Patent Grant
8232319
The present invention relates to a highly safe amino phosphate derivative useful as an S1P (sphingosine-1-phosphate) receptor modulator, and a salt and a hydrate thereof.
Although it was considered that sphingosine-1-phosphate (S1P) was only an intermediate metabolite in sphingosine metabolism, it has been reported that S1P has a cell growth stimulatory activity and a control action of cell movement function. Thus, it is becoming clear that S1P is a new lipid mediator which demonstrates a variety of physiological functions, such as an apoptotic activity, cell morphology regulatory action, and vasoconstriction (Non-patent Documents 1 and 2). Although this lipid has two actions, as an intracellular second messenger and as an intercellular mediator, research concerning its action as an intercellular mediator is especially active. It has been reported that signaling is carried out via a plurality of G protein-conjugated receptors (Endothelial Differentiation Gene, EDG) which are present on the cell membrane surface (Non-patent Documents 1 and 3). Currently, five S1P receptor subtypes are known, Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8, which are respectively referred to as S1P1, S1P3, S1P2, S1P4, and S1P5.
From the various research concerning these S1P receptors, it has been reported that a so-called S1P receptor modulator, which exhibits an agonistic activity or an antagonistic activity against such receptors, demonstrates effectiveness against a wide variety of diseases. For example, it has been disclosed that a compound which acts on Edg-5 (S1P2) is effective against arteriosclerosis, renal fibrosis, hepatic fibrosis, and hepatic fibrosis (Patent Document 1). Furthermore, it has been disclosed that a compound which acts on Edg-1 (S1P1), Edg-3 (S1P3), or Edg-5 is effective as a treatment and a preventive agent for respiratory illnesses such as chronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pneumonitis, idiopathic interstitial pneumonia, lung cancer, and pneumonia hypersensitivity (Patent Document 2). Furthermore, it has been disclosed that a compound which has an Edg-1 agonistic activity is effective as a treatment and a preventive agent for arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease, diabetic neuropathy peripheral arterial disease, septicemia, angiitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous state, arteriosclerosis, varices such as hemorrhoids, anal fissures, and anal fistula, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, bedsores, burns, ulcerative colitis, Crohn's disease, heart transplantation, kidney transplantation, skin grafts, liver transplantation, bone marrow transplantation, bone loss, chronic hepatitis, liver cirrhosis, chronic renal failure, and focal glomerular sclerosis (Patent Document 3).
Furthermore, it has been reported that compounds having an S1P receptor agonistic activity regulate leukocyte migration (Non-patent Documents 4 and 5). It has also been disclosed that, in addition to being effective for various organ transplants and GVHD, the series of derivatives introduced in these Non-patent documents are effective for rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, type I and II diabetes mellitus, autoimmune diseases such as Crohn's disease, allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and allergic contact dermatitis, and inflammatory diseases such as inflammatory bowel disease or ulcerative colitis (Non-patent Documents 4 and 5). Furthermore, a phosphate derivative analogous to what is disclosed in Non-patent Documents 4 and 5 has also been disclosed as an S1P receptor antagonist (Non-patent Document 6). Recently, various compounds, such as amino alcohol derivatives, phosphate derivatives, and carboxylate derivatives, have been disclosed as S1P1 to S1P5 receptor modulators focused on S1P1 receptors, or as immunosuppressive agents (Patent Documents 7 to 62).
Furthermore, since S1P4 receptors are largely concentrated in immunocompetent cells, such as leukocytes, and in organs which greatly contribute to the immune system, it is suggested that S1P4 receptors have a strong contribution to the immune system. In fact, compounds having an S1P4 agonistic activity have been disclosed for autoimmune diseases such as SLE and rheumatism, asthma, allergic diseases such as atopic dermatitis, and inflammatory disease remedies (Patent Documents 30, 35, and 46).
Thus, while a great deal of attention is being paid to S1P receptor agonist drugs which may have hidden potential in a wide variety of medical applications, not all S1P receptor agonist drugs provide a desirable action on the body.
For example, an S1P receptor agonist which has exhibited effectiveness in clinical trials in suppressing organ transplant rejection was found to produce bradycardia as a side effect after administration. This effect was reported to probably be caused by agonistic activity against the S1P3 receptor (Non-patent Documents 6 and 7). Furthermore, agonistic activity against the S1P3 receptor has also been reported to obstruct myocardial blood flow (Non-patent Document 8), and cause cerebral arterial spasms (Non-patent Document 9), and pulmonary edema (Non-patent Document 10).
It is an object of the present invention to provide an amino phosphate derivative having a weak agonistic activity against S1P3, an excellent agonistic activity against S1P1 and/or S1P4 receptors, and few side effects.
As a result of continued intensive research to create a highly safe compound which has an agonistic activity against S1P1 and S1P4 receptors, and a weak agonistic activity against an S1P3 receptor, the present inventors discovered that a novel amino phosphate derivative can achieve the above object, thereby completing the present invention.
Specifically, the present invention relates to:
[wherein R1 represents a chlorine atom or a straight-chain alkyl group having 1 to 3-carbon atoms optionally substituted with halogens, R2 represents a fluorine atom or a chlorine atom, R3 represents a straight-chain alkyl group having 1 to 3 carbon atoms, X represents an oxygen atom or a sulfur atom, and n denotes 2 or 3], or a pharmaceutically acceptable salt or hydrate thereof.
[wherein R3, X, and n are as described above], or a pharmaceutically acceptable salt or hydrate thereof.
[wherein R1 represents a chlorine atom or a straight-chain alkyl group having 1 to 3-carbon atoms optionally substituted with halogens, R2 represents a fluorine atom or a chlorine atom, A represents a halogen atom, X represents an oxygen atom or a sulfur atom, and n denotes 2 or 3], and a compound represented by the general formula (12),
[wherein R3 represents a straight-chain alkyl group having 1 to 3 carbon atoms and R4 represents an alkyl group having 1 to 6 carbon atoms] to act in the presence of a base, a step of subjecting the resultant product to acid decomposition, protecting a nitrogen atom with a t-butoxycarbonyl group, and then reducing the product, a step of reacting the reduction product with a compound represented by the general formula (10),
P(OR6)3 (10)
[wherein R6 represents an alkyl group having 1 to 6 carbon atoms or a benzyl group], and a step of subjecting the resultant product obtained by the previous steps to acidolysis or a halogenosilane treatment, or a pharmaceutically acceptable salt or hydrate thereof.
The present invention has led to the discovery of a novel amino phosphate derivative having an excellent S1P receptor modulatory action. A compound having such an S1P receptor modulatory action is effective as a treatment agent and a preventive agent for arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pneumonitis, idiopathic interstitial pneumonia, lung cancer, pneumonia hypersensitivity, Buerger's disease, diabetic neuropathy peripheral arterial disease, septicemia, angiitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous state, varices, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, bedsores, burns, ulcerative colitis, Crohn's disease and the like. Furthermore, a compound having such an S1P receptor modulatory action is effective as a treatment and a preventive agent for rejection of heart transplants, kidney transplants, skin grafts, liver transplants, and bone marrow transplants, and is also an effective as a treatment and a preventive agent for rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, diabetes mellitus, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis and the like.
In the present invention, the straight-chain alkyl group having 1 to 3 carbon atoms of R1 and R3 is a methyl group, an ethyl group, or an n-propyl group.
In the present invention, the halogen in the “lower alkyl group having 1 to 3 carbon atoms optionally substituted with halogens” of R1 is a fluorine atom or a chlorine atom.
From the perspective of obtaining high safety, R1 is preferably an ethyl group, a propyl group, or a trifluoromethyl group, and more preferably is a trifluoromethyl group. Furthermore, R3 is preferably a methyl group, and n is preferably 3.
Furthermore, from the perspective of obtaining high agonistic activity against the S1P1 receptor, X is preferably a sulfur atom, and the configuration of R3 is preferably a configuration produced as the main product via the below-described synthesis route B (using the compound (12)).
In the present invention, examples of pharmaceutically acceptable salts include alkali metal salts such as sodium salts, potassium salts, magnesium salts, calcium salts, and aluminum salts.
According to the present invention, the compound represented by the general formula (1) can be produced, for example, via the route A shown below.
<Synthesis Route A>
In the synthesis route A, the compound represented by the general formula (3),
[wherein R1, R2, R3, R4, X, and n are as described above], can be produced by allowing a compound represented by the general formula (2),
[wherein R1, R2, A, X, and n are as described above], and a compound represented by the general formula (8),
[wherein R3 and R4 are as described above] to act in the presence of a base (step A-1).
The reaction can be carried out using methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF) or the like as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, and potassium carbonate, at 0° C. to reflux temperature as the reaction temperature, and preferably at 80° C. to 100° C.
In the synthesis route A, the compound represented by the general formula (4),
[wherein R1, R2, R3, R4, X, and n are as described above], can be produced by hydrolyzing the compound represented by the general formula (3) (step A-2).
The reaction can be carried out in the presence of a base such as aqueous sodium hydroxide, aqueous potassium hydroxide, and aqueous lithium hydroxide, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, THF or the like as a reaction solvent, at a reaction temperature of 0° C. to reflux temperature. The reaction is especially preferably carried out using potassium hydroxide as the base, in an ethanol solvent, by reacting at 50° C.
Although the compound according to the present invention is preferably an optically-active compound, the optical resolution timing is not especially limited. At this stage, optical resolution may be carried out by HPLC using a chiral column, whereby the desired compound having a chiral center can be obtained.
In the synthesis route 1, the compound represented by the general formula (5),
[wherein R5 represents an alkyl group having 1 to 6 carbon atoms, and R1, R2, R3, R4, X, and n are as described above], can be produced by subjecting the compound represented by the general formula (4) to Curtius rearrangement (step A-3).
In the reaction, typical techniques for converting a carboxyl group into a carbamate may be employed. For example, a technique which combines, for example, chloroethyl carbonate and NaN3, or oxalyl chloride and NaN3, or a technique which uses only diphenylphosphoryl azide (DPPA) may be utilized. The reaction is preferably carried out by, after heating diphenylphosphoryl azide to reflux in the presence of an organic base, such as triethylamine, in benzene or toluene solvent, charging the resultant product with an alcohol represented by the general formula (9),
R5OH (9)
[wherein R5 is as described above], and continuing to heat the resultant solution under stirring, or after removing the benzene or toluene by distillation, reacting by heating to reflux using the alcohol represented by the general formula (9) as a reaction solvent (step A-3).
