||||||||||||||| USOO5296483A United States Patent (19) 11 Patent Number: 5,296,483 Bodor 45 Date of Patent: Mar. 22, 1994 54 BRAIN-SPECIFICANALOGUES OF site-specific/sustained delivery of centrally acting drug CENTRALLY ACTING AMNES species to the brain, are compounds of the formula 75 Inventor: Nicholas S. Bodor, Gainesville, Fla. 73 Assignee: University of Florida, Gainesville, (I) Fla. 21 Appl. No.: 766,502 22 Filed: Sep. 27, 1991 and the non-toxic pharmaceutically acceptable salts Related U.S. Application Data thereof, wherein D is the residue of a centrally acting 60 Division of Ser. No. 505,910, Apr. 4, 1990, Pat. No. primary, secondary or tertiary amine and 5,082,853, which is a division of Ser. No. 208,872, Jun. 20, 1988, Pat. No. 4,933,438, which is a division of Ser. No. 785,903, Aug. 29, 1985, Pat. No. 4,771,059, filed as PCT/US85/00236, Feb. 15, 1985, which is a continu ation-in-part of Ser. No. 584,800, Feb. 29, 1984, aban doned. 51 Int. Cl...................... A61K 31/55; CO7D 401/06 is an unsubstituted or substituted dihydropyridyl, dihy 52 U.S. C. .................................... 514/217; 514/214; droquinolyl or dihydroisoquinolyl radical. The corre 540/586; 546/141; 546/142; 546/145; 546/146; sponding ionic pyridinium, quinolinium and 546/147; 54.6/150; 546/152; 54.6/153; 546/296; isoquinolinium salts 546/297; 546/299 58) Field of Search ....................... 514/213, 214, 217; 540/586 56) References Cited p-N+ X, PUBLICATIONS Thiel, et al., "Chemical Abstracts', vol. 59, 1963, Col. wherein X is the anion of a non-toxic pharmaceuti 6389e-639 a. cally acceptable acid, are also disclosed. Primary Examiner-C. Warren Ivy Assistant Examiner-James H. Turnipseed Attorney, Agent, or Firm-Burns, Doane, Swecker & Mathis 57 ABSTRACT The subject compounds, which are adapted for the 16 Claims, No Drawings 5,296,483 1 2 cerning the nature of the barrier have been proposed. BRAIN-SPECIFICANALOGUES OF CENTRALLY The widely accepted concept describes the boundary as ACTING AMNES a fat-like layer interspersed with small pores, although the BBB is not a simple, anatomically well-defined uni This application is a divisional of application Ser. No. tary physical entity. Shuttleworth, Prog. Exp. Tumor 07/505,910, filed Apr. 4, 1990, now U.S. Pat. No. Res., 17, 279 (1972). Penetration of such a barrier may 5,082,853, which is divisional of application Ser. No. occur by several processes: lipid soluble substances may 07/208,872, filed Jun. 20, 1988, now U.S. Pat. No. passively penetrate into the cells, while small molecules 4,933,438, which is a divisional of application Ser. No. such as water and urea may pass through the pores. In 06/785,903, filed Aug. 29, 1985, now U.S. Pat. No. 10 addition to these simple physical processes, carrier 4,771,059, which is the U.S. national phase of mediated and active transport processes govern the PCT/US85/00236, filed Feb. 15, 1985 and a continua movement of many molecules through the BBB. Thus, tion-in-part of application Ser. No. 06/584,800, filed it is generally accepted that lipid solubility, degree of Feb. 29, 1984, now abandoned. ionic dissociation or protonation and the ability of tem 15 porary combination with membrane constituents affect FIELD OF THE INVENTION delivery through the BBB. It has been shown, for exam The present invention relates to new derivatives of ple, that in the class of barbiturates, a quantitative corre centrally acting amines in which a primary, secondary lation could be established between their ease to pass or tertiary amine function has been replaced with a into the brain (as reflected by the different times of dihydropyridine/pyridinium salt redox system. The 20 onset of anesthetic action) and their lipid/water parti new dihydropyridine analogues are a delivery system tion coefficient. Mark et al, J. Pharmacol and Exp. for the corresponding new quaternary compounds, Therap, 123, 79 (1957). The role of lipid solubility in which are pharmacologically active in vivo and are drug penetration through the BBB is also exemplified characterized by site-specific and sustained delivery to by the better absorption of the sparingly water-soluble the brain. 