MXPA06011725A - Novel 2-(1-aza-bicyclo [2.2.2]oct-3-yl) -2, 3-dihydroisoindol -l-one/5, 6-dihydro-furo[2, 3-c]pyrrol -4one derivatives ligands for alpha 7 nicotinic acetylcholine receptor - Google Patents
Novel 2-(1-aza-bicyclo [2.2.2]oct-3-yl) -2, 3-dihydroisoindol -l-one/5, 6-dihydro-furo[2, 3-c]pyrrol -4one derivatives ligands for alpha 7 nicotinic acetylcholine receptorInfo
- Publication number
- MXPA06011725A MXPA06011725A MXPA/A/2006/011725A MXPA06011725A MXPA06011725A MX PA06011725 A MXPA06011725 A MX PA06011725A MX PA06011725 A MXPA06011725 A MX PA06011725A MX PA06011725 A MXPA06011725 A MX PA06011725A
- Authority
- MX
- Mexico
- Prior art keywords
- oct
- carbon atoms
- aza
- bicyclo
- dihydro
- Prior art date
Links
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- 239000003446 ligand Substances 0.000 title description 5
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- 108010051895 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 title description 2
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- YGCWQYOIPFWXLF-UHFFFAOYSA-N 5,6-dihydrofuro[2,3-c]pyrrol-4-one Chemical class O1C=CC2=C1CNC2=O YGCWQYOIPFWXLF-UHFFFAOYSA-N 0.000 title 1
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Abstract
This invention encompasses nicotinic acetylcholine receptor-reactive compounds in accord with formula (I) Wherein:D represents O;E represents CH2, NH, O or S;n is 1 or 2 and stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts of such compounds, pharmaceutical compositions and formulations containing them, methods of using them to treat diseases and conditions either alone or in combination with other therapeutically-active compounds or substances, processes and intermediates used to prepare them, uses of them as medicaments, uses of them in the manufacture of medicaments and uses of them for diagnostic and analytic purposes.
Description
NEW DERIVATIVES OF 2- (1-AZA-BICICL0 [2 .2 .2] 0CT-3-IL) -2, 3- DIHYDRO-ISOINDOL-1-ONA / 5,6-DIHYDRO-FURO [2, 3- CJPIRROL-4-ONA,
LINKS FOR THE ALPHA-7-NICOTINIC RECEPTOR OF ACETILCOLINE
FIELD OF THE INVENTION The invention relates to the isoindolones or pharmaceutically acceptable salts thereof, the products for their preparation, and the pharmaceutical compositions containing them, and their use in therapy. This invention particularly relates to the isoindolone compounds which are ligands for the alpha-7-nicotinic acetylcholine receptors (7 nAChRs).
BACKGROUND OF THE INVENTION The use of compounds that bind to nicotinic acetylcholine receptors in the treatment of a range of disorders involving reduced cholinergic function, such as anxiety, depression, schizophrenia, cognitive or stress disorders, Alzheimer's, Parkinson's disease, Tourette's syndrome, and to facilitate cessation of smoking, to provide neuroprotection and induce analgesia, have been discussed in McDonald et al. (1995) "Nicotinic Acetylcholine Receptors: Molecular Bioloby, Chemistry and Pharmacology", Chapter 5 in
Ref .: 175969 Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academia Press Inc., San Diego, CA; and in Williams et al. (1994) "Neuronal Nicotinic Acetylcholine Receptors", Drug News Se Perspectives, Vol. 7, pp. 205-223.
DETAILED DESCRIPTION OF THE INVENTION This invention encompasses the compounds reactive with the nicotinic acetylcholine receptor according to formula I:
where: D represents O; E represents CH, NH, O or S; n is 1 or 2 and R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected from an aromatic, or heteroaromatic, fused, substituted or unsubstituted ring system of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, the aromatic or heteroaromatic rings or the ring systems, when substituted, have substituents selected from alkyl of
1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to
6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, - NR2R3, -NR2C (0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, O -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or -S02R4 or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH2) jG-, wherein G is oxygen, sulfur, NR4, or a bond, j is 0.1 ,
2, 3 or 4 and is 0, 1, 2, 3 0 4, and R 4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl. The particular compounds of the invention are compounds reactive with the nicotinic acetylcholine receptor, according to formula II or III:
p or where:
E represents CH2, NH, O or S; G represents CH or N; R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected of a system of aromatic or heteroaromatic ring, fused, substituted or unsubstituted 8, 9 or 10 members, which has
0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, aromatic or heteroaromatic rings or ring systems, when substituted, have substituents selected from the group consisting of
1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02 , -CF3, -S (0) mR2, where m is 0, 1 or 2, - NR2R3, -NR2C (0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or -S02R4 or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH2) jG-, wherein G is oxygen, sulfur, NR4, or a bond, j is 0.1 , 2, 3 or 4 and k is 0, 1, 2, 3 0 4, and R 4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl. The invention also encompasses stereoisomers, enantiomers, hydrolysable precursors in vivo, and pharmaceutically acceptable salts of the compounds of formulas II or III, pharmaceutical compositions and formulations containing them, methods for using them, for treating diseases and conditions, and either alone or in combination with other compounds or active therapeutic substances, the processes and intermediates used to prepare them, their uses as medicines, their uses for the manufacture of medicines and their uses for diagnostic and analytical purposes . The particular compounds of the invention are compounds reactive with the nicotinic acetylcholine receptor, according to formula II:
wherein: E represents CH2, NH, O or S; R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected of an aromatic or heteroaromatic ring system, fused, substituted or unsubstituted of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms , aromatic or heteroaromatic rings or ring systems, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N0, -CF3, -S (0) mR2, where m is 0, 1 or 2, -NR2R3, -NR2C (0 ) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) .R4 , -C02R4 or -S02R4, or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH2) jG-, where G is oxygen, sulfur, NR4, or a bond, j is 0 , 1, 2, 3 or 4 and k is 0, 1, 2, 3 0 4, and R 4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl.
The stereoisomers, enantiomers, hydrolysable precursors in vivo and the pharmaceutically acceptable salts thereof. Other compounds of the invention are compounds reactive with the nicotinic acetylcholine receptor, according to formula III:
pr where: G represents CH or N; R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected of an aromatic or heteroaromatic ring system, fused, substituted or unsubstituted of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms , aromatic or heteroaromatic rings or ring systems, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, - NR2R3, ~ NR2C ( 0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; ,
R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or - S02R * or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH2) jG-, where G is oxygen, sulfur, NR4, or a bond, j is 0, 1, 2, 3 or 4 and k is 0, 1, 2, 3 or 4, and, R 4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl; The stereoisomers, enantiomers, hydrolysable precursors in vivo and the pharmaceutically acceptable salts thereof. The particular compounds of the invention are those according to formula II or III, wherein, R 1 is selected from hydrogen, halogen, and substituted or unsubstituted phenyl pyridyl, quinolinyl, piperazinyl or morpholinyl, phenyl, pyridyl, quinolinyl, piperazinyl. , or morpholinyl, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -FC3, -S (0) mR2, wherein m is 0, 1 or 2, NR2R3, -CH2NR2R3, -OR2 '"CH2OR2 or -C02R4. Particular compounds of the invention are the R stereoisomers of the compounds of formula II or III, according to formula IV or V,
IV v5 where E, G and R1 are as defined herein. The particular compounds of the invention are those described herein and the pharmaceutically acceptable salts thereof. In a further aspect of the invention it relates to the compounds described herein, wherein one or more of the atoms is a radioisotope of the same element. In a particular form of this aspect of the invention, the compound is labeled with tritium. Such radiolabeled compounds are synthesized either by the incorporation of radiolabeled starting materials, or in the case of tritium, the exchange of hydrogen by tritium by known methods. Known methods include
(1) electrophilic halogenation, followed by reduction of the halogen in the presence of a tritium source, for example, by hydrogenation with tritium gas, in the presence of a palladium catalyst or (2) exchange of hydrogen by tritium, carried out in pres. of tritium gas and a suitable organometallic catalyst (eg palladium). The compounds of the invention, labeled with tritium, are useful for the discovery of new medicinal compounds that bind to, and modulate the activity, by agonism, partial agonism, or antagonism of the nicotinic acetylcholine a7 receptor. Such tritium-labeled compounds can be used in assays that measure the displacement of such compounds to evaluate the binding of ligands that bind to a7-nicotinic acetylcholine receptors. In a further aspect, the invention relates to the compounds described herein, which additionally comprise one or more atoms of a radioisotope. In a particular form of this aspect of the invention, the compound comprises a radioactive halogen. Such radiolabelled compounds are synthesized by incorporation of radiolabeled starting materials, by known methods. Particular embodiments of this aspect of the invention are those in which the radioisotope is selected from 18 F, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br or 82 Br. A more particular embodiment of this aspect of the invention is that in which the radioisotope is 18F.
In still another aspect, the invention relates to the compounds described herein, and to their use in therapy and to the compositions containing them. In still another aspect, the invention encompasses the use of the compounds described herein for the therapy of diseases mediated through the action of nicotinic acetylcholine receptors. A more particular aspect of the invention relates to the use of the compounds for the therapy of diseases mediated through the action of nicotinic acetylcholine a7 receptors. Yet another aspect of the invention encompasses a method of treatment or prophylaxis of diseases or conditions in which activation of the nicotinic a7 receptor is beneficial, which method comprises administering a therapeutically effective amount of a compound of the invention to a suffering subject of the disease or condition. One embodiment of this aspect of the invention is a method of treatment or prophylaxis, wherein the disorder is anxiety, schizophrenia, mania or manic depression. Yet another embodiment of this aspect of the invention is a method of treating or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound of the invention.
