US005389.623A United States Patent (19) 11 Patent Number: 5,389,623 Bodor 45 Date of Patent: Feb. 14, 1995 (54) REDOX CARRIERS FOR BRAIN-SPECIFIC DRUG DELVERY OTHER PUBLICATIONS Wu et al., CA 77: 19978m (1972). 75) Inventor: Nicholas S. Bodor, Gainesville, Fla. Endo et al, CA 92: 21076y (1979). 73) Assignee: University of Florida, Gainesville, Endo et al, CA 87: 53561m (1977). Fla. Bodor et al, Science 190, 155-156 (1975). Shek et al., J. Med. Chem. 19, 113-117 (1976). 21 Appl. No.: 766,528 Bodor et al, in Design of Biopharmaceutical Properties through Prodrugs and Analogs, ed. Edward B. Roche, (22 Filed: Sep. 27, 1991 American Pharmaceutical Association, Washington, D.C., 98-135 (1977). Related U.S. Application Data Bodor et al, J. Pharm. Sci 67, 685-687 (1978). 60 Division of Ser. No. 295,663, Jan. 11, 1989, Pat. No. Bodor et al, Science 214, 1370-1372 (1981). 5,087,618, which is a division of Ser. No. 666,210, Oct. The Friday Evening Post, Health Center Communica 29, 1984, Pat. No. 4,829,070, which is a continuation-in tions, University of Florida, Gainesville, Fla., Aug. 14, part of Ser. No. 379,316, May 18, 1982, Pat. No. 1981. 4,479,932, and Ser. No. 461,543, Jan. 27, 1983, aban Chemical and Engineering News, pp. 24-25, Dec. 21, doned, and Ser. No. 475,493, Mar. 15, 1983, Pat. No. 1981. 4,622,218, and a continuation-in-part of Ser. No. Science News, vol. 121, #1, p. 7, Jan. 2, 1982. 516,382, Jul. 22, 1983, Pat. No. 4,540,564. Brewster III, Dis. Abst. Int. B., vol. 43, #9, p. 2910B (30) Foreign Application Priority Data (1983). Bodor et al., J. Med. Chem. 26, 313-318 (1983). May 12, 1983 WO WIPO ...... PCT/US83/00725 Bodor et al, J. Med. Chem. 26, 528-534 (1983). May 16, 1983 CA) Canada ...... 428.192 Bodor et al, Pharmac. Ther. 19, 337-386 (1983). 51 Int. Cl...... A61K 31/56; A61K 31/455 Bodor et al, J. Pharm. Sci 73, 385-389 (1984). 52 U.S.C...... 514/169; 514/170; Bodor et al, Science 221, 65-67 (1983). 514/356; 540/109; 540/110 Primary Examiner-John W. Rollins 58) Field of Search ...... 540/109, 110; 514/169, Assistant Examiner-James D. Wilson 514/170,356 Attorney, Agent, or Firm-Burns, Doane, Swecker & Mathis 56) References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS Compounds of the formula 3,987,175 10/1976 Cousse ...... 54.6/316 4,065,566 12/1977 Bodor...... 560/40 D--DHC (I) 4,083,996 4/1978 Tanaka et al...... 546/316 4,143,146 5/1979 Saari...... 54.6/316 and the nontoxic pharmaceutically acceptable salt 4,152,521 5/1979 Cousse et al. .. . 546/316 thereof, wherein D is the residue of a centrally acting 4,157,396 6/1979 Tanaka et al. . . 546/316 drug containing at least one reactive functional group 4,195,984 12/1980 Stein et al...... 546/323 selected from the group consisting of amino, hydroxyl, 4,479,932 10/1984 Bodor ...... 424/9 mercapto, carboxyl, amide and imide, said residue being 4,532,251 7/1985 Spatz ...... 54/354 characterized by the absence of a hydrogen atom from 4,540,564 9/1985 Bodor ...... 424/9 4,555,520 11/1985 Misra et al...... 514/546 at least one of said reactive functional groups in said 4,558,150 12/1985 Gordon et al...... 54.6/316 drug; n is a positive integer equal to the number of said 4,727,079 2/1988 Bodor ...... 514/307 functional groups from which a hydrogen atom is ab 5,087,618 2/1992 Bodor ...... 514/45 (Abstract continued on next page.) 5,389,623 Page 2 sent; and DHC) is the reduced, biooxidizable, blood then the alkylene groups can be the same or different brain barrier penetrating lipoidal form of a dihy and the Ro radicals can be the same or different; said dropyridine-pyridinium salt redox carrier, said carrier bivalent radical being so positioned that the terminal comprising a bivalent radical of the formula carbonyl function of the bivalent radical is linked to the drug residue while the terminal amino function of the O bivalent radical is linked to the remaining portion of the I carrier moiety; are adapted for the site-specific/sus t-calypeNH; tained delivery of centrally acting drugs to the brain. R The corresponding pyridinium salt type drug/carrier wherein the alkylene group can be straight or branched entities D-(-QC) qY are also disclosed. and can contain 1 to 3 carbon atoms; R is a radical identical to the corresponding portion of a natural amino acid; and p is 1 or 2, provided that, when p is 2, 28 Claims, No Drawings 5,389,623 1. 2 barrier, BBB. Site-specific delivery and sustained deliv REDOX CARRIERS FOR BRAN-SPECIFIC ORUG ery of drugs to the brain are even more difficult. DELIVERY It has been previously suggested to deliver a drug species, specifically N-methylpyridinium-2-carbaldox CROSS-REFERENCE TO RELATED 5 ime chloride (2-PAM), into the brain, the active nucleus APPLICATIONS of which in and of itself constitutes a quaternary pyri This application is a division of application Ser. No. dinium salt, by way of the dihydropyridine latentiated 07/295,663, filed Jan. 11, 1989, now U.S. Pat. No. prodrug form thereof. Such approach was conspicu 5,087,618, which is a division of application Ser. No. ously delimited to relatively small molecule quaternary 06/666,210, filed Oct. 29, 1984, now U.S. Pat. No. 10 pyridinium ring-containing drug species and did not 4,829,070, which is a continuation-in-part of my earlier provide the overall ideal result of brain-specific, sus applications Ser. No. 06/379,316, filed May 18, 1982, tained release of the desired drug, with concomitant now U.S. Pat. No. 4,479,932; Ser. No. 06/461,543, filed rapid elimination from the general circulation, en Jan. 27, 1983, abandoned in favor of Ser. No. hanced drug efficacy and decreased toxicity. Hence, no 06/733,463, filed May 13, 1985, now U.S. Pat. No. 15 "trapping” in the brain of the 2-PAM formed in situ 4,727,079; Ser. No. 06/475,493, filed Mar. 15, 1983, now resulted, and obviously no brain-specific, sustained de U.S. Pat. No. 4,622,218, and Ser. No. 06/515,382, filed livery occurred as any consequence thereof: the 2-PAM Jul. 22, 1983, now U.S. Pat. No. 4,540,564. Each of said was eliminated as fast from the brain as it was from the earlier applications is hereby expressly incorporated by general circulation and other organs. Compare U.S. reference in its entirely and relied upon. 20 Pat. Nos. 3,929, 813 and 3,962,447; Bodor et al., J. Pharm. Sci, 67, No. 5, pp. 685-687 (1978); Bodor et al, FIELD OF THE INVENTION Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi The present invention relates to a dihydropyridine/- and Bodor, J. Med. Chem, Vol. 19 (1976), pp. 113-117. pyridinium salt type of redox system for the site-specific A more recent extension of this approach is described or sustained delivery (or both) of a wide variety of drug 25 by Brewster, Dissertation Abstracts International, Vol. species to the brain. More especially, this invention 43, No. 09, March 1983, p. 2910B. It has a also been relates to the discovery that a biologically active com speculated to deliver, e.g., an antitumor agent, into the pound coupled to a lipoidal carrier moiety comprising a brain by utilizing a dihydropyridine/pyridinium redox dihydropyridine nucleus readily and easily penetrates carrier moiety therefor, but this particular hypothesis the blood-brain barrier (“BBB”) and attains increased 30 necessarily entails derivatizing the dihydropyridine/- levels of concentration in the brain; oxidation of the pyridinium carrier with a substituent itself critically dihydropyridine carrier moiety in vivo to the ionic designed to control the release rate of the active drug pyridinium salt prevents its elimination from the brain, species itself; Bodor et al., J. Pharm. Sci, supra. See also while elimination from the general circulation is accel Bodor, "Novel Approaches for the Design of Mem erated, resulting in significant and prolongedly sus 35 brane Transport Properties of Drugs', in Design of tained brain-specific drug activity, whether ascribable Biopharmaceutical Properties Through Prodrugs and Ana to the cleavage of the drug/quaternary entity and sus logs, Roche, E. B. (ed.), APhAAcademy of Pharmaceu tained release of the drug in the brain and/or to the tical Sciences, Washington, D.C., pp. 98-135 (1976). drug/quaternary itself. More recently, the present inventor and his cowork ers, in Bodor et al, Science, Vol. 214, December 18, BACKGROUND OF THE INVENTION 1981, pp. 1370-1372, have reported on site-specific sus The delivery of drug species to the brain is ofttimes tained release of drugs to the brain. The Science publica seriously limited by transport and metabolism factors tion outlines a scheme for specific and sustained deliv and, more specifically, by the functional barrier of the ery of drug species to the brain, as depicted in the fol endothelial brain capillary wall deemed the blood-brain lowing Scheme:

SCHEME (D) + (QC)+-Eš s (D-QC* section s(D-DHC) / DELVERY TO BODY ELMINATION D-DHC D-DHC) IN CIRCULATORY SYSTEM IN THE BRAIN AND ORGANS

K IN VEVO K IN VIVO oxIDATION OXDATION 5,389,623 3. 4. -continued SCHEME D-Qch ENZYMATIC ENZYMATIC D-QC+ N THE BRAIN CLEAVAGE CLEAVAGE IN CIRCULATORY SYSTEM

