WO2011024874A1

WO2011024874A1 - Base addition salts

Info

Publication number: WO2011024874A1
Application number: PCT/JP2010/064416
Authority: WO
Inventors: エムディアスペレスビクトル; ヒルジェニファー
Original assignee: 日本新薬株式会社
Priority date: 2009-08-26
Filing date: 2010-08-25
Publication date: 2011-03-03

Abstract

Provided is novel base addition salts of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as "compound (A)"). As an example of the aforesaid base addition salts, a base addition salt composed of compound (A) and a base selected from the group consisting of (a) to (d) can be cited: (a) t-butylamine; (b) potassium; (c) sodium; and (d) dimethylaminoethanol.

Description

Base addition salt

The present invention relates to 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide (hereinafter referred to as “Compound A”). Of the novel base addition salt.

Compound A has an excellent PGI2 receptor agonistic action, and is known to exhibit various medicinal effects such as platelet aggregation inhibitory action, vasodilatory action, bronchial muscle dilator action, lipid deposition inhibitory action, leukocyte activation inhibitory action, etc. (For example, refer to Patent Document 1).
Specifically, Compound A can be used for transient cerebral ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbances (eg, chronic arterial occlusion, intermittent claudication, peripheral arterial embolism, vibrations). Disease, Raynaud's disease), collagen disease (eg systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis syndrome), reocclusion / restenosis after percutaneous coronary angioplasty (PTCA), arteriosclerosis Disease, thrombosis (eg acute cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disease (eg cerebral infarction, myocardial infarction), angina (eg stable angina, unstable narrowness) Heart disease), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcers, pressure ulcers (bed sores), restenosis after coronary intervention such as atherectomy and stent placement, thrombocytopenia due to dialysis, organ Or tissue fibrosis Diseases [eg, renal diseases (eg, tubulointerstitial nephritis), respiratory diseases (eg, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, etc.), gastrointestinal diseases (eg, cirrhosis, Viral hepatitis, chronic pancreatitis, Skills gastric cancer), cardiovascular disease (eg, myocardial fibrosis), bone / joint disease (eg, myelofibrosis, rheumatoid arthritis), skin disease (eg, post-surgical scar, burn scar) , Keloids, hypertrophic scars), obstetric diseases (eg, uterine fibroids), urological diseases (eg, prostatic hypertrophy), other diseases (eg, Alzheimer's disease, sclerosing peritonitis, type I diabetes, postoperative organ adhesion)] Erectile dysfunction (eg diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after intrapelvic surgery for prostatectomy, blood vessels associated with aging and arteriosclerosis Sexual erection All), inflammatory bowel disease (eg ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, intestinal ulcer associated with Behcet's disease), gastritis, gastric ulcer, ischemic eye disease (eg retinal artery occlusion, Retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular osteonecrosis, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib ) Intestinal injuries associated with administration (for example, injuries occurring in the duodenum, small intestine, large intestine, but not limited, for example, mucosal damage and ulcers such as erosion in the duodenum, small intestine, large intestine), spinal stenosis (for example, Cervical spinal stenosis, thoracic spinal stenosis, lumbar spinal stenosis, extensive spinal stenosis, sacral stenosis) It is known to be useful as a prophylactic or therapeutic agent for accompanying symptoms (eg, paralysis, hypoperception, pain, numbness, decreased walking ability) (see, for example, Patent Documents 1 to 6). Compound A is also known to be useful as an angiogenesis promoter such as gene therapy or autologous bone marrow cell transplantation, and an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis (for example, patents). Reference 1).
As described above, although compound A is known to be useful as a therapeutic agent for various diseases, the presence or absence of the salt of compound A is not described.

International Publication No. 2002/088084 International Publication No. 2009/157396 International Publication No. 2009/107736 International Publication No. 2009/154246 International Publication No. 2009/157397 International Publication No. 2009/157398

The main object of the present invention is to provide a novel salt of Compound A. Another object of the present invention is to provide a pharmaceutical composition containing the salt as an active ingredient.

The present inventors consider the pKa of Compound A and its medicinal use potential, 5 acids (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid) and 14 bases. (Potassium hydroxide, sodium hydroxide, L-arginine, calcium hydroxide, magnesium hydroxide, choline, L-lysine, t-butylamine, ethylenediamine, ammonia, dimethylaminoethanol, N-methylglucamine, tromethamine, hydroxyethylmorpholine As a result of diligent investigation as to whether the compound A and the acid or base form a salt, the compound A was found to form a salt with a limited base, and the present invention was completed.

