Brain-specific drug delivery

Claim 2

A compound adapted for the site-specific/sustained delivery of a centrally acting drug species to the brain, said compound being: (a) a compound of the formula [D-DHC] (I) wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR799## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH 2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH 2 or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; or (b) a non-toxic pharmaceutically acceptable salt of a compound of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine ⃡ pyridinium salt redox carrier.

Claim 3

A compound according to claim 1, wherein [DHC] comprises the reduced form of a nicotinic acid derivative.

Claim 4

A compound according to claim 1, wherein [DHC] comprises the reduced form of a trigonelline.

Claim 5

A compound according to claim 1, wherein [DHC] comprises the reduced form of an isoquinoline or of a pyridinium alcohol.

Claim 6

A compound according to claim 1, wherein [DHC] is ##STR800## wherein the ##STR801## substituents in formulae (i), (ii) and (iii) each can be in the 2-, 3- or 4-position on the ring, R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl and R 3 is (CH 2 ) n wherein n is 1, 2 or 3.

Claim 7

A compound according to claim 5, wherein [DHC] is ##STR802##

Claim 8

A compound of the formula [D-QC].sup.+ Y.sup.- (II) wherein Y - is the anion of a non-toxic pharmaceutically acceptable acid, [D] is a centrally acting drug species and [QC] + is the hydrophilic, ionic pyridinium salt form of a dihydropyridine ⃡ pyridinium salt redox carrier, with the proviso that when [QC] + is ##STR803## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH 2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH 2 or OH functional group to the carbonyl function of [QC] + , then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol.

Claim 9

A compound of the formula [D-QC].sup.+ Y.sup.- (II) wherein Y - is the anion of a non-toxic pharmaceutically acceptable acid, [D] is a centrally acting drug species and [QC] + is the hydrophilic, ionic pyridinium salt form of a dihydropyridine ⃡ pyridinium salt redox carrier, with the proviso that when [QC] + is ##STR803## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH 2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH 2 or OH functional group to the carbonyl function of [QC] + , then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol.

Claim 10

A compound according to claim 7, wherein [QC[ + comprises the ionic pyridinium salt form of a nicotinic acid derivative; of an isoquinoline; or of a pyridinium alcohol.

Claim 11

A compound according to claim 8, wherein [QC] + compises the ionic pyridinium salt form of a trigonelline.

Claim 12

A compound according to claim 7, wherein [QC] + is ##STR804## wherein the ##STR805## substituents in formulae (i), (ii) and (iii) each can be in the 2-, 3- or 4-position on the ring, R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl and R 3 is (CH 2 ) n where n is 1, 2 or 3.

Claim 13

A compound as defined by claim 10, wherein [QC] + is ##STR806##

Claim 14

A compound according to claim 1, wherein [D] is a steroid residue.

Claim 15

A compound according to claim 12, wherein the steroid is a steroid sex hormone.

Claim 16

A compound according to claim 13, wherein the steroid sex hormone is an androgen.

Claim 17

A compound according to claim 13, wherein the steroid sex hormone is an estrogen.

Claim 18

A compound according to claim 13, wherein the steroid sex hormone is a progestin.

Claim 19

A compound according to claim 13, wherein the steroid sex hormone is testosterone.

Claim 20

A compound according to claim 13, wherein the steroid sex hormone is methyl testosterone.

Claim 21

A compound according to claim 13, wherein the steroid sex hormone is ethinyl estradiol.

Claim 22

A compound according to claim 13, wherein the steroid sex hormone is norgestrel.

Claim 23

A compound according to claim 13, wherein the steroid sex hormone is mestranol.

Claim 24

A compound according to claim 13, wherein the steroid sex hormone is norethindrone.

Claim 25

A compound according to claim 13, wherein the steroid sex hormone is norethynodrel.

Claim 26

A compound according to claim 13, wherein the steroid sex hormone is ethisterone.

Claim 27

A compound according to claim 13, wherein the steroid sex hormone is estradiol.

Claim 28

A compound according to claim 13, wherein the steroid sex hormone is estriol.

Claim 29

A compound according to claim 13, wherein the steroid sex hormone is estrone.

Claim 30

A compound according to claim 13, wherein the steroid sex homone is dimethisterone.

Claim 31

A compound according to claim 13, wherein the steroid sex hormone is allylestrenol.

Claim 32

A compound according to claim 13, wherein the steroid sex hormone is cingestol.

Claim 33

A compound according to claim 13, wherein the steroid sex hormone is ethynerone.

Claim 34

A compound according to claim 13, wherein the steroid sex hormone is lynestrenol.