K4 K4

\/ (D) + (QC) K3

BBB N \/ ELIMINATION CONHCH2CH2 O 25 O According to the scheme in Science, a drug D is cou N pled to a quaternary carrier (QC) and the D-QC) R which results is then reduced chemically to the lipoidal dihydro form D-DHC). After administration of D DHC) in vivo, it is rapidly distributed throughout the 30 (R = CH2 or CH2 O ). body, including the brain. The dihydro form D-DHC is then in situ oxidized (rate constant, kil) (by the NAD-eNADH system) to the ideally inactive original Testing of the N-methyl derivative in vivo supported D-QC quaternary salt which, because of its ionic, 35 the criteria set forth in the Scheme. Bodor et all specu hydrophilic character, should be rapidly eliminated lated that various types of drugs might possibly be de from the general circulation of the body, while the livered using the depicted or analogous carrier systems blood-brain barrier should prevent its elimination from and indicated that use of N-methylnicotinic acid esters the brain (k3>>k2; k3) >k). Enzymatic cleavage of and amides and their pyridine ring-substituted deriva the D-QC that is “locked' in the brain effects a 40 tives was being studied for delivery of amino- or hy sustained delivery of the drug species D), followed by droxyl-containing drugs, including small peptides, to its normal elimination (k5), metabolism. A properly the brain. No other possible specific carriers were dis selected carrier IQC+ will also be rapidly eliminated closed. from the brain (ké >>K2). Because of the facile elimi Other reports of the present inventor's work have nation of D-QC) from the general circulation, only 45 appeared in The Friday Evening Post, Aug. 14, 1981, minor amounts of drug are released in the body Health Center Communications, University of Florida, (k3d >k4); D will be released primarily in the brain Gainesville, Fla.; Chemical & Engineering News, Dec. (kadk2). The overall result ideally will be a brain 21, 1981, pp. 24–25; and Science News, Jan. 2, 1982, Vol. specific sustained release of the target drug species. 121, No. 1, page 7. These publications do not suggest Bodor et all have reported, in Science, their work with 50 any carrier systems other than the specific N-methyl phenylethylamine as the drug model, which was cou and N-benzyl nicotinic acid-type carriers disclosed in pled to nicotinic acid, then quaternized to give com the Science publication. Other classes of drugs as well as pounds of the formula a few specific drugs are mentioned as possible candi dates for derivatization; for example, steroid hormones, 55 cancer drugs and memory enhancers are indicated as targets for possible future work, as are enkephalins, and specifically, dopamine and testosterone. The publica or "O tions do not suggest how to link such drugs to the car rier except possibly when the drugs are simple struc 60 tures containing a single NH2 or, perhaps, simple struc tures containing a single OH, of the primary or second ary type, as is the case with phenylethylamine or testos (R = CH3 or CH2 terone. There is, for example, no suggestion of how one of ordinary skill in the art would form a drug-carrier 65 combination when the drug has a more complicated chemical structure than phenylethylamine, e.g., dopa which were subsequently reduced by sodium dithionite mine or an enkephalin. For further details concerning to the corresponding compounds of the formula the work with phenylethylamine, dopamine and testos 5,389,623 5 6 terone, see also Bodor et al., J. Med. Chen, Vol. 26, functional groups from which a hydrogen atom is ab March 1983, pp. 313-317; Bodor et al, J. Med. Chem., sent; and DHC) is the reduced, biooxidizable, blood Vol. 26, April 1983, pp. 528-534; Bodor et al., Pharma brain barrier penetrating lipoidal form of a dihy cology and Therapeutics, Vol. 19, No. 3, pp. 337-386 dropyridine-epyridinium salt redox carrier, said carrier (April 1983); Bodor et al, Science, Vol. 221, July 1983, comprising a bivalent radical of the formula pp. 65-67; and Bodor et al., J. Pharm. Sci, Vol. 73, No. 3, March 1984, pp. 385-388. In view of the foregoing, it is apparent that an acutely O serious need exists for a truly effective, generic but -- calkyneNH; nonetheless flexible, method for the site-specific or sus 10 tained delivery, or both, of drug species to the brain. Ro This need has been addressed by the earlier copending wherein the alkylene group can be straight or branched applications referred to hereinabove, and especially by and can contain 1 to 3 carbon atoms; Ro is a radical the Ser. Nos. 379,316 and 516,382, now U.S. Pat. Nos. identical to the corresponding portion of a natural 4,479,932 and 4,540,564, respectively, which provide 15 such a generic method for site-specific, sustained deliv amino acid; and p is 1 or 2, provided that, when p is 2, ery of drugs to the brain utilizing a dihydropyridine then the alkylene groups can be the same or different pyridinium salt type of redox carrier system. According and the Ro radicals can be the same or different; said to those applications, a drug (typically having a reactive bivalent radical being so positioned that the terminal hydroxyl, carboxyl or amino group) can be coupled to carbonyl function of the bivalent radical is linked to the a dihydropyridine(pyridinium carrier; the lipoidal 20 drug residue while the terminal amino function of the dihydro form of the drug-carrier system readily crosses bivalent radical is linked to the remaining portion of the the blood-brain barrier; the dihydropyridine moiety is carrier moiety. then oxidized in vivo to the ideally inactive quaternary In another aspect, the present invention provides, as form, which is "locked in' the brain, while it is facilely 25 novel chemical intermediates to the compounds of for eliminated from the general circulation; enzymatic mula (I), the quaternary salts of the formula cleavage of the "locked in' quaternary effects a sus tained delivery of the drug itself to the brain, to achieve (II) the desired biological effect. The aforementioned ear lier applications disclose a variety of specific carriers 30 wherein D and n are as defined with formula (I); QC) for use in site-specific drug delivery. Nevertheless, a is the hydrophilic, ionic pyridinium salt form of a dihy need still exists for additional specific carriers which dropyridine-pyridinium salt redox carrier, said carrier incorporate the dihydropyridine(pyridinium salt comprising a bivalent radical of the formula redox system and which can be coupled to drugs to deliver them in a sustained, site-specific manner. Such 35 O additional carriers would enhance the flexibility of the present inventor's dihydropyridine/pyridinium salt t-callyn-NH; redox carrier system as described in his earlier copend Ro ing applications, since new dihydropyridine/- pyridinium salt redox carriers could be used to modify wherein Ro, p and the alkylene group are as defined the rate of oxidation of the dihydro form to the corre with formula (I), said bivalent radical being positioned sponding quaternary and/or to modify the rate of re as in formula (I); Y is the anion of a pharmaceutically lease of the drug itself from the "locked in' quaternary acceptable organic or inorganic acid; t is the valence of form. This need is net by the invention described the acid anion; and q is the number which when multi herein. 45 plied by t is equal to n. The pyridinium salts of formula (II) are not only chemical intermediates to the corre SUMMARY OF THE INVENTION sponding compounds of formula (I) but also represent It has now been found that applicant's chemical deliv the form of the present chemical delivery system which ery system as described in his earlier applications can be is "locked in' the brain following administration of the expanded to include use of new classes of dihy SO formula () dihydro derivatives. dropyridine-pyridinium salt type redox carriers; and In yet another aspect, the present invention provides that this expanded system is well suited for an effective a method for specific and/or target enhanced delivery site-specific and/or sustained and/or enhanced delivery to the brain of a wide variety of centrally acting drug of drugs to the brain. species, such brain-specific drug delivery being effected In one aspect, the present invention thus provides, as 55 via the bidirectional transport of the drug species into an effective drug delivery system, novel compounds of and out of the brain by means of the particular dihy the formula dropyridine-pyridinium salt carrier type redox system, (I)-->(II). Thus, the lipoidal form (I) readily crosses the D--DHC) (I) blood-brain barrier; oxidation of (I) in vivo affords the 60 corresponding pyridinium salt(II) which, because of its and the nontoxic pharmaceutically acceptable salts hydrophilic, ionic nature, is "locked in' the brain, while thereof, wherein D is the residue of a centrally acting it is readily eliminated from the general circulation; and drug containing at least one reactive functional group enzymatic cleavage of the “locked in' quaternary ef selected from the group consisting of amino, hydroxyl, fects sustained delivery of the drug itself. The new mercapto, carboxyl, amide and imide, said residue being 65 carriers encompassed by formulas (I) and (II) herein characterized by the absence of a hydrogen atom from make it possible to modify the rate of oxidation of (I) to at least one of said reactive functional groups in said (II). Moreover, these new carriers allow more control drug; n is a positive integer equal to the number of said lable enzymatic cleavage of (II) to release the drug 5,389,623 7 8 itself, because they are a better substrate for peptidase introduced as part of the compound administered. In and esterase than are the corresponding carriers in deed, even when the compound of formula (I) is used in which a bivalent radical of the formula its salt form, the anion of the formula (II) compound in vivo is not necessarily the same as that present in the O formula (I) compound. In fact, the exact identity of the | anionic portion of the compound of formula (II) is im t-callyns-NH; material to the in vivo transformation of (I) to (II). Ro In the expression "at least one reactive functional group selected from the group consisting of amino, as defined hereinabove does not link the drug to the 10 remainder of the carrier moiety. Cleavage of the bond hydroxyl, mercapto, carboxyl, amide and imide' as between the drug portion of the molecule and the termi used herein, the designated reactive functional groups nal carbonyl function of the bivalent radical leads to have the following meanings: release of the drug, while the carrier portion of the The word "amino” means a primary or secondary molecule may be eliminated as such or further cleaved 15 amino function, i.e. -NH2 or -NHR. The secondary between the terminal amino function of the bivalent amino function is also represented herein as -NH-, radical and the remainder of the carrier. The carrier particularly since the exact identity of the R portion of itself is composed of portions having low toxicity; thus, -NHR is immaterial, R being a part of the drug residue enhanced drug efficacy and decreased toxicity as com D itself which is left unchanged by this invention. pared to administration of the drug itself can be ex 20 The word "hydroxyl' means an -OH function. pected from use of the present invention. Moreover, The word 'carboxyl' means a -COOH function. consistent herewith, there is provided enhanced site The word “mercapto' means an -SH function. specific and sustained delivery to the brain of a wide The word "amide' means a carbamoyl (-CONH2) variety of centrally acting agents which are not them or substituted carbamoyl (-CONHR) functional group selves able to penetrate the blood-brain barrier to any 25 or a sulfamoyl (-SO2NH2) or substituted sulfanoyl considerable extent. (-SO2NHR) functional group. The -CONHR group DETAILED DESCRIPTION OF THE may also be represented herein as-CONH-, since the INVENTION exact identity of the Rportion of -CONHR is immate rial, R being a part of the drug residue D itself which is More particularly, in accord with the present inven 30 tion, the following definitions are applicable: left unchanged by this invention. Similarly, the The term “drug' as used herein means any substance -SO2NHR group may also be represented herein as intended for use in the diagnosis, cure, mitigation, treat -SO2NH- since the identity of R is likewise immate ment or prevention of disease or in the enhancement of rial, R being part of the drug residue D itself which is desirable physical or mental development and condi 35 left unchanged by this invention. tions in man or other animal. The word "imide” means a functional group having The term "lipoidal' as used herein designates a car the structure rier moiety which is lipid-soluble or lipophilic. The expression “non-toxic pharmaceutically accept able salts' as used herein generally includes the non toxic salts of products of the invention of structure (I) hereinabove formed with non-toxic, pharmaceutically acceptable inorganic or organic acids of the general formula HY. For example, the salts include those de rived from inorganic acids such as hydrochloric, hydro 45 bromic, sulfuric, sulfanic, phosphoric, nitric and the like; and the salts prepared from organic acids such as that is, the structure which characterizes imides (i.e. acetic, propionic, succinic, glycolic, stearic, lactic, compounds having succinimide-type, or phthalinide malic, tartaric, citric, ascorbic, pamoic, maleic, hydrox type structures and so forth). ymaleic, phenylacetic, glutamic, benzoic, salicylic, Sul 50 The expression "Ris a radical identical to the corre fanilic, fumaric, methanesulfonic, toluenesulfonic and sponding portion of a natural amino acid' is believed to the like. The expression "anion of a pharmaceutically be self-explanatory. Thus, for example, Ro can be hy acceptable organic or inorganic acid' as used herein, drogen, as in glycine; methyl, as in alanine; e.g. in connection with structure (II) above, is intended -CH(CH3)2, as in valine; -CH2-CH(CH3)2, as in to include anions of such HY acids. 