Yet another embodiment of this aspect of the invention is a method of treatment or prophylaxis, wherein the disorder is Alzheimer's disease, learning deficit, deficit of cognition, attention deficit, memory loss, or hyperactivity disorder with attention deficit. Yet another embodiment of this aspect of the invention is a method of treatment or prophylaxis, wherein the disorder is Parkinson's disease., Huntington's disease, Tourette syndrome, or neurodegenerative disorders in which there is loss of the cholinergic synapse. Yet another embodiment of this aspect of the invention is a method of treatment or prophylaxis of air travel, nicotine addiction, anxiety, pain and for ulcerative colitis, which comprises administering a therapeutically effective amount of a compound of the invention. Yet another embodiment of this aspect of the invention is a method for inducing smoking cessation, which comprises administering an effective amount of a compound of the invention. Yet another embodiment of this aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent, lubricant or carrier.
In a further aspect of the invention it relates to a pharmaceutical composition useful for preventing or treating the condition or disorder mentioned herein, arising from dysfunction of the neurotransmission of the nicotinic acetylcholine receptor, in a mammal, preferably a human, which it comprises an amount of a compound of the invention, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, effective in the treatment or prevention of such a disorder or condition, pharmaceutically acceptable additives and carriers. Yet another embodiment of this aspect of the invention relates to the use of a pharmaceutical composition of the invention for the treatment, improvement or prophylaxis of diseases or human conditions in which activation of the a7 nicotinic receptor is beneficial. Yet another embodiment of this aspect of the invention is the use of the pharmaceutical composition of the invention for the treatment or prophylaxis of neurological disorders, psychotic disorders or disorders of intellectual deterioration. Yet another embodiment of this aspect of the invention is the use of the pharmaceutical composition of the invention for the treatment or prophylaxis of Alzheimer's disease, learning deficit, deficit of cognition, attention deficit, memory loss, disorders of hyperactivity with attention deficit, anxiety schizophrenia, or mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which cholinergic synapse is lost, airplane trip, smoking cessation, addiction to nicotine, including that resulting from exposure to products containing nicotine, anxiety, pain and for ulcerative colitis. A further aspect of the invention is the use of a compound according to the invention, an enantiomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or conditions mentioned herein. Yet another embodiment of this aspect of the invention is the use of the compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of diseases or human conditions in which the activation of the nicotinic receptor is beneficial. Yet another embodiment of this aspect of the invention is the use of the compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of neurological disorders, psychotic disorders or disorders of intellectual deterioration. Yet another embodiment of this aspect of the invention is the use of the compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, learning deficit, deficit of the condition, attention deficit, loss of memory, or hyperactivity disorder with attention deficit. Yet another embodiment of this aspect of the invention is the use of the compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of anxiety, schizophrenia, or mania or manic depression. Yet another embodiment of this aspect of the invention is the use of the compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of Parkinson's disease, Hungtington's disease, Tourette's syndrome, or neurodegenerative disorders, in which there is loss of the cholinergic synapse. Yet another embodiment of this aspect of the invention is the use of a compound as described above in the manufacture of a medicament for the treatment or prophylaxis of air travel, pain, or ulcerative colitis. Yet another embodiment of this aspect of the invention relates to the use of the compound of the invention in the manufacture of a medicament for the cessation of smoking or the treatment of nicotine addiction, or anxiety that includes those resulting from exposure to products that contain nicotine. For uses, methods, medicaments and compositions mentioned herein, the amount of the compound used and the dose administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dose of about 0.1 mg to about 20 mg / kg of body weight of the animal. Such doses can be given in divided doses 1 to 4 times a day or in sustained release form. For humans, the total daily dose is in the range of 5 mg to 1400 mg, more preferably 10 mg to 100 mg, and the unit dosage forms suitable for oral administration comprise from 2 mg to 1400 mg of the compound, administered with carriers, lubricants and solid or liquid pharmaceutical diluents. The compounds of the invention, the enantiomers thereof, the pharmaceutically acceptable salts thereof, may be used on their own or in the form of medicinal preparations appropriate for enteral or parenteral administration. According to a fourth aspect of the invention, a pharmaceutical composition is provided which preferably includes less than 80% and more preferably less than 50% by weight of a compound of the invention, in admixture with a pharmaceutically acceptable inert diluent, lubricant or carrier .
Examples of diluents, lubricants and carriers are: for tablets and dragees: lactose, talc, stearic acid; - for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: oils or natural or hardened waxes. A process for the preparation of such a pharmaceutical composition is also provided, which process comprises mixing or composing the ingredients with each other, and forming the mixed ingredients in the following mixed tablets or suppositories, encapsulating the ingredients in capsules or dissolving the ingredients to form solutions injectables. The compounds according to the invention are agonists of the nicotinic acetylcholine receptors. While not wishing to be bound by theory, it is believed that agonists of the a-nicotinic acetylcholine receptor subtype (nAChR) are useful in the treatment or prophylaxis of neurological disorders, or psychotic disorders and intellectual impairment disorders and have advantages over compounds which are also agonists of subtype a4 nAChR. Therefore, compounds that are selective for subtype a7 nAChR are preferred. The compounds of the invention are indicated as pharmaceuticals, in particular in the treatment or prophylaxis of neurological disorders, mood disorders, psychotic disorders and disorders of intellectual deterioration. Examples of psychotic disorders include schizophrenia, mania, and manic depression, and anxiety. Examples of intellectual impairment disorders include Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, and attention deficit hyperactivity disorder. The compounds of the invention may also be useful as analgesics in the treatment of pain, chronic pain and the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome, and neurodegenerative disorders in which there is loss of the synapse. cholinergic The compounds of the invention may also be useful for the treatment or prophylaxis of air travel, for use in the induction of cessation of smoking, anxiety, and for the treatment or prophylaxis of nicotine addiction, including that resulting of exposure to products that contain nicotine. It is also believed that the compounds according to the invention are useful in the treatment and prophylaxis of ulcerative colitis.
The compounds of the invention have the advantage that they can be less toxic, be more effective, be longer acting, have a wider range of activity, be more potent, produce fewer side effects, be more easily absorbed or have other useful pharmacological properties. The compounds of the invention exist in tautomeric or enantiomeric forms, all of which are included within the scope of the invention. The various optical isomers can be isolated by separation of a racemic mixture of the compounds used in conventional techniques, for example, fractional crystallization or chiral HPLC. Alternatively, the individual enantiomers can be made by reaction of the optically active starting materials, suitable under reaction conditions which will not cause racemisation. Pharmaceutically acceptable derivatives include solvates and salts. For example, the compounds of the invention can form acid addition salts with acids such as pharmaceutically acceptable, conventional acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic acids. , tartaric, and methanesulfonic.
PHARMACOLOGY The pharmacological activity of the compounds of the invention can be measured in the tests immediately:
Test A - assay for affinity in subtype a7nAChR The binding of 125I-a-bungarotoxin (BTX) to rat hippocampal membranes. Rat hippocampi were homogenized in 20 volumes of cold homogenization buffer (HB: concentrations of constituents - (mM): tris (hydroxymethyl) amino ethane 50; magnesium chloride 1; sodium chloride 120; potassium chloride 5; pH 7.4). The homogenate was centrifuged for 5 minutes at 1000 g, the supernatant was saved and the cell button was re-extracted. The combined supernatants were centrifuged for 20 minutes at 12,000 g, washed and resuspended in HB. Membranes (30-80 μg) were incubated with 5 nM [125 I] a-BTX, 1 mg / ml BSA (bovine serum albumin), the test drug, 2 mM calcium chloride or 0.5 mM EGTA '[ ethylene glycol bis (β-aminoethyl ether)] for 2 hours at 21 ° C, and then filtered and washed 4 times on Whatman glass fiber filters (thickness C) using a Brandel cell harvester. Pre-treatment of the filters for 3 hours with 1% (BSA / 0.01% PEI (polyethyleneimine) in water was critical for low-filter targets (0.07% of total counts per minute) .The non-specific link was described by (-) -nicotine 100 μM, and the specific binding was typically 75%.
Test B - Assays for affinity to the subtype of a4nAChR
Linkage of [3 H] - (-) nicotine. Using a modified procedure from Martino-Barrows and Kellar (Mol
Pharm (1987) 31: 169-174), rat brain was homogenized
(cortex and hippocampus) as in the [125I] -BTX binding assay, centrifuged for 20 minutes for 12,000 x g, washed twice, and then resuspended in HB containing 100 μM diisopropyl fluorophosphate. After 20 minutes at 4 ° C, the membranes (approximately 0.5 mg) were incubated with 3 nM [3 H] - (-) nicotine, the test drug, 1 μM atropine, and 2 mM calcium chloride or 0.5 mM EGTA for 1 hour to 4SC, and then filtered over Whatman glass fiber filters (thickness C) (pre-treated for 1 hour with 0.5% PEI) using a Brandel cell harvester. The non-specific binding was described by 100 μM carbachol, and the specific binding was typically 84%.
Link data analysis for tests A and B IC50 values and pseudo Hill coefficients (nH) were calculated using the ALLFIT non-linear curve fitting program (DeLean A, Munson PJ and Rodbard D (1977) Am. J Physiol., 235: E97-E102). The saturation curves were adjusted to a one-site model, using the non-linear regression program ENZFITTER (Leatherbarrow, JJ (1987)), yielding KD values of 1.67 and 1.70 nM for ligands [125I] to-BTX and [ 3H] - (-) nicotine respectively. The values of ¿were estimated using the general Chang-Prusoff equation: 'Ki = [C50] / ((2+ ([ligand] / KD]) n) 1 nl) where a value of n = 1 was used provided that nH Y 1.5 and a value of n = 2 was used when nH = 1.5. The samples were evaluated in triplicate and were typically ± 5%. The K ± values were determined using 6 or more concentrations of the drug. The compounds of the invention generally have binding affinities (K ±) of less than 1 μM either in test A and / or in test B.
