apomorphine O.1 O.1 4.8 was a 30% to 60% decrease in open field activity. This Apomorphine 0.5 O 13.7 decrease remained fairly constant for the entire 21 days of Amphetamine 3.0 2.5 0.4 injections indicating that no tolerance was induced by Amphetamine 5.0 3.32 O.92 15 repeated injections during the test period. Beginning at day 8739 34 O.08 O.OS 8739 51 O.08 O.12 22 and daily until day 27, vehicle alone was given to both Controls (uninjected) O.10 O.12 groups. AS shown in FIG. 3, activity returned to its predrug level when the drug administration was discontinued. Controls (uninjected) 0.100.12 The effect of long-term administration of compound 8739 Apomorphine produced a rapid circling behavior to the on the pattern of food consumption of mice was compared contralateral side of the lesion, whereas amphetamine to the long-term effects of the administration of amphet caused circling rapidly to the ipsilateral lesion side. The amine. Daily i.p. injections of compound 8739 (20 mg/kg) enhanced contralateral rotations for apomorphine and ipsi were given to test animals and daily i.p. injections of lateral rotations for amphetamine are consistent with the amphetamine (2 mg/kg) were given to control animals for 21 reported results for these dopaminime agonists. Compound 25 days. 24 hours after the first injection and about every five 8739 did not evoke this behavior. Rather, the rate of circling days after that, the animals were food-deprived for 24 hours was very low, approximately the same as that observed for with water freely available, and then were tested for food uninjected controls. Thus it appears that compound 8739 consumption for one-hour beginning at five minutes after does not evoke all of the effects (side effects) of dopamine receiving their daily injection. agonists. FIG. 4 plots the percent decrease in food consumption Self-stimulation Data Versus time. For amphetamine injected mice, the decrease in A Self-Stimulation test has been used to measure the food intake due to the amphetamine virtually disappeared capacity of a given pharmacological agent to inhibit rats after 15 days indicating complete tolerance to the dosage from receiving Self-induced electrical Stimuli via electrodes employed. With compound 8739 injected mice, the approxi implanted in their brains (lateral hypothalamus). Stellar J. R. 35 mately 40%-50% decrease in food intake persisted for the and Stellar E., The Neurobiology of Motivation and Reward, entire 21 day period indicating no tolerance had developed. Springer-Verlag, New York, 1985. Animals will press levers The pharmacological properties of compound 8739 to receive a pulse of current from the implanted electrode at appear to be characteristic of a partial dopamine agonist. a rate dependent upon the quantity of current that is being Compound 8739 depresses the general motor activity and delivered as a reward. It is believed that the reward obtained 40 food intake behavior in mice. However, many of the prop results from the release of dopamine caused by the electrical erties which might be considered as “side effects” of dopam stimulation (Stellar J. R.). The intensity of the current is ine agonists Such as amphetamine and apomorphine are not varied by raising the frequency at which 250 mV pulses (0.1 obtained. Thus, circling behavior in nigrostriatal lesion to msec duration) are delivered during a 0.5-Sec time span. A animals and motivational effects in Self-Stimulation experi plot of the log of the frequency of the delivered pulses VS. 45 ments do not result following the administration of com the rate of level press for an animal gives the Self-Stimulation pound 8739. reward curve. Injections of drugs which have a neuroleptic Compound 8739 has been administered orally without type or tranquilizing effect can depress the rate of Self any apparent loSS in efficacy, and, therefore, is stable. Stimulation, shifting the response to higher current deliver Moreover, the compound does not bind to the dopamine ies. Pemozide can give a depressed rate by about 90%. 50 receptors in receptor binding assays. Thus, the drug appears Investigations of the efficacy of compound 8739 by this test to be inactive until proteolysis releases the active dopamine. showed that the compound had no effect on either the reward While the mechanism of action of the drug is not fully or the motor aspect of the Self-Stimulation parameters. This understood, and the inventor does not intend to be bound by indicates that compound 8739, even though it is able to any theory, it is believed that the localization of uptake into cause a decrease in the general motor activity of an animal, 55 Synaptic endings may cause site-specific release of the active has no effect on the motivation or the capacity to press for dopamine from the prodrug. Such site-specific release could the “current reward”. The animal continues to press the lever be responsible for some of the favorable properties of the at the rate equivalent to a non-injected control or one drug. Further, that the carrier and drug are natural constitu receiving the vehicle alone. Thus, compound 8739 does not ents of the CNS may contribute to compound 8739's desir produce yet another effect (Side effect) characteristic of 60 able properties. dopamine agonists. The invention is not limited to the foregoing description Tests for Tolerance of the preferred embodiment. Thus, it is contemplated that The effects of daily i.p. injections of compound 8739 at a the Specific carrier described in the preferred embodiment dose of 20 mg/kg on open field activity and food consump and other carriers of the invention described in greater detail tion was tested to determine whether tolerance to the drug 65 below are capable of being linked by an amide bond or was induced over time. The open field activity of six test otherwise to other drugs including other neurotransmitters, mice and six control mice was monitored for five dayS. analogues of neurotransmitters including analogues of US 6,407,137 B2 11 12 dopamine and other neuroactive Substances to facilitate the Anti-cancer Substances are Substances used to treat or delivery of the substance across the blood brain barrier and prevent cancer. Examples of Such Substances include into the CNS. The term drug thus is intended to include methotrexate, cisplatin, prednisone, hydroxyprogesterone agents