Methods and compositions for treatment of central and peripheral nervous system disorders and novel compounds useful therefor

A method of preventing or treating a disease or disorder associated with M1 muscarinic receptors, said method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising at least one compound of the formula (I):

• wherein:
• C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and c;
• A is selected from the group consisting of:
• R is selected from H, C1-C8 straight- or branched-chain alkyl or —CH2—P(O)(OH)2;
• a is —O—, —S— or —S(O)—;
• b is —CR1R2— or —C(R1)═;
• d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and —C═N(R3)═O;
• e is selected from the group consisting of —CH2—, —CHR4—, —NH—, —NR5—, —N(SO2R6)— and —N(C(═O)R6)—;
• R1, R2, R3 and R4 are each independently selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkyl optionally substituted by one to three phenyls;
• R5 is selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, optionally substituted phenyl, heteroaryl, and C1-6 alkyl optionally substituted by one to three phenyls;
• or, when the compound of formula (I) is a dimer, in which both halves of the dimer share a single R5, R5 is selected from the group consisting of —(CH2)n— and —(CH2O)n—, wherein n is 1 to 6;
• and
• R6 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C1-6 alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF3 group, C1-6 alkyl substituted by one to three aryl groups, and Cm alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C1-6 alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
• or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite, prodrug or pharmaceutically acceptable salt thereof,
• with the proviso that when A is
• R is —CH3, a is S, b is —CH(CH2CH3)— and d is —C(═O)—, then e is not —NH— (AF267) or an enantiomer thereof, and
• with the further proviso that when A is
• R is —CH3, a is S, b is —C(CH3)— and d is ═N—, then e is not —CH2— (AF150(S)).

A method for achieving one or more of the following biological effects:

• (1) inhibiting the release or synthesis of beta-amyloid peptide Aβ in a mammalian cell, tissue or organism,
• (2) elevating the level of secreted form of the non-amyloidogenic amyloid precursor protein,
• (3) decreasing the level of Aβ peptide in the brain of a mammal having an elevated level of Aβ in the brain,
• (4) decreasing level of or inhibiting the release or synthesis of Apolipoprotein in a mammalian cell, tissue or organism,
• (5) decreasing tau hyperphosphorylation in a mammalian cell, tissue or organism,
• (6) stimulating the M1 muscarinic receptor and activating α-secretase,
• (7) stimulating the M1 muscarinic receptor and antagonizing one of more of β-secretase, γ-secretase, or M3-muscarinic receptor,
• (8) decreasing paired helical formation in a mammalian cell,
• (9) activating the Wnt signaling pathway in a mammalian cell, tissue or organism,
• (10) enhancing the activity of endogenous growth factors,
• (11) inhibiting GSK3β-mediated effects in a mammal or
• (12) treating or reducing cerebral amyloid angiopathy,
• said method comprising administering to a system or subject in need thereof an effective amount of a pharmaceutical composition comprising a compound or a mixture of compounds selected from the group consisting of compounds according to formula (I), AF267B and AF150 (S), or racemates, enantiomers, geometrical isomers, diasteromers, tautomers and pharmaceutically acceptable salts thereof.

A compound of the formula (II):

• wherein:
• C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and e;
• A is selected from the group consisting of:
• wherein the bridgehead nitrogen is optionally oxidized to form an N-oxide, R is selected from H, O, C1-C8 straight- or branched-chain alkyl, or —CH2—P(═O)(OH)2;
• a is —O—, —S— or —S(O)—;
• b is —CR1R2— or —C(R1)=;
• d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and —C═N(R3)═O;
• e is selected from the group consisting of —CH2—, —CHR4—, —NH—, —NR5—, —N(SO2R6)— and —N(C(═O)R6)—;
• R1, R2, R3 and R4 are each independently selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkyl optionally substituted by one to three phenyls;
• R5 is selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, optionally substituted phenyl, heteroaryl, and C1-6 alkyl optionally substituted by one to three phenyls;
• or, when the compound of formula (II) is a dimer, in which both halves of the dimer share a single R1, R5 is selected from the group consisting of —CH2)n— and —CH2O)n— wherein n is 1 to 6;
• and
• R6 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C1-6 alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF3 group, C1-6 alkyl substituted by one to three aryl groups, and C . . . alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C1-6 alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
• or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite or pharmaceutically acceptable salt thereof,
• with the proviso that when A is
• R is —H or —CH3, a is S, b is —CH(CH CH3)— and d is —C(═O)—, then e is not —NR5—, and
• with the further proviso that when A is
• R is —CH3, a is S, b is —C(CH3)═ and d is ═N—, then e is not —CH2— (AF150(S)).