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United States Patent (19) 11 Patent Number: 4,771,059 Bodor (45) Date of Patent: Sep. 13, 1988 (54) BRAIN-SPECIFIC ANALOGUES OF CENTRALLY ACTING AMINES OTHER PUBLICATIONS Bodor, N. et al., Pharmacelogy and Therapeutics, vol. 75 Inventor: Nicholas S. Bodor, Gainesville, Fla. 19, No. 3, pp. 337-386, (1983). Breckenridge, R. J. et al., Journal of Neurochemistry, (73 Assignee: * University of Florida, Gainesville, 37(4): 837-844, (1981). Fa. Murray, W. J. et al., Chapter 8 of "', Edited by J. A. Vida, Academic Press, New York, 21 Appl. No.: 785,903 (1977). (22) PCT Filed: Feb. 15, 1985 Chemical Abstracts 34:164580z. Chemical Abstracts 81:20899a. (86 PCT No.: PCT/US85/00236 Wolff, M. E., "Burger's Medicinal Chemistry, Fourth S371 Date: Aug. 29, 1985 Edition, Pt. III", (1981), pp. 851-853, 877-885. Primary Examiner-Mary C. Lee S 102(e) Date: Aug. 29, 1985 Assistant Examiner-Dale A. Bjorkman -1 Attorney, Agent, or Firm-Mary Katherine Baumeister; (87 PCT Pub. No.: WO85/03937 Dennis P. Clarke PCT Pub. Date: Sep. 12, 1985 (57) ABSTRACT The subject compounds, which are adapted for the Related U.S. Application Data site-specific/sustained delivery of centrally acting drug (63 Continuation-in-part of Ser. No. 584,800, Feb. 29, 1984, species to the brain, are compounds of the formula abandoned. 51) Int. Cl.' ...... A61K 31/44; A61K 31/47; (I) CO7D 211/90; CO7D 215/54 52 U.S. C...... 514/355; 514/307; p-O 514/309; 514/311; 514/312; 514/345; 514/348; 514/350; 514/354; 514/356; 514/357; 514/358; 546/139; 546/141; 546/142; 546/145; 546/146; and the non-toxic pharmaceutically acceptable salts 546/147; 54.6/150; 54.6/152;546/153; 54.6/155; thereof, wherein D is the residue of a centrally acting 546/156; 546/157; 546/158; 54.6/165; 54.6/169; primary, secondary or tertiary amine and 546/170; 546/172; 54.6/176; 546/180; 546/290; 546/296; 546/298; 546/299; 546/300; 546/301; 546/302; 546/303; 54.6/316; 54.6/318; 54.6/321; 546/322; 54.6/323; 54.6/338; 54.6/345; 54.6/346 -O (58) Field of Search ...... 54.6/316, 323, 139, 141, 546/142, 145, 146, 147, 150, 152, 153, 155, 156, is an unsubstituted or substituted dihydropyridyl, dihy 157, 158, 165, 169, 170, 172, 176, 180,290, 296, droquinolyl or dihydroisoquinolyl radical. The corre 298, 299, 300, 30, 302,303, 318,321, 322, 338, sponding ionic pyridinium, quinolinium and 345, 346; 54/354, 355, 307, 309, 31, 312, 345, isoquinolinium salts 348, 350, 356, 357, 358 (56) References Cited U.S. PATENT DOCUMENTS 3,822, 94 7/1974 Rushmere ...... 54.6/36 4,479,932 10/1984 Bodor ...... 54.6/36 X, wherein X is the anion of a non-toxic pharmaceu FOREIGN PATENT DOCUMENTS tically acceptable acid, are also disclosed. 3303968 11/1983 PCT Int'l Appl. . 822.351 10/1959 United Kingdom. 31 Claims, No Drawings 4,771,059 2 Res., 17, 279 (1972). Penetration of such a barrier may BRAIN-SPECIFIC ANALOGUES OF CENTRALLY occur by several processes: lipid soluble substances may ACTING AMINES passively penetrate into the cells, while small molecules. such as water and urea may pass through the pores. In CROSS-REFERENCE TO RELATED 5 addition to these simple physical processes, carrier APPLICATION mediated and active transport processes govern the This application is a continuation-in-part of appli movement of many molecules through the BBB. Thus, cant's copending application Ser. No. 584,800, filed it is generally accepted that lipid solubility, degree of Feb. 29, 1984, abandoned. ionic dissociation or protonation and the ability of ten 10 porary combination with membrane constituents affect . . FIELD OF THE INVENTION delivery through the BBB. It has been shown, for exam The present invention relates to new derivatives of ple, that in the class of , a quantitative corre centrally acting amines in which a primary, secondary lation could be established between their ease to pass or tertiary amine function has been replaced with a into the brain (as reflected by the different times of dihydropyridine/pyridinium salt redox system. The S onset of anesthetic action) and their lipid/water parti new dihydropyridine analogues are a delivery system tion coefficient. Mark et al., J. Pharmacol and Exp. for the corresponding new quaternary compounds, Therap, 123, 79 (1957). The role of lipid solubility in which are pharmacologically active. in vivo and are drug penetration through the BBB is also exemplified characterized by site-specific and sustained delivery to by the better absorption of the sparingly water-soluble the brain. thiamine propyl disulfide (TPD) as compared to the BACKGROUND OF THE INVENTION water-soluble thiamine hydrochloride (THCl). Thomson et al, Ann. Int. Med., 74,529 (1971). Some The delivery of drug species to the brain is oftimes materials such as glucose and amino acids are trans seriously limited by transport and metabolism factors ported by active mechanism, characterized by satura and, more specifically, by the functional barrier of the 25 tion, bidirectional molecular specificity, bidirectional endothelial brain capillary wall, i.e. the blood-brain competitive inhibition and bidirectional countertran barrier or BBB. Site-specific delivery and sustained sport. Fishman, Am. J. Physiol, 206,836 (1964). delivery of drugs to the brain are even more difficult. Changes in permeability of the BBB can becaused by . Indeed, the barriers separating plasma from the brain several pathological and toxicological processes. Par and cerebrospinal fluid (CSF) are complex systems 30 involving passive and active transport and subserve a dridge, Connor and Crawford, CRC Crit. Rey. Toxicol, number of important functions. The boundary between 179 (1975). A general increase in the barrier permeabil plasma and the central nervous system (CNS) is much ity, such as a nonspecific breakdown of the barrier has, less permeable than that between plasma and other however, several consequences, including cerebral tissue cells to a variety of water soluble substances, such 35 edema...... as organic electrolytes, organic acids and bases, as well It too is well documented that the BBB is relatively. as to large molecules such as proteins. Such a barrier impermeable to the ionized forms of drugs and other also provides a path for clearance from the brain of the molecules. Drugs which are weak organic electrolytes breakdown products of cellular metabolism. The CNS appear to pass from blood to CSF to reach a steady state and its fluids can be considered basically a three-con ratio characteristic of each molecule according to its . . partment system: the blood or the plasma, CSF and pka and the existence of a normal pH gradient between brain tissue. There is a diffusion-controlled exchange blood and CSF. It is clear that it is the most difficult for between CSF and the extracellular fluid (CF) of the quaternary pyridinium or ammonium salts to penetrate brain. It has also been suggested that the permeabilities the BBB. : ...... of blood-CSF and blood-brain barriers are practically 45 And removal of substances from the brain and CSF is identical with respect to drugs and other foreign sub obviously a significant factor in regulating drug concen stances. Mayer et al, J. Pharmacol, and Exp. Therap, trations in the CNS. There are several efflux processes: 125, 185 (1959). bulk flow via the arachnoid villi, diffusion of lipid solu The BBB is, moreover, basically the result of the fact ble substances into brain and blood, active transport and that the endothelial cells in the brain capillaries are 50 metabolism by adjacent meninges. Once a drug or me joined by continuous, tight intercellular junctions, such tabolite enters the CSF from blood or brain by simple that material has to pass through the cells rather than diffusion, it may rapidly be removed, either by nonse. between them in order to move from blood to brain. It lective bulk flow or by active transport mechanism is interesting that there are areas within the brain, such associated with the choroid plexus or other nondefined as the subfornical body and the postremia, in which the 55 structures in the CSF compartment. It is generally ac capillary cells are not closely linked so that they lack cepted that highly lipid-soluble drugs leave the CSF the characteristics of the BBB. They provide the entry more rapidly than poorly lipid-soluble ones, but the of small amounts of compounds which would not ordi barrier to passage of compounds from CSF has only narily enter the barriers. Hoffman and Olszewzki, Neu superficial similarity to the blood-CSF barrier. rology (Minneap.), 11, 1081 (1961). Drug elimination processes from the brain are signifi Foreign compounds which enter organs other than cantly directly related to drug accumulation in the the central nervous system with ease, may penetrate the brain. It is generally assumed that efflux in the opposite CNS slowly or hardly at all. A number of theories con direction involves almost the same processes as for cerning the nature of the barrier have been proposed. entry, except that the role of the bulk flow and the The widely accepted concept describes the boundary as 65 metabolic processes in the brain are not to be over a fat-like layer interspersed with small pores, although looked. the BBB is not a simple, anatomically well-defined uni The two elimination processes studied in the earlier tary physical entity. Shuttleworth, Prog. Exp. Tumor literature and which can be said to have a certain bear 4,771,059 3 4. ing on the present invention involve elimination from lipoidal (i.e. lipophilic) by making its dihydropyridine the brain of ionic species. Thus, it is found that non form (Pro-2-PAM) to enable its penetration through metabolized ionic species, such as the acetate ion, have lipoidal barriers. This simple approach allowed a three times slower elimination rate from the CSF than the compound to get into the brain as well as other from the blood. Freundt, Arz, Forsch., 23, 949 (1973). organs, but this manipulation did not and could not An even more dramatic change in the elimination rate result in any brain specificity. On the contrary, such was found in the case of a quaternary piperidinium salt. approach was delimited to relatively small molecule The quaternary salt, formed in situ after delivery of a quaternary pyridinium ring-containing drug species and haloalkylamine, which undergoes cyclization to the did not provide the overall ideal result of brain-specific, quaternary salt, in the brain, as well, was found to have 10 sustained release of the desired drug, with concomitant an at least ten times slower elimination rate from the rapid elimination from the general circulation, en brain than from the rest of the body. It was concluded hanced drug efficacy and decreased toxicity. No "trap by the authors Ross and Froden, Eur, J. Pharmacol, 13, ping” in the brain of the 2-PAM formed in situ resulted, 46 (1970) that the outflow rate of the quaternary salt and obviously no brain-specific, sustained delivery oc corresponded to the inflow rate. Similar results were 15 curred as any consequence thereof: the 2-PAM was obtained for the erythrocytes: the efflux of the quater eliminated as fast from the brain as it was from the nary salt was very slow. Ross, J. Pharm. Pharmacol., 27, general circulation and other organs. Compare U.S. 322 (1975). Pat. Nos. 3,929,813 and 3,962,447; Bodor et al., J. Pharm. A dihydropyridine-pyridinium redox system has Sci., 67, No. 5, 685 (1978). See also Bodor, "Novel Ap now been successfully applied to delivery to the brain 20 proaches for the Design of Membrane Transport Prop of a number of drugs. Generally speaking, according to erties of Drugs", in Design of Biopharmaceutical Proper this system, a dihydropyridine derivative of a biologi ties Through and Analogs, Roche, E. B. (ed.), cally active compound is synthesized, which derivative APhA Academy of Pharmaceutical Sciences, Washing can enter the CNS through the blood-brain barrier ton, D.C., 98-135 (1976). Subsequent extension of this following its systemic administration. Subsequent oxi 25 first approach to delivering a much larger quaternary dation of the dihydropyridine species to the corre salt, berberine, to the brain via its dihydropyridine pro sponding pyridinium salt leads to delivery of the drug to drug form was, however, found to provide site-specific the brain. sustained delivery to the brain of that anticancer agent. Two main approaches have been used thus far for See Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. delivering drugs to the brain using this redox system. 30 370-372. The first approach involves derivation of selected drugs The second approach for delivering drugs to the which contain a pyridinium nucleus as an integral struc brain using the redox system involves the use of a pyri tural component. This approach was first applied to dinium carrier chemically linked to a biologically active delivering to the brain N-methylpyridinium-2-carbal compound. Bodor et al, Science, Vol. 214, Dec. 18, dioxine chloride (2-PAM), the active nucleus of which 35 1981, pp. 1370-1372, outlines a scheme for this specific constitutes a quaternary pyridinium salt, by way of the and sustained delivery of drug species to the brain, as dihydropyridine latentiated prodrug form thereof. depicted in the following Scheme 1: Thus, a hydrophilic compound (2-PAM) was made

