# US 8,541,443 B2 · Crystal of diamine derivative and method of producing same

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- Number: US 8,541,443 B2
- Document ID: US8541443B2
- Status: Granted
- Kind: B2
- Application number: 13/622,783
- Filed: 2012-09-19
- Published: 2013-02-07
- Granted: 2013-09-24
- Earliest claimed: 2010-03-19
- Assignees: Daiichi Sankyo Company, Limited
- Applicants: Daiichi Sankyo Company, Limited
- Inventors: Tetsuya Suzuki; Makoto Ono
- Web page: https://patentgrep.com/patent/US8541443B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

An object of the present invention is to provide a novel crystal form of a compound that has an inhibitory effect on activated blood coagulation factor X and is useful as a pharmaceutical compound for prevention and/or treatment of thrombotic and/or embolic diseases. The present invention provides a novel crystal form of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate, and method for producing the same.

## Claims

### Claim 1

Form II crystals of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate represented by the following formula (I):
comprising peaks at diffraction angles (2θ) of 13.9±0.2, 14.2±0.2, 15.8±0.2, 16.2±0.2, 18.2±0.2, 21.5±0.2, 22.0±0.2, 22.3±0.2, 23.2±0.2, and 24.3±0.2(°) in powder x-ray diffraction obtained using Cu-Kα rays.

### Claim 2 (depends on 1)

The crystals according to claim 1, wherein the powder x-ray diffraction obtained using Cu-Kα rays shows a pattern represented by line (2) in FIG. 1(a) or by Form II in FIG. 3.

### Claim 3 (depends on 1)

The crystals according to claim 1, wherein the crystals exhibit a differential thermal analysis profile having at least one endothermic peak in any one of the ranges of 160° C. to 170° C. and 215° C. to 225° C.

### Claim 4 (depends on 1)

The crystals according to claim 1, comprising any one absorption band selected from the group consisting of 3313±5, 839±1, and 828±1 (cm−1) in a Fourier-transform infrared absorption spectrum.

### Claim 5 (depends on 1)

The crystals according to claim 1, wherein the crystals have at least one feature selected from the group consisting of the following (a) to (d):
(a) a differential thermal analysis profile having at least one endothermic peak in each of the ranges of 160° C. to 170° C., 215° C. to 225° C., and 260° C. to 270° C.;
(b) differential thermal analysis and thermogravimetry profiles represented by FIGS. 5(a)-5(b);
(c) a Fourier-transform infrared absorption spectrum pattern represented in FIG. 6; and
(d) a Fourier-transform infrared absorption spectrum pattern showing absorption bands and their intensities described in FIG. 7.

### Claim 6

A method for producing Form II crystals of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate represented by the following formula (I):
comprising peaks at diffraction angles (2θ) of 13.9±0.2, 14.2±0.2, 15.8±0.2, 16.2±0.2, 18.2±0.2, 21.5±0.2, 22.0±0.2, 22.3±0.2, 23.2±0.2, and 24.3±0.2(°) in powder x-ray diffraction obtained using Cu-Kα rays, the method comprising the steps of
(a) converting a compound represented by formula (I) to an amorphous or low crystalline solid by the dissolution of the compound represented by formula (I) in water, dioxane, aqueous dioxane, or dimethyl sulfoxide followed by freeze drying; and
(b) exposing the amorphous or low crystalline solid to solvent vapor.

### Claim 7 (depends on 6)

The method according to claim 6, wherein step (a) comprises preparing the amorphous or low crystalline solid by the dissolution of the compound represented by formula (I) in aqueous dioxane followed by freeze drying.

### Claim 8 (depends on 6)

The method according to claim 6, wherein the solvent used in the vapor exposure in step (b) is anisole, acetone, 2-butanone, toluene, acetonitrile, dimethoxyethane, or dimethoxymethane.

### Claim 9 (depends on 6)

The method according to claim 6, wherein the vapor exposure temperature in step (b) is 0° C. to 50° C.

### Claim 10 (depends on 6)

The method according to claim 6, wherein the vapor exposure time in step (b) is 1 day to 10 days.

### Claim 11 (depends on 6)

The method according to claim 6, wherein the compound represented by formula (I) in step (a) is Form I crystals of the compound represented by formula (I).