Examples of the present invention include the following (1) to (22).
(1) Base addition salt of compound A and a base selected from the group consisting of the following (a) to (d) (hereinafter referred to as “the salt of the present invention”):
(A) t-butylamine,
(B) potassium,
(C) sodium, and (d) dimethylaminoethanol,
(2) the base addition salt of (1) above, wherein the base is t-butylamine;
(3) The base addition salt of (2) above, which is a crystal,
(4) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.2 degrees, 9.0 degrees, 13.5 degrees, 19.4 degrees And a base addition salt of (3) (hereinafter referred to as “t-butylamine salt type I crystal”), which exhibits a diffraction peak at 21.0 degrees.
(5) The base addition salt of (1) above, wherein the base is potassium,
(6) The base addition salt of (5) above, which is a crystal,
(7) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.4 degrees, 8.7 degrees, 13.1 degrees, 20.4 degrees And the base addition salt of (6) (hereinafter, referred to as “type I crystal of potassium salt”), which exhibits a diffraction peak at 21.9 degrees.
(8) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.6 degrees, 8.0 degrees, 11.6 degrees, 12.5 degrees And the base addition salt of (6) (hereinafter referred to as “type II crystal of potassium salt”), which exhibits a diffraction peak at 18.7 degrees and 18.7 degrees.
(9) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.5 degrees, 6.5 degrees, 8.4 degrees, 9.7 degrees And the base addition salt of (6) (hereinafter referred to as “III-type crystal of potassium salt”), which exhibits a diffraction peak at 15.2 degrees.
(10) In a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), diffraction peaks are shown at the following diffraction angles 2θ: 4.8 degrees, 7.0 degrees, and 9.7 degrees. , The base addition salt of (6) above (hereinafter referred to as “potassium salt type VI crystal”),
(11) The base addition salt of (1) above, wherein the base is sodium,
(12) The base addition salt of (11), which is a crystal,
(13) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.5 degrees, 12.4 degrees, 19.7 degrees, 20.7 degrees And the base addition salt of (12) (hereinafter referred to as “sodium salt type I crystal”), which exhibits a diffraction peak at 22.9 degrees.
(14) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angle 2θ: 4.8 degrees, 5.6 degrees, 8.9 degrees, 11.2 degrees And the base addition salt of (12) (hereinafter referred to as “type II crystal of sodium salt”), which exhibits a diffraction peak at 17.8 degrees and 17.8 degrees.
(15) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 7.2 degrees, 10.1 degrees, 11.0 degrees, 17.2 degrees And the base addition salt of (12) above (hereinafter referred to as “type III crystal of sodium salt”), which shows a diffraction peak at 23.7 degrees and 23.7 degrees.
(16) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.6 degrees, 11.9 degrees, 21.1 degrees, 21.8 degrees And the base addition salt of (12) (hereinafter referred to as “sodium salt type IV crystal”), which exhibits a diffraction peak at 24.6 degrees.
(17) In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 5.6 degrees, 8.1 degrees, 10.9 degrees, 16.4 degrees And a base addition salt of (12) (hereinafter referred to as “V-form crystal of sodium salt”), which shows a diffraction peak at 23.1 degrees.
(18) The base addition salt of the above (1), wherein the base is dimethylaminoethanol,
(19) The base addition salt of (18), which is a crystal,
(20) In a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.7 degrees, 11.4 degrees, 18.2 degrees, 19.7 degrees And the base addition salt of (19) (hereinafter referred to as “type I crystal of dimethylaminoethanol salt”) showing a diffraction peak at 20.7 degrees
(21) In a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 11.0 degrees, 15.4 degrees, 18.2 degrees, 21.6 degrees And a base addition salt of (19) (hereinafter referred to as “type II crystal of dimethylaminoethanol salt”) showing a diffraction peak at 22.4 degrees, and
(22) A pharmaceutical composition comprising the base addition salt of any one of (1) to (21) as an active ingredient (hereinafter referred to as “the pharmaceutical composition of the present invention”).

The diffraction angle 2θ of the diffraction peak in the present invention should be understood that the obtained value is within the range of the value ± 0.2 degrees, preferably within the range of the value ± 0.1 degrees.

Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]). Represents a powder X-ray diffraction spectrum. The horizontal axis represents the diffraction angle (2θ [°]).

The salt of the present invention is a base addition salt of compound A and a base selected from the group consisting of the following (a) to (d).
(A) t-butylamine,
(B) potassium,
(C) sodium, and (d) dimethylaminoethanol.
The salt of the present invention may be an anhydride, hydrate, or solvate. Further, the salt of the present invention may be a crystal.

Examples of the t-butylamine salt of Compound A include type I crystals of t-butylamine salt.
Type I crystals of t-butylamine salt can be produced, for example, by the method described in Example 1 described later. Form I crystals of t-butylamine salt are at least 8.2 degrees, 9.0 degrees, 13.5 degrees, 19. in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54１．５). It is characterized by showing diffraction peaks at diffraction angles (2θ) of 4 degrees and 21.0 degrees.

Examples of the potassium salt of Compound A include potassium salt I-IV crystals.
The potassium salt type I crystal can be produced, for example, by the method described in Example 2 described later. Type I crystals of potassium salt are at least 4.4 degrees, 8.7 degrees, 13.1 degrees, 20.4 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 21.9 degrees.
Type II crystals of potassium salt can be produced, for example, by the method described in Example 3 described later. Type II crystals of potassium salt are at least 4.6 degrees, 8.0 degrees, 11.6 degrees, 12.5 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 18.7 degrees.
The type III crystal of the potassium salt can be produced, for example, by the method described in Example 4 described later. Type III crystals of potassium salt are at least 4.5 degrees, 6.5 degrees, 8.4 degrees, 9.7 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 15.2 degrees.
The IV salt crystal of potassium salt can be produced, for example, by the method described in Example 5 described later. Potassium salt type IV crystals have diffraction angles (2θ) of at least 4.8, 7.0 and 9.7 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54１．５). ) Is a diffraction peak.

