Use of dual H3/M2 antagonists in the treatment of cognition deficit disorders

BACKGROUND

[0002] This invention relates to the treatment of cognition deficit disorders by administering a dual histamine H3 receptor antagonist/m2 muscarinic antagonist, or a combination of an histamine H3 receptor antagonist and a m2 muscarinic antagonist. In particular, the invention relates to the treatment of cognition deficit diseases such as Alzheimer's Disease (AD) or other CNS learning disorders such as attention deficit disorder and autism.

[0003] European Patent Application No. 0 420 396 A2 and Howson et al., Bioorg. & Med. Chem. Letters, Vol. 2 No. 1 (1992), pp. 77-78, describe imidazole derivatives having an amidine group as H3 agonists. Van der Groot et al. (Eur. J. Med. Chem. (1992) Vol. 27, pp. 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine H3 receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al, J. Psychopharmacol. (British Assn. for Psychopharmacology, Jul. 25-28 1993, Abstr. Book), A17] describes the ability of histamine H3 receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al., Brit. J. Pharm. Suppl., 1993, 110, Abstract 65P, presents results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H3 receptors in the modulation of cognitive function. Yokoyama et al, Eur. J. Pharmacol., vol. 234 (1993), pp. 129-133, reports how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. WO 9301812-A1 describes the use of S-[3-(4(5)-imidazolyl) propyl]-isothiourea as a histamine H3 antagonist, especially for treating cognitive disorders, e.g. Alzheimer's disease and age-related memory impairment. Schlicker et al. describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group or an amide group (including thioamide and urea), and compare these to thioperamide. Leurs et al., Progr. Drug Res. (1992) vol. 39, pp. 127-165, and Lipp et al. The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pp. 57-72, review a variety of synthetic H3 receptor antagonists, and Lipp et al. (ibid. ) have defined the necessary structural requirements for an H3 receptor antagonist.

[0004] Several muscarinic receptor subtypes have been identified, i.e., m1, m2, m3, m4 and m5, and the potential therapeutic effects of the various subtypes have been the subject of many publications. See, for example, U.S. Pat. No. 5,446,057, wherein the m1 receptor was identified as mediating gastric secretion; m2 and m3 receptors were identified as mediating nasal mucosal secretions; and m2 was identified as mediating cardiovascular conditions and CNS conditions associated with release of acetylcholine, e.g., Alzheimer's disease and other dementias. Muscarinic receptors in general were reported to be mediators of cholinergic neurotransmission.

SUMMARY OF THE INVENTION

[0005] This invention relates to a method of treating cognition deficit disorders comprising administering to a mammal in need of such treatment an effective amount of a dual histamine H3 receptor antagonist/m2 muscarinic antagonist, or a combination of an histamine H3 receptor antagonist and a m2 muscarinic antagonist. In particular, the method relates to the treatment of Alzheimer's Disease, attention deficit disorder or autism comprising administering an effective amount of a dual H3/m2 antagonist, or a combination of an H3 antagonist and a m2 antagonist.

[0006] The dual H3/m2 antagonist compounds of the invention are preferably administered as a pharmaceutical composition comprising the dual antagonist and a pharmaceutically acceptable carrier. When separate H3 and m2 antagonists are used in combination, an effective amount of the combination of a H3 antagonist and a m2 antagonist can be combined with a pharmaceutically acceptable carrier in a single pharmaceutical composition. Alternatively, a pharmaceutical composition comprising a H3 antagonist and a separate pharmaceutical composition comprising a m2 antagonist can be administered, simultaneously or sequentially, wherein the individual antagonists are administered in amounts chosen so that the combination is effective to treat cognition deficit disorders. Kits comprising separate H3 and m2 pharmaceutical compositions in a single package are also contemplated.

[0007] In still another aspect, the invention relates to a method for treating a cognitive disease or neurodegenerative disease comprising administering to a mammal in need of such treatment an effective amount of a dual histamine H3 receptor antagonist/m2 muscarinic antagonist, or a combination of an histamine H3 receptor antagonist and a m2 muscarinic antagonist, in further combination with an acetylcholinesterase inhibitor. Pharmaceutical compositions comprising a dual histamine H3 receptor antagonist/m2 muscarinic antagonist and an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, or separate H3 and m2 antagonists and an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier are contemplated. Kits comprising separate dual H3/m2 antagonist and acetylcholinesterase inhibitor pharmaceutical compositions, and separate H3, m2 and acetylcholinesterase inhibitor pharmaceutical compositions in a single package are also contemplated.

DETAILED DESCRIPTION

[0008] Dual H3/m2 antagonists of the present invention are exemplified by the compounds shown in the following table:

1CompoundNumberStructure1

[0009] Other compounds having dual H3/m2 antagonist activity can be identified by evaluating the compounds for activity at H3 receptors and activity at m2 receptors using the test methods described below.

[0010] The currently known histamine H3 receptor antagonists cannot be easily classified chemically, but include, without limitation: thioperamide, impromidine, burimamide, clobenpropit, impentamine, mifetidine, clozapine, S-sopromidine, R-sopromidine, ciproxifam, SKF-91486, GR-175737, GT-2016, GT-2331 and UCL-1199.

[0011] Certain H3 antagonists are disclosed in several US patents. U.S. Pat. No. 5,463,074 discloses the following compounds:

[0012] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0013] (A) m is an integer selected from the group consisting of: 0, 1, and 2;

[0014] (B) n and p are integers and are each independently selected from the group consisting of: 0, 1, 2, and 3 such that the sum of n and p is 2 or 3;

[0015] (C) each R1, R2, R3, R4, R6, R7, and R8 is independently selected from the group consisting of:

[0016] (1) H;

[0017] (2) C1 to C6 alkyl;

[0018] (3) C3 to C6 cycloalkyl; and

[0019] (4) —(CH2)q—R9 wherein q is an integer of: 1 to 7, and R9 is selected from the group consisting of: phenyl, substituted phenyl, —OR10, —C(O)OR10, —C(O)R10, —OC(O)R10, —C(O)NR10R11, CN and —SR10 wherein R10 and R11 are as defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: —OH, —O—(C1 to C6)alkyl, halogen, C1 to C6 alkyl, —CF3, —CN, and —NO2, and wherein said substituted phenyl contains from 1 to 3 substituents;

[0020] (D) R5 is selected from the group consisting of:

[0021] (1) H;

[0022] (2) C1 to C20 alkyl;

[0023] (3) C3 to C6 cycloalkyl;

[0024] (4) —C(O)OR10′; wherein R10′ is the same as R10 defined below except that R10′ is not H;

[0025] (5) —C(O)R10;

[0026] (6) —C(O)NR10R11;

[0027] (7) allyl;

[0028] (8) propargyl; and

[0029] (9) —(CH2)q—R9, wherein q and R9 are as defined above with the proviso that when q is 1 then R9 is not —OH or —SH;

[0030] (E) R10 and R11 are each independently selected from the group consisting of: H, C1 to C6 alkyl, and C3 to C6 cycloalkyl; and, for the substituent —C(O)NR10R11, R10 and R11, together with the nitrogen to which they are bound, can form a ring having 5, 6, or 7 atoms;

[0031] (F) the dotted line (------) represents a double bond that is optionally present when m is 1, and T is a 5-membered ring, and n is not 0, and p is not 0, and when said double bond is present then R2 and R8 are absent;

[0032] (G) when m is 2, each R1 is the same or different substituent for each m, and each R2 is the same or different substituent for each m;

[0033] (H) when n is 2 or 3, each R3 is the same or different substituent for each n, and each R4 is the same or different substituent for each n; and

[0034] (I) when p is 2 or 3, each R6 is the same or different substituent for each p, and each R7 is the same or different substituent for each p.

