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Compound having agonistic activity to somatostatin receptor and medicinal use thereof

A compound and drug technology, applied in the field of compounds with somatostatin receptor agonistic activity and their pharmaceutical use

Inactive Publication Date: 2016-05-18
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] However, none of the background art documents disclose the compounds described herein, their salts, their N-oxides or solvates thereof, or their prodrugs, or their pharmaceutical use, which may not be possible from any combination of background art documents. derived

Method used

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  • Compound having agonistic activity to somatostatin receptor and medicinal use thereof
  • Compound having agonistic activity to somatostatin receptor and medicinal use thereof
  • Compound having agonistic activity to somatostatin receptor and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0472] The present invention is specifically described below by way of examples and biological examples, which do not limit the present invention. Compounds of the invention and compounds described in the Examples were named using ACD / Name (version 6.00, available from Advanced Chemistry Development Inc.) or Chemdraw Ultra (version 12.0, available from CambridgeSoft).

[0473] Solvents stated in parentheses in the sections of chromatographic separation and TLC refer to elution solvents or developing solvents used and ratios are represented by volume ratios. For "NH silica gel" is meant the use of CHROMATOREX NHTLCPLATE (catalogue number: 3800003) available from Fuji Silysia Chemical Ltd.

[0474] "Hi-flashSI" and "Hi-flashNH" mentioned in parentheses in the medium pressure preparative liquid chromatography section indicate the type of column used, respectively (Hi-flashSI: silica gel (available from Yamazen Corporation) and Hi-flashNH: aminopropyl Bonded silica gel (available...

Embodiment 2

[0531] tert-Butyl N-{1-[3-(3,5-dichlorophenyl)-5-nitro-4-pyridyl]-4-piperidinyl}carbamate

[0532]

[0533] To a solution of the compound (128.35 g) prepared in Reference Example 1 in 1,4-dioxane (1283 mL) was added 2M aqueous tripotassium phosphate (39.72 mL), 3,5-dichlorophenylboronic acid (CAS# 67492-50-6) (64.08 g) and tetrakis(triphenylphosphine)palladium(0) (1.84 g) and the mixture was stirred at 100° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and washed with water and saturated sodium chloride solution. After drying, the organic layer was concentrated to obtain a residue (168 g) containing the title compound having the following physical properties. The resulting residue was used in the next reaction without purification.

[0534] Properties: yellow powder;

[0535] TLC (Rf): 0.40 (n-hexane: ethyl acetate=4:1);

[0536] MASS(ESI,Pos.):467(M+H) + .

[0537] Reference example 3:

[0538] tert-butyl N-{1-[3-am...

Embodiment 1

[0557] 1-{3-(3,5-Dichlorophenyl)-5-[4-(trifluoromethyl)phenyl]-4-pyridyl}-4-piperidinamine

[0558]

[0559] The compound of the present invention having the following physical properties was obtained by the same operation as in Reference Example 2→Reference Example B1, using the compound prepared in Reference Example 4 instead of the compound prepared in Reference Example 1, and using 4-(three Fluoromethyl)phenylboronic acid (CAS# 128796-39-4) was substituted for 3,5-dichlorophenylboronic acid.

[0560] Properties: white powder;

[0561] Purity (UPLC-MS / ELSD): 99.9% (retention time: 0.58min.);

[0562] TLC (Rf): 0.71 (ethyl acetate:methanol=9:1, NH silica gel);

[0563]NMR (300MHz, methanol-d4): δ8.20(s, 1H), 8.19(s, 1H), 7.80(d, J=8.1Hz, 1H), 7.62(d, J=8.1Hz, 1H), 7.53 -7.50(m, 1H), 7.43(d, J=1.8Hz, 2H), 2.91(br.d, J=13.0Hz, 2H), 2.52-2.35(m, 3H), 1.49-1.37(m, 2H ), 1.06-0.88 (m, 2H);

[0564] MASS(ESI,Pos.):466(M+H) + .

[0565] Example 2:

[0566] 1-{3-(3-Chloro...

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PUM

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Abstract

Provided is a somatostatin receptor subtype-2 agonist. A compound represented by general formula (I) [wherein each symbol has the same meaning as defined in the description], a salt thereof, an N-oxide thereof or a solvate thereof, or prodrugs of the same, which are low-molecular compounds having potent agonistic activity to somatostatin receptor subtype-2 and, therefore, can be administered in a simpler manner and have high safety and low toxicity, are useful in preventing and / or treating somatostatin-related diseases such as acromegaly and gastrointestinal obstruction.

Description

technical field [0001] The present invention relates to a compound represented by the following general formula (I), its salt, its N-oxide or its solvate, or Their prodrugs, and pharmaceutical uses 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 with pharmacotherapy with exogenous administration ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4545A61P1/00A61P5/08A61P43/00
CPCA61K45/06A61K31/4545C07D401/14C07D498/04C07D401/04A61P1/00A61P43/00A61P5/08A61K2300/00A61K31/5383
Inventor 石田昭治松下岳史关口哲也冈部泰之驹形龙哉西尾拓也
Owner ONO PHARMA CO LTD
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