Examples of the sodium salt of Compound A include sodium salt type I to V crystals.
The sodium salt type I crystal can be produced, for example, by the method described in Example 6 described later. Sodium salt Form I crystals are at least 8.5 degrees, 12.4 degrees, 19.7 degrees, 20.7 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 22.9 degrees.
Sodium salt type II crystals can be produced, for example, by the method described in Example 7 described later. Sodium salt type II crystals are at least 4.8 degrees, 5.6 degrees, 8.9 degrees, 11.2 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 17.8 degrees.
Sodium salt type III crystals can be produced, for example, by the method described in Example 8 described later. Sodium salt type III crystals are at least 7.2 degrees, 10.1 degrees, 11.0 degrees, 17.2 degrees in a powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 23.7 degrees.
Sodium salt type IV crystals can be produced, for example, by the method described in Example 9 described later. Sodium salt type IV crystals are at least 4.6 degrees, 11.9 degrees, 21.1 degrees, 21.8 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 24.6 degrees.
Sodium salt V-type crystals can be produced, for example, by the method described in Example 10 described later. Sodium salt V-type crystals are at least 5.6 degrees, 8.1 degrees, 10.9 degrees, 16.4 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å). And a diffraction peak at a diffraction angle (2θ) of 23.1 degrees.

Examples of the dimethylaminoethanol salt of Compound A include type I and II crystals of dimethylaminoethanol salt.
Type I crystals of dimethylaminoethanol salt can be produced, for example, by the method described in Example 11 described later. Form I crystals of dimethylaminoethanol salt are at least 8.7 degrees, 11.4 degrees, 18.2 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), It is characterized by showing diffraction peaks at diffraction angles (2θ) of 19.7 degrees and 20.7 degrees.
Type II crystals of dimethylaminoethanol salt can be produced, for example, by the method described in Example 12 described later. Form II crystals of dimethylaminoethanol salt are at least 11.0 degrees, 15.4 degrees, 18.2 degrees in the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), It is characterized by showing diffraction peaks at diffraction angles (2θ) of 21.6 degrees and 22.4 degrees.

A drug or bulk drug with improved hygroscopicity reduces the storage and quality control problems at humidity in its storage state. Moreover, when manufacturing solid preparations, such as a tablet and a capsule, the problem on the preparation based on the weight change of an active ingredient is reduced.
In particular, as shown in the test examples to be described later, since the t-butylamine salt type I crystal is extremely stable even under high humidity conditions, stable storage and easy quality control can be expected, so that certain effects can be expected. It is of high quality and has a form that is industrially easy to handle.

A. Production of Compound A Compound A can be produced , for example, by the method described in Patent Document 1, but can also be produced by the production method described below.

Process 1
6-iodo-2,3-diphenylpyrazine can be produced by reacting 6-chloro-2,3-diphenylpyrazine with sodium iodide. This reaction is performed in an organic solvent (for example, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixed solvent thereof) in the presence of an acid. Examples of the acid used include acetic acid, sulfuric acid, and mixed acids thereof. The amount of sodium iodide used is, for example, suitably in the range of 1 to 10 moles per mole of 6-chloro-2,3-diphenylpyrazine, preferably 2 to 3 moles. Is within the range. The reaction temperature varies depending on the raw materials used and the type of acid, but is usually within the range of 60 ° C to 90 ° C. The reaction time varies depending on the raw materials to be used, the type of acid, and the reaction temperature, but is usually within the range of 9 to 15 hours.

Process 2
5,6-Diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine can be produced by reacting 6-iodo-2,3-diphenylpyrazine with 4-hydroxybutyl (isopropyl) amine. This reaction is performed in the presence of a base in an organic solvent (for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethyl sulfoxide, or a mixed solvent thereof). Examples of the base to be used include sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate or a mixed base thereof. The amount of 4-hydroxybutyl (isopropyl) amine used is, for example, suitably within the range of 1.5 mol to 5.0 mol with respect to 1 mol of 6-iodo-2,3-diphenylpyrazine, preferably It is in the range of 2 mol to 3 mol. The reaction temperature varies depending on the raw materials used and the type of base, but is usually within the range of 170 ° C to 200 ° C. The reaction time varies depending on the raw materials and bases used and the reaction temperature, but it is usually within the range of 5 to 9 hours.

Process 3
Compound A can be prepared by reacting 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine with N- (2-chloroacetyl) -methanesulfonamide. This reaction is carried out in an organic solvent (N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof) in the presence of a base. Examples of the base used include potassium t-butoxide, sodium t-butoxide, and mixed bases thereof. The amount of N- (2-chloroacetyl) -methanesulfonamide used is, for example, from 2 mol to 4 mol per mol of 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine. The range is appropriate, preferably in the range of 2 to 3 moles. The reaction temperature varies depending on the raw materials used and the type of base, but is usually within the range of −20 ° C. to 20 ° C. The reaction time varies depending on the raw materials and bases used and the reaction temperature, but it is usually within the range of 0.5 to 2 hours.

Each compound used as a raw material in the said manufacturing method of compound A is a well-known compound, or can be manufactured according to a well-known method.

