Selective Binding Compounds for 5-Hydroxytryptamine 1-A-Receptors and Pharmaceutical Compositions Containing Them

Europaisches Patentamt 0 338 877 3 European Patent Office Publication number: A1 Office europeen des brevets EUROPEAN PATENT APPLICATION @ Application number: 89400817.6 int.ci.4: C 07 D 209/08 C 07 D 215/20, © Date of filing: 23.03.89 C 07 C 103/64, C 07 C 103/44, C 07 C 103/50, C 07 C 93/14, A 61 K 31/40, A 61 K 31/47, A 61 K 31/165 @ Priority: 25.03.88 US 173442 ® Applicant: THE BOARD OFTRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY of Stanford University © Date of publication application : Stanford California 94305 (US) 25.10.89 Bulletin 89/43 Pitha, Josef @ Designated Contracting States: 417 S. Anglesea Street AT BE CH DE ES FR GB GR IT LI LU NL SE Baltimore Maryland 21224 (US) @ Inventor: Peroutka, Stephen J. 861 AllardiceWay Stanford California 94305 (US) Pitha, Josef 417 S. Anglesea Street Baltimore Maryland 21224 (US) @ Representative: Ahner, Francis et al CABINET REGIMBEAU 26, avenue Kleber F-75116 Paris (FR) @ Selective binding compounds for 5-hydroxytryptamine 1 -A-receptors and pharmaceutical compositions containing them. (g) Compounds that selectively bind 5-HTia receptors in preference to other 5-HT receptors are provided along with methods for their use. Such compounds have the formula A-0-CH2CH0HCH2-N-X-Y-N-Z J R wherein A is an aromatic group selected to provide, with the glycidyl residue that forms the next portion of the molecule, a 5-HT-like portion of the molecule that represents the primary binding site of the molecule with a 5-HT receptor; X represents a quarternary carbon and its attached alkyl groups; Y represents a hydrocarbon linking group; Z represents hydrogen or an organic group containing up to 12 carbon and/or heteroatoms in its skeletal structure; and R1 and R2 independ- 00 ently represent hydrogen or an alkyl group. The aromatic group CO is most preferably indole or an indole derivative. CO UJ Bundesdruckerei Berlin EP 0 338 877 A1 Description SELECTIVE BINDING COMPOUNDS FOR 5-HYDROXYTRYPTAMINE 1-A-RECEPTORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM This invention relates to compounds that exhibit binding affinity for 5-hydroxytryptamine-1 A receptors and is 5 particularly directed to compounds that interact specifically with such receptors in preference to other 5-hydroxytryptamine receptors and/or (3-adrenergic receptors. 5-Hydroxytryptamine (serotonin) is a widely distributed neurotransmitter that stimulates or inhibits a variety of smooth muscles and nerves. The endogenous compound is involved in a wide spectrum of responses including the cardiovascular, respiratory, and gastrointestinal systems. 10 5-Hydroxytryptamine, often abbreviated 5-HT, operates by interaction with receptors on cell surfaces. There are a number of distinct types of receptors for 5-HT, as evidenced by their wide range of susceptibilities to different blocking drugs. Radioligand-binding studies, principally in brain tissue, have identified two broad 5-HT receptor types. The first is preferentially labeled with [3H]-5-HT and is referred to as 5-HTi receptors. A second broad class, termed 5-HT2, is preferentially labeled with [3H]-spiperone. However, it is clear that there 15 are more than two types of 5-HT binding sites. Evidence suggests the existence of several subpopulations of receptors. One such subpopulation is identified by labeling with [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin (HDAT), referred to as 5-HTia receptors. See Gozlan etal., "Identification of presynaptic serotonin autore ceptors using a new ligand: 3H-PAT", Nature (1983) 305:140-143. The receptor is distinct from 5-HTib and 5-HT2 receptors 20 that have been defined in brain membranes and does not appear to be related to M or D serotonergic receptors that have been identified in the periphery. The anxiolytic effects of buspirone and TVX Q 7821 appear to be mediated by central 5-HTia receptors. See, Peroutka, "Selective Interaction of Novel Anxiolytics with 5-HydroxytryptamineiA Receptors", Biol. Phychiatry (1985) 20:971-979. Interaction of antimigraine drugs with 5-HTia receptors has also been demonstrated. See, Hiner et al., "Antimigraine Drug Interactions with 25 5-HydroxytryptamineiA Receptors", Annals of Neurology (1986) ^9:511-513. Chemical structures of compounds that interact with 5-HTia receptors vary widely. Buspirone, TVX Q 7821, methylsergide, cyproheptadine, pizotifen, and (-)-propranolol are all potent inhibitors of [3HJ-8-0H-DPAT binding to 5-HTia receptors. A particularly desirable characteristic for a 5-HT-iA-binding molecule, in addition to high binding affinity, is 30 selectivity specifically for 5-HTia receptors in preference to other 5-HT receptors. Additional classes of compounds other than those already known that can be readily prepared and which have the desired selectivity will greatly extend the therapeutic uses of 5-HTiA-binding compounds. The present invention provides a class of 5-HT-receptor-binding compounds that are capable of