55 leucine; - It will be appreciated from the foregoing that a com pound of formula () may be administered as the free CH3 base or in the form of a non-toxic pharmaceutically acceptable salt thereof, i.e. a salt which can be repre -CH-CHs, sented by the formula 60 as in isoleucine; D--DHC HY wherein D, DHC, n and HY are defined as before; and that, regardless of the actual form in which the com 65 -CH2 y pound is administered, it will be converted in vivo to a quaternary salt of formula (II), the anion Y being present in vivo. It is not necessary that the anion be as in phenylalanine; 5,389,623 9 10 and oxymorphone, which are natcotic analgesics; desi pramine, nortriptyline, octriptyline, maprotiline, opi -CH2-C y pramol and protriptyline, which are cerebral stimu lants/tricyclic antidepressants of the dibenzazapine NN type used, e.g., in endogenous depressions; clonidine H and methyldopa, which are sympatholytic agents used, e.g., in hypertension; biperiden, cycrimine and procycli as in tryptophan; -CH2OH, as in serine; dine, which are centrally acting anticholinergics; tran -CHOH-CH3, as in threonine; -(CH2)2-SCH3, as ylcypromine, a sympathomimetic cerebral stimulant in methionine, -CH2-CONH2, as in asparagine; /MAO inhibitor and antidepressant; acetophenazine, -CH2CH2-CONH2, as in glutamine; carphenazine, fluphenazine, perphenazine and piperacetazine, which are phenothiazine-type tranquil izers; benzoctamine, a sedative/muscle relaxant which structurally is an analogue of the phenothiazine tran -CH2 OH, 15 quilizers; chlordiazepoxide, clorazepate, nitrazepam and temazepam, which are benzodiazepine-type tran quilizers; noracy methadol, a narcotic analgesic of the as in tyrosine; -CH2SH, as in cysteine, -CH2COOH, methadone-type; piminodine, a narcotic analgesic of the as in aspartic acid; and -CH2CH2COOH, as in glu meperidine type; tracazolate, a sedative/hypnotic; tiler tamic acid. The expression "natural amino acid” as used 20 amine, an anticonvulsant; prizidilol, a centrally acting herein does not encompass dopa or L-DOPA. Preferred hypotensive; sulpiride, an antidepressant/psychotropic; amino acids encompassed by the Ro term include gly haloperidol and clopenthixol, which are tranquilizers; cine, alanine, valine, leucine, phenylalanine, isoleucine, norepinephrine, a sympathetic stimulant/adrenergic methionine, asparagine and glutamine. agent; nalorphine and naloxone, narcotic antagonists; By "centrally acting' drug species, active agent or 25 hydralazine, a hypotensive; ethotoin, phenobarbital and compound as utilized herein, there is of course intended aminoglutethimide, anticonvulsants; epinephrine, an any drug species or the like, a significant (usually, prin adrenergic agent; ethamivan, a medullary stimulant; cipal) pharmacological activity of which is CNS and a bemegride, a barbiturate antagonist; amiphenazole, a result of direct action in the brain. stimulant; iopydol, iodopyracet, iodouppurate (o- Exemplary such centrally acting drug species are the 30 iodohippuric acid), iodamide and iopanoic acid, which CNS-amines and other nervous system agents, whether are radiodiagnostics; ephedrine; pseudoephedrine, ox sympathetic or parasympathetic, e.g., phenylethylamine ymetazoline and phenylephrine, which are sympatho (a stimulant), dopamine (a neurotransmitter and dopa minergic agent used, e.g. in the treatment of Parkinson mimetic amines and decongestants; estradiol, estrone ism or hyperprolactinemia), tyramine (a stimulant), 35 and estriol, the natural estrogens; amoxicillin, oxacillin, L-DOPA (a dopamine precursor, used, for example, in carbenicillin, benzylpenicillin, phenoxymethylpenicil the treatment of Parkinsonism); muscle relaxants, tran lin, methicillin, nafcillin, ticarcillin, bacampicillin, epi quilizers and antidepressants, e.g., benzodiazepine tran cillin, hetacillin, pivampicillin, the methoxymethylester quilizers such as oxazepam and phenothiazine tranquil of hetacillin and ampicillin, which are penicillin-type izers such as carphenazine, fluphenazine and the like; antibiotics; amobarbital, a sedative; trihexyphenidyl, a mild and strong analgesics and narcotics; sedatives and centrally acting anticholinergic; hydroxyzine, a tran hypnotics; narcotic antagonists; vascular agents; stimu quilizer; chlortetracycline, demeclocycline, minocy lants; anesthetics; antiepileptic and anticonvulsant drugs cline, doxycycline, oxytetracycline, tetracycline and generally, including hydantoins such as phenytoin and methacycline, which are tetracycline-type antibiotics; ethotoin; barbituates such phenobarbital; hormones, 45 clindamycin, lincomycin, nalidixic acid, oxolinic acid such as the steroid hormones, e.g., estradiol, testoster and phenazopyridine, antibacterials/antibiotics; one, 17 a-ethynyl testosterone (ethisterone), and the bromazepam, demoxepam and lorazepam, benzod like (recent studies on histological mapping of hor tazeptine tranquilizers; phenytoin, an anticonvulsant; mone-sensitive and specific steroid binding cells in the glutethimide, a mild hypnotic/sedative; bethanidine and brain have underscored the importance of the steroid 50 guanethidine, hypotensives/sympatholytics; captopril, action in the brain on sexual behavior); amphetamine a hypotensive; methylprylon, a mild hypnotic; amedalin, like drugs; anticancer and anti-Parkinsonism agents; bupropion, cartazolate, daledalin, difluanine, fluoxetine antihypertensives; agents to enhance learning capacity and nisoxetine, which are cerebral stimulants; diclox and the memory processes, including treatment of de acillin, a penicillin-type antibacterial; butalbital, a barbi mentias, such as Alzheimer's disease; antibacterials; 55 turate sedative; y-vinyl GABA and y-acetylenic growth promoters; centrally active hypotensive agents; GABA, derivatives of the neurotransmitter GABA for centrally acting prostaglandins; diagnostic agents, such possible use in epilepsy; valproic acid and its metabo as radiopharmaceuticals; monoamine oxidase (MAO) lites such as 5-hydroxy-2-n-propylpentanoic acid, 4 inhibitor drugs; and any like centrally acting com hydroxy-2-n-propylpentanoic acid and 3-hydroxy-2-n- pounds. propylpentanoic acid, also for use as anticonvulsants; Other illustrative ultimate species of centrally active valpromide, a valproic acid derivative for use as an drug entities are: amphetamine, dextroamphetamine, anticonvulsant; apomorphine, a narcotic depressant/e- levamphetamine, aletamine, cypenamine, fencamfamin, metic, which has been used in the treatment of photo fenozolone, Zylofuramine, methamphetamine, phenmet sensitive epilepsy; pholcodine, a narcotic antitussive; razine and phentermine, which are sympathomimetic 65 methotrexate, mitoxantrone, podophyllotoxin deriva amines/cerebral stimulants and appetite suppressants; tives (etopside, teniposide), doxorubicin, daumamycin etryptamine, a cerebral stimulant; codeine, oxycodone, and cyclophosphamide, anticancer/antitumor agents; pentazocine, anileridine, hydromorphone, morphine methylphenidate, a stimulant; thiopental, an anesthetic; 5,389,623 11 12 ethinyl estradiol and mestranol, estrogens; meptazinol, antitumor agents, there can be mentioned Ara-AC, cyclazocine, phenazocine, profadol, metopon, drocode pentostatin (2'-deoxycoformycin), Ara-C (cytarabine), and myfadol, which are narcotic analgesics; buprenor 3-deazaguanine, dihydro-5-azacytidine, tiazofurin, san phine, nalbuphine, butorphanol, levallorphan, naltrex givamycin, Ara-A (vidarabine), 6-MMPR, PCNU, one, alazocine, oxilorphan and nahmexone, which are spiromustine, btsbenzimtdazole, L-alanosine, DON (6- narcotic antagonists or agonist-antagonists; norgestrel diazo-5-oxo-L-norleucine), L-ICRF, trimethyl TMM, and norethindrone, progestins; cephalothin, cephalexin, 5-methyltetrahydrohomofolic acid, glyoxylic acid sul cefazolin, cefoxitin, moxalactam, ceforanide, cefroxa fonylhydrazone, DACH, SR-2555, SR-2508, desme dine and cephapirin, cephalosporin antibiotics; atenolol, thylmisonidazole, mitoxantrone, menogarol, aclacino propranolol, nadolol, timolol and metoprolol, 3-block 10 mycin A, phyllanthoside, bactobolin, aphidocolin, ers/hypotensives; sulfadiazine and other sulfonamide homoharringtonine, levonantradiol, acivicin, strep antibiotics; ribavarin and acyclovir, antiviral agents; tozotocin, hydroxyurea, chlorambucil, cyclophospha chlorambucil and melphalan, nitrogen mustard-type mide, uracil mustard, melphalan, 5-FUDR (floxuridine), anticancer/antitumor agents; methotrexate and aminop Vincristine, vinblastine, cytosine arabinoside, 6-mercap terin, which are folic acid antagonist-type anticancer 15 topurine, hioguanine, 5-azacytidine, methotrexate, adria /antitumor agents; platinum coordination complexes, mycin (doxorubicin), daunomycin (daunorubicin), lar i.e. cisplatin analogue-type anticancer/antitumor gomycine polypeptide, aminopterin, dactinomycin, mi agents; dactinomycin and mitomycin C, used in cancer tomycin C and podophyllotoxin derivatives, such as chemotherapy; thioguanine, a purine/pyrimidine antag etoposide (VP-16) and teniposide. Among the antiviral onist used in cancer treatment; vincristine and vinblas agents, there can be mentioned ribavarin; acyclovir tine, anticancer alkaloids; hydroxyurea and DON, anti (ACV); amantadine (also of possible value as an anti cancer urea derivatives; N,N'-bis(dichloracetyl)-1,8- Parkinsonism agent); diarylamidines such as 5-amidino octamethylenediamine (fertilysin), an agent for male 2-(5-amidino-2-benzofuranyl)indole and 4,6- fertility inhibition; levorphanol, a narcotic, analgesic; diimidazolino-2-phenylbenzo(b)thiophene; 2-aminox benzestrol and diethylstilbestrol, synthetic estrogens; 25 azoles such as 2-guanidino-4,5-di-n-propyloxazole and ethyl 9-carboline-3-carboxylate, a benzodiazepine an 2-guanidino-4,5-diphenyloxazole; benzinidazole ana tagonist; furosemide, a diuretic/antihypertensive; dipy logues such as the syn and anti isomers of 6-(hydrox ridamole and nifedipine, coronary vasodilators; proga yimino)phenyl)-methyl)-1-(1-methylethyl)sulfonyl bide, a GABA-agonist and prodrug of GABA. Yet 1H-benzimidazol-2-amine; bridgehead C-nucleosides other ultimate species include nonsteroidal antiinflam 30 such 2S 5,7-dimethyl-2-6-D-ribofuranosyl-s- matory agents/non-narcotic analgesics, e.g., propionic triazole(1,5-a)pyrimidine; glycosides such as 2-deoxy acid derivatives, acetic acid derivatives, fenamic acid D-glycose, glycosamine, 2-deoxy-2-fluoro-D-mannose derivatives and biphenylcarboxylic acid derivatives. and 6-amino-6-deoxy-D-glucose; phenyl glucoside de Specific NSAID's/nonnarcotic analgesics contem rivatives such as phenyl-6-chloro-6-deoxy-6-D- plated for use herein include ibuprofen, naproxen, flur 35 glycopyranoside; (S)-9-(2,3-dihydroxy-propyl)adenine; biprofen, zomepirac, sulindac, indomethacin, fenbufen, 6-azauridine; idoxuridine; trifluridine; BDVU (bisdihy fenoprofen, indoprofen, ketoprofen, fluprofen, bucloxic droxyvinyluridine); and 5,6-dichloro-1-3-D- acid, tolmetin, alclofenac, fenclozic acid, ibufenac, ribofuranosylbenzimidazole. Among the tranquilizers, flufenisal, pirprofen, flufenamic acid, mefenamic acid, there can be mentioned benzodiazepine tranquilizers clonixeril, clonixin, meclofenamic acid, flunixin, di such as oxazepam, lorazepam, chlordiazepoxide, clofenac, carprofen, etodolac, fendosal, prodolic acid, bromazepam, chlorazepate, nitrazepam and temazepam; sermetacin, indoxole, tetrydamine, diflunisal, naproxol, hydantoin-type tranquilizers/anticonvulsants such as piroxican, metazamide, flutiazin and tesicam. phenytoin, ethotoin and mephenytoin; phenothiazine Preferred classes of centrally acting drugs for use type tranquilizers such as acetophenazine, carphena herein are the central neurotransmitters, steroids, anti 45 zine, fluphenazine, perphenazine and piperacetazine; cancer and antitumor agents, antiviral agents, tranquil and others. Among the hypotensives, there can be men izers, memory enhancers, hypotensives, sedatives, anti tioned clonidine, methyldopa, bethanidine, debrisoquin, psychotics and cerebral stimulants (especially tricyclic hydralazine, and guanethidine and its analogues. antidepressants). Among the neurotransmitters, there Among the sedatives, tranquilizers and antipsychotics, can be mentioned catecholamines, such as doramine, 50 there can be mentioned the many specific compounds of norepinephrine and epinephrine; serotonin, histamine this type already disclosed above, especially the pheno and tryptamine. Among the steroids, there can be men thiazines and benzodiazepines and their analogues. tioned antiinflammatory adrenal cortical steroids such Among the cerebral stimulants, there can also be men as hydrocortisone, betamethasone, cortisone, dexa tioned the many specific compounds set forth herein methasone, flunethasone, fluprednisolone, mepredni 55 above, particularly the sympathomimtic amine-type sone, methyl prednisolone, prednisolone, prednisone, cerebral stimulants and the tricyclic antidepressants, triancinolone, cortodoxone, fludrocortisone, fluran especially preferred tricyclics being the dibenzazepines drenolone acetonide (flurandrenolide), paramethasone and their analogues. and the like; male sex hormones (androgens), such as Also illustrative of the centrally acting drug species testosterone and its close analogues, e.g. methyl testos 60 contemplated by this invention are centrally active terone (17-methyltestosterone); and female sex hor metabolites of centrally acting drugs. Such metabolites mones, both estrogens and progestins, e.g., progestins are typified by hydroxylated metabolites of tricyclic such as norgestrel, norethindrone, norethynodrel, ethis antidepressants, such as the E- and Z-isomers of 10 terone, dimethisterone, allylestrenol, cingestol, ethyner hydroxynortriptyline, 2-hydroxyimipramine, 2-hydrox one, lynestrenol, norgesterone, norvinisterone, 65 ydesipramine and 8-hydroxychlorimipramine; hydrox ethynodiol, oxogestone and tigestol, and estrogens such ylated metabolites of phenothiazine tranquilizers, e.g. as ethinyl estradiol, nestranol, estradiol, estriol, estrone 7-hydroxychlorpromazine; and desmethyl metabolites and quinestrol and the like. Among the anticancer and of N-methyl benzodiazepine tranquilizers, e.g. desme 5,389,623 13 14 thyldiazepam. Other CNS active metabolites for use DOPA, is not classified as an amino acid according to herein will be apparent to those skilled in the art, e.g. this application or its parent Ser. Nos. 379,316 and SL7502, which is an active metabolite of progabide, a 516,382, now U.S. Pat. Nos. 4,479,932 and 4,540,564, GABA agonist. Typically, these CNS active metabo respectively, but rather as a CNS amine and dopaminer lites have been identified as such in the scientific litera gic agent used, for example, in the treatment of Parkin ture but have not been administered as drugs them sonism; thus, L-DOPA is not intended to be excluded selves. In many cases, the active metabolites are be from derivation according to this invention, but on the lieved to be comparable in CNS activity to their parent contrary is a particularly significant centrally acting drugs; frequently, however, the metabolites have not drug encompassed hereby. been administered per se because they are not them 10 selves able to penetrate the blood-brain barrier. It will be apparent from the known structures of the As indicated hereinabove, diagnostic agents, includ many drug species exemplified above, that in many ing radiopharmaceuticals, are