Test C - Assay for P-glycoprotein-mediated efflux P-mediated glycoprotein (Pgp) transport was evaluated in Madin-Darby canine kidney cells expressing human P-glycoprotein (MDR1-MDCK) as follows. The MDR1-MDCK cell lines were maintained in culture in Dulbecco's essential medium (DMEM) containing 10% fetal bovine serum (FBS) at 37 aC and 5% C02, and passed twice weekly. To perform the assay, the cells are seeded on the apical side (A) of 12-well Costar plates at 0.5 ml per well, at a density of 300,000 cells per ml, or within 24-well Falcon plates at 0.4 ml per Well, at a cell density of 150,000 cells per ml and 1.5 ml (12-well plates) or 1 ml (24-well plates) of the medium are added to the transozous basolateral chambers (B). The medium is replaced daily and the monolayers are used for the transportation tests 3 days after sowing. The monolayers are fed 2 hours before carrying out a transport test. Stick electrodes are placed to be in contact with the medium on both sides of a monolayer, and resistance is determined through the monolayer. The normal values for the resistance through a monolayer are 130 to 160 Ohms / c 2. The transport tests are carried out manually with plates of 12 wells and run in the directions basolateral to apical (B to A) and apical to basolateral (A to B) in triplicate. The test compounds are dissolved in DMSO and diluted to the test concentrations with HBSS with the final concentration of DMSO in the.
test solutions < 1% . The transpozos are washed with HBSS at 372C for 20 to 40 minutes, and complement plates are prepared. For experiments A to B, 1.5 ml of HBSS is added to the well, followed by 0.5 ml of the test solution to the insert. For experiments B to A, 1.5 ml of a test solution is added to the well, followed by 0.5 ml of HBSS to the insert. The inserts are transferred to the complement plate and the plates are incubated in a water bath at 372C with a stirring speed of 70 rpm for 60 minutes. At the end of each experiment, the inserts are removed from the plates and the samples are transferred from the donor and receiver chambers to the HPLC bottles and analyzed by conventional methods by LC / MS / MS. Calibration standards of 0, 0.005, 0.05, and 0.5 μM were used. Calculations of the results: The apparent permeability is calculated according to the following equations: Papp = [(Vr x Cr) + (A xtx Co)] x 1,000,000 (10"6 cm / sec) Flow rate = Papp (B a A) + P pp A to B) MB (% recovery) = { [Vr x Cr) + (Vd x Cd)] + (Vd x Co).}. X 100 Where: Vr = volume of the receiver in cm; Cr = concentration in the receiver at 60 minutes; Co = initial concentration in the donor; Vd = donor volume; Cd = concentration in the donor at 60 minutes; A = surface area of the transpozos and t = 60 minutes. The compounds of the invention generally have an A-B / B-A ratio of less than 2.5 in this test.
PREPARATION OF THE COMPOUNDS OF THE INVENTION The compounds of the invention can be prepared according to reaction scheme 1.
Reaction scheme I:
General Experimental Procedures and Definitions. Unless otherwise indicated, halo includes chlorine, bromine, fluorine and iodine; Alkyl of 1 to 6 carbon atoms includes methyl, ethyl and propyl, butyl, pentyl or hexyl linear, cyclic or branched; C2-C6 alkenyl includes linear, branched or cyclic ethenyl, 1-propenyl, 2-propenyl, or 3-propenyl and butenyl, pentenyl or hexenyl;
alkynyl of 2 to 6 carbon atoms includes ethynyl or propynyl; alkyl groups of 1 to 4 carbon atoms referred to herein, for example, methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, either alone or as part of another group, they can be straight or branched chain, and alkyl groups of 3 to 4 carbon atoms can also be cyclic, for example, cyclopropyl, or cyclobutyl. The alkyl groups referred to herein may have one, two or three substituents of the halogen atom on them. Unless otherwise indicated, aryl refers to a phenyl group which may have 1, 2 or 3 substituents as described herein. Unless indicated otherwise, heteroaryl refers to a 5 or 6 membered aromatic or heteroaromatic ring containing 0 to 3 nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, with the condition that the ring contains at least one nitrogen, oxygen or sulfur atom, which may have one or more substituents as described herein. Unless indicated otherwise, in the following examples: (i) the operations were carried out at room temperature, for example, in the range of 17 to 252C and under an atmosphere of an inert gas, such as argon or nitrogen: (ii) the evaporations were carried out by rotary evaporation in vacuum and the treatment procedures were carried out after the removal of the residual solids by filtration; (iii) column chromatography (by instantaneous procedure) and medium pressure liquid chromatography (MPLC) were performed on ICN Ecochrom silica gel of 60 Angstrom. In the cases where reverse phase high pressure liquid chromatography (RP-HPLC) was used as a purification method, the Gilson instrumentation (Injector 215, Pumps 333 and Detector 155 UV / Vis) and a column of Varian C8 reverse phase (irregular charge of 60 Angstrom with a particle size of 8 μm, 41.4 mm internal diameter x 250 mm) Gradient elution was used with 0.1% aqueous trifluoroacetic acid / acetonitrile with 0.1% trifluoroacetic acid The collection of samples was based on the signal at 254 nm unless otherwise indicated.In cases where normal phase high pressure liquid chromatography (NP-HPLC) was required, the Dynamax instrumentation was used (pumps double SD-1 and UV-1 UV / Vis detector with a Superprep flow cell and a normal Rainin silica phase column (irregular load of 60 Angstrom in 8 μm particle size, 41.4 mm internal diameter x 250 mm The elution isoc This was done with 0.5% isopropyl alcohol in hexanes. Supercritical fluid chromatography (SFC) was performed on a Berger Autoprep SFC system using in general methanol (containing 0.5% dimethylethylamine) in carbon dioxide and a Berger Diol column (5 microns, pore size 60 A). (iv) in general, the structures of the final products of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectral (MS) techniques; AP / CI mass spectral data were obtained using a Waters Platform LCZ spectrometer and, where appropriate, either positive ion data or negative ion data were collected.; the chemical shift values of nuclear magnetic resonance (NMR) were measured on the delta scale [proton magnetic resonance spectrum were determined using a Bruker Avance 300 spectrometer operating at a field strength of 300 MHz; The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q quadruple; m, multiplet; broad br; (v) the structures and purity of intermediaries were evaluated by thin layer chromatography, HPLC, infra-red (IR) and / or NMR analysis; (vi) the melting points were determined using a Meltemp 3.0 melting point apparatus or an oil bath apparatus; the melting points for the compounds were determined after crystallization from an appropriate organic solvent or a mixture of solvents; (viii) DMSO is dimethyl sulfoxide.
INTERMEDIARY AND INITIAL MATERIALS Initial materials for the compounds described herein were either obtained commercially or were prepared by standard methods from known materials. For example, the following methods illustrate, but do not limit, the preparation of intermediaries and initial materials.
Method A: 2- (R) -l-aza-bicyclo [2 .2 .2] oct-3-yl-6-bromo-2,3-dihydro-isoindol-1-one
In general, the procedure of
Cappelli et al, (Bioorganic &Medicinal Chemistry (2002),
(3), 779-801.). The hydrochloride salt of (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) amine (1.14 g, 5.72 mmol) and sodium carbonate (2.43 g, 23 mmol) were heated to reflux in ethanol (60 ml) for 1 hour. The solution was cooled to 0aC in an ice bath. Allyl bromide (657 mg, 5.43 mmol) was added and the reaction was stirred at 0 ° C for 15 minutes, at room temperature for 15 minutes, and finally at reflux for 30 minutes. The resulting (R) -1-allyl-1-aza-bicyclo [2.2.2] oct-3-ylamine was then directly treated with the 5-bromo-2-bromomethyl-benzoic acid methyl ester (5.72 mmol) in a minimum amount of ethanol and heated to reflux overnight. The resulting mixture was filtered while still hot and the filtrate was concentrated under reduced pressure. The residue was taken up in 60 ml of N, N'-dimethylformamide (60 ml) and treated sequentially with palladium bistriphenylphosphine bichloride (110 mg, 0.16 mmol) and diisopropyl mine (3.6 ml, 25.7 mmol). The solution was heated to 1002C for 1 hour. HPLC indicated complete conversion to the deprotected product. The solvent was removed under a high vacuum and the resulting suspension was partitioned between 1 N hydrochloric acid and chloroform (2 x 80 ml). After vigorous stirring, the layers were separated and the aqueous layer was extracted with 2 80 ml portions of chloroform. The aqueous layer was adjusted to pH > 12 with 5N sodium hydroxide, and again extracted with 3 portions of 80 ml of chloroform.
The last organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give a solid. The solid was triturated in acetone / diethyl ether and filtered to give the title compound as a tan solid (490 mg, 27%). A portion of this solid was purified for analytical purposes by reverse phase HPLC using a gradient of 20 to 60% acetonitrile in water with 0.1% trifluoroacetic acid as the eluent. The compound was obtained as a white solid (58% recovery). NMR? (300.132 MHz, DMSO) d 7.79 (s, 1H), 7.77 (dd, J = 6.6 Hz, J = 1.9 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 4.67 (q, J = 18.8 Hz, 2H), 4.19 (t, J = 8.1 Hz, 1H), 3.12 (ddd, J = 14.1, 9 .9, 2.1 Hz, 1H), 3.00 - 2.88 (m, 2H), 2.73 (t, J = 7.7 Hz, 3H), 2.00 (q, J = 2.8 Hz, 1H), 1.84 - 1.70 (m, 1H), 1.69 - 1.56 (m, 1H), 1.47 - 1.34 (m, 1H), 1.24 (s, 1H ); MS m / z: 321/323 (M + H) M
-Bromo-2-bromomethyl-benzoic acid methyl ester 5-bromo-2-methyl-benzoic acid methyl ester (1.31 g, 5.72 mmol) was dissolved in 40 ml of carbon tetrachloride. 10-20 mg of benzoyl peroxide and NBS (1.01 g, 5.72 mmol) were added, and the reaction mixture was heated to reflux at 100 ° C. The course of the reaction was followed by HPLC and determined to be complete after 1.25 hours. Silica gel was added and the solvent was removed under reduced pressure. The material was purified on silica gel using 5% ethyl acetate in hexanes as the eluent and determined to be 85% pure by NMR (containing 10% of the starting material and 5% of the methyl ester of 5-bromo-2 acid) , 2-dibromomethyl-benzoic acid) and then used without further purification. RMN ^? (300.132 MHz, CDC13) d 8.10 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.3, 2.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 4.90 (s, 2H) ), 4.90 (s, 3H).