selectively binding with the 1 A receptor in preference to other 5-HT receptors. These compounds have the formula 35 A-0-CHoCH0HCHo-N-X-Y-N-Z 40 Formula 1 wherein A is an aromatic group selected to provide, with the glycidyl residue that forms the next portion of the molecule^ a 5-HT-like portion of the molecule that represents the primary binding site of the molecule with a 5-HT receptor. The remainder of the molecule comprises a diamine at the end of the glycidyl side chain that 45 modifies binding to select specifically for the 5-HTia receptors. The diamine can be unsubstituted or can be terminally substituted with an alkylating or other binding group to provide for covalent or otherwise prolonged binding. The substituents R1 and R2 on the nitrogens are generally hydrogen but can represent small organic residues, typically methyl. A linking group X-Y between the two nitrogens of the diamine comprises two portions, a proximal portion X comprising a quarternary carbon attached to the proximal nitrogen of the 50 diamine, and a distal portion Y that can vary significantly in length and/or bulk while still providing the desired selectivity. Compounds of the invention can be used to interact with 5-HTia receptors in a variety of pharmacological situations. Investigations in the laboratories of the present inventors have uncovered a new class of compounds active as 5-hydroxytryptamineiA- receptors. These compounds resemble propranolol in that they comprise an 55 aromatic phenol (naphthol in propranolol) attached as an ether to an aminohydroxypropyl group (1-amino-2,3-dihydroxypropane in propranolol). They differ from propranolol, however, in having the terminal amino group of the aminohydroxypropyl group replaced by a diamine. The proximal amino group of the diamine replaces the terminal amino group of propranolol or of a related compound with a different aromatic group (particularly propranolol-like compounds known to have high affinity for 5-HT receptors). The distal amino 60 group of the diamine is attached to the proximal amino group by means of a two-part linking group X-Y in which the proximal X portion is a sterically hindered carbon, particularly a quarternary carbon. The distal Y portion of the linking group can vary widely in length, polarity, and/or bulk as described beiow. The two amino groups can be substituted by small organic groups, particularly methyl, although hydrogens are preferred. The distal EP 0 338 877 A1 amino group can also be bonded to a strong-binding group, such as an alkylating group that will react with amino acid side chains or otherwise interact with the receptor to provide strong binding. The diamine portion of the molecule appears to direct binding specifically to 5-HTia receptors in preference to other 5-HT receptor types. This selectivity is believed to be based on differences in steric structure at moderate distances from the primary binding site that is believed to be in the region of the aromatic ring (and 5 possibly the hydroxypropyl side chain), which is responsible for binding to all types of 5-HT receptors. Propranolol-like molecules typically have an aromatic group selected from (1) fused bicyclic aromatic rings comprising 5- to 7-membered rings (preferably 5- or 6-membered rings) and 0 to 4 (preferably 0 or 1) heteroatoms and (2) monocyclic aromatic rings containing one 5- or 6-membered ring and 0 or 1 heteroatoms and having a hydrocarbon-containing side chain with at least one site of unsaturation and 0 to 2 heteroatoms. It 10 is not required that all atoms of the rings be involved in the aromaticity of the aromatic ring system. Typical fused bicyclic aromatic rings include naphthalene, indene, benzofuran, benzothiofuran, indole, indolenine, 2-isobenzazole, benzoxazole, Tetralin, Decalin, 1,2-benzopyran, coumaran, quinoline, isoquinoline, cinnoline, pyrido[3,4-b]pyridine, and purine. Typical monocyclic aromatic rings include benzene, furan, thiophene, pyrole, and thiazole substituted with C2-C4 alkyl, alkenyl, or alkynyl groups optionally containing oxygen (in the chain 15 to form an ether or as a functional group, typically hydroxy, oxo, or carboxy), or a corresponding nitrogen- or sulfur-containing moiety. Attachment of the hydroxypropyl side chain to the aromatic group typically occurs at a position ortho to a fused ring or ortho or meta to a side chain for monocyclic aromatics. For example, the following positions are preferred for the indicated residues: 1-naphthyl; 4-indolyl; 2-allylphenyl. 20 Additionally, the aromatic group can be substituted. Typical aromatic substituents can be present on the rings and typical non-aromatic substituents can be present at other locations. Typical aromatic substituents include alkyl, alkenyl, alkynyl, cyano, halo, acyl (especially alkanoyl), carboxy, hydroxy, amino, hydrocarbyloxy (especialy alkyloxy), mono- and di-alkylamino, amido, nitro, and other well-known aromatic substituents, preferably containing two or fewer carbons, more preferably 1 or 0 carbons.

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