encompassed by the ex cases the selected drug will possess more than one reac pression 'centrally acting drug' or the like as used tive functional group, and, in particular, that the drug herein. Any diagnostic agent which can be derivatized 15 may contain hydroxyl or carboxyl or amino or other to afford a compound of formula (I) which will pene functional groups in addition to the groups to which the trate the BBB and concentrate in the brain in its quater carrier will be linked and that these additional groups nary form (II) and can be detected therein is encom will at times benefit from being protected during syn passed by this invention. The diagnostic may be “cold thesis and/or during administration. The nature of such and be detected by X-ray (e.g. radiopaque agents) or protection is described in more detail below. Obviously, other means such as mass spectrophotometry, NMR or such protected drug species are encompassed by the other non-invasive techniques (e.g., when the com definition of "drug' set forth hereinabove. pound includes stable isotopes such as C 13, N 15, O 18, The expression "hydroxyl protective group' as used S 33 and S 34). The diagnostic alternatively may be hereinbelow is intended to designate a group which is 'hot', i.e. radiolabeled, such as with radioactive iodine 25 (I 123, I 125, I 131) and detected/imaged by radiation inserted in place of the hydrogen atom(s) of an OH detection/imaging means. Typical “cold” diagnostics group or groups in order to prevent premature metabo for derivation herein include o-iodohippuric acid, io lism of said OH group or groups prior to the com thalamic acid, iopydol, iodamide and iopanoic acid. pound's reaching the desired site in the body. Typical Typical radiolabeled diagnostics include diohippuric hydroxyl protective groups contemplated by the pres acid (I 125, I 131), diotyrosine (I 125, I 131), o-iodohip 30 ent invention are acyl groups and carbonates. puric acid (I 131), iothalamic acid (I 125, I 131), thyrox When the hydroxyl protective group is acyl (i.e., ine (I 125, I 131), iotyrosine (I 131) and when it is an organic radical derived from a carboxylic iodometaraminol (I 123), which has the structural for acid by removal of the hydroxyl group), it preferably mula represents an acyl radical select ed from the group 35 consisting of alkanoyl having 2 to 8 carbon atoms; al CH3 kenoyl having one or two double bonds and 3 to 8 carbon atoms; HO CHCHNH2. OH It cycloalkyl-CH2-C- In the case of diagnostics, unlike the drugs which are wherein the cycloalkyl portion contains 3 to 7 ring for treatment or prevention of disease, the "locked in' atoms and r is zero, one, two or three; phenoxyacetyl; quaternary form will be the form that is imaged or 45 detected, not the original diagnostic itself. Moreover, pyridinecarbonyl; and any of the centrally acting drugs encompassed by this invention which are intended for the treatment or pre O vention of medical disorders or the like which can be phenyl-CH2-C- radiolabeled, e.g. with a radioisotope such as iodine, or 50 labeled with a stable isotope, can thus be converted to a wherein ris zero, one, two or three and phenyl is unsub diagnostic for use herein. Put another way, any com stituted or is substituted by 1 to 3 alkyl each having 1 to pound of formula (I) of this invention which can have 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, incorporated into its structure such a radioactive or halo, trifluoromethyl, dialkylamino having 2 to 8 car stable isotope either directly or through incorporation 55 of the isotope into the structure of the corresponding bon atoms or alkanoylamino having 2 to 6 carbon compound of formula (IX) can be used for diagnostic atOnS. purposes. When the acyl group is alkanoyl, there are included Specifically excluded from the scope of the expres both unbranched and branched alkanoyl, for example, sion "centrally acting' drug species, compound or the acetyl, propionyl, butyryl, isobutyryl, valleryl, isovale like as used herein are amino acids, small peptides, such ryl 2-methylbutanoyl, pivalyl (pivaloyl), 3-methylpen as di-, tri-, tetra- and pentapeptides, and other small tanoyl, 3,3 -dimethylbutanoyl, 2,2-dimethylpentanoyl 2-20 amino acid unit containing peptides, e.g. enkepha and the like. Pivalyl, isobutyryl and isovaleryl are espe lins and endorphins, as well as larger peptides. The cially preferred. specifically excluded amino acids include tryptophan, 65 When the acyl group is alkenoyl, there are included, GABA, glycine, glutamic acid, tyrosine, aspartic acid for example, crotonyl, 2,5-hexadienoyl and 3,6-octadi and other natural amino acids such as those typically enoyl. incorporated into protein. However, dopa, or L When the acyl group is 5,389,623 15 16 wherein the cycloalkyl portion contains 3 to 7 ring atoms and r is zero, one, two or three; phenoxy; 2-, 3-, cycloalkyl-CH2-C-, or 4-pyridyl; or phenyl-CH2 there are included cycloalkanecarbonyl and cycloalk anealkanoyl groups wherein the cycloalkane portion wherein ris zero, one, two or three and phenyl is unsub can optionally near 1 or 2 alkyl groups as substituents, stituted or is substituted by 1 to 3 alkyl each having 1 to e.g. cyclopropanecarbonyl, 1-methylcyclopropanecar 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, bonyl, cyclopropaneacetyl, a-methylcyclopropanea O halo, trifluoromethyl, dialkylamino having 2 to 8 car cetyl, 1-methylcyclopropaneacetyl, cyclopropanepro bon atoms or alkanoylamino having 2 to 6 carbon pionyl, a-methylcyclopropanepropionyl, 2-isobutylcy atoms. Most preferably, Y is C1-C7 alkyl, particularly clopropanepropionyl, cyclobutanecarbonyl, 3,3-dime ethyl or isopropyl. thylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2- Similarly, the expression "carboxyl protective dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecar 15 group’ as used hereinbelow is intended to designate a bonyl, cyclohexaneacetyl, cyclohexanecarbonyl, cy group which is inserted in place of the hydrogen cloheptanecarbonyl and cycloheptanepropionyl. Cy atom(s) of a COOH group or groups in order to prevent clohexanecarbonyl is especially preferred. premature metabolism of said COOH group or groups When the acyl group is pyridinecarbonyl, there are prior to the compound's reaching the desired site in the included picolinoyl (2-pyridinecarbonyl), nicotinoyl 20 body. Typical carboxyl protective groups are the (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, other carboxyl protecting groups may be selected in 25 order to achieve greater control over the rate of in vivo O hydrolysis of the ester back to the acid and thus enhance phenyl-CH2-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, gen of the -COOH group: a-phenylpropionyl, S-phenylpropionyl, p-toluyl, m-tol 30 uyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4- dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6- -CH2-C C-CH3, trimethylbenzoyl, m-methylphenylacetyl, p-isobutyl ON C -O phenylacetyl, 6(p-ethylphenyl)propionyl, p-anisoyl, 35 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, 3-(3,4,5-trimethoxyphenyl)propio O nyl, o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, I p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-tri -alk-OCO-alkyl, chlorobenzoyl, p-chlorophenylacetyl, a-(m-bromo phenyl)propionyl, p-trifluoromethylbenzoyl, 2,4-di(tri OT fluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, 45 -alk-O-alkyl, As-(3-methyl-4-chlorophenyl)propionyl, p-dime thylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, wherein alk is C1-C6 straight or branched alkylene and o-acetamidobenzoyl, m-propionamidobenzoyl, 3 the alkyl radical is straight or branched and contains 1 chloro-4-acetamidophenylacetyl, p-n-butoxybenzoyl, to 7 carbon atoms 2,4,6-triethoxybenzoyl, 3-(p-trifluoromethylphenyl)- 50 propionyl, 2-methyl-4-methoxybenzoyl, p-acetamido phenylpropionyl and 3-chloro-4-ethoxybenzoyl. When the hydroxyl protective group is a carbonate (e.g. -Hocochsch, grouping, it has the structural formula CH3 55 O CH3 -CH2OC-C-CH3 N CH3 i.e., it is an organic radical which can be considered to 60 be derived from a carbonic acid by removal of the hy and droxyl group from the COOH portion. Y' preferably -CHOCH3). represents alkyl having 1 to 7 carbon atoms; alkenyl having one or two double bonds and 2 to 7 carbon The expression "amino protective group' as used atoms; 65 hereinbelow is intended to designate a group which is inserted in place of the hydrogen atom(s) of an amino cycloalkyl-CH2 group or groups in order to prevent unwanted reaction of the amino function(s) during chemical synthesis. 5,389,623 17 18 Such protective groups are well-known in the art and It too will be appreciated that by "dihydropyridine include t-butoxycarbonyl and carbobenzoxy (i.e. ben carrier' or "DHC', there is intended any nontoxic zyloxycarbonyl). Other appropriate amino protective carrier moiety comprising, containing or including the groups will be apparent to those skilled in the art. Un like the instant hydroxyl and carboxyl protective dihydropyridine nucleus, whether or not a part of any groups described above, which not only prevent un larger basic nucleus, and whether substituted or unsub wanted chemical reaction but also protect those hy stituted, the only criteria therefor being (1) capacity for droxyl and carboxyl functions from premature metabo BBB penetration and in vivo oxidation thereof to the lism in vivo, the amino protective groups are primarily corresponding quaternary pyridinium salt carrier intended for use during synthesis and are typically re O QC), and (2) incorporation therein of the bivalent moved by well-known procedures at an appropriate radical stage of the synthetic pathway after they have achieved their protective function and are no longer needed. Occasionally, however, an amino protective function will be retained in the compound of formula (I) to also 15 t-callyn-NH; protect the amino group in vivo. R0 In accord with the present invention, the sustained delivery of a drug to the brain in sufficient concentra wherein the structural variables are defined as herein tions to achieve the desired pharmacological effect can above. As aforesaid, the ionic pyridinium salt drug/car be accomplished with much lower concentrations in the peripheral circulation and other tissues. The present rier prodrug entity D--QC) which results from such invention of course will allow such treatment of any in vivo oxidation is prevented from efflux from the other organs or glands in which sufficient drug accumu brain, while elimination from the general circulation is lates. Thus, for example, it is expected that the quater accelerated. Subsequently, the bond coupling the drug nary form (II) which is locked in the brain will be 25 species to the quaternary carrier (QC) is metabolically locked in the testes as well. See my earlier copending cleaved which results in sustained delivery of the drug application Ser. No. 475,493 now U.S. Pat. No. in the brain and facile elimination of the carrier moiety 4,622,218. QC). And the cleavage of the quaternary compound The novel chemical delivery system of this invention (II) to sustainedly deliver the drug species in the brain begins with the preparation of the novel quaternary with concomitant facile elimination of the carrier moi intermediates of formula (II). The preparation of those ety QC is characteristically enzymatic cleavage, e.g., intermediates will be tailored to the particular drug by esterase, peptidase, amidase, cholinesterase or hy portion and carrier portion to be combined, and espe drolytic enzyme, albeit any type of in brain cleavage cially to the nature of the chemical bond between them, which might result, whether enzymatic, metabolic or e.g. whether the linkage is an ester or amide linkage, as 35 well as to the presence or absence of ocher reactive otherwise, of course remains within the ambit of this functional groups (amino, mercapto, carboxyl, hy invention. Thus, the drug release rate controlling pa droxy) in either the drug or carrier portion. Typically, rameter of the compounds of this invention is imparted if such other reactive groups are present, they are found via the clearable bonding between drug and carrier, and in the drug portion or in the Roportion of the carrier. In not by any release rate controlling substituent(s). any event, when such groups are present and it is de Dihydropyridine(pyridinium salt redox carrier moi sired to protect them, a step that introduces appropriate eties for use herein include the following quaternaries protecting groups can be incorporated at a suitable and the corresponding dihydro forms: stage of the synthetic pathway. Typical protective (1) For linkage to a drug having at least one hydroxyl groups are well known in the art and have been defined 45 or mercapto or primary or secondary amino functional hereinabove. When carbonate protecting groups for grouping, replacing a hydrogen atom from at least one alcoholic hydroxyl radicals are desired, the step of in of said functional groupings with one of the following troducing the protecting groups will involve reacting QC) groupings: the alcohol with a halocarbonate of the type ROCOCl or ROCOBr (formed by reaction of ROH with COCl2 50 or COBr2, R typically being lower alkyl). For acyl (a) protecting groups, the alcoholic hydroxyl is reacted with an acyl halide RC1 or RBr, Ribeing-COCH3 or ci-NHaylenect. -COC(CH3)3. Yet other reaction schemes and reac Ro tants will be readily apparent to those skilled in the art 55 O as will the appropriate means for removing such protec tive groups after they have achieved their function and +N are no longer needed. As already explained above, car R boxyl and hydroxyl protecting groups are typically retained in the compounds of formula (I) and (II) rather X (b) than being removed, so that they can perform their protective function in vivo as well. In forming the intermediates of formula (II), at least O one amino, hydroxy,l mercapto, carboxyl, amide or imide group in a drug will be bonded to QC, the 65 t hydrophilic, ionic pyridinium salt form of a dihy R-i-NHaylenect. dropyridine-pyridinium salt redox carrier comprising O Ro a divalent radical as defined hereinabove. 5,389,623 19 20 -continued 3 or 4 position of the quinolinium ring; and the carbo O O OI (c)C nyl-containing groupings in formulas (g) and () and the l X substituent in formula (h) can each be attached at the cochscFNHaylenect. 1, 3 or 4 position of the isoquinolinium ring; R0 5 (2) For, the linkage to a drug having at least one O carboxyl functional grouping, replacing a hydrogen atom from at least one of said carboxyl groupings with one of the following (QC) groupings: 10 (a) When there are one or more -COOH groups to O O (d)d be derivatized: C-i-NH-alkylene-C, O O (i) I I 15 ct-NHaylenecio-z- t R0 R