B. Production of the salt of the present invention The salt of the present invention can be obtained, for example, by the following method.
The salt of the present invention comprises compound A in an appropriate solvent (for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile). After dissolution and addition of the desired base, the mixed solution is concentrated, if necessary, or the precipitate produced by standing at room temperature or cooling under stirring or standing is collected by filtration. The desired salt of the present invention can be obtained by washing with an appropriate solvent. In addition, when cooling, it may be effective not only to cool, but also to obtain a good crystal by slow cooling or rapid cooling. In addition, adding an ether solvent (eg, t-butyl methyl ether), an ester solvent (eg, ethyl acetate), or an aromatic hydrocarbon (eg, toluene) is effective for obtaining good crystals. There is a case.

The amount of the solvent used for dissolving Compound A is, for example, suitably in the range of 10 ml to 300 ml with respect to 1 g of Compound A.
The amount of the base used for producing the salt of the present invention is suitably in the range of 0.5 mol to 1.2 mol with respect to 1 mol of compound A, for example.
Moreover, this invention salt which is a crystal | crystallization can be obtained by the method as described in the below-mentioned Example, for example.

C. Medicinal Use / Pharmaceutical Composition of the Present Invention The salt of the present invention or the pharmaceutical composition of the present invention, like compound A, is used for transient cerebral ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulation disorder (for example, Chronic arterial occlusion, intermittent claudication, peripheral arterial embolism, vibration disease, Raynaud's disease), collagen disease (eg systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitis syndrome), percutaneous coronary angioplasty Re-occlusion / restenosis after surgery (PTCA), arteriosclerosis, thrombosis (eg acute cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disease (eg cerebral infarction, myocardial infarction) , Angina pectoris (eg, stable angina pectoris, unstable angina pectoris), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bed sore), atherectomy and stent placement, etc. Restenosis after coronary intervention in children , Dialysis-induced thrombocytopenia, diseases involving fibrosis of organs or tissues [eg, renal diseases (eg, tubulointerstitial nephritis), respiratory diseases (eg, interstitial pneumonia (pulmonary fibrosis), chronic obstruction) Pulmonary diseases, etc.), gastrointestinal diseases (eg, cirrhosis, viral hepatitis, chronic pancreatitis, Skills gastric cancer), cardiovascular diseases (eg, myocardial fibrosis), bone / joint diseases (eg, myelofibrosis, rheumatoid arthritis) Skin diseases (eg, post-surgical scars, burn scars, keloids, hypertrophic scars), obstetric diseases (eg, uterine fibroids), urological diseases (eg, prostatic hypertrophy), other diseases (eg, Alzheimer's disease, Sclerosis peritonitis, type I diabetes, postoperative organ adhesion)], erectile dysfunction (eg, diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction due to chronic renal failure, pelvis for prostatectomy Erectile dysfunction after surgery, vascular erectile dysfunction associated with aging or arteriosclerosis), inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease, intestinal tuberculosis, ischemic colitis, intestinal ulcer associated with Behcet's disease), Gastritis, gastric ulcer, ischemic eye disease (eg, retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular osteonecrosis, nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, diclofenac) , Meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) intestinal injury (for example, duodenum, small intestine, large intestine) is not particularly limited, for example, duodenum, small intestine, large intestine Mucosal injury and ulcers such as erosion), spinal stenosis (eg, cervical spinal stenosis, thoracic spinal stenosis, It is useful as a prophylactic or therapeutic agent for symptoms associated with lumbar spinal canal stenosis, extensive spinal canal stenosis, sacral stenosis (eg, paralysis, hypoperception, pain, numbness, decreased walking ability). In addition, the salt of the present invention or the pharmaceutical composition of the present invention is also useful as an accelerator for angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation, and an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.

When the salt of the present invention is administered as a pharmaceutical, the salt of the present invention is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, within a range of 0.001 to 99.5% by weight. Preferably, it is contained within the range of 0.01% to 90% by weight.
Examples of the carrier include auxiliaries such as solid, semi-solid or liquid diluents, fillers, and other commonly used excipients. One or more of these can be used.

