Patent Application
20080103158
The present invention is in the filed of medicinal chemistry and relates to amyloid β deposition inhibitor containing a heterocyclic compound having a specific structure.
Alzheimer' diseases is dementing neurodegenarative disorder for which there is no effective treatment at present. Genetic and biological studies provide evidence that the production and deposition of amyloid-β(Aβ) contribute to the etiology of Alzheimer' disease (for example, see Drug News & Perspectives. Vol. 17, No. 5, June 2004, Trends Neurosci., 20. 154-159 (1997), and Science, 297, 353-356 (2002)). Therefore an amyloid β deposition inhibitor will be useful agent as Alzheimer's disease progression inhibitor
γ-Secretase inihibitors are developing for inhibiting the production of amyloid β, but these compounds will have adverse side effects because of their inhibitory activity of Notch gene or N-Cadherin (for example, see J. Biol. Chem., 276, 45394-45402 (2001)). Curcumin is a component of Curcuma longa contained in curry in a large amount and has antiinflammatory and antioxidative activity equivalent to prescribed nonsteroidal antiinflammatory drugs (NSAIDs). Studies have shown that curcumin inhibits amyloid-related pathologies. However, curcumin does not inhibit β amyloid deposition at satisfactory levels (for example, see Pharmacia, Japanese Pharmacology Association, Vol. 38, No. 9, 891-892, 2002). Therefore there is a strong demand for development of effective drugs having an sufficient effect and fewer side effects.
Booklet of International Publication No. WO01/009131; and Booklet of International Publication No. WO01/060907 disclose brain function improvers containing heterocyclic compounds having specific structures. The heterocyclic compounds are disclosed as brain function improvers leading to treatment for memory loss and memory acquisition/retention disorder in senile dementia, Alzheimer's disease and related disorders. But the inhibitory activity of amyloid β deposition and the inhibitory activity of progression of Alzheimer's disease are not disclosed (for example, see Booklet of International Publication No. 01/009131; and Booklet of International Publication No. 2002/060907).
The present invention provides an amyloid β deposition inhibitor containing a heterocyclic compound having the general Formula (I):
or a pharmaceutically acceptable salt or hydrate thereof.
In the general Formula (I), the structural unit having the general formula (II) is one or more structural units selected from multiple types of structural units having the general Formula (III).
In the general Formula (I), R1 and R2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C1-C6 alkyl group, C1-C6 alkoxy group, and —O—(CH2)n-R5, wherein R5 is a vinyl group, C3-C6 cycloalkyl group, or phenyl group, and n is 0 or 1.
Furthermore, in the general Formula (I), R3 and R4 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C1-C6 alkyl group, C3-C8 cycloalkyl group, and —CH(R7)—R6; alternatively, R3 and R4 together form a spiro ring having the general Formula (IV):
R6 is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C1-C6 alkyl group, C1-C6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C1-C6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group. The above R7 is a hydrogen atom or C1-C6 alkyl group.
Furthermore, in the general Formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general Formula (V). The structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
R8 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C1-C6 alkoxy group, cyano group, and trifluoromethyl group.
The compounds of Formula (I) may be used as an a delayer of the progression of Alzheimer's disease.
The invention also relates to a method of inhibiting amyloid deposition in an mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the general Formula (I).
The invention also relates to a method of delaying the progression of Alzheimer's disease in a human in need thereof, comprising administering to the human an effective amount of a compound having the general Formula (I).
Embodiments of the present invention are described hereafter. Embodiments below relate to an amyloid β deposition inhibitor composition containing a heterocyclic compound having the above described specific structure (azaindolizinone derivatives) and pharmaceutically acceptable carriers or diluents, as well as methods for inhibiting amyloid deposition and methods for delaying the progression of Alzheimer's disease.
The compounds useful in the present invention all contain a heterocyclic compound having the general Formula (I):
or a pharmaceutically acceptable salt or hydrate thereof.
In the general Formula (I), the structural unit having the general Formula (II) is one or more structural units selected from multiple types of structural units having the general Formula (III).
Furthermore, in the general formula (I), R1 and R2 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C1-C6 alkyl group, C1-C6 alkoxy group, and —O—(CH2)n-R5, wherein R5 is a vinyl group, C3-C6 cycloalkyl group, or phenyl group, and n is 0 or 1.
Furthermore, in the general Formula (I), R3 and R4 each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C1-C6 alkyl group, C3-C8 cycloalkyl group, and —CH(R7)—R6; alternatively, R3 and R4 together form a spiro ring having the general formula (IV):
The above R6 is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C1-C6 alkyl group, C1-C6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C1-C6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group), phenethyl group, pyridyl group, thienyl group, and furyl group. The above R7 is a hydrogen atom or C1-C6 alkyl group.
In the general Formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general Formula (V). The structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.
Here, R5 is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C1-C6 alkoxy group, cyano group, and trifluoromethyl group.
When the heterocyclic compound having the general Formula (I) has asymmetric carbon atoms in the structure, its isomer from asymmetric carbon atoms and their mixture (racemic modification) is present. In such cases, all of them are included in the heterocyclic compound used in the embodiments described later.
The heterocyclic compound has the general Formula (I). In the general Formula (I), the following terms have the meanings specified below along with their examples.
The term “C1-C6” refers to 1 to 6 carbon atoms unless otherwise defined. The term “C3-C8” refers to 3 to 8 carbon atoms unless otherwise defined. The term “C1-C6 alkyl” includes linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl. The term “C1-C6 alkoxy” includes linear or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, and n-hexyloxy. The term “C3-C8 cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “halogen atom” includes fluorine, chlorine, bromine, and iodine.
The heterocyclic compound useful in the practice of the present invention is not particularly restricted as long as it has the above described specific structure. For example, the following compounds can be used.
The heterocyclic compound of Formula (I) can be in the form of hydrate or acid addition salts as a pharmaceutically acceptable salt. Possible acid addition salts include inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts and organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and salicylate salts.
The administration method, formulation, and dosage of the heterocyclic compound in mammals, particularly in human, are described hereafter. The heterocyclic compound can be administrated orally or parenterally. Formulations for oral administration include tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups. Formulations for parenteral administration include injectable solutions (including those freeze-dried and dissolved for use), adhesive skin patches, and suppositories.
These formulations can be prepared using pharmaceutically acceptable fillers, binders, lubricants, disintegrators, suspending agents, emulsifiers, antiseptic agents, stabilizing agents, and dispersing agents such as lactoses, saccharoses, starches, dextrines, crystalline celluloses, kaolins, calcium carbonate, talc, magnesium stearate, and distilled water or saline. Particular pharmaceutically acceptable components include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The dosage varies according to the symptom, age, and body weight of patients. An adult can take 0.1 to 60 mg per day in one to three doses.