At this stage, optical resolution may be carried out by HPLC using a chiral column, whereby the desired compound having a chiral center can be obtained.
In the synthesis route A, the compound represented by the general formula (6),
[wherein R1, R2, R3, R5, X, and n are as described above], can be produced by reducing the compound represented by the general formula (5) (step A-4).
The reaction can be carried out using borane, an alkyl borane derivative like 9-borabicyclo[3.3.1]nonane (9-BBN), or a metal hydride complex compound, such as diisobutylaluminum hydride ((iBu)2AlH), sodium borohydride (NaBH4), lithium borohydride (LiBH4), and lithium aluminum hydride (LiAlH4), preferably LiBH4, using THF, 1,4-dioxane, ethanol, or methanol as a reaction solvent, at a temperature of 0° C. to reflux temperature, and preferably at room temperature.
Furthermore, at this stage, optical resolution may be carried out by HPLC using a chiral column, whereby the desired compound having a chiral center can be obtained.
In the synthesis route A, the compound represented by the general formula (7),
[wherein R6 represents an alkyl group having 1 to 6 carbon atoms or a benzyl group, and R1, R2, R3, R5, X, and n are as described above], can be produced by reacting the compound represented by the general formula (6) with a compound represented by the general formula (10),
P(OR6)3 (10),
[wherein R6 is as described above] (step A-5).
The reaction may be carried out in the presence of carbon tetrabromide and pyridine, without a solvent or using a small amount of a solvent such as methylene chloride, chloroform, acetonitrile, ethyl acetate, THF, and ether, at 0° C. to room temperature.
Furthermore, at this stage, optical resolution may be carried out by HPLC using a chiral column, whereby the desired compound having a chiral center can be obtained.
In the synthesis route A, the compound represented by the general formula (1) can be produced by subjecting the compound represented by the general formula (7) to acidolysis or by treating it with a halogenosilane such as trimethylsilyl bromide or trimethylsilyl iodide (step A-6).
In the case of an acidolysis reaction, the reaction can be carried out in an inorganic acid such as hydrochloric acid or hydrobromic acid, or in a mixed solution of an organic solvent such as methanol or ethanol and an inorganic acid, under heating to reflux. Furthermore, preferably methylene chloride or acetonitrile is used as the reaction solvent, and trimethylsilyl bromide or trimethylsilyl iodide are used at a temperature of 0° C. to room temperature, or trimethylsilyl chloride and sodium bromide or sodium iodide are allowed to act.
In the synthesis route A, among the compounds represented by the general formula (5), compounds in which R5 represents a t-butyl group, specifically, a compound represented by the general formula (5a),
[wherein Boc represents a t-butoxycarbonyl group, and R1, R2, R3, R4, X, and n are as described above], among the compounds represented by the general formula (6) in the synthesis route A, a compound in which R5 represents a t-butyl group, specifically, a compound represented by the general formula (6a),
[wherein R1, R2, R3, X, Boc, and n are as described above], and among the compounds represented by the general formula (7) in the synthesis route A, a compound in which R5 represents a t-butyl group, specifically, a compound represented by the general formula (7a),
[wherein R1, R2, R3, R6, X, Boc, and n are as described above], can be produced by the synthesis route B.
<Synthesis Route B>
In the synthesis route B, the compound represented by the general formula (11),
[wherein R1, R2, R3, R4, X, and n are as described above], can be produced by allowing the compound represented by the general formula (2) and a compound represented by the general formula (12),
[wherein R3 and R4 are as described above] to act in the presence of a base (step B-1)
The reaction can be carried out using a reaction solvent such as 1,4-dioxane, THF, and ether, using a base such as n-butyllithium and lithium diisopropyl amide, preferably n-butyllithium, and treating a compound represented by the general formula (12) at −78° C., then allowing a compound represented by the general formula (2) to act at −78° C., and reacting while gradually increasing the temperature to room temperature.
In the synthesis route B, the compound represented by the general formula (5a) can be produced by subjecting the compound represented by the general formula (11) to acid decomposition, and then protecting the nitrogen atom with a t-butoxycarbonyl group (Boc group) (step B-2).
It is preferred to carry out the reaction using methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate in which hydrochloric acid is dissolved, and preferably 1,4-dioxane containing hydrochloric acid, by reacting at reflux temperature, then neutralizing with a base to obtain an amino ester, and then using ethylacetate, THF, DMF, 1,4-dioxane, methylenechloride, chloroform, methanol, ethanol, acetonitrile or the like as a solvent, allowing it to act with Boc2O at 0° C. to room temperature.
In the synthesis route B, the compound represented by the general formula (6a) can be produced by reducing the compound represented by the general formula (5a) (step B-3).
The reaction can be carried out using borane, an alkyl borane derivative like 9-BBN, or a metal hydride complex compound, such as (iBu)2AlH, NaBH4, LiBH4, and LiAlH4, preferably LiBH4, using THF, 1,4-dioxane, ethanol, or methanol as a reaction solvent, at a temperature of 0° C. to reflux temperature, and preferably at room temperature.
In the synthesis route B, the compound represented by the general formula (7a) can be produced by reacting the compound represented by the general formula (6a) and the compound represented by the general formula (10) (step B-4).
The reaction may be carried out in the presence of carbon tetrabromide and pyridine, without a solvent or using a small amount of a solvent such as methylene chloride, chloroform, acetonitrile, ethyl acetate, THF, and ether, at 0° C. to room temperature.
It is noted that concerning the synthesis method of the compound represented by the general formula (2), the compound may be produced by the methods described in the respective pamphlets of WO 03029184, WO 03029205, WO 04026817, WO 04074297, and WO 050444780.
The compound according to the present invention is effective as a treatment agent and a preventive agent for arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pneumonitis, idiopathic interstitial pneumonia, lung cancer, pneumonia hypersensitivity, Buerger's disease, diabetic neuropathy peripheral arterial disease, septicemia, angiitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous state, varices, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, bedsores, burns, ulcerative colitis, Crohn's disease and the like. Furthermore, the compound according to the present invention is effective as a treatment and a preventive agent for rejection of heart transplants, kidney transplants, skin grafts, liver transplants, and bone marrow transplants, and is also an effective as a treatment and a preventive agent for rheumatoid arthritis, lupusnephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, diabetes mellitus, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis and the like.
In the case of using as above, the required dose of course depends on the administration method, the specific condition to be treated, and the desired effects. However, generally, a daily dose of about 0.03 to 2.5 mg per kg of body weight is preferred. For mammals such as humans, the recommended daily dose is in the range of about 0.5 mg to about 100 mg. Preferably, administration is carried out in divided doses of four times or less per day, or in retard form. A suitable unit dose form for oral administration includes about 1 to 50 mg of active ingredient.
The compound of the present invention may be administered by an arbitrary conventional route, especially enterally, for example orally, for example in the form of a tablet or a capsule, or parenterally, for example in the form of an injectable solution or a suspension, locally, for example in the form of a lotion, a gel, an ointment, or a cream, or nasally or in the form of a suppository. A pharmaceutical composition containing the compound of the present invention in free form or a pharmaceutically acceptable salt thereof together with at least one kind of pharmaceutically acceptable carrier or diluent may be produced by a conventional method of mixing with the pharmaceutically acceptable carrier or diluent.
The present invention can express even higher effects by using together with an immunosuppressive agent and/or a pharmaceutical which has an anti-inflammatory activity based on another mechanism. Examples of substances which can be used together include immunosuppressive agents used in the treatment and prevention of acute or chronic rejection of allogeneic transplants and heterologous transplants, inflammatory diseases, and autoimmune diseases, immunosuppressive agents having an immunomodulatory activity and/or anti-inflammatory agents having an anti-inflammatory or malignant cell growth inhibition activity. Specific examples include the calcineurin inhibitors cyclosporin A and FK506, the mTOR inhibitors rapamycin, 40-O-(2-hydroxymethyl)-rapamycin, CCI779, and ABT578, the ascomycins ABT281 and ASM981 which have an immunosuppressive activity, mycophenolic acid, mycophenolate mofetil, azathioprine, mizoribine, cyclophosphamide and the like. Further examples include the antifolate methotrexate, adrenal cortical steroids which exhibit broad anti-inflammatory activity, auranofin, actarit, mesalazine, or sulfasalazine and the like which have an immunomodulatory activity, infliximab which is an anti-TNFα antibody, MRA which is an anti-IL-6 receptor antibody, natalizumab which is an anti-integrin antibody and the like.
Next, the present invention will be described with the following specific examples. However, the present invention is not limited by these examples.
Furthermore, as the intermediates and the like represented by the general formula (2), the compounds in the pamphlets of WO 03029184, WO 03029205, WO 04026817, WO 04074297, and WO 050444780 may be utilized. Furthermore, (5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine, (5S)-3,6-dimethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine, and (5S)-2-allyl-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine may be synthesized according to Ulrich Shollkopf et. al, Synthesis 969 (1981) and Chunrong Ma et. al., J. Org. Chem., 66, 4525 (2001). Intermediates and the like which were newly synthesized based on the experiment procedures described in these reference documents will now be described as the following reference examples.
1,4-diazabicyclo[2.2.2]octane (9.03 g) and dimethylthiocarbamoyl chloride (9.95 g) were added into a solution of 3-difluoromethylphenol (6.44 g) in N,N-dimethylformamide (149 mL), and the resultant solution was stirred for 4 hours at room temperature. Water was added into the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the target product (7.04 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 3.36 (3H, s), 3.46 (3H, s), 6.66 (1H, t, J=57 Hz), 7.19 (1H, dt, J=7.9, 1.2 Hz), 7.23 (1H, br s), 7.39 (1H, d, J=7.9 Hz), 7.48 (1H, t, J=7.9 Hz).
EIMS (+): 231 [M]+.
A solution of the compound of Reference Example 1 (2.34 g) in diphenyl ether (12 g) was stirred at 250° C. for 2.5 hours. The temperature of the reaction solution was returned to room temperature, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the target product (1.92 g) as a yellow oil.
1H-NMR (CDCl3, 400 MHz): δ 3.04 (3H, s), 3.10 (3H, s), 6.65 (1H, t, J=57 Hz), 7.48 (1H, t, J=7.9 Hz), 7.54 (1H, d, J=7.9 Hz), 7.61 (1H, t, J=7.9 Hz), 7.64 (1H, s).