[0035] U.S. Pat. No. 5,807,872 discloses the following compounds:

[0036] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0037] (A) m is 1 or 2;

[0038] (B) n and p are independently selected from 0, 1, 2, 3, and 4 such that the sum of n and p is 4 and T is a 6-membered ring;

[0039] (C) R3 and R4 are each independently bound to the same or different carbon atom of ring T such that there is only one R3 group and one R4 group in ring T, and each R1, R2, R3, and R4 is independently selected from the group consisting of:

[0040] (1) H;

[0041] (2) C1 to C6 alkyl; and

[0042] (3) —(CH2)q—R6 wherein q is an integer of: 1 to 7, and R6 is selected from the group consisting of: phenyl, substituted phenyl, —OR7, —C(O)OR7, —C(O)R7, —OC(O)R7, —C(O)NR7R8, CN and —SR7 wherein R7 and R8 are as defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: —OH, —O—(C1 to C6)alkyl, halogen, C1 to C6 alkyl, —CF3, —CN, and —NO2, and wherein said substituted phenyl contains 1 to 3 substituents;

[0043] (D) R5 is selected from the group consisting of:

[0044] (1) H;

[0045] (2) C1 to C20 alkyl;

[0046] (3) C3 to C6 cycloalkyl;

[0047] (4) —C(O)OR7′; wherein R7′ is the same as R7 defined below except that R7′ is not H;

[0048] (5) —C(O)R7;

[0049] (6) —C(O)NR7R8;

[0050] (7) allyl;

[0051] (8) propargyl; and

[0052] (9) —(CH2)q—R6, wherein q and R6 are as defined above, and when q is equal to 1, then R6 is not OH or SH;

[0053] (E) R7 and R8 are each independently selected from the group consisting of: H, C1 to C6 alkyl, and C3 to C6 cycloalkyl;

[0054] (F) the dotted line (------) represents a double bond that is optionally present when m is 1, and n is not 0, and p is not 0, and when said double bond is present then R2 is absent; and

[0055] (G) when m is 2, each R1 is the same or different substituent for each m, and each R2 is the same or different substituent for each m, and at least two of the substituents R1 and/or R2 are H.

[0056] U.S. Pat. No. 5,633,250 discloses the following compounds:

[0057] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0058] (A) n is 1 or 2;

[0059] (B) R1 is selected from the group consisting of:

[0060] (1) H;

[0061] (2) C1 to C6 alkyl;

[0062] (3) allyl; and

[0063] (4) propargyl;

[0064] (C) R3 and R4 are independently selected from the group consisting of:

[0065] (1) H;

[0066] (2) C1 to C6 alkyl;

[0067] (3) allyl;

[0068] (4) propargyl; and

[0069] (5) —(CH2)q—R5 wherein q is an integer of: 1 to 7, and R5 is selected from the group consisting of: phenyl, substituted phenyl, —OR6, —C(O)OR6, —C(O)R6, —OC(O)R6, —C(O)NR6R7, CN and —SR6 wherein R6 and R7 are as defined below, and wherein the substituents on said substituted phenyl are each independently selected from the group consisting of: —OH, —O—(C1 to C6)alkyl, halogen, C1 to C6 alkyl, —CF3, —CN, and —NO2, and wherein said substituted phenyl contains 1 to 3 substituents;

[0070] (D) R6 and R7 are each independently selected from the group consisting of: H and C1 to C6 alkyl; and

[0071] (E) R3 and R4 are each independently bound to the same or different carbon atom of ring T.

[0072] U.S. Pat. No. 5,578,616 discloses the following compounds:

[0073] Wherein:

[0074] A is selected from —O—CO—NR1—, —O—CO—, —NR1—CO—NR1—, —NR1—CO—, —NR1—, —O—, —CO—NR1—, —CO—O—, and —C(:NR1)—NR1—;

[0075] the groups R1, which may be the same or different when there are 2 or 3 such groups in the molecule shown above, are selected from H, and lower alkyl, aryl, cycloalkyl, heterocyclic and heterocyclyl-alkyl groups, and groups of the formula —(CH2)y—G, where G is selected from CO2R3, COR3, CONR3R4, OR3, SR3, NR3R4 heteroaryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloloweralkyl, and y is an integer from 1 to 3;

[0076] R2 is selected from H and halogen atoms, and alkyl, alkenyl, alkynyl and trifluoromethyl groups, and groups of the formula OR3, SR3 and NR3R4;

[0077] R3 and R4 are independently selected from H, and lower alkyl and cycloalkyl groups, or R3 and R4 together with the intervening nitrogen atom can form a saturated ring containing 4 to 6 carbon atoms that can be substituted with 1 or 2 lower alkyl groups;

[0078] with the proviso that, when y is 1 and G is OR3, SR3 or NR3R4, then neither R3 nor R4 is H;

[0079] the group —(CH2)n—A—R1 is at the 3- or 4-position, and the group R2 is at any free position;

[0080] m is an integer from 1 to 3; and

[0081] n is 0 or an integer from 1 to 3;

[0082] or a pharmaceutically acceptable acid addition salt thereof;

[0083] or a pharmaceutically acceptable salt thereof with a base when G is CO2H;

[0084] including a tautomeric form thereof.

[0085] U.S. Pat. No. 6,100,279 discloses the following compounds:

[0086] or pharmaceutically acceptable salts or solvates thereof, wherein:

[0087] X is a straight chain alkyl group having 1 to 7 carbon atoms or an alkene or alkyne group with 2 to 4 carbon atoms; wherein said alkyl or alkene groups are optionally substituted with up to two R7 groups;

[0088] n is 0, 1 or 2,

[0089] m and p are 0 to 4;

[0090] when m is 0 to 4, Y represents —SO2—; —CS—; —CO—; —CONR5—; —CO (CH2)wO—(with w being 1 to 4); —COO—; —CON(OR5)—; —C(NR5)NR5—; —SO2NR5— or —CSNR5—;

[0091] when m is 2 to 4, Y represents all the groups above when m is 0 to 4 and, in addition, Y represents —CHOR5—; —O—; —NR5CONR5−; —NR5CO—; —NR5—; —OCONR5—; —NR5C(NR5)NR5−; —NR5CSNR5; —NR5CS— or —NR5SO2—; —NR5C(O)O—; or —CSNR5;

[0092] each R5 independently represents H, alkyl or benzyl;

[0093] R6 represents aryl, heteroaryl, or a 3- to 7-membered heterocyclic group having one to three heteroatoms in the ring, wherein the heteroatoms are selected from N, S and O, and wherein said R6 group is optionally substituted by one to three substituents as defined below;

[0094] when Y is —SO2—, then R6, in addition to the above groups, also represents alkyl having 1 to 7 carbon atoms or a group —NR10R11 wherein R10 and R11 are independently selected from H, alkyl or trihalomethyl;

[0095] each R1 is independently H, alkyl or trihalomethyl;

[0096] each R7 is independently selected from H, alkyl, trihalomethyl, phenyl or benzyl, wherein said phenyl and benzyl are optionally substituted by one to three substituents independently selected from of alkyl, halogen, trihalomethyl, CN, NO2, OR10 or NR10R11, wherein R10 and R11 are as above defined.