In another embodiment, the invention provides an amyloid β deposition inhibitor composition comprising a compound having Formula (I). The invention also provides a method of inhibiting amyloid deposition in an mammal in need thereof, comprising administration to the mammal an effective amount of a compound having the general Formula (I).
The inventors found that a compound of Formula (I), in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], exhibits inhibitory activity of amyloid β deposition in the hippocampus by amyloid β immunohistochemistry as described later in the examples. Screening of derivatives of the compound for amyloid β deposition inhibitory activity showed that azaindolizinone derivatives in which an indan ring forms a spiro ring have potent amyloid β deposition inhibitory activity. The above compound exhibits amyloid β deposition inhibitory activity based on a novel mechanism different from antioxidative activity. The compound has also been shown to be highly safe in the preclinical study.
The amyloid β deposition inhibitor of Formula (I), in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], is effective at lower dosages based on a mechanism which is different from curcumin, a component of Curcuma longa contained in curry in a large amount and which has antioxidative activity. Therefore, it is a new amyloid β deposition inhibitor having a mechanism of action different from curcumin.
The amyloid β deposition inhibitor of this embodiment is preferably spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan] as this compound was shown to have excellent inhibitory activity of amyloid β deposition in the hippocampus amyloid β immunohistochemistry, which is a typical animal model test for inhibitory activity of amyloid β deposition, as described later in the examples.
The amyloid β deposition inhibitor compound may be administered by any means which achieves reduction in amyloid β deposition in a mammal. Preferably, the amyloid β deposition inhibitor compound of this embodiment is orally administered. In another embodiment, the amyloid β deposition inhibitor compound may be administered as part of an adhesive skin patch. Alternatively, the amyloid β deposition inhibitor compound may be formulated into tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups, as the amyloid β deposition inhibitor in the form of oral formulations is easily administered in mammals, including human beings.
The amyloid β deposition inhibitor compound of this embodiment is preferably administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher. In one embodiment, the compound is administered as part of a unitary pharmaceutical dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg. When the amyloid β deposition inhibitor is administered at an effective oral dosage of this lower limit or higher, the amyloid β deposition inhibitory activity in mammals including human beings is improved compared to when lower doses are administered.
In another embodiment, the invention provides an Alzhiemer's disease progression inhibitor composition comprising a compound of Formula (I). The invention also provides a method of delaying the progression of Alzheimer's disease comprising administering to a human in need thereof an effective amount of a compound having Formula (I).
As discussed above, amyloid β deposition inhibitor of Formula (I), in particular, spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan], exhibits excellent inhibitory activity of amyloid β deposition. Since amyloid β is neurotoxic and associated with the etiology of Alzheimer's disease, it is expected that administration of a compound of Formula (I) to a human patient in need thereof will slow or inhibit the progression of Alzheimer's disease. Such a human patient may exhibit the very early to late stages of Alzheimer's disease. For example, the human patient may exhibit very mild cognitive decline (stage 2), mild cognitive decline (early Alzheimer's disease, stage 3), moderate cognitive decline (mild or early-stage Alzheimer's disease, stage 4), moderately severe cognitive decline (moderate or mid-stage Alzheimer's disease, stage 5), severe cognitive decline (moderately severe or mid-stage Alzheimer's disease, stage 6), or very severe cognitive decline (severe or late-stage Alzheimer's disease, stage 7).
The Alzheimer's disease progression inhibitor compound may be administered by any means which achieves the slowing or inhibiting of the progression of Alzheimer's disease. Preferably, the Alzheimer's disease progression inhibitor compound of this embodiment is orally administered. In another embodiment, the Alzheimer's disease progression inhibitor compound may be administered as part of an adhesive skin patch. Alternatively, the Alzheimer's disease progression inhibitor compound may be formulated into tablets, coated tablets, powder, granules, capsules, microcapsules, and syrups, as the amyloid β deposition inhibitor in the form of oral formulations is easily administered in mammals, including human beings.
The Alzheimer's disease progression inhibitor compound of this embodiment is preferably administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher. In one embodiment, the compound is administered as part of a unitary pharmaceutical dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.
Embodiments of the present invention are described above. These embodiments are given by way of example. The present invention can be realized in many other ways as the invention is not so limited.
For example, some preferable ranges of effective oral dosages are defined in the above embodiments. However, other ranges of effective dosages can be determined for other administration forms. For example, a preferable range of effective dosages for administration by injection can be determined as appropriate. Furthermore, preferable ranges of administration intervals can be determined for particular administration forms in addition to the effective dosages with no more than routine experimentation.
The present invention is further described using examples. However, the present invention is not restricted thereto.
In order to show that compounds having Formula (I) have amyloid β deposition inhibitory activity, the activity of Compound 1 on amyloid β deposition was examined.
Senescene accelerated mice (SAMP8) (male, 8 months old at the beginning of the study) were used for experiment. Approximately 0.1 mg/kg/day of Compound 1 was given in drinking water. Eight weeks after the dosing, the mouse brain was removed, Methacarn-fixed (methanol:chloroform:acetic acid=6:3:1), and paraffin-embedded. Then, sections of 8 μm in thickness were prepared using a microtome.
The sections were immunostained with streptavidin-biotin using a VECTASTATIN ABC kit. After one hour of incubation in 10% normal goat serum, the anti-amyloid β (Aβ) antibody was diluted with PBS to ten fold and incubated at 4° C. overnight. The following day, PBS rinsing, 1.5 hours of incubation with biotinylated anti-rabbit secondary antibody, PBS rinsing, and 1.5 hours of incubation with peroxidase-labeled streptavidin were conducted. The immunoreaction was visualized with DAB and specimens were prepared.
Immunoreactive Aβ-like granules in the hippocampus were counted under the microscope. The Aβ-like immunoreactive granule was observed as brown deposits in the hippocampus. The count was made for one section per individual.
As shown in
As described above, Compound 1 inhibits amyloid β deposition. Amyloid-related pathologies for which Compound 1 may be used the method for inhibiting of the progression of Alzheimer's disease in which amyloid β is considered to be a factor of the disorder.
As described above, a compound having Formula (I) was shown to have inhibitory activity of amyloid β deposition in an amyloid β immunohistochemistry.
Preparation of Compounds Referred to in the Embodiments
Some of the heterocyclic compound having the general Formula (I) and prepared by the method in examples of Booklet of International Publication No. 01/09131 are described hereafter by way of example. More specifically, they were synthesized with reference to Booklet of International Publication No. 01/09131 and Booklet of International Publication No. 2002/060907 Brochure.