The pharmaceutical composition of the present invention is a solid or liquid dosage unit, and is an orally administered preparation such as powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, troche, etc. Any form of parenteral preparations such as injections and suppositories can be used. Further, it may be a sustained-release preparation.
The powder can be produced by using the salt of the present invention as it is or by making it fine.
The powder can be produced by subjecting the salt of the present invention as it is or to an appropriate fineness and then mixing it with a pharmaceutical carrier, for example, an edible carbohydrate such as starch or mannitol. A flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance and the like can be optionally added.
Capsules can be produced by first filling powdery powders, powders or tablets granulated as described above into gelatin capsules, for example.
Lubricants and fluidizing agents such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powders and powders and then filled. Can be manufactured. When disintegrators and solubilizers are added, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate In addition, the effectiveness of the medicine can be improved. Alternatively, the fine powder of the salt of the present invention may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant and wrapped in a gelatin sheet to form a soft capsule.
Tablets are prepared by adding the excipients of the salt of the present invention as they are or by making them fine to make a powder mixture, granulating or slugging, adding a disintegrating agent or lubricant, and then tableting. Can be manufactured.
In addition to excipients, the powder mixture may contain a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), a dissolution delaying agent (for example, paraffin), Absorbents (for example, quaternary salts), adsorbents (for example, bentonite, kaolin) and the like can be added.
The powder mixture is first moistened with a binder (eg, syrup, starch paste, gum arabic, cellulose solution or polymer solution), stirred, mixed, granulated, dried and pulverized into granules. it can. Instead of granulating the powder in this way, it is also possible to first pulverize the resulting incomplete slag after it is subjected to a compressor. As a lubricant, for example, stearic acid, stearate, talc, mineral oil or the like can be added to the granules thus produced for tableting.
A tablet can also be produced by directly compressing the salt of the present invention after mixing it with a fluid inert carrier without going through the granulation step as described above.
Film tablets and sugar coatings can be applied to the tablets thus produced. A transparent or translucent protective coating made of shellac coating, a coating of sugar or polymer material, a polishing agent made of wax, or the like can be used.
Other oral dosage forms, such as solutions, syrups, troches, elixirs, can also be in dosage unit form so that a given quantity contains a certain amount of a salt of the invention.
A syrup can be produced by dissolving the salt of the present invention in an appropriate flavor aqueous solution. An elixir can be produced by using a non-toxic alcoholic carrier.
The suspension can be produced by dispersing the salt of the present invention in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin) and the like can be added. .
If necessary, dosage unit formulations for oral administration can be microencapsulated. The pharmaceutical composition can also be provided with a coating or embedded in a polymer / wax to prolong the action time or provide sustained release.
A parenteral preparation can take the form of a liquid dosage unit, for example, a solution or suspension, which is subcutaneously, intramuscularly or intravenously injected. The parenteral preparation is prepared by suspending or dissolving a certain amount of the salt of the present invention in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then sterilizing the suspension or solution. Can be manufactured. In addition, stabilizers, preservatives, emulsifiers, and the like can be added.
Suppositories are solids in which the salt of the present invention is soluble or insoluble in low-melting water, for example, polyethylene glycol, cacao butter, semi-synthetic fats and oils [for example, Witepsol (registered trademark)], higher esters (for example, palmitic acid). Myristyl ester) or a mixture thereof.

The dose varies depending on the patient's condition such as body weight and age, administration route, nature and degree of illness, etc., but generally, 0.001 mg per day as the amount of the salt of the present invention for adults. The range of ˜100 mg is suitable, and the range of 0.01 mg to 10 mg is preferable.
In some cases, this may be sufficient, and vice versa. Moreover, it can be administered once to several times a day or at intervals of 1 day to several days.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples.
The powder X-ray diffraction spectrum was measured by Bruker AXS C2 GADDS (target: Cu, voltage: 40 kV, current: 40 mA, Cu Kα radiation (λ = 1.54Å), two-dimensional detector, effective 2θ width: 3.2 ° to 29 °. 7 degrees, measurement time: 120 seconds, measurement error: 2θ ± 0.1 degrees (hereinafter referred to as “B apparatus”), or Rigaku RINT-Ultima III (target: Cu, voltage: 40 kV, current: 40 mA, Cu Kα radiation (λ = 1.54 mm), effective 2θ width: 4.0 ° to 40.0 °, measurement time: 540 seconds, measurement error: 2θ ± 0.1 ° (hereinafter “R device”) Obtained). Needless to say, the diffraction angle (2θ) in the powder X-ray diffraction spectrum may vary slightly from instrument to instrument or from sample to sample. Therefore, the value of the diffraction angle (2θ) should not be interpreted as an absolute value.
The endothermic peak was measured using a differential scanning calorimeter: DSC-50 (manufactured by Shimadzu Corporation) under the following conditions.
Temperature increase rate: 10 ° C / min Atmosphere: Nitrogen Measurement temperature range: 30-300 ° C
Cell: Aluminum Sealed cell Although the endothermic peak varies slightly depending on the measurement sample, the obtained value should be understood as being within the range of the value ± 2 degrees, preferably within the range of the value ± 1 degree. .
¹ H-NMR spectrum was obtained by Bruker DRX400.

The ¹ H-NMR spectrum data of Compound A used in the following Examples is as follows.

¹ H-NMR (DMSO-d ₆ ): δ 11.73 (s, 1H), 8.14 (s, 1H), 7.18-7.40 (m, 10H), 4.73-4.82 ( m, 1H), 4.04 (s, 2H), 3.50 (t, 2H), 3.45 (t, 2H), 3.34 (s, 3H), 1.55-1.70 (m , 4H), 1.23 (d, 6H)

The present inventors have selected a base (potassium hydroxide, sodium hydroxide, L-arginine, calcium hydroxide, magnesium hydroxide, choline, L-lysine, a compound selected in consideration of the pKa of Compound A and its medicinal use potential. (t-Butylamine, ethylenediamine, ammonia, dimethylaminoethanol, N-methylglucamine, tromethamine, hydroxyethylmorpholine) and various forms of solvent, temperature, precipitation conditions, etc. . As a result, the base addition salts of Compound A shown in Examples 1 to 12 below were found.

