A novel compound which is useful as an agent for treating and/or preventing emesis, vomiting and/or constipation. A compound represented by the formula (I):
##STR00001##
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0. 20. A compound of the formula:
##STR00439##
or a pharmaceutically acceptable salt thereof.
##STR00437##
##STR00438##
or a pharmaceutically acceptable salt thereof.
##STR00433##
##STR00434##
##STR00435##
##STR00436##
or a pharmaceutically acceptable salt thereof.
##STR00432##
wherein
R1 is hydrogen;
R2 is lower alkyl optionally substituted with lower alkoxy or with a heterocyclic group that is optionally substituted with aryl; phenyl optionally substituted with lower alkyl or with lower alkoxy; cycloalkyl substituted with lower alkylcarbonyl; or a heterocyclic group substituted with lower alkoxy or with aryl;
R3 is hydroxyl; R4 is hydrogen; and
R5 is cyclopropylmethyl; or a pharmaceutically acceptable salt thereof.
##STR00431##
wherein
R1 is hydrogen; R2 is selected from lower alkyl optionally substituted with lower alkoxy, lower alkoxycarbonyl, or a heterocyclic group optionally substituted with lower alkyl or phenyl; phenyl optionally substituted with lower alkyl, lower alkoxy, halogen, or cyano lower alkyl; cycloalkyl optionally substituted with lower alkoxycarbonyl or lower alkoxy lower alkyl; or a heterocyclic group optionally substituted with lower alkoxy or oxo;
R3 is hydroxyl;
R4 is hydrogen; and
R5 is cyclopropylmethyl;
or a pharmaceutically acceptable salt thereof.
##STR00428##
wherein R1 and R2 are each independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkylsulfonyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted arylsulfonyl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to form optionally substituted heterocycle;
R3 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower alkoxy, mercapto, optionally substituted lower alkylthio, optionally substituted amino, optionally substituted carbamoyl, optionally substituted acyl, optionally substituted acyloxy, optionally substituted aryl, or an optionally substituted heterocyclic group; or
a the group represented by the formula:
##STR00429##
may be is selected from:
##STR00430##
wherein ring A and ring b are each independently optionally substituted nitrogen-containing heterocycle optionally containing additional nitrogen atom, oxygen atom, and/or sulfur atom in the ring;
broken line indicates the presence or the absence of a bond;
when broken line indicates the presence of a bond, p is 0;
when a broken line indicates the absence of a bond, p is 1; Ra is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted lower alkynyl; and
Rb is hydrogen or oxo;
R4 is hydrogen or lower alkyl; and
R5 is hydrogen, lower alkyl, cycloalkyl lower alkyl or lower alkenyl, or a pharmaceutically acceptable salt thereof.
2. The compound according to
3. The compound according to
4. The compound in any one of
5. A pharmaceutical composition containing a compound in any one of
6. A composition having an opioid receptor antagonistic activity containing a compound in any one of
7. A composition for treating and/or preventing emesis, vomiting and/or constipation containing a compound in any one of
8. A composition for alleviating and/or preventing a side effect induced by a compound having opioid receptor agonistic activity containing a compound in any one of
9. An agent for treating and/or preventing a side effect according to
10. A composition for treatment and/or prevention according to
11. A composition for analgesic containing a compound having an opioid receptor agonistic activity, and an effective amount of compound according to any one of
16. A composition for analgesic containing:
a compound having an opioid receptor agonistic activity,
and an effective amount of compound according to
17. A composition for analgesic containing:
a compound having an opioid receptor agonistic activity,
and an effective amount of compound according to
18. A composition for analgesic containing:
a compound having an opioid receptor agonistic activity,
and an effective amount of compound according to
19. A composition for analgesic containing:
a compound having an opioid receptor agonistic activity,
and an effective amount of compound according to
0. 21. The compound of claim 20 wherein the compound is
##STR00440##
0. 22. The compound of claim 20 wherein the compound is a pharmaceutically acceptable salt of
##STR00441##
0. 23. The compound of claim 22 wherein the pharmaceutically acceptable salt is the p-toluene sulfonic acid salt.
0. 24. A pharmaceutical composition comprising the compound of claim 20 or a pharmaceutically acceptable salt thereof.
0. 25. A pharmaceutical composition comprising the compound of claim 23.
0. 26. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity.
0. 27. A composition comprising a compound having an opioid receptor agonistic activity and an effective amount of the compound of claim 23, for alleviating and/or preventing a side effect induced by administering of the compound having an opioid receptor agonistic activity.
0. 28. The composition of claim 27 wherein the compound having the opioid receptor agonistic activity is morphine, oxycodone, or a pharmaceutically acceptable salt thereof.
0. 29. The composition according to claim 25 in the form of a tablet.
0. 30. The composition according to claim 27 in the form of a tablet.
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M.P.E. (%)={(small intestine transport rate (%) of each individual of test compound administration group−average small intestine transport rate (%) of solvent administration group)/(average small intestine transport rate (%) of control group−average small intestine transport rate (%) of solvent administration group)}×100
An ED50 value is calculated by reverse estimation of regression a SAS program using % MPE and letting a value of a control group to be 100%.
The present compound has the opioid receptor (particularly, opioid δ and μ receptors) antagonistic activity. Therefore, the present compound is effective in treating and/or preventing digestive tract passage disorder which occurs by a cause such as acute dyspepsia, acute alcoholism, food poisoning, cold, stomach ulcer, duodenum ulcer, stomach cancer, ileus, appendicitis, peritonitis, cholelithiasis, hepatitis, liver inflammation, encephalitis, meningitis, increased brain pressure, head trauma, motion sickness, vomiting of pregnancy, side effect due to chemotherapy, side effect due to radiation therapy, side effect due to anti-cancer agent, pressure•stenosis of digestive tract, and intestinal tract coalescence after operation, treating and/or preventing emesis and vomiting which occurs by a cause such as increase in brain pressure due to brain tumor•brain bleeding•meningitis•irradiation of brain with radiation, and treating and/or preventing acute constipation derived from a cause such as ileus, duodenum ulcer or appendicitis, relaxing constipation derived from a cause such as nervous disorder, low nutrient, general prostration, vitamin deficiency, anemia, sensitivity reduction or mechanical stimulation insufficiency, or convulsive constipation derived from a cause such as stress, in addition to emesis•vomiting•constipation induced by a compound having the opioid receptor agonistic activity.
Since the present compound has low brain transition, it exhibits the high alleviating effect on a side effect such as emesis, vomiting, constipation and the like induced by an opioid receptor agonistic activity almost without inhibiting the analgesic activity of a compound having the opioid receptor agonistic activity which is administered to the patient with a decease accompanying pain (e.g. cancerous pain (pain due to bone transition, nervous pressure, increased intracranial pressure, soft tissue infiltration, pain due to constipation or spasm of muscle, pain of internal organ, muscle, fascia, waist or shoulder joint periphery, chronic pain after operation), AIDS etc.). In addition, the present compound has pure antagonistic activity on an opioid receptor, and also has an advantage in safety point that the hERG channel inhibitory activity is low, there is no cardiac toxicity, and so on. Further, the present compound also has an advantageous characteristic in dynamics in a body such as high oral absorbability, high stability in human plasma, high bioavailability and the like, and is very effective as a medicament.
When the present compound is administered against emesis, vomiting, or constipation induced by a compound having the opioid receptor agonistic activity, the administration may be any of before, after or at the same time with administration of the compound having the opioid receptor agonistic activity. An administration interval between these two kinds of drugs is not particularly limited. For example, when the present compound is administered after administration of the compound having the opioid receptor agonistic activity, if the administration is immediately after to in about 3 days, preferably immediately after to in about 1 day from administration of the compound having the opioid receptor agonistic activity, the present compound works more effectively. In addition, when the present invention is administered before administration of the compound having the opioid receptor agonistic activity, if the administration is immediately before to before about 1 day, preferably immediately before to before about 12 hours from administration of the compound having the opioid receptor agonistic activity, the present compound works more effectively.
When the present compound is administered as an agent for treating and/or preventing emesis, vomiting and/or constipation, it may be used jointly with other agent for treating and/or preventing emesis, vomiting and/or constipation. For example, it is possible to administer the agent jointly with ondansetrone hydrochloride, adrenal cortical steroid (methylprednisolone, prednisolone, dexamethasone etc.), prochlorperazine, haloperidol, thymiperone, perphenazine, metoclopramide, domperidone, scopolamine, chlorpromazine hydrochloride, droperidol, stimulating laxative (sennoside, picosulfate sodium etc.), osmotic laxative (lactulose etc.), or salt laxative (magnesium oxide etc.).
Alternatively, a combination agent between the present compound and a compound having the opioid receptor agonistic activity, or a combination agent between the present compound and other agent for treating and/or preventing emesis, vomiting and/or constipation can be administered.
When the present compound is administered to a human, it can be administered orally as powders, granules, tablets, capsules, pills, solutions, or the like, or parenterally as injectables, suppositories, transdermal absorbable agents, absorbable agents, or the like. Oral agents are preferable.
In addition, the present compound can be formulated into pharmaceutical preparations by adding pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants and the like, which are suitable for formulations and, an effective amount of the present compound.
The present compound may be formulated into medical mixtures in which a compound having the opioid receptor agonistic activity and/or other agent for treating and/or preventing emesis, vomiting and/or constipation and, if necessary, various pharmaceutical additives.
A dose is different depending on state of a disease, an administration route, and an age and a weight of a patient, and is usually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day when orally administered to an adult, and is usually 0.1 μg to 10 g/day, preferably 0.1 to 2 g/day when parenterally administered.
Following Examples and Test Examples illustrate the present invention in more detail, but the present invention is not limited by these Examples.
##STR00135##
wherein Bn indicates benzyl, Et indicates ethyl, and Pri indicates isopropyl.
(First Step) 7-ethoxycarbonylnaltrexone
To a suspension of 3-O-benzyl-7-ethoxycarbonylnaltrexone described in Non-Patent Literature 2 (11.16 g, 22.15 mmol) in ethyl acetate (50 mL) and methanol (50 mL) was added palladium hydroxide (Perlman's catalyst) (1.2 g), and the mixture was vigorously stirred for 2 hours under a hydrogen atmosphere. After filtration of the catalyst, the filtrate was concentrated, and the residue was crystallized from ethyl acetate and hexane to obtain 8.96 g (92%) of the title compound as colorless crystals.
NMR (300 MHz, CDCl3) δ 0.14-0.17 (m, 2H), 0.55-0.58 (m, 2H), 0.86 (m, 1H), 1.23-1.29 (m, 3H), 1.67 (d, 1H, J=9.6 Hz), 2.02 (dd, 1H, J=1.2, 16.2 Hz), 2.20-2.79 (m, 8H), 3.08 (d, 1H, J =18.6 Hz), 3.24 (br, 1H), 4.12-4.20 (m, 2H), 4.96 (s, 1H), 5.17 (br, 1H), 6.59 (d, 1H, J=8.1 Hz), 6.72 (d, 1H, J=8.1 Hz), 12.12 (s, 1H).
Elemental analysis (C23H27NO6.0.2H2O) (Calculated value) C, 66.24; H, 6.62; N, 3.36. (Found value) C, 66.29; H, 6.50; N, 3.45.
(Second Step) 7-isopropylaminocarbonylnaltrexone
A solution of 7-ethoxycarbonylnaltrexone obtained in the first step (200 mg, 0.484 mmol), isopropylamine (0.412 mL, 4.84 mmol) and triethylamine (0.202 mL, 1.45 mmol) in 2-methoxyethanol (1.5 mL) was stirred at 180° C. for 45 minutes under microwave irradiation. After cooled to room temperature, 7 mL of 5 mol/L hydrochloric acid was added to the reaction mixture, and stirring was continued at 70° C. for 20 minutes. After the reaction solution was cooled, pH value was adjusted to 8.5 with aqueous ammonia, followed by extraction with ethyl acetate. The organic layer was washed with water, and dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 94:6) to obtain 140 mg of the title compound at a yield of 68%.
NMR (300 MHz, d6-DMSO) δ 0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J=6.6 Hz), 1.08 (d, 3H, J=6.6 Hz), 1.41 (d, 1H, J=11.4 Hz), 1.85 (d, 1H, J=15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J=18.6 Hz), 3.24 (m, 1H), 3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J=8.4 Hz), 6.56 (d, 1H, J=8.4 Hz), 7.40 (br d, 1H, J=7.2 Hz), 9.16 (s, 1H), 14.50 (s, 1H).
Elemental analysis (C24H30N2O5.0.2H2O) (Calculated value) C, 67.02; H, 7.12; N, 6.51. (Found value) C, 67.02; H, 7.20; N, 6.49.