Schene BBB, BLOOD-BRAIN BARRIER. (D)+(QC)* EstD-QC) RETNs (D-DHC)

DELIVERY Kr

TO BODY ELIMINATION (D-DHC) (D-DHC) N THE BRAIN IN CIRCULATORY SYSTEM AND ORGANS N VIVO IN VEVO Ki OXIDATION K OXIDATION 4,771,059 -continued Schene 1 BBB, BLOOD-BRAIN BARRIER... (D-Qct ENZYMATIC ENZYMATIC (D-QC) IN THE BRAIN CLEAVAGE CLEAVAGE IN CIRCULATORY SYSTEM K4. K.

K2 (D -- (QC) (D - (QC) K

BBB

Elimination

25 According to the scheme in Science, a drug (D) is coupled to a quaternary carrier (QC) and the re (D-QC) which results is then reduced chemically to N O the lipoidal dihydro form (D-DHC). After administra R

tion of D-DHC in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form D-DHC) is then in situ oxidized (rate constant, (R ki) (by the NADeNADH system) to the ideally inac tive original (D-QClt quaternary salt which, because of 35 its ionic, hydrophilic character, should be rapidly elimi nated from the general circulation of the body, while Testing of the N-methyl derivative in vivo supported the blood-brain barrier should prevent its elimination the criteria set forth in Scheme 1. Bodor et al speculated from the brain (k3>>k2; k3>>k7). Enzymatic cleav that various types of drugs might possibly be delivered age of the (D-QC that is "locked" in the brain effects using the depicted or analogous carrier systems and a sustained delivery of the drug species (D), followed by indicated that use of N-methylnicotinic acid esters and its normal elimination (ks), metabolism. A properly amides and their pyridine ring-substituted derivatives. selected carrier (QC will also be rapidly eliminated was being studied for delivery of amino- or hydroxyl from the brain (ks) > k2). Because of the facile elimina containing drugs, including small peptides, to the brain. tion of D-QClt from the general circulation, only 45 No other possible specific carriers were disclosed. minor amounts of drug are released in the body Other reports of this work with the redox carrier system (k3>>k4); D will be released primarily in the brain have appeared in The Friday Evening Post, August 14, (k4> k2). The overall result ideally will be a brain 1981, Health Center Communications, University of specific sustained release of the target drug species. Florida, Gainesville, Fla.; Chemical % Engineering Specifically, Bodor et all worked with phenylethyla 50 News, Dec. 21, 1981; pp. 24-25; and Science News, Jan. mine as the drug model. That compound was coupled to 2, 1982, Vol. 121, No. 1, page 7. More recently, the nicotinic acid, then quaternized to give compounds of redox carrier system has been substantially extended in the formula terms of possible carriers and drugs to be delivered. See International Patent Application No. 55 PCT/US83/00725, filed May 12, 1983 and published Nov. 24, 1983 under International Publication No. WO83/03968. Also see Bodor etal, Pharmacology and (6 or Therapeutics, Vol. 19, No. 3, pp. 337-386 (1983). N t : Nevertheless, serious need also exists in this art for R 60 new, centrally acting drugs which can be site-specifi cally and sustainedly delivered to the brain, while at the same time avoiding the aforesaid noted and notable (R = CH3 or CH, ), disadvantages and drawbacks associated with penetra tion of the blood-brain barrier, with dihydropyridine 65 latentiated prodrug forms of drug species themselves. comprising a pyridinium salt active nucleus, with the which were subsequently reduced by sodium dithionite necessity for. introducing critically coordinated and to the corresponding compounds of the formula designed, release rate-controlling substituents onto any 4,771,059 7 8 particular drug carrier moiety, and/or with the limita fused rings; and each R is independently selected from tion of delivery of only known drug entities. the group consisting of halo, C1-C7 alkyl, C1-C, alkoxy, C2-C3 alkoxycarbonyl, C2-C3 alkanoyloxy, C1-C7 halo SUMMARY AND OBJECTS OF THE alkyl, C1-C7 alkylthio, C1-C7 alkylsulfinyl, C1-C7 alkyl INVENTION sulfonyl, -CH=NOR" wherein R" is H or C1-C, Accordingly, a major object of the present invention alkyl, and -CONR'R' wherein R' and R", which can is the provision of a new approach for delivering drugs be the same or different, are each H or C1-C, alkyl. to the brain using the redox system. This approach Preferably, n,m, p or q is one and R is located in the 3 provides new derivatives of centrally acting amines in position of the dihydropyridine ring, in the 3 position of which a primary, secondary or tertiary amine function O the dihydroquinoline ring system or in the 4 position of has been replaced with a dihydropyridine/pyridinium the dihydroisoquinoline ring system. Most preferably, salt redox system. The new dihydropyridine analogues R is -CONH2. of the invention are characterized by the structual for The nontoxic pharmaceutically acceptable salts of nula the compounds of formula (I) are also within the ambit 15 of this invention. The new dihydropyridine analogues of formula (I) (I) act as a delivery system for the corresponding quater nary compounds in vivo; the quaternary derivatives, which also are chemical intermediates to the dihydro 20 compounds, are pharmacologically active and are char Wherein D is the residue of a centrally acting primary, acterized by site-specific and sustained delivery to the secondary or tertiary amine, and brain when administered via the corresponding dihy dropyridine form. The new quaternary salts are charac terized by the structural formula 25 -O (II) is a radical of the formula

wherein D is defined as with formula (I), X is the anion of a non-toxic pharmaceutically acceptable acid and