Example 1 A t-butylamine salt type I crystalline compound A (40 mg) was dissolved in 0.5 mL of dimethoxyethane (hereinafter referred to as “DME”), t-butylamine (1.1 equivalents) was added, and 25 Stir for 18 hours at ° C. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain type I crystals (39.9 mg) of t-butylamine salt. FIG. 1 shows the powder X-ray diffraction spectrum of the I-type crystal of t-butylamine salt obtained using the B apparatus.
Melting point: 152.5 ° C
Elemental analysis (as _{_{_{_{C 30 H 43 N 5 O 4}}}} S + 0.03H 2 O)
Calculated Value (%) C: 63.18 H: 7.61 N: 12.28
Actual value (%) C: 62.85 H: 7.64 N: 12.52
¹ H-NMR (DMSO-d ₆ ): δ 8.15 (s, 1H), 7.55-7.80 (m, 2H), 7.10-7.45 (m, 10H), 4.70- 4.85 (m, 1H), 3.66 (s, 2H), 3.47 (t, 2H), 3.45 (t, 2H), 2.73 (s, 3H), 1.50-1 .75 (m, 4H), 1.23 (s, 9H), 1.22 (d, 6H)

Example 2 Potassium salt type I crystalline compound A (40 mg) was dissolved in 12 mL of tetrahydrofuran (hereinafter referred to as “THF”), 0.1 M aqueous potassium hydroxide solution (1.1 equivalents) was added, and 40 ° C. And stirred for 15 minutes. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (200 μL). The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This process was repeated two more times and then held at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain potassium salt type I crystals. FIG. 2 shows a powder X-ray diffraction spectrum of a potassium salt type I crystal obtained using the B apparatus.
¹ H-NMR (DMSO-d ₆ ): δ 8.14 (s, 1H), 7.18-7.38 (m, 10H), 4.72-4.84 (m, 1H), 3.65 ( s, 2H), 3.47 (t, 2H), 3.45 (t, 2H), 2.72 (s, 3H), 1.55-1.70 (m, 4H), 1.23 (d , 6H)

Example 3 Type II crystalline compound A (40 mg) of potassium salt was dissolved in 12 mL of THF, 0.1 M aqueous potassium hydroxide solution (1.1 equivalent) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (200 μL). The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain type II crystals of potassium salt. FIG. 3 shows a powder X-ray diffraction spectrum of a type II crystal of potassium salt obtained using the B apparatus.

Example 4 Acetonitrile (1 mL) was added to type III crystalline compound A (100 mg) of potassium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. To the solution was added 3.5M potassium hydroxide / ethanol solution (1.1 equivalent) and stirred at 20 ° C. for 200 minutes. The mixture was heated to 70 ° C. with stirring, stirred for 1 hour, and then cooled to 10 ° C. over 10 hours. The mixture was further heated to 60 ° C. with heating, t-butyl methyl ether (0.3 mL) was added, and the mixture was cooled to 20 ° C. over 10 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain potassium salt type III crystals (75 mg). FIG. 4 shows a powder X-ray diffraction spectrum of a potassium salt type III crystal obtained using an R apparatus. Further, in the differential scanning calorimetry, an endothermic peak was observed around 74 ° C.
Elemental analysis value (as C ₂₆ H ₃₁ N ₄ O ₄ SK + 0.78H ₂ O)
Calculated value (%) C: 56.91 H: 5.98 N: 10.21
Actual value (%) C: 56.61 H: 5.55 N: 10.36

Example 5 Ethyl acetate (1 mL) was added to type IV crystalline compound A (50 mg) of potassium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. To the solution was added 3.5M potassium hydroxide / ethanol solution (2.2 equivalents), and the mixture was stirred at 20 ° C. for 23 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain potassium salt IV type crystals (41 mg). FIG. 5 shows a powder X-ray diffraction spectrum of the IV type crystal of the potassium salt obtained using the R apparatus. Further, in the differential scanning calorimetry, an endothermic peak was observed at about 91 ° C.

Example 6 Sodium salt type I crystalline compound A (40 mg) was dissolved in 12 mL of acetonitrile, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was stirred with heating at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. To the residue was added t-butyl methyl ether (400 μL). The mixture was heated to 50 ° C. while shaking and allowed to cool to 25 ° C. over 8 hours, and then the mixture was heated to 50 ° C. and allowed to cool to 25 ° C. over 8 hours. Further, the mixture was heated to 50 ° C. and allowed to cool for 2 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain sodium salt Form I crystals (19.92 mg). FIG. 6 shows a powder X-ray diffraction spectrum of a sodium salt type I crystal obtained using the B apparatus. In the differential scanning calorimetry, an endothermic peak was observed at around 96 ° C.
¹ H-NMR (DMSO-d ₆ ): δ 8.14 (s, 1H), 7.16-7.40 (m, 10H), 4.72-4.85 (m, 1H), 3.66 ( s, 2H), 3.47 (t, 2H), 3.45 (t, 2H), 2.72 (s, 3H), 1.55-1.72 (m, 4H), 1.23 (d , 6H)

Example 7 Sodium salt type II crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 μL) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain sodium salt type II crystals. FIG. 7 shows a powder X-ray diffraction spectrum of a sodium salt type II crystal obtained using the B apparatus. In the differential scanning calorimetry, an endothermic peak was observed at around 77 ° C.
¹ H-NMR (DMSO-d ₆ ): δ 8.15 (s, 1H), 7.10-7.41 (m, 10H), 4.74-4.85 (m, 1H), 3.66 ( s, 2H), 3.47 (t, 2H), 3.46 (t, 2H), 2.72 (s, 3H), 1.55-1.72 (m, 4H), 1.23 (d , 6H)

Example 8 Sodium salt type III crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 μL) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 3 days to obtain sodium salt type III crystals. FIG. 8 shows a powder X-ray diffraction spectrum of a sodium salt type III crystal obtained using the B apparatus.