##STR00136##
wherein Bn indicates benzyl, Me indicates methyl, Et indicates ethyl, and Pri indicates isopropyl.
(First Step) 3-O-benzyl-7-ethoxycarbonyl-6-O-methylnaltrexone
To a solution of 3-O-benzyl-7-ethoxycarbonylnaltrexone described in Non-Patent Literature 2 (504 mg, 1 mmol) in tetrahydrofuran (10 mL) were successively added 1,1′-azodicarbonylpiperidine (379 mg, 1.5 mmol), tri-n-butylphosphine (370 μL, 1.5 mmol) and methanol (41 μl, 1 mmol), and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (421 mg, 81%) as colorless oil.
1H NMR (CDCl3, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 1.26 (t, J=6.6 Hz, 3H), 1.67 (d, J=11.4 Hz, 1H), 2.15-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.93 (s, 3H), 4.05-4.20 (m, 2H), 4.86 (br s, 1H), 5.15 (s, 2H), 5.18 (br s, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H), 7.28-7.45 (m, 5H)
(Second Step) 3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone
To a mixed solution of 3-O-benzyl-7-ethoxycarbonyl-6-O-methylnaltrexone obtained in the first step (145 mg, 0.28 mmol) in methanol (6 mL) and dioxane (2 mL) was added a 50% potassium hydroxide aqueous solution (2 mL), and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was cooled to room temperature, and adjusted to pH=4 with 0.5M an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was successively washed with water, brinebrine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crystalline residue, 3-O-benzyl-7-carboxy-6-O-methylnaltrexone was used in the next reaction without purification. To a solution of the above residue in dimethylformamide (3 mL) were successively added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (40 mg, 0.2 mmol), 1-hydroxybenzotriazole (27 mg, 0.2 mmol) and isopropylamine (16 μL, 0.182 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and this was extracted with ethyl acetate, and the organic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain the title compound (39 mg, 44%) as a colorless foam.
1H NMR (CDCl3, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 1.13 (d, J=2.1 Hz, 3H), 1.15 (d, J=1.8 Hz, 3H), 1.58 (d, J=11.4 Hz, 1H), 2.08-2.80 (m, 8H), 2.99-3.30 (m, 2H), 3.94 (s, 3H), 4.06 (m, 1H), 4.83 (br s, 1H), 5.14 (d, J=2.4 Hz, 2H), 5.23 (br s, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 7.28-7.45 (m, 6H)
(Third Step) 7-isopropylaminocarbonyl-6-O-methylnaltrexone
To a solution of 3-O-benzyl-7-isopropylaminocarbonyl-6-O-methylnaltrexone obtained in the second step (33 mg, 0.073 mmol) in tetrahydrofuran (5 mL) was added palladium hydroxide (33 mg), and the mixture was stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain the title compound (13 mg, 41%) as a colorless foam.
1H NMR (CDCl3, δ ppm): 0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m, 1H), 1.12 (d, J=0.9 Hz, 3H), 1.14 (d, J=0.9 Hz, 3H), 1.66 (d, J=11.4 Hz, 1H), 2.06-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (m, 1H), 4.80 (br s, 1H), 5.26 (br s, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H)
##STR00137##
wherein Bn indicates benzyl, Me indicates methyl, and Et indicates ethyl.
(First Step)
A solution of compound (1) (28.7 g, 57.0 mmol) in tetrahydrofuran (250 mL) was cooled to −10° C. and to the solution were 1,1′-azodicarbonylpiperidine (21.6 g, 85.5 mol), tri-n-butylphosphine (21.4 mL, 85.5 mmol) and benzyl alcohol (6.50 mL, 62.7 mmol) successively added, and the mixture was stirred at room temperature for 6 hours and 45 minutes. The reaction solution was filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform/methanol=50/1) to obtain quantitatively the objective compound (2) (33.8 g) as a pale yellow oil.
1H NMR (CDCl3, δ ppm): 0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.88 (m, 1H), 0.94 (t, J=7.2 Hz, 3H), 1.20-3.60 (m, 11H), 4.14 (q, J=7.2 Hz, 2H), 5.10-5.35 (m, 5H), 6.58 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 7.15-7.50 (m, 10H)
(Second Step)
To a mixed solution of compound (2) obtained in the first step (33.8 g, 57.0 mmol) in methanol (130 mL) and dioxane (43 mL) was added a 4N-potassium hydroxide aqueous solution (43 mL), and the mixture was stirred at 50° C. for 14 hours and 35 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure, and the residue was adjusted to pH=3 to 4 with ice-water and 2N-hydrochloric acid, followed by extraction with a mixed solution of ethyl acetate and tetrahydrofuran. The organic layer was successively washed with water, and brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was converted into a powder with ether to obtain the objective compound (3) (24.8 g, 77%) as a colorless powder.
1H NMR (DMSO-d6, δ ppm): 0.20-0.40 (m, 2H), 0.50-0.65 (m, 2H), 0.95 (m, 1H), 1.30-3.60 (m, 11H), 5.00-5.25 (m, 5H), 5.39 (s, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 7.27-7.52 (m, 10H)
(Third Step)
To a solution of compound (3) obtained in the second step (350 mg, 0.619 mmol) in tetrahydrofuran (4 mL) were successively added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg, 0.743 mmol), 1-hydroxybenzotriazole (100 mg, 0.743 mmol.), dimethylglycine methyl ester hydrochloride (114 mg, 0.743 mmol) and N-methyl-morpholine (82 μL, 0.743 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice-water and a saturated sodium bicarbonate aqueous solution, followed by extracted with ethyl acetate, and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated under the reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain the objective compound (4) (300 mg, 73%) as a pale yellow foam.
1H NMR (CDCl3, δ ppm): 0.08-0.20 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m, 1H), 1.13 (s, 3H), 1.22 (s, 3H), 1.55-2.80 (m, 11H), 3.62 (s, 3H), 4.85 (br s, 1H), 5.13-5.40 (m, 5H), 6.58 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 7.26-7.48 (m, 10H), 7.94 (s, 1H)
(Fourth Step)
To a solution of compound (4) obtained in the third step (290 mg, 0.436 mmol) in methanol (4 mL) was added palladium hydroxide (60 mg), followed by stirring for 3 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was crystallized with hexane/ethyl acetate to obtain the objective compound (I-49) (181 mg, 86%) as colorless crystals.
1H NMR (DMSO-d6, δ ppm): 0.10-0.20 (m, 2H), 0.40-0.57 (m, 2H), 0.84 (m, 1H), 1.33 (s, 3H), 1.37 (s, 3H), 1.40-3.40 (m, 11H), 3.55 (s, 3H), 4.72 (s, 1H), 4.77 (br s, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 7.68 (br s, 1H), 9.18 (br s, 1H), 13.78 (br s, 1H)
According to the same procedure, other compounds (I) can be synthesized. Structural formulas and physical constants are shown below.
In Tables, Me indicates methyl, Et indicates ethyl, Pri indicates isopropyl, and Ph indicates phenyl.
In addition, in Tables,
##STR00138##
TABLE 9
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-1
##STR00139##
0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.87 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.68 (d, J = 11.4 Hz, 1H), 2.20-2.80 (m, 7H), 3.00-3.35 (m, 5H), 4.94 (s, 1H), 5.40 (m, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 14.20 8br s, 1H)
I-2
##STR00140##
0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.85 (m, 1H), 1.41 (d, J = 11.4 Hz, 1H), 1.90-3.40 (m, 14H), 4.71 (s, 1H), 4.73 (br s, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 7.77 (br s, 1H)
I-3
##STR00141##
(CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.81- 0.98 (m, 4H), 1.24-1.74 (m, 6H), 2.21-2.77 (m, 7H), 3.05-3.30 (m, 5H), 4.93 (s, 1H), 5.40 (br t, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 14.21 (s, 1H).
I-4
##STR00142##
0.12-0.15 (m, 2H), 0.44-0.53 (m, 2H), 0.83 (m, 1H), 1.02 (d, 3H, J = 6.6 Hz), 1.08 (d, 3H, J = 6.6 Hz), 1.41 (d, 1H, J = 11.4 Hz), 1.85 (d, 1H, J = 15.6 Hz), 2.04-2.62 (m, 8H), 3.04 (d, 1H, J = 18.6 Hz), 3.24 (m, 1H), 3.96 (m, 1H), 4.71 (s, 1H), 4.74 (s, 1H), 6.51 (d, 1H, J = 8.4 Hz), 6.56 (d, 1H, J = 8.4 Hz), 7.40 (br d, 1H, J = 7.2 Hz), 9.16 (s, 1H), 14.50 (s, 1H)
I-5
##STR00143##
0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.40-1.60 (m, 4H), 1.83-3.20 (m, 11H), 4.41 (br s, 1H), 4.72 (s, 1H), 4.74 (s, 1H), 6.51 (d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H). 9.15 (br s, 1H), 14.42 (s, 1H).
I-6
##STR00144##
0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.42 (d, J = 11.7 Hz, 1H), 1.83-2.64 (m, 10H), 2.10 (s, 6H), 3.00-3.18 (m, 3H), 4.72 (s, 1H), 4.74 (s, 1H), 6.51 (d, J = 8.7 Hz), 6.56 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 9.10 (br s, 1H).
I-7
##STR00145##
0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 1.90 (m, 1H), 1.57 (dd, J = 2.4, 12.6 Hz, 2H), 1.85-2.80 (m, 10H), 3.00-3.25 (m, 3H), 3.35-3.60 (m, 3H), 4.20 (m, 1H), 4.76 (br s, 1H), 5.85 (br s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H)
TABLE 10
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-8
##STR00146##
0.10-0.20 (m, 2H), 0.45-0.68 (m, 2H), 1.88 (m, 1H), 1.35 (d, J = 11.4 Hz, 1H), 1.65-2.20 (m, 4H), 2.30-3.60 (m, 13H), 4.29 (dd, J = 4.8, 12.6 Hz, 1H), 5.08 (s, 1H), 5.23 (br s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 9.25 (br s, 1H)
I-9
##STR00147##
(CDCl3) 0.10-0.25 (m, 2H), 0.50-0.62 (m, 2H), 0.85 (m, 1H), 1.62-2.77 (m, 6H), 3.07 (d, J = 18.6 Hz, 1H), 3.23 (d, J = 7.2 Hz, 1H), 4.42 (d, J = 5.4 Hz, 2H), 4.93 (s, 1H), 5.66 (br s, 1H), 6.55 (d, J = 8.7 Hz), 6.72 (d, J = 8.7 Hz, 1H), 7.22-7.39 (m,5H), 14.15 (s, 1H).