that may be used on or administered to animals as an caproate, medroxyprogesterone acetate, megestrol acetate, aid in diagnosis, treatment or prevention of disease or other diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone abnormal conditions, for relief of pain or Suffering, or to propionate, fluoxymesterone, vinblastine (VLB), Vincristine, Vindesline, etoposide, tenipoSide, dactinomycin control, affect, maintain or improve a physiological or (actinomycin D), daunorubicin (daunomycin; rubidomycin), pathological condition. The term animal is intended to doxorubicin, bieomycin, plicamycin (mithramycin), mito include those animals having central nervous System, and mycin (mitomycin C), -asparaginase, hydroxyurea, procar particularly those with a blood brain barrier and susceptible bazine (N-methylhydrazine, MIH), mitotane, to the problems encountered when attempting to transport aminoglutethimide, mechlorethamine, cyclophosphamide, drugs acroSS the blood brain barrier. Examples of amimals melphalan (-Sarcolysin), uracil mustard, chlorambucil, includes mammals, e.g. humans, domestic household, Sport busulfan, carmustine (BCNU), lomusline (CCNU), semus or farm animals. Such as Sheep, goats, cattle, horses, mice, tine (methyl-CCNU), Streptuzocin (Steptozotocin), dacarba rats, guinea pigs, fish, aviens, reptiles, and ZOO animals. 15 zine (DTIC: dimethyltriazenomidazolecarboxamide), meth The preferred carrier has been coupled, for example, to a otrexate (amethopterin), fluorouracil (5-fluorouracil: 5-FU), Met-enkephalin derivative of the following formula cytarabine (cytosine arabinoxide), mercaptopurine YGGFMK, in which the carrier is coupled via a peptide (6-mercaptopurine: 6-MP), thioguanine (6-thioguanine: bond to the gamma amino group of lysine (K). This TG). compound, when injected into mice at a dose of 20 mg/kg Antibiotics are art recognized and are Substances which body weight, was effective as an analgesic at a tenfold lower inhibit the growth of or kill microorganisms. Antibiotics can dose as compared to the carrier free Met-enkephalin (Paw be produced Synthetically or by microorganisms. Examples Lift Latency Hotplate Test). The preferred carrier has also of antibiotics include pennicillin, tetracycline, minocycline, been coupled via an amide bond to the free amino group of doxycycline, Vanomycin, bacitracin, kanamycin, neomycin, norepinephrin. This compound had an eightfold higher BPI 25 erythromicin and cephalosporins. Examples of cephalospor than norepinephirn. ins include cephalothin (keflin, Seffin), cephapirin (cefadyl), Classes of drugs which are intended to be included within cefazolin (ancef, kefaol), cephalexin (keflex), cephradine this invention include neurotransmitters, anorectic (anspor, Velosef), cefadroxil (duricef, ultracef), cefamandole compounds, anti-aids Substances, anti-cancer Substances, (mandol), cefoxitin (mefoxin), cefaclor (ceclor), cefuroxime antibiotics, drugs effecting adenosine concentrations, (Zinacef), cefonicid (monocid), ceforanide (precef), cefo adrenergics, cholinergics, benzodiazepines, drugs effecting taxime (claforan), moxalactam (moxam), ceftizoxime cocaine receptors, drugs effecting cyclic nucleotide (cefiZox), ceftriaxone (rocephin), and cefopera Zone pathways, dopaminergics, enzyme inhibitors, excitatory (cefobid). amino acids, GABA-ergics, histaminergics, ion channel DrugS effecting adenosine concentration include both modulators, neurotoxins, opioids, drugs effecting PCP/ 35 adenosine agonists and adenosine antagonists. Examples of Sigma receptors, cyrotonergics, hypnotics, psychic adenosine agonists include adenosine, adenosine amine con energizers, tranquilizers, benzodiazepines, anti-convulsants, gener (ADAC), N-benzyladenosine, 2-chloroadenosine, muscle relaxants, anti-parkinson agents, anti-hypertensives, 2-phenyla mino a de no Sine (CV-1808), analgesics, anti-pyretics and anti-inflammatory agents, local N'-cyclohexyladenosine (CHA), N'-cyclopentyladenosine anesthetics, anti-Spasmodics and muscle contractants, 40 (CPA), 5'-(N-cyclopropyl)carboxamidoadenosine, 1-deaza prostaglandins, anti-bacterials, anti-Septics, anti 2-chloro-N'-cyclopenty ladenosine, N°-20(3,5- depressants, anti-migraine preparations, central nervous SyS dimethoxyphenyl)-2-(2-methylphenyl)adenosine (DPMA), tem Stimulants, imaging agents, Specific targeting agents, N'-(2S)-2-endo-norbornyl)adenosine (ENBA), 5'-N- proteins, peptides, anti-Viral agents, anti-psychotic agents, ethylcarboxamidoadenosine (NECA), N-methyladenosine, anti-addiction agents and anti-emetics. 45 5'-N-methylcarboxamidoadenosine, 1-methylisoguanosine, Neurotransmitters are Substances which are released from 2-methylthio - ATP, N-phenylade no sine, a neuron on excitation and travel to either inhibit or excite N-phenylethyladenosine, N'-(2-phenylisopropyl) a target cell. Examples of neurotransmitters include adenosine R(-) isomer, and S(+)-N'-(2-phenylisopropyl) dopamine, Serotonin, y-aminobutyric acid, norepinephrine, adenosine. histamine, acetylcholine, and epinephrine. 50 Adenosine antagonists include aminophylline, 7-(B- Neuroactive amino acids include amino acids having at chloroethyl) the ophylline, 8-cyclop entyl-1,3- least Some activity in the brain. Examples of neuroactive dimethylxanthine, 8-cyclopentyl-1,3-dipropylxanthine, 1,3- amino acids include glycine, aspartic acid, glutamic acid and diethyl-8-phenylxanthine, 1,3-dimethylxanthine taurine. (theophylline), 1,7-dimethylxanthine (paraxanthine), 3,7- Anorectic compounds are Substances which reduce or 55 dimethylxanthine (theobromine), 1,3-dipropyl-7- diminsh appetite. Examples of Such compounds include methylxanthine, 1,3-dipropyl-8-p-Sulfophenylxanthine, amphetamine, phefluoramine, and diethylpropion. Although 7-(B-hydroxyethyl)the ophylline, 3-isobutyl-1- the CNS uptake of the anorectic compounds is Satisfactory, methylxanthne (IBMX), 1,3-dipropyl-8-(2-amino-4- when these compounds are coupled to the preferred carriers chlorophenyl)-xanthine (PACPX), 8-phenyltheophylline, localized delivery of these compounds into the SynaptoSo 60 3-(n-propyl)-xanthine (enprofylline), 8-(p-Sulfophenyl)- mal membranes of the CNS is facilitated. theophylline, 1,3,7-trimethylxanthine (caffeine), Xanthine Anti-AIDS Substances are Substances used to treat or amine congener (XAC). Other drugs effecting adenosine prevent Autoimmune Deficiency