(e) 20 X (ii)

+N O R3-i-NH-alkylene-C, 25 I R-it-NHalpinecio-z- O RO O R0

O O O (f) (iii) coch;ct-NHaylenec, 30 O O O 4. Ro cochscenHalpinecio-z- t R0 R1 35 (iv)

O O (g) t-NHaylenecio-z- is Il Ro O2+N ci-NHayleneci, 40 N Ro R1 +N R (h)

4. 3 -X 45 (v) Q, +N O N R3-i-NH-aliylene-C,I O Ro O 50 o R-it-NHalpenscio-z- O O O (j) O RO I (vi) O +N cochsc-NHaylenecy. YN R0 R coch;ct-NHaylenecio-z- R0 wherein alkylene, Ro and pare as defined with formula (I) hereinabove; R1 is C1-C7 alkyl, C1-Chaloalkyl or R C7-C10 aralkyl; R3 is C1 to C3 alkylene; X is 60 -CONR'R' wherein R and R', which can be the same (vii) or different, are each H or C1-C7 alkyl, or X is -CH= NOR" wherein R" is H or C1-C, alkyl; the carbonyl ci-NHalpinecio-z- containing groupings in formulas (a) and (c) and the X R0 substituent in formula (b) can each be attached at the 2, 65 3 or 4 position of the pyridinium ring; the carbonyl-con taining groupings in formulas (d) and (f) and the X substituent in formula (e) can each be attached at the 2, 5,389,623 21 22 -continued -continued X (viii) O O ers (xiv) / y Ct-NH-alkylene-CNH-i- --, 5 N-R-it-NHaylenecio-z- Ro y O Ro N (A)nv N R1 O 1O (ix) wherein is the skeleton of a sugar molecule; n is a positive integer equal to the total number of -OH coch;ct-NHaylenecio-z- functions in the sugar molecule from which said skele RO ton is derived; n is a positive integer one less than the 15 total number of -OH functions in the sugar molecule N N from which said skeleton is derived; each A in each of R structures (xii), (xiii) and (xiv) can independently be hydroxy or D, D'being the residue of a centrally acting wherein alkylene, Ro and pare as defined with formula 20 drug containing one reactive carboxyl functional group, (I) hereinabove; Z is C1-C8 straight or branched alkyl said residue being characterized by the absence of a ene, preferably C1-C3 straight or branched alkylene; Q hydrogen atom from said carboxyl functional group in said drug; and each R4 in each of structures (x) and (xi) is -O-or-NH-; R1 is C1-C7 alkyl, C1-C7 haloalkyl can independently be hydroxy, or C7-C10 aralkyl; R3 is C1-C3 alkylene; X is 25 -CONRTR' wherein R' and R', which can be the same or different, are each H or C1-C, alkyl, or X is -CH=NOR' where in R' is Hor C1-C, alkyl; the X -oil-styl-O s substituent in formula (ii) and the carbonyl-containing R0 +N groupings in formulas (i) and (iii) can each be attached 30 at the 2, 3 or 4 position of the pyridinium ring; the X R Substituent in formula (v) and the carbonyl-containing O O groupings, informulas (iv) and (vi) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the 35 -of-callylene NH;c s X substituent in formula (viii) and carbonyl-containing Ro +N groupings informulas (vii) and (ix) can each be attached at the 1, 3 or 4 position of the isoquinolinium ring; R (b) Alternatively when there is only one -COOH 40 group to be derivatized: -of-callen-NH;c or D', R0 N' (R4)5 R1 45 wherein alkylene, Ro and p are defined as with formula (I); D' is defined as with structure (xii), (xiii) and (xiv); R1 is C1-C7 alkyl, C1-C7 haloalkyl or C7-C10 aralkyl; e - a (xi) / y and the depicted carbonyl-containing groupings can be (R4)iv-- - -, SO attached at the 2, 3 or 4 position of the pyridinium or ' 's st 7 quinolinium ring, or at the 1, 3 or 4 position of the isoquinolinium ring; with the proviso that at least one O O es (xii) R4 in each of structures (x) and (xi) is ci-NHaylenec, NH- , - 55 +N Ro A k (A)nv -oil-l'EORO +N y O O - (xiii) 60 R I v O O ct-NHaylenec, NH- V -- +N R0 y -of-callen-NH;c ot k (A)nv 65 RO +N

o 5,389,623 23 24 -continued -continued O O O O O (p) I -o- C-alkylene-NH3C coch;ct-NHayleneciott RO R wherein alkylene, R p and R1 and the position of the carbonyl-containing groupings are defined as above; 10 and with the further proviso that when more than one O O (q) of the R4 radicals in a given compound are the aforesaid * S I carbonyl-containing groupings, then all such carbonyl O2 +N ci-NHaylenecio H-. containing groupings in said compound are identical. N R0 R (3) For linkage to a drug having at least one -NH 15

functional group which is part of an amide or imide structure or at least one low pKa primary or secondary (r) amine functional group, replacing a hydrogen atom from at least one of said functional groupings with one 20 O of the following QC) groupings: R-i-NHaylene-choh O Ro R (k) Or ci-NHaipiensciott 25 (s) (3) RO R O cochsci-NHayleneciogh +N Ro R 30 R1 wherein alkylene, Ro and p are as defined with formula (); R1 is C1-C7 alkyl, C1-C7 haloalkyl or C7-C10 aral kyl; R is hydrogen, C1-C7 alkyl, C3-C8 cycloalkyl, 35 C1-C7 haloalkyl, furyl, phenyl, or phenyl substituted by 35 (1) one or more halo, lower alkyl, lower alkoxy, carbam oyl, lower alkoxycarbonyl, lower alkanoyloxy, lower t haloalkyl, mono(lower alkyl)carbamoyl, di(lower al R3- ft-NHaylene-choh kyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or O Ro R lower alkylsulfonyl; R3 is C1 to C3 alkylene; X is -CONR'R' wherein R' and R', which can be the (m) same or different, are each H or C1-C7 alkyl, or X is -CH=NOR' wherein R" is H or C1-C, alkyl; the coCH-C-NHaylenecioh carbonyl-containing groupings in formulas (k) and (m) 45 and the X substituent in formula (1) can each be at (3) Ro R tached at the 2, 3 or 4 position of the pyridinium ring; +N the carbonyl containing groupings in formulas (n) and (p) and the X substituent in formula (o) can each be R1 attached at the 2, 3 or 4 position of the quintolinium 50 ring; and the carbonyl-containing groupings in formulas O (n) (q) and (s) and the X substituent in formula (r) can each be attached at the 1, 3 or 4 position of the ci-NHaylenecio H-. isoquinolinium ring. Here and throughout this applica R tion, the expression "C1-C7 haloalkyl” means C1-C7 55 alkyl substituted by one or more halogen atoms. Also here and throughout this application, the alkyl radicals, including alkyl and alkylene portions of other radicals, can be straight or branched unless otherwise specified. Drugs containing secondary or tertiary hydroxyl X (o) 60 functional groups can be linked to any of the QC) CS groupings (k) through (s) above in which the 1 2 HO t R R-i-NHaylenecioth O Ro R portion is derived from an aldehyde RCH2O capable of reacting with said drug to form the corresponding 5,389,623 25 26 hemiacetal, as discussed in more detail in Method K' -continued hereinafter. (g") The dihydro forms DHC) corresponding to the aforementioned quaternaries are as follows: it-NHaylenect, (1) For Group (1) above: N R0