35

is a radical of the formula

3 N (R)n or (d) 45 wherein the dotted line in formula (a) indicates the presence of a double bond in either the 4 or 5 position of (R) (R) (R) the dihydropyridine ring; the dotted line in formula (b) (a) (b) (c) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system; m is zero 50 wherein n, p, q and R are defined as with formula (I). or one; n is zero, one or two; p is zero, one or two, Briefly then, the present invention features a dihy provided that when p is one or two, each R in formula dropyridine-pyridinium salt redox system for the spe (b) can be located on either of the two fused rings; q is cific and sustained delivery of a centrally acting drug to zero, one, or two, provided that when q is one or two, 55 each Rin formula (c) can be located on either of the two the brain according to the following Scheme 2:

SCHEME 2. P-O (I) ADMINISTRATION 4,771,059 9 10 -continued SCHEME 2. - Sa - K Sa BLOOD & OHER TISSUES S. DISTRIBUTION S- BRAIN K6 OXIDATION BBB K3 OXIDATION

d-a-N- ) X- (II) D-O X- (II). / N. / N. ExcRETION METABOLISM EXCRETION METABOLISM Ks > K7 Ks >> Ks Scheme 2 shows the expected sequence of events following administration of a compound of formula (I). Due to its lipophilic nature, the dihydropyridine com pound of formula (I) will distribute throughout the 20 carbon atoms and bearing one or more halo substituents body and has easy access to the brain through the (F, Cl, Br or I), which can be the same or different. .. blood-brain barrier. Upon oxidation, which occurs Preferably, when Rishaloalkyl, the group contains 1 or throughout the body, the formula (I) compound will be 2 carbon atoms and bears l to 3 halogen substituents, converted to the corresponding quaternary of formula e.g. chloromethyl or trifluoromethyl. (II). The quaternary form will be "locked" preferen 25 The term "C-C7 alkylthio" includes straight and tially in the brain, since it can be excreted easily periph erally, but cannot move readily through the BBB. Sus branched chain radicals of the type tained levels of the formula (II) quaternary will be pres ent at the site of action, the brain, resulting in longer duration of action. wherein C-C, alkyl is defined as before. When R is 30 alkylthio, it is preferably methylthio. DETAILED DESCRIPTION OF THE The terms "C-C, alkylsulfinyl" and "C-C, alkylsul INVENTION fonyl" designate radicals of the formulas. More particularly in accord with the present inven tion, the following definitions are applicable: (C-C7 alkyl)-SO The term "lipoidal" as used herein is intended to 35 mean lipid-soluble or lipophilic. W and The term "halo" encompasses fluoro, chloro, bromo (C-C7 alkyl)-SO2-, and iodo. The term "C1-C, alkyl" includes straight and respectively, wherein C1-C, alkyl is defined as before. branched lower alkyl radicals having up to seven car When R is alkylsulfinyl or alkylsulfonyl, methylsulfinyl bonatoms. When R, R", R', and/or R'' are C1-C7 alkyl, and methylsulfonyl are preferred...... they are preferably methyl or ethyl. When R is -CH=NOR", it is preferably -CH The term "C-C7 alkoxy” includes straight and NOH When Ris-CONR'R'', is is preferably -CONH2 or . branched chain lower alkoxy radicals having up to 45 seven carbon atoms. When R is C1-C7 alkoxy, it is pref -CONCCH3)2. w ... erably methoxy or ethoxy. The expression "hydroxyl protective group" as used The term "C-C8 alkoxycarbonyl" designates hereinbefore is intended to designate a group which is inserted in place of the hydrogen aton(s) of a OH group. straight and branched chain radicals of the formula or groups in order to prevent premature metabolism of SO said OH group or groups prior to the compound's reaching the desired site in the body. Typical hydroxyl (C-C, alkyl)-o-c- protective groups contemplated by the present inven tion are acyl groups and carbonates. wherein the C1-C7 alkyl group is defined as above. When the hydroxyl protective group is acyl (i.e., When Risalkoxycarbonyl, it is preferably ethoxycarbo 55 when it is an organic radical derived from a carboxylic nyl or isopropoxycarbonyi. . acid by removal of the hydroxyl group), it preferably The term "C2-C8 alkanoyloxy" designates straight represents an acyl radical selected from the group con and branched chain radicals of the formula sisting of alkanoyl having 2 to 8 carbon atoms; alkenoyl having one or two double bonds and 3 to 8 carbon atons; (C-C alkyl)-C-O- wherein the C-C7 alkyl group is defined as above. cycloalkyl-CH2-C- When R is alkanoyloxy it is preferably acetoxy, pivaly 65 loxy or isobutryloxy. wherein the cycloalkyl portion contains 3 to 7 ring The term "C-C7 haloalkyl" designates straight and atoms and r is zero, one, two or three; phenoxyacetyl; branched chain lower alkyl radicals having up to seven pyridinecarbonyl; and 4,771,059 11 12 chloro-4-acetamidophenylacetyl, p-n-butoxybenzoyl, O 2,4,6-triethoxybenzoyl, (3-(p-trifluoromethylphenyl)- propionyl, 2-methyl-4-methoxybenzoyl, p-acetamido phenyl-CH2-C- phenylpropionyl, and 3-chloro-4-ethoxybenzoyl. wherein r is zero, one, two or three and phenyl is unsub When the hydroxyl protective group is a carbonate stituted or is substituted by l to 3 alkyl each having 1 to grouping, it has the structural formula 4 carbon atoms, alkoxy having 1 to 4 carbon atons, halo, trifluoromethyl, dialkylamino having 2 to 8 car O bon atoms or alkanoylamino having 2 to 6 carbon 10 Y'am Osas C atOS. When the acyl group is alkanoyl, there are included i.e., it is an organic radical which can be considered to both unbranched and branched alkanoyl, for example, acetyl, propionyl, butyryl, isobutyryl, Valeryl, isovale be derived from a carbonic acid by removal of the hy ryl, 2-methylbutanoyl, pivalyl (pivaloyl), 3-methylpen droxyl group from the COOH portion. Y' preferably tanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl 15 represents alkyl having 1 to 7 carbon atoms; alkenyl and the like. Pivaly, isobutyryl and isovaleryl are espe having one or two double bonds and 2 to 7 carbon cially preferred. atons; When the acyl group is alkenoyl, there are included, cycloalkyl-CH2 for example, crotonyl, 2,5-hexadienoyl and 3,6-Octadi 20 enoyl. wherein the cycloalkyl portion contains 3 to 7 ring When the acyl group is atoms and r is zero, one, two or three; phenoxy; 2-, 3-, or 4-pyridyl; or cycloalkyi-CH2-C-, phenyl-CH2 there are included cycloalkanecarbonyi and cycloalk wherein r is zero, one, two or three and phenyl is unsub anealkanoyl groups wherein the cycloalkane portion stituted or is substituted by 1 to 3 alkyl each having 1 to can optionally bear 1 or 2 alkyl groups as substituents, 4 carbon atoms, alkoxy having 1 to 4 carbon atons, e.g. cyclopropanecarbonyl, 1-methylcyclopropanecar 30 halo, trifluoromethyl, dialkylanino having 2 to 8 car bonyl, cyclopropaneacetyl, a-methylcyclopropanea bon atoms or alkanoylamino having 2 to 6 carbon cetyl, 1-methylcylopropaneacetyl, cyclopropanepro atoms. Most preferably, Y" is C1-C7 alkyl, particularly pionyl, a-methylcyclopropanepropionyl, 2-isobutylcy ethyl or isopropyl. clopropanepropionyl, cyclobutanecarbonyl, 3,3-dime Similarly, the expression "carboxyl protective thylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2- 35 group" as used hereinbelow is intended to designate a dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecar group which is inserted in place of the hydrogen bonyl, cyclohexaneacetyl, cyclohexanecarbonyl, cy atoms(s) of a COOH group or groups in order to pre cloheptanecarbonyl and cycloheptanepropionyl. Cy vent premature metabolism of said COOH group or clohexanecarbonyl is especially preferred. groups prior to the compound's reaching the desire site When the acyl group is pyridinecarbonyl, there are