Syndrome (AIDS). concentrations include (R)-2-azido-N-p- Examples of such substances include CD4, 3'-azido-3'- hydroxyphenylisopropyl-adenosine (AHPIA), and dipy deoxythymidine (AZT), 9-(2-hydroxyethoxymethyl)- 65 ridamole. guanine acyclovir (acyclovir), phosphonoformic acid, Adrenergics are compounds that are agonists or antago 1-adamantanamine, peptide T, and 2',3' dideoxycytidine. nists of Substances capable of Stimulating or activating nerve US 6,407,137 B2 13 14 Systems that are responsive to norephinephrine and ephi An example of a benzodiazepine antagonist is peripheral nephrine. Adrenergics include both adrenergic agonists and benzodiazepine antagonist and examples of benzodiazepine antagonists. Examples of adrenergic agonists include inverse agonists include ethyl 3-carboline-3-carboxylate albuterol hemisulfate (salbutamol), p-aminoclonidine HCl, (B-CCE), methyl B-carboline-3-carboxylate (B-CCM), pro 4-3-(1,1-dimethylethyl)amino-2-hydroxypropoxy]-1,3- pyl B-carboline-3-carboxylate (B-CCP), 3-hydroxymethyl dihydro-2H-benzimidazol-2-one hydrochloride, clonidine B-carboline 3-HMC, methyl-6,7-dimethoxy-4-ethyl-B- HCl, ephedrine HCl, (-)-, epinephrine bit artrate, carboline-3-carboxylate (DMCM), N-methyl-B-carboline-3- 6-fluoronorepinephrine HCl, isoproterenol bitartrate,(-)-, carboxamide (FG-7142). Other benzodiazepines include BZ isoproterenol bitartrate.(+)-, isoproterenol HCl,(t)-, norepi receptor preparation, diazepam,desmethyl-, chloraZepate, nephrine HCl, Octopamine.(t)-, and p-iodoclonidine HC1. diazepam, and Oxazepam. Examples of adrenergic antagonists include alprenolol DrugS effecting cocaine receptors are Substances which HCl, bromoacetyl alprenolol methane (BAAM), benextra interact or interfere in Some manner with a cocaine receptor. mine HCl, benoxathian HCl, efaroXan, idazoxan, phenoxy Examples of Such drugs include buprenorphine, cocaine benzamine HCl, phentolamine meSylate, pindolol, praZoSin HCl, ecgonidine methyl ester, ecgonine HCl, CFT naphtha HCl, propranolol HCl,(-)-, propranolol HCl(+)-, propra 15 lene disulfonate (WIN35,428). nolol HCl,(+)-, rauwolscine HCl, 2-2-(2-methoxy-1,4- DrugS effecting cyclic nucleotide pathways are Substances benzo dioxanyl)imidazoline HCl, 2-(2,6- which interact or interfere in Some manner with the cyclic dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane nucleotide pathways. Examples of Such drugs include hydrochloride, yohimbine HC1. Other adrenergics include forskolin, forskolin,7B-y-(morpholino)-butyryl-, forskolin, amphetamine Sulfate, (+)-, amphetamine Sulfate,(-)-, 6f-piperidino-propionyl-, and forskolin, 1,9-dideoxy-. p-azidoclonidine oxalate, bretylium tosylate, chloroethyl Dopaminergics are drugs which in Some manner effect, clonidine HCl, diethylpropion HCl, N-(2-chlorethyl)-N- interact, or interfere with the dopaminergic pathways. The ethyl-2-bromobenzylamine hydrochloride, metanephrine term is intended to include both dopamine agonists and HCl, methamphetamine HCl(+)-, methamphetamine HCl, dopamine antagonists. Dopamine agonists include (-)-, 4-hydroxy-3-methoxyphenylglycol piperazine Salt,3- 25 N-allylnorapomorphine HBr,R(-)-, (+)-2-amino-5,6- methoxy-4-hydroxy-phenylglycol pipera Zine Salt, dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide 4-hydroxy-3-methoxyphenylglycol-4-Sulfate potassium Salt, (5,6-ADTN HBr), (+)-2-amino-5,6-dihydroxy-1,2,3,4- 3-methoxy-4-hydroxyphenylglycol-4-Sulfate potassium Salt, tetrahydronaphthalene hydrobromide (6,7-ADTN HBr), normetanephrine HCl, pindobind,(+)-, prazobind, threo apocodeine HCl,R(-)-, apomorphine HCl,R(-)-, bromocrip dihydroxyphenylserine(+)-, and xylamine HC1. tine mesylate, (+)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl Cholinergics are compounds that are agonists or antago 2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide;6- nists of Substances capable of Stimulating or activating nerve chloro-N-allyl-SDK-38393 hydrobromide, (+)-2- Systems that are activated by acetyl choline. Cholinergics dimethyla mino-5,6-dihydroxy-1,2,3,4- include both cholinergic agonists and cholinergic antago tetrahydronaphthalene hydrobromide (M-7), (+)-2- nists. Examples of cholinergic agonists include acetylcho 35 dimethyla mino - 6, 7-dihydroxy-1,2,3,4- line chloride, arecoline HBr, bethanechol chloride, tetrahydronaphthalene hydrobromide (TL-99), (+)-2- carbachol, cis-dioxolane,(+)-, (4-hydroxy-2-butynyl)-1- dip ropyla mino-6,7-dihydroxy-1,2,3,4- trimethylammonium m-chlorocarbonilate chloride, metha tetrahydronaphthalene hydrobromide, dipropyldopamine choline chloride, metoclopramide HCl, muscarine chloride, HBr, dopamine HCl, 2-hydroxyapomorphine HBr,R(-)-, (E)-, muscarine chloride(+)-, nicotine tartrate,S(-)-, cis-2- 40 R(-)-10, 11-methylene dioxy-N-n-propylnoraporphine methyl-5-trimethylammonium methyl-1,3-oxathiolane hydrochloride, N-methyldopamine HCl,(epinine), mor iodide (OXA-22), oxotremorine, oxotre morine phothebaine HCl, (+)-2-(N-phenylethyl-N-propyl)amino-5- Sesquifumarate, and pilocarpine HCl,(+)-. hydroxytetralin hydrochloride, R(+)-3-(3-hydroxyphenyl)- Examples of cholinergic antagonists include atropine N-propylpipe ridine hydrochloride, S(-)-3-(3- Sulfate, benztropine meSylate, 4-diphenylacetoxy-N- 45 hydroxyphenyl)-N-propylpiperidine hydrochloride, methylpiperidine methiodide, dexetimide HCl,S(+)-, propylnorapomorphine HCl,R(-)- (NPA), quinpirole HCl, levetimide HCl,R(-)-, ipratropium bromide, mecamylamine 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol HCl, methoctramine HCl, pirenzepine HCl, RS(+)- hydrochloride, R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- quinuclidinyl benzilate, R(-)-quinuclidinyl benzilate, S(+)- benzazepine-7,8-diol hydrochloride, S(-)-1-phenyl-2,3,4,5- quinuclidinyl benzilate, RS(+)-3-quinuclidinyl Xanthene-9- 50 tetrahydro-(1H)-3-benzazepine-7,8-diol hyrdrochloride, carboxylate he mioxalate, Scopolamine HBr, (-)-, (+)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H Scopolamine HBr,(+)-, Scopolamine n-butyl bromide,(-)-, 3-benz azepine hydrochloride, tyramine HCl, and Scopolamine methyl bromide,(-)-, Scopolamine methyl m-tyramine HC1. bromide, (+)-, Succinylcholine chloride, d-tubocurarine Dopamine antagonists include amoxapine, apomorphine chloride, tetraethylammonium chloride. Other cholinergic 55 HCl,S(+)-, azidoclebopride, bulbocapnine,(+)-, butaclamol drugs include acetylethylcholine