Exemplary Preparation 1
An exemplary preparation of spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan] (Compound 1) having the general formula below is described hereafter.
An amount of 56.1 g (1.04 mol) of sodium methoxide was dissolved in 15 L of methanol, and an amount of 90.0 g (0.0345 mol) of 2-amino-1-(ethoxycarbonylmethyl)pyridinium bromide and 60.0 g (0.0342 mol) of α,α′-dichloro-o-xylene were added successively at room temperature. The reaction mixture was stirred at room temperature over night and then the solvent was removed under reduced pressure. Dichloromethane was added to the residue and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel column (ethyl acetate:methanol=15:1) to give crude product. The crude product was washed by using ethyl acetate and then recrystallized from methanol to give an amount of 36 g (40%) of the title compound in the form of white crystals. Results of analysis of the obtained compound are given below. The results show that the obtained compound was the targeted compound
Melting Point: 206° C. (decomposition);
NMR (CDCl3) δ: 3.16 (2H, d, J=16 Hz), 3.89 (2H, d, J=16 Hz), 6.49 (1H, t, J=7 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (4H, m), 7.61 (1H, t, J=7 Hz);
MS m/z: 236 (M+).
Exemplary Preparation 2
Compounds 2 to 40 of Formulae (I) were each prepared from the respective starting materials in the same manner as in Exemplary Preparation 1. Results of analysis of the obtained compounds are given for each compound. The results show that the obtained compounds were the targeted Compounds 2 to 40.
Melting Point: 247-248° C.;
NMR (CDCl3) δ: 1.03 (6H, d, J=6 Hz), 3.15 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 4.60 (1H, sept., J=6 Hz), 6.48 (1H, t, J=7 Hz), 6.79 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
MS m/z: 372 (M+)
Melting Point: 274-275° C.;
NMR (CDCl3) δ: 3.17 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 3.69 (3H, s), 6.49 (1H, t, J=7 Hz), 6.67 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
MS m/z: 344 (M+).
Melting Point: 236-237° C.;
NMR (CDCl3) δ: 0.12 (2H, q, J=5 Hz), 0.45 (2H, q, J=6 Hz), 0.99 (1H, m), 3.16 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 3.73 (2H, d, J=7 Hz), 6.47 (1H, t, J=7 Hz), 6.76 (1H, d, J=8 Hz), 7.0-7.2 (11H, m);
MS m/z: 384 (M+).
Melting Point: 246-248° C.;
NMR (CDCl3) δ: 3.16 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.70 (1H, d, J=10 Hz), 7.0-7.2 (12H, m);
MS m/z: 348 (M+).
Melting Point: 214-215° C.;
NMR (CDCl3) δ: 3.16 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 4.4-4.5 (2H, m), 5.0-5.2 (2H, m), 5.7-5.9 (1H, m), 6.47 (1H, t, J=7 Hz), 6.74 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
MS m/z: 370 (M+).
Melting Point: 240-241° C.;
NMR (CDCl3) δ: 3.17 (2H, d, J=14 Hz), 3.57 (2H, d, J=14 Hz), 5.03 (2H, s), 6.39 (1H, t, J=8 Hz), 6.65 (1H, d, J=8 Hz), 7.0-7.2 (16H, m);
MS m/z: 420 (M+).
Melting Point: 234-235° C.;
NMR (CDCl3) δ: 1.52 (6H, d, J=7 Hz), 3.51 (2H, q, J=7 Hz), 5.11 (2H, s), 6.14 (1H, t, J=7 Hz), 6.41 (1H, d, J=7 Hz), 6.63 (1H, d, J=8 Hz), 7.0-7.2 (15H, m);
MS m/z: 448 (M+).
Melting Point: 262-263° C.;
NMR (CDCl3) δ: 2.05 (3H, s), 3.31 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 6.60 (1H, t, J=7 Hz), 6.9-7.2 (12H, m);
MS m/z: 328 (M+).
Melting Point: 237-238° C.;
NMR (CDCl3) δ: 2.07 (3H, s), 2.80 (3H, s), 3.40 (2H, d, J=15 Hz), 3.71 (2H, d, J=15 Hz), 6.11 (1H, s), 6.34 (1H, s), 7.0-7.2 (10H, m);
MS m/z: 342 (M+).
Melting Point: >300° C.;
NMR (DMSO-D6) δ: 3.39 (4H, s), 6.60 (1H, d, J=9 Hz), 6.8-7.2 (11H, m), 7.56 (1H, t, J=7 Hz), 8.75 (1H, d, J=7 Hz);
MS m/z: 314 (M+).
Melting Point: 268-269° C.;
NMR (CDCl3) δ: 1.4-1.7 (8H, m), 3.15 (2H, d, J=14 Hz), 3.55 (1H, d, J=14 Hz), 4.7-4.9 (1H, m), 6.47 (1H, t, J=7 Hz), 6.72 (1H, d, J=8 Hz), 6.9-7.2 (11H, m);
MS m/z: 398 (M+).
Melting Point: 260-261° C.;
NMR (CDCl3) δ: 3.17 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.9-7.3 (11H, m), 7.41 (1H, d, J=2 Hz);
MS m/z: 382 (M+).
Melting Point: 234-236° C.;
NMR (CDCl3) δ: 3.22 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.9-7.0 (4H, m), 7.1-7.4 (7H, m), 7.51 (1H, d, J=2 Hz);
MS m/z: 416 (M+).
Melting Point: 233-235° C.;
NMR (CDCl3) δ: 2.20 (6H, s), 3.14 (2H, d, J=14 Hz), 3.48 (2H, d, J=14 Hz), 5.05 (2H, s), 6.38 (1H, t, J=7 Hz), 6.68 (1H, d, J=8 Hz), 6.7-7.3 (14H, m);
MS m/z: 448 (M+).
Melting Point: 228-230° C.;
NMR (CDCl3) δ: 2.01 (3H, s), 3.13 (2H, d, J=14 Hz), 3.60 (2H, d, J=14 Hz), 6.60 (1H, t, J=7 Hz), 6.95 (4H, d, J=6 Hz), 7.22 (1H, d, J=7 Hz), 7.46 (1H, d, J=7 Hz), 8.40 (4H, d, J=6 Hz);
MS m/z: 330 (M+).
Melting Point: 290-292° C.;
NMR (CDCl3) δ: 3.13 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 6.62 (1H, t, J=7 Hz), 6.7-6.9 (5H, m), 6.9-7.1 (4H, m), 7.39 (1H, t, J=7 Hz), 7.52 (1H, brd, J=7 Hz);
MS m/z: 350 (M+).