I-10
##STR00148##
0.10-0.24 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 11.1 Hz, 1H), 1.70-3.40 (m, 10H), 4.78 (s, 1H), 4.82 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 7.05 (m, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 9.14 (s, 1H), 9.24 (br s, 1H), 13.90 (br s, 1H)
I-11
##STR00149##
0.10-0.22 (m, 2H), 0.44-0.58 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.75-3.40 (m, 10H), 4.78 (s, 1H), 4.83 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 8.7 Hz, 2H), 7.48- 7.56 (m, 2H), 9.17 (s, 1H), 9.27 (br s, 1H), 13.90 (br s, 1H)
I-12
##STR00150##
0.10-0.18 (m, 2H), 0.52-0.60 (m, 2H), 0.80-0.98 (m, 2H), 0.98-3.21 (m, 26H), 4.41 (br, s, 1H), 4.70 (d, J = 12.3 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H)
I-13
##STR00151##
0.10-0.25 (m, 2H), 0.50-0.60 (m, 2H), 0.87 (m, 1H), 1.58 (d, J = 111.7 Hz, 1H), 2.05-2.50 (m, 6H), 2.55- 2.90 (m, 5H), 3.00-3.30 (m, 2H), 4.42 (s, 1H), 4.81- 4.87 (m, 2H), 5.55 (br s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 7.20-7.40 (m,5H)
I-14
##STR00152##
0.10-0.22 (m, 2H), 0.45-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 2.10-3.40 (m, 10H), 3.78 (s, 3H), 4.96 (s, 1H), 6.36 (br s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.98 (br s, 1H), 7.29 (d, J = 9.0 Hz, 2H), 14.00 (br s, 1H)
TABLE 11
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-15
##STR00153##
0.05-0.20 (m, 2H), 0.45-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 2.00-3.35 (m, 10H), 3.78 (s, 3H), 4.34 (d, J = 5.1 Hz, 2H), 4.91 (s, 1H), 5.61 (br s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 14.13 (br s, 1H)
I-16
##STR00154##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.84 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.30-7.38 (m, 2H), 7.53-7.60 (m, 2H), 9.17 (s, 1H), 9.28 (br s, 1H), 13.80 (br s, 1H)
I-17
##STR00155##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 13H), 4.77 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 9.17 (s, 1H), 9.27 (br s, 13.90 (br s, 1H)
I-18
##STR00156##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.65-3.40 (m, 10H), 3.80 (s, 3H), 4.81 (br s, 2H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.87 (m, 1H), 6.98-7.10 (m, 2H), 7.82 (m, 1H), 9.19 (s, 1H), 9.70 (br s, 1H), 12.90 (br s, 1H)
I-19
##STR00157##
I-20
##STR00158##
0.12-0.14 (d, J = 4.5 Hz, 2H), 0.46-0.52 (t, J = 8.3 Hz, 2H), 0.71- 0.85 (m, 4H), 0.98-1.06 (dd, J = 6.8, 17.3 Hz, 4H), 1.35-1.45 (m, 4H), 1.82-1.92 (m, 2H), 2.44-2.61 (m), 3.04 (d, J = 18.9 Hz, 1H), 3.19-3.24 (m, 1H), 3.71-3.82 (m, 1H), 4.71-4.76 (m, 2H), 6.50- 6.57 (dd, J = 8.1, 14.4 Hz, 2H), 7.31-7.38 (m, 1H), 9.15 (br s, 1H), 14.52 (br s, 1H)
I-21
##STR00159##
0.12-0.14 (d, J = 4.2 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.69-0.86 (m, 6H), 1.32-1.47 (m, 5H), 1.88 (d, J = 15.3 Hz, 1H), 2.06-2.30 (m, 4H), 2.45-2.61 (m), 3.04 (d, J = 18.0 Hz, 1H), 3.19-3.24 (m, 1H), 4.71-4.75 (m, 2H), 6.05-6.58 (dd, J = 8.8, 14.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 9.15 (br s, 1H), 14.55 (br s, 1H)
TABLE 12
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-22
##STR00160##
0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H), 1.06 (m, 1H), 1.16-1.28 (m, 4H), 1.39-1.43 (d, J = 11.4 Hz, 1H), 1.54-1.70 (m, 6H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.08-2.60 (m, 6H), 3.00-3.07 (d, J = 18.6 Hz, 1H), 3.17-3.24 (m, 1H), 3.60 (br s, 1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.37 (d, J = 9.0 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H)
I-23
##STR00161##
0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.83-0.92 (m, 4H), 1.19-1.70 (m, 9H), 1.83-1.93 (m, 1H), 2.06-2.61 (m, 9H), 3.01- 3.07 (d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 4.2 Hz, 1H), 3.67 (m, 1H), 4.71-4.76 (m, 2H), 6.52-6.55 (dd, J = 8.1, 14.4 Hz, 2H), 9.13 (br s, 1H), 14.48 (br s, 1H)
I-24
##STR00162##
0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.0 Hz, 2H), 0.83-0.87 (m, 1H), 1.34-1.55 (m, 12H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.09-2.60 (m, 9H), 3.00-3.07 (d, J = 18.3 Hz, 1H), 3.17-3.19 (d, J = 6.0 Hz, 1H), 3.78-3.81 (m, 1H), 4.71-4.76 (m, 2H), 6.49- 6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.39 (d, J = 8.1 Hz, 1H), 9.13 (br s, 1H), 14.46 (br s, 1H)
I-25
##STR00163##
0.13-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 7.8 Hz, 2H), 0.85 (m, 1H), 1.39-1.43 (d, J = 11.1 Hz, 1H), 1.56-1.64 (m, 2H), 1.85- 2.32 (m, 12H), 2.43-2.61 (m), 3.01-3.07 (d, J = 18.3 Hz, 1H), 3.18-3.20 (d, J = 6.0 Hz, 1H), 4.16-4.27 (m, 1H), 4.72-4.73 (m, 2H), 6.50-6.57 (dd; J = 8.1, 18.9 Hz, 2H), 7.77 (d, J = 7.5 Hz, 1H), 9.12 (br s, 1H), 14.41 (br s, 1H)
I-26
##STR00164##
0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46 (d, J = 11.2 Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.17-3.40 (m, 6H), 3.24 (s, 3H), 4.77 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br t, 1H), 9.15 (s, 1H), 14.33 (s, 1H).
I-27
##STR00165##
0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.90 (m, 1H), 1.10 (t, J = 6.8 Hz, 3H), 1.46 (d, J = 11.2 Hz, 1H), 1.92 (d, J = 15.6 Hz, 1H), 2.04-2.66 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.17-3.46 (m, 8H),, 4.77 (s, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.77 (br, 1H), 9.15 (s, 1H), 14.32 (s, 1H).
I-28
##STR00166##
0.16-0.17 (m, 2H), 0.50-0.63 (m, 2H), 0.89 (m, 1H), 1.46 (d, J = 12.0 Hz, 1H), 1.92 (d, J = 15.2 Hz, 1H), 2.06 (s, 3H), 2.06-2.70 (m, 6H), 3.08 (d, J = 18.4 Hz, 1H), 3.20-3.32 (m, 6H), 4.77 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.76 (br s, 1H), 9.16 (s, 1H), 14.31 (s, 1H).
TABLE 13
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-29
##STR00167##
0.17-0.18 (m, 2H), 0.51-0.57 (m, 2H), 0.90 (m, 1H), 1.46 (d, J = 11.6 Hz, 1H), 1.93 (d, J = 16.0 Hz. 1H), 2.11-2.78 (m, 6H), 3.08 (d, J = 18.4 Hz, 1H), 3.21 (d, J = 6.0 Hz, 1H), 3.27-3.32 (m, 5H), 4.77 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.19-7.32 (m, 5H), 7.86 (br s, 1H), 9.16 (s, 1H), 14.38 (s, 1H).
I-30
##STR00168##
0.16-0.19 (m, 2H), 0.48-0.57 (m, 2H), 0.88 (m, 1H), 1.46 (d, J = 11.2 Hz, 1H), 1.94 (d, J = 15.6 Hz, 1H), 2.11-2.71 (m, 6H), 3.08 (d, J = 18.8 Hz, 1H), 3.49-3.51 (m, 2H), 3.96-4.4.05 (m, 2H), 4.79 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.94-6.97 (m, 3H), 7.27-7.34 (m, 2H), 7.94 (br, 1H), 9.17 (s, 1H), 14.28 (s, 1H).
I-31
##STR00169##
0.10-0.28 (m, 2H), 0.44-0.65 (m, 2H), 0.94 (m, 1H), 1.50 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.80 (m, 4H), 9.16 (s, 1H), 9.32 (s, 1H), 13.90 (br s, 1H)
I-32
##STR00170##
0.10-0.25 (m, 2H), 0.42-0.62 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.75 (br s, 1H), 4.84 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.41-7.54 (m, 4H), 9.17 (s, 1H), 9.28 (s, 1H), 13.85 (br s, 1H)
I-33
##STR00171##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.81 (s, 1H), 5.98 (s, 2H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.82-6.95 (m, 2H), 7.15 (d, J = 1.8 Hz, 1H), 9.16 (s, 1H), 9.26 (s, 1H), 13.98 (br s, 1H)
I-34
##STR00172##
0.20-0.40 (m, 2H), 0.45-0.65 (m, 2H), 0.96 (m, 1H), 1.50 (m, 1H), 1.70-3.40 (m, 10H), 4.65 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.60-7.80 (m, 4H), 9.17 (s, 1H), 9.30 (s, 1H), 14.00 (br s, 1H)
I-35
##STR00173##
0.10-0.20 (m, 2H), 0.50-0.62 (m, 2H), 0.88 (m, 1H), 1.65 (d, J = 10.8 Hz, 1H), 2.00-3.60 (m, 14H), 3.78 (s, 3H), 4.93 (s, 1H), 5.46 (br s, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 14.17 (br s, 1H)
TABLE 14
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-36
##STR00174##
0.10-0.25 (m, 2H), 0.43-0.63 (m, 2H), 0.88 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 3.71 (s, 3H), 4.77 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.64 (m, 1H), 7.00-7.25 (m, 3H), 9.17 (s, 1H), 9.27 (s, 1H), 13.90 (br s, 1H)
I-37
##STR00175##
0.12-0.14 (d, J = 4.5 Hz, 2H), 0.49 (t, J = 8.1 Hz, 2H), 0.85 (m, 1H), 1.06 (m, 1H), 1.39-1.62 (m, 18H), 1.84-1.89 (d, J = 15.6 Hz, 1H), 2.08-2.34 (m, 5H), 2.43-2.54 (m), 2.58- 2.60 (d, J = 6.9 Hz, 1H), 3.00-3.07 (d, J = 18.6 Hz, 1H), 3.18-3.20 (d, J = 6 Hz, 1H), 3.87 (br s, 1H), 4.71-4.76 (m, 2H), 6.49-6.57 (dd, J = 8.1, 14.7 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 9.13 (br s, 1H), 14.47 (br s, 1H)
I-38
##STR00176##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.89 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.82 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 9.17 (s, 1H), 9.27 (s, 1H), 14.00 (br s, 1H)
I-39
##STR00177##
0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.87 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 16H), 4.76 (s, 1H), 4.80 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 9.10 (br s, 2H), 14.20 (br s, 1H)
I-40
##STR00178##
0.10-0.30 (m, 2H), 0.45-0.65 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.77 (s, 1H), 4.85 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.25-7.35 (m, 2H), 7.64 (d, J = 9.0 Hz, 2H), 9.18 (s, 1H), 9.29 (s, 1H), 13.90 (br s,
TABLE 15
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-41
##STR00179##
0.20-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.96 (m, 1H), 1.50 (m, 1H), 1.70-3.40 (m, 13H), 4.67 (br s, 1H), 4.88 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.76 (s, 4H), 9.18 (s, 1H), 9.31 (s, 1H), 14.00 (br s, 1H)
I-42
##STR00180##
0.18 (br, s, 2H), 0.42-0.63 (m, 3H), 0.80-0.97 (m, 2H), 1.20- 3.43 (m, 24H), 4.92 (s, 1H), 5.89 (br, s, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 14.13 (br, s, 1H)
I-43
##STR00181##
0.12-0.19 (m, 2H), 0.41-0.58 (m, 2H), 0.74 (d, J = 3.3 Hz, 6H), 1.43 (m, 1H), 1.88-3.41 (m, 16H), 4.56 (br, s, 1H), 4.65-4.80 (m, 2H), 6.50-6.62 (m, 2H), 7.51 (br, s, 1H), 9.13 (s, 1H), 14.23 (br, s, 1H)
I-44
##STR00182##
0.10-0.15 (m, 2H), 0.50-0.70 (m, 2H), 0.85 (m, 1H), 1.12 (d, J = 0.9 Hz, 3H), 1.14 (d, J = 0.9 Hz, 3H), 1.66 (d, J = 11.4 Hz, 1H), 2.06-2.80 (m, 8H), 3.00-3.30 (m, 2H), 3.92 (s, 3H), 4.05 (m, 1H), 4.80 (br s, 1H), 5.26 (br s, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H)
I-45
##STR00183##
TABLE 16
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-46
##STR00184##
0.15-0.35 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.50 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.54-7.74 (m, 4H), 9.16 (s, 1H), 9.27 (s, 1H), 14.00 (br s, 1H)
I-47
##STR00185##
0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.86 (m, 1H), 1.42 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 3.61 (s, 3H), 3.82 (d, J = 5.7 Hz, 2H), 4.77 (s, 2H), 6.53 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.21 (br t, J = 5.7 Hz, 1H), 9.17 (s, 1H), 13.87 (br s, 1H)
I-48
##STR00186##
0.10-0.20 (m, 2H), 0.50-0.65 (m, 2H), 0.89 (m, 1H), 0.90 (d, J = 4.5 Hz, 3H), 0.94 (d, J = 4.5 Hz, 3H), 1.45 (s, 9H), 1.66 (d, J = 10.8 Hz, 1H), 2.10-3.40 (m, 11H), 4.43 (dd, J = 4.5, 8.1 Hz, 1H), 4.94 (s, 1H), 6.00 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 13.99 (br s, 1H)
I-49
##STR00187##
0.10-0.30 (m, 2H), 0.45-0.70 (m, 2H), 0.90 (m, 1H), 1.34 (s, 3H), 1.38 (s, 3H), 1.50-3.40 (m, 11H), 3.56 (s, 3H), 4.77 (br s, 2H), 6.58 (br s, 2H), 7.69 (br s, 1H), 9.20 (br s, 1H), 13.76 (br s, 1H)
I-50
##STR00188##
0.10-0.20 (m, 2H), 0.40-0.60 (m, 2H), 0.88 (m, 1H), 1.44 (d, J = 11.7 Hz, 1H), 1.90-3.40 (m, 10H), 3.68 (d, J = 4.5 Hz, 2H), 4.77 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 8.00 (br t, J = 4.5 hz, 1H), 9.18 (br s, 1H), 14.00 (br s, 1H)
TABLE 17
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-51
##STR00189##
##STR00190##
0.30-0.50 (m, 2H), 0.55-0.75 (m, 2H), 0.89 (d, J = 3.3 Hz, 3H), 0.91 (d, J = 3.3 Hz, 3H), 1.04 (m, 1H), 1.65 (d, J = 13.5 Hz, 1H), 2.00- 3.92 (m, 11H), 4.10 (t, J = 6.6 Hz, 1H), 4.95 (s, 1H), 6.64 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 9.43 (s, 1H), 13.66 (br s, 1H)
I-52
##STR00191##
0.10-0.25 (m, 2H), 0.45-0.60 (m, 2H), 0.89 (m, 1H), 1.34 (s, 3H), 1.36 (s, 3H), 1.46 (d, J = 9.6 Hz, 1H), 1.90-3.40 (m, 10H), 4.75 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 9.21 (br s, 1H), 14.11 (br s, 1H)
I-53
##STR00192##
0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (m, 1H), 1.63-2.10 (m, 6H), 2.30-2.70 (m, 4H), 2.96-3.58 (m, 6H), 4.06- 4.23 (m, 3H), 5.04 (s, 1H), 5.23 (br, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 8.08 (br, 1H), 9.23 (br, 1H).