[0097] U.S. Pat. No. 6,034,251 discloses the following compounds:

[0098] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0099] the double bond (a) is E or Z;

[0100] each R1 is independently selected from the group consisting of H, lower alkyl, trihalomethyl, phenyl and benzyl;

[0101] each R7 is independently selected from the group consisting of H, lower alkyl, halogen, trihalomethyl, NR10R11, or a group OR10, whereby R10 and R11 are independently selected from H, lower alkyl or trihalomethyl;

[0102] X is —CONR5—; —SO2—, —S—; —CO—; —COO—; —CN(OR5)NR5—; —C(NR5)NR5—; —SONR5—; —SO2NR5— and, provided p is not zero, X may also be —O—; —NR5—; —NR5CONR5—; —OCONR5—; —O—CO— or —NR5CO—;

[0103] Y is C1-C3-alkyl, optionally substituted at any carbon atom of the group by one substituent R5;

[0104] Z is C(R1)2; wherein no more than two R1 groups are other than H;

[0105] n is 1 or 2;

[0106] m is 0 or 1;

[0107] p is 0 or 1;

[0108] q is 0 or 1;

[0109] R is selected from C3 to C7 cycloalkyl, heterocyclic groups, aryl or heteroaryl, wherein said R groups are optionally substituted with 1-3 substituents;

[0110] each R5 independently represents H, lower alkyl or poly-haloloweralkyl; and

[0111] R15 represents H or lower alkyl (e.g., methyl).

[0112] U.S. Pat. No. 5,990,147 discloses the following compounds:

[0113] or a pharmaceutically acceptable acid addition salt or solvate thereof (or tautomer thereof), wherein:

[0114] A is —CH2—NH—CO—NH—; —CH2—O—CO—NH— or —CH2CH2—CO—NH—(CH2)m—;

[0115] m is 0, 1 or 2;

[0116] R is the group

[0117] Wherein at least two of R1, R2, R3 and R4 are H and the two others are independently selected from H, halogen, CH3, CF3, OCH3, OCF3 or CN; and with the proviso, that when A is —CH2—O—CO—NH— and R1, R3 and R4 are all H, then R2 can not be Cl.

[0118] U.S. patent application Ser. No. 09/978,267 discloses the following compounds:

[0119] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0120] (1) R1 is selected from aryl, heteroaryl, heterocycloalkyl, alkyl, cycloalkyl, or alkylaryl; wherein said R1 groups are optionally substituted with 1 to 4 substituents independently selected from: halogen, hydroxyl, lower alkoxy, —CF3, CF3O—, —NR4R5, phenyl, NO2, —CO2R4, —CON(R4)2 wherein each R4 is the same or different, —S(O)mN(R20)2 wherein each R20 is the same or different H or alkyl group, or —CN; or

[0121] (2) R1 and X taken together form a group selected from:

[0122] (3) X is selected from: ═C(O), ═C(NOR3), ═C(NNR4R5),

[0123] (4) M1 and M2 are independently selected from C or N;

[0124] (5) M3 and M4 are independently selected from C or N;

[0125] (6) Y is selected from: is —CH2—, ═C(O), ═C(NOR20), or ═C(S);

[0126] (7) Z is a C1-C6 alkyl group;

[0127] (8) R2 is a five or six-membered heteroaryl ring, said heteroaryl rings being optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxyl, lower alkyl, lower alkoxy, —CF3, CF3O—, —NR4R5, phenyl, —NO2, —CO2R4, —CON(R4)2 wherein each R4 is the same or different, —CH2NR4R5, —(N)C (NR4R5)2, or —CN;

[0128] (9) R3 is selected from H, C1-C6 alkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, —(CH2)e—C(O)N(R4)2 wherein each R4 is the same or different, —(CH2)e—C(O)OR4, —(CH2)e—C(O)R30 wherein R30 is a heterocycloalkyl group, including

[0129] —CF3, or —CH2CF3;

[0130] wherein said aryl, heteroaryl, heterocycloalkyl, and the aryl portion of said arylalkyl are optionally substituted with 1 to 3 substituents selected from: halogen, —OH, —OCF3, —CF3, —CN, —N(R45)2, —CO2R45, or —C(O)N(R45)2, wherein each R45 is independently selected from: H, alkyl, alkylaryl, or alkylaryl wherein said aryl moiety is substituted with 1 to 3 substituents independently selected from —CF3, —OH, halogen, alkyl, —NO2, or —CN;

[0131] (10) R4 is selected from: H, C1-C6 alkyl, aryl, alkylaryl, said aryl and alkylaryl groups being optionally substituted with 1 to 3 substituents selected from: halogen, —CF3, —OCF3, —OH, —N(R45)2, —CO2R45, —C(O)N(R45)2, or —CN; wherein R45 is as defined above;

[0132] (11) R5 is selected from: H, C1-C6 alkyl, —C(O)R4, —C(O)2R4, or —C(O)N(R4)2 wherein each R4 is independently selected, and R4 is as defined above;

[0133] (12) or R4 and R5 taken together with the nitrogen atom to which they are bound forms a five or six membered heterocycloalkyl ring;

[0134] (13) R6 is selected from: alkyl, aryl, alkylaryl, halogen, hydroxyl, lower alkoxy, —CF3, CF3O—, —NR4R5, phenyl, —NO2, —CO2R4, —CON(R4)2 wherein each R4 is the same or different, or —CN;

[0135] (14) R12 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;

[0136] (15) R13 is selected from: alkyl, hydroxyl, alkoxy, or fluoro;

[0137] (16) a is 0 to 2;

[0138] (17) b is 0 to 2;

[0139] (18) c is 0 to 2;

[0140] (19) e is 0 to 5;

[0141] (20) m is 1 or 2;

[0142] (21) n is 1, 2 or 3, with the proviso that when M1 and M2 are both nitrogen, then n is 2 or 3; and

[0143] (22) p is 1, 2 or 3, with the proviso that when M3 and M4 are both nitrogen, then p is 2 or 3.

[0144] U.S. Provisional Application No. 60/275,417 discloses the following compounds:

[0145] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0146] (A) R1 is selected from aryl, heteroaryl, heterocycloalkyl, alkyl, —C(O)N(R48)2, cycloalkyl, arylalkyl, heteroarylheteroaryl or a group selected from:

[0147] said aryl, heteroaryl, aryl portion of arylalkyl, phenyl ring of formula IIa, phenyl ring of formula IIIa, phenyl rings of formula IVBa, or phenyl rings of formula IVDa are optionally substituted with 1 to 3 substituents independently selected from halogen; hydroxyl; lower alkoxy; —Oaryl; —SR22; —CF3; —OCF3; —OCHF2; —NR4R5; phenyl; NO2; —CO2R4; —CON(R4)2, wherein each R4 is the same or different; —S(O)2R22; —S(O)2N(R20)2, wherein each R20 is the same or different; —N(R24)S(O)2R22; —CN; —CH2OH; —OCH2CH2OR22; alkyl; substituted phenyl wherein said phenyl has 1 to 3 substituents independently selected from alkyl, halogen, —CN, —NO2, —OCHF2, —Oalkyl; —Oalkylaryl wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens; or phenyl;

[0148] (B) X is selected from alkyl or —S(O)2—;

[0149] (C) Y represents a single bond; or Y is selected from —C(O)—, —C(S)—, —(CH2)q—, or —NR4C(O)—; with the provisos that when M1 is N, then Y is not —NR4C(O)—; and when Y is a bond, then M1 and M2 are both carbon;

[0150] (D) M1 and M2 are independently selected from C or N;

[0151] (E) Z is selected from: C1-C6 alkyl, —SO2—, —C(O)— or —C(O)NR4—;