Melting Point: >300° C.;
NMR (CDCl3) δ: 2.86 (12H, s), 3.09 (2H, d, J=14 Hz), 3.37 (2H, d, J=14 Hz), 6.4-6.6 (5H, m), 6.7-6.9 (5H, m), 7.2-7.3 (1H, m), 7.37 (1H, t, J=7 Hz);
MS m/z: 400 (M+).
Melting Point: 271-272° C.;
NMR (CDCl3) δ: 3.14 (2H, d, J=14 Hz), 3.53 (2H, d, J=14 Hz), 6.66 (1H, t, J=7 Hz), 6.80 (1H, d, J=7 Hz), 6.9-7.2 (8H, m), 7.43 (1H, t, J=7 Hz), 7.51 (1H, brd, J=7 Hz);
MS m/z: 382 (M+).
Melting Point: 248-251° C.;
NMR (CDCl3) δ: 3.66 (6H, s), 3.67 (2H, d, J=15 Hz), 4.00 (2H, d, J=15 Hz), 6.59 (4H, d, J=9 Hz), 6.93 (4H, d, J=9 Hz), 7.50 (1H, t, J=7 Hz), 6.71 (1H, d, J=7 Hz), 7.91 (1H, t, J=7 Hz), 9.78 (1H, d, J=7 Hz);
MS m/z: 374 (M+).
Melting Point: >300° C.;
NMR (CDCl3) δ: 3.25 (2H, d, J=14 Hz), 3.62 (2H, d, J=14 Hz), 6.58 (1H, t, J=7 Hz), 6.77 (1H, d, J=7 Hz), 7.11 (4H, d, J=7 Hz), 7.3-7.6 (16H, m);
MS m/z: 466 (M+).
Melting Point: 294° C. (decomposition);
NMR (CDCl3) δ: 3.19 (2H, d, J=14 Hz), 3.70 (2H, d, J=14 Hz), 6.6-6.8 (2H, m), 7.13 (4H, d, J=7 Hz), 7.43 (1H, t, J=7 Hz), 7.45 (4H, d, J=7 Hz), 7.62 (1H, brd, J=7 Hz);
MS m/z: 364 (M+).
Melting Point: 276.5-277.5° C.;
NMR (CD3OD-CDCl3(1:1)) δ: 3.62 (2H, d, J=14 Hz), 3.66 (2H, d, J=14 Hz), 6.58 (4H, d, J=9 Hz), 6.78 (4H, d, J=9 Hz), 7.17 (1H, d, J=7 Hz), 7.63 (1H, t, J=7 Hz), 8.12 (1H, t, J=7 Hz), 9.25 (1H, d, J=7 Hz);
MS m/z: 346 (M+).
Melting Point: 64-66° C.;
NMR (CDCl3) δ: 2.56 (2H, dd, J=9 Hz, J=14 Hz), 2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.99 (2H, dd, J=1 Hz, J=7 Hz), 5.04 (2H, d, J=1 Hz), 5.4-5.6 (2H, m), 6.67 (1H, t, J=7 Hz), 7.17 (1H, d, J=7 Hz), 7.52 (1H, d, J=7 Hz), 7.59 (1H, d, J=7 Hz);
MS m/z: 214 (M+).
Melting Point: 160-162° C.;
NMR (CDCl3) δ: 2.54 (2H, dd, J=8 Hz, J=14 Hz), 2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.96 (2H, dd, J=1 Hz, J=5 Hz), 5.01 (2H, d, J=1 Hz), 5.29 (2H, s), 5.4-5.6 (2H, m), 6.53 (1H, dd, J=7 Hz, J=8 Hz), 6.94 (1H, d, J=7 Hz), 7.16 (1H, d, J=8 Hz), 7.3-7.5 (5H, m);
MS m/z: 320 (M+).
Melting Point: 227-228° C.;
NMR (CDCl3) δ: 0.9-1.1 (2H, m), 1.4-1.6 (2H, m), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 2.3-2.5 (2H, m), 2.5-2.7 (2H, m), 6.61 (1H, t, J=7 Hz), 7.0-7.1 (4H, m), 7.1-7.3 (8H, m), 7.58 (1H, t, J=7 Hz);
MS m/z: 370 (M+).
Melting Point: 262° C. (decomposition);
NMR (CDCl3): 3.12 (2H, d, J=17 Hz), 3.98 (2H, d, J=17 Hz), 6.18 (1H, t, J=7 Hz), 6.48 (1H, d, J=7 Hz), 7.24 (1H, d, J=7 Hz), 7.34 (2H, d, J=7 Hz), 7.4-7.6 (3H, m), 7.86 (2H, d, J=7 Hz);
MS m/z: 286 (M+).
Melting Point: 269-271° C.;
NMR (CDCl3) δ: 3.38 (2H, d, J=14 Hz), 3.47 (2H, d, J=14 Hz), 6.5-6.7 (3H, m), 6.7-6.8 (3H, m), 7.2-7.5 (3H, m), 7.6-7.7 (1H, m);
MS m/z: 368 (M+).
Melting Point: 73-75° C.;
NMR (CDCl3) δ: 0.7-0.9 (8H, m), 1.1-1.3 (2H, m), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 6.73 (1H, t, J=7 Hz), 7.19 (1H, d, J=7 Hz), 7.50 (1H, d, J=7 Hz), 7.63 (1H, t, J=7 Hz);
MS m/z: 218 (M+).
Melting Point: 289.5° C. (decomposition);
NMR (CDCl3) δ: 3.41 (2H, d, J=15 Hz), 3.70 (2H, d, J=15 Hz), 6.64 (1H, t, J=7 Hz), 6.7-7.0 (5H, m), 7.07 (2H, dd, J=1 Hz, J=5 Hz), 7.38 (1H, d, J=7 Hz), 7.48 (1H, t, J=7 Hz);
MS m/z: 326 (M+).
Melting Point: 235-237° C.;
NMR (CDCl3) δ: 2.05 (3H, s), 3.20 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.61 (1H, t, J=7 Hz), 6.9-7.1 (4H, m), 7.1-7.2 (7H, m), 7.78 (1H, brs), 8.39 (1H, d, J=7 Hz);
MS m/z: 371 (M+).