EIMS (+): 231 [M]+.
A solution of the compound of Reference Example 2 (4.17 g) in diethyl ether (12 mL) was added dropwise under ice cooling to a solution of lithium aluminum hydride (959 mg) in diethyl ether (48 mL). The resultant solution was then stirred for 20 minutes under ice cooling. 0.5 mol/L hydrochloric acid (30 mL) was added to the reaction mixture, extracted with diethyl ether, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was reacted with 2-chloro-4-fluorobenzaldehyde according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a colorless powder.
1H-NMR (CDCl3, 400 MHz) δ 6.67 (1H, t, J=56 Hz), 7.09 (1H, dd, J=7.9, 1.8 Hz), 7.16 (1H, d, J=7.9 Hz), 7.53-7.64 (3H, m), 7.68 (1H, s), 7.79 (1H, d, J=7.9 Hz), 10.37 (1H, s)
EIMS (+): 298 [M]+.
Under an argon atmosphere, ethyldiisopropylamine (7.0 mL), tris(dibenzylideneacetone) dipalladium(0) chloroform adduct (518 mg), xantphos (578 mg), and 3-trifluordmethylthiophenol (3.56 g) were added at room temperature into a solution of 4-bromo-2-fluorobenzaldehyde (4.06 g) in 1,4-dioxane (42 mL), and the resultant solution was heated to reflux for 5 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate 30:1) to obtain the target product (4.08 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 6.86 (1H, dd, J=10, 1.8 Hz), 7.02 (1H, dd, J=7.9, 1.8 Hz), 7.58 (1H, t, J=7.9 Hz), 7.68-7.73 (2H, m), 7.76 (1H, t, J=7.9 Hz), 7.80 (1H, s), 10.26 (1H, s)
EIMS (+): 300 [M]+.
3-Chlorobenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029205 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 7.11 (1H, dd, J=9.2, 1.8 Hz), 7.17 (1H, d, J=1.8 Hz), 7.36-7.44 (3H, m), 7.52 (1H, t, J=1.8 Hz), 7.80 (1H, d, J=7.9 Hz), 10.37 (1H, s)
EIMS (+): 282 [M]+.
m-Cresol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a colorless powder.
1H-NMR (CDCl3, 400 MHz): δ 2.38 (3H, s), 6.87-6.96 (4H, m), 7.07 (1H, d, J=7.3 Hz), 7.31 (1H, t, J=7.6 Hz), 7.90 (1H, d, J=8.6 Hz), 10.36 (1H, s).
EIMS (+): 246 [M]+.
3-Ethylbenzenethiol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029205 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, t, J=7.3 Hz), 2.680 (2H, q, J=7.3 Hz), 7.04-7.11 (2H, m), 7.28-7.40 (4H, m), 7.76 (1H, d, J=8.6 Hz), 10.35 (1H, s).
EIMS (+): 276 [M]+.
3-Propylphenol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a pale brown oil.
1H-NMR (CDCl3, 400 MHz): δ 0.95 (3H, t, J=7.3 Hz), 1.62-1.68 (2H, m), 2.61 (2H, t, J=7.3 Hz), 6.89-6.94 (3H, m), 6.96 (1H, d, J=2.1 Hz), 7.08 (1H, d, J=7.9 Hz), 7.31-7.35 (1H, m), 7.90 (1H, d, J=8.9 Hz), 10.36 (1H, d, J=0.6 Hz).
EIMS (+): 274 [M]+.
The compound of Reference Example 7 was reacted according to the same experiment procedures as in Reference Example 326 of the pamphlet of WO 04074297 to obtain the target product as a pale yellow oil.
The compound of Reference Example 7 was reacted according to the same experiment procedures as in Reference Example 10 of the pamphlet of WO 03029205 to obtain the target product as a pale yellow oil.
EIMS (+): 346 [M]+.
The compound of Reference Example 10 was reacted according to the same experiment procedures as in Reference Example 19 of the pamphlet of WO 03029205, and the resultant product was then reduced according to the same experiment procedures as in Reference Example 35 of the pamphlet of WO 03029205, to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 1.84-1.90 (2H, m), 2.62 (2H, q, J=7.6 Hz), 2.78-2.82 (2H, m), 3.69 (2H, t, J=6.1 Hz), 7.10-7.18 (4H, m), 7.23-7.29 (3H, m).
The compound of Reference Example 8 was successively reacted according to the same experiment procedures as in Reference Example 10 and then Reference Example 11 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.94 (3H, t, J=7.3 Hz), 1.37 (1H, br s), 1.58-1.68 (2H, m), 1.85-1.92 (2H, m), 2.57 (2H, t, J=7.6 Hz), 2.80 (2H, t, J=7.6 Hz), 3.70 (2H, dt, J=6.1, 4.6 Hz), 6.80-6.85 (3H, m), 6.95 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=2.8 Hz), 7.17 (1H, d, J=8.3 Hz), 7.24 (1H, t, J=7.9 Hz).
EIMS (+): 304 [M]+.
The compound of Reference Example 4 was successively reacted according to the same experiment procedures as in Reference Example 10 and then Reference Example 11 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.88 (2H, tt, J=6.7, 6.1 Hz), 2.75 (2H, t, J=6.7 Hz), 3.69 (2H, t, J=6.1 Hz), 7.05 (1H, dd, J=10, 1.8 Hz), 7.10 (1H, dd, J=7.9, 1.8 Hz), 7.20 (1H, t, J=7.9 Hz), 7.38-7.51 (3H, m), 7.55 (1H, s).
The compound of Reference Example 5 was successively reacted according to the same experiment procedures as in Reference Example 10 and then Reference Example 11 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.33 (1H, br s), 1.83-1.95 (2H, m), 2.81-2.85 (2H, m), 3.70 (2H, br s), 7.15-7.23 (5H, m), 7.24-7.29 (1H, m), 7.38 (1H, d, J=1.8 Hz).
The compound of Reference Example 6 was successively reacted according to the same experiment procedures as in Reference Example 10 and then Reference Example 11 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.31 (1H, brs), 1.87-1.90 (2H, m), 2.34 (3H, s), 2.80 (2H, t, J=7.3 Hz), 3.70 (2H, dd, J=11.6, 6.1 Hz), 6.79-6.86 (3H, m), 6.94 (1H, d, J=7.3 Hz), 6.99 (1H, d, J=2.4 Hz), 7.18 (1H, d, J=7.9 Hz), 7.22 (1H, t, J=7.3 Hz).
EIMS (+): 276 [M]+.
The compound of Reference Example 3 was successively reacted according to the same experiment procedures as in Reference Example 10 and then Reference Example 11 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.32 (1H, t, J=4.9 Hz), 1.85-1.93 (2H, m), 2.81-2.85 (2H, m), 3.70 (2H, q, J=6.7 Hz), 6.59 (1H, t, J=56 Hz), 7.17-7.23 (2H, m), 7.36-7.41 (4H, m), 7.45 (1H, s).
The compound of Reference Example 9 was reacted according to the same experiment procedures as in Reference Example 327 of the pamphlet of WO 04074297 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 2.63 (2H, q, J=7.3 Hz), 3.23-3.28 (2H, m), 3.32-3.35 (2H, m), 7.09-7.29 (7H, m).
EIMS (+): 402 [M]+.
The compound of Reference Example 11 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 2.12 (2H, quintet, J=7.3 Hz), 2.63 (2H, q, J=7.3 Hz), 2.81 (2H, t, J=7.3 Hz), 3.19 (2H, t, J=7.3 Hz), 7.09-7.19 (4H, m), 7.24-7.28 (3H, m).
EIMS (+): 416 [M]+.
The compound of Reference Example 12 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a pale yellow oil.
1H-NMR (CDCl3, 400 MHz): δ 0.94 (3H, t, J=7.3 Hz), 1.60-1.68 (2H, m), 2.10-2.17 (2H, m), 2.57 (2H, t, J=7.6 Hz), 2.81 (2H, t, J=7.6 Hz), 3.21 (2H, t, J=7.0 Hz), 6.80-6.85 (3H, m), 6.96 (1H, d, J=7.9 Hz), 6.99 (1H, d, J=2.4 Hz), 7.19 (1H, d, J=8.3 Hz), 7.25 (1H, t, J=7.9 Hz).
EIMS (+): 414 [M]+.
The compound of Reference Example 13 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 2.13 (2H, quintet, J=7.3 Hz), 2.76 (2H, t, J=7.3 Hz), 3.18 (2H, t, J=6.7 Hz), 7.03 (1H, dd, J=10, 1.8 Hz), 7.09 (1H, dd, J=7.9, 1.8 Hz), 7.20 (1H, t, J=7.9 Hz), 7.39-7.52 (3H, m), 7.57 (1H, s).
EIMS (+): 404 [M]+.
The compound of Reference Example 14 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 2.14 (2H, tt, J=7.3, 6.7 Hz), 2.84 (2H, t, J=7.3 Hz), 3.20 (2H, t, J=6.7 Hz), 7.16-7.25 (5H, m), 7.28 (1H, t, J=1.8 Hz), 7.36 (1H, d, J=1.8 Hz).
EIMS (+): 422 [M]+.
The compound of Reference Example 15 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a yellow oil.
1H-NMR (CDCl3, 400 MHz): δ 2.13 (2H, quint, J=7.3 Hz), 2.34 (3H, s), 2.81 (2H, t, J=7.3 Hz), 3.21 (2H, t, J=7.3 Hz), 6.81-6.84 (3H, m), 6.95 (1H, d, J=7.9 Hz), 6.99 (1H, d, J=2.4 Hz), 7.18 (1H, d, J=7.9 Hz), 7.23 (1H, t, J=7.9 Hz).
EIMS (+): 386 [M]+.
The compound of Reference Example 16 was reacted according to the same experiment procedures as in Reference Example 164 of the pamphlet of WO 03029184 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 2.10-2.17 (2H, m), 2.84 (2H, t, J=7.3 Hz), 3.20 (2H, t, J=6.7 Hz), 6.60 (1H, t, J=56 Hz), 7.18 (1H, dd, J=7.9, 1.2 Hz), 7.22 (1H, d, J=7.9 Hz), 7.36 (1H, d, J=1.2 Hz), 7.41 (3H, d, J=1.2 Hz), 7.47 (1H, s).