Claim 35

A compound according to claim 13, wherein the steroid sex hormone is norgesterone.

Claim 36

A compound according to claim 13, wherein the steroid sex hormone is norvinisterone.

Claim 37

A compound according to claim 13, wherein the steroid sex hormone is ethynodiol.

Claim 38

A compound according to claim 13, wherein the steroid sex hormone is oxogestone.

Claim 39

A compound according to claim 13, wherein the steroid sex hormone is tigestol.

Claim 40

A compound according to claim 13, wherein the steroid sex hormone is quinestrol.

Claim 41

A compound according to claim 12, wherein the steroid is an antiinflammatory steroid.

Claim 42

A compound according to claim 39, wherein the antiinflammatory steroid is hydrocortisone.

Claim 43

A compound according to claim 39, wherein the antiinflammatory steroid is betamethasone.

Claim 44

A compound according to claim 39, wherein the antiinflammatory steroid is cortisone.

Claim 45

A compound according to claim 39, wherein the antiinflammatory steroid is dexamethasone.

Claim 46

A compound according to claim 39, wherein the antiinflammatory steroid is flumethasone.

Claim 47

A compound according to claim 39, wherein the antiinflammatory steroid is fluprednisolone.

Claim 48

A compound according to claim 39, wherein the antiinflammatory steroid is meprednisone.

Claim 49

A compound according to claim 39, wherein the antiinflammatory steroid is methyl prednisolone.

Claim 50

A compound according to claim 39, wherein the antiinflammatory steroid is prednisolone.

Claim 51

A compound according to claim 39, wherein the antiinflammatory steroid is prednisone.

Claim 52

A compound according to claim 39, wherein the antiinflammatory steroid is triamcinolone.

Claim 53

A compound according to claim 39, wherein the antiinflammatory steroid is cortodoxone.

Claim 54

A compound according to claim 39, wherein the antiinflammatory steroid is fludrocortisone.

Claim 55

A compound according to claim 39, wherein the antiinflammatory steroid is flurandrenolone acetonide.

Claim 56

A compound according to claim 39, wherein the antiinflammatory steroid is paramethasone.

Claim 57

A compound adapted for the site-specific/sustained delivery of a centrally acting drug species to the brain, said compound being: (i) a compound of the formula D'"(--Q").sub.n (I'") wherein D'" is the residue of a centrally acting drug containing at least one --OH or --SH functional group, said residue being formed by removal of a hydrogen atom from at least one of the --OH or --SH functional groups in said drug; n" is a positive integer equal to the number of said --OH or --SH functional groups from which a hydrogen atom has been removed; and --Q" is a radical of the formula ##STR807## wherein the dotted line in formulae (a), (b), (c), (d) or (e) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formulae (g), (i), (k), (l) and (n) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring; R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl; R 3 is C 1 to C 3 alkylene; X is --CONR'R" wherein R' and R", which can be the same or different, are each H or C 1 -C 7 alkyl, or X is --CH═NOR'" wherein R'" is H or C 1 -C 7 alkyl, the ##STR808## groupings in formulae (a), (b), (c) and (e) and the X substituent in formula (d) can each be attached at the 2, 3 or 4 position of the dihydropyridine ring; the ##STR809## groupings in formulae (g), (i), (k) and (n) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the dihydroquinoline ring; and the ##STR810## groupings in the formulae (f), (h), (j) and (o) and the X substituent in formula (m) can each be attached at the 1, 3 or 4 position of the dihydroisoquinoline ring; or (ii) a non-toxic pharmaceutically acceptable salt of a compound of formula (I'"); with the proviso that when the compound is other than a salt as claimed in (ii) above, when n is 1, when --Q" is ##STR811## wherein R 1 is defined as above, and when the centrally acting drum from which D'" is derived contains only one primary or secondary --OH functional group, no other --OH functional groups and no --NH 2 , --NH--, --SH or --COOH functional groups, then D'" must be the residue of a centrally acting drug other than a steroid sex hormone or long chain alkanol.

Claim 58

A compound according to claim 55, wherein D'" is the residue of a steroid sex hormone.

Claim 59

A compound according to claim 56, wherein D'" is the residue of an androgen.

Claim 60

A compound according to claim 56, wherein D'" is the residue of an estrogen.

Claim 61

A compound according to claim 56, wherein D'" is the residue of a progestin.

Claim 62

A compound according to claim 56, wherein D'" is the residue of testosterone.

Claim 63

A compound according to claim 56, wherein D'" is the residue of methyl testosterone.

Claim 64

A compound according to claim 56, wherein D'" is a residue of estradiol.