[0152] (F) R2 is selected from: a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N—O, with the remaining ring atoms being carbon; a five-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur with the remaining ring atoms being carbon; an alkyl group; an aryl group wherein said substituted phenyl is substituted with 1 to 3 substituents independently selected from halogen, —Oalkyl, —OCF3, —CF3, —CN, —NO2, —NHC(O)CH3, or —O(CH2)qN(R10A)2; —N(R11A)2 wherein each R11A is independently selected from H, alkyl or aryl; a group of the formula

[0153] or a heteroarylheteroaryl group;

[0154] said five membered heteroaryl ring or six-membered heteroaryl ring is optionally substituted with 1 to 3 substituents selected from halogen; hydroxyl; lower alkyl; lower alkoxy; —CF3; —NR4R5; phenyl; —NO2; —C(O)N(R4)2 (wherein each R4 is the same or different); —C(O)2R4; or phenyl substituted with 1 to 3 substituents independently selected from: halogen, —Oalkyl, —OCF3, —CF3, —CN, —NO2 or —O(CH2)qN(R10A)2;

[0155] (G) R3 is is selected from aryl; heteroaryl; heterocycloalkyl; alkyl; or cycloalkyl; wherein said aryl or heteroaryl R3 groups is optionally substituted with 1 to 3 substituents independently selected from halogen; hydroxyl; lower alkoxy; —Oaryl; —SR22; —CF3; —OCF3; —OCHF2; —NR4R5; phenyl; —NO2; —CO2R4; —CON(R4)2 wherein each R4 is the same or different; —S(O)2R22; —S(O)2N(R20)2 wherein each R20 is the same or different; —N(R24)S(O)2R22; —CN; —CH2OH; —OCH2CH2OR22; or alkyl;

[0156] (H) R4 is selected from hydrogen; C1-C6 alkyl; cycloalkyl; cycloalkylalkyl; heterocycloalkylalky; bridged bicyclic cycloalkyl ring; aryl having a fused heterocycloalkyl ring bound to said aryl ring; aryl; arylalkyl; alkylaryl; —(CH2)dCH(R12A)2 wherein d is 1 to 3, and each R12A is independently selected from phenyl or substituted phenyl, said substituted phenyl being substituted with 1 to 3 substituents independently selected from: halogen, —Oalkyl, —OCF3, —CF3, —CN, or —NO2; heterocycloalkylheteroaryl; or —(C1 to C6)alkylene—O—R22;

[0157] wherein the aryl R4 group, the aryl portion of the arylalkyl R4 group, or the aryl portion of the alkylaryl R4 group is optionally substituted with 1 to 3 substituents independently selected from halogen; hydroxyl; lower alkyl; lower alkoxy; —CF3; —N(R20)(R24); phenyl; —NO2; —C(O)N(R20)2 (wherein each R20 is the same or different); —C(O)R22; —(CH2)k-cycloalkyl; —(CH2)q-aryl; or —(CH2)m—OR22;

[0158] (I) each R4B is independently selected from: H, heteroaryl, alkyl, alkenyl, a group of the formula

[0159] arylalkyl, or arylalkyl wherein the aryl moiety is substitued with 1-3 substituents independently selected from: halogen;

[0160] (J) R5 is selected from: hydrogen, C1-C6 alkyl, —C(O)R20, —C(O)2R20, —C(O)N(R20)2 (wherein each R20 is the same or different);

[0161] (K) each R10A is independently selected from H or C1 to C6 alkyl, or each R10A, taken together with the nitrogen atom to which they are bound, forms a 4 to 7 membered heterocycloalkyl ring;

[0162] (L) R12 is selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when R12 is hydroxy or fluoro then R12 is not bound to a carbon adjacent to a nitrogen; or R12 forms an alkyl bridge from one ring carbon to another ring carbon;

[0163] (M) R13 is selected from alkyl, hydroxyl, alkoxy, or fluoro, provided that when R13 is hydroxy or fluoro then R13 is not bound to a carbon adjacent to a nitrogen; or R13 forms an alkyl bridge from one ring carbon to another ring carbon;

[0164] (N) R20 is selected from hydrogen, alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from: halogen, —CF3, —OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;

[0165] (O) R22 is selected from: heterocycloalkyl, alkyl or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, —CF3, —OCF3, hydroxyl, or methoxy;

[0166] (P) R24 is selected from: hydrogen, alkyl, —SO2R22, or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, —CF3, —OCF3, hydroxyl, or methoxy;

[0167] (Q) a is 0 to 2;

[0168] (R) b is 0 to 2;

[0169] (S) k is 1 to 5;

[0170] (T) m is 2 to 5;

[0171] (U) n is 1, 2 or 3 with the proviso that when M1 is N, then n is not 1;

[0172] (V) p is 1, 2 or 3 with the proviso that when M2 is N, then p is not 1;

[0173] (W) q is 1 to 5; and

[0174] (X) r is 1, 2, or 3 with the proviso that when r is 2 or 3, M2 is C and p is 1.

[0175] Other H3 receptor antagonists can be identified by the test method described below.

[0176] Preferred H3 antagonists are clobenpropit, impromidine, GT-2331, GR-175737, UCL-1199, and those disclosed in U.S. Pat. No. 5,990,147, U.S. patent application Ser. No. 09/978,267 and U,S, Provisional Application No. 60/275,417.

[0177] Muscarinic antagonists, in particular those having m2 activity, are disclosed in several U.S. patents. U.S. Pat. No. 5,883,096 and a divisional thereof, U.S. Pat. No. 6,037,352, disclose the following compounds:

[0178] including all isomers and pharmaceutically acceptable salts, esters, and solvates thereof,

[0179] wherein one of Y and Z is N and the other is N, CH, or C-alkyl;

[0180] X is —O—, —S—, —SO—, —SO2—, —NR6—, —CO—, —CH2—, —CS—, —C(OR5)2—, —C(SR5)2—, —CONR20—, —C(alkyl)2—, —C(H)(alkyl)—, —NR20—SO2—, —NR20CO—,

[0181] hydrogen, acyl, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with up to two alkyl groups, cycloalkenyl, bicycloalkyl, arylalkenyl, benzyl, benzyl substituted with up to three independently selected R3 groups, cycloalkylalkyl, polyhaloacyl, benzyloxy-alkyl, hydroxyC2-C20alkyl, alkenylcarbonyl, alkylarylsulfonyl, alkoxycarbonylamino-acyl, alkylsulfonyl, or arylsulfonyl, additionally, when X is —CH2—, R may also be —OH; in further addition, when X is not N, R may also be hydroxymethyl, in further addition, R and X may combine to form the group Prot-(NOAA)r—NH— wherein r is an integer of 1 to 4, Prot is a nitrogen protecting group and when r is 1, NOAA is a naturally occuring amino acid or an enantiomer thereof, or when r is 2 to 4, each NOAA is a peptide of an independently selected naturally occuring amino acid or an enantiomer thereof;

[0182] R1 and R21 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, alkynyl, cyano, aminoalkyl, alkoxycarbonyl, aminocarbonyl, hydroxyguanidino, alkoxycarbonylalkyl, phenyl alkyl, alkylcarbonlyoxyalkyl,

[0183] H, —OH, (provided R1 and R21 are both not —OH and Y is not N), formyl, —CO alkyl, —COacyl, —COaryl, and hydroxyalkyl; additionally R1 and R21 together may form the group

[0184] ═CH2, ═N—OR5, ═N—CN, ═N—N(R5)2, ═CH-Alkyl, alkylene, ═O, ═

[0185] 50 C(halo)2, in further addition, R1 and R21 together with the carbon atom to which

