# US 2014/0155414 A1 · Crystals of 2- {4- [n- (5,6-diphenylpyrazin-2-yl) -n-isopropylamino]butyloxy}-n- (methylsulfonyl) acetamide

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- Number: US 2014/0155414 A1
- Document ID: US20140155414A1
- Status: Published application
- Kind: A1
- Application number: 14/160,699
- Filed: 2014-01-22
- Published: 2014-06-05
- Earliest claimed: 2009-06-26
- Assignees: Nippon Shinyaku Co., Ltd.
- Inventors: Hideyuki ITOU; Koji NAKAMICHI; Takashi TOSAKA
- Web page: https://patentgrep.com/patent/US20140155414A1

## CPC

- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- A61K 31/4965: Non-condensed pyrazines
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- 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 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A main object of the present invention is to provide a novel crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”). A Form-I crystal of compound A shows diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees in the powder X-ray diffraction spectrum thereof. A Form-II crystal of compound A shows diffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in the powder X-ray diffraction spectrum thereof. A Form-III crystal of compound A shows diffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees in the powder X-ray diffraction spectrum thereof.

## Claims

### Claim 1

A crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, showing diffraction peaks in its X-ray powder diffraction spectrum at least at the following angles of diffraction 2θ: 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation.

### Claim 2

A crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, showing diffraction peaks in its X-ray powder diffraction spectrum at least at the following angles of diffraction 2θ: 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα radiation.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising the crystal of claim 1 as an active ingredient.

### Claim 4 (depends on 2)

A pharmaceutical composition comprising the crystal of claim 2 as an active ingredient.

### Claim 5 (depends on 1)

A method for producing the crystal of claim 1, comprising the step of
crystallizing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide from a solvent selected from the group consisting of an alcoholic solvent, a ketone solvent, a saturated hydrocarbon solvent, an ether solvent, water, and a mixed solvent thereof.

### Claim 6 (depends on 2)

A method for producing the crystal of claim 2, comprising the step of
crystallizing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide from an ester solvent or an aromatic hydrocarbon solvent.

### Claim 7 (depends on 1)

A method for preventing or treating transient ischemic attack, diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance, connective tissue disease, reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis, hypertension, pulmonary hypertension, ischemic disorder, angina, glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved, erectile dysfunction, inflammatory bowel disease, gastritis, gastric ulcer, ischemic ophthalmopathy, sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent, or symptoms associated with lumbar spinal canal stenosis, comprising the step of administering the crystal of claim 1 as an active ingredient to a subject.

### Claim 8 (depends on 2)

A method for preventing or treating transient ischemic attack, diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance, connective tissue disease, reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis, hypertension, pulmonary hypertension, ischemic disorder, angina, glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved, erectile dysfunction, inflammatory bowel disease, gastritis, gastric ulcer, ischemic ophthalmopathy, sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent, or symptoms associated with lumbar spinal canal stenosis, comprising the step of administering the crystal of claim 2 as an active ingredient to a subject.

### Claim 9 (depends on 1)

A method for accelerating gene therapy or angiogenesis therapy by autologous bone marrow transplantation, comprising the step of administering the crystal of claim 1 as an active ingredient to a subject.

### Claim 10 (depends on 2)

A method for accelerating gene therapy or angiogenesis therapy by autologous bone marrow transplantation, comprising the step of administering the crystal of claim 2 as an active ingredient to a subject.

### Claim 11 (depends on 1)

A method for accelerating angiogenesis in restoration of peripheral artery or angiogenic therapy, comprising the step of administering the crystal of claim 1 as an active ingredient to a subject.

### Claim 12 (depends on 2)

A method for accelerating angiogenesis in restoration of peripheral artery or angiogenic therapy, comprising the step of administering the crystal of claim 2 as an active ingredient to a subject.