(a) N 2 N R ci-NHaylenect. 10 RO (h) N X 2 N O N I 15 R-FNHaylenect. (b) O RO

X (h") 20 N N R-FNHaylenect. sy-S2 N O O Ro R-i-NHaylenec, 25 O Ro O O O (c) I I O O O (j")

coch;ct NHagency. R0 S I 2 coch;ct-NHaylenec, 30 1 N Ro R

O 35 (d") G")

ci-NHaylenect, ochsci-NHaylenec, Ro N R0 N- N R

(e) wherein alkylene, Ro and p are as defined with formula 45 (I); the dotted line informulas (a), (b) and (c) indicates the presence of a double bond in either the 4 or 5 posi tion of the dihydropyridine ring; the dotted line in for mulas (d), (e) and (f) indicates the presence of a double R-it-NHaylene-cy, 50 bond in either the 2 or 3 position of the dihydroquino O Ro line ring; R1 is C1-C7 alkyl, C1-C7 haloalkyl or C7-C10 aralkyl; R3 is C1 to C3 alkylene; X is -CONR'R'' (f) wherein R' and R', which can be the same or different, 55 are each H or C1-C7 alkyl, or X is -CH=NOR"

cochsc-NHaylenect. Ro wherein R' is H or C1-C7 alkyl; the carbonyl-contain ing groupings informulas (a) and (c) and the X substit uent in formula (b) can each be attached at the 2, 3 or 4 position of the dihydropyridine ring; the carbonyl containing groupings in formulas (d) and (f) and the X substituent in formula (e) can each be attached at 2, 3 or O O (g) 4 position of the dihydroquinoline ring; and the carbo Y nyl-containing groupings in formulas (g) and (j) and ci-NHaylenec, 65 2 N Ro the X substituent informula (h') can each be attached at R1 1, 3 or 4 position of the dihydroisoquinoline ring; (2) For Group (2) (a) above: 5,389,623 27 28 -continued O O (vii") ct NHaylenecio- Z'-, it NHaylenecio-z- N Ro N : N R O (viii) N X (ii) 2 N O N 15 R-it-NHaylenecio- Z'-, O Ro

X (viii") R3- it NHaylenecio-z- O RO 20 N syt 2 N O (iii) R-i-NHaylenecio- Z'-s, cochsci-NHaylenecio-z- 25 O Ro ...' RO O O O (ix) S I N 2 N coch;ct-NHaylenecio-z- 30 N Ro R1 R

O O (iv) d (ix)

ci-NHaylenecio-z- 35 Ro COCH2C- NHaylenecio-z- N R0 N : N R1 wherein alkylene, Ro and p are as defined with formula (I) hereinabove; the dotted line in formulas (i), (i) and 45 (iii) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulas (iv), (v) and (vi) indicates the presence of a double bond in either the 2 or 3 position of R-i-NHaylenecio-z- the dihydroquinoline ring; Z is C1-C8 straight or O Ro 50 branched alkylene, preferably C1-C3 straight or branched alkylene; Q is -O- or -NH-; R1 is C1-C7 O O O (vi) alkyl, C1-C7 haloalkyl or C7-C10 aralkyl; R3 is C1-C3 alkylene; X is -CONR'R' wherein R' and R", which coch;ct-NHaylenecio-z- 55 can be the same or different, are each H or C1-C7 alkyl; or Xis-CH=NOR" wherein R" is Hor C1-C, alkyl; the X substituent in formula (ii) and the carbonyl-con taining grouping in formulas (i) and (iii) can each be attached at the 2, 3 or 4 position of the dihydropyridine 60 ring; the X substituent in formula (v) and the carbonyl containing grouping in formulas (iv) and (vi) can each be attached at the 2, 3 or 4 position of the dihydroquino line ring; and the X substituent in formula (viii) and the ct-NHaylenecio-z- 65 carbonyl-containing groupings in formulas (vii) and (ix) can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring. (3) For Group (2) (b) above: 5,389,623 29 30

(R4)5 (x) % 4 y : 5 5 ot-capiens-NH;c 6 RO R (xi) 1 1 n (R),iv-- - -, 10 Y--1 -of-capiens-NH;c

O O e - e. (xii) Ro I y . c- NH-alkylene-Cl NH--- -- 15 'a - O O R0 I 21 (A)nv -of-c-alkylene-NHC s N 2 1 Ro / 20 R

-- (xiii) -of-c-alkylene-NHC C-- NH-alkylene-it NH-i- ---, k a Ro W y- 25 N or O' (A)nv R - N4

S O O --- (xiv) 30 wherein alkylene, Ro and p are defined as with formula 4 S 8t-NHaylene NH (1); the dotted line is defined as with structures (xii) and 2 N W (xiii); D' is defined as with structures (xii), (xiii), (xiv) Yr R0 y- and (xiv'); R1 is C1-C7 alkyl, C1-C7 haloalkyl or (A)nv C7-C10 aralkyl; and the depicted carbonyl groupings 35 can be attached at the 2, 3 or 4 position of the pyridin o ium or quinolinium ring or, except where otherwise -i-. specified, at the 1, 3 or 4 position of the isoquinolinium --- ring; with the proviso that at least one R4 in each of t-NH-alkylene NH- --, 40 structures (x) and (xi) is N k ---- N (A)nv a 4 S N N -of-callen-NH);c 6 1 R1 45 R0 N wherein alkylene, Ro and p are as defined with formula R

(I) above; the dotted line in formula (xii) indicates the O O presence of a double bond in either the 4 or 5 position of SO the dihydropyridine ring; the dotted line in formula -of-callen-NH;c y (xiii) indicates the presence of a double bond in either Ro the 2 or 3 position of the dihydroquinoline ring; is the skeleton of a sugar molecule; n is a positive integer equal to the total number of-OH functions in the sugar 55 O O molecule from which said skeleton is derived; n is a I a1 positiveas integera one less than the total number ofs -OH -of-c-alkylene-NHick N 2 . d functions in the sugar molecule from which said skele- R? ton is derived; each A in each of structures (xii), (xiii), 60 (xiv) and (xiv') can independently be hydroxy or D', D' being the residue of a centrally acting drug contain- -o-f-c-alkylene-NHC ing one reactive carboxyl functional group, said residue R. 21 being characterized by the absence of a hydrogen atom 65 y from said carboxyl functional group in said drug; and N 21 each R4 in each of structures (x) and (xi) can indepen dently be hydroxy, 5,389,623 31 32 wherein alkylene, Ro, p, R1, the dotted lines and the position of the carbonyl-containing groupings are de -continued fined as above; and with the further proviso that when O O (q.")Ft more than one of the R4 radicals in a given compound are the aforesaid carbonyl-containing groupings, then t-NHayleneci, oh all such carbonyl-containing groupings in said com pound are identical. N R0 R (4) For Group (3) above: S 3N R1 O O (k") 10 Ci-NH-alkylene-CIOCH-, (r) Ro R S. X 15 N R-i-NHayleneciogh O Ro R

(1) 20 sy 2 N O N O R-i-NHaylenec;oghI R3- st-NH-alkylene-CoH-, 25 I O RO R O R0 R O O (s) O (m') 3 l cochsci-NHalpenschoh cochet-NHaylenec, OCH-, 30 2 N N Ro R R R

ot

O 35 (s") ochsc-NHaylenecioI H-. R

C-i-NH-alkylene-COH-, N-N R1 wherein alkylene, Ro and pare as defined with formula (); R is hydrogen, C1-C7 alkyl, C3-C8 cycloakyl, 45 C1-Chaloalkyl, furyl, phenyl, or phenyl substituted by (o) one or more halo, lower alkyl, lower alkoxy, carban oyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)carbamoyl, di(lower al kyl)carbamoyl, lower alkylthio, lower alkylsulfinyl or 50 lower alkylsulfonyl; the dotted line in formulas (k’), (1) and (m) indicates the presence of a double bond in R-i-NHaipiens-choh either the 4 or 5 position of the dihydropyridine ring; O R0 R the dotted line informulas (n), (o) and (p) indicates the O (p) 55 presence of a double bond in either the 2 or 3 position of I the dihydroquinoline ring; R1 is C1-C7 alkyl, C1-C7 haloalkyl or C7-C10 aralkyl; R3 is C1 to C3 alkylene, X is cochsci-NHalpinecroph Ro R -CONRR', wherein R and R', which can be the same or different, are each H or C1-C7 alkyl, or X is 60 -CH-NOR' wherein R' is H or C1-C7 alkyl; the carbonyl-containing groupings in formulas (k) and (m) and the X substituent in formula (1) can each be at tached at the 2, 3 or 4 position of the dihydropyridine (q) ring; the carbonyl-containing groupings in formulas (n) 65 and (p) and the X substituent in formula (o) can each ci-NHaylenecioli be attached at the 2, 3 or 4 position of the dihydroquino Ro R line ring; and the carbonyl-containing groupings in formulas (q) and (s) and the X substituent in formulas 5,389, 623 33 34 (r) can each be attached at the 1, 3 or 4 position of the Substituent in formula (viii) and the depicted carbonyl dihydroisoquinoline ring. containing groupings is formulas (vii) and (ix) are at The presently preferred dihydropyridinee tached at the 4-position; and the depicted carbonyl-con pyridinium salt redox carrier moieties of this invention taining groupings encompassed by formulas (x), (xi), are those wherein alkylene is -CH2-; p is 1; Rois H, 5 (xii), (xiii) and (xiv) are in the 3-position of the pyridin -CH3, -CH(CH3)2, -CH2-CH(CH3)2, ium or quinolinium ring and in the 4-position of the isoquinolinium ring; all R4's in structures (x) and (xi) are -OH except for the one Rain each structure which CH3 must be the carrier moiety; all A's in structures (xii), -CH-CH5, -CH2 -(CH2)2-SCH3. 10 (xiii) and (xiv) are -OH, C is skeleton of a glucose molecule; Rinformulas the (k), () and (m) is hydrogen, methyl or CCl3; and the depicted carbonyl-containing -CH2-CONH2 groupings in formulas (k) through (s) are in the 3-posi tion of the pyridinium or quinolinium ring and in the or -CH2CH2-CONH2, R1, when present, is -CH3; 15 4-position of the isoquinolinium ring; and the corre R3, when present, is -CH2CH2-; X when present, is sponding dihydro moieties. -CONH2; the depicted carbonyl -containing group Especially preferred dihydropyridine-pyridinium ings in formulas (a) and (c) and the X substituent in salt redox carrier moieties are the quaternaries of Group formula (b) are attached at the 3-position; the depicted (1), structures (a), (b), (d), (e), (g) and (h); those of carbonyl-containing groupings in formulas (d) and (f) 20 Group (2), structures (), (ii), (iv), (v), (vii), (viii), (x) and and the X substituent in formula (e) are attached at the (xii); and those of Group 3, structures (k), (), (n), (o), (q) 3-position; the depicted carbonyl-containing groupings and (r); and the corresponding dihydro forms, most formulas (g) and () and the X substituent in formula (h) especially when they contain the preferred structural are attached at the 4-position; Z", when present, is C2 or variables identified in the preceding paragraph. C3 straight or branched alkylene; Q, when present, is 25 The following synthetic schemes illustrate various -NH-; the X substituent in formulas (ii) and (v) and approaches to the preparation of the compounds of this the depicted carbonyl-containing groupings in formulas invention. (i), (iii), (iv) and (vi) are attached at the 3-position; the X

SCHEME

OH OCC(CH3)3 (CH3)3CC-Cl OH 9. OCC(CH3)3 --> (H. (H. fH, (H. NH2.HBr NH2.HY dopamine hydrobramide 2 1. O O II I H2NCH2COH + CHOCC 3 4 O O I OCC(CH3)3 OCC(CH3)3 2 -- CHoNHCH2OH DCC Se OCC(CH3)33 H/Pd2/Pde. OCC(CH3)y 33 5 SH: (H. H: H. NHCH-NHCoch NHCH-NH. O 7 O nicotinic or/

5,389,623 41 42

SCHEME 4 OH OH OH N OH -- HoCH-NH O DCC e. O O fH, SH: H-cooch, sh-cooch, NH2 NHCCH2NHCEO L-DOPA O-methyi ester

29 O N 30 pivalyl chloride

O O OCC(CH3)3 OCC(CH3)3 ocCH.) ocCH): O < CH3IC O CH in? CH3 CH2 gh-cooch, N sh-cooch, N I- NHCCH2NHC O NHCCH2NHCI O O O O O 32 Niso 31 OCC(CH3)3 ocCH) O