Example 9 Sodium salt type IV crystalline compound A (40 mg) was dissolved in 12 mL of THF, 0.1 M aqueous sodium hydroxide solution (1.1 equivalents) was added, and the mixture was heated with stirring at 40 ° C. for 15 min. Thereafter, the solvent was distilled off under reduced pressure. Toluene (200 μL) was added to the residue. The mixture was heated to 50 ° C. with shaking and allowed to cool to 25 ° C. over 8 hours. This operation was repeated two more times and then held at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then left in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain sodium salt type IV crystals. FIG. 9 shows a powder X-ray diffraction spectrum of a sodium salt type IV crystal obtained using the B apparatus.

Example 10 Toluene (1 mL) was added to V-form crystal compound A (50 mg) of sodium salt and stirred while heating to dissolve compound A, and then cooled to 20 ° C. A 3.5 M sodium hydroxide / ethanol solution (1.1 equivalent) was added to the solution, and a small amount of sodium salt type IV crystals was added, followed by stirring at 20 ° C. for 17 hours. Thereafter, the solvent was distilled off under reduced pressure. Toluene (0.5 mL) was added to the residue, followed by stirring at 20 ° C. for 17 hours and 30 minutes. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain sodium salt V-type crystals (35 mg). FIG. 10 shows a powder X-ray diffraction spectrum of a sodium salt V-type crystal obtained using an R apparatus.
Elemental analysis value (as C ₂₆ H ₃₁ N ₄ O ₄ SNa)
Calculated value (%) C: 60.22 H: 6.02 N: 10.80
Actual value (%) C: 60.83 H: 5.93 N: 10.22

Example 11 Form I crystalline compound A (40 mg) of dimethylaminoethanol salt was dissolved in 0.5 mL of DME, dimethylaminoethanol (1.1 equivalents) was added, and the mixture was stirred at 25 ° C. for 18 hours. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration and dried under reduced pressure to obtain type I crystals (30.09 mg) of dimethylaminoethanol salt. FIG. 11 shows an X-ray powder diffraction spectrum of a type I crystal of dimethylaminoethanol salt obtained using the B apparatus.
¹ H-NMR (DMSO-d ₆ ): δ 8.14 (s, 1H), 7.15-7.35 (m, 10H), 5.05-5.20 (brs, 1H), 4.72- 4.85 (m, 1H), 3.75 (s, 2H), 3.64 (t, 2H), 3.47 (t, 2H), 3.45 (t, 2H), 2.96 (t , 2H), 2.85 (s, 3H), 2.64 (s, 6H), 1.55-1.70 (m, 4H), 1.23 (d, 6H)

Example 12 A dimethylaminoethanol salt type II crystalline compound A (40 mg) was dissolved in 0.5 mL of DME, dimethylaminoethanol (1.1 equivalents) was added, and the mixture was stirred at 25 ° C. for 18 hours. Thereafter, t-butyl methyl ether (1 mL) was added to the reaction solution and kept at −20 ° C. for 3 hours. The resulting precipitated crystals were collected by filtration, dried under reduced pressure, and then allowed to stand in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75% for 7 days to obtain type II crystals of dimethylaminoethanol salt. FIG. 12 shows a powder X-ray diffraction spectrum of a type II crystal of dimethylaminoethanol salt obtained using the B apparatus. In the differential scanning calorimetry, an endothermic peak was observed at about 125 ° C.
Elemental analysis (as _{_{_{_{C 30 H 43 N 5 O 5}}}} S + 0.05H 2 O)
Calculated value (%) C: 61.42 H: 7.40 N: 11.94
Actual value (%) C: 61.92 H: 6.99 N: 11.83

Test Example 1 Study on Formation of Acid Addition Salt of Compound A The present inventors also selected an acid (hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, methane) in consideration of the pKa of Compound A and its pharmaceutical use. Whether to form a salt with compound A using sulfonic acid or benzenesulfonic acid was examined by the following method.
Compound A (15 mg) was dissolved in THF (150 μL) or acetonitrile (150 μL), 1.1 equivalents of acid was added to Compound A, and the mixture was stirred at room temperature for 1 hour. Thereafter, the mixture was cooled to −20 ° C. over 18 hours, and the solvent was slowly distilled off over 48 hours. Furthermore, it dried under reduced pressure at 25 degree | times and the residue was obtained. The obtained residue was subjected to structural analysis by ¹ H-NMR and HPLC to confirm whether or not an acid addition salt of Compound A was formed.

The measurement conditions of HPLC (reverse phase liquid chromatography) are as follows.