Under an argon atmosphere, a solution of n-butyllithium in hexane (1.54 mol/L, 3.59 mL) was added at −78° C. into a solution of (5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (905 mg) in THF (16 mL), and the resultant solution was stirred at −78° C. for 30 minutes. Next, A solution of 2-chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenoxy)benzene (2.47 g) in THF (4 mL) was added to the reaction mixture, and the resultant solution was stirred at −78° C. for 30 minutes and then at 0° C. for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain the target product (1.59 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.70 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=6.7 Hz), 1.18-1.50 (9H, m), 1.32 (3H, s), 1.86-1.97 (1H, m), 2.21-2.30 (1H, m), 2.65 (2H, t, J=7.6 Hz), 3.90 (1H, d, J=2.1 Hz), 3.97-4.21 (4H, m), 6.84 (1H, dd, J=7.9, 2.4 Hz), 7.00 (1H, d, J=2.4 Hz), 7.15 (2H, d, J=7.9 Hz), 7.24 (1H, br s), 7.36 (1H, d, J=7.9 Hz), 7.44 (1H, t, J=7.9 Hz).
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenylthio)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.63 (3H, d, J=6.7 Hz), 1.07 (3H, d, J=6.7 Hz), 1.18-1.29 (10H, m), 1.34-1.66 (2H, m), 1.79-1.91 (1H, m), 2.25-2.33 (1H, m), 2.70 (2H, t, J=7.6 Hz), 3.85 (1H, br s), 3.99-4.23 (4H, m), 7.16 (2H, d, J=7.9 Hz), 7.20 (1H, dd, J=7.9, 1.8 Hz), 7.36-7.42 (3H, m), 7.44-7.50 (1H, m), 7.52 (1H, br s).
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(2-iodoethyl)-4-(3-trifluoromethylphenoxy)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.72 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=6.7 Hz), 1.29 (6H, t, J=7.3 Hz), 1.36 (3H, s), 1.74-1.82 (1H, m), 2.13-2.20 (1H, m), 2.25-2.32 (1H, m), 2.39-2.56 (2H, m), 3.95 (1H, d, J=3.1 Hz), 4.02-4.22 (4H, m), 6.83 (1H, dd, J=8.6, 2.4 Hz), 6.99 (1H, d, J=2.4 Hz), 7.12-7.15 (2H, m), 7.23 (1H, br s), 7.35 (1H, d, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz).
EIMS (+): 524 [M]+.
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(2-iodoethyl)-4-(3-trifluoromethylphenylthio)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.72 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=6.7 Hz), 1.28 (6H, t, J=7.3 Hz), 1.35 (3H, s), 1.68-1.90 (1H, m), 2.10-2.19 (1H, m), 2.38-2.57 (1H, m), 3.95 (1H, d, J=3.1 Hz), 4.02-4.22 (4H, m), 7.13 (1H, d, J=7.9 Hz), 7.18 (1H, dd, J=7.9, 2.4 Hz), 7.35-7.42 (3H, m), 7.43-7.48 (1H, m), 7.54 (1H, br s).
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 17 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.72 (3H, d, J=6.7 Hz), 1.07 (3H, d, J=6.7 Hz), 1.21 (3H, t, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz), 1.29 (3H, t, J=7.3 Hz), 1.34 (3H, s), 1.70-1.79 (1H, m), 2.09-2.16 (1H, m), 2.24-2.32 (1H, m), 2.35-2.52 (2H, m), 2.61 (2H, q, J=7.3 Hz), 3.95 (1H, d, J=3.1 Hz), 4.03-4.20 (4H, m), 7.04-7.15 (4H, m), 7.21-7.26 (3H, m).
ESIMS (+): 501 [M+H]+.
(5S)-3,6-dimethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 22 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.68 (3H, d, J=6.7 Hz), 1.07 (3H, d, J=6.7 Hz), 1.33 (3H, s), 1.36-1.43 (1H, m), 1.55-1.62 (1H, m), 1.86-1.92 (1H, m), 2.24-2.26 (1H, m), 2.34 (3H, s), 2.62 (2H, t, J=7.9 Hz), 3.65 (3H, s), 3.66 (3H, s), 3.94 (1H, d, J=3.7 Hz), 6.79-6.82 (3H, m), 6.93 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=7.9 Hz), 7.22 (1H, t, J=7.9 Hz).
EIMS (+): 456 [M]+.
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 18 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.68 (3H, d, J=6.7 Hz), 1.04 (3H, d, J=6.7 Hz), 1.20-1.26 (9H, m), 1.31 (3H, s), 1.36-1.43 (1H, m), 1.50-1.57 (1H, m), 1.85-1.92 (1H, m), 2.21-2.28 (1H, m), 2.60-2.65 (4H, m), 3.88 (1H, d, J=3.7 Hz), 4.00-4.16 (4H, m), 7.06-7.16 (4H, m), 7.22-7.27 (3H, m).
ESIMS (+): 515 [M+H]+.
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 21 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.69 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=6.7 Hz), 1.18-1.29 (7H, m), 1.31 (3H, s), 1.34-1.47 (1H, m), 1.50-1.63 (1H, m), 1.85-1.95 (1H, m), 2.20-2.30 (1H, m), 2.65 (2H, t, J=7.6 Hz), 3.89 (1H, d, J=3.1 Hz), 3.99-4.23 (4H, m), 7.11-7.23 (6H, m), 7.35 (1H, d, J=1.8 Hz).
ESIMS (+) 521 [M+H]+.
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 20 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.67 (3H, d, J=6.7 Hz), 1.06 (3H, d, J=6.7 Hz), 1.18-1.29 (7H, m), 1.33 (3H, s), 1.36-1.66 (2H, m), 1.85-1.95 (1H, m), 2.23-2.33 (1H, m), 2.67 (2H, t, J=7.6 Hz), 3.89 (1H, d, J=3.1 Hz), 3.99-4.23 (4H, m), 7.02 (1H, dd, J=9.8 Hz, 1.8 Hz), 7.08 (1H, dd, J=7.9 Hz, 2.4 Hz), 7.13 (1H, t, J=7.9 Hz), 7.38-7.50 (3H, m), 7.55 (1H, s).
(5S)-2-allyl-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine and 2-chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenylthio)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.67 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=6.7 Hz), 1.23 (3H, t, J=6.4 Hz), 1.25 (3H, t, J=6.4 Hz), 1.30-1.64 (3H, m), 1.80-1.90 (1H, m), 2.23-2.39 (2H, m), 2.53 (1H, dd, J=12.4, 7.3 Hz), 2.65 (2H, t, J=7.6 Hz), 3.83 (1H, d, J=3.1 Hz), 4.03-4.18 (4H, m), 4.92-5.04 (2H, m), 5.60-5.73 (1H, m), 7.13 (2H, d, J=7.9 Hz), 7.18 (1H, dd, J=7.9 Hz, 1.8 Hz), 7.36 (1H, d, J=1.8 Hz), 7.38-7.42 (2H, m), 7.44-7.49 (1H, m), 7.55 (1H, br s).
5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and the compound of Reference Example 23 were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.70 (3H, d, J=6.7 Hz), 1.06 (3H, d, J=6.7 Hz), 1.20-1.32 (7H, m), 1.33 (3H, s), 1.35-1.48 (1H, m), 1.58-1.60 (1H, m), 1.85-1.95 (1H, m), 2.24-2.32 (1H, m), 2.66 (2H, t, J=7.3 Hz), 3.90 (1H, d, J=3.7 Hz), 3.99-4.22 (4H, m), 6.61 (1H, t, J=56 Hz), 7.14 (1H, d, J=7.9 Hz), 7.19 (1H, dd, J=7.9, 1.8 Hz), 7.36 (1H, d, J=1.8 Hz), 7.39 (3H, s), 7.46 (1H, s).
ESIMS (+): [M+H]+.
To A solution of the compound of Example 1 (1.59 g) in 1,4-dioxane (60 mL) was added 0.5 mol/L hydrochloric acid (30 mL). The resultant solution was stirred at room temperature for 1 hour, and then left to stand at room temperature overnight. The solution was concentrated, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The extract was concentrated, and the resultant residue was dissolved in acetonitrile (15 mL). To this solution was added di-tert-butoxydicarbonate (1.55 g), and the resultant solution was stirred at room temperature for 4 hours and then left to stand at room temperature overnight. To the reaction solution was added water, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane ethyl acetate=9:1) to obtain the target product (1.00 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, t, J=7.3 Hz), 1.43 (9H, s), 1.53 (3H, s), 1.45-1.68 (2H, m), 1.80-1.90 (1H, m), 2.12-2.30 (1H, m), 2.69 (2H, t, J=7.6 Hz), 4.16-4.24 (2H, m), 5.33 (1H, br s), 6.85 (1H, dd, J=7.9 Hz, 2.4 Hz), 7.02 (1H, d, J=2.4 Hz), 7.15 (1H, dd, J=7.9 Hz, 2.4 Hz), 7.17 (1H, d, J=7.9 Hz), 7.24 (1H, br s), 7.37 (1H, d, J=7.9 Hz), 7.45 (1H, t, J=7.9 Hz).
The compound of Example 9 was reacted in the same manner as in Example 12 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, t, J=7.3 Hz), 1.42 (9H, s), 1.51 (3H, s), 1.45-1.68 (2H, m), 1.77-1.86 (1H, m), 2.09-2.20 (1H, m), 2.69 (2H, t, J=7.6 Hz), 4.13-4.23 (2H, m), 5.29 (1H, br s), 7.02 (1H, dd, J=9.8 Hz, 1.8 Hz), 7.08 (1H, dd, J=7.9 Hz, 2.4 Hz), 7.13 (1H, t, J=7.9 Hz), 7.38-7.50 (3H, m), 7.55 (1H, s).
The compound of Example 10 was reacted in the same manner as in Example 12 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz) δ 1.24 (3H, t, J=7.3 Hz), 1.29-1.39 (1H, m), 1.43 (9H, s), 1.60-1.70 (1H, m), 1.78-1.86 (1H, m), 2.32-2.50 (2H, m), 2.66-2.73 (2H, m), 2.99-3.10 (1H, m), 4.19 (2H, q), 5.03 (1H, d, J=3.1 Hz), 5.09 (1H, s), 5.49 (1H, br s), 5.54-5.68 (1H, m), 7.16 (1H, d, J=7.9 Hz), 7.19 (1H, dd, J=7.9, 1.8 Hz), 7.35 (1H, d, J=1.8 Hz), 7.39-7.44 (2H, m), 7.45-7.50 (1H, m), 7.54 (1H, br s).
