Novel crystalline arylalkylamine compound and process for producing the same

Patent metadata

Field	Value
Publication number	US-2016200679-A1
Application number	US-201414916859-A
Country	US
Kind code	A1
Filing date	Sep 5, 2014
Priority date	Sep 5, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

The present invention provides novel crystal forms of arylalkylamine compounds. Specifically, the novel crystal forms of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid have excellent stability and therefore are useful as pharmaceutical ingredients. The present invention also provides industrially advantageous processes for producing the arylalkylamine compounds.

First claim

1 . A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid.

2 . A crystal according to claim 1 , which is a form A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid showing peaks at 17.3°±0.2° and 22.6°+0.2° as diffraction angles expressed as 2θ in the powder X-ray diffraction spectrum.

3 . (canceled)

4 . (canceled)

5 . A crystal according to claim 1 , which is a form A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid of which a powder X-ray diffraction spectrum has a pattern illustrated in FIG. 1 .

6 . A crystal according to claim 1 , which is a form A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid having a melting point of 174 to 177° C. as measured by differential scanning calorimetry.

7 . A crystal according to claim 1 , which is a form B crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid showing peaks at 15.9°±0.2° and 21.4°±0.2° as diffraction angles expressed as 2θ in the powder X-ray diffraction spectrum.

8 . (canceled)

9 . (canceled)

10 . A crystal according to claim 1 , which is a form B crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid of which a powder X-ray diffraction spectrum has a pattern illustrated in FIG. 3 .

11 . A crystal according to claim 1 , which is a form B crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid having a melting point of 164 to 167° C. as measured by differential scanning calorimetry.

12 . A medicine comprising the crystal according to claim 1 .

13 . A pharmaceutical composition comprising the crystal according to claim 1 , and a pharmacologically acceptable carrier.

14 . A CaSR agonist comprising the crystal according to claim 1 .

15 . A drug for the prevention or treatment of hyperparathyroidism comprising the crystal according to claim 1 .

16 . A process for producing a crystal according to claim 1 which is a form A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid, comprising crystallizing 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid in an appropriate solvent in the presence of a base by adding an acid at 50 to 70° C.

17 . A process for producing a crystal according to claim 1 which is a form B crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid, comprising rapidly crystallizing 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid in an appropriate solvent in the presence of a base by adding an acid at 20 to 40° C.

18 . A process for producing a crystal according to claim 1 which is a form A crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid, comprising seeding a form A crystal to a slurry of a form B crystal of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid and crystallizing the form A crystal at 40 to 70° C., or dissolving a form B crystal into a solution comprising a good solvent and a poor solvent at 40 to 60° C. and then recrystallizing the form A crystal at 20 to 25° C.

19 . A process for producing a compound represented by Formula (4):

or a salt thereof
comprising:
reacting a compound represented by Formula (1):

(wherein P 1 is an amino-protecting group)
with a 2-nitrobenzenesulfonyl halide to form a compound represented by Formula (2):

(wherein Ns is 2-nitrobenzenesulfonyl and P 1 is the same as defined above);
reacting the compound with 1R-(1-naphthyl)ethylamine in the presence of a base to form a compound represented by Formula (3):

(wherein P 1 is the same as defined above); and
deprotecting the compound.

20 . A process for producing a crystal according to claim 1 , comprising:
reacting a compound represented by Formula (4):

or a salt thereof, after it is treated with a base as necessary, with a compound represented by Formula (5):

(wherein Hal is a halogen and R is a carboxylic acid-protecting group)
in the presence of a palladium catalyst, a base and a ligand to form a compound represented by Formula (6):

(wherein R is the same as defined above)

or a salt thereof; and
hydrolyzing the compound or the salt with a base followed by neutralization with an acid.

21 . A process for producing a crystal according to claim 1 , comprising:
reacting a compound represented by Formula (1):

(wherein P 1 is an amino-protecting group)
with a 2-nitrobenzenesulfonyl halide to form a compound represented by Formula (2):

(wherein Ns is 2-nitrobenzenesulfonyl and P 1 is the same as defined above);
reacting the compound with 1R-(1-naphthyl)ethylamine in the presence of a base to form a compound represented by Formula (3):

(wherein P 1 is the same as defined above);
deprotecting the compound to form a compound represented by Formula (4):

or a salt thereof
reacting the compound or the salt, after it is treated with a base as necessary, with a compound represented by Formula (5):

(wherein Hal is a halogen and R is a carboxylic acid-protecting group)
in the presence of a palladium catalyst, a base and a ligand to form a compound represented by Formula (6):

(wherein R is the same as defined above)

or a salt thereof; and
hydrolyzing the compound or the salt with a base followed by neutralization with an acid.

22 . A compound represented by Formula (6):

(wherein R is a carboxylic acid-protecting group)

or a salt thereof.

23 . The compound or the salt thereof according to claim 22 , wherein R is ethyl.

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Miyazaki Hiroshi
• Komasaka Takao
• Tsurumoto Joji
• Uemura Takeshi
• Morita Yuuji

Classifications

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D207/50 Primary

  Nitrogen atoms · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/20 Primary

  for decreasing, blocking or antagonising the activity of PTH · CPC title

• A61K31/402 Primary

  1-aryl substituted, e.g. piretanide · CPC title