I-54
##STR00193##
0.13-0.14 (m, 2H), 0.47-0.49 (m, 2H), 0.88 (m, 1H), 1.30 (d, J = 12.0 Hz, 1H), 1.63-2.12 (m, 6H), 2.28-2.70 (m, 4H), 2.97-3.53 (m, 6H), 4.06-4.23 (m, 3H), 5.06 (s, 1H), 5.22 (br, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H), 9.23 (br, 1H), 10.97 (s, 1H).
TABLE 18
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-55
##STR00194##
0.10-0.25 (m, 2H), 0.40-0.60 (m, 2H), 0.90 (m, 1H), 1.45 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.42 (s, 2H), 4.77 (s, 1H), 5.12 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.28 (s, 1H), 14.00 (br s, 1H)
I-56
##STR00195##
0.10-0.40 (m, 2H), 0.45-0.70 (m, 2H), 0.92 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.49 (d, J = 9.0 Hz, 1H), 1.70- 3.40 (m, 10H) 4.26 (q, J = 7.2 Hz, 2H), 4.72 (br s, 1H), 4.86 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.0 Hz, 2H), 9.18 (s, 1H), 9.29 (s, 1H)
I-57
##STR00196##
0.25-0.40 (m, 2H), 0.50-0.70 (m, 2H), 1.00 (m, 1H), 1.56 (d, J = 10.8 Hz, 1H), 1.70-3.40 (m, 10H), 4.87 (s, 1H), 4.92 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 9.33 (br s, 2H)
I-58
##STR00197##
0.08-0.20 (m, 2H), 0.43-0.57 (m, 2H), 0.88 (m, 1H), 1.22-3.40 (m, 11H), 4.76 (s, 1H), 4.84 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.62-6.81 (m, 3H), 7.06-7.16 (m, 2H), 7.73 (s, 1H), 9.16 (s, 1H), 9.61 (s, 1H), 13.80 (br s, 1H)
I-59
##STR00198##
0.08-0.10 (m, 2H), 0.38-0.58 (m, 2H), 0.86 (m, 1H), 1.22-3.40 (m, 17H), 4.71 (s, 2H), 6.51 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 8.1 Hz, 1H), 8.58 (s, 1H), 9.15 (s, 1H), 14.30 (br s, 1H)
TABLE 19
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-60
##STR00199##
0.10-0.20 (m, 2H), 0.45-0.55 (m, 2H), 0.88 (m, 1H), 1.81 (t, J = 7.2 Hz, 3H), 1.20-3.75 (m, 20H), 4.07 (q, J = 7.2 Hz, 2H), 5.13 (s, 1H), 5.21 (br s, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 9.21b (br s, 1H)
I-61
##STR00200##
0.11-0.39 (m, 2H), 0.53-0.70 (m, 2H), 0.95 (m, 1H), 1.10-1.20 (m, 3H), 1.66-1.73 (m, 1H), 1.82-3.99(m, 24H), 4.90 (s, 1H), 6.32 (br, s, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.68-6.73 (m, 1H), 14.03 (br, s, 1H)
I-62
##STR00201##
0.10-0.18 (m, 2H), 0.42-0.56 (m, 2H), 0.85 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 1.41 (m, 1H), 1.88 (d, J = 15.6 Hz, 1H), 2.04- 2.31 (m, 4H), 2.42-2.62 (m, 6H), 3.04 (d, J = 18.0 Hz, 1H), 3.17-3.35 (m, 7H), 3.87 (m, 1H), 4.64 (t, J = 5.7 Hz, 1H), 4.72 (s, 1H), 6.50-6.57 (m, 2H), 7.27 (d, J = 8.1 Hz, 1H), 9.13 (s, 1H), 14.45 (s, 1H)
I-63
##STR00202##
0.13 (d, J = 4.2 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H), 1.41 (d, J = 10.8 Hz, 1H), 1.89 (d, J = 15.9 Hz, 1H), 2.04-2.32 (m, 4H), 2.43-2.63 (m, 3H), 3.04 (d, J = 18.3 Hz, 1H), 3.19-3.40 (m, 11H), 3.86 (m, 1H), 4.72 (s, 1H), 6.50-6.58 (m, 2H), 7.24 (m, 1H), 9.14 (s, 1H), 14.41 (br, s, 1H)
TABLE 20
Compound
No.
Chemical structure
NMR 1H-NMR (d6-DMSO) δ)
I-64
##STR00203##
0.13 (d, J = 4.8 Hz, 2H), 0.43-0.55 (m, 2H), 0.85 (m, 1H), 1.41 (d, J = 12.3 Hz, 1H), 1.92 (d, J = 16.2 Hz, 1H), 2.06- 2.32 (m, 4H), 2.43-2.61 (m, 3H), 3.04 (d, J = 18.3 Hz, 1H), 3.20 (d, J = 6.6 Hz, 1H), 3.33-3.44 (m, 4H), 3.82 (m, 1H), 4.59 (t, J = 5.7 Hz, 1H), 4.68 (t, J = 5.7 Hz, 1H), 4.73 (s, 2H), 6.50-6.59 (m, 2H), 7.14 (br, s, 1H), 9.14 (s, 1H), 14.33 (br, s, 1H)
I-65
##STR00204##
0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.35 (br s, 9H), 1.71-3.49 (m, 14H), 3.95- 4.20 (m, 3H), 5.10 (br, 1H), 5.26 (br, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 7.10 (br, 1H), 8.35 (s, 1H), 9.24 (s, 1H).
I-66
##STR00205##
0.41 (m, 1H), 0.50 (m, 1H), 0.60 (m, 1H), 0.69 (m, 1H), 1.08 (m, 1H), 1.56 (m, 1H), 1.76-4.29 (m, 17H), 5.19 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 8.14 (br, 1H), 8.20 (br, 1H), 8.98 (br, 1H).
I-67
##STR00206##
0.41 (m, 1H), 0.50 (m, 1H), 0.59 (m, 1H), 0.69 (m, 1H), 1.09 (m, 1H), 1.30-4.29 (m, 18H), 5.19 (s, 1H), 5.75 (br, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 8.21 (br, 1H), 8.26 (br, 1H), 8.99 (br, 1H).
TABLE 21
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-68
##STR00207##
0.17-0.18 (m, 2H), 0.51-0.53 (m, 2H), 0.92 (m, 1H), 1.34 (m, 1H), 1.43 (br s, 9H), 1.71-2.03 (m, 5H), 2.18-2.74 (m, 4H), 2.92-3.69 (m, 5H), 3.95-4.20 (m, 2H), 5.07 (s, 1H), 5.26 (br, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.20 (br, 1H), 9.25 (s, 1H).
I-69
##STR00208##
0.10-0.26 (m, 2H), 0.42-0.60 (m, 2H), 0.90 (m, 1H), 1.47 (d, J = 10.5 Hz, 1H), 1.90-3.40 (m, 10H), 3.84 (s, 3H), 4.81 (br s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 7.80 (br s, 1H), 8.08 (br s, 1H), 9.18 (br s, 1H), 11.60 (br s, 1H)
I-70
##STR00209##
0.10-0.20 (m, 2H), 0.40-0.55 (m, 2H), 0.88 (m, 1H), 1.30- 4.35 (m, 20H), 5.13 (s, 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 9.20 (br s, 1H)
I-71
##STR00210##
0.25-0.45 (m, 2H), 0.45-0.70 (m, 2H), 0.97 (m, 1H), 1.64 (d, J = 11.1 Hz, 1H), 2.00-3.40(m, 10H), 4.07 (br s, 1H), 4.97 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 5.4 Hz, 1H), 9.44 (br s, 1H), 13.40 (br s, 1H)
I-72
##STR00211##
0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 2H), 0.79-0.92 (m, 13H), 1.25 (br, s, 1H), 1.41 (m, 1H), 1.907 (s, 1H), 2.11- 2.64 (m, 8H), 3.03 (m, 1H), 3.21-3.77 (m, 8H), 3.03 (m, 1H) 3.21-3.77 (m, 4H), 4.53 (br, s, 1H), 4.72-4.80 (m, 2H), 6.50-6.58 (m, 2H), 6.95-7.22 (m, 2H), 9.13 (s, 1H), 14.39 (br, s, 1H)
TABLE 22
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-73
##STR00212##
0.14 (d, J = 4.5 Hz, 2H), 0.40-0.58 (m, 3H), 0.74-1.01 (m, 10H), 1.25-1.61 (m, 4H), 1.88 (m, 1H), 2.06-2.62 (m, 8H), 3.03 (m, 1H), 3.21 (d, J = 6.0 Hz, 1H), 3.45 (t, J = 5.4 Hz, 2H) 3.68 (m, 1H), 4.57 (m, 1H), 4.72 (s, 1H), 4.76 (br, s, 1H), 6.51-6.58 (m, 2H), 7.14-7.27 (m, 2H), 9.15 (s, 1H), 14.44 (s, 1H)
I-74
##STR00213##
0.16-0.18 (m, 2H), 0.52 (br d, J = 7.6 Hz, 2H), 0.92(m, 1H), 1.35 (d, J = 11.2 Hz, 1H), 1.72-3.48 (m, 16H), 4.11-4.29 (m, 3H), 4.73-5.25 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 9.23 (s, 1H), 11.16 (s, 1H).
I-75
##STR00214##
0.14-0.15 (m, 2H), 0.43-0.57 (m, 2H), 0.87 (m, 1H), 1.44 (d, J = 11.2 Hz, 1H), 1.97 (d, J = 15.6 Hz, 1H), 2.08-3.22 (m, 10H), 4.15-4.48 (m, 2H), 4.76 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.75 (m, 1H), 8.48-8.54 (m, 2H).
I-76
##STR00215##
0.16-0.71 (m, 2H), 0.50-0.56 (m, 2H), 0.89 (m, 1H), 1.43 (br d, 1H), 1.97 (d, J = 15.6 Hz, 1H), 2.11-3.21 (m, 10H), 4.30-4.46 (m, 2H), 4.77 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 7.29 (s, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 8.42 (br, 1H), 9.17 (br, 1H), 14.19 (s, 1H).
TABLE 23
Compound
No.