To a solution of the compound of Example 14 (400 mg) in ethyl acetate (20 mL) was added palladium-carbon/ethylene diamine complex (100 mg), and the resultant solution was stirred at room temperature for 24 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated. The resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain the target product (293 mg) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.91 (3H, t, J=7.3 Hz), 1.42 (9H, s), 1.15-1.77 (8H, m), 2.72 (2H, t, J=7.3 Hz), 3.63 (1H, d, J=12 Hz), 3.67 (1H, d, J=12 Hz), 4.52 (1H, br s), 7.19-7.22 (2H, m), 7.39 (1H, s), 7.40-7.50 (3H, m), 7.54 (1H, br s).
FABMS (+): 532 [M+H]+.
To a solution of the compound of Example 12 (1.00 g) in THF (14 mL) was added under ice cooling lithium borohydride (229 mg), and then ethanol (1.4 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the target product (910 mg) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.16 (3H, s), 1.43 (9H, s), 1.53-1.74 (3H, m), 1.81-1.93 (1H, m), 2.73 (2H, t, J=7.3 Hz), 3.61 (1H, d, J=12 Hz), 3.65 (1H, d, J=12 Hz), 4.58 (1H, br s), 4.58 (1H, br s), 6.86 (1H, dd, J=7.9, 2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 7.16 (1H, dd, J=7.9 Hz, 2.4 Hz), 7.21 (1H, d, J=7.9 Hz), 7.24 (1H, br s), 7.37 (1H, d, J=7.9 Hz), 7.45 (1H, t, J=7.9 Hz).
The compound of Example 2 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.42 (9H, s), 1.48-1.76 (4H, m), 1.81-1.90 (1H, m), 2.74 (2H, t, J=6.7 Hz), 3.61 (1H, d, J=12 Hz), 3.65 (1H, d, J=12 Hz), 4.56 (1H, br s), 4.58 (1H, br s), 7.20 (2H, d, J=1.2 Hz), 7.37-7.50 (4H, m), 7.54 (1H, br s).
Optical Rotation: [α]D27+14.31 (c 0.63, CHCl3).
The compound of Example 3 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, s), 1.45 (9H, s), 1.80-1.88 (1H, m), 2.05-2.12 (1H, m), 2.66-2.80 (2H, m), 3.68 (1H, d, J=11.6 Hz), 3.73 (1H, d, J=11.6 Hz), 4.70 (1H, br s), 6.86 (1H, dd, J=8.5, 2.5 Hz), 7.03 (1H, d, J=2.5 Hz), 7.13-7.16 (1H, m), 7.22-7.24 (2H, m), 7.37 (1H, d, J=7.9 Hz), 7.45 (1H, t, J=7.9 Hz).
FABMS (+): 474 [M+H]+.
The compound of Example 4 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (3H, s), 1.44 (9H, s), 1.79-1.89 (1H, m), 2.05-2.13 (1H, m), 2.66-2.83 (2H, m), 3.68 (1H, d, J=12 Hz), 3.71 (1H, d, J=12 Hz), 4.69 (1H, br s), 7.20-7.23 (2H, m), 7.37-7.42 (3H, m), 7.45-7.50 (2H, m), 7.55 (1H, br s).
The compound of Example 5 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 1.24 (3H, s), 1.44 (9H, s), 1.77-1.85 (1H, m), 2.02-2.09 (1H, m), 2.62 (2H, q, J=7.3 Hz), 2.63-2.78 (2H, m), 3.64-3.73 (2H, m), 4.08 (1H, br), 4.68 (1H, br s), 7.10-7.17 (4H, m), 7.22-7.28 (3H, m).
ESIMS (+): 450 [M+H]+.
The compound of Example 6 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.15 (3H, s), 1.43 (9H, s), 1.61-1.67 (3H, m), 1.83-1.87 (1H, m), 2.34 (3H, s), 2.70 (2H, t, J=7.0 Hz), 3.62-3.65 (2H, m), 4.57 (1H, s), 6.81-6.84 (3H, m), 6.94 (1H, d, J=7.3 Hz), 6.98 (1H, d, J=3.1 Hz), 7.15 (1H, d, J=7.9 Hz), 7.22 (1H, t, J=7.9 Hz).
ESIMS (+): 434 [M+H]+.
The compound of Example 7 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.22 (3H, t, J=7.3 Hz), 1.43 (9H, s), 1.54-1.70 (3H, m), 1.79-1.89 (1H, m), 2.62 (2H, q, J=7.3 Hz), 2.70 (2H, t, J=7.0 Hz), 3.57-3.66 (2H, m), 4.05 (1H, br), 4.55 (1H, br s), 7.10-7.17 (4H, m), 7.17-7.28 (3H, m).
ESIMS (+): 464 [M+H]+.
The compound of Reference Example 19 and (5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine were reacted in the same manner as in Example 1. The resultant compound was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.94 (3H, t, J=7.3 Hz), 1.15 (3H, s), 1.24-1.28 (2H, m), 1.43 (9H, s), 1.60-1.69 (3H, m), 1.80-1.90 (1H, m), 2.57 (2H, t, J=7.6 Hz), 2.70 (2H, t, J=7.6 Hz), 3.58-3.67 (2H, m), 4.11 (1H, br s), 4.58 (1H, br s), 6.79-6.85 (3H, m), 6.95 (1H, d, J=7.9 Hz), 6.99 (1H, d, J=2.8 Hz), 7.15 (1H, d, J=8.3 Hz), 7.24 (1H, t, J=7.9 Hz).
The compound of Example 8 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.43 (9H, s), 1.58-1.74 (3H, m), 1.79-1.92 (1H, m), 2.73 (2H, t, J=6.7 Hz), 3.61 (1H, d, J=12 Hz), 3.64 (1H, d, J=12 Hz), 4.08 (1H, br s), 4.57 (1H, br s), 7.17-7.27 (6H, m), 7.37 (1H, s).
ESIMS (+): 470 [M+H]+.
The compound of Example 13 was reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.42 (9H, s), 1.55-1.74 (3H, m), 1.75-1.85 (1H, m), 2.65 (2H, t, J=6.7 Hz), 3.58-3.64 (2H, m), 4.03 (1H, br s), 4.55 (1H, br s), 7.04 (1H, dd, J=9.8 Hz, 1.8 Hz), 7.10 (1H, dd, J=7.9 Hz, 1.8 Hz), 7.17 (1H, t, J=7.9 Hz), 7.38-7.50 (3H, m), 7.54 (1H, br s).
The compound of Example 15 was reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.92 (3H, t, J=7.3 Hz), 1.42 (9H, s), 1.14-1.80 (8H, m), 2.72 (2H, t, J=7.3 Hz), 3.62 (1H, d, J=12 Hz), 3.66 (1H, d, J=12 Hz), 4.54 (1H, br s), 7.16-7.22 (2H, m), 7.39 (1H, s), 7.40-7.48 (3H, m), 7.55 (1H, br s).
FABMS (+): 532 [M+H]+.
The compound of Example 11 was reacted in the same manner as in Example 12 to obtain an ester, which was then reacted in the same manner as in Example 16 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.42 (9H, s), 1.51-1.73 (3H, m), 1.79-1.92 (1H, m), 2.73 (2H, t, J=6.7 Hz), 3.57-3.67 (2H, m), 4.05 (1H, br s), 4.57 (1H, br s), 6.60 (1H, t, J=56 Hz), 7.19 (2H, d, J=1.2 Hz), 7.36 (1H, s), 7.39 (3H, br s), 7.44 (1H, s).
ESIMS (+): 537[M+H]+.
To a solution of the compound of Example 16 (456 mg) in pyridine (5 mL) was added under ice cooling carbon tetrabromide (620 mg) and trimethyl phosphite (219 μL), and the resultant solution was then stirred at 0° C. for 1 hour. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the target product (533 mg) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, s), 1.42 (9H, s), 1.52-1.70 (3H, m), 1.86-1.97 (1H, m), 2.71 (2H, t, J=7.6 Hz), 3.78 (6H, d, J=11 Hz), 4.00 (1H, dd, J=9.8, 4.9 Hz), 4.16 (1H, dd, J=9.8, 4.9 Hz), 4.52 (1H, br s), 6.86 (1H, dd, J=7.9, 2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 7.16 (1H, dd, J=7.9, 2.4 Hz), 7.19 (1H, d, J=7.9 Hz), 7.24 (1H, br s), 7.37 (1H, d, J=7.9 Hz), 7.45 (1H, t, J=7.9 Hz).
The compound of Example 17 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (3H, s), 1.42 (9H, s), 1.53-1.68 Hz (3H, m), 1.85-1.97 (1H, m), 2.73 (2H, t, J=7.6 Hz), 3.77 (6H, d, J=11 Hz), 3.98 (1H, dd, J=9.8, 4.9 Hz), 4.15 (1H, dd, J=9.8, 4.9 Hz), 4.52 (1H, br s), 7.18-7.21 (2H, m), 7.38 (1H, d, J=2.4 Hz), 7.40-7.43 (2H, m), 7.46 7.50 (1H, m), 7.54 (1H, br s).
The compound of Example 18 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.38 (3H, s), 1.45 (9H, s), 1.77-1.85 Hz (1H, m), 2.04-2.17 (1H, m), 2.66-2.79 (2H, m), 3.79 (6H, d, J=11 Hz), 4.04 (1H, dd, J=9.8, 4.9 Hz), 4.24 (1H, dd, J=9.8, 4.9 Hz), 4.64 (1H, br s), 6.86 (1H, dd, J=8.5, 2.5 Hz), 7.02 (1H, d, J=2.5 Hz), 7.14-7.16 (1H, m), 7.21 (1H, d, J=8.5 Hz), 7.24 (1H, bs s), 7.36-7.38 (1H, m), 7.45 (1H, t, J=8.0 Hz).
FABMS (+): 582 [M+H]+.