[0186] they are attached may form the group

[0187] or R1 and R21 together with the carbon atom to which they are attached may form a saturated heterocyclic ring containing 3 to 7 carbon atoms and one group selected from S, O, and NH;

[0188] R2 is H, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R3 groups, cycloalkenyl, hydroxyC2-C20alkyl, alkynyl, alkylamide, cycloalkylalkyl, hydroxyarylalkyl, bicycloalkyl, alkynyl, acylaminoalkyl, arylalkyl, hydroxyalkoxyalkyl, azabicyclo, alkylcarbonyl. alkoxyalkyl, aminocarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylamino(alkyl)alkyl; alkylcarbonyloxyalkyl, arylhydroxyalkyl, alkylcarbonylamino(alkyl)alkyl, dialkylamino,

[0189] (wherein q is an integer of 0 to 2)

[0190] wherein n is 1-3

[0191] wherein m is an integer of 4 to 7,

[0192] wherein t is an integer of 3 to 5,

[0193] (wherein R29 is H, alkyl, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl),

[0194] (wherein Q is O, NOH, or NO-alkyl), or when Z is —CH—, R2 may also be alkoxycarbonyl, hydroxymethyl, —N(R8)2;

[0195] R3, R4, R22, R24, and R25 are independently selected from the group consisting of H, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, haloalkyl, polyhaloalkyl, nitro, cyano, sulfonyl, hydroxy, amino, alkylamino, formyl, alkylthio, polyhaloalkoxy, acyloxy, trialkylsilyl, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl alkylsulfinyl; —OCONH2, —OCONH-alkyl, —OCON(alkyl)2, —NHCOO-alkyl, —NHCO-alkyl, phenyl, hydroxyalkyl, or morpholino;

[0196] each R5 and R6 is independently selected from the group consisting of H and alkyl, provided that when X is C(OR5)2 or C(SR5)2, both R5 groups cannot be H, and in addition, when X is C(OR5)2 or C(SR5)2, the two R5 groups in X may be joined to form —(CH2)p— wherein p is an integer of 2 to 4;

[0197] R7 is independently selected from the group consisting of H, alkyl, arylalkyl, cycloalkyl, aryl and aryl substituted with R3 and R4 as defined herein;

[0198] each R8 is independently selected from the group consisting of H, hydroxyalkyl, or alkyl or two R8 groups may be joined to form an alkylene group;

[0199] R9 is H, alkyl, or acyl;

[0200] R20 is H, phenyl or alkyl; and

[0201] R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl, additionally R27 and R28 may combine to form an alkylene group.

[0202] U.S. Pat. No. 5,889,006 and a divisional thereof, U.S. Pat. No. 6,043,255, disclose compounds of the formula

[0203] Wherein R, R1, R3, R4, R21, R27, and R28 are as described in U.S. Pat. No. 5,883,096, but wherein R2 is:

[0204] Wherein

[0205] R29 is H, alkyl, —CO-alkyl, alkoxycarbonyl, aminocarbonyl, aryloxycarbonyl alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, or arysulfonyl;

[0206] R30 is H, alkyl, aryl, cycloalkyl, hydroxyalkyl, aminoalkyl, —COOR20, —CON(R20)2 or cyano;

[0207] R31 and R32 are the same as R30 and in addition, two R30, R31 and R32 groups may form the group —(CH2)r—(wherein r is 1 to 6), in further addition, R31 and R32 can also be hydroxy, —N(R20)2, —O-acyl, —N(R20)acyl, —OCOOR20, or —OCON(R20) 2;

[0208] R33 is aryl or heteroaryl, with the proviso that when R33 is heteroaryl, the CO—R33 bond is to a carbon atom in the R33 group; and

[0209] R34 is alkyl, cycloalkyl or aryl and in addition R34 may also be H when R1 and R21 together with the carbon atom to which they are attached form a saturated heterocyclic ring containing 3 to 7 carbon atoms and two groups independently selected from S, O, and N—R20.

[0210] U.S. Pat. No. 5,952,349 discloses the following compounds:

[0211] or an isomer, pharmaceutically acceptable salt, ester or solvate thereof, wherein

[0212] X is a bond, —O—, —S—, —SO—, —SO2—, —CO—, —C(OR7)2—, —CH2—O—, —O—CH2—, —CH═CH—, —CH2—, —CH(C1-C6 alkyl)—, —C(C1-C6 alkyl)2—, —CONR17—, —NR17CO—, —SO2NR17— or —NR17SO2—;

[0213] R is C3-C6 cycloalkyl,

[0214] R1 is H, —CN, —CF3, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 alkenyl, —COR15, —COO(C1-C6 alkyl), —COO(aryl), —COO(heteroaryl), —COO((C1-C6 alkyl)aryl), —COO((C1-C6 alkyl)heteroaryl), —(C1-C6 alkyl)aryl, —(C1-C6 alkyl)heteroaryl or —CON(R13)2;

[0215] R2 is C3-C6 cycloalkyl, C3-C6 cycloalkenyl, t-butoxycarbonyl or

[0216] R3 and R4 are independently selected from the group consisting of H, halo, —CF3, C1-C6 alkyl, C1-C6 alkoxy and —OH;

[0217] R5 and R6 are independently selected from the group consisting of H, C1-C6 alkyl, —CF3, C1-C6 alkoxy, —OH, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, R13CONH—, R14OCONH—, R13NHCONH— and NH2CONR13—;

[0218] R7 is independently selected from the group consisting of H and alkyl, provided that both R7 groups are not H; or the two R7 groups may be joined to form —(CH2)p— wherein p is an integer of 2 to 4;

[0219] R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, benzyloxy substituted by —NO2 or —N(R14), halo C1-C6 alkyl, polyhalo C1-C6 alkyl, —NO2, —CN, —SO2, —OH, —NH2, —N(R14)2, —HCO, polyhalo C1-C6 alkoxy, acyloxy, (C1-C4 alkyl)3Si—, (C1-C6 alkyl)SO0-2, arylsulfonyl, heteroaryl-sulfonyl, acyl, (C1-C6 alkoxy)CO—, —OCON(R14)2, —NHCOO—(C1-C6)alkyl, —NHCO—(C1-C6 alkyl), phenyl, hydroxy(C1-C6 alkyl) or morpholino;

[0220] R13 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, —(C1-C6 alkyl)COOR15, aryl, heteroaryl, —(C1-C6 alkyl)aryl, —(C1-C6 alkyl)heteroaryl and adamantyl;

[0221] R14 is independently selected from the group consisting of H and C1-C6 alkyl;

[0222] R15 is H, C1-C20 alkyl, C1-C6 cycloalkyl, aryl or heteroaryl;

[0223] R16 is H, C1-C6 alkyl, —COR15, C1-C6 alkoxycarbonyl, (R14)2NCO— or —SO1-2—R15; and

[0224] R17 is H, C1-C6 alkyl, aryl or heteroaryl.