-Bromo-2-methyl-benzoic acid methyl ester A 60:40 mixture of 5-bromo-2-methylbenzoic acid and 3-bromo-2-methylbenzoic acid (8.0 g, 0.037 mol) was dissolved in 130 ml of N, N'-dimethylformamide. Methyl iodide (2.28 ml, 2.3 mol) and potassium carbonate were added
(5.11 g, 0.037 mol) in sequence at room temperature. The mixture was stirred at room temperature for 2 hours, at which point the reaction was determined to be complete by HPLC. The solvent was removed under high vacuum and the resulting residue was passed through a column of silica gel using 5% ethyl acetate in hexanes as the eluent. The mixture of isomers was obtained as an oil and then separated by preparative normal phase HPLC using 0.5% isopropyl alcohol in hexanes as the eluent. The title compound was obtained as a white solid (1.38 g, 29%). NMR XH (300.132 MHz, CDC13) d 8.04 (d, J = 2.2 Hz3 1H), 7.50 (dd, J = 8.2, 2.2 Hz, 1H) 3 7.12 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 2.54 (s, 3H).
-Bromo-2-methylbenzoic acid A round bottom flask was charged with bromine (4 ml, 78 mmol) and 300 mg of iron, and cooled to 02C. 2-Methylbenzoic acid (5.0 g, 37 mmol) was added and the suspension was stirred at room temperature overnight. The mixture was carefully triturated with water to provide a reddish tan solid which was isolated by filtration and dried at 50 ° C. for 4 hours. The material (8.0 g, quantitative) was determined by NMR as a 60:40 mixture of the 5- and 3-bromo isomers. 1 H NMR (300.132 MHz, CDC13) d 8.19 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H) 3 2.61 (s, 3H). The subsequent purification was carried out on a separate batch of the 60:40 mixture, taking 12.5 grams of the mixture and dissolving it in 200 ml of methanol. While stirring at room temperature, 200 ml of 0.1 N aqueous hydrochloric acid was slowly added, yielding a white solid. This solid was filtered and dried at 60 ° C under vacuum to yield 4.31 grams of an off-white solid as the simple isomer of 5-bromotoluic acid. XH NMR (300.132 MHz, DMSO) d 7.91 (d, J = 2.2 Hz, 1H) 3 7.64 (dd, J = 7.9, 2.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.17 (s) , 1H), 2.47 (s, 3H). Method B: Method B uses the initial materials described in method A, and the process described in example 2.
Method C: 5- (R) -l-aza-bicyclo [2 .2.2] oct-3-yl-2-bromo-5,6-dihydro-furo [2,3-c] pyrrol-4-one
3. 92 mmol of the 2- acid. { [(R) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -methyl} -5-bromo-furan-3-carboxylic acid were dissolved in 35 ml of pyridine and cooled to 0aC. Thionyl chloride (572 μL, 7.84 mmol) was added in one portion, and the reaction was stirred at room temperature overnight. HPLC indicated that the initial material was still present. Additional thionyl chloride (286 μL, 3.92 mmol) was added at 02C. After 1 hour at room temperature, HPLC indicated that all the initial material had been consumed. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in chloroform and washed with 1 N hydrochloric acid. The aqueous layer was extracted with chloroform and then made alkaline to pH 12 with 5 N sodium hydroxide. aqueous alkaline was then extracted with chloroform. The last organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to provide a brown oil. The oil was taken up in diethyl ether and evaporated twice to give a solid powdery roasted coffee.
The solid was washed with diethyl ether, isolated by filtration, and dried under vacuum overnight to give the title compound as a brown solid (509 mg, 41%). X H NMR (300.132 MHz, DMSO) d 6.91 (s, 1H), 4.67 (q, J = 17.1 Hz, 2H), 4.09 (t, J = 7.9 Hz, 1H), 3.09 (t, J = 12.1 Hz, lH ), 2.93 - 2.79 (m, 2H), 2.70 (t, J = 7.4 Hz, 3H), 1.93 (d, J = 2.5 Hz, 1H), 1.79 - 1.66 (m, 1H), 1.64 - 1.52 (m, 2H), 1.45-1.31 (m, 1H); MS m / z: 311/313 (M + H)
Acid 2-. { [R) -l-aza-bicyclo [2.2.2] oct-3-yl) amino] -methyl) -5-bromo-furan-3-carboxylic acid ethyl ester 2-. { [(R) - (1-azabicyclo [2.2.2] oct-3-yl) amino] -methyl} -5-bromo-furan-3-carboxylic acid (1.4 g, 3.92 mmol) was dissolved in 30 ml of tetrahydrofuran. A solution of lithium hydroxide (94 mg, 3.92 mmol) in 30 mL of water was added, and the mixture was heated to 902C for 45 minutes, 50aC for 1 hour, and then 802C for 0.5 hours. Additional lithium hydroxide was added
(20 mg, 0.83 mmol) and 1 ml of ethanol, and the reaction was heated to 802C for 0.5 hours and then to reflux for 15 minutes. At this point, the HPLC analysis indicated that the reaction had reached completion. The solvents were removed under reduced pressure. The residue was purified from toluene (1 time) and used directly in the next reaction. MS m / z: 329/331 (M + H) M Ethyl ester of 2- acid. { [(R) - (1-aza-bicyclo [2 .2.2] oct-3-yl) amino] -methyl} -5-bromo-furan-3-carboxylic acid
The title compound was prepared from the hydrochloride salt of (R) - (1-aza-bicyclo [2 .2.2] oct-3-yl) amine and the methyl ester of 5-bromo-2 acid -bromomethyl-furan-3-carboxylic acid according to the procedure detailed in Method A. Instead of the expected cyclization, the transesterification of the methyl ester to the ethyl ester occurred. After the usual treatment, a portion of the material (4.66 g, dark brown oil) was purified by reverse phase HPLC using a gradient of 10 to 30% acetonitrile in water with 0.1% trifluoroacetic acid as the eluent
(Reverse phase column C8 5 cm (2 inches), system
Gilson). The fractions were combined and concentrated to provide an oil which was taken up in 1.0 N sodium hydroxide, and extracted with chloroform. The organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as a clear oil. The remainder of the material was purified on silica gel using 5% 7N ammonia in methanol in chloroform as the eluent. The compound was obtained as a white solid. NMR aH (300.132 MHz, IMSO) d 10.81 (bs, 1H), 6.99 (s, 1H), 4.48 (bs, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.76 - 3.05 (m, 7H) , 2.31-2.17 (m, 1H), 2.03-1.71 (m, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.0 Hz, 1H); MS m / z: 357/359 (M + H) \
-Bromo-2-bromomethyl-furan-3-carboxylic acid methyl ester The title compound was prepared as described by Khatuya (Tetrahedron Letters (2001), 42 (14), 2643-2644.). The methyl ester of 2-methyl-furan-3-carboxylic acid (5.0 g, 35.7 mmol) was dissolved in 10 ml of N, N'-dimethylformamide and cooled to 0 ° C. N-bromosuccinimide (NBS) (15.88 g, 89.2 mmol) was added in portions. Approximately 6.5 grams of NBS was added in 45 minutes, at which point it was determined by HPLC that the complete formation of 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester had occurred. The reaction was allowed to warm to room temperature and the remainder of the NBS was added in 1.5 hours. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was extracted with ether and the combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The N, N'-dimethylformamide was removed under high vacuum and the material was absorbed onto silica gel and passed through a column of silica gel using 5% ethyl acetate in hexanes as the eluent. The title compound was obtained as a very pale greenish waxy solid (4.86 g, 46%). NMR - "" H (300.132 MHz, DMSO) d 6.93 (s, 1 H), 4.93 (s, 2 H), 3.82 (s, 3 H).
Method D: Method D uses the initial materials described in method A, and the process described in example 4.
Method E: Method E uses as initial materials a product of Method A and the process described in Example 5.