Melting Point: 205° C. (decomposition);
NMR (CDCl3) δ: 3.37 (4H, s), 6.11 (2H, d, J=3 Hz), 6.23 (2H, dd, J=2 Hz, J=3 Hz), 6.56 (1H, t, J=7 Hz), 6.97 (1H, d, J=7 Hz), 7.20 (2H, d, J=2 Hz), 7.22 (1H, d, J=7 Hz), 7.51 (1H, t, J=7 Hz);
MS m/z: 294 (M+).
Melting Point: 200-202° C.;
NMR (CD3OD-CDCl3(1:1)) δ: 1.93 (6H, s), 7.72 (1H, t, J=7 Hz), 7.78 (1H, d, J=7 Hz), 8.50 (1H, t, J=7 Hz), 9.01 (1H, d, J=7 Hz);
MS m/z: 162 (M+).
Melting Point: 100.5-102° C.;
NMR (CDCl3) δ: 0.6-0.9 (8H, m), 1.0-1.3 (6H, m), 1.6-1.8 (2H, m), 2.0-2.2 (2H, m), 6.71 (1H, t, J=7 Hz), 7.19 (1H, d, J=7 Hz), 7.50 (1H, d, J=7 Hz), 7.62 (1H, t, J=7 Hz);
MS m/z: 246 (M+).
Melting Point: 172-175° C.;
NMR (CDCl3) δ: 2.07 (2H, t, J=3 Hz), 2.80 (2H, dd, J=3 Hz, J=17 Hz), 3.08 (2H, dd, J=2.6 Hz, J=17 Hz), 6.75 (1H, t, J=7 Hz), 7.24 (1H, d, J=7 Hz), 7.69 (1H, t, J=7 Hz), 8.02 (1H, d, J=7 Hz);
MS m/z: 210 (M+).
Melting Point: 283-285° C.;
NMR (CDCl3) δ: 3.20 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.58 (1H, t, J=7 Hz), 6.87 (1H, d, J=7 Hz), 6.9-7.0 (4H, m), 7.07 (1H, d, J=7 Hz), 7.1-7.2 (6H, m);
MS m/z: 330 (M+).
Melting Point: 250° C.;
NMR (CDCl3) δ: 3.42 (2H, d, J=14 Hz), 3.70 (2H, d, J=14 Hz), 4.35 (2H, d, J=6 Hz), 6.93 (1H, d, J=7 Hz), 7.0-7.3 (16H, m), 7.48 (1H, d, J=7 Hz), 8.66 (1H, brs);
MS m/z: 419 (M+).
Melting Point: >300° C.;
NMR (CD3OD-CDCl3(1:1)) δ: 3.21 (2H, d, J=14 Hz), 3.67 (2H, d, J=14 Hz), 6.66 (1H, t, J=7 Hz), 6.75 (1H, d, J=7 Hz), 7.15 (4H, d, J=9 Hz), 7.39 (1H, t, J=7 Hz), 7.42 (4H, d, J=9 Hz), 7.56 (1H, d, J=7 Hz);
MS m/z: 404 (M+).
Melting Point: 283-285° C.;
NMR (CDCl3) δ: 3.17 (2H, d, J=14 Hz), 3.53 (2H, d, J=14 Hz), 4.06 (2H, brs), 6.4-6.5 (2H, m), 6.94 (1H, t, J=7 Hz), 7.0-7.1 (4H, m), 7.1-7.2 (6H, m);
MS m/z: 330 (M+).
Melting Point: 289-290° C.;
NMR (CDCl3) δ: 3.22 (2H, d, J=14 Hz), 3.66 (2H, d, J=14 Hz), 3.86 (6H, s), 6.60 (1H, t, J=7 Hz), 6.70 (1H, d, J=7 Hz), 7.0-7.1 (4H, m), 7.35 (1H, t, J=7 Hz), 7.50 (1H, d, J=7 Hz), 7.8-7.9 (4H, m);
MS m/z: 430 (M+).
Exemplary Preparation 3
An exemplary preparation of 5,5-bis(4-fluorobenzyl)imidazo[2,1-b]thiazol-6(5H)-one (Compound 43) having the general formula below is described hereafter.
First, 300 mg (1.4 mmol) of 2-amino-3-ethoxycarbonylmethylthiazolium bromide and then 1.15 ml (9.0 mmol) of p-fluorobenzyl bromide were added to an ethanol solution (10 ml) of sodium ethoxide prepared from 210 mg (9.0 mmol) of metallic sodium while cooling over ice and stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure and water was added to the residue. The resultant mixture was extracted several times using ethyl acetate, rinsed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was chromatographed over silica gel column (ethyl acetate:methanol=10:1). An amount of 852 mg (80.0%) of the title compound was obtained in the form of crystals. Recrystallization from ethanol yielded white crystals having a melting point of higher than 300° C.
Results of analysis of the obtained compound are given below. The results show that the obtained compound was the targeted compound.
NMR (CD3OD-CDCl3(1:1)) δ: 3.23 (2H, d, J=14 Hz), 3.43 (2H, d, J=14 Hz), 6.66 (1H, d, J=4 Hz), 6.8-6.9 (4H, m), 6.9-7.1 (4H, m), 7.28 (1H, d, J=4 Hz);
MS m/z: 356 (M+).
Exemplary Preparation 4
Compounds 44 to 68 having the general formulae corresponding to starting materials were each prepared in the same manner as in Exemplary Preparation 3. Results of analysis of the obtained compounds are given below. The results show the obtained compounds were the targeted compounds.
Melting Point: >300° C.;
NMR (DMSO-d6) δ: 3.69 (2H, d, J=15 Hz), 3.74 (2H, d, J=15 Hz), 7.27 (1H, d, J=4 Hz), 7.3-7.4 (4H, m), 7.5-7.6 (6H, m), 8.44 (1H, d, J=4 Hz);
MS m/z: 320 (M+).
Melting Point: >300° C.;
NMR (DMSO-d6) δ: 3.42 (4H, dd, J=14 Hz, J=16 Hz), 6.9-7.0 (5H, m), 7.1-7.2 (6H, m), 8.46 (1H, dd, J=3 Hz, J=5 Hz), 9.07 (1H, dd, J=2 Hz, J=6 Hz);
MS m/z: 315 (M+).
Melting Point: >300° C.;
NMR (DMSO-d6) δ: 2.20 (6H, s), 3.24 (2H, d, J=14 Hz), 3.36 (2H, d, J=14 Hz), 6.84 (4H, d, J=8 Hz), 6.89 (1H, d, J=4 Hz), 6.97 (4H, d, J=8 Hz), 8.03 (4H, d, J=4 Hz);
MS m/z: 348 (M+).