[0225] U.S. Pat. No. 5,935,958 discloses the following compounds:

[0226] including all stereoisomers and pharmaceutically acceptable salts, esters, and solvates thereof, wherein:

[0227] Z is N, CH or C-alkyl;

[0228] X is —O—, —S—, —SO—, —SO2—, —CO—, —CH2—, —CONR20—, —NR20—SO2—, —NR20CO—, or —SO2—NR20—;

[0229] Q is —O—, —S—, —SO—, —SO2—, or —CH2—;

[0230] R is

[0231] R1 and R21 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, phenylalkyl, and hydroxyalkyl;

[0232] R2 is cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R3 groups, cycloalkenyl, cycloalkylalkyl,

[0233] (wherein Ry is H, alkyl, alkenyl, SO2Rz or CORz wherein Rz is alkyl, alkenyl, aryl, heteroaryl, or cycloalkyl), with the proviso that R2 is R3-substituted-1-piperidinyl only when Z is CH or C-alkyl; or, when Z is CH, R2 may also be alkoxycarbonyl, —N(R9)(hydroxyalkyl) wherein R9 is H, hydroxyalkyl, or alkyl, or —N(R9)2 wherein the two R9 groups may be joined to form an alkylene group;

[0234] R3, R4, R5, R6, R22, R24, and R25 are independently selected from the group consisting of H, alkyl, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, polyhaloalkyl, nitro, sulfonyl, hydroxy, amino, alkylamino, formyl, alkylthio, acyloxy, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl, alkylsulfinyl, —OCONH2, —OCONH-alkyl, —OCON(alkyl)2, —NHCOO-alkyl, —NHCO-alkyl, phenyl, hydroxyalkyl, and 1-morpholinyl;

[0235] R8 is hydrogen, lower alkyl or cyclopropyl;

[0236] R20 is H, phenyl or alkyl;

[0237] R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, mercaptoalkyl, alkylthioalkyl, and carboxyalkyl, and additionally R27 and R28 may be joined to form an alkylene group; and

[0238] n is 0 or an integer from 1 to 3.

[0239] U.S. Pat. No. 6,066,636 discloses the following compounds:

[0240] including all stereoisomers and pharmaceutically acceptable salts and solvates thereof,

[0241] wherein one of Y and Z is —N— and the other is —N— or —CH—;

[0242] X is —O—, —S—, —SO—, —SO2— or —CH2—;

[0243] Q is

[0244] R is (C1-C20)alkyl, (C3-C12)cycloalkyl, aryl, R8-aryl or heteroaryl;

[0245] R1, R2 and R3 are independently selected from the group consisting of H and (C1-C20)alkyl;

[0246] R4 is (C1-C20)alkyl, (C3-C12)cyclolalkyl or

[0247] R5 is H, (C1-C20)alkyl, —C(O)(C1-C20)alkyl, R9-arylcarbonyl, —SO2(C1-C20)alkyl, R9-arylsulfonyl —C(O)O(C1-C20)alkyl, R9-aryloxy-carbonyl, —C(O)NH—(C1-C20)alkyl or R9-arylaminocarbonyl;

[0248] R6 is H or (C1-C20)alkyl;

[0249] R7 is H, (C1-C20)alkyl, hydroxy(C1-C20)alkyl or (C1-C20)-alkoxy (C1-C20)alkyl;

[0250] R8 is 1-3 substituents independently selected from the group consisting of H, (C1-C20)alkyl, halogen, hydroxy, (C1-C20)alkoxy or hydroxy(C1-C20)alkyl, or two adjacent R8 groups may be joined to form a (C1-C2)alkylenedioxy group; and

[0251] R9 is 1-3 substituents independently selected from the group consisting of H, (C1-C20)alkyl, halogen, amino or (C1-C20)alkylamino.

[0252] U.S. Pat. No. 5,977,138 discloses the following compounds:

[0253] or an isomer, pharmaceutically acceptable salt, ester or solvate thereof, wherein

[0254] X is a bond, —O—, —S—, —SO—, —SO2—, —CO—, —C(OR7)2—, —CH2—O—, —O—CH2—, —CH═CH—, —CH2—, —CH(C1-C6 alkyl)—, —C(C1-C6 alkyl)2—, —CONR17—, —NR17CO—, —O—C(O)NR17—, —NR17C(O)—O—, —SO2NR17— or —NR17SO2—;

[0255] R is C3-C6 cycloalkyl,

[0256] n is 1, 2 or 3;

[0257] R2 is H, C2-C7 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted by 1 to 4 groups independently selected from R18, C3-C6 cycloalkenyl, t-butoxycarbonyl or

[0258] R3 and R4 are independently selected from the group consisting of H, halo, —CF3, C1-C6 alkyl, C1-C6 alkoxy and —OH;

[0259] R5 and R6 are independently selected from the group consisting of H, C1-C6 alkyl, —CF3, C1-C6 alkoxy, —OH, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, R13CONH—, (R13)2NCO—, R13OCONH—, R13NHCONH— and NH2CONR13—;

[0260] R7 is independently selected from the group consisting of C1-C6 alkyl; or the two R7 groups may be joined to form —(C(R14)2)p— wherein p is an integer from 2-4;

[0261] R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, halo, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, benzyloxy substituted by —NO2 or —N(R14), halo C1-C6 alkyl, polyhalo C1-C6 alkyl, —NO2, —CN, —SO2, —OH, —NH2, —N(R14)2, —CHO, polyhalo C1-C6 alkoxy, acyloxy, (C1-C4 alkyl)3Si—, (C1-C6 alkyl)SO0-2, arylsulfonyl, heteroaryl-sulfonyl, acyl, (C1-C6 alkoxy)CO—, —OCON(R14)2, —NHCOO—(C1-C6)alkyl, —NHCO—(C1-C6 alkyl), phenyl, hydroxy(C1-C6 alkyl) or morpholino;

[0262] R13 is independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, —(C1-C6 alkyl)COOR15, aryl, heteroaryl, —(C1-C6 alkyl)aryl, —(C1-C6 alkyl)heteroaryl and adamantyl;

[0263] R14 is independently selected from the group consisting of H and C1-C6 alkyl;

[0264] R15 is independently selected from the group consisting of H, C1-C20 alkyl, C3-C6 cycloalkyl, aryl substituted by 1 to 3 groups independently selected from R3 and heteroaryl substituted by 1 to 3 groups independently selected from R3;

[0265] R16 is H, C1-C6 alkyl, —COR20, C1-C6 alkoxycarbonyl, —CON(R14)2, —CONH(R3-aryl), —SO1-2—R15, —SO1-2—(CH2)m—R21, —SON(R14)2, —COSR14 or

[0266] R17 is H, C1-C6 alkyl, aryl or heteroaryl;

[0267] R18 is independently selected from the group consisting of halo, —CF3, C1-C6 alkyl, C1-C6 alkoxy, —OH, ═O, —CON(R14)2 and —N(R14)COR15;

[0268] R19 is H, —OH, C1-C20 alkyl, C3-C6 cycloalkyl, aryl substituted by 1 to 3 groups independently selected from R3 or heteroaryl substituted by 1 to 3 groups independently selected from R3;

[0269] R20 is H, C1-C20 alkyl, C1-C6 alkoxy(C1-C6)alkyl, C3-C6 cycloalkyl, aryl, aryl(C1-C6 alkyl)—, aryloxy, aryloxy(C1-C6 alkyl)—, tetrahydrofuranyl or heteroaryl, wherein the aryl or heteroaryl group is substituted by 1 to 3 groups independently selected from R3;

[0270] m is 0 to 3; and

[0271] R21 is C7-C10 bridged cycloalkyl or C7-C10 bridged cycloalkyl wherein the cycloalkyl portion is substituted by 1 or 2 substituents selected from the group consisting of C1-C6 alkyl or ═O.

[0272] A genus of selective m2 muscarinic antagonists, disclosed in U.S. Pat. No. 6,294,554 B1, has the following structural formula:

[0273] or a pharmaceutically acceptable salt, ester or solvate thereof, wherein

[0274] Q and Q1 are each —CH═, or one of Q and Q1 is —CH═ and the other is —N═;

[0275] X is —CH2— or

[0276] Y and Z are independently selected from the group consisting of —C(R5)═, or one of Y and Z is —C(R5)═ and the other is —N═;

[0277] R1 is 1 to 3 substituent independently selected from the group consisting of H, halogen and (C1-C6)alkoxy;

[0278] R2 and R5 are independently 1 to 3 substituents independently selected from the group consisting of H, halogen, (C1-C6)alkyl and (C1-C6)alkoxy; and

[0279] R3 and R4 are independently selected from the group consisting of H and (C1-C6)alkyl.