in the body. Typical carboxyl protective groups are the included picolinoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl) and isonicotinoyl (4-pyridinecar groups encompassed by Y." above, especially C1-C7 bonyl). alkyl, particularly ethyl, isopropyl and t-butyl. While When the acyl group is such simple alkyl esters and the like are often useful, 45 other carboxyl protecting groups may be selected in order to achieve greater control over the rate of in vivo hydrolysis of the ester back to the acid and thus enhance phenyl-CH-C-, drug delivery. To that end, carboxyl protecting groups such as the following may be used to replace the hydro there are included, for example, benzoyl, phenylacetyl, 50 gen of the -COOH group: a-phenylpropionyl, g-phenylpropionyl, p-toluyl, n-tol uyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4- dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6- -chi- (-CH, trimethylbenzoyl, m-methylphenylacetyl, p-isobutyl O-O phenylacetyl, g-(p-ethylphenyl)propionyl, p-anisoyl, SS C m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxy O phenylacetyl, m-isobutoxyphenylacetyl, m-die thylaminobenzoyl, 3-methoxy-4-ethoxybenzoyl, 3,4,5- trimethoxybenzoyl, p-dibutylaminobenzoyl, 3,4-die -alk-OC-alkyl, thoxyphenylacetyl, 6-(3,4,5-trimethoxyphenyl)propio nyl, o-iodobenzoyl, m-bronobenzoyl, p-chlorobenzoyl, O p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-tri -alk-OCO-alkyl or chlorobenzoyl, p-chlorophenylacetyl, a-(n-bromo phenyl)propionyl, p-trifluoromethylbenzoyl, 2,4-di(tri -alk-O-alkyl, fluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, 65 £3-(3-methyl-4-chlorophenyl)propionyl, p-dime wherein alk is C1-C6 straight or branched alkylene and thylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, the alkyl radical is straight or branched and contains 1 o-acetamidobenzoyl, m-propionamidobenzoyl, 3 to 7 carbon atoms 4,771,059 13 14 - sive; bacampicillin and pivampicillin, which are penicil lin-type antibiotics; ceforanide and cefroxadine, which are cephalosporin-type antibiotics; and 6EI(hydrox (e.g. -Hocochsch, yimino)phenyl)methyl)-1-((methylethyl)sulfonyl)-1H CH benzinidazol-2-amine, an antiviral agent. Exemplary centrally acting secondary amines in ac O CH3 / cord with this invention and the classes of drugs of which they are representative are as follows: nitoxan -choc–cch, and -CH2OCH3). trone, an anticancer/antitumor agent; epinephrine, an . CH3 O adrenergic agent; , a sympathomimetic By "centrally acting primary, secondary or tertiary amine/decongestant; noracymethadol, a narcotic anal annine" as used herein there is intended any drug species gesic of the -type; piminodine, a narcotic or the like which contains a primary amino, secondary analgesic of the meperidine-type; tracazolate, a sedati amino or tertiary amino function, a significant (usually, ve/hypnotic; tiletamine, an ; proprano principal) pharmacological activity of which is CNS 15 lol, , , and , which are and a result of direct action in the brain. The term g-blockers; prizidilol, a centrally acting hypotensive; "drug" as used herein means any substance intended for , a sedative/muscle relaxant which struc use in the diagnosis, cure, mitigation, treatment or pre turally is an analogue of the tranquilizers; vention of disease or in the enhancement of desirable , a tranquilizer of the physical or mental development and conditions in man 20 type; methamphetamine, fencamfamin, fenozolone and or animal. zylofuramine, which are sympathomimetic... amines/- Exemplary such centrally acting primary amines are cerebral stimulants; , , octrip sympathetic stimulants and related nervous system tyline, andmaprotiline, which are cerebral agents, e.g., phenylethylamine (a stimulant), stimulants/ of the dibenzaze (a neurotransmitter and dopaminergic agent used, e.g., 25 pine-type; amedalin, , cartazolate, daledalin, in the treatment of Parkinsonism or hyperprolac difluanine, fluxoetine and nisoxetine, which also are tinemia), tyramine (a stimulant), L-DOPA (a dopamine cerebral stimulants; bethanidine, a hypotensive; and precursor used, for example, in the treatment of Parkin and , which are sympatho sonism); narcotic analgesics; other stimulants; small ... peptides, such as the di-, tri-, tetra- and pentapeptides, mimeticExemplary amines. such centrally acting tertiary amines- - - - - and- - - and other small 2-20 amino acid unit containing pep the classes of drugs of which they are representative are tides, e.g., the enkephalins (for example, Tyr-Gly-Gly as follows: methadone, levomethadyl acetate, dex Phe-Leu), which, besides being analgesics, initiate epi tromoramide, propoxyphene, carbiphene and pyrroli leptic activity in the brain at doses that are about tenfold phine, which are narcotic analgesics of the methadone lower than for effecting analgesic activity; larger pep 35 type; phenampromide and tilidine, which are narcotic tides, such as pituitary hormones and related agents; analgesics of the meperidine-type; methotrimeprazine, growth-promoting substances; -like drugs; which is a phenothiazine analgesic; and perla - anticancer and anti-Parkinsonism agents; antihyperten pine, which are sedatives/hypnotics/anticonvulsants of sives; agents to enhance learing capacity and the mem the benzodiazepine-type; cloperidone, a sedative/hyp ory processes, including treatment of dementias, such as notic of the quinazolone-type; atolide, an anticonvul - Alzheimer's disease; antibacterials; monoamine oxidase sant; guanethidine, a hypotensive; chlor (MAO) inhibitor drugs; CNS or brain important/essen , , , trifluopera tial amino acids, such as (which is an antide pressant as well as a nutrient); and any like centrally zine, promazine, , acepromazine, aceto acting primary amines. 45 phenazine, , carphenazine, fluiphenazine, . Other illustrative ultimate species of centrally active , , and drug entities containing a primary amino group and the palmitate, which are tranquilizers/antip classes of drugs of which they are representative are as sychotics of the phenothiazine-type, a number of which follows: amphetamine, dextroamphetamine, levan are also useful as sedatives (e.g. , propis. . phetamine, aletanine, cypenamine and phentermine, 50 omazine, periphenazine and ); chlorpro which are sympathomimetic amines/cerebral stimulants thixine, a thioxanthine calming agent which structurally and appetite Suppressants; etryptamine, a cerebral stin is an analogue of the phenothiazine tranquilizers; thio ulant; anilleridine, which is a narcotic analgesic; methyl thixine, a thioxanthine alerting agent (used, e.g., in dopa, which is a sympatholytic agent used, e.g., in hy chronic withdrawn schizophrenia) which structurally is pertension; , a sympathomimetic cere 55 an analogue of the phenothiazine tranquilizers; bral stimulant/MAO inhibitor and ; nor and , tricyclic antidepressants which structur epinephrine, a sympathetic stimulant/adrenergic agent; ally are dibenzoxapine analogues of the phenothiazine. hydralazine, a hypotensive; amoxicillin and ampicillin, tranquilizers; , a tranquilizer/ which are penicillin-type antibiotics; guanethidine, a (used, e.g., in treating chronic and acute schizophrenia). hypotensive/sympatholytic; GABA, y-vinyl GABA which structurally is an analogue of the phenothiazine and y-acetylenic GABA, neurotransmitters for possible : tranquilizers; clomacran, clopenthixoland clothiapine, use in epilepsy; doxorubicin and daunamycin, antican which are which structurally are ana cer/antitumor agents; cephalexin, a cephalosporin anti logues of the phenothiazine tranquilizers; clozapine, biotic; ACTH (corticotropin); LH-RH, a neurotrans dimeprozan, periapine and , which also are mitter; nephalan, a nitrogen