EXAMPLES Example 1: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-phenyl-2,3-dihydro-isoindol-1-one
2- (R) -Oct-3-yl-6-bromo-2,3-dihydro-isoindol-1-one (200 mg, 0.62 mmol), f-enylboronic acid (89.7 mg, 0.75 mmol), palladium dichloride Bistrifenilfosf ina (56 mg, 0.08 mmol), and cesium carbonate
(403 mg, 1.24 mmol) were combined in a Smith microwave flask and dissolved in a mixture of ethylene glycol dimethyl ether / water / ethanol (1: 1: 1, 3 ml). The mixture was heated in a Smith microwave at 150 ° C for 10 minutes. The reaction mixture was cooled and treated with 1 N sodium hydroxide and extracted with chloroform (3 times). The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the product as an oil. The material was purified by reverse phase HPLC using a gradient of 20 to 60% acetonitrile: water with 0.1% trifluoroacetic acid in 25 minutes. The fractions containing the product were combined and partitioned between 2 N sodium hydroxide and chloroform. The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (67 mg, 34%). 1B NMR. (300.132 MHz, DMSO) d 7.90 (dd, J = 8.2 Hz, J = 1.8 Hz, 1H), 7.88 (s, 1H), 7.72 (t, J = 6.6 Hz, 2H), 7.70 (q, J = 7.0 Hz, 1H) 3 7.49 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 4.74 (q, J = 18.5 Hz, 2H), 4.24 (t, J = 8.3 Hz, 1H), 3.15 (ddd, J = 14.7, 10.1, 1.7 Hz, 1H), 3.04 - 2.90 (m, 2H), 2.75 (t, J = 8.1 Hz, 3H), 2.06 - 1.99 (m, 1H), 1.88 - 1.76 (m, 1H), 1.71 - 1.58 (m, 2H), 1.50 - 1.38 (m, 1H), - MS m / z: 319 (MH-H) M Example 2: 2- (R) -aza- bicyclo [2.2.2] oct-3-yl-5- (4-methyl-piperazin-l-yl) -2,3-dihydro-isoindol-l-one
A 50 ml round bottom flask was charged with 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-bromo-2,3-dihydro-isoindol-1-one ( 250 mg, 0.778 mmol), tris (dibenzylideneacetone) -dipaladium (0) (Pd2 (dba) 3) (15 mg, 0.016 mmol), 2,2 '-bis (diphenylphosphino) -1, 1'-bupropyl (BINAP) (30 mg, 0.047 mmol) and 8 ml of toluene. The reaction mixture was treated sequentially with sodium t-butoxide (94 mg, 1.09 mmol) and 1-methylpiperazine (0.104 mL, 0.934 mmol). The reaction mixture was heated to 80 ° C overnight. The solvent was removed under reduced pressure and the residue was suspended in 5% methanol in chloroform and filtered through a pad of diatomaceous earth. The solvent was removed under reduced pressure and the material was purified by reverse phase HPLC using a gradient of 10 to 40% acetonitrile in water with 0.1% trifluoroacetic acid as the eluent. The fractions were combined and concentrated to give an oil which was taken up in 1.0 N sodium hydroxide and extracted with chloroform. The organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (114 mg, 43%). XH NMR (300.132 MHz, DMSO) d 7.45 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 7.03 (d, J = 9.1 Hz, 1H), 4.56 (q, J = 18.1 Hz, 2H ), 4.14 (t, J = 8.0 Hz, 1H), 3.25 (t, J = 5.2 Hz, 4H), 3.08, (t, J = 11.8 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.72 ( t, J = 7.2 Hz, 3H), 2.45 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.94 (t, J = 3.0 Hz, 1H), 1.83 - 1.71 (m, 1H), 1.67-1.53 (m, 2H), 1.47-1.34 (m, 1H); MS m / z: 341 (M + H) M
Example 3: 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-phenyl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one
The title compound was prepared as a pale green solid in 28% yield from 5- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-2-bromo-5,6. -dihydro-furo [2, 3-c] pyrrol-4-one and phenylboronic acid, in a manner similar to that described in example A, except that the UV detection during the purification was at 280 nm. 1 H NMR (300.132 MHz, DMSO) d 7.75 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.5 Hz *, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.21 (s, 1H), 4.74 (q, J = 17.3 Hz, 2H), 4.13 (t, J = 8.1 Hz, 1H), 3.12
(ddd, J = 13.4, 9.9, 1.8 Hz, 1H), 2.96 - 2.85 (m, 2H),
2. 71 (t, J = 7.3 Hz, 3H), 1.96 (q, J = 2.8 Hz, 1H),
1. 84-1.71 (m, 1H), 1.66-1.56 (m, 2H), 1.46-1.33 (m, 1H); MS m / z: 309 (M + H) M
Example 4: 2- (R) -l-aza-bicyclo [2.2, 2] oct-3-yl-6- (4-chloro-f-enyl) -2,3-dihydro-isoindol-l-one
The 2- (R) -1-aza-bi cycle [2.2.2] oct-3-yl-6-bromo-2,3-dihydro-isoindol-l-one (130 mg, 0.41 mmol), acid
4-chlorophenylboronic acid (70 mg, 0.45 mmol), palladium-bistriphenylphosphine bichloride (57 mg, 0.081 mmol), and cesium carbonate (395 mg, 1.21 mmol) were dissolved in ethanol / ethylene glycol dimethyl ether / water (7: 3). 2 ml). It was heated at 802C for 30 minutes. The mixture was cooled and the volatile materials were removed under reduced pressure. The residue was taken up in methanol at
% in chloroform and filtered through a frit of
0. 2 micrometers The solvent was removed under reduced pressure and the material was purified by reverse phase HPLC using a gradient of 10 to 40% acetonitrile in water with 0.1% trifluoroacetic acid as the eluent. The fractions were combined and concentrated to give an oil which was taken up in 1.0 N sodium hydroxide and extracted with chloroform. The organic layers were dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid (98 mg, 68%) .- 1 H NMR (300.132 MHz, DMSO) d 7.92-7.87 (, 2H) , 7.76 (d, J = 10.2 Hz, 2H), 7.68 (d, J = 11.3 Hz, 1H), 7.53 (d, J = 16.2 Hz, 2H), 4.80 and 4.68 (AB, J = 18.5 Hz, 2H) , 4.24 (t, J = 7.9 Hz, 1H), 3.14 -3.08 (m, 1H), 3.06 - 2.91 (m, 2H), 2.76 (t, J = 11.1 Hz, 1H), 2.02 (s, 1H), 1.87-1.77 (m, 2H), 1.70-1.59 (m, 2H), 1.51-1.38 (m, 2H); MS m / z: 353 (M + H) M
Example 5: N- [3 - ((R) -2-l-aza-bicyclic or [2. 2. 2] oct-3-yl-3-oxo-2, 3-dihydro-lH-isoindol- 5 - il) -f enyl] -but ir amide
6- (3-Amino-phenyl) -2- (R) -1-aza-bicyclo [2.2.2] oct-3-i1-2, 3-dihydro-isoindol-l-one (84 mg, 0.252 mmol ) was dissolved in 4 ml of tetrahydrofuran. To this solution was added butyryl chloride in a single portion. This solution was then stirred at room temperature. The course of the reaction was followed by HPLC and determined to be complete after 1.5 hours. The solvent was removed under reduced pressure. The material was purified by silica gel using 5% 7N ammoniacal methanol in chloroform. The compound was obtained as a tan solid (58% recovery). XR-NMR (300.132 MHz, DMSO) d 9.98 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.83 (s, 2H), 7.69
(d, J = 7.7 Hz, 1H), 7.63 - 7.57 (, 2H), 7.42 - 7.38 (m,
2H), 4.82 and 4.69 (AB, J = 18 Hz, 2H), 4.25 (t, J = 7.9 Hz,
1H), 3.15 (t, J = 11.6 Hz, 1H), 3.04 - 2.91 (m, 2H), 2.76 (t,
J = 9.6 Hz, 1H), 2.34 (q, J = 8.6 Hz, 2H), 2.01 (s, 1H), 1.89 - 1.73 (m, 1H), 1.72 - 1.57 (m, 1H), 1.49 - 1.37 (m , 1H), 1.10 (t, J = 10.5 Hz, 3H); MS m / z: 390 (M + H) M
Examples 6-23: The compounds of examples 6 to 23 according to the following formula
were prepared according to the procedures described herein.
Example 6: 2- (R) -l-aza-bicyclo [2 .2.2] oct-3-yl-6-bromo-2, 3-dihydro-isoindol-1-one Compound obtained as a white solid, with a 27% yield. (See Method A.) XH NMR (300.132 MHz, DMSO) d 7.79 (s, 1H), 7.77 (dd, J = 6.6 Hz, J = 1.9 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H) , 4.67 (q, J = 18.8 Hz, 2H), 4.19 (t, J = 8.1 Hz, 1H), 3.12 (ddd, J = 14.1, 9.9, 2.1 Hz5 1H), 3.00 - 2.88 (m, 2H) 5 2.73 (t, J = 7.7 Hz, 3H), 2.00 (q, J = 2.8 Hz, 1H), 1.84 - 1.70 (m, 1H), 1.69 - 1.56 (? rr, 1H), 1.47 - 1.34 (m, 1H) , 1.24 (s, 1H); MS m / z: 321/323 (M + H) M
Example 7: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-pyridin-3-yl-2, 3-dihydro-isoindol-l-one Compound prepared as an off-white solid with a yield of 22% from the acid 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-bromo-2,3-dihydro-isoindol-l-one and 3- pyridylboronic acid as described in Example 1. NMR (300.132 MHz, DMSO) d 8.95 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 4.6, 1.4 Hz, 1H), 8.15 (dt, J = 8.3 , 1.9 Hz, 1H), 7.96 (m, 2H), 7.72 (d, J = 8.4 Hz5 1H), 7.51 (dd, J = 8.1, 4.8 Hz, 1H), 4.76 (q, J = 18.6 Hz, 2H), 4.24 (t5 J = 8.3 Hz, 1H), 3.16 (ddd, J = 14.1, 10.1, 1.8 Hz, 1H), 3.06 - 2.89 (m, 2H), 2.75 (t, J = 7.5 Hz, 3H) , 2.05 - 2.00 (m5 1H), 1.89 - 1.75 (m, 1H), 1.72 - 1.59 (m, 2H), 1.50 - 1.38 (m, 1H); MS m / z: 320 (M + H) M Example 8: 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-pyridin-4-yl-2,3-dihydro -isoindole-1-one Compound prepared as an off-white solid in 23% yield from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-6-bromo-2, 3-dihydro-isoindol-l-one and the 4-pyridylboronic acid described in Example 1. "NMR"? (300.132 MHz, DMSO) d 8.66 (d, J = 5.9 Hz, 2H), 8.04 (s, 1H), 8.03 (dd, J = 5.9, 1.7 Hz, 1H), 7.79 (dd, J = 4.5, 1.6 Hz , 1H), 7.76 (t, J = 8.3 Hz, 2H), 4.77 (q, J = 18.9 Hz, 2H), 4.24 (t, J = 8.3 Hz, 1H), 3.15 (ddd, J = 14.3, 10.1, 1.7 Hz, 1H), 3.06-2.89 (m, 2H), 2.75 (t, J = 7.7 Hz, 3H), 2.03 (q, J = 2.7 Hz, 1H), 1.88 - 1.75 (m, 1H), 1.72 - 1.58 (m, 2H), 1.50-1.37 (m, 1H); MS m / z: 320 (M + H) +.