[0280] Of those compounds, preferred are compounds wherein both Y and Z are —C(R5)═, and wherein R5 is preferably H, methyl or halogen. Also preferred are compounds wherein Y is —CH═, Z is —N═ and R2 is hydrogen. R1 is preferably halogen, more preferably chloro, or methoxy, and in particular, R1 is 3-chloro or 4-methoxy. Q and Q1 are preferably each —CH═. Preferred R2 substituents are Cl, F and methyl, with 3-methyl being more preferred. R3 and R4 are preferably each H.

[0281] U.S. Provisional Application No. 60/257,853, filed Dec. 22, 2000 discloses compounds having the following structure:

[0282] or a pharmaceutically acceptable salt, ester or solvate thereof, wherein

[0283] R1 is R5—(C3-C8)cycloalkyl, R5—(C3-C8)cycloalkyl(C1-C6)alkyl, R5-aryl, R5-aryl-(C1-C6)alkyl or R5-heteroaryl;

[0284] R2 is H, (C1-C6)alkyl, R6—(C3-C8)cycloalkyl, R6—(C3-C8) cycloalkyl-(C1-C6)alkyl, R6-heterocycloalkyl, R6—(C6-C10)bridged cycloalkyl, or R6-bridged heterocycloalkyl;

[0285] R3 is C1-C6 alkyl or —CH2OH;

[0286] R4 is H or C1-C6 alkyl;

[0287] R5 is 1-4 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, —OH, C1-C6 alkoxy, CF3, —CN, —CO2R4, —CONHR4, —SO2NHR4, —NHSO2R4 and —NHC(O)R4; and

[0288] R6 is 1-4 substituents independently selected from the group consisting of H, C1-C6 alkyl, halogen, —OH, C1-C6 alkoxy, CF3, —NH2, (C1-C6)alkylamino, phenyl, C1-C2 alkylenedioxy, and (C1-C6)alkoxycarbonyl.

[0289] U.S. Provisional Application No. 60/328,356, filed Oct. 10, 2001 discloses compounds having the following structure:

[0290] including enantiomers, stereoisomers, rotamers, tautomers and prodrugs of said compound, or pharmaceutically acceptable salts, esters or solvates of said compound or of said prodrugs, wherein:

[0291] Z is N, CH, or C-alkyl;

[0292] X is —O—, —S—, —SO—, —SO2—, —CO—, —CH2—, or —CS;

[0293] R is

[0294] R2 is

[0295] R3 is alkoxy or halo;

[0296] R4 is hydrogen, alkyl or alkylhalide;

[0297] R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl; or R27 and R28 may combine to form an alkylene group;

[0298] R29 is H, alkyl, —CO-alkyl, —CO-cycloalkyl, alkoxycarbonyl, amino-carbonyl, aryloxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arysulfonyl or —SO2—NH—R35;

[0299] R31 and R32 are each independently H, alkyl, aryl, cycloalkyl, hydroxyalkyl, or aminoalkyl, and in addition, R31 and R32 can form the group —(CH2)r—(wherein r is 1 to 6), in further addition, R31 and R32 can also be hydroxy, —N(R 35)2, —O-acyl, —N(R35)acyl, —OCOOR35, or —OCON(R35)2;

[0300] R33 is aryl or heteroaryl, with the proviso that when R33 is heteroaryl, the CO—R33 bond is to a carbon atom in the R33 group; and

[0301] R35 is H, aryl or alkyl.

[0302] Preferred m2 antagonists are those claimed in U.S. Pat. No. 6,043,255.

[0303] An especially preferred m2 antagonist has the structure

[0304] The U.S. patents and applications cited herein are incorporated herein by reference.

[0305] Other m2 antagonists can be identified by the test methods described below.

[0306] The H3 antagonist and m2 antagonist compounds are prepared by known methods. The dual H3/m2 antagonists listed above are prepared by methods described in the m2 antagonist patents listed above.

[0307] The combination of H3 and m2 antagonists can also comprise more than one H3 antagonist (e.g., 2-3) and/or more than one m2 antagonist (e.g., 2-3).

[0308] In the aspect of the invention relating to a combination of a dual H3/m2 antagonist in combination with an acetylcholinesterase inhibitor, or a combination of an H3 antagonist and a m2 antagonist with an acetylcholinesterase inhibitor, examples of acetylcholinesterase inhibitors are donepezil, heptylphysostigmine, tacrine, rivastigmine and galantamine.

[0309] Test Methods:

[0310] Compounds can readily be evaluated to determine activity at H3 receptors by known methods, including the guinea pig brain membrane assay and the guinea pig neurogenic ileum contraction assay, both of which are described in U.S. Pat. No. 5,352,707. Another useful assay utilizes rat brain membranes and is described by West et al., “Identification of Two H3-Histamine Receptor Subtypes,” Molecular Pharmacology, Vol. 38, pages 610-613 (1990).

[0311] A particularly useful screening assay measures binding to sites in guinea pig brain membranes. This test is described in detail by Korte et al., “Characterization and Tissue Distribution of H3 Histamine Receptors in Guinea Pigs by Nα-Methylhistamine,” in Biochemical and Biophysical Research Communications, Vol. 168, pages 979-986 (1990), and quantifies the displacement of bound radiolabeled Nα-methylhistamine from tissues by candidate compounds. Results are expressed as “Ki” values, in nanoMolar (nM) units, which values can be considered as being dissociation constants for the H3 antagonist on the H3 receptor system, or an index of antagonist affinity for the receptor. In general, Klvalues less than about 200 nM are considered necessary for an agent to be useful as an H3 antagonist in the invention. More preferably, the agent will exhibit Ki values of 100 nM or less.

[0312] The compound of interest also is tested for its ability to inhibit binding to the cloned human m1, m2 and m4 muscarinic receptor subtypes. The sources of receptors in these studies were membranes from stably transfected CHO cell lines which were expressing each of the receptor subtypes. Following growth, the cells were pelleted and subsequently homogenized using a Polytron in 50 volumes cold 10 mM Na/K phosphate buffer, pH 7.4 (Buffer B). The homogenates were centrifuged at 40,000×g for 20 minutes at 4° C. The resulting supernatants were discarded and the pellets were resuspended in Buffer B at a final concentration of 20 mg wet tissue/ml. These membranes were stored at −80° C. until utilized in the binding assays described below.

[0313] Binding to the cloned human muscarinic receptors was performed using 3H-quinuclidinyl benzilate (QNB) (Watson et al., 1986). Briefly, membranes (approximately 8, 20, and 14 μg of protein assay for the m1, m2, and m4 containing membranes, respectively) were incubated with 3H-QNB (final concentration of 100-200 pM) and increasing concentrations of unlabeled drug in a final volume of 2 ml at 25° C. for 90 minutes. Non-specific binding was assayed in the presence of 1 μM atropine. The incubations were terminated by vacuum filtration over GF/B glass fiber filters using a Skatron filtration apparatus and the filters were washed with cold 10 mM Na/K phosphate butter, pH 7.4. Scintillation cocktail was added to the filters and the vials were incubated overnight. The bound radioligand was quantified in a liquid scintillation counter (50% efficiency). The resulting data were analyzed for IC50 values (i.e. the concentration of compound required to inhibit binding by 50%) using the EBDA computer program (McPherson, 1985).