mustard-type anticancer 65 analogues of the phenothiazine tranquilizers and are /antitumor agents; DON, an anticancer urea derivative; variously used as sedatives, hypnotics and tranquilizers; ninustine, an anticancer/antitumor nitrosourea deriva , an antipsychotic; flurazepam, adinazo tive; amiphenazole, a stimulant; debrisoquin, a hypoten lam, and , sedatives of the ben 4,771,059 15 16 zodiazepine-type, some of which are also used as hyp anine-type cerebral stimulants and the tricyclic antide notics; doxapram, a medullary stimulant; dimethazan, a pressants, especially preferred being the xanthine-type cerebral stimulant; prolintane and and dibenzoxapines and their analogues. thozalinone, sympathomimetic amine-type cerebral Also illustrative of the centrally acting drug species stimulants; gamfexine, a cerebral stimulant of the diphe containing primary, secondary or tertiary amine groups nylmethane analogue type; , a muscle contemplated by this invention are centrally active relaxant; clodazon, an antidepressant; , metabolites of centrally acting drugs. Such metabolites , , doxepin, cidoxepin, , are typified by hydroxylated metabolites of tricyclic , , , , antidepressants, such as the E- and Z-isomers of 1 dothiepin, , ketipramine, and 10 hydroxynortriptyline, 2-hydroxyimipramine, 2-hydrox , which are tricyclic antidepressants/cere ydesipramine and 8-hydroxychloripramine; and hy bral stimulants of the -type (i.e. diben droxylated metabolites of phenothiazine tranquilizers, zazepines and their analogues such as dibenzoxepines), e.g. 7-hydroxychlorpromazine. Other CNS active me all of which can be considered as analogues of the phe tabolites for use herein will be apparent to those skilled nothiazine tranquilizers; and cyclindole, difluamine, 15 in the art. Typically, these CNS active metabolites have fantridone, flubanilate, , modaline, piranda been identified as such in the scientific literature but mine, pyrovalerone, , thiazesin, have not been administered as drugs themselves. In and trebenzonine, which also are cerebral stimulants. many cases, the active metabolites are believed to be Preferred classes of centrally acting primary, second comparable in CNS activity to their parent drugs; fre ary and tertiary amines encompassed hereby are the 20 quently, however, the metabolites have not been admin central neurotransmitters, anticancer and antitumor istered per se because they are not themselves able to agents, antiviral agents, memory enhancers, hypoten penetrate the blood-brain barrier, sives, sedatives, tranquilizers, antipsychotics, narcotic As indicated hereinabove, diagnostic agents, includ analgesics and cerebral stimulants, especially preferred ing radiopharmaceuticals, are encompassed by the ex cerebral stimulants being the tricyclic antidepressants. 25 pression "centrally acting drug" or the like as used Among the neurotransmitters, there can be mentioned herein. Any diagnostic agent which can be derivatized amino acids, such as GABA, GABA derivatives and to afford a compound of formula (I) which will pene other omega-amino acids, as well as glycine, glutamic trate the BBB and concentrate in the brain in its quater acid, tyrosine, aspartic acid and other natural anino nary form (II) and can be detected therein is encom acids; catecholamines, such as dopamine and norepi 30 passed by this invention. The diagnostic may be "cold" nephrine; , and ; and pep and be detected by X-ray (e.g. radiopaque agents) or tides such as neurotensin, luteinizing hormone-releasing other means such as mass spectrophotometry, NMR or hormone (LHRH), somatostatin, enkephalins such as other non-invasive techniques (e.g. when the compound met-enkephalin and leu-enkephalin, endorphins such includes stable isotopes such as C 13, N 15, O 18, S 33 as y-, a- and B-endorphins, and vasopressin. Synthetic 35 and S 34). The diagnostic alternatively may be "hot", and semi-synthetic analogues, e.g. analogues of LHRH i.e. radiolabeled, such as with radioactive iodine (I 123, in which one or more amino acid(s) has/have been I 125, I 131) and detected/imaged by radiation detec eliminated and/or replaced with one or more different tion/imaging means. Typical radiolabeled diagnostics amino acid(s), and which may be or antago include diotyrosine (I 125, I 131), p-iodo-N-iso nists, are also contemplated, e.g. the primary and sec propylamphetamine (I 123), iotyrosine (I 131) and ondary amine LHRH analogues disclosed in U.S. Pat. iodonetaraminol (I 123), which has the structural for No. 4,377,574, 3,917,825, 4,034,082 and 4,338,305. Among the anticancer and antitumor agents, there can mula be mentioned L-alanosine, DON, bactobolin, acivicin, melphalan, adriamycin (doxorubicin), daunomycin, 45 th. mitoxantrone and nimustine. Among the antiviral HO CHCHNH2. agents, there can be mentioned anantadine (also of possible value as an anti-Parkinsonism agent); OH diarylamidines such as 5-amidino-2-(5-amidino-2-ben I zofuranyl)indole and 4,6-diimidazolino-2-phenylben 50 zo(b)thiophen; 2-amino-oxazoles such as 2-guanidino Yet other radiolabeled diagnostics include p-iodophene 4,5-di-n-propyloxazole and 2-quanidino-4,5-diphenylox thylamine and p-iodobenzylamine (labeled, e.g. with I azole; benzinidazole analogues such as the syn and anti 123 or I 125). In the case of diagnostics, as in the case of isomers of 6(hydroxyinino)phenyl)methyl)-1-(1- drugs which are for the treatment of disease, the methylethyl)sulfonyl)-1H-benzimidazol-2-amine; and 55 "locked in' quaternary form will be the form that is glycosides such as glucosamine and 6-amino-6-deoxy imaged or otherwise detected, not the original diagnos D-glucose. Among the hypotensives, there can be men tic itself. Moreover, any of the centrally acting drugs tioned , debrisoquin, hydralazine, and gua encompassed by this invention which are intended for nethidine and its analogues. Among the sedatives, tran the treatment or prevention of medical disorders but quilizers and antipsychotics, there can be mentioned the which can be radiolabeled, e.g. with a radioisotope such many specific compounds of this type already disclosed as iodine, or labeled with a stable isotope, can thus be above, especially the and benzodiaze converted to a diagnostic for use herein. Put another pines and their analogues. Among the narcotic analge way, any compound of formula (I) of this invention sics, there can be mentioned in particular the metha which can have incorporated into its structure such a done-type and meperidine-type compounds specified 65 radioactive or stable isotope either directly or through hereinabove. Among the cerebral stimulants, there can incorporation of the isotope into the structure of the also be mentioned the many specific compounds set corresponding compound of formula (II) can be used forth hereinabove, particularly the sympathomimetic for diagnostic purposes. 4,771,059 17 18 It will be apparent from the known structure of the many drug species exemplified above, the in many cases the selected drug will possess more than one reactive functional group, and, in particular, that the drug may contain hydroxyl or carboxyl, or other functional groups in addition to the amino group or groups which is/are to be replaced with the redox system, and that these additional groups will at times benefit from being protected during synthesis and/or during administra Similarly, and epinephrine, which are tion. The nature of such protection is described in more O adrenergic agents and have a primary amino group and detail below. Obviously, such protected drug species a secondary amino group, respectively, share the same are encompassed by the definition of "drug' set forth residue, i.e...... hereinabove.