Claim 65

A compound according to claim 56, wherein D'" is a residue of estriol or estrone.

Claim 66

A compound according to claim 56, wherein D'" is a residue of ethinyl estradiol.

Claim 67

A compound according to claim 56, wherein D'" is the residue of mestranol.

Claim 68

A compound according to claim 56, wherein D'" is the residue of quinestrol.

Claim 69

A compound according to claim 56, wherein D'" is the residue of norethindrone.

Claim 70

A compound according to claim 56, wherein D'" is the residue of norgestrel.

Claim 71

A compound according to claim 56, wherein D'" is the residue of ethisterone.

Claim 72

A compound according to claim 56, wherein D'" is the residue of dimethisterone.

Claim 73

A compound according to claim 56, wherein D'" is the residue of allylestrenol.

Claim 74

A compound according to claim 56, wherein D'" is the residue of cingestol or ethynerone.

Claim 75

A compound according to claim 56, wherein D'" is the residue of lynestrenol.

Claim 76

A compound according to claim 56, wherein D'" is the residue of norgesterone or norvinisterone.

Claim 77

A compound according to claim 56, wherein D'" is a residue of ethynodiol.

Claim 78

A compound according to claim 56, wherein D'" is the residue of oxogestone or tigestol.

Claim 79

A compound according to claim 56, wherein D'" is the residue of of norethynodrel.

Claim 80

A compound according to claim 56, wherein D'" is the residue of an anti-inflammatory steroid.

Claim 81

A compound according to claim 27, wherein D'" is a residue of cortisone or hydrocortisone.

Claim 82

A compound according to claim 27, wherein D'" is a residue of betamethasone, dexamethasone, flumethasone, fluprednisolone, methyl, prednisolone, meprednisone, prednisolone, prednisone, cortodoxone, fludrocortisone, paramethasone or triamcinolone.

Claim 83

A non-toxic pharmaceutically acceptable quaternary salt having the formula D'"(--Q".sup.⊕).sub.n"Y.sub.n".sup.⊖ (II'") wherein D'"and n" are as defined in claim 55, Y.sup.⊖ is the anion of a non-toxic pharmaceutically acceptable acid and --Q".sup.⊕ has the formula ##STR812## wherein R 1 is C 1 -C 7 alkyl or C 7 -C 10 aralkyl; R 3 is C 1 to C 3 alkylene; X is --CONR'R" wherein R' and R", which can be the same or different, are each H or C 1 -C 7 alkyl, or X is --CH═NOR'" wherein R'" is H or C 1 -C 7 alkyl; the ##STR813## groupings in formulae (a), (b), (c) and (e) and the X substituent in formula (d) can each be attached at the 2, 3 or 4 position of the pyridinium ring; the ##STR814## groupings in formulae (g), (i), (k) and (n) and the X substituent in formula (1) can each be attached at the 2, 3 or 4 position of the quinolinium ring; and the ##STR815## groupings in formulae (f), (h), (j) and (o) and the X substituent in formula (m) can each be attached at the 1, 3 or 4 position of the isoquinolinium ring; with the proviso that when n is 1, when --Q.sup.⊕ is ##STR816## wherein R 1 is defined as above, and when the centrally acting drug from which D'" is derived contains only one primary or secondary --OH functional group, no other --OH functional groups and no --NH 2 , --NH--, --SH or --COOH functional groups, then D'" must be the residue of a centrally acting drug other than a steroid sex hormone or long chain alkanol.

Claim 84

A method for site-specifically/sustainedly delivering a centrally acting drug species to the brain, comprising administering to an animal in need of such treatment a quantity of a compound as claimed in claim 1 sufficient to release a pharmacologically effective amount of said centrally acting drug species to the brain.

Claim 85

A method according to claim 82, wherein the compound is administered in the form of a pharmaceutically acceptable sustained release composition or wherein the compound is administered via a route of administration capable of slowly releasing the compound into the body.

Claim 86

A pharmaceutical composition of matter comprising a compound as claimed in claim 1 and a non-toxic pharmaceutically acceptable carrier thereof.

Claim 87

A pharmaceutical composition of matter, in unit dosage form, for use in delivering a pharmacologically effective amount of a centrally acting drug species to the brain, said composition comprising: (i) an amount of a compound as claimed in claim 1 sufficient to release a pharmacologically effective amount of a centrally acting drug species to the brain; and (ii) a non-toxic pharmaceutically acceptable carrier therefor.

Claim 88

A pharmaceutical composition as claimed in claim 85, said composition being a pharmaceutically acceptable sustained release composition.