[0314] Affinity values (Ki) are determined using the following formula;

K_{i} = \frac{{IC}_{50}}{1 + [\frac{concentration of radioligand}{affinity (K_{D}) of  radioligand}]}

[0315] Hence, a lower value of Ki indicates greater binding affinity.

[0316] To determine the degree of selectivity of a compound for binding the m2 receptor, the Ki value for m1 receptors was divided by the Ki value for m2 (or m4) receptors. A higher ratio indicates a greater selectivity for binding the m2 muscarinic receptor.

[0317] The following procedure is used to show that a compound functions as a m2 antagonist.

[0318] Surgery:

[0319] For these studies, male Sprague-Dawley Rats (250-350 g) were anesthetized with sodium pentobarbital (54 mg/kg, ip) and placed on a Kopf sterotaxic apparatus. The skull was exposed and drilled through to the dura at a point 0.2 mm anterior and 3.0 mm lateral to the bregma. At these coordinates, a guide cannula was positioned at the outer edge of the dura through the drilled opening, lowered perpendicularly to a depth of 2.5 mm, and permanently secured with dental cement to bone screws. Following the surgery, rats were given ampicillin (40 mg/kg, ip) and individually housed in modified cages. A recovery period of approximately 3 to 7 days was allowed before the microdialysis procedure was undertaken.

[0320] Microdialysis:

[0321] All of the equipment and instrumentation used to conduct in vivo microdialysis was obtained from Bioanalytical Systems, Inc. (BAS). The microdialysis procedure involved the insertion through the guide cannula of a thin, needle-like perfusable probe (CMA/12,3 mm×0.5 mm) to a depth of 3 mm in striatum beyond the end of the guide. The probe was connected beforehand with tubing to a microinjection pump (CMA/100). Rats were collared, tethered, and, following probe insertion, were placed in a large, clear, plexiglass bowl with litter material and access to food and water. The probe was perfused at 2 μl/min with Ringer's buffer (NaCl 147 mM; KCI 3.0 mM; CaCl2 1.2 mM; MgCl2 1.0 mM) containing 5.5 mM glucose, 0.2 mM L-ascorbate, and 1 μM neostigmine bromide at pH 7.4). To achieve stable baseline readings, microdialysis was allowed to proceed for 90 minutes prior to the collection of fractions. Fractions (20 μl) were obtained at 10 minute intervals over a 3 hour period using a refrigerated collector (CMA/170 or 200). Four to five baseline fractions were collected, following which the drug or combination of drugs to be tested was administered to the animal. Upon completion of the collection, each rat was autopsied to determine accuracy of probe placement.

[0322] Acetylcholine (ACh) Analysis:

[0323] The concentration of ACh in collected samples of microdialysate was determined using HPLC/electrochemical detection. Samples were auto-injected (Waters 712 Refrigerated Sample Processor) onto a polymeric analytical HPLC column (BAS, MF-6150) and eluted with 50 mM Na2HPO4, pH 8.5. To prevent bacterial growth, Kathon CG reagent (0.005%) (BAS) was included in the mobile phase. Eluent from the analytical column, containing separated ACh and choline, was then immediately passed through an immobilized enzyme reactor cartridge (BAS, MF-6151) coupled to the column outlet. The reactor contained both acetylcholinesterase and choline oxidase covalently bound to a polymeric backbone. The action of these enzymes on ACh and choline resulted in stoichiometric yields of hydrogen peroxide, which was electrochemically detected using a Waters 460 detector equipped with a platinum electrode at a working potential of 500 mvolts. Data acquisition was carried out using an IBM Model 70 computer equipped with a microchannel IEEE board. Integration and quantification of peaks were accomplished using “Maxima” chromatography software (Waters Corporation). Total run time per sample was 11 minutes at a flow rate of 1 ml/min. Retention times for acetylcholine and choline were 6.5 and 7.8 minutes, respectively. To monitor and correct for possible changes in detector sensitivity during chromatography, ACh standards were included at the beginning, middle and end of each sample queue.

[0324] Increases in ACh levels are consistent with presynaptic m2 receptor antagonism.

[0325] Affinity values for the H3 and m2 receptors were determined for the dual antagonists identified above. The results of the test procedures are as follows:

2CompoundH3m2NumberKiKi1180.1721400.0135000.12546203.454302.661601.27220.07860.0592900.2210150.0191180.018121704.813120.81420.715430.17

[0326] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

[0327] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0328] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

[0329] Liquid form preparations may also include solutions for intranasal administration.

[0330] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

[0331] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0332] The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0333] Preferably the compound or combination is administered orally.

[0334] Preferably, the pharmaceutical preparation comprising a dual H3/m2 antagonist is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0335] The quantity of active dual H3/m2 antagonist compound in a unit dose of preparation may be varied or adjusted from about 1 mg to 100 mg, preferably from about 1 mg. to 50 mg, more preferably about 1 to about 25 mg, according to the particular application.

[0336] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0337] The amount and frequency of administration of the dual compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen for dual H3/m2 antagonist is oral administration of from 1 mg to 300 mg/day, preferably 1 to 50 mg/day, in two to four divided doses to provide relief from cognition deficit disorders such as Alzheimer's disease.

[0338] When the invention comprises a combination of separate H3 antagonist and m2 antagonist compounds, the two active components may be co-administered simultaneously or sequentially, or a single pharmaceutical composition comprising a H3 antagonist and an m2 antagonist in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc. The dosage of the H3 antagonist can be determined from published material, and may range from 1 to 1000 mg per dose. The m2 antagonist can be administered in a dosage range of 1 mg to about 100 mg, preferably from about 1 mg. to 50 mg, and more preferably about 1 to about 25 mg. When used in combination, the dosage levels of the individual components are preferably lower than the recommended individual dosages because of the advantageous effect of the combination.

[0339] The dosage of the acetylcholinesterase inhibitor used in a combination may range from 0.001 to 100 mg/kg body weight.

[0340] When separate H3 and m2 pharmaceutical compositions are to be administered, they can be provided in a kit comprising in a single package, one container comprising an H3 antagonist in a pharmaceutically acceptable carrier, and a separate container comprising a m2 antagonist in a pharmaceutically acceptable carrier, with the H3 and m2 antagonists being present in amounts such that the combination is effective to treat cognition deficit disorders. When an acetylcholinesterase inhibitor is also administered, a separate container comprising an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier can also be added to the kit. A kit is advantageous for administering a combination when, for example, the components must be administered at different time intervals or when they are in different dosage forms.

[0341] The compounds are non-toxic when administered within this dosage range.

[0342] The following are examples of pharmaceutical dosage forms which contain a dual compound of the invention, although those skilled in the art will recognize that similar dosage forms will be suitable for separate H3 and m2 antagonists, or for combinations of the separate actives. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided.

3EXAMPLE ATabletsPharmaceutical Dosage Form ExamplesNo.Ingredientsmg/tabletmg/tablet1.Active compound1005002.Lactose USP1221133.Corn Starch, Food Grade, as a 30 4010% paste in Purified Water4.Corn Starch, Food Grade 45 405.Magnesium Stearate 3 7Total300700

Method of Manufacture

[0343] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine.

4EXAMPLE BCapsulesNo.Ingredientmg/capsulemg/capsule1.Active compound1005002.Lactose USP1061233.Corn Starch, Food Grade 40 704.Magnesium Stearate NF 7 7Total253700

Method of Manufacture

[0344] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

[0345] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Use of dual H3/M2 antagonists in the treatment of cognition deficit disorders

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