Chemical structure
NMR (1H-NMR (d6-DMSO) δ)
I-77
##STR00216##
0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.88 (m, 1H), 1.45 (d, 2 = 11.1 Hz, 1H), 1.70-3.40 (m, 13H), 4.78 (s, 1H), 4.81 (s, 1H), 6.53 (d, 2 = 8.1 Hz, 1H), 6.58 (d, 2 = 8.1 Hz, 1H), 7.46 (d, 2 = 9.0 Hz, 2H), 7.48 (d, 2 = 9.0 Hz, 2H), 9.15 (s, 1H), 9.25 (s, 1H), 9.88 (s, 1H), 14.00 (br s, 1H)
I-78
##STR00217##
0.10-0.25 (m, 2H), 0.44-0.60 (m, 2H), 0.89 (m, 1H), 1.17 (t, 2 = 7.2 Hz, 3H), 1.45 (d, 2 = 11.4 Hz, 1H), 1.70-3.40 (m, 10H), 3.60 (s, 2H), 4.06 (q, 2 = 7.2 Hz, 2H), 4.78 (s, 1H), 4.83 (s, 1H), 6.58 (d, 2 = 8.1 Hz, 1H), 7.17 (d, 2 = 8.7 Hz, 2H), 7.45 (d, 2 = 8.7 Hz, 2H), 9.16 (s, 1H), 9.26 (s, 1H), 13.95 (br s, 1H)
I-79
##STR00218##
0.12-0.30 (m, 2H), 0.44-0.62 (m, 2H), 0.90 (m, 1H), 1.48 (d, J = 11.4 Hz, 1H), 1.70-3.40 (m, 10H), 3.51 (s, 2H), 4.81 (s, 1H), 6.55 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 9.20 (s, 1H), 9.40 (br s, 1H), 14.00 (br s, 1H)
I-80
##STR00219##
0.10-0.17 (m, 2H), 0.46-0.52 (m, 2H), 0.86 (m, 1H), 1.41 (d, J = 13.2 Hz, 1H), 1.87 (m, 1H), 2.09-2.64 (m, 8H), 3.00-3.50 (m, 15H), 4.57 (m, 1H), 4.73 (br, s, 2H), 6.50-6.57 (m, 2H), 7.73 (br, s, 1H), 9.14 (s, 1H), 14.38 (br, s, 1H)
I-81
##STR00220##
0.30-0.50 (m, 2H), 0.50-0.70 (m, 2H) 1.05 (m, 1H), 1.50-3.40 (m, 11H), 4.58 (s, 1H), 5.39 (s, 1H), 6.52 (d, J = 6.0 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 6.84 (br s, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 9.15 (m, 1H)
TABLE 24
Compound
NMR
No.
Chemical structure
(1H-NMR (d6-DMSO) δ)
I-82
##STR00221##
1H-NMR (CDCl3 + CD3OD) d: 0.17 (brs, 2H), 0.59 (brs, 2H), 0.89 (brs, 1H), 1.71 (d, J = 10.8 Hz, 1H), 2.17 (d.d, J = 17.1 & 1.8 Hz, 1H), 2.22- 2.57 (m, 4H), 2.60-2.84 (m, 3H), 3.06 (d, J = 15.6 Hz, 1H), 3.24 (brs, 1H), 4.07 (s, 3H), 5.31 (s, 1H), 6.56 (d, J = 8.4 Hz, 1 Hz, 1H), 7.02-7.10 (m, 1H), 7.26-7.32 (m, 2H), 7.39 (d.d, J = 8.4 & 0.9 Hz, 2H), 9.61 (s, 1H).
I-83
##STR00222##
1H-NMR (CDCl3 + CD3OD) d: 0.15 (brs, 2H), 0.58 (brs, 2H), 0.88 (brs, 1H), 1.49 (t, J = 6.9 Hz, 3H), 1.68 (d, J = 9.9 Hz, 1H). 2.15 (d.d, J = 17.1 & 1.5 Hz, 1H), 2.28 (brs, 2H), 2.39 (brs, 2H). 2.60-2.80 (m, 3H), 3.06 (d, J = 18.3 Hz, 1H), 3.26 (brs, 1H), 4.29 (q, J = 6.9 Hz, 1H), 4.48 (q, J = 6.9 Hz, 1H), 5.27 (s, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 7.03-7.09 (m, 1H), 7.26-7.31 (m, 2H), 7.50 (d.d, J = 8.7 & 0.9 Hz, 2H).
I-84
##STR00223##
1H-NMR (CDCl3 + CD3OD) d: 0.16 (brs, 2H), 0.57 (brs, 2H), 0.86 (brs, 1H), 1.13 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.66 (d, J = 9.0 Hz, 1H), 2.08 (d.d, J = 17.1 & 1.5 Hz, 1H), 2.21 (brs, 2H), 2.38 (brs, 2H), 2.58-2.77 (m, 3H), 3.03 (d, J = 18.6 Hz, 1H), 3.21 (brs, 1H), 4.03 (quint, J = 6.6 Hz, 1H), 4.20 (q, J = 6.9 Hz, 1H), 4.40 (q, J = 6.9 Hz, 1H), 5.19 (s, 1H), 6.54 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H).
TABLE 25
Compound
NMR
No.
Chemical structure
(1H-NMR (d6-DMSO) δ)
I-85
##STR00224##
1H-NMR (CDCl3 + CD3OD) d: 0.14 (brs, 2 H), 0.56 (brs, 2 H), 0.86 (brs, 1 H), 1.14 (d, J = 6.6 Hz, 3 H), 1.15 (d, J = 6.6 Hz, 3 H), 1.32 (d, J = 4.8 Hz, 1 H), 1.34 (d, J = 4.8 Hz, 3 H), 1.64 (d, J = 9.9 Hz, 1 H), 2.10 (d.d, J = 17.1 & 1.5 Hz, 1 H), 2.27 (brs, 2 H), 2.39 (brs, 2 H), 2.55-2.77 (m, 3 H), 3.04 (d, J = 18.3 Hz, 1 H), 3.22 (brs, 1 H), 4.03 (quint, J = 6.6 Hz, 1 H), 4.81 (quint., J = 6.0 Hz, 1 H), 5.10 (s, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 8.4 Hz, H), 7.76 (d, J = 6.9 Hz, 1 H).
I-86
##STR00225##
1H-NMR CDCl3 + CD3OD) d: 0.16 (brs, 2 H), 0.568 (brs, 2 H), 0.87 (brs, 1 H), 1.67 (d, J = 9.9 Hz, 1 H), 2.14 (d.d, J = 18.3 & 1.2 Hz, 1 H), 2.27 (brs, 2 H), 2.41 (brs, 2 H), 3.05 (d, J = 18.6 Hz, 1 H), 3.25 (brd, J = 4.5 Hz, 1 H), 3.92 (s, 1 H), 4.46 (d, J = 5.7 Hz, 2 H), 5.23 (s, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 7.20-7.36 (m, 5 H), 8.03 (bit, J = 5.7 Hz, 1 H).
I-87
##STR00226##
1H-NMR (CDCl3 + CD3OD) d: 0.26 (brs, 2 H), 0.63 (brs, 2 H), 0.94 brs, 1 H), 1.72 (brd, J = 9.0 Hz, 1 H), 2.09-2.93 (m, 8 H), 3.15 (d, J = 18.9 Hz, 1 H), 4.97 (s, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 8.1 Hz, 1H), 7.04-7.08 (m, 1 H), 7.69-7.75 (m, 1 H), 8.13 (d, J = 14.0 Hz, 2 H), 8.23 (d, J = 3.9 Hz, 1 H).
TABLE 26
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-89
##STR00227##
m/z 462 [M + H]+ 0.94 min
I-90
##STR00228##
m/z 511 [M + H]+ 0.63 min
I-91
##STR00229##
m/z 500 [M + H]+ 0.44 min
I-92
##STR00230##
m/z 462 [M + H]+ 0.44 min
I-93
##STR00231##
m/z 487 [M + H]+ 0.50 min
TABLE 27
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-94
##STR00232##
m/z 540 [M + H]+ 1.07 min
I-95
##STR00233##
m/z 537 [M + H]+ 1.12 min
I-96
##STR00234##
m/z 581 [M + H]+ 1.15 min
I-97
##STR00235##
m/z 512 [M + H]+ 0.50 min
I-98
##STR00236##
m/z 531 [M + H]+ 0.50 min
TABLE 28
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-99
##STR00237##
m/z 537 [M + H]+ 1.17 min
I-100
##STR00238##
m/z 581 [M + H]+ 1.15 min
I-101
##STR00239##
m/z 581 [M + H]+ 1.03 min
I-102
##STR00240##
m/z 538 [M + H]+ 0.85 min
I-103
##STR00241##
m/z 540 [M + H]+ 1.05 min
TABLE 29
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-104
##STR00242##
m/z 581 [M + H]+ 1.12 min
I-105
##STR00243##
m/z 538 [M + H]+ 0.90 min
I-106
##STR00244##
m/z 537 [M + H]+ 1.05 min
I-107
##STR00245##
m/z 581 [M + H]+ 1.09 min
TABLE 30
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-108
##STR00246##
m/z 581 [M + H]+ 1.03 min
I-109
##STR00247##
m/z 488 [M + H]+ 0.50 min
I-110
##STR00248##
m/z 518 [M + H]+ 0.50 min
I-111
##STR00249##
m/z 518 [M + H]+ 0.56 min
I-112
##STR00250##
m/z 519 [M + H]+ 0.50 min
TABLE 31
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-113
##STR00251##
m/z 511 [M + H]+ 0.50 min
I-114
##STR00252##
m/z 486 [M + H]+ 0.57 min
I-115
##STR00253##
m/z 462 [M + H]+ 0.44 min
I-116
##STR00254##
m/z 497 [M + H]+ 0.63 min
I-117
##STR00255##
m/z 513 [M + H]+ 0.69 min
TABLE 32
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-118
##STR00256##
m/z 493 [M + H]+ 1.06 min
I-119
##STR00257##
m/z 469 [M + H]+ 0.44 min
I-120
##STR00258##
m/z 538 [M + H]+ 0.94 min
I-121
##STR00259##
m/z 559 [M + H]+ 0.69 min
I-122
##STR00260##
m/z 559 [M + H]+ 0.69 min
TABLE 33
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-123
##STR00261##
m/z 555 [M + H]+ 0.56 min
I-124
##STR00262##
m/z 543 [M + H]+ 0.63 min
I-125
##STR00263##
m/z 425 [M + H]+ 0.50 min
I-126
##STR00264##
m/z 525 [M + H]+ 0.56 min
I-127
##STR00265##
(CDCl3 + CD3OD) d: 0.10-0.21 (m, 2 H), 0.48-0.63 (m, 2 H), 0.78-0.94 (m, 1 H), 1.67 (d, J = 9.6 Hz, 1 H), 2.10-2.50 (m, 6 H), 2.57-2.80 (m, 2 H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (brs, 1 H), 5.10 (d, J = 1.7 Hz, 1 H), 6.31-6.40 (m, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 8.1 Hz, 1 H), 7.02-7.12 (m, 1 H), 7.22-7.34 (m, 2 H), 7.44-7.56 (m, 2 H).