By "residue of a centrally acting primary, secondary 5 Yo. gh or tertiary amine" as used herein there is meant that CHCH portion of the centrally acting amine which would re main after removal of the respective primary, second ary or tertiary annino group therefron, e.g., in the case Yo of phenethylamine, which has the structural formula wherein each Y is defined as above. As a further exam ple, one can mention the tertiary amine phenothiazine tranquilizers/antipsychotics, acepromazine and aceto phenazine, which have the structures - CHCH;NH2, 25 the corresponding residue would be 30 CO CHCH-. and .

In the case of centrally acting amines which also con 35 tain one or more hydroxy groups and/or one or more lic carboxy functions, the residue thereof may contain one * ... or more of those hydroxy and/or carboxy functions in ... protected form. Thus, for example, when the centrally acting primary annine is levodopa, which has the struc I tural formula Cric respectively, and which have the same residue, i.e.

HO CH-CH-NH2, (HCHCH- ". . COOH Ho the corresponding residue would be CDC SO It will also be apparent from the foregoing that the YO CH-gH exact structure of the amino function in the centrally acting amine/parent drug is immaterial insofar as con COOY cerns the structure of the instant compounds of formu Yo 55 las (I) and (II), for in formulas (I) and (II) the entire amino function in the parent drug has been replaced wherein each Y is hydrogen or a hydroxyl protective with a dihydropyridine/pyridinium salt redox system. group as defined hereinabove (typically, acyl or carbon Thus, virtually any centrally acting primary amine ate) and Y" is hydrogen or a carboxyl protective group D-NH2, secondary amine D-NHR or tertiary amine as defined hereinabove (typically, C1-C, alkyl). D-NR2R3 can provide the drug residue. D- in the It will be apparent from the foregoing that different instant compounds. Without being limited to specific centrally acting primary, secondary and/or tertiary definitions of the R, R2 and R3 groups in the secondary amines may have the same residue as defined herein and and tertiary amines, the following definitions of illustra as represented by D in formulas (I) and (II). Thus, for tive radicals are given: example, desipramine, which is a tricyclic antidepres 65 R can be alkyl, preferably C1-Cio alkyl; cycloalkyl, Sant having a secondary amine function, and imipra preferably C3-C8 cycloalkyl; alkenyl, preferably nine, which is a having a ter C2-Cto alkenyl; cycloalkenyl, preferably C3-C8 cy tiary amine function, both have the same residue, i.e. cloalkenyl; or aryl, preferably C6-C10 aryl, particularly 4,771,059 19 20 phenyl. Any of the foregoing R radicals can optionally di(lower alkyl)amino; N-lower alkyl-N-benzylamino: be substituted by one or more (typically l to 3) substitu N-lower alkyl-N-phenethylamino; piperidino: pyrroli ents which may be the same or different. Possible sub din-1-yl; piperazin-1-yl; morpholino; piperidino substi stituents on the alkyl and alkenyl radicals include C6-C10 aryl; hydroxy; hydroxy(lower alkyl)amino; Sub tuted in the 4-position by hydroxy-substituted lower stituted C6-C10 aryl wherein the substituent(s) is/are alkyl, C2-C20 alkanoyloxy-substituted lower alkyl, car selected from the aryl substituents defined below; bamoyl or piperidino; and piperazin-1-yl substituted in C3-C8 cycloalkyl; substituted C3-C8 cycloalkyl wherein the 4-position by lower alkyl, C2-C20 alkanoyloxy-sub the substituent(s) is/are selected from the cycloalkyl stituted lower alkyl, lower monoalkylcarbamoyl-sub substituents defined below; halo; lower alkoxy; lower O stituted lower alkyl, hydroxy-substituted lower alkyl, alkylthio; lower alkylsulfinyl; lower alkylsulfonyl; phenylamino-substituted lower alkyl or halophenyl. Expecially preferred -NR2R3 groupings include di methylamino, 4-(2-phenylamino)ethyl)piperazin-1-yl, piperidino, pyrrolidin-1-yl, 4-(3'-chlorophenyl)pipera -NHC(C-Clo alkyl); and -OC(C1-C10 alkyl). 15 zin-1-yl, 4-methylpiperazin-1-yl, 4-(2'-hydroxyethyl)- Possible substituents on the aryl radicals include lower piperidino, 4-(2-hexadecanoyloxy)ethyl)piperidino, alkyl, halo, lower alkoxy, carbamoyl, lower alkoxycar 4-(2'-hydroxyethyl)piperazin-1-yl, 4-2'-(N-methylcar bonyl, lower alkanoyloxy, lower haloalkyl, mono(- bamoyl)ethyl)piperazin-1-yl, piperazin-1-yl, (N-benzyl lower alkyl)amino, di(lower alkyl)amino, mono(lower N-methyl)amino, diethylamino, morpholino, (4-car alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl bamoyl-4-piperidino)piperidino, (N-methyl-N-phene and lower alkysulfonyl. Possible cycloalkyl substituents thyl)amino and 4-(2'-acetoxyethyl)piperazin-1-yl. include lower alkyl; C6-C10 aryl; substituted lower The expression "non-toxic pharmaceutically accept alkyl wherein the substituent(s) can be any of the alkyl substituents defined above; substituted C6-C10 aryl able salts' as used herein generally includes the non wherein the substituent(s) can be any of the aryl substit 25 toxic salts of compounds of formula (I) formed with uents defined above; halo; lower alkoxy; lower alkyl nontoxic, pharmaceutically acceptable inorganic or thio; lower alkylsulfinyl; lower alkylsulfonyl; organic acids HX. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and 30 the like; and the salts prepared from organic acids such -NHC(C1-Clo alkyl); and -OC(C1-C10 alkyl). as acetic, propionic, succinic, glycolic, Stearic, lactic, Preferred secondary amino groups -NHR are lower malic, tartaric, citric, ascorbic, panoic, maleic, hydrox alkylamino unsubstituted or substituted by hydroxy or ymaleic, phenylacetic, glutamic, benzoic, salicylic, sul hydroxy(lower alkyl)amino and phenylamino. Particu 35 fanilic, funaric, methanesulfonic, toluenesulfonic and larly preferred secondary amino groups include me the like. The expression "anion of a non-toxic pharma thylamino, phenylamino, tert-butylamino, iso ceutically acceptable acid" as used herein, e.g. in con propylamino, n-butylamino, ethylamino, 2-hydroxye nection with structure (II), is intended to include anions thylamino and 2-(2'-hydroxyethylamino)ethylamino. of such inorganic or organic acids HX. R2 and R3, which can be the same or different, can It too will be appreciated that the radical represented each be any one of the R radicals defined above, or R2 by and R3 can be combined such that -NR2R3 represents a saturated monocyclic tertiary amino group, prefera bly derived from a secondary amine monocycle having 5 to 7 ring atoms, optionally containing another hetero 45 aton (-O-, -S- or -N-) in addition to the indi cated nitrogen atom, and optionally bearing one or -O more (typically l to 3) substituents such as lower alkyl, in formula (I) must enable the compound of formula (I) Substituted lower alkyl, C6-C10 aryl, substituted C6-C10 to penetrate the BBB and must also be capable of being aryl, saturated monocyclic tertiary amino and carbam 50 oyl. The substituted lower alkyl groups include alkyl oxidized in vivo to the corresponding quaternary struc groups substituted by one or more (typically 1 to 3) ture. The ionic entity which results from such in vivo C6-C10 arylamino, hydroxy, C2-C20 akanoyloxy, oxidation is prevented from efflux from the brain, while mono(lower alkyl)carbamoyl, C6-C10 aryl or any of the elimination from the general circulation is accelerated. other alkyl substituents defined in connection with R. 55 In contradistinction to the drug-carrier entities dis above. The substituted aryl groups include aryl groups closed, for example, in Science, Vol 214, December 18, substituted by one or more (typically 1 to 3) substituents 1981, pp. 1370-1372, however, there is no readily meta which can be halo or any of the other aryl substituents bolically cleavable bond between drug and quaternary defined in connection with R1 above. Illustrative of portions, and the active species delivered in the present saturated monocyclic tertiary amine groups encom 60 passed by the -NR2R3 term are morpholino, 1-pyr case is not the original drug from which the compound rolidinyl, 4-benzyl-l-piperazinyl, perhydro-1,2,4-oxa of formula (I) was derived, but rather is the formula (II) thiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, quaternary itself. piperidino, hexamethyleneimino, 4-phenylpiperidino, It will also be appreciated that a compound of for 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-meth 65 mula (I) may be administered as the free base or in the yl-l-imidazolidinyl, l- or 3-imidazolidinyl, 4-benzyl form of a non-toxic pharmaceutically acceptable salt piperidino and 4-phenyl-1-piperazinyl. Preferred ter thereof, i.e. a salt which can be represented by the for tiary amine groups encompassed by -NR2R3 include mula 4,771,059 21 22 D-Ox SCHEME 3 wherein D, CONH; O O?ci N-- and HX are defined as before; and that, regardless of the actual form in which the compound is administered, it NO will be converted in vivo to a quaternary salt of formula 5 (II), the anion X-being present in vivo. It is not neces sary that the anion be introduced as part of the con pound administered. Indeed, even when the compound --NO2 (Zincke reagent) - iethylamiEse of formula (I) is used in its salt form, the anion of the OH methano formula (II) compound is not necessarily the same as 20 that present in the formula (I) compound. Indeed, the OH exact identity of the anionic portion of the compound of formula (II) is immaterial to the in vivo transformation of (I) to (II). - In a presently preferred embodiment of the present 25 GH: invention, the centrally acting amine of which D is the residue is dopamine and the instant redox system is thus (H. designed to elicit a sustained and brain-specific dopam NH2.HBr inergic (e.g. anti-Parkinsonism or anti-hyperprolac 30 tinemia) response in the animal to which the formula (I) derivative is administered; it is believed that this effect is achieved via in vivo conversion of the formula (I)

compound to the pharmacologically active formula (II) CONH; quaternary, which is essentially "locked in" the brain. 35 In analogous fashion, the instant redox system I-II in C which D is the residue of any other centrally acting primary, secondary or tertiary amine is designed to Na2S2O4. elicit the kind of pharmacological response which sists H: would be obtained by delivery of the primary, second ethyl : ary or tertiary amine itself to the brain, i.e. when the acetate. centrally acting amine/parent drug is an antitumor/an ticancer agent, the instant redox system is employed to elicit an antitumor/anticancer response; when the par OH ent drug is a sympathetic stimulant, the instant redox 45 system is used to elicit a sympathetic stimulant or am H phetamine-like response; when the parent drug is pivaloyl chloride GABA or a related compound, the instant redox system trifluoroacetic is used to elicit an antiepileptic/anticonvulsant or anal acid gesic response; when the parent drug is a tranquilizer, 50 the instant system is used to elicit a tranquilizing re sponse; when the parent drug is an antidepressant, the instant system is used to elicit an antidepressant re sponse; and so forth. CONH2 With respect to the preferred embodiment referred to 55 CFCO2 above, with dopamine as the parent amine, the catechol moiety thereof in certain instances being acylated, e.g. Na2S2O4. acetylated or pivalylated, and selecting NaHCO,ethyl : se 60 aceae CONH2