mustard hydrochloride, HCl, (+)-, but a clamol HCl, (-)-, domperidone, N-aminodeanol HCl, eseroline fumarate, hemicholinium-3, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, eticlo Vesamicol HCl,(t)-, Vesamicol HCl,(-)-, and Vesamicol pride HCl,S(-)-, eticlopride HCl,R(+)-, fluphenazine HCl, HCl(+)-. flupentiXol,cis(Z)-, fluspirilene, haloperidol, haloperidol, Benzodiazepines are a type of tranquilizer having a com 60 chlorinated analog, metoclopramide HCl, pimozide, mon molecular structure of phenylthiazines and Similar prochlorperazine dimaleate, propylnorapomorphine HCl,S pharmacological activities Such as anti-anxiety, muscle (+)-(NPA), R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2, relaxing, Sedative, and hypnotic effects. Benxodiazepines 3,4,5-tetra-hydro-1H-3-benzazepine hydrochloride, S(-)-7- include benzodiazepine agonists, benzodiazepine antago chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro nists and benzodiazepine inverse agonists. Examples of 65 1H-3-benzazepine hydrochloride, (+)-7-bromo-8-hydroxy benzodiazepine agonists include chlordiazepoxide HCl, 3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine diazepam, flurazepam HCl, and flunitrazepam. hydrochloride, Spiperone HCl, Sulpiride.(t)-, Sulpiride,S US 6,407,137 B2 15 16 (-)-, SullDiride.R(+)-, thiothixine HCl, trifluoperazine HCl, include baclofen,(+)-, y-aminobutyric acid (GABA), isogu trifluoperidol HCl, thioridazine. Other dopaminergics Vacine HCl, isonipecotic acid, kojic amine, muscimol HBr, include amantadine HCl, amfonelic acid, bupropion HCl, piperidine-4-sulfonic acid, thiomuscimol HBr, and 4,5,6,7- Y-butyrolactone, chloroethylnorapomorphine HCl, L-3,4- tetrahydroisoxazolo5,4-cpyridin-3-ol HC1. dihydroxyphenylala nine (L-DOPA), D-3,4- Examples of GABA antagonists include 5-aminoValeric dihydroxyphenylala nine (DOPA, D-), L-3,4- acid HCl, bicuculline, bicuculline methchloride, bicuculline dihydroxyphenylalanine methyl ester hydrochloride, 3,4- methbromide, bicuculline methiodide, 2-hydroxySaclofen, dihydroxyphenylacetic acid (DOPAC), 1-2-(Bis(4- pha clofen, 2-(3-carboxypropyl)-3-amino - 6-(4- fluorophenyl)methoxyethyl-4-3-phenylpropylpiperaz ine methoxyphenyl)pyridazinium bromide. Other GABA-ergics dihydrochloride, haloperidol metabolite I, haloperidol include 4-aminopyridine, butylbicyclophosphorothionate metabolite II, haloperidol metabolite III, homovanillic acid, (TBPS), GABA receptor preparation, guvacine HCl, cis-4- 3-O-methyldopamine HCl, 4-O-methyldopamine HCl, hydroxynipecotic acid, Y-hydroxybutyric acid, nipecotic nomifensine, reserpine, and tetrahydro-L-biopterin HCl. acid, (+)-, pentylenetetrazole, picrotoxin, and 4,5,6,7- Enzyme inhibitors are Substances which inhibit an enzy tetrahydroisoxazolo 4.5-cpyridin-3-ol (THPO HBr). matic reaction. Examples of enzyme inhibitors include edro 15 Histaminergics are Substances which interact or interfere phonium chloride, N-methylphysostigmine.(-)-, neostig in Some manner with histamine and/or histamine receptors. mine bromide, physostigmine sulfate, tacrine HCL (THA), HistaminergicS include both histamine agonists and hista tacrine, 1-hydroxy male ate, io do tuber cidin, mine antagonists. Histamine agonists include dimaprit, his p-bromotetramisole, (-)-, 10-(C.-diethylaminopropionyl) tamine HCl, histamine.C.-methyl oxalate,R(-)-. Histamine phenothiazine hydrochloride (AS-1397), calmidazolium antagonists include cimetidine, chlorpheniramine maleate, chloride, hemicholinium-3, 3,5-dinitrocatechol (OR-486), (t)-, chlorpheniramine maleate,(+)-, cyproheptadine HCl, diacylglycerol kinase inhibitor I (R59022), diacylglycerol ranitidine HCl, pyrilamine maleate. Other histaminergics kinase inhibitor II (R59949), 3-phenylpropargylamine, include histidine HCl,L-, and histidine HCl,D-. N-mono methyl-L-arginine acetate, carbidopa, Ion channel modulators are compounds that modify the 3-hydroxybenzylhydrazine HCl (NSD-1015), hydralazine 25 activity of receptors controlling the flow of ions into cells. HCl (apresoline), clorgyline HCl, deprenyl HCl, L(-)-, Ion channel modulators include both ion channel activators deprenyl HCl, D(+)-, hydroxylamine HCl, iproniazid and ion channel antagonists. An example of an ion channel phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide, activator includes 1,4-dihydro-2,6-dimethyl-5-nitro-4-2- pargyline HCl, quinacrine HCl, Semicarbazide HCl, tranyl (trifluoromethyl)-phenyl-3-pyridinecarboxylic acidmethyl cy promine HCl, N,N-diethylaminoethyl-2,2- ester. Examples of ion channel antagonists include amiloride diphenylvale rate hydrochloride, 3-isobutyl-1- HCl, amiloride,5-(N,N-dimethyl)HCl, amiloride,5-(N.N- methylxanthne, papaverine HCl, indome thacind, hexamethylene)-, amiodarone HCl, benzamil HCl, bepridil 2-cyclooctyl-2-hydroxyethylamine hydrochloride (CONH), HCl, clofilium tosylate, co-conotoxin GVIA, cyproheptadine (+)-2,3-dichloro-C.-methylbenzylamine (DCMB),(LY HCl, diltiazem HCl, R(+)-(2-n-butyl-6,7-dichloro-2- 78335), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine 35 cyclopentyl-2,3-dihydro-1-oxo-1H-inden-7-yl), oxyacetic hydro chloride, p - a mino glute thim ide, (+)-, acid, flunarizine HCl, fluspirilene, R(+)-(6,7-dichloro-2- p-aminoglutethimide tartrate,R(+)-, p-aminoglutethimide cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)- tartrate,S(-)-, 3-iodotyrosine, L-, C.-methyltyrosine,L-, oxyacetic acid, lidocaine N-ethyl iodide, methoxyvera C.