### Claim 12 (depends on 6)

The method according to claim 6, wherein the Form II crystals exhibit a pattern represented by line (2) in FIG. 1(a) or by Form II in FIG. 3 in the powder x-ray diffraction obtained using Cu-Kα rays.

### Claim 13 (depends on 6)

The method according to claim 6, wherein the Form II crystals exhibit a differential thermal analysis profile having at least one endothermic peak in any one of the ranges of 160° C. to 170° C. and 215° C. to 225° C.

### Claim 14 (depends on 6)

The method according to claim 6, wherein the Form II crystals comprise any one absorption band selected from the group consisting of 3313±5, 839±1, and 828±1 (cm−1) in a Fourier-transform infrared absorption spectrum.

### Claim 15 (depends on 6)

The method according to claim 6, wherein the Form II crystals have at least one feature selected from the group consisting of the following (a) to (d):
(a) a differential thermal analysis profile having at least one endothermic peak in each of the ranges of 160° C. to 170° C., 215° C. to 225° C., and 260° C. to 270° C.;
(b) differential thermal analysis and thermogravimetry profiles represented by FIGS. 5(a)-5(b);
(c) a Fourier-transform infrared absorption spectrum pattern represented by FIG. 6; and
(d) a Fourier-transform infrared absorption spectrum pattern showing absorption bands and their intensities described in FIG. 7.

### Claim 16 (depends on 6)

Form II crystals of a compound represented by formula (I)
obtained by a method according to claim 6.

### Claim 17 (depends on 6)

A pharmaceutical drug containing Form II crystals of a compound represented by formula (I)
comprising peaks at diffraction angles (2θ) of 13.9±0.2, 14.2±0.2, 15.8±0.2, 16.2±0.2, 18.2±0.2, 21.5±0.2, 22.0±0.2, 22.3±0.2, 23.2±0.2, and 24.3±0.2(°) in powder x-ray diffraction obtained using Cu-Kα rays or Form II crystals of a compound represented by formula (I) obtained by a method according to claim 6.

### Claim 18 (depends on 17)

The pharmaceutical drug according to claim 17, wherein the pharmaceutical drug is an activated blood coagulation factor X (FXa) inhibitor.

### Claim 19 (depends on 18)

The pharmaceutical drug according to claim 18, wherein the pharmaceutical drug is an agent for treating thrombus or embolism.

### Claim 20 (depends on 19)

The pharmaceutical drug according to claim 19, wherein the pharmaceutical drug is an agent for treating cerebral infarction, cerebral embolism, pulmonary infarction, pulmonary embolism, myocardial infarction, angina pectoris, acute coronary syndrome, thrombus and/or embolism accompanying nonvalvular atrial fibrillation, deep vein thrombosis, deep vein thrombosis after surgery, thrombosis after prosthetic valve/joint replacement, thromboembolism after total hip replacement, thromboembolism after total knee replacement, thromboembolism after hip fracture surgery, thrombosis and/or reocclusion after revascularization, Buerger's disease, disseminated intravascular coagulation syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, thrombosis at the time of extracorporeal circulation, or blood coagulation at the time of blood collection.

### Claim 21 (depends on 6)

A pharmaceutical composition comprising Form II crystals of a compound represented by formula (I)
comprising peaks at diffraction angles (2θ) of 13.9±0.2, 14.2±0.2, 15.8±0.2, 16.2±0.2, 18.2±0.2, 21.5±0.2, 22.0±0.2, 22.3±0.2, 23.2±0.2, and 24.3±0.2(°) in powder x-ray diffraction obtained using Cu-Kα rays or Form II crystals of a compound represented by formula (I) obtained by a method according to claim 6, and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 9)

A pharmaceutical composition comprising a compound represented by formula (I)
wherein the pharmaceutical composition comprises Form II crystals of a compound represented by formula (I) comprising peaks at diffraction angles (2θ) of 13.9±0.2, 14.2±0.2, 15.8±0.2, 16.2±0.2, 18.2±0.2, 21.5±0.2, 22.0±0.2, 22.3±0.2, 23.2±0.2, and 24.3±0.2(°) in powder x-ray diffraction obtained using Cu-Kα rays or Form II crystals of a compound represented by formula (I) obtained by a method according to claim 9, in an amount of 0.01 wt. % to 99.9 wt. % with respect to the total weight of compound I in the pharmaceutical composition.