TABLE 34
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-128
##STR00266##
m/z 553 [M + H]+ 0.94 min
I-129
##STR00267##
m/z 559 [M + H]+ 0.63 min
I-130
##STR00268##
m/z 529 [M + H]+ 0.75 min
I-131
##STR00269##
m/z 497 [M + H]+ 0.63 min
I-132
##STR00270##
m/z 529 [M + H]+ 0.88 min
TABLE 35
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-133
##STR00271##
m/z 511 [M + H]+ 0.97 min
0.12-0.16 (m, 2 H), 0.46-0.52 (m, 2 H), 0.86 (m, 1 H), 1.42 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.65 (m, 15 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.26 (d, J = 5.9 Hz, 1 H), 3.55 (s, 3 H), 4.73 (s 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.76 (brs, 1 H), 9.31 (brs, 1 H), 13.8 (brs, 1 H)
I-134
##STR00272##
m/z 498 [M + H]+ 0.96 min
0.13-0.16 (m, 2 H), 0.48-0.54 (m, 2 H), 0.87 (m, 1 H), 1.43 (d, J = 10.5 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.67 (m, 15 H), 3.06 (d, J = 18.6 Hz, 1 H), 3.27 (d, J = 6.0 Hz, 1 H), 4.73 (s 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.72 (brs, 1 H), 9.20 (brs, 1 H), 14.1 (brs, 1 H)
I-135
##STR00273##
m/z 483 [M + H]+ 0.87 min
0.12-0.14 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 1.06-1.09 (m, 2 H), 1.35-1.36 (m, 2 H), 1.41 (d, J = 11.7 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.17-2.61 (m, 7 H), 3.03 (d, J = 18.3 Hz, 1 H), 3.17 (d, J = 6.0 Hz, 1 H), 3.56 (s, 3 H), 4.74 (s, 1 H), 4.77 (brs, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.17 (brs, 1 H), 14.1 (brs, 1 H)
I-136
##STR00274##
m/z 469 [M + H]+ 0.89 min
0.12-0.16 (m, 2 H), 0.43-0.51 (m, 2 H), 0.85 (m, 1 H), 1.06-1.12 (m, 2 H), 1.35-1.36 (m, 2 H), 1.42 (d, J = 11.7 Hz, 1 H), 1.86 (d, J = 15.6 Hz, 1 H), 2.06-2.63 (m, 7 H), 3.02 (d, J = 18.3 Hz, 1 H), 3.13 (d, J = 5.4 Hz, 1 H), 4.76 (s 1 H), 4.77 (brs, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 9.18 (brs, 1 H), 14.1 (brs, 1 H)
TABLE 36
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-137
##STR00275##
m/z 539 [M + H]+ 0.50 min
I-138
##STR00276##
m/z 466 [M + H]+ 0.57 min
I-139
##STR00277##
m/z 486 [M + H]+ 0.44 min
I-140
##STR00278##
m/z 520 [M + H]+ 0.56 min
I-141
##STR00279##
m/z 510 [M + H]+ 0.75 min
TABLE 37
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-142
##STR00280##
m/z 521 [M + H]+ 0.50 min
I-143
##STR00281##
m/z 553 [M + H]+ 0.88 min
I-144
##STR00282##
m/z 494 [M + H]+ 0.57 min
I-145
##STR00283##
m/z 469 [M + H]+ 0.83 min
I-146
##STR00284##
m/z 467 [M + H]+ 1.01 min
TABLE 38
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-147
##STR00285##
m/z 467 [M + H]+ 1.00 min
I-148
##STR00286##
m/z 559 [M + H]+ 1.16 min**
I-149
##STR00287##
m/z 598 [M + H]+ 1.34 min**
I-150
##STR00288##
m/z 514 [M + H]+ 0.50 min
I-151
##STR00289##
m/z 538 [M + H]+ 0.63 min
TABLE 39
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-152
##STR00290##
m/z 494 [M + H]+ 0.56 min
I-153
##STR00291##
m/z 465 [M + H]+ 0.90 min
I-154
##STR00292##
m/z 465 [M + H]+ 0.96 min
I-155
##STR00293##
m/z 544 [M + H]+ 1.00 min
I-156
##STR00294##
m/z 483 [M + H]+ 0.35 min
TABLE 40
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-157
##STR00295##
m/z 510 [M + H]+ 0.96 min
0.11-0.14 (m, 2 H), 0.46-0.50 (m, 2 H), 0.83 (m, 1 H), 0.87 (t, J = 7.2 Hz, 1 H), 0.99 (d, J = 4.2 Hz, 3 H), 1.01 (d, J = 4.2 Hz, 3 H), 1.08-1.43 (m, 5 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.11-2.65 (m, 7 H), 2.96-3.16 (m, 4 H), 3.78 (q, J = 7.5 Hz, 1 H), 4.78 (brs, 1 H), 5.21 (s, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.41 (t, J = 5.1 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 9.02 (brs, 1 H)
I-158
##STR00296##
m/z 496 [M + H]+ 0.93 min
0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.85 (m, 1 H), 1.01 (d, J = 4.1 Hz, 3 H), 1.02 (d, J = 4.2 Hz, 3 H), 1.07 (d, J = 4.0 Hz, 3 H), 1.09 (d, J = 4.0 Hz, 3 H), 1.40 (d, J = 11.1 Hz, 1 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.09-2.63 (m, 7 H), 2.98 (d J = 18.1 Hz, 1 H), 3.13 (d, J = 5.4 Hz, 1 H), 3.82 (q, J = 6.6 Hz, 1 H), 3.88 (q, J = 6.9 Hz, 1 H), 5.24 (brs, 1 H), 5.76 (s, 1 H), 6.50 (d, J = 7.5 Hz, 1 H), 6.55 (d, J = 7.5 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 7.54 (d, J = 6.9 Hz, 1 H), 9.01 (brs, 1 H)
I-159
##STR00297##
m/z 536 [M + H]+ 0.95 min
0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.83 (m, 1 H), 0.99 (d, J = 3.0 Hz, 3 H), 1.01 (d, J = 3.0 Hz, 3 H), 1.15-1.38 (m, 6 H), 1.40 (d, J = 11.1 Hz, 1 H), 1.52-1.80 (m, 4 H), 1.97 (d, J = 17.1 Hz, 1 H), 2.09-2.65 (m, 7 H), 2.98 (d, J = 18.6 Hz, 1 H), 3.13 (d, J = 5.7 Hz, 1 H), 3.58 (m, 1 H), 3.79 (q, J = 6.9 Hz, 1 H), 5.23 (s, 1 H), 6.50 (d, J = 7.8 Hz, 1 H), 6.55 (d, J = 7.8 Hz, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 9.00 (brs, 1 H)
TABLE 41
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-160
##STR00298##
m/z 522 [M + H]+ 1.04 min
0.12-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 0.99 (d, J = 3.3 Hz, 3 H), 1.01 (d, J = 3.3 Hz, 3 H), 1.15-1.49 (m, 7 H), 1.91 (d, J = 16.5 Hz, 1 H), 2.08-2.65 (m, 7 H), 2.98 (d, J = 17.5 Hz, 1 H), 3.12 (d, J = 5.7 Hz, 1 H), 3.16-3.34 (m, 4 H), 3.79 (q, J = 6.9 Hz, 1 H), 4.76 (brs, 1 H), 5.01 (s, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.58 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 1 H), 9.01 (brs, 1 H)
I-161
##STR00299##
m/z 524 [M + H]+ 0.92 min
0.12-0.14 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.99 (d, J = 3.3 Hz, 3 H), 1.01 (d, J = 3.3 Hz, 3 H), 1.41 (d, J= 11.1 Hz, 1 H), 1.95 (d, J = 17.1 Hz, 1 H), 2.08-2.67 (m, 11 H), 2.98 (d, J = 17.5 Hz, 1 H), 3.12 (d, J = 5.7 Hz, 1 H), 3.49- 3.60 (m, 4 H), 3.82 (q, J = 6.9 Hz, 1 H), 4.78 (brs, 1 H), 5.01 (s, 1 H), 6.54 (d, J = 8.1 Hz, 1 H), 6.58 (d, J = 8.1 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 9.13 (brs, 1 H)
I-162
##STR00300##
m/z 530 [M + H]+ 0.94 min
0.13-0.14 (m, 2 H), 0.47-0.51 (m, 2 H), 0.83 (m, 1 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.44 (d, J = 10.5 Hz, 1 H), 2.02 (d, J = 16.8 Hz, 1 H), 2.11-2.65 (m, 7 H), 3.03 (d, J = 18.6 Hz, 1 H), 3.17 (d, J= 5.7 Hz, 1 H), 3.58 (m, 1 H), 3.74 (q, J = 6.3 Hz, 1 H), 4.86 (brs, 1 H), 5.39 (s, 1 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 7.03 (t, J = 7.2 Hz, 1 H), 7.26 (t, J = 7.8 Hz, 2 H), 7.56 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 2 H), 9.01 (brs, 1 H), 9.70 (brs, 1 H)
TABLE 42
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-163
##STR00301##
m/z 445 [M + H]+ 0.83 min
I-164
##STR00302##
0.14-0.22 (m, 2 H), 0.48-0.61 (m, 2 H), 0.91 (m, 1 H), 1.12 (d, J = 6.6 Hz, 6 H), 1.53-1.66 (m, 1 H), 2.15-2.22 (m, 2 H), 2.23-2.30 (m, 2 H), 2.35-2.49 (m, 2 H), 2.70 (d.d, J = 18.9 & 6.6 Hz, 2 H), 3.13 (d, J = 18.9 Hz, 1 H), 3.27 (d, J = 6.6 Hz, 1 H), 3.98 (quintet, J = 6.6 Hz, 1 H), 4.99-5.04 (m, 1 H), 6.32-6.36 (m, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 6.58 (d, J = 8.4 Hz, 1 H).
I-165
##STR00303##
m/z 543 [M + H]+ 0.63 min
I-166
##STR00304##
m/z 446 [M + H]+ 0.94 min
TABLE 43
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-167
##STR00305##
(CD3OD) d: 0.12-0.22 (m, 2 H), 0.48- 0.63 (m, 2 H), 0.82-1.00 (m, 1 H), 1.63 (d, J= 8.1 Hz, 1 H), 2.10-2.50 (m, 7 H), 2.72 (d.d, J= 18.6 & 6.6 Hz, 2 H), 3.15 (d, J = 18.6 Hz, 1 H), 5.10 (brs, 1 H), 6.50-6.65 (m, 3 H), 7.67 (d.d, J = 4.8 & 1.5 Hz, 1 H), 8.36 (d.d, J = 4.8 & 1.5 Hz, 1 H).
I-168
##STR00306##
m/z 582 [M + H]+ 0.90 min
I-169
##STR00307##
m/z 541 [M + H]+ 1.15 min
I-170
##STR00308##
m/z 480 [M + H]+ 0.37 min
I-171
##STR00309##
m/z 509 [M + H]+ 0.75 min
TABLE 44
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-172
##STR00310##
m/z 505 [M + H]+ 0.97 min
0.11-0.13 (m, 2 H), 0.46-0.50 (m, 2 H), 0.84 (m, 1 H), 0.98 (d, J = 3.1 Hz, 3 H), 1.01 (d, J = 3.1 Hz, 3 H), 1.37 (d, J = 10.8 Hz, 1 H), 2.08 (d, J = 17.4 Hz, 1 H), 2.11- 2.24 (m, 2 H), 2.35 (d, J = 6.6 Hz, 1 H), 2.51-2.63 (m, 2 H), 3.01 (d, J = 18.3 Hz, 1 H), 3.13 (d, J = 5.7 Hz, 1 H), 3.54 (s, 3 H), 3.86 (q, J = 7.2 Hz, 1 H), 4.79 (brs, 1 H), 4.98 (brs, 1 H), 5.76 (s, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 9.16 (brs, 1 H)
I-173
##STR00311##
m/z 426 [M + H]+ 0.90 min
0.12-0.14 (m, 2 H), 0.46-0.52 (m, 2 H), 0.85 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.38 (d, J = 10.2 Hz, 1 H), 1.86 (d, J = 15.0 Hz, 1 H), 2.02 (d, J = 15.0 Hz, 1 H), 2.10-2.17 (m, 2 H), 2.28 (dd, J = 6.9, 6.9 Hz, 1 H), 2.43 (dd, J = 6.9, 8.4 Hz, 1 H), 2.54-2.62 (m, 2 H), 3.01 (d, J = 18.3 Hz, 1 H), 3.17 (d, J = 5.7 Hz, 1H), 3.58 (m, 1 H), 3.88 (q, J = 7.2 Hz, 1 H), 4.62 (brs, 1 H), 4.68 (s, 1 H), 6.47 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 6.94 (brs, 1 H), 9.06 (brs, 1 H)
I-174
##STR00312##
(CD3OD) d: 0.10-0.25 (m, 2 H), 0.48-0.63 (m, 2 H), 0.83-1.00 (m, 1 H), 1.55 (d, J = 8.1 Hz, 1 H), 2.01 (d, J = 15.6 Hz, 1 H), 2.22-2.57 (m, 6 H), 2.70 (d.d, J = 18.3 & 7.2 Hz, 2 H), 3.12 (d, J = 18.3 Hz, 1 H), 4.67 (s, 1 H), 6.44-6.62 (m, 3 H), 7.54 (d.d, J = 9.6 & 3.6 Hz, 1 H), 8.00 (d, J = 3.6 Hz, 1 H).