Example 9: 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-bromo-2,3-dihydro-isoindol-1-one Compound prepared as a white solid with a yield of 30% from the hydrochloride salt (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) amine and the methyl ester of 4-bromo-2-bromomethyl-benzoic acid as described in Example 1. XH NMR (300.132 MHz, EMSO) d 7.83 (s, 1H), 7.63 (q, J = 10.1 Hz, 1H), 7.61 (s, 1H), 4.69 (q, J = 18.7 Hz, 2H) , 4.18 (t, J = 7.9 Hz5 1H), 3.13 (ddd, J = 14.9, 10.2, 1.6 Hz, 1H), 3.00 - 2.86 (, 2H), 2.73 (t, J = 7.6 Hz, 3H), 2.02 - 1.96 (, 1H), 1.84 - 1.71 (m, 1H), 1.68 - 1.55 (m, 2H), 1.48 - 1.29 (m, 1H); MS m / z: 321/323 (MH-H) M Example 10: 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-phenyl-2, 3-dihydro-isoindole -1-one Compound prepared as a white solid with a yield of 17% from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-5-bromo-2,3-dihydro -isoindol-1-one and phenylboronic acid described in Example 1. "NMR"? (300.132 MHz, CDC13) d 7.90 (d, J = 7.7 Hz, 1H), 7.71 - 7.58 (m, 4H), 7.51 - 7.37 (m, 3H), 4.65 (dd, J = 22.8, 16.6 Hz, 2H) , 4.45 (t, J = 8.4 Hz, 1H), 3.38 (ddd, J = 14.8, 10.3, 2.0 Hz, 1H), 3.07 (dd, J = 14.2, 6.9 Hz, 2H), 2.91 (t, J = 7.7 Hz, 3H), 2.16 (q, J = 2.9 Hz, 1H), 1.93 -1.78 (m, 1H), 1.77-1.51 (m, 3H); MS m / z: 319 (M + H) +.
Example 11: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-pyridin-2-yl-2, 3-dihydro-isoindol-l-one Compound prepared as a white solid with a 38% yield from 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-bromo-2,3-dihydro-isoindol-l-one and the acid 3-pyridylboronic acid described in Example 1. * XB NMR. (300.132 MHz, CDC13) d 8.88 (d, J = 1.9 Hz, 1H), 8.65 (dd, J = 4.8, 1.4 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.91 (dt, J = 8.0, 2.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.66 (s, 1H), 7.41 (dd, J = 8.2, 4.9 Hz, 1H), 4.67 (dd, J = 22.6, 16.8 Hz, 2H), -4.45 (t, J = 8.3 Hz, 1H), 3.39 (ddd, J = 15.3, 10.2, 2.2 Hz, 1H), 3.07 (dd, J = 13.9, 6.6 Hz, 2H), 2.91 (t, J = 7.3 Hz, 3H), 2.16 (q, J = 2.9 Hz, 1H), 1.91 - 1.78 (m, 1H), 1.77 - 1.52 (m, 3H); MS m / z: 320 (M + H) M Example 12: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-pyridin-4-yl-2,3-dihydro -isoindole-1-one Compound prepared as a brown / white residue residue with a yield of 17% from 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-bromine -2, 3-dihydro-isoindol-l-one and the 4-pyridylboronic acid described in Example 1 * Mt NMR (300.132 MHz, CDC13) d 8.71 (dd, J = 4.4, 1-4 Hz, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.71 (s, 1H), 7.52 (dd, J = 4.4, 1.6 Hz, 2H), 4.67 (dd, J = 24.4, 16.6 Hz, 2H), 4.45 (t, J = 8.3 Hz, 1H), 3.39 (ddd, J = 14.6, 10.1, 1.9 Hz, 1H), 3.07 (dd, J = 14.7, 6.7 Hz, 2H), 2.91 (t, J = 7.4 Hz, 3H), 2.16 (q, J = 2.8 Hz, 1H), 1.95 - 1.78 (m, 2H), 1.78 - 1.65 (m, 1H), 1.64 - 1.51 (m, 1H); MS m / z: 320 (M + H) M
Example 13: 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-4-bromo-2,3-dihydro-isoindol-1-one Compound prepared as a light brown solid with a yield 36% from the hydrochloride salt of (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) amine and the 3-bromo-2-bromomethyl-benzoic acid methyl ester described in Example 1. ** NMR 4í (300.132 MHz, DMSO) d 7.86 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H ), 4.66 (dd, J = 45.8, 17.6 Hz, 2H), 4.50 (t, J = 8.5 Hz, 1H), 3.65 (d, J = 8.6 Hz, 2H), 3.50 - 3.11 (m, '4H), 2.45 - 2.40 (m, 1H), 2.34 - 2.28 (m, 1H), 2.21 - 2.04 (m, 2H), 2.01 - 1.70 (m, 1H); MS m / z: 321/323 (M + H) M Example 14: 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-4-phenyl-2, 3-dihydro-isoindole -1-one Compound prepared as a white solid with a 33% yield from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-4-bromo-2,3-dihydro -isoindol-l-one and phenylboronic acid. as described in Example 1. RMR Mr
(300.132 MHz, CDC13) d 7.89 - 7.82 (m, 1H) ', 7.57 - 7.42 (, 7H), 4.61
(dd, J = 27.0, 17.0 Hz, 2H), 4.40 (t, J = 8.3 Hz, 1H), 3.35 (ddd, J =
14. 6, 10.0, 2.0 Hz, 1H), 3.10 - 2.95 (m, 2H), 2.88 (t, J = 7.5 Hz, 3H), 2.13 (q, J = 2.8 Hz, 1H), 1.86 - 1.64 (, 3H) , 1.55 - 1.45 (,
1 HOUR); MS m / z: 319 (M + H) \
Example 15: 2- (R) -l-aza-biciclor [2 .2 .2] oct-3-yl-4-pyridin-3-l, 2-, 3-dihydro-isoindol-l-one Compound prepared or a white foam with a yield of 17% from the 2- (R) -l-aza-bicyclo [2. .2] oct-3-yl-4-bromo-2,3-dihydro-isoindol-l-one and the 3-pyridylboronic acid described in Example 1. 1 H NMR (300.132 MHz, CDC13) d 8.77 (s, 1H ), 8.69 (d, J = 4.1 Hz, 1H), 7.91 (dd, J = 7.3, 0.9 Hz, 1H), 7.80 (dt, J = 7.9, 1.8 Hz, 1H), 7.61 (t, J = 7.5 Hz , 1H), 7.55 (dd, J = 7.6, 1.0 Hz, 1H), 7.46 (dd, J = 8.1, 4.9 Hz, 1H), 4.61 (dd, J = 24.4, 16.9 Hz, 2H), 4.40 (t, J = 8.3 Hz, lH), 3.36 (ddd, J = 14.1, 10.1, 1.9 Hz, 1H), 3.09 - 2.95 (m, 2H), 2.94 -2.81 (, 3H), 2.13 (q, J = 2.9 Hz, 1H), 1.87-1.47 (, 4H); MS m / z: 320 (M + H) M Example 16 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-4-pyridin-4-yl-2,3-dihydro- isoindol-l-one Compound prepared as a light brown solid with a yield of 20% from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-4-bromo-2, 3-dihydro-isoindol-l-one and the 4-pyridylboronic acid described in Example 1. "NMR"?
(300.132 MHz, CDC13) d 8.75 (dd, J = 4.3, 1.6 Hz, 2H), 7.93 (dd, J =
6. 5, 2.1 Hz, 1H), 7.61 (q, J = 6.7 Hz, 1H), 7.59 (t, J = 6.4 Hz, 1H),
7. 40 (dd, J = 4.4, 1.6 Hz, 2H), 4.63 (dd, J = 27.0, 17.0 Hz, 2H), 4.40 (t, J = 8.4 Hz, 1H), 3.37 (ddd, J = 13.9, 9.9, 2.1 Hz, 1H), 3.10
- 2.96 (m, 2H), 2.95 - 2.82 (m, 3H), 2.13 (q, J = 2.9 Hz, 1H) 1.87 - 1.47 (m, 4H); MS m / z: 320 (M + H) +.
Example 17: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-7-bromo-2,3-dihydro-isoindol-1-one Compound prepared as an off-white solid with a yield of 54% from the hydrochloride salt of the (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) amine and the 2-bromo-6-bromomethyl-benzoic acid methyl ester described in Example 1 ** NMR XH (300.132 MHz, DMSO) d 7.63 (dd, J = 17.1, 7.7 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 4.67 (q, J = 18.2 Hz, 2H), 4.37 (t, J = 8.0 Hz, 1H), 3.50 (t, J = 11.7 Hz, 1H), 3.36 (dd, J = 13.6, 6.8 Hz, 1H), 3.26 (td, J = 11.8, 4.8 Hz, 1H), 3.09 (t, J = 7.7 Hz, 3H), 2.26 (q, J = 3.1 Hz, 1H), 2.06 - 1.94 (, 1H), 1.90 - 1.79 (m, 2H), 1.69 (t, J = 12.2 Hz, 1H); MS m / z: 321/323 (M + H) M
Example 18: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-7-phenyl-2, 3-dihydro-isoindol-1-one Compound prepared as a pale yellow solid with a yield 26% from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-7-bromo-2,3-dihydro-isoindol-l-one and the phenylboronic acid described in Example 1. RMN ""? (300.132 MHz, CDC13) d 7.57 (t, J = 7.2 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.47 - 7.36 (m, 5H), 4.61 (dd, J = 22.2, 16-.6 Hz5 2H) 5 4.40 (t5 J = 8.3 Hz, 1H), 3.33 (ddd, J = 14.5, 10.3, 2.3 Hz, 1H), 3.05 - 2.80 (m, 5H), 2.11 (q, J = 2.8 Hz, 1H) , 1.89-1.71 (m, 3H), 1.70-1.60 (m, 1H); MS m / z: 319 (M + H) +.