CHfrig / CH3 gh-cooch, N NHCH-NH / / O O

33 Similar schemes can be shown for the preparation of the other compounds of the invention. The acylation steps which introduce the hydroxyl protecting groups apparent to those skilled in the art. Also, insofar as in Scheme 1, 2 and 4, for example, are only needed concerns the quaternary compounds, when an anion when there are hydroxyl groups which it is desired to 55 different from that obtained is desired, the anion in the protect. Moreover, carbonate rather than acyl protect quaternary salt may be subjected to anion exchange via ing groups could be introduced instead, as already dis an anion exchange resin or, more conveniently, by use cussed hereinabove. Also, as shown in Schemes 2 and 3, of the method of Kaminski et al, Tetrahedron, Vol. 34, the order of steps may be altered; quaternization, fol pp. 2857-2859 (1978). According to the Kaminski et al lowed by reduction, need not always constitute the final 60 method, a methanolic solution of an HY acid will react two steps but may be carried out earlier in the reaction with a quaternary ammonium halide to produce the sequence. Yet other reaction schemes, reactants, sol methyl halide and the corresponding quaternary.Y salt. vents, reaction conditions, etc. (e.g. using an anhydride Moreover, the manner in which the ultimate compound rather than an acyl halide for the acylation step, or is prepared should be tailored to the presence of any preparing a different acyl derivative, e.g. the acetyl 65 other reactive groups in the molecule. For example, rather than the pivalyl derivative, or using a different when the parent drug contains an -OH or -NH2 anino acid or nicotinoyl derivative thereof in place of group to be derivatized as well as one or more carboxy glycine or nicotinuric acid, respectively) will be readily functions, such carboxy functions will typically be es 5,389,623 43 44 terified, e.g. converted to the corresponding ethyl ester, tion (1970). Obviously, the choice of suitable carriers or otherwise suitably protected, usually prior to forma will depend upon the exact nature of the particular tion of the quaternary compound. Thus, a wide variety dosage form selected, as well as upon the identity of the of synthetic approaches can be utilized, depending on compound to be administered. The therapeutic dosage the desired structure of the final product. And com range for administration of a compound according to pounds containing more than one category of reactive this invention will generally be the same as, or less than, functional groups may be derivatized in a variety of those which would characteristically be used in this art ways; for example, a compound containing reactive for administration of the parent drug itself. Naturally, hydroxyl and carboxyl groups may have the hydroxyl such therapeutic dosage ranges will vary with the size group(s) protected and the carboxyl group(s) linked to 10 of the patient, the condition for which the compound is the carrier, or the hydroxyl(s) may be linked to the administered, the particular dosage form employed, carrier and the carboxyl(s) protected. route of administration and the like. The quantity of Various illustrative synthetic schemes as applied to given dosage form needed to deliver the desired dose specific compounds of the invention are set forth below will of course depend upon the concentration of the in the section entitled "Illustrative Synthetic Methods'. 15 compound of formula (I) in any given pharmaceutical While the sequence of reaction steps can be varied in composition/dosage form thereof. Obviously, in the many cases, in general the final step (except in the case case of diagnostic agents, the dosage of formula (I) of optional salt formation or possibly in the case of compound used will be a quantity sufficient to deliver radiolabeling) will be reduction of a quaternary com to the target body area an amount of radioisotope, stable pound of formula (II) to the corresponding dihydro 20 isotope or the like which can be effectively detected by compound of formula (I). The reduction is usually con radio-imaging or other detection means. The amount of ducted at a temperature from about -10 C. to room radioisotope, stable isotope or the like present in the temperature, for a period of time from about 10 minutes dosage form will be within or below the ranges conven to 2 hours, conveniently at atmospheric pressure. Typi tionally used for diagnostic purposes. cally, a large excess of reducing agent is employed, e.g. 25 The ability of the topic compounds to cross the BBB a 1:5 molar ratio of reducing agent to starting com and to be "locked into the brain allows administration pound of formula (II). The process is conducted in the in a site-specific manner. A combination of the present presence of a suitable reducing agent, preferably an dihydropyridine)pyridinium salt redox carrier system alkali metal dithionite such as sodium dithionite or an with a sustained release system will further enhance this alkalimetal borohydride such as sodium borohydride or 30 site-specificity. Thus, a preferred embodiment of the lithium aluminum borohydride, in a suitable solvent. invention comprises formulating the compound of for Sodium dithionite reduction is conveniently carried out mula (I) or its salt utilizing a sustained release carrier in an aqueous solution; the dihydro product of formula system and/or route of administration capable of slowly () is usually insoluble in water and thus can be readily releasing the chemical, e.g. sustained release tablets and separated from the reaction medium. In the case of 35 capsules for oral administration; subcutaneous injection, sodium borohydride reduction, an organic reaction or implantation of drugs in solid pellet form (for exam medium is employed, e.g. a lower alkanol such as meth ple, distributed in a biodegradable polymer); intramus anol, an aqueous alkanol or other protic solvent. cular injection of the compound in solution in oil or In a presently preferred embodiment of the present suspended in a repository vehicle; a transdermal deliv invention, the centrally acting drug of which D is the ery device or form such as an ointment to be applied residue is dopamine or L-DOPA or a protected coun locally to the desired site (when the drug is susceptible terpart thereof, and the instant redox system is thus of delivery through the skin), slow intravenous infusion designed to elicit a sustained and brain-specific dopam and the like. The rate of release of compound from the inergic (e.g. anti-Parkinsonism or anti-hyperprolac sustained release system should be comparable to the tinemia) response in the animal to which the formula (I) rate of in vivo oxidation of the dihydro form of the derivative is administer ed. In analogous fashion, the redox system in order to achieve the greatest degree of instant redox carrier system I-II in which D is the enhancement of specificity. residue of any other centrally acting drug as defined In applicant's copending application Ser. No. herein is designed to elicit the kind of pharmacological 632,314, filed Jul. 19, 1984 (itself a continuation-in-part response which would be obtained by delivery of the 50 of the earlier Ser. No. 379,316, now U.S. Pat. No. drug itself to the brain, i.e. when the centrally acting 4,479,932; Ser. No. 461,543, abandoned in favor of Ser. parent drug is an antitumor/anticancer agent, the in No. 733,463, filed May 13, 1985, now U.S. Pat. No. stant redox system is employed to elicit an antitumor 4,727,079; Ser. No. 475,493 now U.S. Pat. No. /anticancer response; when the parent drug is a sympa 4,622,218; and Ser. No. 516,382 now U.S. Pat. No. thetic stimulant, the instant redox system is used to elicit 55 4,540,564), Ser. No. 632,314 being abandoned in favor a sympathetic stimulant or amphetamine-like response; of Ser. No. 879,120, filed Mar. 19, 1986, in turn aban when the parent drug is an anticonvulsant compound, doned in favor of Ser. No. 088,523, filed Aug. 21, 1987, the instant redox system is used to elicit an anticonvul now U.S. Pat. No. 4,963,688), the concept of applicant's Sant response; when the parent drug is a tranquilizer, the redox carrier system was expanded to provide novel instant system is used to elicit a tranquilizing response; 60 carrier-containing chelating agents, precursors thereto when the parent drug is an antidepressant, the instant and radiopharmaceuticals derived therefrom, utilizing system is used to elicit an antidepressant response; and the dihydropyridine-pyridinium salt type carriers dis so forth. closed in the four earlier applications. The teachings of Suitable nontoxic pharmaceutically acceptable carri Ser. No. 632,314, which is incorporated by reference ers for use with the topic compounds of formula (), e.g. 65 herein in its entirety and relied upon, can be readily those less toxic than the target drug species themselves, combined with the teachings of the present application will be apparent to those skilled in this art. Compare, for to expand the classes of chelating agents, precursors and example, Rennington's Pharmaceutical Sciences, 4th Edi radiopharmaceuticals defined therein to specifically 5,389,623 45 46 include dihydropyridine-pyrdinium salt redox carriers group, followed by reaction with nicotinoyl chloride or comprising a bivalent radical of the formula nicotinic anhydride, or with nicotinic acid in the pres ence of dicyclohexylcarbodiimide or other suitable cou pling agent, to afford the nicotinuramide. The nicotinuramide may then be quaternized and the quate t-callen-NH; nary reduced as described in the preceding paragraph. RO The procedure of the second paragraph of this method may be repeated using picolinic acid or its acid as defined herein. chloride or anhydride, or isonicotinic acid or its acid O chloride or anhydride, in place of nicotinic acid or its ILLUSTRATIVE SYNTHETIC METHODS acid chloride or anhydride, respectively, to convert I. Methods for Derivatizing -NH2 or -NH drugs such as those specifically mentioned for derivatiz Functions in Drugs ing by this method to the corresponding glycyl Method A picolinamides and glycyl isonicotinamides and then to The drug is reacted with nicotinuric acid chloride, 15 the corresponding compounds of formula (II) and (I). with nicotinuric acid anhydride, or with nicotinuric The procedure of the first paragraph of this method acid in the presence of a suitable coupling agent such as may be similarly adapted. Moreover, any of these pro dicyclohexylcarbodiimide, in an appropriate organic cedures may be repeated, substituting a different amino solvent, to afford the corresponding glycylnicotina acid or nicotinic acid derivative thereof for the glycine mide, or nicotinuramide. The nicotinuramide is then 20 or nicotinuric acid used above, e.g. replacing glycine quaternized, typically by treatment with methyl iodide with alanine, valine, leucine, phenylalanine, isoleucine, in a suitable organic solvent, to afford the quaternary methionine, asparagine or glutamine. derivative of formula (II), which is then reduced by Alternatively, the drug may be reacted with an acti treatment with sodium dithionite or sodium borohy vated ester of nicotinuric acid or the like, e.g. a dride as generally described hereinabove to afford the 25 sucinimidyl ester such as desired compound of formula (I). The representative drugs depicted below may be derivatized in this manner to the corresponding compounds of formulas (II) and V O o (I). Bupropion, difluamine, propranolol, ethyl g-carbo 30 line-3-carboxylate, prizidilol, pseudoephedrine, 5 CNHCH2CON amidino-2-(5-anidino-2-benzofuranyl)indole, 4,6- diimidazolino-2-phenylbenzo(b)thiophene, 2-guanidino ar,O 4,5-di-n-propyloxazole, 2-guanidino-4,5-diphenylox N azole, glucosamine, 6-amino-6-deoxy-D-glucose and 6(hydroxyimino)phenyl)methyl-1-(methylethyl)sul 35 and the product quaternized and then reduced as de fonyl-1H-benzimidazol-2-amine may be similarly scribed in the first paragraph of this method to afford derivatized. the identical products. As yet another alternative, the Alternatively, glycine may be first reacted with a activated ester, e.g. the succinimidyl ester depicted reagent capable of introducing an amino protecting above, may be quaternized (e.g. by treatment with group such as benzyloxycarbonyl or t-butoxycarbonyl methyl iodide) and the quaternized activated ester then (e.g. as in Scheme 1 or 2 hereinabove) and the N reacted with the drug. The quaternary compound of protected glycine then reacted with the drug in the formula (II) thus obtained may then be reduced as de presence of a coupling agent such as dicyclohexylcar scribed in the first paragraph of this method to give the bodiimide, followed by removal of the N-protecting 45 corresponding compound of formula (I).

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5,389,623 100 Method B Obviously, other esters may be similarly prepared in the first step by use of other esterifying agents. This is a variation of Method A used when the drug The representative drugs depicted below may be contains at least one -COOH function which is to be derivatized in this manner to the corresponding com protected. 5 pounds of formulas (II) and (I). Ceforanide, furosemide and acivicin may be similarly derivatized. The drug is first converted to the corresponding The glycyl picolinamide and glycyl isonicotinamide t-butyl ester by conventional esterification techniques. quaternary and dihydro derivatives of the drugs specifi cally mentioned for derivatizing according to this That ester is then used as the starting material and 10 method may be similarly prepared, as may derivatives Method A is repeated. of other amino acids. See Method A, last paragraph.

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65 5,389,623 101 102

5,389,623 105 106

penu?uoo 5,389,623 107 108 Method C acted with trimethylacetyl chloride to form the pro This is a variation of Method A used when the drug tected nicotinuramide. contains one or more OH functions which are to be Various other hydroxy protecting groups may be introduced in similar fashion. protected. The representative drugs depicted be low may be The drug is first reacted with excess trimethylacetyl derivatized in this manner to the corresponding com chloride to convert the hydroxy group(s) to pivalyloxy pounds of formulas (II) and (I). The corresponding group(s). (This process is generally conducted in the glycyl picolinamide and glycyllisonicotin amide quater presence of a base; however, strongly acid conditions nary and dihydro derivatives may be similarly pre O pared, as may derivatives of amino acids other than are used when an amine function is present.) That pro glycine. See Method A, last paragraph. Moreover, tected derivative is then used as the starting material drugs such as norepiniphrine, epinephrine, phenyleph and subjected to Method A. Alternatively, the first two rine, atenolol, metoprolol, pentostatin (2'-deoxycofor steps may be reversed, i.e. the drug may be first con mycin), glucosamine, 6-amino-6-deoxy-D-glucose and verted to the nicotinuramide, which may then be re 15 pseudoephedrine may be similarly derivatized.