-methyltyrosine,D L-, and allopurinol. pamil HCl, (+)-, methoxy verapamil HCl, S(-)-, Excitatory amino acids are amino acids used to activate or 40 methoxyve rapamil HCl,R(+)-, nifedipine, pimozide, excite neurons involved in the glutaminergic or aspartic acid ryanodine, 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate Stimulated pathways. Excitatory amino acids include both hydrochloride, Verapamil HCl,(+)-, Verapamil HCl,S(-)-, agonists and antagonists. Exictatory amino acid agonists verapamil HCl,R(+)-. Other ion channel modulators include include (R,S)-O-amino-3-hydroxy-5-methylisoxazole-4- calmidazolium chloride, fluphenazine N-mustard, phenoxy propionic acid hydrobromide, (R.S)-C-amino-3-hydroxy-5- 45 benzamine HCl, trifluoperazine HCl, N-(6-aminohexyl)-5- methylisoxazole-4-propionic acid, aspartic acid,L-, glutamic chloro-1-naphthalenesulfonamide hydrochloride, N-(4- acid HCl, L-, glutamic acid diethyl ester HCl, L-, ibotenic aminobutyl)-5-chloro-2-naphthalene sulfonamide acid, kainic acid, N-methyl-D-aspartic acid (NMDA), cis hydrochloride, D(+)-myo-inositor-1,4,5-triphosphate piperidine-2,3-dicarboxylic acid, and quisqualic acid,(+)-. (Synthetic), N-(2-guanidino ethyl)-5- Excitatory amino acid antagonists include 3-amino-1- 50 iso quinoline Sulfonamide hydrochloride, 1-(5- hydroxy-2-pyrrollidone (HA-966), 7-chlorokynurenic acid, isoquinolineSulfonyl)-2-methylpiperazine kihydrochloride, 6-cyano-7-nitroquinoxaline-2,3-dione, dextromethorphan N-2-(methylamino)ethyl-5-isoquinolinesulfonamide HBr, dextrorphan, 6,7-dinitroquinoxaline-2,3-dione, dihydrochloride, N-(2-amino ethyl)-5- 5-fluoroindole-2-carboxylic acid, kynurenic acid, 2-amino isoquinolineSulfonamide dihydrochloride, diacylglycerol 3-phosphonopropionic acid (AP-3), (t)-2-amino-4- 55 kinase inhibitor I (R59022), diacylglycerol kinase inhibitor phosphonobutyric acid (AP-4), 2-amino-5- II (R59949), and N-(n-hepty 1)-5-chloro-1- phosphon opentanoic acid (AP-5), (+)-2-amino-7- naphthaleneSulfonamide. phosphonoheptanoic acid (AP-7), (+)-3-(2- Neurotoxins are Substances which have a toxic effect on carboxypiperazin-4-yl)-propyl-1-phosphonic acid, ketamine the nervous System, e.g. nerve cells. Neurotoxins include HCl, (+)-5-methyl-10,11-dihydro-5H-dibenzoa,d) 60 adrenergic neurotoxins, cholinergic neurotoxins, dopamin cyclohep-ten-5,10-imine hydrogen maleate, (-)-5-methyl ergic neurotoxins, and other neurotoxins. Examples of adr 10,11-dihydro-5H-dibenzoa,d)cyclohep-ten-5,10-imine energic neurotoxins include N-(2-chloroethyl)-N-ethyl-2- hydrogen maleate. bromobenzylamine hydrochloride. Examples of cholinergic GABA-ergics are Substances capable of interacting in neurotoxins include acetylethylcholine mustard hydrochlo Some manner with neurons that have gamma-aminobutyric 65 ride acetyl AF-64. Examples of dopaminergic neurotoxins acid receptorS. GABA-ergics include both GABA agonists include 6-hydroxydopamine HBr, 1-methyl-4-(2- and GABA antagonists. Examples of GABA agonists methylphenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride, US 6,407,137 B2 17 18 1-methyl-4-phenyl-2,3-dihydropyridinium perchlorate, psychic energizers include isocarboxazid, nialamide, N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine HCl, phenelZine, imipramine, amitryptyline hydrochloride, 1-methyl-4-phenylpyridinium iodide. Other neurotoxins tranylcypromine, pargylene, and protryptyline hydrochlo include L-B-methyl-C., B-diaminopropionic acid ride. hydrochloride, (+)-f3-methyl-O.f3-diaminopropionic acid Tranquilizers are Substances which provide a tranquiliz hydrochloride, L-3-oxalyl-C.f3-diaminopropionic acid, and ing effect. Examples of tranquilizers include chloropromazine, promazine, fluphenZaine, reserpine, quinolinic acid. deSerpidine, and meprobamate. Opioids are Substances having opiate like effects that are Anticonvulsants are Substances which have an effect of not derived from opium. Opioids include opioid agonists preventing, reducing, or eliminating convulsions. Examples and opioid antagonists. Opioid agonists include codeine of Such agents include primidone, phenytoin, Valproate, Chk Sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide and ethoSuximide. HCl, morphine Sulfate, noScapine, nor codeine, Muscle relaxants and anti-parkinson agents are agents normorphine, thebaine. Opioid antagonists include nor which relax muscles or reduce or eliminate Symptoms binaltorphimine HCl, buprenorphine, B-chlornaltrexamine asSociated with Parkinson's disease. Examples of Such 2HCl, B-funaltrexamione HCl, nalbuphine HCl, nalorphine 15 agents include mephenesin, methocarbomal, cyclobenza HCl, naloxone HCl, naloxonazine, naltrexone HCl, and prine hydrochloride, trihexylphenidyl hydrochloride, naltrindole HCl(NTI). levodopa/carbidopa, and biperiden. Drugs effecting PCP/Sigma receptors include both recep Antihypertensives are Substances capable of counteract tor agonists and receptor antagonists. Receptor agonists ing high blood pressure. Examples of Such Substances include N-allylnormetazocine HCl, (+)-(SKF-10047), include C.-methyldapa and the pivaloyloxyethyl ester of N-allylnormetazocine HCl(-)-, 1,3-Di(2-tolyl)guanidine C.-methyldapa. (DTG), phencyclidine HCl, 1-1-(2-thienyl)cyclohexyl Analgesics are Substances capable of preventing, piperidine hydrochloride (TCP). Receptor antagonists reducing, or relieving pain. Examples of analgesics include include metaphit methaneSulfonate, and R(+)-3-(3- morphine Sulfate, codeine Sulfate, meperidine, and nalor hydroxyphenyl)-N-propylpiperidine hydrochloride. 25 phine. Serotonergics are Substances that interact or interfere in Antipyretics are Substances capable of relieving or reduc Some manner with nerve cells having Serotonin receptors. ing fever and anti-inflammatory agents are Substances Serotonergics include Serotonin agonists and other Seroton capable of counteracting or Suppressing inflammation. ergicS. Serotonin agonists include carboxamidotryptamine Examples of Such agents include aspirin (Salicylic acid), maleate (5-CT), 1-(3-chlorophenyl)piperazine HCl, indomethacin, Sodium indome thacin trihydrate, 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo1,2-a Salicylamide, naproxen, colchicine, fenoprofen, Sulindac, quino Saline, 1:2 male ate Salt, dip ropyl-5- diflunisal, diclofenac, indoprofen and Sodium Salicylamide. carboxamidotryptamine (DP-5-CT), (t)-1-(2,5-dimethoxy Local anesthetics are Substances which have an anesthetic 4-iodophenyl)-2-aminopropane HCl, (+)-1-(4- effect in a localized region. Examples of Such anesthetics bro mop he nyl-2,5-dimethoxy)-2-amino propane 35 include procaine, lidocain, tetracaine and dibucaine. hydrobromide, 1-(2,5-dimethoxyphenyl)-2-aminopropane Antispasmodics and muscle contractants are Substances hydrochloride (DMA), (+-2-dipropylamino-8-hydroxy-1,2, capable of preventing or relieving muscle Spasms or con 3,4-tetrahydro naphthale ne HBr, (+)-8- tractions. Examples of Such agents include atropine, hydroxydipropylaminotetralin HBr, 5-methoxy-N,N- Scopolamine, oxyphenonium, and papaverine. dimethyltryptamine hydrogen oxalate, 1-(2-methoxyphenyl) 40 Prostaglandins are art recognized and are a class of pipe razine HCl, 5-methoxy tryptamine HCl, naturally occurring chemically related, long-chain hydroxy 2-methylserotonin maleate, C.