Melting Point: 264-267° C.;
NMR (CDCl3) δ: 3.23 (2H, d, J=14 Hz), 3.56 (2H, d, J=14 Hz), 6.54 (1H, d, J=6 Hz), 7.02 (1H, d, J=6 Hz), 7.15 (4H, d, J=9 Hz), 7.51 (4H, d, J=9 Hz);
MS m/z: 370 (M+).
Melting Point: >300° C.;
NMR (CD3OD-CDCl3 (1:1)) δ: 2.34 (3H, d, J=1 Hz), 3.28 (2H, d, J=13 Hz), 3.43 (2H, d, J=13 Hz), 7.0-7.1 (4H, m), 7.1-7.3 (7H, m);
MS m/z: 334 (M+).
Melting Point: 286° C. (decomposition);
NMR (CDCl3) δ: 3.43 (2H, d, J=15 Hz), 3.60 (2H, d, J=15 Hz), 6.49 (1H, d, J=5 Hz), 6.7-7.0 (5H, m), 7.12 (2H, dd, J=1 Hz, J=6 Hz);
MS m/z: 332 (M+).
Melting Point: 192° C. (decomposition);
NMR (CD3OD-CDCl3(1:1)) δ: 3.54 (2H, d, J=15 Hz), 3.76 (2H, d, J=15 Hz), 6.7-6.9 (5H, m), 7.11 (2H, dd, J=1 Hz, J=5 Hz), 8.23 (1H, dd, J=2 Hz, J=6 Hz), 8.62 (1H, dd, J=2 Hz, J=4 Hz);
MS m/z: 327 (M+).
Melting Point: 233-236° C.;
NMR (CDCl3) δ: 3.03 (2H, d, J=14 Hz), 3.23 (2H, t, J=7 Hz), 3.41 (2H, d, J=14 Hz), 3.63 (2H, t, J=7 Hz), 7.1-7.2 (4H, m), 7.2-7.3 (6H, m);
MS m/z: 322 (M+).
Melting Point: 205° C. (decomposition);
NMR (CD3OD-CDCl3(1:1)) δ: 3.41 (1H, d, J=15 Hz), 3.76 (1H, d, J=15 Hz), 6.72 (1H, t, J=7 Hz), 7.02 (1H, d, J=9 Hz), 7.29 (1H, d, J=9 Hz), 7.4-7.5 (2H, m), 7.58 (2H, brs), 7.6-7.9 (4H, m);
MS m/z: 274 (M+).
Melting Point: 214° C. (decomposition);
NMR (CD3OD-CDCl3(1:1)) δ: 3.33 (2H, d, J=16 Hz), 4.02 (2H, d, J=16 Hz), 6.58 (1H, t, J=7 Hz), 7.16 (1H, d, J=7 Hz), 7.24 (1H, d, J=9 Hz), 7.5-7.6 (2H, m), 7.74 (1H, t, J=8 Hz), 7.8-7.9 (4H, m);
MS m/z: 286 (M+).
Melting Point: 182° C. (decomposition);
NMR (CDCl3) δ: 3.09 (1H, dd, J=8 Hz, J=15 Hz), 3.64 (1H, dd, J=4 Hz, J=15 Hz), 4.58 (1H, dd, J=4 Hz, J=8 Hz), 6.47 (1H, t, J=7 Hz), 7.0-7.1 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (3H, m), 7.54 (1H, t, J=7 Hz);
MS m/z: 224 (M+).
Melting Point: 149.5° C. (decomposition);
NMR (CDCl3) δ: 1.55 (6H, d, J=6 Hz), 2.51 (2H, dd, J=8 Hz, J=15 Hz), 2.76 (2H, dd, J=8 Hz, J=15 Hz), 5.1-5.3 (2H, m), 5.4-5.7 (2H, m), 6.69 (1H, dd, J=5 Hz, J=6 Hz), 7.75 (1H, dd, J=2 Hz, J=6 Hz), 8.7 (1H, dd, J=2 Hz, J=5 Hz);
MS m/z: 243 (M+).
Melting Point: 148.0° C. (decomposition);
NMR (CDCl3) δ: 3.24 (2H, dd, J=18 Hz, J=22 Hz), 3.88 (2H, t, J=18 Hz), 6.55 (1H, t, J=7 Hz), 7.01 (1H, t, J=9 Hz), 7.10 (1H, d, J=7 Hz), 7.2-7.3 (3H, m), 7.63 (1H, t, J=8 Hz);
MS m/z: 254 (M+).
Melting Point: 150.0-152.0° C.;
NMR (CDCl3) δ: 3.08 (2H, dd, J=6 Hz, J=17 Hz), 3.8-4.0 (5H, m), 6.49 (1H, t, J=7 Hz), 6.8-6.9 (2H, m), 7.1-7.3 (3H, m), 7.60 (1H, t, J=7 Hz);
MS m/z: 266 (M+).
Melting Point: 167-171° C.;
NMR (CDCl3) δ: 3.14 (2H, dd, J=6 Hz, J=17 Hz), 3.82 (2H, dd, J=17 Hz, J=18 Hz), 6.57 (1H, t, J=7 Hz), 7.08 (1H, d, J=8 Hz), 7.1-7.3 (2H, m), 7.6-7.7 (3H, m);
MS m/z: 362 (M+).
Melting Point: 247.7° C. (decomposition);
NMR (CDCl3) δ: 3.26 (2H, dd, J=3 Hz, J=18 Hz), 3.93 (2H, dd, J=6 Hz, J=18 Hz), 6.56 (1H, t, J=7 Hz), 7.15 (1H, d, J=7 Hz), 7.23 (1H, d, J=9 Hz), 7.44 (1H, d, J=8 Hz), 7.6-7.7 (3H, m);
MS m/z: 261 (M+).
Melting Point: 201-203° C.;
NMR (CDCl3) δ: 3.22 (2H, d, J=17 Hz), 3.91 (2H, d, J=17 Hz), 6.74 (1H, d, J=7 Hz), 6.89 (1H, d, J=7 Hz), 7.32 (4H, s), 7.6-7.7 (2H, m), 7.79 (1H, t, J=7 Hz), 8.63 (1H, d, J=8 Hz);
MS m/z: 286 (M+).
Melting Point: 86-88° C.;
NMR (CDCl3—CD3OD(1:1)) δ: 3.44 (2H, d, J=18 Hz), 4.00 (2H, d, J=18 Hz), 6.71 (1H, t, J=7 Hz), 7.2-7.4 (2H, m), 7.81 (1H, t, J=7 Hz), 7.97 (2H, s);
MS m/z: 294 (M+).