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5,389,623 111 112 Method D other protecting groups can be introduced instead. The amine function is derivatized according to Method A. This variation of Method A can be used when the The representative drugs listed below may be deriva drug contains one or more OH and COOH functions tized in this manner to the corresponding compounds of which are to be protected. The protecting groups, for formulas (II) and (I). The corresponding glycyl picolinamide and glycyl isonicotinamide quaternary example, the t-butyl ester and pivalyloxy groups, are and dihydro derivatives may be similarly prepared, as introduced as described in Methods B and C, in the may derivatives of amino acids other than glycine. See sequence considered most convenient. Obviously, Method A, last paragraph. O

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65 5,389,623 113 114 5,389,623 115 116 Method E This method is of particular use when the -NH function is part of an amide or imide or a very low pKa primary or secondary amine. 5 The drug is first reacted with an aldehyde (e.g. form function may be replaced with steps analogous to those detailed in the second paragraph of Method A. aldehyde, benzaldehyde, acetaldehyde or chloral The procedure of the preceding paragraph may be (Cl3CCHO); for example, in the case of formaldehyde, repeated using picolinic acid or its acid chloride or one converts the -NH-function to a anhydride, or isonicotinic acid or its acid chloride or 10 anhydride, in place of nitotinic acid or its acid chloride or anhydride, respectively (as called for in the second sh;OH paragraph of Method A), to convert drugs such as those -N- specifically mentioned for derivatizing according to this Method to the corresponding glycyl picolinic acid es function and thus forms a suitableo bridging group. The 15 ters and glycyl isonicotinic acid esters and then to the resultant compound is then reacted with nicotinuric corresponding compounds of formulas (II) and (I). De rivatives of amino acids other than glycine may be simi acid in the presence of a suitable dehydrating agent, or larly prepared. See Method A, last paragraph. with nicotinuric acid chloride or nicotinuric acid anhy As yet another alternative, the intermediate com dride, to form the corresponding nicotinuric acid ester 20 pound containing the of the partial formula (H.OH N N 25 group or the like may be reacted with thionyl chloride -N-sesh;occHNHC O to afford the corresponding compound containing a The resultant intermediate is then quaternized and re CH2Cl duced as in Method A. The alternative process utilizing -N- an activated ester or quaternary derivative thereof which is described in Method A may be utilized here as or similar group. That derivative may then be reacted with a metallic salt (especially a silver or thallous salt) well. 35 of nicotinuric acid or the like (formed, e.g. by reacting The representative starting drugs depicted below nicotinuric acid or the like with fresh silver hydroxide may be derivatized in this manner to the corresponding or oxide or with thallous ethoxide). The resultant nico compounds of formulas (II) and (I). Drugs such as tinuric acid ester of the partial formula minocycline, doxycycline, oxytetracycline, tetracy cline, methacycline, atenolol, sulfadiazine, cyclophos O N phamide, dactinomycin, mitomycin, 3-deazaguanine, I progabide and 6-mercaptopurine may be similarly Hoc-CHNHC O derivatized. Alternatively, the steps subsequent to formation of 45 or like derivative is then quaternized and subsequently the reduced as in Method A.

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5,389,623 127 128

ponu?uoo 5,389,623 129 130

penu?uoo

5,389,623 135 136 Method F pared. The ester is then used as the starting material and Method E is repeated. This method is a variation of Method E which can be The representative starting drugs depicted below used when the -NH-function is part of an amide or may be derivatized in this manner to the corresponding imide or low pKa primary or secondary amine and the compounds of formulas (II) and (). Drugs such as car drug contains one or more -COOH functions which benicillin, phenoxymethylpenicillin, methicillin, nafcil is/are to be protected. Typically, the carboxyl group or lin, ticarcillin, dicloxacillin, cefazolin, cefoxitin, nox alactam, aminopterin, furosemide, and 5-methyltetrahy groups is/are first converted to the corresponding drohomofolic acid may be similarly derivatized. pivaloyloxymethyl ester by known esterification tech O The alternative procedures described in Method E, niques. Obviously, other esters may be similarly pre last paragraph, may be used in Method Faiso.

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5,389,623 143 144. Method G tive is then used as the starting material and subjected to Method E. This is a variation of Method E used when the drug Other hydroxy protecting groups may be introduced in similar fashion. also contains one or more hydroxy functions which are 5 The representative drugs depicted below may be to be protected. Typically, the drug is first reacted with derivatized in this manner to the corresponding com pounds of formulas (II) and (I). excess trimethylacetyl chloride to convert the hydroxy The alternative procedures described in Method E, group(s) to pivalyloxy group(s). That protected deriva last paragraph, may be used in Method G also. 10

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5,389,623 147 48 Method H boxylic acid derivatives of the drugs mentioned with The procedure of the second paragraph of Method A those methods. The procedure of the first paragraph of this method is followed, except that removal of the N-protecting may be repeated using 4-isoquinolinecarboxylic acid or group is followed by reaction with 3-quinolinecarboxy 5 its acid chloride or anhydride to convert drugs such as lic acid or its acid chloride or anhydride instead of those mentioned with Methods A, B, C, D, E, F or G to nicotinic acid or its acid chloride or anhydride. the corresponding 4-isoquinolinecarboxylic acid deriva The representative drugs depicted below may be tives. derivatized in this manner to the corresponding com The procedure of the first or fourth paragraph of this pounds of formulas (II) and (I), as may the remaining 10 method may be repeated, substituting a different amino drugs mentioned with Method A. acid, e.g. alanine, valine, leucine, phenylalanine, isoleu cine, methionine, asparagine or glutamine, for the gly The procedure of the first paragraph of Method A cine used in the first step. (See Method A, second para may be similarly adapted to the production of the 3 graph). quinolinecarboxylic acid derivatives. Moreover, 15 The general procedures described above may be uti Method H may be combined with Methods B, C, D, E, lized to provide the 1,2-dihydro derivatives as well as F or G to afford the corresponding 3 -quinolinecar the depicted 1,4-dihydros.

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5,389,623 153 154 Method I tively, in the preparation of the reactant depicted above. The procedure of the second paragraph of Method is This variation affords a reactant of the formula followed, except that a reactant of the formula N COOCH2COOH O COOCH2COOH o

N is used place of nicotinic acid. (That starting material 1. O may be prepared by reacting nicotinic anhydride, nico N O COOCH2COOH tinoyl chloride or nicotinic acid with glycolic acid.) The representative drugs depicted below may be derivatized in this manner to the corresponding com pounds of formulas (II) and (I), as may the remaining 15 which can then be used in place of nicotinic acid to drugs listed with Method A. prepare derivatives of drugs such as those mentioned Similarly, Method I may be combined with Methods with Methods A, B, C or D. B, C or D to afford the corresponding derivatives, e.g. The procedure of the first or fourth paragraph of this of the drugs mentioned with those methods. method may be repeated, substituting a different amino The foregoing procedure can be repeated using pico 20 acid, e.g. alanine, valine, leucine, phenylalanine, isoleu linic acid or its acid chloride or anhydride, or isonico cine, methionine, asparagine or glutamine, for the gly tinic acid or its acid chloride or anhydride, in place of cine used in the first step. (See Method A, second para nicotinic acid or its acid chloride or anhydride, respec graph). 25

3 O

3 5

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5,389,623 157 158

panu?uoo 5,389,623 159) 160

pemuguoo

5,389,623 163 164 Method J Similarly, Method j may be combined with Methods B, C or D to afford the corresponding derivatives, e.g. The procedure of the second paragraph of Method A of the drugs mentioned with those methods. is followed, except that a reactant of the formula The procedure described above can be repeated using picolinamide or isonicotinamide in place of nicotina mide in the preparation of the reactant depicted above. CONH2 This variation affords a reactant of the formula O I CONH2 N+ 10 (CH2)COOH Ol I or (6) I wherein n = 1-3, preferably 2, is used in place of nico N+ CONH2 N+ tinic acid. (That reactant may be prepared from nicotin 15 (CH2)COOH (CH2)COOH amide, e.g. when n=2, by reacting 3-iodopropionic acid which can then be used in place of nicotinic acid in the with nicotinamide.) The quaternary salt of formula (II) procedure of the first paragraph of this method, to af. thus obtained may then be reduced as described in ford the corresponding derivatives, e.g. of the drugs 20 mentioned with Methods A, B, C or D. Method A. The procedure of the first or fourth paragraph of this The drugs depicted below may be derivatized in this method can be repeated, substituting a different amino manner to the corresponding compounds of formulas acid, e.g. alanine, valine, leucine, phenylalanine, isoleu cine, methionine, asparagine or glutamine, for the gly (II) and (I), as may the remaining drugs mentioned with 25 cine used in the first step. (See Method A, second para Method A. graph).

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5,389,623 169 170 then be quaternized and the quaternary reduced as de II. Methods for Derivatizing -OH and -SH scribed in the preceding paragraph. Functions in Drugs The representative drugs depicted below may be Method K derivatized in this manner to the corresponding com The drug is reacted with nicotinuric acid chloride, 5 pounds of formulas (II) and (I). Estriol, lincomycin, with nicotinuric acid anhydride, or with nicotinuric apomorphine, meptazinol, cyclazocine, phenazocine, acid in the presence of a suitable coupling agent such as metopon, myfadol, naltrexone, alazocine, oxilorphan, dicyclohexyl carbodiimide, in an appropriate organic nalmexone, thioguanine, levorphanol, benzestrol, dieth solvent, to afford the corresponding glycylnicotinate, ylstilbestrol, pentostatin (2'-deoxycoformycin), tiazofu or nicotinurate. The nicotinurate is then quaternized 10 and subsequently reduced as described above in Method rin, sangivamycin, 2 -deoxy-D-glucose, 2-deoxy-2- A. When the drug contains more than one reactive fluoro-D-mannose and phenyl-6-chloro-6-deoxy-3-D- hydroxyl or thiol function, reaction conditions may be glucopyranoside may be similarly derivatized. varied so that more than one hydroxyl or thiol function The procedure of the second paragraph of this will be converted to nicotinurate groupings. The alter 15 method may be repeated using picolinic acid or its acid native process utilizing an activated ester or quaternary chloride or anhydride, or isonicotinic acid or its acid derivative thereof which is described in Method A may chloride or anhydride, in place of nicotinic acid or its be utilized here as well. acid chloride or anhydride, respectively, to convert Alternatively, glycine may be first reacted with a drugs such as those specifically mentioned for derivatiz reagent capable of introducing an amino protecting 20 ing by this method to the corresponding glycyl pico group such as benzyloxycarbonyl or t-butylcarbonyl linic acid esters or glycyl isonicotinic acid esters and (e.g. as in Scheme 1 or 2 hereinabove) and the N- pro then to the corresponding compounds of formulas (II) tected glycine then reacted with the drug in the pres and (). The procedure of the first paragraph of this ence of a coupling agent such as dicyclohexylcarbodi method may be similarly adapted. Moreover, any of imide, followed by removal of the N- protecting group, 25 these procedures may be repeated, substituting a differ followed by reaction with nicotinoyl chloride or nico ent amino acid or nicotinic acid derivative thereof for tinic anhydride, or with nicotinic acid in the presence of the glycine or nicotinuric acid used above, e.g. replac dicyclohexylcarbodiimide or other suitable coupling ing glycine with alanine, valine, leucine, phenylalanine, agent, to afford the nicotinurate. The nicotinurate may isoleucine, methionine, asparagine or glutamine. 30

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penu?uoo

5,389,623 185 186

ponu?uoo

5,389,623 189 190

ponu?uoo 5,389,623 1911 192

panu?uoo