Example 19: 2- (R) l-aza-bicyclo [2.2.2] oct-3-yl-7-pyridin-3-yl-2, 3-dihydro-isoindol-l-one Compound prepared as a pale yellow solid with a yield of 22% from 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-7-bromo-2,3-dihydro-isoindol-l-one and the acid 3-pyridylboronic acid described in Example 1. NMR "" "H
(300.132 MHz, CDC13) d 8.72 (d, J = 2.0 Hz, 1H), 8.62 (dd, J = 4.8,
1. 5 Hz, 1H), 7.95 (dt, J = 7.8, 1.9 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H),
7. 51 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.35 (dd, J =
7. 7, 5.0 Hz, 1H), 4.63 (dd, J = 23.8, 16.8 Hz, 2H), 4.39 (t, J = 8.1 Hz, 1H), 3.34 (ddd, J = 14.3, 9.9, 2.2 Hz, 1H), 3.07 - 2.77 (m, 5H), 2.11 (q, J = 2.8 Hz, 1H), 1.89 - 1.48 (, 4H); MS m / z: 320 (M + H) M
Example 20: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-7-pyridin-4-yl-2, 3-dihydro-isoindol-l-one Compound prepared as an off-white solid with a yield of 96% from 2- (R) -l-azabicyclo [2.2.2] oct-3-yl-7-bromo-2,3-dihydro-isoindol-l-one and the acid 4-pyridylboronic described in Example 1. "NMR" H (300.132 MHz, CDC13) d 8.67 (dd, J = 4.6, 1.6 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.53 (d , J = 7.4 Hz, 1H), 7.47 (dd, J = 4.6, 1.5 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 4.64 (dd, J = 23.6, 17.0 Hz, 2H), 4.39 (t, J = 8.2 Hz, 1H), 3.34 (ddd, J = 14.3, 10.3, 2.0 Hz, 1H), 3.09 -2.78 (m, 5H), 2.11 (q, J = 2.8 Hz, 1H), 1.90 - 1.63 (m, 3H), 1.63-1.49 (m, 1H); MS m / z: 320 (M + H) +.
Example 21: (R) -2- (l-aza-bicyclo [2.2, 2] oct-3-yl) -2, 3-dihydro-isoindol-1-one Compound prepared as a light brown solid with a yield of 4 % from the hydrochloride salt of the (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) amine and of the 2-bromo-methyl-benzoic acid methyl ester described in Example 1 . *
NMR (300.132 MHz, CDC13) d 7.85 (d, J = 7.5 Hz, 1H), 7.58 - 7.41
(m, 3H), 4.59 (dd, J = 23.8, 16.5 Hz, 3H), 4.43 (t, J = 8.1 Hz, 1H),
3. 36 (ddd, J = 14.1, 10.0, 2.1 Hz, 1H), 3.05 (q, J = 7.0 Hz, 2H), 2.90 (t, J = 7.6 Hz, 3H), 2.13 (q, J = 2.8 Hz, 1H ), 1.91 - 1.76 (m, 2H), 1.75 - 1.64 (m, 1H), 1.61 - 1.49 (m, 1H); MS m / z: 243 (M + H) +.
Example 22: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5- (4-methyl-piperazin-1-yl) -2, 3-dihydro-isoindol-1-one Compound obtained as a white solid with a yield of 43%. (See Example 2.) XH NMR (300.132 MHz, EMSO) d 7.45 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 7.03 (d, J = 9.1 Hz, 1H), 4.56 (q, J = 18.1 Hz, 2H), 4.14 (t, J = 8.0 Hz, 1H), 3.25 (t, J = 5.2 Hz, 4H), 3.08 (t, J = 11.8 Hz, 1H), 2.98 - 2.85 (m, 2H), 2.72 (t, J = 7.2 Hz, 3H), 2.45 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.94 (t, J = 3.0 Hz, 1H), 1.83 - 1.71 ( m, 1H), 1.67-1.53 (m, 2H), 1.47-1.34 (m, 1H); MS m / z: 341 (M + H) M
Example 23: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-morph olin-4-J1-2, 3-dihydro-isoindol-l-one Compound prepared as a solid white with a 23% yield from 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5-bromo-2,3-dihydro-isoindol-l-one and morpholine in a manner similar to that described for Example 2. NMR (300.132 MHz, DMSO) d 7.48 (d, J = 8.1 Hz, 1H), 7.06 (s,
1H), 7.04 (dd, J = 9.4, 2.0 Hz, 1H), 4.57 (q, J = 18.3 Hz, 2H), 4.15
(t, J = 8.0 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 3.22 (t, J = 4.8 Hz,
4H), 3.09 (ddd, J = 13.9, 10.1, 1.8 Hz, 1H), 2.94 (dd, J = 14.2, 6.7
Hz, 2H), 2.72 (t, J = 7.6 Hz, 3H), 1.96 (q, J = 2.7 Hz, 1H), 1.84 -1.71 (m, 1H), 1.62 (dd, J = 8.6, 2.9 Hz, 2H ), 1.48 - 1.35 (m, 1H);
MS m / z: 328 (M + H) +.
Examples 24-27: The compounds of examples 24 to 27 according to the following formula
were prepared according to the procedures described herein.
Example 24: 5- (R) -l-aza-bicyclo [2. 2 . 2] oct-3-yl-2-bromo-5,6-dihydro-f uro [2, 3-c] pyrrol-4-one Compound obtained as a brown solid with a yield of 41%. (See Method B.) NMR (300.132 MHz, DMSO) d 6.91 (s, 1H), 4.67
(q, J = 17.1 Hz, 2H), 4.09 (t, J = 7.9 Hz, 1H), 3.09 (t, J = 12.1 Hz,
1H), 2.93 - 2.79 (, 2H), 2.70 (t, J = 7.4 Hz, 3H), 1.93 (d, J = 2.5
Hz, 1H), 1.79-1.66 (m, 1H), 1.64-1.52 (m, 2H), 1.45-1.31 (m, 1H);
MS m / z: 311/313 (M + H) +.
Example 25: 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-phenyl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one Compound obtained as a pale green solid with a yield of 28%. (See Example 3.) X-ray NM ?. (300.132 MHz, DMSO) d 7.75 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.35 (t,, J = 7.2 Hz, 1H), 7.21 (s, lH) , 4.74 (q, J = 17.3 Hz, 2H), 4.13 (t, J = 8.1 Hz, 1H), 3.12 (ddd, J = 13.4, 9.9, 1.8 Hz, 1H), 2.96 - 2.85 (m, 2H), 2.71 (t, J = 7.3 Hz, 3H), 1.96 (q, J = 2.8 Hz, 1H), 1.84 - 1.71 (m, 1H), 1.66 - 1.56 (m, 2H), 1.46 - 1.33 (m, 1H); MS m / z: 309 (M + H) +. -
Example 26: 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-pyridin-3-yl-5,6-dihydro-furo [2, 3-c] pyrrol-4 -one Compound prepared as a white solid with a yield of 30% from 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-bromo-5,6-dihydro- furo [2,3-c] pyrrol-4-one and 3- (5,5-dimethyl- [1,3,2] dioxaborinan-2-yl) -pyridine in a manner similar to that described in Example 3 .NMRH (300.132 MHz, EMSO) d 9.00 (d, J = 2.0 Hz, 1H), 8.54 (dd, J = 4.9, 1.6 Hz, 1H), 8.12 (dt, J = 8.0, 1.9 Hz, 1H) , 7.49 (dd, J = 8.1, 4.8 Hz, 1H), 7.38 (s, lH), 4.76 (q, J = 17.3 Hz, 2H), 4.14 (t, J = 7.3 Hz, 1H), 3.12 (ddd, J = 14.8, 12.1, 3.3 Hz, 1H), 2.90 (dd, J = 12.5, 6.3 Hz, 2H), 2.71 (t, J = 6.6 Hz, 3H), 1.97 (q, J = 2.7 Hz, 1H), 1.85-1.71 (m, 1H), 1.66-1.57 (m, 2H), 1.47-1.33 (m, 1H); MS m / z: 310 (M + H) +.
Example 27: 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-pyridin-4-yl-5,6-dihydro-f-uro [2, 3-c] pyrrol- 4-one Compound prepared as a white solid with a 21% yield from 5- (R) -1-azabicyclo [2.2.2] oct-3-yl-2-bromo-5,6-dihydro -furo [2, 3-c] pyrrol-4-one and 4-pyridylboronic acid in a manner similar to that described in Example 3. XH NMR (300.132 MHz, DMSO) d 8.63 (dd, J- = 4.5, 1.4 Hz, 2H), 7.70 (dd, J = 4.7, 1.4 Hz, 2H), 7.56 (s, 1H), 4.78 (q, J = 17.6 Hz, 2H), 4.14 (t, J =
7. 6 Hz, 1H), 3.12 (ddd, J = 13.2, 9.8, 1.7 Hz, 1H), 2.90 (dd, J = 14.2, 6.7 Hz, 2H), 2.72 (t, J = 7.1 Hz, 3H), 1.97 (q, J =
2. 7 Hz, 1H), 1.84-1.71 (m, 1H), 1.61 (septet, J = 3.7 Hz, 2H), 1.47-1.33 (m, 1H); MS m / z: 310 (M + H) M * - The compounds of examples 11, 12, and 21 were purified by preparative SFC using 38% methanol (containing 0.5% dimethylethylamine) in carbon dioxide. and a Berger Diol column (5 microns, 60 A pore size) * * - Material of methods 13 and 17 obtained as an oil was collected in diethyl ether / chloroform and treated with an excess of 1.0 M hydrochloric acid in diethyl ether , to form a solid. The solid was isolated by filtration and then converted to the free base by washing in 2 N sodium hydroxide and chloroform. The organic layers were dried over sodium sulfate, filtered and concentrated to provide the desired compound as a solid. Other compounds of the invention are: 2- (R) -l-aza-bicyclo [2 .2.2] oct-3-yl-6- (3-chlorophenyl) -2,3-dihydro-isoindol-1-one;
2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (4-chloro-phenyl) -2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-quinolin-8-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-benzo [1,3] dioxol-5-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (2-chloro-phenyl) -2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (2-methoxy-phenyl) -2, 3-dihydro-isoindol-1-one; N- [3- ((R) -2-1-aza-bicyclo [2.2.2] oct-3-yl-3-oxo-2,3-dihydro-lH-isoindol-5-yl) -phenyl] - acetamide; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-morpholin-4-yl-2,3-dihydro-isoindol-1-one, and 4- ((R) - 2-1-aza-bicyclo [2.2.2] oct-3-yl-3-oxo-2, 3-dihydro-lH-isoindol-5-yl) -N, N-dimethyl-benzamide.