TABLE 45
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-175
##STR00313##
m/z 458 [M + H]+ 0.86 min
I-176
##STR00314##
ESI: m/z 458 [M + H]+
I-177
##STR00315##
m/z 460 [M + H]+ 1.20 min
0.13-0.17 (m, 2 H), 0.47-0.50 (m, 2 H), 0.87 (m, 1 H), 1.41 (d, J = 10.5 Hz, 1 H), 2.07 (d, J = 15.0 Hz, 1 H), 2.10-2.25 (m, 2 H), 2.32 (dd, J = 5.7, 6.9 Hz, 1 H), 2.45 (dd, J = 5.7, 6.0 Hz, 1 H), 2.63 (dt, J = 6.3, 11.7, 2 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.19 (d, J= 6.0 Hz, 1 H), 4.67 (brs, 1 H), 4.75 (s, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 6.96 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 8.4 Hz, 1 H), 7.25 (d, J = 3.6 Hz, 2 H), 7.52 (d, J = 7.5 Hz, 2 H), 8.38 (brs, 1 H), 9.07 (brs, 1 H)
TABLE 46
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-178
##STR00316##
m/z 636 [M + H]+ 1.11 min
0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 11.1 Hz, 1 H), 1.87 (d, J = 18.0 Hz, 1 H), 2.11-2.63 (m, 7 H), 2.25 (s, 3 H), 3.03 (d, J = 17.4 Hz, 1 H), 3.18 (brs, 1 H), 3.84 (q, J = 7.2 Hz, 1 H), 4.71 (brs, 1 H), 5.45 (brs, 1 H), 6.50 (brs, 1 H), 6.57 (brs, 1 H), 7.61-8.19 (m, 4 H), 9.03 (brs, 1 H), 10.7 (brs, 1 H), 12.7 (brs, 1 H)
I-179
##STR00317##
m/z 581 [M + H]+ 1.06 min
0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.86 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 11.1 Hz, 1 H), 1.87 (d, J = 18.0 Hz, 1 H), 2.09 (s, 3 H), 2.11-2.63 (m, 7 H), 3.03 (d, J = 17.4 Hz, 1 H), 3.18 (brs, 1 H), 3.84 (q, J = 7.2 Hz, 1 H), 4.69 (brs, 1 H), 5.45 (brs, 1 H), 6.48 (d, J = 7.2 Hz, 1 H), 6.55 (d, J = 7.2 Hz, 1 H), 7.33 (brd, J = 5.4 Hz, 2 H), 7.54 (brs, 1 H), 7.74 (d, J = 7.5 Hz, 2 H), 9.11 (brs, 1 H), 12.3 (brs, 1 H)
TABLE 47
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-180
##STR00318##
m/z 597 [M + H]+ 1.03 min
0.11-0.13 (m, 2 H), 0.46-0.51 (m, 2 H), 0.85 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.46 (d, J = 9.9 Hz, 1 H), 1.87 (d, J = 17.4 Hz, 1 H), 2.11-2.62 (m, 7 H), 3.01 (d, J = 17.7 Hz, 1 H), 3.15 (d, J = 4.6 Hz, 1 H), 3.82 (s, 3 H), 3.83 (q, J = 5.4 Hz, 1 H), 4.67 (brs, 1 H), 5.44 (s, 1 H), 6.49 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 2 H), 7.52 (brd, J = 9.3 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 9.12 (brs, 1 H), 12.2 (brs, 1 H)
I-181
##STR00319##
m/z 502 [M + H]+ 0.35 min
I-182
##STR00320##
m/z 553 [M + H]+ 0.68 min
I-183
##STR00321##
m/z 539 [M + H]+ FAB-MS
TABLE 48
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-184
##STR00322##
m/z 458 [M + H]+ 0.97 min
I-185
##STR00323##
m/z 519 [M + H]+ 0.43 min
I-186
##STR00324##
m/z 519 [M + H]+ 1.67 min**
I-187
##STR00325##
m/z 539 [M + H]+ 0.50 min
TABLE 49
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-188
##STR00326##
m/z 505 [M + H]+ 0.35 min
I-189
##STR00327##
m/z 505 [M + H]+ 0.42 min
I-190
##STR00328##
m/z 597 [M + H]+ 0.77 min
I-191
##STR00329##
m/z 523 [M + H]+ 1.20 min
I-192
##STR00330##
m/z 546 [M + H]+ 1.00 min
TABLE 50
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-193
##STR00331##
m/z 580 [M + H]+ 1.09 min
I-194
##STR00332##
m/z 474 [M + H]+ 0.88 min
I-195
##STR00333##
m/z 458 [M + H]+ 1.08 min
I-196
##STR00334##
0.12-0.16 (m, 2 H), 0.46-0.55 (m, 2 H), 0.88 (m, 1 H), 1.43 (d, J = 12.4 Hz, 1 H), 1.65-2.65 (m, 12 H), 2.97-3.70 (m, 6 H), 3.59 (s, 3 H), 4.74 (s 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 7.68 (brs, 1 H), 9.16 (brs, 1 H), 13.5 (brs, 1 H)
TABLE 51
Com-
NMR
pound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-197
##STR00335##
0.20-0.40 (m, 2 H), 0.46-0.65 (m, 2 H), 0.97 (m, 1 H), 1.54 (d, J = 6.8 Hz, 1 H), 1.80-2.10 (m, 3 H), 2.31-3.69 (m, 15 H), 4.83 (s 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 7.56 (brs, 1 H), 9.29 (brs, 1 H), 13.6 (brs, 1 H)
I-198
##STR00336##
m/z 533 [M + H]+ 0.95 min
0.11-0.13 (m, 2 H), 0.46-0.52 (m, 2 H), 0.86 (m, 1 H), 1.03 (d, J = 6.3 Hz, 3 H), 1.08 (d, J = 6.3 Hz, 3 H), 1.46 (brd, J = 8.4 Hz, 1 H), 1.94 (d, J = 17.7 Hz, 1 H), 2.71-2.60 (m, 7 H), 2.81 (s, 6 H), 3.04 (d, J = 17.1 Hz, 1 H), 3.18 (brs, 1 H), 3.95 (q, J = 5.4 Hz, 1 H), 4.77 (brs, 1 H), 5.45 (s, 1 H), 6.51 (d, J = 7.5 Hz, 1 H), 6.57 (d, J = 7.5 Hz, 1 H), 7.64 (brs, 1 H), 9.14 (brs, 1 H), 12.2 (brs, 1 H)
I-199
##STR00337##
m/z 497 [M + H]+ 0.97 min
0.13-0.15 (m, 2 H), 0.48-0.52 (m, 2 H), 0.86 (m, 1 H), 1.41 (d, J = 11.4 Hz, 1 H), 1.85 (t, J = 7.8 Hz, 2 H), 1.93 (d, J = 16.5 Hz, 1 H), 2.07-2.62 (m, 11 H), 3.05 (d, J = 18.3 Hz, 1 H), 3.21 (d, J = 6.0 Hz, 1 H), 3.59 (s, 3 H), 4.72 (s, 1 H), 4.77 (brs, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 8.1 Hz, 1 H), 8.26 (brs, 1 H), 9.15 (brs, 1 H), 14.1 (brs, 1 H)
I-200
##STR00338##
m/z 553 [M + H]+ 0.47 min
TABLE 52
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-201
##STR00339##
m/z 601 [M + H]+ 1.01 min
I-202
##STR00340##
m/z 563 [M + H]+ 0.58 min
I-203
##STR00341##
m/z 583 [M + H]+ 0.54 min
I-204
##STR00342##
m/z 539 [M + H]+ 0.33 min
I-205
##STR00343##
m/z 573 [M + H]+ 0.62 min
TABLE 53
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-206
##STR00344##
m/z 535 [M + H]+ 0.41 min
I-207
##STR00345##
m/z 484 [M + H]+ 0.32 min
I-208
##STR00346##
m/z 507 [M + H]+ 1.05 min
I-209
##STR00347##
m/z 518 [M + H]+ 1.14 min**
I-210
##STR00348##
m/z 495 [M + H]+ 1.64 min**
TABLE 54
NMR
Compound
(1H-NMR
No.
Chemical structure
LC/MS*1
(d6-DMSO) δ)
I-211
##STR00349##
m/z 503 [M + H]+ 1.33 min**
I-212
##STR00350##
m/z 512 [M + H]+ 1.67 min**
I-213
##STR00351##
m/z 500 [M + H]+ 1.41 min**
I-214
##STR00352##
m/z 536 [M + H]+ 1.69 min**
TABLE 55
Compound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-215
##STR00353##
m/z 485 [M + H]+ 1.60 min**
I-216
##STR00354##
m/z 565 [M + H]+ 1.82 min**
I-217
##STR00355##
m/z 548 [M + H]+ 1.17 min**
I-218
##STR00356##
m/z 512 [M + H]+ 0.95 min**
I-219
##STR00357##
m/z 512 [M + H]+ 1.66 min**
I-220
##STR00358##
m/z 525 [M + H]+ 1.60 min**
I-221
##STR00359##
m/z 521 [M + H]+ 1.35 min**
TABLE 56
Compound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-222
##STR00360##
m/z 509 [M + H]+ 1.57 min**
I-223
##STR00361##
m/z 479 [M + H]+ 1.50 min**
I-224
##STR00362##
m/z 555 [M + H]+ 1.76 min**
I-225
##STR00363##
m/z 519 [M + H]+ 1.67 min**
I-226
##STR00364##
m/z 505 [M + H]+ 1.53 min**
I-227
##STR00365##
m/z 505 [M + H]+ 1.64 min**
I-228
##STR00366##
m/z 503 [M + H]+ 1.38 min****
TABLE 57
Compound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-229
##STR00367##
m/z 626 [M + H]+ 1.74 min**
I-230
##STR00368##
m/z 521 [M + H]+ 1.56 min**
I-231
##STR00369##
m/z 500 [M + H]+ 1.40 min**
I-232
##STR00370##
m/z 630 [M + H]+ 1.72 min**
I-233
##STR00371##
m/z 501 [M + H]+ 1.25 min**
I-234
##STR00372##
m/z 505 [M + H]+ 1.46 min**
I-235
##STR00373##
m/z 515 [M + H]+ 1.56 min**
TABLE 58
Compound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-236
##STR00374##
m/z 565 [M + H]+ 1.77 min**
I-237
##STR00375##
m/z 501 [M + H]+ 1.17 min**
I-238
##STR00376##
m/z 546 [M + H]+ 1.29 min**
I-239
##STR00377##
m/z 518 [M + H]+ 1.21 min**
I-240
##STR00378##
m/z 542 [M + H]+ 1.31 min**
I-241
##STR00379##
m/z 520 [M + H]+ 1.50 min**
I-242
##STR00380##
TABLE 59
Compound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-243
##STR00381##
m/z 493 [M + H]+ 1.05 min
I-244
##STR00382##
m/z 460 [M + H]+ 1.02 min
0.11-0.13 (m, 2 H), 0.48-0.51 (m, 2 H), 0.87 (m, 1 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.48 (d, J = 11.1 Hz, 1 H), 1.88 (d, J = 18.0 Hz, 1 H), 2.10 (s, 3 H), 2.18-2.57 (m, 7 H), 3.04 (d, J = 16.8 Hz, 1 H), 3.19 (brs, 1 H), 3.78 (q, J = 6.9 Hz, 1 H), 4.68 (brs, 1 H), 5.43 (brs, 1 H), 6.49 (d, J = 6.6 Hz, 1 H), 6.51 (d, J = 6.6 Hz, 1 H), 7.35-7.37 (m, 2 H), 7.54 (brs, 1 H), 7.85 (d, J = 6.9 Hz, 2 H), 9.09 (brs, 1 H), 12.4 (brs, 1 H)
I-245
##STR00383##
m/z 601 [M + H]+ 0.76 min
I-246
##STR00384##
m/z 505 [M + H]+ 1.38 min**
I-247
##STR00385##
m/z 521 [M + H]+ 1.58 min**
TABLE 60
Com-
pound
NMR
No.
Chemical structure
LC/MS*1
(1H-NMR (d6-DMSO) δ)
I-248
##STR00386##
m/z 493 [M + H]+ 1.69 min**
I-249
##STR00387##
m/z 479 [M + H]+ 1.55 min**
I-250
##STR00388##
m/z 519 [M + H]+ 1.74 min**
I-251
##STR00389##
m/z 512 [M + H]+ 0.38 min
I-252
##STR00390##
0.10-0.15 (m, 2 H), 0.34-0.38 (m, 2 H), 0.73 (m, 1 H), 1.26 (d, J = 9.6 Hz, 1 H), 1.93-2.54 (m, 10 H), 2.94 (d, J = 18.4 Hz, 1 H), 3.10 (d, J = 6.0 Hz, 1 H), 3.67 (s, 3 H), 3.72 (s, 3 H), 4.58 (s, 1 H), 4.84 (s,1 H), 6.42 (d, J = 8.0 Hz, 2 H), 6.48 (d, J = 8.0 Hz, 2 H), 6.61 (d, J = 9.3 Hz, 2 H), 6.69 (d, J = 9.2 Hz, 2 H), 7.56 (dd, J = 2.8, 8.8 Hz, 1 H), 7.66 (dd, J = 2.8, 8.8 Hz, 1 H), 8.00 (d, J = 2.4 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.76 (s, 1 H), 8.97 (s, 1 H), 10.78 (s, 1 H).
TABLE 61
Compound No.
Chemical structure
I-253
##STR00391##
I-254
##STR00392##
I-255
##STR00393##
I-256
##STR00394##
I-257
##STR00395##
TABLE 62
Com-
pound
No.
Chemical structure
I-258
##STR00396##
I-259
##STR00397##
I-260
##STR00398##
I-261
##STR00399##
I-262
##STR00400##
TABLE 63
Compound No.
Chemical structure
I-253
##STR00401##
I-254
##STR00402##
I-255
##STR00403##
TABLE 64
Com-
pound
No.
Chemical structure
I-266
##STR00404##
m/z 457.91 [M + H]+ 0.97 min
I-267
##STR00405##
m/z 457.91 [M + H]+ 0.62 min
I-268
##STR00406##
m/z 457.91 [M + H]+ 0.87 min
I-269
##STR00407##
m/z 473.91 [M + H]+ 0.69
I-270
##STR00408##
m/z 457.91 [M + H]+ 0.97 min
TABLE 65
Compound
No.
