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Phenyl or heteroaryl amino alkane derivatives as IP receptor antagonist

A technology for heteroarylaminoalkane and derivatives, which is applied in the field of phenyl or heteroarylaminoalkane derivatives, can solve the problems of undisclosed phenyl or heteroarylaminoalkane derivatives, and achieve excellent IP receptor antagonism Active, disease-relieving effects

Inactive Publication Date: 2006-02-15
BAYER HEALTHCARE AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, neither this nor other references disclose phenyl or heteroarylaminoalkane derivatives having IP receptor antagonistic activity

Method used

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  • Phenyl or heteroaryl amino alkane derivatives as IP receptor antagonist
  • Phenyl or heteroaryl amino alkane derivatives as IP receptor antagonist
  • Phenyl or heteroaryl amino alkane derivatives as IP receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0476] N-(6-chloropyrimidin-4-yl)-D-phenylalanine methyl ester

[0477]

[0478] To a mixture of 4,6-dichloropyrimidine (57 g, 383 mmol), D-propylalanine methyl ester hydrochloride (75 g, 348 mmol) and 1,4-dioxane (440 mL) was added N , N-diisopropylethylamine (123ML, 730mmol), and the mixture was stirred overnight at 80°C. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate 3:1) to obtain N-(6-chloropyrimidin-4-yl)-D-phenylalanine methyl ester (99.3 g, 96 %), as a brown oil.

[0479] N-{6-[4-(Benzyloxy)phenyl]pyrimidin-4-yl}-D-phenylalanine methyl ester

[0480]

[0481] Under argon atmosphere, N-(6-chloropyrimidin-4-yl)-D-phenylalanine methyl ester (30....

Embodiment 1-2

[0493] N-{6-[4-(cyclopropylmethoxy)phenyl]pyrimidin-4-yl}-D-phenylalanine methyl ester

[0494]

[0495] Under argon atmosphere, N-(6-chloropyrimidin-4-yl)-D-phenylalanine methyl ester (1.27 g, 4.34 mmol), 4-(cyclopropylmethoxy)phenylboronic acid [ To a mixture of starting compound 1A] (1.0 g, 5.21 mmol) and benzene (8.7 mL) was added potassium carbonate (1.2 g, 8.68 mmol) followed by tetrakis(triphenylphosphine)palladium (0.25 g, 0.22 mmol). The mixture was stirred overnight at reflux. After cooling to room temperature, the mixture was filtered through a pad of celite, and the filtrate was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (hexane:ethyl acetate 8:2) to obtain N-{6-[4-(cyclopropylmethoxy)phenyl]pyrimidin-4-yl}-D- Phenylalanine methyl ester (1.05 g, 60%), as pale yello...

Embodiment 1-3

[0507] D-norleucine ethyl ester hydrochloride

[0508]

[0509]A solution of D-norleucine (1.50 g, 114 mmol) in ethanol (300 mL) was cooled to -70°C, and thionyl chloride (25.0 mL, 343 mmol) was added dropwise over 30 minutes. The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain D-norleucine ethyl ester hydrochloride (22.2 g, quantitative yield) as a colorless solid.

[0510] N-(6-chloropyrimidin-4-yl)-D-norleucine ethyl ester

[0511]

[0512] To a mixture of 4,6-dichloropyrimidine (15.0 g, 101 mmol) and D-norleucine ethyl ester (21.7 g, 111 mmol) in dioxane (440 mL) was added dropwise N, N'- Diisopropylethylamine (38.6 mL, 222 mmol). The mixture was stirred overnight at 65°C and then at 80°C for 4 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organi...

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Abstract

The present invention relates to a phenyl or heteroaryl amino alkane derivatives which are useful as an active ingredient of pharmaceutical preparations. The phenyl or heteroaryl amino alkanes of the present invention have IP receptor antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with IP receptor antagonistic activity. Such diseases include urological diseases or disorder as follows: bladder outlet obstruction, overactive bladder, urinary incontinence, detrusor hyper-reflexia, detrusor instability, reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benighn prostatic hypertrophy (BPH), prostatitis, urinary frequency, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity. The compounds of the present invention are also useful for treatment of pain including, but not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, dental pain, premenstrual pain, visceral pain, headaches, and the like; hypotension; hemophilia and hemorrhage; and inflammation, since the diseases also is alleviated by treatment with an IP receptor antagonist.

Description

[0001] Detailed description of the invention technical field [0002] The present invention relates to phenyl or heteroarylaminoalkane derivatives for use as active ingredients of pharmaceutical preparations. The phenyl or heteroarylaminoalkane derivatives of the present invention have IP receptor antagonistic activity, and can be used for the prevention and treatment of diseases associated with IP receptor antagonistic activity. [0003] More specifically, the phenyl or heteroarylaminoalkane derivatives of the present invention are useful in the treatment and prevention of urinary diseases or disorders. [0004] The compounds of the invention are also useful in the treatment of pain; hypertension; hemophilia and haemorrhage; inflammation; respiratory disorders of allergy origin or asthma, since these diseases are also alleviated by treatment with IP receptor antagonists. Background of the invention [0005] Prostaglandins (or prostaglandins, PGs) are a class of bioactive ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/64C07D213/74C07D213/38C07D239/42C07D241/20C07D261/14C07D277/42C07D401/12C07D401/10C07D403/12C07D403/10C07D401/04C07D401/14C07D405/10A61K31/415
Inventor 村田俊树梅田雅臣吉川悟K・厄巴恩斯J・古普塔樱井修
Owner BAYER HEALTHCARE AG
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