(Measurement condition)
HPLC apparatus:
Detector: UV spectrophotometer Column: ODS column Column temperature: 40 ° C
Mobile phase: acetonitrile / 0.1% aqueous phosphoric acid / 1M sodium n-propylsulfonate (500/500/1)

Although the above examination was conducted, none of the compounds formed an acid addition salt of Compound A.

Test Example 2 Study on stability of the salt of the present invention under high humidity conditions To examine the stability of t-butylamine salt, dimethylaminoethanol salt, potassium salt, and sodium salt under high humidity conditions, It was left for 3 to 7 days in a constant temperature and humidity chamber with a humidity of 75%.
After standing, the crystal obtained was subjected to structural analysis using a powder X-ray diffractometer (B apparatus) to confirm the crystal form of the crystal. The results are shown in Table 1.

Claims

2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide and the group consisting of the following (a) to (d) Base addition salts with selected bases:
(A) t-butylamine,
(B) potassium,
(C) sodium, and (d) dimethylaminoethanol.
The base addition salt according to claim 1, wherein the base is t-butylamine.
The base addition salt according to claim 2, which is a crystal.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.2 degrees, 9.0 degrees, 13.5 degrees, 19.4 degrees and 21. The base addition salt according to claim 3, which shows a diffraction peak at 0 degree.
The base addition salt according to claim 1, wherein the base is potassium.
The base addition salt according to claim 5, which is a crystal.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.4 degrees, 8.7 degrees, 13.1 degrees, 20.4 degrees and 21. The base addition salt according to claim 6, which shows a diffraction peak at 9 degrees.
In powder X-ray diffraction spectra obtained using Cu Kα radiation (λ = 1.54Å), diffraction angles of at least 4.6 degrees, 8.0 degrees, 11.6 degrees, 12.5 degrees and 18.7 degrees The base addition salt according to claim 6, which shows a diffraction peak at (2θ).
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.5 degrees, 6.5 degrees, 8.4 degrees, 9.7 degrees and 15. The base addition salt according to claim 6, which shows a diffraction peak at 2 degrees.
The powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å) exhibits diffraction peaks at the following diffraction angles 2θ: 4.8 degrees, 7.0 degrees, and 9.7 degrees. 6. A base addition salt according to 6.
The base addition salt according to claim 1, wherein the base is sodium.
The base addition salt according to claim 11, which is a crystal.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.5 degrees, 12.4 degrees, 19.7 degrees, 20.7 degrees and 22. The base addition salt according to claim 12, which exhibits a diffraction peak at 9 degrees.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.8 degrees, 5.6 degrees, 8.9 degrees, 11.2 degrees and 17. The base addition salt according to claim 12, which exhibits a diffraction peak at 8 degrees.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 7.2 degrees, 10.1 degrees, 11.0 degrees, 17.2 degrees and 23. The base addition salt according to claim 12, which exhibits a diffraction peak at 7 degrees.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 4.6 degrees, 11.9 degrees, 21.1 degrees, 21.8 degrees and 24. The base addition salt according to claim 12, which exhibits a diffraction peak at 6 degrees.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 5.6 degrees, 8.1 degrees, 10.9 degrees, 16.4 degrees and 23. The base addition salt according to claim 12, which exhibits a diffraction peak at 1 degree.
The base addition salt according to claim 1, wherein the base is dimethylaminoethanol.
The base addition salt according to claim 18, which is a crystal.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 8.7 degrees, 11.4 degrees, 18.2 degrees, 19.7 degrees and 20. The base addition salt according to claim 19, which exhibits a diffraction peak at 7 degrees.
In the powder X-ray diffraction spectrum obtained using Cu Kα radiation (λ = 1.54Å), the following diffraction angles 2θ: 11.0 degrees, 15.4 degrees, 18.2 degrees, 21.6 degrees and 22. The base addition salt according to claim 19, which exhibits a diffraction peak at 4 degrees.
A pharmaceutical composition comprising the base addition salt according to any one of claims 1 to 21 as an active ingredient.
A PGI2 receptor agonist comprising the base addition salt according to any one of claims 1 to 21 as an active ingredient.
A transient cerebral ischemic attack, diabetic neuropathy, diabetic gangrene, peripheral circulatory disorder, collagen disease, percutaneous coronary artery formation comprising the base addition salt according to any one of claims 1 to 21 as an active ingredient Re-occlusion / restenosis after surgery (PTCA), arteriosclerosis, thrombosis, hypertension, pulmonary hypertension, ischemic disease, angina, glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchi Asthma, ulcers, pressure sores (bed sores), restenosis after coronary intervention such as atherectomy and stent placement, dialysis thrombocytopenia, diseases involving organ or tissue fibrosis, erectile dysfunction, inflammatory bowel disease, gastritis, A prophylactic or therapeutic agent for gastric ulcer, ischemic eye disease, sudden hearing loss, avascular osteonecrosis, intestinal injury associated with administration of nonsteroidal anti-inflammatory drugs (NSAIDs), and symptoms associated with spinal stenosis.
An agent for promoting angiogenesis in gene therapy or autologous bone marrow cell transplantation, comprising the base addition salt according to any one of claims 1 to 21 as an active ingredient.
An angiogenesis promoter for peripheral vascular reconstruction or angiogenesis therapy, comprising the base addition salt according to any one of claims 1 to 21 as an active ingredient.