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Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof

A kind of compound and halogen technology, applied in the compound with somatostatin receptor agonistic activity and the field of medical use thereof

Inactive Publication Date: 2019-10-01
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Also, the drug is a peptide drug and thus needs to be administered by injection, and its sustained-release formulation is reported to be accompanied by significant pain when injected intramuscularly once in several weeks

Method used

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  • Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof
  • Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof
  • Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0542] 2-{4-[(3S,4R)-4-amino-3-hydroxy-1-piperidinyl]-5-(3,5-difluorophenyl)-2-(1-methyl-1H- Pyrazol-4-yl)-3-pyridyl}-1H-benzimidazole-7-carboxylic acid methyl ester

[0543] [C34]

[0544]

[0545] To a solution of the compound prepared in Reference Example 5 in dichloromethane (1.0 mL) was added trifluoroacetic acid (87 µL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by medium-pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate:methanol=100:0 to 80:20) to obtain the present compound (7 mg ).

[0546] HPLC retention time (min): 0.57;

[0547] MS (ESI, Positive): 560 (M+H) + ;

[0548] 1 H-NMR (CD 3 OD): δ 8.38, 8.04, 8.02, 7.51-7.41, 7.28-7.18, 7.08-6.98, 6.85, 3.96, 3.72, 3.37-3.28, 3.21-3.09, 2.93-2.73, 2.46-2.37, 2.23-2.17, 1.09- 0.79.

[0549] Embodiment 1(1) to 1(4)

[0550] The compound of ...

Embodiment 2

[0578] (3S,4R)-4-amino-1-[5-(3-chloro-5-fluorophenyl)-3-(6-methoxy-1H-benzimidazol-2-yl)-2- Methyl-4-pyridyl]-3-piperidinol

[0579] [C35]

[0580]

[0581] The compound of the present invention having the following properties was prepared in a similar manner to that in Reference Example 4→Reference Example 5→Example 1, wherein the compound prepared in Reference Example 6 was used instead of the compound prepared in Reference Example 3, 3- Chloro-5-fluorophenylboronic acid instead of 3,5-difluorophenylboronic acid, 4-methoxybenzene-1,2-diamine instead of methyl 2,3-diaminobenzoate.

[0582] HPLC retention time (min): 0.52;

[0583] MS (ESI, positive): 482 (M+H) + ;

[0584] 1 H-NMR (CD 3 OD): δ 8.21, 7.58-7.42, 7.37-7.20, 7.18-7.09, 7.00-6.90, 3.87, 3.43-3.36, 3.11-2.98, 2.91-2.70, 2.50-2.39, 2.36, 2.19-2.07, 1.12-0.95.

[0585] Embodiment 2(1) to 2(13)

[0586] The compound of the present invention having the following properties is prepared in the same steps ...

Embodiment 3

[0656] (3S,4R)-1-[5-(3-chloro-5-fluorophenyl)-3-(6-methoxy-1H-benzimidazol-2-yl)-2-methyl-4- Pyridyl]-4-(3-oxetanylamino)-3-piperidinol

[0657] [C37]

[0658]

[0659] Under a nitrogen atmosphere, acetic acid (30 μL) was added to a suspension of the compound prepared in Example 2 (48 mg) in methanol (1.0 mL), to which 3-oxetanone (58 μL) and 2-picoline were added Borane complex (19.3 mg), and the mixture was stirred at room temperature. After 13 hours, 3-oxetanone (39 μL) and 2-picoline borane complex (13.9 mg) were further added, and the mixture was stirred at room temperature for 13 hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by medium-pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate:methanol=100:5 to 80:20) to obtain the present compound (45 mg) having the fo...

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PUM

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Abstract

Provided is a somatostatin receptor subtype 2 agonist. A compound disclosed in the present invention that is represented by general formula (I) (wherein each symbol has the same meaning as defined inthe description) or a salt thereof is a low molecular compound having a strong agonistic activity to somatostatin receptor subtype 2. The compound according to the present invention can be orally administered and, therefore, can be easily taken and contribute to the reduction of patient's pain associated with a therapeutic treatment. Moreover, the compound according to the present invention has sufficiently weak hERG inhibitory activity and / or phospholipidosis effect, compared with the SSTR2 agonistic activity thereof, and, therefore, can inhibit or suppress side effects caused by the aforesaid activity and / or effect.

Description

technical field [0001] The present invention relates to a compound represented by the following general formula (I) or a salt thereof having a somatostatin receptor (especially somatostatin receptor subtype 2) agonistic activity, and a medical use thereof. Background technique [0002] Acromegaly is a hormone disorder caused by excessive secretion of growth hormone by the pituitary gland caused by pituitary adenoma. Affected patients suffer from hypertrophy of the head, bones in the hands and feet, and soft tissues. The prevalence of acromegaly is about 60 patients per 1 million people, which is not necessarily high. However, this disease affects the life of the patient due to a part of the body aberration and it is a serious disease with an increased risk of death because heart disease occurs in one third of the patients. [0003] In addition to surgical resection of growth hormone-secreting adenomas and radiation therapy, patients with acromegaly are currently treated wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/4545A61K31/48A61K31/5377A61K38/00A61K45/00A61P1/00A61P5/00A61P43/00C07D405/14
CPCA61K31/4545A61K31/48A61K31/5377A61K38/00A61K45/00A61P5/00A61P43/00C07D401/14C07D405/14A61K31/4985A61K45/06A61P1/00A61K47/02A61K47/12A61K47/38C07D413/14
Inventor 石田昭治吉田笃史宫田英典正野知行
Owner ONO PHARMA CO LTD
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