Melting Point: 271.5° C. (decomposition);
NMR (CDCl3) δ: 3.39 (2H, d, J=16 Hz), 4.04 (2H, brd, J=16 Hz), 6.77 (1H, d, J=7 Hz), 6.81 (1H, d, J=7 Hz), 7.6-7.8 (2H, m), 7.82 (1H, brs, J=8 Hz), 7.95 (2H, brs), 8.65 (1H, d, J=8 Hz);
MS m/z: 344 (M+).
Melting Point: 195.5° C. (decomposition);
NMR (CDCl3) δ: 3.17 (2H, d, J=17 Hz), 3.92 (2H, d, J=17 Hz), 6.53 (1H, dd, J=5 Hz, J=6 Hz), 7.44 (1H, dd, J=2 Hz, J=6 Hz), 7.32 (4H, s), 8.72 (1H, dd, J=2 Hz, J=5 Hz);
MS m/z: 237 (M+).
Melting Point: 176.5-179.5° C.;
NMR (CDCl3) δ: 3.25 (2H, d, J=17 Hz), 3.92 (2H, d, J=17 Hz), 6.57 (1H, t, J=7 Hz), 7.1-7.2 (2H, m), 7.44 (1H, d, J=8 Hz), 8.5-8.7 (3H, m);
MS m/z: 304 (M+).
Melting Point: 256.0° C. (decomposition);
NMR (CDCl3) δ: 3.33 (1H, d, J=17 Hz), 3.56 (1H, d, J=17 Hz), 4.09 (2H, t, J=17 Hz), 6.50 (1H, t, J=7 Hz), 7.22 (1H, d, J=9 Hz), 7.29 (1H, d, J=7 Hz), 7.42 (1H, d, J=8 Hz), 7.5-7.7 (4H, m), 7.83 (1H, d, J=8 Hz), 7.92 (1H, d, J=6 Hz);
MS m/z: 286 (M+).
Melting Point: 64-66° C.;
NMR (CDCl3) δ: 2.56 (2H, dd, J=9 Hz, J=14 Hz), 2.86 (2H, dd, J=6 Hz, J=14 Hz), 4.99 (2H, dd, J=1 Hz, J=7 Hz), 5.40 (2H, d, J=1 Hz), 5.4-5.6 (2H, m), 6.67 (1H, t, J=7 Hz), 7.17 (1H, d, J=7 Hz), 7.52 (1H, d, J=7 Hz), 7.59 (1H, d, J=7 Hz);
MS m/z: 214 (M+).
Melting Point: 245-247° C.;
NMR (CDCl3) δ: 1.4-2.0 (12H, m), 2.9-3.1 (2H, m), 5.29 (1H, brd, J=10 Hz), 5.8-6.0 (3H, m), 6.62 (1H, t, J=7 Hz), 7.17 (1H, d, J=9 Hz), 7.5-7.7 (2H, m);
MS m/z: 294 (M+).
Melting Point: 108-110° C.;
NMR (CDCl3) δ: 2.62 (2H, dd, J=8 Hz, J=14 Hz), 2.89 (2H, dd, J=6 Hz, J=14 Hz), 4.9-5.1 (4H, m), 5.4-5.6 (2H, m), 6.91 (1H, d, J=7 Hz), 7.25 (1H, d, J=7 Hz), 7.6-7.7 (2H, m), 7.80 (1H, t, J=8 Hz), 8.57 (1H, d, J=8 Hz);
MS m/z: 264 (M+).
Exemplary Preparation 5
An exemplary preparation of spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,4′-(1′-cyclopentene)] (Compound 69) having the general formula below is described hereafter.
An amount of 80 mg of Grubbs reagent (0.24 mmol) was added to a chloroform solution (80 ml) of 1.0 g (3.8 mmol) of 3,3-diallylimidazo[2,1-a]isoquinolin-2(3H)-one obtained in the same manner as in Exemplary Preparation 1 under an argon atmosphere and heated under flux for 14 hours. The reaction mixture was allowed to stand for cooling and the solvent was removed by distillation under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane several times. The extracted layers were rinsed together with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was chromatographed over silica gel column for purification (ethyl acetate:methanol=10:1) to obtain 748 mg (83.5%) of the title compound in the form of light brown crystals.
Results of analysis of the obtained compound are given below. The results show that the obtained compound was the targeted compound.
Melting Point: 173.5° C. (decomposition);
NMR (CDCl3) δ: 2.70 (2H, d, J=17 Hz), 3.30 (2H, d, J=17 Hz), 5.92 (2H, s), 6.89 (1H, d, J=7 Hz), 7.33 (1H, d, J=7 Hz), 7.6-7.8 (2H, m), 7.79 (1H, t, J=7 Hz), 8.60 (1H, d, J=7 Hz);
MS m/z: 236 (M+).
Exemplary Preparation 6
Compound 70 having the general formula below corresponding to starting materials was prepared in the same manner as in Exemplary Preparation 5. Results of analysis of the obtained compound are given below for each compound. The results show that the obtained compound was the targeted Compound 70.
Melting Point: 178.5-180.5° C.;
NMR (CDCl3) δ: 2.64 (2H, d, J=16 Hz), 3.29 (2H, d, J=16 Hz), 5.30 (2H, s), 5.88 (2H, s), 6.49 (1H, dd, J=6 Hz, J=8 Hz), 6.94 (1H, dd, J=6 Hz, J=8 Hz), 6.94 (1H, d, J=8 Hz), 7.2-7.5 (5H, m);
MS m/z: 292 (M+).
Exemplary Preparation 7
An exemplary preparation of 3,3-dipropyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2(3H)-one (Compound 71) having the general formula below is described hereafter.
An amount of 100 mg of 10% palladium on carbon was added to an ethanol solution (30 ml) of 300 mg (1.4 mmol) of 3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one obtained in the same manner as in Exemplary Preparation 5 and the mixture was subject to catalytic reduction at room temperature under a hydrogen atmosphere overnight. The insoluble substances were filtered off and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was chromatographed over silica gel column (hexane:ethyl acetate=10:1) to obtain 281 mg (90.3%) of the title compound in the form of crystals. Recrystallization from hexane-ethyl acetate (10:1) yielded white crystals having a melting point of 98.5-101° C.
Results of analysis of the obtained compound are given below. The results show that the obtained compound was the targeted compound.
NMR (CDCl3) δ: 0.86 (6H, t, J=7 Hz), 0.9-1.1 (2H, m), 1.1-1.2 (2H, m), 1.4-1.6 (2H, m), 1.7-2.0 (6H, m), 2.79 (2H, t, J=6 Hz), 3.19 (2H, t, J=6 Hz);
MS m/z: 222 (M+).