-methylserotonin maleate, fatty acids that have a variety of biological effects. Examples p-aminophenylethyl-m-trifluoromethylphenyl piperazine;4 of Such agents include E2, and E1. 2-4-3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl Anti-bacterials are Substances which destroy or Suppress benzeneamine, 1-phenylbiguanide, quipazine maleate Sero 45 the growth or reproduction of bacteria. Examples of anti tonin creatinine Sulfate, Serotonin HCl, Serotonin oxalate, bacterials include trimethoprin, Sulfamethoxazole, Spiro Xatrine, m-trifluoromethylphenylpipe razine cefoperaZone, chloroamphenicol, polymycin, and metron hydrochloride, cyproheptadine HCl, 3-tropanyl-indole-3- idazole. carboxylate (ICS 205,930), 3-tropanyl-indole-3-carboxylate Antiseptics are Substances capable of inhibiting the methiodide, ketan Serin tart rate, 3-tropanyl-3,5- 50 growth and development of microorganisms without neces dichlorobenzoate (MDL-72222), metoclopramide HCl, Sarily destroying them. Examples of antiseptics include mianserin HCl, 1-(1-naphthyl)piperazine HCl, piremperone, those discussed above as anti-bacterials and other Sulfona propranolol HCl,S(-)-, propranolol HCl,R(+)-, propranolol mide Substances. HCl,(+)-, ritanserin, Spiperone HCl, Zacopride maleate. Anti-depressants are Substances capable of preventing or Other Serotonergics include p-chlorophenylalanine, clomi 55 relieving depressant. Examples of anti-depressants include pramine HCl, fenfluramine,S(+)-, fenfluramine,R(-)-, imipramine, amitriptyline, nortriptyline, protriptyline, 5-hydroxy-L-tryptophan, imipramine HCl, L-tryptophan, de Sipramine, amoxapine, do Xepin, map rotiline, Zacopride maleate,(t)-, and Zimelidine HC1. tranylcypromine, phenelZine, and isocarboxazide. Hypnotics are Substances which produce a hypnotic Anti-migraine preparations are Substances capable of pre effect. Hypnotics include pentobarbital Sodium, 60 venting or relieving migraine headaches. Examples of Such phenobarbital, Secobarbital, thiopental and mixtures, Substances include ergotamine tartrate, caffeine, dihydroen thereof, heterocyclic hypnotics, dioxopipe ridines, gotamine meSylate propanolol HCl, acetominophin, and glutarimides, diethyl isoValeramide, C.-bromoisovaleryl Salicylic acid. urea, urethanes and disulfanes. Central nervous System Stimulants are Substances capable Psychic energizers are Substances that raise the energy 65 of Stimulating the central nervous System. Examples of Such level of the brain, Such as compounds that raise the level of Substances include amphetamine, phenylalanine, ATP or inhibit its breakdown in nerve cells. Examples of picrotoxinin, and methylphenidate. US 6,407,137 B2 19 20 Imaging agents are agents capable of imaging a desired a drug which is Structurally similar to the foregoing list of Site, e.g. tumor, in Vivo. Examples of imaging agents include drugs and is capable of achieving the same or Substantially Substances having a label which is detectable in Vivo, e.g. the same function or activity. An equivalent is an agent antibodies attached to fluorescent labels. The term antibody capable of achieving the same or Substantially the same includes whole antibodies or fragments thereof. intended function or activity. Specific targeting agents include agents capable of deliv The drug compound and carrier may be coupled using a ering a therapeutic agent to a desired site, e.g. tumor, and providing a therapeutic effect. Examples of targeting agents variety of reactions involving treating the neuroactive com include agents which can carry toxins or other agents which pound (or a protected derivative thereof) having one, free provide beneficial effects. The targeting agent can be an hydroxyl or amino group with the corresponding fatty acid antibody linked to a toxin, e.g. ricin A or an antibody linked carrier or an activated derivative thereof. For example, a to a drug. dopamine derivative having its two hydroxyl groups pro The term protein is art-recognized and for purposes of this tected with acetonide may be reacted with the carrier in the invention also encompasses peptides. Examples of proteins presence of a water-removing compound Such as dicyclo include antibodies, hormones, and growth factors, e.g. nerve hexyl carbodiimide in a Solvent Such as dioxane, tetrahy growth factors and an example of a peptide includes nerve 15 drofurane and methylpyrrolidone or N.N dimethylforma growth factor peptide. mide at ambient temperature. The Solvent then may be The proteins or peptides may be any bioactive protein or removed and the desired product may be extracted from the peptide, naturally occurring or Synthetic. The term peptide is formed dicyclohexylurea using a Suitable Solvent Such as intended to include the classes of peptides known as neu methylene chloride. The protecting group then may be ropeptides and regulatory peptides. Specific examples of removed by treatment with a suitable acid such as 4N HCl Such factors include growth hormone and growth hormone in dioxane. The amine group of a neuroactive compound releasing hormone, gonadotorpin-releasing hormone, and its may be coupled to the carboxyl group of the carrier also by agonist and antagonist analogues, Somatostatin and its using the acid chloride or a low carbon ester derivative of the analogues, gonadotropins Such as luteinizing hormone and carrier and forming amide bonds by liberating HCl or an follicle-stimulating hormone, peptide-T, thyrocalcitonin, 25 alcohol respectively. Drugs containing alcohol groups (OH) parathyroid hormone, glucagon, Vasopressin, oxytocin, may be coupled via ester bonds to the fatty acid carrier by alpha and beta melanocyte-stimulating hormones, peptide Similar procedures as described above (e.g. using the anhy molecules which Stimulate erythrocytes, leucotyte and dride derivative, the acid chloride derivative for the free acid immunocyte growth and function Such as colony Stimulating of the carrier). Alternate couplings Such as phosphoramide, factors (CFS 1 and 2), erythropoitin and lymphokines Sulfate, Sulfonate, phosphate or urethane also may be used as (including interleukin I and II), angiotensin I and II, will be recognized by one of ordinary skill in the art to bradykinin, kallidin, adrenocorticotropic hormone, thyroid coupled carrier molecules to drugs. Stimulating hormone, insulin, glucagon and the numerous Amide bonds are preferred because they may Survive