25 thiamine propyl disulfide (TPD) as compared to the water-soluble thiamine hydrochloride (THCl). BACKGROUND OF THE INVENTION Thomson et al, Ann. Int, Med., 74, 529 (1971). Some The delivery of drug species to the brain is of times materials such as glucose and amino acids are trans seriously limited by transport and metabolism factors ported by active mechanism, characterized by satura and, more specifically, by the functional barrier of the 30 tion, bidirectional molecular specificity, bidirectional endothelial brain capiliary wall, i.e. the blood-brain competitive inhibition and bidirectional countertran barrier or BBB. Site-specific delivery and sustained sport. Fishman, Am. J. Physiol, 206, 836 (1964). delivery of drugs to the brain are even more difficult. Changes in permeability of the BBB can be caused by Indeed, the barriers separating plasma from the brain several pathological and toxicological processes. Par and cerebrospinal fluid (CSF) are complex systems 35 dridge, Connor and Crawford, CRC Crit. Rey. Toxicol., Involving passive and active transport and subserve a 179 (1975). A general increase in the barrier permeabil number of important functions. The boundary between ity, such as a nonspecific breakdown of the barrier has, plasma and the central nervous system (CNS) is much however, several consequences, including cerebral less permeable than that between plasma and other edema. tissue cells to a variety of water soluble substances, such It too is well documented that the BBB is relatively as organic electrolytes, organic acids and bases, as well impermeable to the ionized forms of drugs and other as to large molecules such as proteins. Such a barrier molecules. Drugs which are weak organic electrolytes also provides a path for clearance from the brain of the appear to pass from blood to CSF to reach a steady state breakdown products of cellular metabolism. The CNS ratio characteristic of each molecule according to its and its fluids can be considered basically a three-com 45 pka and the existence of a normal pH gradient between partment system: the blood or the plasma, CSF and blood and CSF. It is clear that it is the most difficult for brain tissue. There is a diffusion-controlled exchange quaternary pyridinium or ammonium salts to penetrate between CSF and the extra-cellular fuid (CF) of the the BBB. brain. It has also been suggested that the permeabilities And removal of substances from the brain and CSF is of blood-CSF and blood-brain barriers are practically SO obviously a significant factor in regulating drug concen identical with respect to drugs and other foreign sub trations in the CNS. There are several efflux processes: stances. Mayer et al., J. Pharmacol and Exp. Therap, bulk flow via the arachnoid villi, diffusion of lipid solu 125, 185 (1959). ble substances into brain and blood, active transport and The BBB is, moreover, basically the result of the fact metabolism by adjacent meninges. Once a drug or me that the endothelial cells in the brain capillaries are 55 tabolite enters the CSF from blood or brain by simple joined by continuous, tight intercellular junctions, such diffusion, it may rapidly be removed, either by nonse that material has to pass through the cells rather than lective bulk flow or by active transport mechanism between them in order to move from blood to brain. It associated with the choroid plexus or other nondefined is interesting that there are areas within the brain, such structures in the CSF compartment. It is generally ac as the subfornical body and the postremia, in which the cepted that highly lipid-soluble drugs leave the CSF capillary cells are not closely linked so that they lack more rapidly than poorly lipid-soluble ones, but the the characteristics of the BBB. They provide the entry barrier to passage of compounds from CSF has only of small amounts of compounds which would not ordi superficial similarity to the blood-CSF barrier. narily enter the barriers. Hoffman and Olszewzki, Neu Drug elimination processes from the brain are signifi rology (Minneap.), 11, 1081 (1961). 65 cantly directly related to drug accumulation in the Foreign compounds which enter organs other than brain. It is generally assumed that efflux in the opposite the central nervous system with ease, may penetrate the direction involves almost the same processes as for CNS slowly or hardly at all. A number of theories con entry, except that the role of the bulk flow and the 5,296,483 3 4. metabolic processes in the brain are not to be over dihydropyridine latentiated prodrug form thereof. looked. Thus, a hydrophilic compound (2-PAM) was made The two elimination processes studied in the earlier lipoidal (i.e. lipophilic) by making its dihydropyridine literature and which can be said to have a certain bear form (Pro-2-PAM) to enable its penetration through ing on the present invention involve elimination from lipoidal barriers. This simple prodrug approach allowed the brain of ionic species. Thus, it is found that non the compound to get into the brain as well as other metabolized ionic species, such as the acetate ion, have organs, but this manipulation did not and could not a three times slower elimination rate from the CSF than result in any brain specificity. On the contrary, such from the blood. Freundt, Arz, Forsch, 23, 949 (1973). approach was delimited to relatively small molecule An even more dramatic change in the elimination rate O quaternary pyridinium ring-containing drug species and was found in the case of a quaternary piperidinium salt.