OCOC(CH3)3 OCOC(CH3)3 65 OCOC(CH3)3 ÖCOC(CH3); the following reaction scheme has been devised for preparation of the formula (I) analogues: 4,771,059 25 26 tants, solvents, reaction conditions, etc. (e.g. using an (I) is usually insoluble in water and thus can be readily anhydride rather than an acyl halide for the acylation separated from the reaction medium. In the case of step, or preparing a different acyl derivative, e.g. the sodium borohydride reduction, an organic reaction acetyl rather than the pivalyl derivative, or using a medium is employed, e.g., a lower alkanol such as meth different Zincke reagent for the exchange reaction) will anol, an aqueous aikanol or other protic Solvent. be readily apparent to those skilled in the art. Also, When a Zincke reagent is utilized in the reaction insofar as concerns the quaternary compounds, when an sequence, e.g. when Scheme 3 is employed, such rea anion different from the one obtained is desired, the gent can be prepared by reacting 1-chloro-2,4-dinitro anion in the quaternary salt may be subjected to anion benzene with a compound of the formula exchange via an anion exchange resin or, more conve O niently, by use of the method of Kaminski et al, Tetrahe H H dron, Vol. 34, pp. 2857-2859 (1978). According to the N N Kaminski et al method, a methanolic solution of an HX acid will react with a quaternary ammonium halide to O produce the methyl halide and the corresponding qua ternary X salt. Moreover, the manner in which the ultimate compound is prepared should be tailored to the (R) (R) presence of any other reactive groups in the molecule. For example, when the parent amine contains one or more carboxy functions, such functions will typically be HN esterified, e.g. converted to the corresponding ethyl ester, or otherwise suitably protected, usually prior to formation of the quaternary compound. Thus, a wide (R) variety of synthetic approaches can be utilized, depend ing on the desired structure of the final product. 25 wherein R, n, p and q are defined as with formula (I), to The process exemplified in Scheme 3, i.e. reacting a afford the corresponding Zincke reagent of the formula starting material containing an -NH2 group with a Zincke reagent, can be used to derive the instant com pounds wherein D is the residue of a centrally acting primary amine directly from the corresponding cen 30 (R) (R) trally acting primary amine/parent drugs. However, if it is desired to prepare the instant compounds wherein D is the residue of a centrally acting secondary or ter tiary amine via the process shown in Scheme 3, then one N-- N+ will not use the parent secondary or tertiary amine as 35 C- NO Cl- or the starting material but would instead use the corre sponding primary annine as the starting material. Alter O NO2 natively, a compound of the formula D-Hall 40 NO NO2 wherein Hal is chloro or brono and D is the residue of (R) a centrally acting primary, secondary or tertiary amine can be reacted with nicotinamide or the like (as de picted in Scheme 4) to afford to desired compounds of 45 N the invention, regardless of whether the parent drug is a primary, secondary or tertiary annine. NO2 Cl-, Various illustrative synthetic schemes as applied to specific compounds of the invention are set forth below in the section entitled "Illustrative Synthetic Methods'. 50 While the sequence of reaction steps can be varied in NO2 many cases, in general the final step (except in the case of optional salt formation or possibly in the case of respectively. Thus, for example, the specific Zincke radiolabeling) will be reduction of a quaternary com reagent depicted in Scheme 3 can be prepared by react pound of formula (II) to the corresponding dihydro 55 ing nicotinamide with 1-chloro-2,4-dinitrobenzene. See compound of formula (I). The reduction is usually con also Zincke et al, Annalen, 1904, 333, 296; Lettré, An ducted at a temperature from about -10' C. to room malen, 1953, 579, 123; Keijzer et al, Hetrocycles, Vol. 16, temperature, for a period of time from about 10 minutes No. 10, 1981, 1687. to 2 hours, conveniently at atmospheric pressure. Typi In the case of radiodiagnostics, the synthetic method cally, a large excess of reducing agent is employed, e.g., of choice generally involves introducing the radioactive a 1:5 molar ratio of reducing agent to starting com element toward the end of the reaction sequence, rather pound of formula (II). The process is conducted in the than using the radiolabeled parent drug itself as the presence of a suitable reducing agent, preferably an starting material. Schemes 5 and 6 below are illustrative alkali metal dithionite such as sodium dithionite or an of such instances of tailoring chemical synthesis to the alkali metal borohydride such as sodium borohydride or 65 particular drug involved. Scheme 5 depicts synthesis of aluminum borohydride, in a suitable solvent. an analogue of I. 123 labeled materaminoli; Scheme 6 Sodium dithionite reduction is conveniently carried out depicts a synthetic route to radioiodinagted benzyl in an aqueous solution; the dihydro product of formula amine and phenethylamine analogues. 4,771,059 23 24 -continued -continued SCHEME 3 SCHEME 3 OH CONH2 OH

N N Na2S2O4. CH2 (H. side H. CH2 ethyl CH CH O acetae 12 . NH2.HBr

pivaloyltrifluoroacetic chloride acid OCOC(CH(CH3)3 OCOC(CH3); maleic acid 15 OCOC(CH3)3 OCOC(CH3)3 An alternate reaction Scheme for preparation of the dopamine analogues is depicted below.

SCHEME 4 OH CONH CONH NH OH - O 2 () 2 r" 2 N N *N Bral- silie N th: CH2 ethyl CH2 CH2 CH2 acetate th. Br OH OH OH OH, pivaloyl chloride trifluoroacetic acid OCOC(CH3)3 CONH; CONH2. OCOC(CH3)3 CONH2 . . . -- G N R- Na2S2O4. G. N N Br NaHCO3 w CH2 ethyl CH2 CH2 acetate CH2 CH2

CH2 Br OCOC(CH3); C OCOC(CH3)3 OCOC(CH3)3 OCOC(CH3)3 Similar schemes can be shown for the preparation of the other compounds of the invention. The acylation step, which introduces the hydroxyl protecting groups, 55 is only needed when there are hydroxyl groups which it is desired to protect. Moreover, when carbonate rather OCOC(CH3) than acyl protecting groups are desired, the step of --Zincke reagent introducing the protecting groups will involve reacting -ococcCH3) - traine se the hydroxy-containing compound with a halocarbon methanol 60 ate of the type Y'OCOC or Y'OCOBr (formed by reac tion of Y'OH with COCl2 or COBr2), rather than with an acyl halide YC1 or YBr, Y and Y being as generi CH COOH cally defined hereinabove except that here neither Y th. ch, nor Y can be hydrogen. Also, as shown in Schemes 3 65 and 4, the order of steps may be altered; quaternization, NH, CH, followed by reduction, need not always constitute the COOH final two steps but may be carried out earlier in the reaction sequence. Yet other reaction schemes, reac 4,771,059 29 30 -continued SCHEME 6 - CONH CONH NaI, HF s (CH2)-N O < 12- N-NN (CH2)-N O Cl- c Na2SO4.