the analogues and congeners of the foregoing peptides. It should environment of the Stomach and the prodrug may be admin be understood that the term peptide is intended to include 35 istered orally. However, it should be recognized that bonds Small proteins and particularly those molecules having on incapable of Surviving the environment of the Stomach Such the order of about 100 amino acids or less. Other larger as an ester bond still may be used to link the carrier of the proteins are intended to be encompassed by the term protein. invention and a drug, with the resulting conjugate capable of The protein or peptide preferably has a molecular weight crossing the blood brain barrier. Such a prodrug may be of less than about 5,000 and more preferably less than about 40 injected or protected from the environment of the Stomach 1,500. by, for example, coatings, well-known to those skilled in the Anti-Viral agents are Substances capable of destroying or art. Such a coating may be called for even in the presence of Suppressing the replication of viruses. Examples of anti-Viral an amide bond between the carrier and the drug. agents include C.-methyl-l-adamantane methylamine (ri The compounds of the invention can be prepared in mantadine), 1-?3-D-ribofuranosyl-1,2,4-triazole-3 carboxa 45 pharmaceutical preparations containing the compounds mide (ribavirin), 9-2-hydroxy-ethoxymethylguanine themselves and a pharmaceutically acceptable carrier. Such (Acyclovir), adamantanamine, and 5-iodo-2'-deoxyuridine carriers include those that facilitate administration of the (Idoxuridine), adenine arabinoside (Vidarabine) and prodrug, prolong Shelf life of the prodrug, allow a particular interferon, Synthetic or naturally occuring. mode of administration of the prodrug, or provide or facili Anti-psychotic agents are Substances which modify psy 50 tate formulation of a particular dose of the prodrug. The chotic behavior. Examples of Such agents include pharmaceutically acceptable carrier may be Solid or liquid. phenothiazines, butyrophenones and thioxanthenes. Examples of liquid carriers include water, an aqueous Solu Anti-emetics are Substances which prevent or alleviate tion of non-toxic Salts, Such as Sterile physiological Solutions nausea or vomiting. An example of Such a Substance of Saline, or aqueous Solutions containing organic Solevents, includes dramamine. 55 Such as ethanol. Also Suitable are emulsions, Such as oil-in The examples discussed above may be listed in the Salt or water emulsions. Solid carriers include both nutritative non-salt form but for purposes of this invention both forms carriers, Such as Sucrose or gelatin, and non-nutritative are intended to be encompassed. Further, if a particular carriers, Such as cellulose or talc. Such carriers, for example, Salt-form of a drug, e.g. naloxone HCl, is listed, other art permit formation of tablets containing a particular dose of recognized biologically accepted Salts can be used in place 60 the prodrug. Also included are carriers of the implantable of the listed Salt-form. Examples of acceptable Salts include type which permit Sustained-release of the prodrug. hydrochlorides, hydrobromine, Sulfate, laurelate, palmatate, Slow-release capsules and other protective mediums are phosphate, nitrate, borate, acetate, maleate, tartrate, oleate, suitable for the oral administration of the compounds of the Salisilate, Salts of metals, means or organic cations, e.g. invention due to the protection afforded against hydrolysis in quarternary ammonium. 65 the gastrointestinal tract. Preferred are those capsules which This invention is also intended to encompass derivatives permit the compounds to bypass the Stomach. When the or equivalents of the above discussed drugs. A derivative is present compounds are to be administered peritoneally, they US 6,407,137 B2 21 22 can be administered by Subcutaneous, intramuscular or the carrier molecule is between 16 and 22 carbon atoms in intravenous injections. length and occurs naturally in the brain. Among the fatty Amounts of the compounds of the invention useful for acids occurring naturally in the brain are those with 16 promoting the uptake of the drug by the brain may vary from carbon atoms and 0, 1 or 2 double bonds (C16:0; C16:1 and individual to individual, as well as varying from the par C16:2), those with 18 carbon atoms and 1, 2 or 3 double ticular disorder being treated and the particular effect bonds (C18:1; C18:2; and C18:3), those with 20 carbon desired. Such amounts can be determined by experimenta atoms and 1, 2 or 4 double bonds (C20:1; C20:2; and C20:4) tion as is well understood by those skilled in the pharma and those with 22 carbon atoms and 4, 5 or 6 double bonds ceutical arts. For Suppressing appetite with Dopamine (C22:4; C22:5 and C22:6). While the position of the double bonds may be between any of the carbon atoms in the fatty conjugates, amounts in the range of about 100-20000 micro acids, the preferred loci are those which occur naturally in grams per kilogram body weight are preferred. the fatty acids of the CNS. Among the naturally-occurring Generally, compounds are most active when administered fatty acids, C16:0 and C22:6 are preferred due to their intravenously than by the other preferred routes. However, preference for concentrating in the Synaptosomal when an amide bond is used to conjugate the drug and membranes, with C22:6 most preferred. It also has been carrier, oral administration of the drug appears to work quite 15 found that C18:3 acts above average in its ability to deliver well. In any event, when the conjugates of the invention are a compound acroSS the blood brain barrier. used to promote the uptake of a drug into the central nervous The fatty acids of this invention include both substituted System, they are administered to humans in amounts Suffi and unsubstituted fatty acids. In the Substituted fatty acid, at cient to promote the crossing of the blood brain barrier. least one hydrogen along the fatty acid chain is replaced with When the therapy involves restoring a deficiency of a a Substituent. Examples of Such Substituents include alkyl neuro-transmitter in a human, the conjugate is administered groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, and in an amount Sufficient to cause the normalization of the pentyl. Only those Substituents that do not