Exemplary Preparation 8
Compounds 72 to 77 having the general formulae corresponding to starting materials were prepared in the same manner as in Exemplary Preparation 7. Results of analysis of the obtained compounds are given below for each compound. The results show that the obtained compounds were the targeted Compounds 72 to 77.
Melting Point: 218-220° C.;
NMR (CDCl3) δ: 0.9-1.4 (8H, m), 1.5-2.0 (18H, m), 2.79 (2H, t, J=6 Hz), 3.30 (2H, t, J=6 Hz);
MS m/z: 302 (M+).
Melting Point: 35-40° C.;
NMR (CDCl3) δ: 0.88 (6H, t, J=7 Hz), 0.9-1.4 (8H, m), 1.6-2.2 (8H, m), 3.2-3.4 (4H, m);
MS m/z: 250 (M+).
Melting Point: 270.5° C. (decomposition);
NMR (CDCl3) δ: 1.8-2.2 (10H, m), 2.3-2.5 (2H, m), 2.6-2.8 (4H, m), 6.44 (1H, d, J=7 Hz), 7.35 (1H, d, J=7 Hz);
MS m/z: 242 (M+).
Melting Point: 164.5-167.5° C.;
NMR (CDCl3) δ: 1.8-2.3 (6H, m), 2.4-2.6 (2H, m), 6.94 (1H, d, J=7 Hz), 7.33 (1H, d, J=7 Hz), 7.6-7.7 (2H, m), 7.79 (1H, t, J=6 Hz), 8.60 (1H, d, J=8 Hz);
MS m/z: 238 (M+).
Melting Point: 252.5° C. (decomposition);
NMR (CDCl3—CD3OD(1:1)) δ: 1.9-2.1 (4H, m), 3.0-3.2 (4H, m), 3.50 (2H, d, J=18 Hz), 3.79 (2H, d, J=18 Hz), 7.4-7.5 (2H, m), 7.75 (2H, s), 7.8-7.9 (2H, m);
MS m/z: 290 (M+).
Melting Point: 276.5° C. (decomposition);
NMR (CDCl3-CD3OD (1:1)) δ: 1.9-2.1 (4H, m), 3.0-3.3 (4H, m), 3.45 (2H, d, J=17 Hz), 3.66 (2H, d, J=17 Hz), 7.30 (4H, s);
MS m/z: 240 (M+).
Exemplary Preparation 9
Compounds 78 to 81 having the general formulae corresponding to starting materials were each prepared in the same manner as in Exemplary Preparation 1. Results of analysis of the obtained compounds are given below for each compound. The results show that the obtained compounds were the targeted Compounds 78 to 81.
Melting Point: 293.0-296.0 (° C.).
1H-NMR (CDCl3) δ: 3.11 (2H, d, J=14 Hz), 3.55 (2H, d, J=14 Hz), 6.62 (1H, t, J=7 Hz), 6.78 (1H, d, J=8 Hz), 6.94 (4H, d, J=8 Hz), 7.12 (4H, d, J=8 Hz), 7.40 (1H, t, J=7 Hz), 7.47 (1H, d, J=7 Hz);
MS m/z: 382 (M+)
Melting Point: 139.0-142.0 (° C.);
1H-NMR (CDCl3) δ: 0.35-0.40 (2H, m), 0.60-0.65 (2H, m), 1.30-1.40 (1H, m), 2.50-2.60 (2H, m), 2.80-2.90 (2H, m), 3.94 (2H, d, J=7 Hz), 4.96 (2H, brs), 5.02 (2H, brs), 5.40-5.65 (2H, m), 6.57 (1H, t, J=7 Hz, J=8 Hz), 6.91 (1H, d, J=8 Hz), 7.16 (1H, d, J=7 Hz);
MS m/z: 284 (M+).
Melting Point: 240.0° C. (dec.);
1H-NMR (CD3OD) δ: 3.17 (1H, d, J=17 Hz), 3.19 (1H, d, J=17 Hz), 3.50 (1H, d, J=17 Hz), 3.61 (1H, d, J=17 Hz), 6.63 (1H, d, J=8 Hz), 6.70-6.80 (2H, m), 7.07 (1H, d, J=8 Hz), 7.12 (1H, d, J=9 Hz), 7.51 (1H, d, J=7 Hz), 7.81 (1H, d, J=8 Hz);
MS m/z: 352 (M+).
Melting Point: 285.0-290.0° C.;
1H-NMR (CDCl3) δ: 3.22 (2H, d, J=17 Hz), 3.91 (2H, d, J=17 Hz), 6.57 (1H, dd, J=6 Hz, J=7 Hz), 6.82 (1H, d, J=6 Hz), 7.27 (1H, d, J=7 Hz), 7.31 (4H, s);
MS m/z: 352 (M+).
Exemplary Preparation 10
Compounds 82 to 83 having the general formulae corresponding to starting materials were each prepared in the same manner as in Exemplary Preparation 5. Results of analysis of the obtained compounds are given below for each compound. The results show that the obtained compounds were the targeted Compounds 82 to 83.
Melting Point: 200.0-202.0° C.;
1H-NMR (CDCl3): 2.64 (2H, d, J=17 Hz), 3.29 (2H, d, J=17 Hz), 3.96 (3H, s), 5.88 (2H, s), 6.57 (1H, dd, J=7 Hz, J=8 Hz), 6.91 (1H, d, J=8 Hz), 7.29 (1H, d, J=7 Hz);
MS m/z: 216 (M+).
Melting Point: 134.0-137.0° C.;
1H-NMR (CDCl3) δ: 0.35-0.40 (2H, m), 0.60-0.70 (2H, m), 1.30-1.40 (1H, m), 2.64 (2H, d, J=16 Hz), 3.28 (2H, d, J=16 Hz), 3.98 (2H, d, J=7 Hz), 5.88 (2H, s), 6.54 (1H, dd, J=7 Hz, J=8 Hz), 6.92 (1H, d, J=8 Hz), 7.28 (1H, d, J=7 Hz);
MS m/z: 256 (M+).
Exemplary Pharmaceutical Formulation
The following table shows a typical pharmaceutical composition that may be administered according to the invention.
The present invention is described above using examples. The examples are given by way of example. It is understood by a person in the art that various modifications are available and those modifications are included in the scope of the present invention.
For example, the above examples used mice as a mammal. However, other mammals including human can be used. Even in such cases, the above Compounds 1 to 83 exhibit antidepressant, neuroprotection, amyloid β deposition inhibitory, or age retardant activity in other mammals including human.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-280768 | Oct 2006 | JP | national |
