2-[[[2-[(Hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzenesulfonate, crystal of same, crystal polymorph thereof, and methods for production thereof

Patent metadata

Field	Value
Publication number	US-9902698-B2
Application number	US-201615368028-A
Country	US
Kind code	B2
Filing date	Dec 2, 2016
Priority date	Jul 17, 2009
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

In the course of developing 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide(compound A), there are the multiple problems: 1) compound A or its salt is difficult to be recrystallized, the storage stability largely differs depending on the kind of the salt, and it is very difficult to obtain a salt of compound A having excellent storage stability; 2) in a crystallization process of compound A, it is very difficult to control a crystal polymorph, and 3) compound A (free body) causes mineral deposition in the stomach when it is orally administered repeatedly. For solving these problems, we made examination focusing on the kind of the salt and, as a result, found that 1) benzenesulfonate of compound A does not decompose by light, humidity and other factors in a 1-week preliminary stability test (severe test), and has no problem in its storage stability, 2) a method of selectively producing two kinds of crystal forms of benzenesulfonate of compound A, and that 3) no mineral deposition in the stomach is observed even after a 4-week repeated oral administration.

First claim

The invention claimed is:

1. A method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide having characteristic peaks at 4.4 angstroms, 3.8 angstroms, and 2.3 angstroms as a d value of powder X-ray diffraction pattern, comprising the steps of: adding 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide to a first solvent solution substantially containing only benzenesulfonic acid wherein the first solvent is dimethylsulfoxide or N, N-dimethylformamide; and sequentially adding a second solvent that is selected from the group consisting of water, a lower alkyl alcohol, a lower alkyl ketone and a lower alkylcarboxylic acid ester to the reaction solution.

2. A method of producing a so-called α-form crystal of benzenesulfonate of 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide, having characteristic peaks at 4.4 angstroms, 3.8 angstroms and 2.3 angstroms as a d value of powder X-ray diffraction pattern, comprising the steps of: adding at least either of benzenesulfonic acid and its hydrate to a first solvent solution substantially containing only 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-N-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide, wherein the first solvent is dimethylsulfoxide or N, N-dimethylformamide; and sequentially adding a second solvent that is selected from the group consisting of water, a lower alkyl alcohol, a lower alkyl ketone and a lower alkylcarboxylic acid ester to the reaction solution.

3. The production method according to claim 1 , wherein the second solvent is water, ethanol, acetone or ethyl acetate.

4. The production method according to claim 2 , wherein the second solvent is water, ethanol, acetone or ethyl acetate.

5. The production method according to claim 3 , wherein the second solvent is ethanol.

6. The production method according to claim 4 , wherein the second solvent is ethanol.

Assignees

• Santen Pharmaceutical Co Ltd

Inventors

• Niwa Masashi
• Deguchi Hiroshi

Classifications

• A61P35/00

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• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title