The compound of Example 19 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.37 (3H, s), 1.45 (9H, s), 1.74-1.84 (1H, m), 2.06-2.18 (1H, m), 2.64-2.81 (2H, m), 3.79 (6H, d, J=11.0 Hz), 4.03 (1H, dd, J=9.8, 4.9 Hz), 4.23 (1H, dd, J=9.8, 4.9 Hz), 4.64 (1H, br s), 7.20 (2H, d, J=1.2 Hz), 7.38 (1H, d, J=2.4 Hz), 7.40-7.42 (1H, m), 7.42 (1H, d, J=1.2 Hz), 7.45-7.50 (1H, m), 7.55 (1H, br s).
The compound of Example 20 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 1.36 (3H, s), 1.44 (9H, s), 1.73-1.81 (1H, m), 2.06-2.18 (1H, m), 2.64 (2H, q, J=7.3 Hz), 2.65-2.76 (2H, m), 3.78 (6H, d, J=11.0 Hz), 4.03 (1H, dd, J=9.8, 4.9 Hz), 4.22 (1H, dd, J=9.8, 4.9 Hz), 4.62 (1H, br s), 7.09-7.17 (4H, m), 7.22-7.27 (3H, m).
ESIMS (+): 558 [M+H]+.
The compound of Example 21 was reacted in the same manner as in Example 28 to obtain the target product as a yellow oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, s), 1.42 (9H, s), 1.58-1.65 (3H, m), 1.89-1.91 (1H, m), 2.34 (3H, s), 2.69 (2H, t, J=7.3 Hz), 3.77 (6H, t, J=11.0 Hz), 4.00 (1H, dd, J=9.8, 4.9 Hz), 4.15 (1H, dd, J=9.8, 4.9 Hz), 4.52 (1H, brs), 6.79-6.84 (3H, m), 6.94 (1H, d, J=7.3 Hz), 6.98 (1H, d, J=2.4 Hz), 7.13 (1H, d, J=7.9 Hz), 7.22 (1H, t, J=7.9 Hz).
ESIMS (+): 542 [M+H]+.
The compound of Example 22 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.22 (3H, t, J=7.3 Hz), 1.26 (3H, s), 1.41 (9H, s), 1.53-1.65 (3H, m), 1.84-1.93 (1H, m), 2.63 (2H, q, J=7.3 Hz), 2.66-2.71 (2H, m), 3.76 (3H, d, J=11.0 Hz), 3.78 (3H, d, J=11.0 Hz), 3.98 (1H, dd, J=9.8, 4.9 Hz), 4.14 (1H, dd, J=9.8, 4.9 Hz), 4.50 (1H, br s), 7.11-7.27 (7H, m).
ESIMS (+): 572 [M+H]+.
The compound of Example 23 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.94 (3H, t, J=7.3 Hz), 1.26 (3H, s), 1.42 (9H, s), 1.56-1.68 (5H, m), 1.85-1.95 (1H, m), 2.57 (2H, t, J=7.6 Hz), 2.69 (2H, t, J=7.3 Hz), 3.77 (3H, d, J=11.0 Hz), 3.78 (3H, d, J=11.0 Hz), 4.00 (1H, dd, J=9.8, 4.9 Hz), 4.15 (1H, dd, J=9.8, 4.9 Hz), 4.52 (1H, br s), 6.79-6.85 (3H, m), 6.95 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=2.4 Hz), 7.13 (1H, d, J=8.3 Hz), 7.24 (1H, t, J=7.9 Hz).
ESIMS (+): 570 [M+H]+.
The compound of Example 24 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (3H, s), 1.42 (9H, s), 1.58-1.67 Hz (3H, m), 1.86-1.96 (1H, m), 2.72 (2H, t, J=6.7 Hz), 3.77 (6H, d, J=11 Hz), 3.98 (1H, dd, J=9.8, 4.9 Hz), 4.15 (1H, dd, J=9.8, 4.9 Hz), 4.52 (1H, br s), 7.15-7.24 (5H, m), 7.36 (1H, d, J=1.8 Hz).
ESIMS (+) 578 [M+H]+.
The compound of Example 25 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (3H, s), 1.42 (9H, s), 1.53-1.68 Hz (3H, m), 1.85-1.97 (1H, m), 2.73 (2H, t, J=6.7 Hz), 3.56 (3H, d, J=11 Hz), 3.57 (3H, d, J=11 Hz), 3.98 (1H, dd, J=9.8, 4.9 Hz), 4.13 (1H, dd, J=9.8, 4.9 Hz), 4.50 (1H, br s), 7.03 (1H, dd, J=9.8 Hz, 1.8 Hz), 7.08 (1H, dd, J=7.9 Hz, 1.8 Hz), 7.16 (1H, t, J=7.9 Hz), 7.38-7.51 (3H, m), 7.55 (1H, br s).
ESIMS (+) 596 [M+H]+.
The compound of Example 26 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 0.91 (3H, t, J=7.3 Hz), 1.18-1.31 (3H, m), 1.41 (9H, s), 1.48-1.58 (4H, m), 1.75-1.88 (1H, m), 2.71 (2H, t, J=7.3 Hz), 3.76 (6H, d, J=10 Hz), 4.07 (1H, dd, J=9.7, 4.3 Hz), 4.14 (1H, dd, J=9.7, 4.3 Hz), 4.40 (1H, br s), 7.19 (1H, s), 7.20 (1H, d, J=1.8 Hz), 7.38 (1H, d, J=1.8 Hz), 7.41-7.49 (3H, m), 7.55 (1H, br s).
FABMS (+): 640 [M+H]+.
The compound of Example 27 was reacted in the same manner as in Example 28 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.24 (3H, s), 1.42 (9H, s), 1.51-1.67 Hz (3H, m), 1.83-1.99 (1H, m), 2.73 (2H, t, J=7.6 Hz), 3.77 (6H, d, J=11 Hz), 4.00 (1H, dd, J=9.8, 4.9 Hz), 4.17 (1H, dd, J=9.8, 4.9 Hz), 4.54 (1H, br s), 6.61 (1H, t, J=56 Hz), 7.19 (2H, d, J=1.2 Hz), 7.34-7.42 (4H, m), 7.45 (1H, s).
ESIMS (+): 594 [M+H]+.
Iodotrimethylsilane (478 μL) was added dropwise under ice cooling and under an argon atmosphere to a solution of the compound of Example 28 (533 mg) in acetonitrile (8 mL), and the resultant solution was stirred under ice cooling for 30 minutes. The solution was charged with water (100 mL), and then further stirred under ice cooling for 30 minutes. The precipitated crystals were then filtered off, thoroughly washed with water and ethyl acetate, and then dried to obtain the target product (310 mg) as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.16 (3H, s), 1.51-1.71 (4H, m), 2.66 (2H, t, J=7.9 Hz), 3.78 (1H, dd, J=11.0, 4.9 Hz), 3.83 (1H, dd, J=11.0, 4.9 Hz), 6.98 (1H, d, J=7.9 Hz), 7.13 (1H, br s), 7.26 (1H, d, J=7.9 Hz), 7.27 (1H, br s), 7.35 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=7.9 Hz), 7.57 (1H, t, J=7.9 Hz).
FABMS (+): 468 [M+H]+.
Elemental Analysis: Measured: C, 48.28%, H, 4.62%, N, 2.86%, Calcd. for C19H22ClF3NO5P.1/4 H2O: C, 48.32%, H, 4.80%, N, 2.97%.
Optical Rotation: [α]D25+6.62 (c 0.55, DMSO -1% TFA)
The compound of Example 29 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.15 (3H, s), 1.49-1.68 (4H, m), 2.67 (2H, t, J=7.4 Hz), 3.76 (1H, dd, J=11.0, 4.9 Hz), 3.81 (1H, dd, J=11.0, 4.9 Hz), 7.32 (1H, dd, J=7.9, 2.4 Hz), 7.38 (1H, d, J=7.9 Hz), 7.46 (1H, d,J=2.4 Hz ), 7.53 (1H, d, J=7.9 Hz), 7.56 (1H, d, J=7.9 Hz), 7.60 (1H, br s), 7.62 (1H, t, J=7.9 Hz).
FABMS (+): 484 [M+H]+.
Elemental Analysis: Measured: C 46.85%, H, 4.35%, N, 2.66%, Calcd. for C19H22ClF3NO4PS: C, 47.16%, H, 4.58%, N, 2.89%
Optical Rotation: [α]D25+7.27 (c0.55, DMSO-1%TFA).
The compound of Example 30 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.30 (3H, s), 1.70-1.90 (2H, m), 2.72 (2H, t, J=8.6 Hz), 3.88 (1H, dd, J=11.0, 5.5 Hz), 3.94 (1H, dd, J=11.0 Hz, 5.5 Hz), 7.04 (1H, dd, J=7.9, 2.4 Hz), 7.20 (1H, d, J=2.4 Hz), 7.30 (1H, dd, J=7.9, 2.4 Hz), 7.34 (1H, br s), 7.39 (1H, d, J=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.62(1H, d, J=7.9 Hz).
FABMS (+): 454 [M+H]+.
Elemental Analysis: Measured: C, 47.83%, H, 4.33%, N, 3.02%, Calcd. for C18H20ClF3NO5P.1/2 H2O: C, 46.72%, H, 4.57%, N, 3.03%.
The compound of Example 31 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.28 (3H, s), 1.70-1.90 (2H, m), 2.73 (2H, t, J=8.6 Hz), 3.87 (1H, dd, J=11.0, 4.9 Hz), 3.94 (1H, dd, J=11.0 Hz, 4.9 Hz), 7.33 (1H, d, J=7.9 Hz), 7.39 (1H, d, J=7.9 Hz), 7.46 (1H, br s), 7.50-7.58 (3H, m).
FABMS (+): 470 [M+H]+.
Elemental Analysis: Measured: C, 45.32%, H, 4.09%, N, 2.90%, Calcd. for C18H20ClF3NO4PS.1/4 H2O: C, 45.57%, H, 4.36%, N, 2.95%.
The compound of Example 32 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.37 (3H, t, J=7.3 Hz), 1.28 (3H, s), 1.72-1.85 (2H, m), 2.58 (2H, t, J=7.3 Hz), 2.67-2.72 (2H, m), 3.86 (1H, dd, J=11.0, 4.9 Hz), 3.93 (1H, dd, J=11.0, 4.9 Hz), 7.17-7.21 (3H, m), 7.25-7.26 (2H, m), 7.31 (2H, t, J=7.3 Hz).