Examples 28-72: The compounds shown in the following table according to the following formula were synthesized in a manner analogous to the previous examples.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Claims (18)
1. A compound according to formula I: characterized in that: D represents O; E represents CH, NH, O or S; n is 1 or 2 and R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected from an aromatic, or heteroaromatic, fused, substituted or unsubstituted ring system of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 atoms. of sulfur, aromatic or heteroaryl rings or ring systems, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, -NR2R3, - NR2C (0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or -S02R4 or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH2) jG-, wherein G is oxygen, sulfur, NR4, or a bond, j is 0.1 ,. 2, 3 or 4 and k is 0, 1, 2, 3 or 4, and R * is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl; or a stereoisomer, enantiomer, hydrolysable precursor in vivo and the pharmaceutically acceptable salts thereof. 2. A compound according to formula II or III:
H m characterized in that: E represents CH2, NH, O or S; G represents CH or N;
R1 is selected from hydrogen, halogen or a substituted or unsubstituted aromatic or heteroaromatic ring of 5 or 6 members, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected from an aromatic or heteroaromatic, fused, substituted or unsubstituted ring system of 8, 9 or 10 members, which has 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, aromatic or heteroaromatic rings or ring systems, when substituted, have substituents selected from the group consisting of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, -NR2R3, -NR2C (0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or -S02R4 or R2 and R3 in combination is - (CH2) G (CH2) k- or -G (CH2) -G-, where G is oxygen, sulfur, NR4, or a bond, j is 0 , 1, 2, 3 or 4 and k is 0, 1, 2, 3 or 4, and R4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl. or a stereoisomer, enantiomer, hydrolysable precursor in vivo and the pharmaceutically acceptable salts thereof. 3. A compound according to formula II: p characterized in that: E represents CH2, NH, O or S; R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected of an aromatic or heteroaromatic ring system, fused, substituted or unsubstituted of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms , the aromatic or heteroaromatic rings or the ring systems, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, - NR2R3, -NR2C ( 0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or - S02R4, or R > 2"and tR-3 in combination is - (CH2) pG (CH2) k- or
-G (CH2) jG-, where G is oxygen, sulfur, .NR4, or a bond, j is 0, 1, 2, 3 or 4 and k is 0, 1, 2, 3 0 4, and R4 is selected independently at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl; or a stereoisomer, enantiomer, hydrolysable precursor in vivo and the pharmaceutically acceptable salts thereof. . A compound according to claim 2, according to formula III: characterized in that G represents CH or N R1 is selected from hydrogen, halogen or a substituted or unsubstituted 5-or 6-membered aromatic or heteroaromatic ring, having 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom, or selected from an aromatic, or heteroaromatic, fused, substituted or unsubstituted ring system of 8, 9 or 10 members, having 0, 1, 2 or 3 nitrogen atoms, 0 or 1 oxygen atoms, and 0 or 1 sulfur atoms, the aromatic or heteroaromatic rings or the ring systems, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, -CN, -N02, -CF3, -S (0) mR2, where m is 0, 1 or 2, -NR2R3, -NR2C (0) R3, -CH2NR2R3, OR2, -CH2OR2, -C (0) NR2R3, or -C02R4; R2 and R3 are independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, -C (0) R4, -C02R4 or -S02R4, or R2 and R3 in combination is - (CH2) jG (CH2) k- or -G (CH) jG-, wherein G is oxygen, sulfur, NR4, or a bond, j is O, 1, 2, 3 or 4 and k is 0, 1, 2, 3 or 4, and R 4 is independently selected at each occurrence of hydrogen, alkyl of 1 to 4 carbon atoms, aryl or heteroaryl; or a stereoisomer, enantiomer, hydrolysable precursor in vivo and the pharmaceutically acceptable salts thereof.
5. A compound according to claim 3 or 4, characterized in that, R1 is selected from hydrogen, halogen, and substituted or unsubstituted phenyl pyridyl, quinolinyl, piperazinyl or morpholinyl, phenyl, pyridyl, quinilonyl, piperazinyl, or morpholinyl, when substituted, have substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms , halogen, -CN, -N02, -CF3, -S (0) mR2, wherein m is 0, 1 or 2, NRR3, -CH2NR2R3, -OR2 '~ CH20R2 or -C02R4.
6. A compound according to claim 2, characterized in that: the compound is an R-stereoisomer according to formula IV or V, vv. 7 A compound, characterized in that it is selected from: 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-phenyl-2,3-dihydro-isoindol-1-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5- (4-methyl-piperazin-1-yl) -2, 3-dihydro-isoinol-1-one; 5- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-2-phenyl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-bromo-2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-pyridin-3-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-pyridin-4-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2 .2.2] oct-3-yl-5-bromo-2,3-dihicro-isoi dol-l-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-phenyl-2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-pyridin-3-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-pyridin-4-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-4-bromo-2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-4-phenyl-2,3-dihydro-isoindol-1-one; 2- (R) -l-aza-bicyclo [2 .2.2] oct-3-yl-4-pyridin-3-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-4-pyridin-4-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2 .2.2] oct-3-yl-7-bromo-2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-7-phenyl-2,3-dihydro-isoindol-1-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-7-pyridin-3-yl-2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-7-pyridin-4-yl-2, 3-dihydro-isoindol-1-one; (R) -2- (1-aza-bicyclo [2.2.2] oct-3-yl) -2, 3-dihydro-isoindol-l-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-5- (4-methyl-piperazin-1-yl) -2,3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-5-morpholin-4-yl-2, 3-dihydro-isoindol-1-one; 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-bromo-5,6-dihydro-furo [2,3-e] pyrrol-4-one; 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-phenyl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one; 5- (R) -1-aza-bicyclo [2,22] oct-3-yl-2-pyridin-3-yl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one; 5- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-2-pyridin-4-yl-5,6-dihydro-furo [2, 3-c] pyrrol-4-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (3-chloro-phenyl) -2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (4-chloro-phenyl) -2, 3-dihydro-isoindol-1-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-quinolin-8-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6-benzo [1,3] dioxol-5-yl-2, 3-dihydro-isoindol-1-one; 2- (R) -1-aza-bicyclo [2.2.2] oct-3-yl-6- (2-chloro-phenyl) -2, 3-dihydro-isoindol-1-one; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6- (2-methoxy-phenyl) -2, 3-dihydro-isoindol-1-one; N- [3- ((R) -2-1-aza-bicyclo [2 .2.2] oct-3-yl-3-oxo-2, -dihydro-lH-isoindol-5-yl) -phenyl] -acetamide; 2- (R) -l-aza-bicyclo [2.2.2] oct-3-yl-6-morpholin-4-yl-2, 3-dihydro-isoindol-1-one, or 4- ((R) - 2-1-aza-bicyclo [2.2.2] oct-3-yl-3-oxo-2, 3-dihydro-lH-isoindol-5-yl) -N, N-dimethyl-benzamide. 8. A compound according to claim 1 or 2, characterized in that one or more of the atoms is a radioisotope of the same element. 9. A compound according to claim 1 or 2, further characterized in that one or more atoms are selected from tritium, 18F, 123I, 125I, 131I, 75Br, 76Br, 77Br, or 82Br. A method of treatment or prophylaxis of diseases or conditions in which the activation of nicotinic receptor a7 is beneficial, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1 or 2, to a subject suffering from a disease or condition. The method of treatment or prophylaxis according to claim 10, characterized in that the disorder is anxiety, schizophrenia, mania or manic depression. 12. A method of treatment or prophylaxis of neurological disorders, psychotic disorders or disorders of intellectual deterioration, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1 to a subject suffering from said disease or condition. 13. The method of treatment or prophylaxis according to claim 12, characterized in that the disorder is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss or attention deficit hyperactivity disorder. The method of treatment or prophylaxis according to claim 12, characterized in that the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is loss of cholinergic synpasis. 15. A method of treatment or prophylaxis of air travel, nicotine addiction, anxiety, pain and for ulcerative colitis, characterized in that it comprises administering a therapeutically effective amount of a compound according to claim 1 or 2 16. A method to induce cessation of smoking, characterized in that it comprises administering an effective amount of a compound according to claim 1. 1
7. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable diluent, lubricant or carrier. The use of a compound according to claim 1, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of neurological disorders, psychotic disorders or selected intellectual impairment disorders of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss or deficit hyperactivity disorder, of attention, anxiety, schizophrenia or mania, manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome , neurodegenerative disorders in which there is loss of cholinergic synpasis, jet lag syndrome, pain or ulcerative colitis.
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SE0400970-0 | 2004-04-14 |
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