CONH2 s (CH2)-N

Suitable nontoxic pharmaceutically acceptable carri vivo oxidation of the dihydro form of the redox system ers for use with the topic compounds of formula (I), in order to achieve the greatest degree of enhancement e.g., those less toxic than the target drug species them of specificity. selves, will be apparent to those skilled in this art. Com pare, for example, Remington's Pharmaceutical Sciences, ILLUSTRATIVE SYNTHETIC METHODS 4th Edition (1970). Obviously, the choice of suitable Method A carriers will depend upon the exact nature of the partic ular dosage form selected, as well as upon the identity The primary amine is reacted with the Zincke rea of the compound to be administered. The therapeutic 25 gent of the formula dosage range for administration of a compound accord ing to this invention will generally be the same as, or less than, those characteristically used in this art for administration of the known primary, secondary or 30 tertiary amine/parent drug of which the instant com N-- Cl pound is an analogue. Naturally, such therapeutic dos age ranges will vary with the size of the patient, the NO2 condition for which the compound is administered, the particular dosage form employed, route of administra tion and the like. The quantity of given dosage form 35 needed to deliver the desired dose will of course depend NO; upon the concentration of the compound of formula (I) in any given pharmaceutical composition/dosage form in the presence of a suitable base, e.g. triethylamine, in thereof. Obviously, in the case of diagnostic agents, the an appropriate organic solvent, e.g. methanol, to afford dosage of formula (I) compound used will be a quantity the corresponding quaternary derivative of formula sufficient to deliver an amount of radioisotope, stable (II), which is then reduced by treatment with sodium isotope or the like which can be effectively detected by dithionite or sodium borohydride as generally described radioimaging or other detection means. The amount of hereinabove to afford the desired compound of formula radioisotope, stable isotope or the like present in the (I). dosage form will be within or below the ranges conven 45 The representative primary amines listed below may tionally used for diagnostic purposes. be derivatized in this manner to the corresponding pyri The ability of the topic compounds to cross the BBB dinium and dihydropyridine analogues of this invention. and to be "locked into' the brain allows administration The foregoing procedure may be repeated using a in a site-specific manner. A combination of the present Zincke reagent of the formula dihydropyridinese pyridinium salt redox system with a SO sustained release system will further enhance this site CONH2 specificity. Thus, a preferred embodiment of the inven tion comprises formulating the compound of formula (I) or its salt utilizing a sustained release carrier system and/or route of administration capable of slowly releas 55 CONH2 ing the chemical, e.g., sustained release tablets and cap N C or N C sules for oral administration; subcutaneous injection, or implantation of drugs in solid pellet form (for example, . distributed in a biodegradable polymer); intramuscular O NO2 NO injection of the compound in solution in oil or sus pended in a repository vehicle; a transdermal delivery NO; NO device or form such as an ointment to be applied locally to the desired site (when the drug is susceptible of deliv prepared from picolinamide or isonicotinamide, respec ery through the skin), slow intravenous infusion and the tively, to convert primary amines such as those specifi like. The rate of release of compound from the sustained 65 cally mentioned in connection with this method to the release system should be comparable to the rate of in corresponding quaternary and dihydro derivatives.

4,771,059 43 44 Method B nary and dihydro compounds. Omega amino acids in addition to GABA (which is shown below), other natu This is a variation of Method A used when the parent rai amino acids such as glycine, aspartic acid and glu primary amine contains a -COOH function which is to tamic acid, and small peptides (2-20 amino acids, e.g. be protected. met-enkephalin and leu-enkephalin) may be similarly The parent compound is first converted to the corre sponding ethyl or t-butyl ester by conventional esterifi derivatized. cation techniques. That ester is then used as the starting The picolinamide and isonicotinamide quaternary material in Method A and that method is repeated. and dihydro derivatives of the drugs specifically men Obviously, other esters may be similarly prepared in O tioned for derivatizing of the drugs specifically men the first step by use of other esterifying agents. tioned for derivatizing according to this method may be The representative compounds listed below may be similarly prepared, using the appropriate Zincke rea derivatized in this manner to the corresponding quater gent. See Method A. S

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4,771,059 53 54. tected quaternary, which may then be reacted with. Method C trimethylacetyl chloride to form the protected quater This is a variation of Method A used when the parent nary. The protected quaternary may then be reduced to primary amine contains one or more OH functions the protected dihydro compound as in Method A. which are to be protected. Various other hydroxy protecting groups may be The drug is first reacted with excess trimethylacetyl introduced in similar fashion. . . . . chloride, under strongly acid conditions, to convert the The representative drugs listed below may be deriva hydroxy group(s) to pivalyloxy group(s). That pro tized in this manner to the corresponding quaternary tected derivative is then used as the starting material in and dihydro compounds. The corresponding picolina Method. A and that method is repeated. Alternatively, O mide and isonicotinamide quaternary and dihydrode the first two steps may be reversed, i.e., the drug may be rivatives may be similarly prepared, using the appropri first reacted with the Zincke reagent to form the unpro ate Zincke reagent. See Method A.

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4,771,059 57 58 sequence considered most convenient. The amine func Method D tion is derivatized according to Method A. The representative drugs listed below may be deriva This variation of Method. A can be used when the tized in this manner to the corresponding quaternary. drug contains one or more OH and COOH functions 5 and dihydro compounds. The corresponding picolina which are to be protected. The protecting groups, typi mide and isonicotinamide quaternary and dihydro de cally the ethyl or t-butyl ester and pivalyloxy groups, rivatives may be similarly prepared, using the appropri are introduced as described in Methods B and C, in the ate Zincke reagent. See Method A. 10

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4,771,059 61 62 Similarly, Method E may be combined with Methods Method E B, C and D to afford the corresponding 3-quinolinecar Method A is followed, using a Zincke reagent of the boxamide derivatives, e.g. of the drugs listed with those formula methods. The foregoing procedure may be repeated using a Zincke reagent of the formula . N CONH2 CONH2 a s N-- C N NO2 NO, C

NO derived from 4-isoquinolinecarboxamide, in place of the prepared from 3-quinolinecarboxamide, in place of the Zincke reagent shown above, to convert drugs such as Zincke reagent shown in Method A. those mentioned with Methods A, B, C, or . D. to the The representative starting materials listed below corresponding 4-isoquinolinecarboxamide derivatives. may be derivatized in this manner to the corresponding The general procedures depicted above may be uti quaternary and dihydro compounds, as may the remain lized to provide the 1,2-dihydro derivatives as well as ing drugs listed with Method A. the depicted 1,4-dihydros.

SARTING MATERIAL QUATERNARY INTERMEDIATE(CATION) DIHYDRO DERVATIVE CONH2 CH-CH-NH2 N / \ C CHCH-N H2 N / C H2

TRANYLCYPROMINE

NNH2 scONH2 CONH2

a N--

AMANTADINE

Ch;HCH CHCHCH CH2CHCHs

NH2 N+ s

21 CONH2 AMPHETAMINE

NH2CH2CH2

A. co-C) NCHCH CONH2 CONH2 PHENYLEHYLAMINE 4,771,059 64 -continued STARTING MATERAL QUATERNARY INTERMEDIATE(CATION) DIHYDRO DERIVATIVE

was sas aS N N N CONH2 CONH2 N N N 1. 1. 1. NH-NH NHamN / \ NH-N

HYDRALA2INE ---

()-algic ()-age ()-age NH2 N+ N 2/

CONH2 CONH2 g-isomer g-isomer g-isomer DEXTROAMPHETAMINE

NH2 N+ N

cóSS1CO CONH isomer isomer isomer LEVAMPHETAMINE H. CONH2 CONH CH-i-NH, fH, 7 \ sh; CH3 ch--N: CH-5-N O CH3 CH3

PHENERMINE

-continued

50 CH2CHCH3 (from amphetamine) Method F C N An ether solution of a compound of formula (I) is treated with an equivalent amount of anhydrous p-tol uenesulfonic acid and dissolved in dry ether. Mixing at CONH2 room temperature is continued until the inninium salt 55 precipitates out of solution. The salt is then removed by CONH2 filtration. Imminium salts which may be prepared in this man CH /s ner include those derived from the following com- ch--N (from phen termine) pounds of the invention: 60 CH3 Vs/

N-CHCH (from phenethylamine) Method G 65 The compounds of formulas (I) and (II) correspond CONH2 ing to the secondary amines/parent drugs listed below are prepared by selecting the corresponding primary 65 4,771,059 66 The picolinamide and isonicotinamide: quaternary amines as the starting materials and following Method and dihydro derivatives corresponding to the depicted C described hereinabove. Thus, the hydroxy groups are nicotinamide derivatives may be similarly prepared, first protected, the protected primary amines are then using the appropriate Zincke reagents, as described in reacted with the Zincke reagent to afford the quater Method A. Method E described hereinabove may be combined nary derivatives and the quaternaries are then reduced with Method G to afford the corresponding. 3 to afford the desired compounds of formula (I). quinolinecarboxamide and 4-isoquinolinecarboxamide Different protecting groups from those shown may derivatives, e.g. of the parent drugs listed with this be introduced in a similar manner. O method. -

1S

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* 4,771,059 69 70 Method H or 4-quinolinecarboxamide in place of the compounds of formulas (I) and (II) corresponding to parent drugs The compounds of formulas (I) and (II) correspond ing to the secondary and tertiary amines/parent drugs such as those specifically mentioned below. listed below are prepared by selecting the correspond When the parent secondary and tertiary amines con ing compounds of the formula tain OH and/or COOH groups in need of protection, suitable protecting groups can be introduced before or D-Hal after formation of the quaternary derivatives. See, for example, Scheme 4 and Methods B, C and D herein as the starting materials, reacting those starting materi O als with nicotinamide to afford the quaternary interme above. diates and then reducing the quaternaries with Na2S2O4 Method H can also be employed to prepare the con to afford the desired dihydro derivatives. pounds of formulas (I) and (II) corresponding to the The foregoing procedure may be repeated using primary amines listed in Methods A through E; see, for picolinamide, isonicotinamide, 3-quinolinecarboxamide 15 example, Scheme 4. -

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4,771,059 137 138

tioionalv

4,771,059 149 150

4,771,059 153 154

tHNOO

Naovalitaw