ESIMS (+): 430 [M+H]+.
Elemental Analysis Measured: C, 52.56%, H, 5.79%, N, 3.21%, Calcd. For C19H25ClNO4PS.1/4H2O: C, 52.53%, H, 5.79%, N, 3.21%.
The compound of Example 33 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.17 (3H, s), 1.53-1.71 (4H, m), 2.28 (3H, s), 2.59-2.69 (2H, m), 3.78-3.83 (2H, m), 6.80 (1H, dd, J=7.9, 2.4 Hz), 6.84 (1H, s), 6.92 (1H, dd, J=7.9, 2.4 Hz), 6.98 (1H, d, J=7.9 Hz), 7.02 (1H, d, J=2.4 Hz), 7.27 (1H, t, J=7.9 Hz), 7.33 (1H, d, J=7.9 Hz).
HRESIMS (+): 414.12313 (Calcd. for C19H26ClNO5P 414.12371).
Elemental Analysis Measured: C, 54.87%, H, 5.89%, N, 3.27%, Calcd. for C19H25ClNO5P: C, 55.14%, H, 6.09%, N, 3.38%.
Optical Rotation: [α]D25+7.93 (c 1.20, DMSO-1% TFA).
The compound of Example 34 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.41 (3H, t, J=7.3 Hz), 1.16 (3H, s), 1.51-1.69 (4H, m), 2.58 (2H, t, J=7.3 Hz), 2.63-2.80 (2H, m), 3.78 (1H, dd, J=11.0, 4.9 Hz), 3.81 (1H, dd, J=11.0, 4.9 Hz), 7.16-7.33 (7H, m).
ESIMS (+): 444 [M+H]+.
Elemental Analysis Measured: C, 53.87%, H, 6.04%, N, 3.11%, Calcd. for C20H27ClNO4PS: C, 54.11%, H, 6.13%, N, 3.16%.
The compound of Example 35 was reacted in the same manner as in Example 40 to obtain the target product as a pale yellow powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 0.86 (3H, t, J=7.3 Hz), 1.17 (3H, s), 1.51-1.67 (6H, m), 2.53 (2H, t, J=7.3 Hz), 2.64 (2H, t, J=7.3 Hz), 3.78 (1H, dd, J=11.0, 4.9 Hz), 3.83 (1H, dd, J =11.0, 4.9 Hz), 6.81 (1H, dd, J=7.9, 1.8 Hz), 6.86 (1H, t, J=1.8 Hz), 6.91 (1H, dd, J=8.6, 2.4 Hz), 7.00 (1H, d, J=7.9 Hz), 7.02 (1H, d, J=2.4 Hz), 7.29 (1H, t, J=7.9 Hz), 7.33 (1H, t, J=8.6 Hz).
ESIMS (+): 442 [M+H]+.
Elemental Analysis Measured: C, 56.80%, H, 6.40%, N, 3.04%, Calcd. for C21H29ClNO5P: C, 57.08%, H, 6.61%, N, 3.17%.
Optical Rotation: [α]D25+8.33 (c 0.90, DMSO-1% TFA).
The compound of Example 36 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.17 (3H, s), 1.53-1.71 (4H, m), 2.68 (2H, t, J=6.7 Hz), 3.78 (1H, dd, J=11, 4.9 Hz), 3.83 (1H, dd, J=11, 4.9 Hz), 7.24 (1H, dt, J=7.3, 1.8 Hz), 7.28-7.40 (5H, m), 7.43 (1H, d, J=1.8 Hz).
ESIMS (+): 450 [M+H]+.
Elemental Analysis Measured: C, 47.64%, H, 4.72%, N, 3.07%, Calcd. for C18H22Cl2NO4PS: C, 48.01%, H, 4.92%, N, 3.11%.
Optical Rotation: [α]D25+8.12 (c 0.55, DMSO-1% TFA).
The compound of Example 37 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.16 (3H, s), 1.54-1.66 (4H, m), 2.60 (2H, br s), 3.77 (1H, dd, J=11, 4.9 Hz), 3.82 (1H, dd, J=11, 4.9 Hz), 7.19 (1H, dd, J=7.9, 1.8 Hz), 7.23 (1H, dd, J=9.8, 1.8 Hz), 7.36 (1H, t, J=7.9 Hz), 7.52-7.66 (4H, m).
ESIMS (+): 468 [M+H]+.
Elemental Analysis Measured: C, 48.00%, H, 4.59%, N, 2.88%, Calcd. for C19H22F4NO4PS.1/2H2O: C, 47.90%, H, 4.87%, N, 2.94%.
The compound of Example 38 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): 0.84 (3H, t, J=7.3 Hz), 1.21 (2H, q, J=7.4 Hz), 1.42-1.62 (6H, m), 2.64-2.71 (2H, m), 3.81 (2H, d, J=4.9 Hz), 7.34 (1H, dd, J=7.9, 1.8 Hz), 7.40 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=1.8 Hz), 7.53 (1H, d, J=7.9 Hz), 7.54-7.66 (3H, m).
FABMS (+): 512 [M+H]+.
Elemental Analysis Measured: C, 47.89%, H, 4.94%, N, 2.65, Calcd. for C21H26ClF3NO4PS.H2O: C, 47.65%, H, 5.33%, N, 2.65%.
The compound of Example 39 was reacted in the same manner as in Example 40 to obtain the target product as a white powder.
1H-NMR (DMSO-d6-dTFA, 400 MHz): δ 1.16 (3H, s), 1.50-1.71 (4H, m), 2.62-2.73 (2H, m), 3.78 (1H, dd, J=11.0, 4.9 Hz), 3.83 (1H, dd, J=11.0, 4.9 Hz), 6.98 (1H, dd, J=56, 1.8 Hz), 7.27 (1H, dd, J=7.9, 1.8 Hz), 7.37 (1H, d, J=7.9 Hz), 7.39 (1H, d, J=1.8 Hz), 7.43-7.56 (4H, m).
ESIMS (+): 466 [M+H]+.
Elemental Analysis Measured: C, 48.51%, H, 4.79%, N, 2.93%, Calcd. for C19H23ClF2NO4PS.1/5H2O: C, 48.51%, H, 5.02%, N, 2.98%.
Optical Rotation: [α]D25+5.32 (c0.50, DMSO-1% TFA).
2-Chloro-1-(3-iodopropyl)-4-(3-trifluoromethylphenylthio)benzene and diethyl 2-methylmalonate were reacted according to the same procedures as in Example 152 of WO 04026817 to obtain the target product as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (6H, t, J=7.4 Hz), 1.40 (3H, s), 1.51-1.63 (2H, m), 1.90-1.97 (2H, m), 2.73 (2H, t, J=7.9 Hz), 4.17 (4H, q, J=7.4 Hz), 7.17-7.23 (2H, m), 7.38 (1H, d, J=2.2 Hz), 7.39-7.44 (2H, m), 7.45-7.50 (1H, m), 7.55 (1H, s).
EIMS (+): 502 [M]+.
To a solution of the compound of Example 52 (16.8 g) in ethanol (167 mL) was added potassium hydroxide (2.40 g), and the resultant solution was stirred at 50° C. for 24 hours. To the reaction solution was added water, neutralized with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (11.2 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.26 (3H, t, J=7.4 Hz), 1.47 (3H, s), 1.55-1.66 (2H, m), 1.87-2.06 (2H, m), 2.73 (2H, t, J=7.9 Hz), 4.22 (2H, q, J=7.4 Hz), 7.18 (1H, d, J=7.9 Hz), 7.20 (1H, dd, J=7.9, 1.8 Hz), 7.38 (1H, d, J=1.8 Hz), 7.39-7.44 (2H, m), 7.45-7.50 (1H, m), 7.54 (1H, s).
ESIMS (+): 475 [M+H]+.
To a solution of the compound of Example 53 (15.8 g) in benzene (166 mL) was added diphenylphosphoryl azide (7.86 mL) and triethylamine (6.01 mL), and the resultant solution was heated to reflux for 1.5 hours. The temperature of the reaction solution was returned to room temperature, and methanol (20 mL) was added dropwise thereto over 20 minutes. The resultant solution was heated to reflux for 30 minutes, and then sodium methoxide (3.58 g) was added to the reaction mixture. The resultant solution was heated to reflux for 1.5 hours. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the target product (15.6 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.25 (3H, t, J=7.3 Hz), 1.32-1.47 (1H, m), 1.52-1.67 (1H, m), 1.57 (3H, s), 1.80-1.90 (1H, m), 2.20-2.37 (1H, m), 2.62-2.76 (2H, m), 3.64 (3H, s), 4.15-4.25 (2H, m), 5.62 (1H, br s), 7.16 (1H, d, J=7.9 Hz), 7.20 (1H, dd, J=7.9, 1.8 Hz), 7.38 (1H, d, J=1.8 Hz), 7.40-7.44 (2H, m), 7.45-7.50 (1H, m), 7.55 (1H, s).
ESIMS (+): 504 [M+H]+.
To a solution of the compound of Example 54 (15.6 g) in THF (249 mL) was added under ice cooling lithium borohydride (3.75 g), and then ethanol (16.6 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (12.9 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.18 (3H, s), 1.54-1.74 (3H, m), 1.78-1.89 (1H, m), 2.73 (2H, t, J=7.9 Hz), 3.63 (3H, s), 3.56-3.70 (2H, m), 4.23 (1H, br s), 7.17-7.22 (2H, m), 7.38-7.50 (4H, m), 7.54 (1H, s).
ESIMS (+): 462 [M+H]+.
To a solution of the compound of Example 55 (12.9 g) in THF (60 mL) and methanol (120 mL) was added under ice cooling 5 mol/L aqueous potassium hydroxide solution (60 mL), and the resultant solution was heated to reflux for 86 hours. To the reaction solution was added water, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The extract was concentrated, the residue was dissolved in 1,4-dioxane (279 mL), and the resultant solution was charged with di-tert-butoxydicarbonate (9.13 g). The solution was stirred at room temperature for 2 hours and then left to stand at room temperature overnight. To the reaction solution was added water, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the target product (13.0 g) as a colorless oil.
1H-NMR (CDCl3, 400 MHz): δ 1.14 (3H, s), 1.42 (9H, s), 1.53-1.74 (3H, m), 1.79-1.92 (1H, m), 2.74 (2H, t, J=7.9 Hz), 3.58-3.69 (2H, m), 4.05 (1H, br s), 4.57 (1H, br s), 7.20-7.22 (2H, m), 7.38-7.50 (4H, m), 7.54 (1H, s).