greatly adversely deficiency. When the compounds of the present invention effect the ability of the carrier to perform its intended are used for treating Parkinsonism or hyperprolactinemia or functions, including crossing the blood brain barrier and/or for Suppressing appetite, then they are administered to a 25 human in need of Such treatment in an amount Sufficient to targeting the drug to a particular area of the brain, e.g. D. affect the desired result. receptors, can be used. In addition to the foregoing fatty Administration, of course, may be made by any method acids, branched chain fatty acids having between 16 and 26 which allows the active compound to reach the bloodstream carbon atoms may be used. Particular examples include and penetrate through the blood brain barrier. Typical meth analogues of the naturally-occurring polyisoprenoids ods include oral, rectal, peritoneal and topical administration (dolicols) Such as of the compounds. When the compounds are administered orally, the composition can be in the form of dragees, tablets, CH-C=CH-CH-CH-CH=C-CH-CH-COOH Syrups or ampules. When the compounds are administered CH CH rectally, the composition can be in the form of a Suppository. 35 In addition, when the compounds of the invention are to be administered by topical application, they can be in the form This invention further pertains to methods for introducing of pomade or a gel. a drug into the central nervous System. The method com The ability of the bond between the drug and the carrier prises introducing a pharmaceutically effective amount of to be broken once the prodrug is in the CNS will influence 40 the prodrugs described above into the bloodstream of a the choice of bonds. Likewise, the desired delivery site in the patient. A pharmaceutically effective amount is that amount CNS may affect the choice of bonds as the enzymes respon necessary to prevent, treat, or reduce the Symptoms associ Sible for breaking various bonds are concentrated in par ated with a particular condition or disease being treated. ticular locations. This invention also pertains to methods for manufacturing Variations of the particular carrier described in the pre 45 pharmaceutical preparations, including coupling a fatty acid ferred embodiment also are contemplated. For example, it to a drug to form a prodrug, and then forming a pharma has been found that a Straight chain fatty acid that does not ceutical dose containing the prodrug and a pharmaceutically occur naturally in the brain and having 12 carbon atoms and acceptable carrier. no double bonds coupled to dopamine does not effectively Having now fully described this invention, it will be croSS the blood brain barrier and is completely inactive as an 50 appreciated by those of ordinary skill in the art that the same appetite-Suppressant. Likewise, another Straight chain fatty can be practiced with a wide and equivalent range of acid that does not occur naturally in the brain and having 22 compositions, modes of administration, therapeutic treat carbon atoms and no double bonds coupled to dopamine ments and the like, without affecting the Spirit or Scope of the does not effectively cross the blood brain barrier and is invention or any embodiment thereof. essentially inactive as an appetite-SuppreSSant. However, a 55 What is claimed is: Straight chain fatty acid occurring naturally in the brain and 1. A compound comprising: having 18 carbon atoms and 3 double bonds coupled to a fatty acid coupled to an anticancer agent Selected from dopamine is partially active. This molecule crosses the blood the group consisting of methotrexate, cisplatin, brain barrier, and it has Some effect on locomotor activity prednisone, hydroxyprogesterone caproate, medroX although no Substantial effect on appetite. Thus, it appears 60 y proge Sterone acetate, mege Strol acetate, that the length of the fatty acid, the degree of Saturation and diethylstilbestrol, ethinyl estradiol, tamoxifen, test whether the fatty acid is naturally occurring in the brain osterone propionate, fluoxymesterone, vinblastine affects the ability of the carrier to be combined with a drug (VLB), Vincristine, Vindesine, etoposide, teniposide, to form a prodrug that will cross the blood brain barrier and dactinomycin (actinomycin D), daunorubicin effectively deliver and liberate the drug at an active site. The 65 (daunomycin; rubidomycin), doxorubicin, bieomycin, carrier molecule preferably is a Straight-chained fatty acid of plicamycine (mithramycine), mitomycin (mitomycin between 16 and 26 carbon atoms in length. More preferably C), -asparaginase, hydroxyurea, procarbazine US 6,407,137 B2 23 24 (N-methylhdrazine, MIH), mitot ane, 8. The compound of claim 1, wherein the fatty acid is a mino glute timide, me chlor eth a mine, C18:3. cyclophosphamide, mel phalan (-Sarcolysin), 9. The compound of claim 1, wherein the fatty acid is chlorambucil, busulfan, carmustine (BCNU), lomus C2O:1. line (CCNU), semustine (methyl-CCNU), streptuzocin 10. The compound of claim 1, wherein the fatty acid is (step to Zoto cin), da carbazine (DTIC: C2O:2. dimethyltriazenomidazolecarboxamide), methotrexate 11. The compound of claim 1, wherein the fatty acid is (amethopterin), cytarabine (cytosine arabinoxide), mer C2O:3. captopurine (6-mercaptopurine: 6-MP), thioguanine 12. The compound of claim 1, wherein the fatty acid is (6-thioguanine: TG). C20:4. 2. The compound of claim 1, wherein the fatty acid is 13. The compound of claim 1, wherein the fatty acid is selected from the group consisting of C16:0; C16:1; C16:2; C22:4. C18:1; C18:2; C18:3; C20:1: C20:2; C20:3; C20:4; C22:4; 14. The compound of claim 1, wherein the fatty acid is C22:5; C22:6; and C24:4. C22:5. 3. The compound of claim 1, wherein the fatty acid is 15 15. The compound of claim 1, wherein the fatty acid is C16:0. C22:6. 4. The compound of claim 1, wherein the fatty acid is 16. The compound of claim 1, wherein the fatty acid is C16:1. C24:4. 5. The compound of claim 1, wherein the fatty acid is 17. A pharmaceutical preparation containing the com C16:2. pound of claim 1 and a pharmaceutically-acceptable carrier. 6. The compound of claim 1, wherein the fatty acid is 18. A pharmaceutical preparation containing the com C18:1. pound of claim 2 and a pharmaceutically-acceptable carrier. 7. The compound of claim 1, wherein the fatty acid is C18:2. k k k k k