Chemical structure
LC/MS*1
I-271
##STR00409##
m/z 520 [M + H]+ 1.63 min**
I-272
##STR00410##
m/z 513 [M + H]+ 0.45 min
I-273
##STR00411##
m/z 513 [M + H]+ 0.38 min
I-274
##STR00412##
m/z 499 [M + H]+ 0.38 min
I-275
##STR00413##
m/z 548 [M + H]+ 0.38 min
TABLE 66
Compound
No.
Chemical structure
LC/MS*1
I-276
##STR00414##
m/z 559 [M + H]+ 0.53 min
I-277
##STR00415##
m/z 610 [M + H]+ 0.46 min
I-278
##STR00416##
m/z 545 [M + H]+ 0.38 min
I-279
##STR00417##
m/z 495 [M + H]+ 0.31 min
I-280
##STR00418##
m/z 545 [M + H]+ 0.97 min
TABLE 67
Compound No.
Chemical structure
LC/MS*1
I-281
##STR00419##
m/z 531 [M + H]+ 0.92 min
I-282
##STR00420##
m/z 455 [M + H]+ 0.87 min
I-283
##STR00421##
m/z 469 [M + H]+ 0.94 min
I-284
##STR00422##
m/z 571 [M + H]+ 0.68 min
I-285
##STR00423##
m/z 509 [M + H]+ 0.32 min
TABLE 68
Compound No.
Chemical structure
LC/MS*1
I-286
##STR00424##
m/z 471 [M + H]+ 0.32 min
I-287
##STR00425##
m/z 455 [M + H]+ 0.90 min
I-288
##STR00426##
m/z 501 [M + H]+ 0.32 min
I-289
##STR00427##
m/z 584 [M + H]+ 0.46 min
(LC/MS conditions of measurements)*1:
Column: Chromolith Flash ROD RP-18e, 25 × 4.6 mm LD.
Flow Rate: 2 ml/min
UV Detector: 280 nm
Solvent System: [A] = H2O_0.05% HCOOH
[B] = MeOH_0.05% HCOOH
Gradient: 0 min; 90% [A]_10% [B]
0.2 mm; 90% [A]_10% [B]
1.0 mm; 10% [A]_90% [B]
1.80 mm; 10% [A]_90% [B]
Proviso, values with symbol ** follow below conditions of measurement
Column: Phenomenex Luna 5μ C18(2) 100 A, size 50 × 4.60 mm
Gradient: 10%-100% Acetnitrile linear during 3.0 mm at 3.0 mL/min
1) Method of Preparing Membrane Specimen for Binding Assay
A rat cerebrum (Slc: SD) which had been stored at −80° C. was used. To a cerebrum which had been weighed was added a 20-fold amount of ice-cooled 10 mM Tris-HCl buffer (pH 7.0), and the mixture was homogenized (25000 rpm, 30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600×g for 20 minutes. To the resulting pellet was added 15 ml of the same buffer, and the mixture was treated with Histocolon similarly, and centrifuged. This washing work was performed two times. After centrifugation, to the resulting pellet was added 15 mL of a 50 mM Tris-HCl buffer (pH 7.4), and this was treated with Histocolon, and finally resuspended in a 10-fold amount of the same buffer, which was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). The prepared membrane specimen was frozen and stored at −80° C., and at an assay, the specimen was rapidly thawed, and diluted to about 900 μg/mL with a 50 mM Tris-HCl buffer (pH 7.4) after the centrifugation and Histocolon treatment, and was used in an experiment. For measuring a protein concentration of the membrane specimen, Micro BCA Protein Assay Kit (PIERCE) was used.
To a solution of 10 μl of the test compound diluted at 10-fold stage was added 10 μl of final 3 nM [3H]-DADLE (51.5 Ci/mmol: PerkinElmer) as a ligand. Into a tube was placed 480 μl of a rat cerebrum membrane fraction to which 100 mM choline chloride, 3 mM MnCl2 and 100 nM DAMGO had been added, and this was incubated at 25° C. for 2 hours. After incubation, this was suction-filtered with a Whatman GF/C filter which had been pre-treated with 0.5% polyethyleneimine, and washed with 2.5 mL of an ice-cooled 10 mM Tris-HCl buffer (pH7.4) four times. After washing, the filter was transferred to a mini vial for liquid scintillation counter, 5 mL of a scintillator (Cleasol I) was added, this was allowed to stand overnight, and the radioactivity was measured for 3 minutes with a liquid scintillation counter Tri-Carb 2200CA (PACKARD). DMSO was used for total binding (Total bound: TB) for data analysis, and 20 μM levallorphan was used for non-specific binding (Non-specific bound: NB), and a Ki value of the test compound was calculated using a KD value (2.93 nM) obtained in advance by Scatchard plot analysis.
Results are shown in Table 69.
TABLE 69
test compound
Ki (nM)
I-3
8.76
I-4
7.38
I-7
7.4
I-10
19.92
I-13
5.02
I-30
5.34
I-39
41.8
I-49
3.99
I-92
5.23
I-118
27.65
I-133
9.85
I-135
9.76
I-145
13.87
I-188
3.01
I-199
12.77
I-208
13.28
I-229
5.9
I-240
11.5
I-243
5.2
I-244
0.56
I-267
41.46
I-283
3.73
I-284
0.91
I-285
5.77
I-286
2.46
I-288
5.36
I-289
0.47
From the above results, it is seen that compound (1) has an affinity for an opioid δ receptor.
1) Method of Preparing Membrane Specimen for Binding Assay
A rat cerebrum (Slc: SD) which had been stored at −80° C. was used. To a cerebrum which had been weighed was added a 20-fold amount of ice-cooled 10 mM Tris-HCl buffer (pH 7.0), the mixture was homogenized (25000 rpm, 30 seconds) with Histocolon (NITI-ON), and centrifuged at 36600×g for 20 minutes. To the resulting pellet was added 15 ml of the same buffer, and the mixture was treated with Histocoln similarly, and centrifuged. This washing work was performed two times. After centrifugation, to the resulting pellet was added 15 mL of a 50 mM Tris-HCl buffer (pH 7.4), this was treated with Histocolon, and this was finally resuspended in a 10-fold amount of the same buffer, which was used as a crude membrane fraction (Life Sci. 48, 111-116, 1991). The prepared membrane specimen was frozen and stored at −80° C., and at a test, the specimen was rapidly thawed, and diluted to about 900 μg/mL with a 50 mM Tris-HCl buffer (pH 7.4) after the centrifugation and Histocolon treatment, and was used in an experiment. For measuring a protein concentration of the membrane specimen, Micro BCA Protein Assay Kit (PIERCE) was used.
2) Method of μ Receptor Binding Assay and Data Analysis
To a solution of 10 μl of the test compound diluted at 10-fold stage diluted test compound was added 10 μl of final 2 nM [3H]-DAMGO (51.5 Ci/mmol: PerkinElmer) as a ligand, further, 480 μl of a rat cerebrum membrane fraction was placed into a tube, and this was incubated at 25° C. for 2 hours. After incubation, this was suction-filtered with a Whatman GF/C filter which had been pre-treated with 0.5% polyethyleneimine, and washed with 2.5 mL of an ice-cooled 10 mM Tris-HCl buffer (pH 7.4) four times. After washing, the filter was transferred to a mini vial for liquid scintillation counter, 5 mL of a scintillator (Cleasol I) was added, and this was allowed to stand overnight, and the radioactivity was measured for 3 minutes with a liquid scintillation counter Tri-Carb 2200CA (PACKARD). DMSO was used for total binding (Total bound: TB) for data analysis, and 20 μM levallorphan was used for non-specific binding (Non-specific bound: NB), and a Ki value of the test compound was calculated using a KD value (1.72 nM) obtained in advance by Scatchard plot analysis (Anal.Biochem. 107(1), 220-239, 1980).
Results are shown in Table 70.
TABLE 70
test compound
Ki (nM)
I-4
5.18
I-10
4.05
I-39
0.33
I-49
16.49
I-118
2.29
I-122
2.7
I-123
1.68
I-124
3.9
I-133
4.99
I-135
1.58
I-138
15.53
I-145
28.09
I-188
17.27
I-199
9.45
I-208
5.89
I-229
1.3
I-240
6.85
I-243
5.28
I-244
11.02
I-267
0.84
I-283
20.14
I-284
1.13
I-285
7.29
I-286
13.98
I-288
14.38
I-289
12.95
1) Preparation of Test Diet (Carbon Powder)
Using a 10 w/v % arabic gum aqueous solution, a 5 w/v % active carbon solution was prepared, which was used as a test diet.
2) Animal
A ddY line male mouse (5 to 6 weeks old) was used. The mouse was fasted from about 20 or more hours before assay initiation, and water was given ad lib.
3) Test Compound and Medium
The test compound was dissolved in a solvent (DMAA/Solutol/5% meglumine=15/15/70).
DMAA: N,N-dimethylacetamide
Solutol: Solutol (registered trademark) HS15
Meglumine: D(−)-N-methylglucamine
Morphine hydrochloride was dissolved in a physiological saline. The test compound, the above solvent and morphine were all administered at a liquid amount of 10 mL/kg.
4) Assay Method
The test compound 3 mg/kg (test compound administration group) or the solvent (solvent administration group) were subcutaneously administered and, after 15 minutes, amount of 3 mg/kg of morphine was administered to all groups. As a control group, the solvent was subcutaneously administered and, after 15 minutes, a physiological saline was administered.
The test diet 10 mL/kg was orally administered at 15 minutes after administration of morphine. At thirty minutes after administration of the test diet (60 minutes after administration of the test substance), all mice were isolated from esophagus to an ileocecal part near a stomach cardia part. A distance from pyloric part of the stomach to an ileocecal part (full length of small intestine) and a distance until a carbon powder reaching front part (carbon powder movement distance) were measured. The antagonistic activity on the carbon powder transport of inhibitory activity by morphine was calculated as MPE (%) using the following equation. Results are shown in Table 71.
Transport rate (%)=(carbon powder movement distance)/full length of small intestine (cm))×100
M.P.E.(%)={(small intestine transport rate (%) of each individual of test compound administration group−average small intestine transport rate (%) of solvent administration group)/(average small intestine transport rate (%) of control group−average small intestine transport rate (%) of solvent administration group)}×100
TABLE 71
test compound
M.P.E. (%)
I-39
52
I-49
80
I-118
55.6
I-122
31.5
I-123
44.1
I-124
46.6
I-133
106.9
I-135
59.7
I-138
55.8
I-145
60.2
I-188
74.6
I-199
62.8
I-208
81.2
I-229
39.7
I-240
36.3
I-243
52.6
I-244
71.6
I-267
60
I-283
63.7
I-284
79.6
I-285
82.5
I-286
70.6
I-288
101.3
I-289
67
A granule containing the following ingredients is prepared.
Ingredient
Compound represented by formula (I)
10
mg
Lactose
700
mg
Corn starch
274
mg
HPC-L
16
mg
1000
mg
The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with a V-type mixer. To a mixed powder is added a HPC-L (lower viscosity hydroxypropylcellulose) aqueous solution, the materials are kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm), and dried. The resulting dry granule is passed through a sieve using a vibration sieve (12/60 mesh) to obtain a granule.
A granule for filling into a capsule containing the following ingredients is prepared.
Ingredient
Compound represented by formula (I)
15
mg
Lactose
90
mg
Corn starch
42
mg
HPC-L
3
mg
150
mg
The compound represented by the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed, to a mixed powder is added a HPC-L solution, the materials are kneaded, granulated, and dried. The resulting dry granule is size-adjusted, 150 mg of which is filled into a No. 4 hard gelatin capsule.
A tablet containing the following ingredients is prepared.
Ingredient
Compound represented by the formula (I)
10
mg
Lactose
90
mg
Microcrystalline cellulose
30
mg
CMC-Na
15
mg
Magnesium stearate
5
mg
150
mg
The compound represented by the formula (I), lactose, microcrystallinecellulose, CMC-NA (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve, and mixed. Into a mixed powder is mixed magnesium stearate to obtain a mixed powder for tabletting. The present mixed powder is compressed to obtain 150 mg of a tablet.
The following ingredients are warmed, mixed, and sterilized to obtain an injectable.
Ingredient
Compound represented by the formula (I)
3
mg
Nonionic surfactant
15
mg
Purified water for injection
1
ml
The present invention is useful as an agent for alleviating a side effect such as emesis, vomiting and/or constipation.
Hasegawa, Tsuyoshi, Tamura, Yoshinori, Inagaki, Masanao, Hara, Shin-ichiro, Haga, Nobuhiro, Goto, Yoshihisa
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