ESIMS (+): 504 [M+H]+.
The compound of Example 56 was subjected to optical resolution using high performance liquid chromatography (CHIRALCEL OJ-H, hexane:isopropanol:diethylamine=98:2:0.1 (v/v), measurement wavelength: UV 278 nm, flow rate: 1.0 mL/min). From the pre-elution portion, a colorless oil having [α]D25+15.08 (c 0.63, CHCl3) was obtained (Example 57), and from the post-elution portion, a colorless oil with [α]D26-13.91 (c 0.63, CHCl3) was obtained (Example 58).
The compound of Example 57 was reacted in the same manner as in Example 16, and the resultant compound was then reacted in the same manner as in Example 28 to obtain a phosphate, which was then reacted in the same manner as in Example 40 to obtain the target product as a white powder.
FABMS (+): 484 [M+H]+
Optical Rotation: [α]D25+8.86 (c 1.00, DMSO-1% TFA)
Next, results which support the utility of the compound of the present invention will be shown by an experiment example.
Human S1P receptors expressing CHO-K1 cells (hS1P1 receptors expressing CHO-K1 cells, hS1P3 receptors expressing CHO-K1 cells, and hS1P4 receptors expressing CHO-K1 cells), were maintained in Ham's F-12 medium containing 10% fetal bovine serum and 400 μg/mL Geneticin. Into a black, clear bottom, culture plate (BD Falcon) with 96 wells, 7×104 cells/well of the hS1P1 and hS1P3 receptors expressing CHO-K1 cells were plated, and ×104 cells/well of the hS1P4 receptors expressing CHO-K1 cells were plated. The cells were incubated overnight at 37° C. at 5% CO2. The medium in the wells were removed by suction. A loading buffer included in a Calcium Kit-Fluo 3 reagent (Dojindo Laboratories) was added as a fluorescent Ca2+-binding indicator. The cells were incubated for 80 minutes at 37° C. at 5% CO2. After the incubation, the wells were washed with PBS. A recording buffer included in a Calcium Kit-Fluo 3 reagent was added, and the cells were incubated for 20 minutes at 37° C. at 5% CO2. Using a microplate spectrophotofluorometer (FLEX Station, Molecular Devices), the fluorescence intensity at an excitation wavelength of 485 nm and a detection wavelength of 525 nm was measured. S1P and the subject compound prepared in medium so that the concentration was 10-fold that of the final concentration (final DMSO concentration of 0.1%). The solution was added 18 seconds after the fluorescence measurement was started, and then fluorescence intensity was continuously measured every 1.5 seconds until 100 seconds after addition. A value (fluorescence increase) obtained by subtracting the minimum fluorescence intensity from the maximum fluorescence intensity was calculated from the measurement data. Taking the difference between the fluorescence increase when the solvent was added and the fluorescence increase when the S1P was allowed to act at 10−6 M as 100%, the fluorescence increase ratio (%) of the subject compound was calculated. Taking this value as the intracellular calcium mobilization induced activity of the subject compound, the EC50 value was determined using PRISM software (GraphPad). In Table 1, 10 nmol/L>EC50 value ≧1 nmol/L is indicated as a +, and 1 nmol/L>EC50 value is indicated as a ++.
From the above results, it was determined that the compound of the present invention has a weak activity on a human S1P3 receptor, and a strong activity on S1P1 and S1P4 receptors.
The present invention has led to the discovery of a novel amino phosphate derivative and addition salt thereof, which have an excellent S1P receptor modulatory action. A compound having such an S1P receptor modulatory action is effective as a treatment and a preventive agent for arteriosclerosis, arteriosclerosis obliterans, thromboangiitis obliterans, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pneumonitis, idiopathic interstitial pneumonia, lung cancer, pneumonia hypersensitivity, Buerger's disease, diabetic neuropathy peripheral arterial disease, septicemia, angiitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edematous state, varices, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, bedsores, burns, ulcerative colitis, Crohn's disease and the like. Furthermore, a compound having such an S1P receptor modulatory action is effective as a treatment and a preventive agent for rejection of heart transplants, kidney transplants, skin grafts, liver transplants, and bone marrow transplants, and is also an effective as a treatment and a preventive agent for rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, diabetes mellitus, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis and the like.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-215280 | Aug 2006 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2007/065397 | 8/7/2007 | WO | 00 | 6/1/2009 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2008/018427 | 2/14/2008 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5447922 | Lawrence et al. | Sep 1995 | A |
| 5604229 | Fujita et al. | Feb 1997 | A |
| 5948820 | Fujita et al. | Sep 1999 | A |
| 6004565 | Chiba et al. | Dec 1999 | A |
| 6214873 | Adachi et al. | Apr 2001 | B1 |
| 6489331 | Shimada et al. | Dec 2002 | B1 |
| 6960692 | Kohno et al. | Nov 2005 | B2 |
| 6963012 | Kohno et al. | Nov 2005 | B2 |
| 7456157 | Kohno et al. | Nov 2008 | B2 |
| 7482491 | Kohno et al. | Jan 2009 | B2 |
| 20020040050 | Xu et al. | Apr 2002 | A1 |
| 20020091105 | Mandala et al. | Jul 2002 | A1 |
| 20020143034 | Taniguchi et al. | Oct 2002 | A1 |
| 20030236297 | Nishi et al. | Dec 2003 | A1 |
| 20040058894 | Doherty et al. | Mar 2004 | A1 |
| 20040067908 | Nakade et al. | Apr 2004 | A1 |
| 20040087662 | Bigaud et al. | May 2004 | A1 |
| 20040110728 | Macdonald et al. | Jun 2004 | A1 |
| 20040138462 | Sakurai et al. | Jul 2004 | A1 |
| 20040147490 | Albert et al. | Jul 2004 | A1 |
| 20040224941 | Seko et al. | Nov 2004 | A1 |
| 20040235794 | Nakade et al. | Nov 2004 | A1 |
| 20040242654 | Kohno et al. | Dec 2004 | A1 |
| 20040248952 | Pan et al. | Dec 2004 | A1 |
| 20040254222 | Kohno et al. | Dec 2004 | A1 |
| 20050009786 | Pan et al. | Jan 2005 | A1 |
| 20050020837 | Doherty et al. | Jan 2005 | A1 |
| 20050033055 | Bugianesi et al. | Feb 2005 | A1 |
| 20050043386 | Nishi et al. | Feb 2005 | A1 |
| 20050107345 | Doherty et al. | May 2005 | A1 |
| 20050222422 | Lynch et al. | Oct 2005 | A1 |
| 20050245575 | Chen et al. | Nov 2005 | A1 |
| 20060046979 | Foster et al. | Mar 2006 | A1 |
| 20060089334 | Budhu et al. | Apr 2006 | A1 |
| 20060135622 | Kohno et al. | Jun 2006 | A1 |
| 20060135786 | Saha et al. | Jun 2006 | A1 |
| 20060148830 | Terakado et al. | Jul 2006 | A1 |
| 20060148844 | Nakade et al. | Jul 2006 | A1 |
| 20060160771 | Kohno et al. | Jul 2006 | A1 |
| 20060161005 | Doherty et al. | Jul 2006 | A1 |
| 20060166940 | Buehlmayer et al. | Jul 2006 | A1 |
| 20060211656 | Albert et al. | Sep 2006 | A1 |
| 20060211658 | Hinterding et al. | Sep 2006 | A1 |
| 20060252741 | Colandrea et al. | Nov 2006 | A1 |
| 20060264403 | Albert | Nov 2006 | A1 |
| 20070010494 | Ehrhardt et al. | Jan 2007 | A1 |
| 20070043014 | Doherty et al. | Feb 2007 | A1 |
| 20070088002 | Lynch et al. | Apr 2007 | A1 |
| 20070135501 | Hinterding et al. | Jun 2007 | A1 |
| 20070149597 | Nishi et al. | Jun 2007 | A1 |
| 20070167410 | Pan et al. | Jul 2007 | A1 |
| 20070167425 | Nakade et al. | Jul 2007 | A1 |
| 20070191468 | Nishi et al. | Aug 2007 | A1 |
| 20070203100 | Pan et al. | Aug 2007 | A1 |
| 20070225260 | Hinterding et al. | Sep 2007 | A1 |
| 20080025973 | Fleenor et al. | Jan 2008 | A1 |
| 20080027508 | Chu | Jan 2008 | A1 |
| 20080032923 | Kudou et al. | Feb 2008 | A1 |
| 20080153882 | Nishi et al. | Jun 2008 | A1 |
| 20080161410 | Kusters et al. | Jul 2008 | A1 |
| 20080200438 | Albert et al. | Aug 2008 | A1 |
| 20080207584 | Habashita et al. | Aug 2008 | A1 |
| 20080207941 | Tsubuki et al. | Aug 2008 | A1 |
| 20080249093 | Colandrea et al. | Oct 2008 | A1 |
| 20090023797 | Azzaoui et al. | Jan 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 2002-53575 | Feb 2002 | JP |
| 2002-316985 | Oct 2002 | JP |
| 2003-137894 | May 2003 | JP |
| 2003-267936 | Sep 2003 | JP |
| 2004-137208 | May 2004 | JP |
| 2004-307439 | Nov 2004 | JP |
| 2004-307440 | Nov 2004 | JP |
| 2004-307441 | Nov 2004 | JP |
| 2004-307442 | Nov 2004 | JP |
| 2005-47899 | Feb 2005 | JP |
| 2005-247691 | Sep 2005 | JP |
| 0198301 | Dec 2001 | WO |
| 03040097 | May 2003 | WO |
| 03051876 | Jun 2003 | WO |
| 2004074297 | Sep 2004 | WO |
| 2005014525 | Feb 2005 | WO |
| 2005014603 | Feb 2005 | WO |
| 2005063671 | Jul 2005 | WO |
| 2006041015 | Apr 2006 | WO |
| 2006063033 | Jun 2006 | WO |
| 2006129688 | Dec 2006 | WO |
| 2007043433 | Apr 2007 | WO |
| 2007043568 | Apr 2007 | WO |
| 2007091501 | Aug 2007 | WO |
| 2007126042 | Nov 2007 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20090325907 A1 | Dec 2009 | US |
