JP2001294526A - TNF-alpha INHIBITOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a TNF-α inhibitor excellent in prophylactic and therapeutic effects on TNF-α related diseases such as inflammatory diseases and having sufficiently excellent properties as a medicine such as no found adverse effect. SOLUTION: This TNF-α inhibitor comprises at least one of a compound selected from cerivastatin, atorvastatin, simvastatin, pravastain, itavastain and (+)-(3R,5S)-7-7[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesu lfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid or salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to cerivastatin,
Atorvastatin, simvastatin, pravastatin,
Itavastatin and (+)-(3R, 5S) -7-
[4- (4-fluorophenyl) -6-isopropyl-
2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E)
The present invention relates to a TNF-α inhibitor which contains at least one compound selected from heptenoic acid or a salt thereof, and is useful as a prophylactic / therapeutic agent for TNF-α-related diseases such as inflammatory diseases.

[0002]

2. Description of the Related Art TNF (tumor necrosis factor) -α is considered to play an important role in various diseases. For example, in rheumatoid arthritis, which is an inflammatory disease, it is thought that the production of TNF-α is enhanced, which causes destruction of joint tissues.

[0003]

The development of a TNF-.alpha. Inhibitor having excellent properties as a medicament, such as being excellent in the effects of preventing and treating inflammatory diseases and showing no side effects, has been desired. ing.

[0004]

The present invention relates to (1) cerivastatin ((+)-(3R, 5S, 6E) -7- [4-
(4-fluorophenyl) -2,6-diisopropyl-
5-methoxymethyl-3-pyridyl] -3,5-dihydroxy-6-heptenoic acid), atorvastatin ((β
R, δR) -2- (4-fluorophenyl) -β, δ-
Dihydroxy-5-isopropyl-3-phenyl-4-
(Phenylcarbamoyl) pyrrole-1-heptanoic acid), simvastatin (2,2-dimethylbutanoic acid)
1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8- [2- (tetrahydro-4-hydroxy-
2-oxo-2H-pyran-2-yl) ethyl] -1-
Naphthalenyl ester), pravastatin (1,2,2
6,7,8,8a-Hexahydro-β, δ, 6-trihydroxy-2-methyl-8- (2-methyl-1-oxobutoxy) -1-naphthaleneheptanoic acid), itavastatin (bis ｛(3R , 5S, 6E) -7- [2-Cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5-dihydroxy-6-heptenoic acid) and (+)-(3R, 5S)-. 7- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-
Methanesulfonylamino) pyrimidin-5-yl]-
A TNF-α inhibitor comprising at least one compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or a salt thereof; (2) the TNF according to (1) above, wherein the compound is cerivastatin The TNF-α according to the above (1), wherein the compound is atorvastatin;
An inhibitor, (4) the TNF-α inhibitor according to the above (1), which is a preventive or therapeutic agent for a disease associated with TNF-α, and (5) the TNF-α inhibitor according to the above (4), which is an anti-inflammatory agent. , (6)
Cerivastatin, atorvastatin, simvastatin,
Pravastatin, Itavastatin and (+)-(3
R, 5S) -7- [4- (4-fluorophenyl) -6
-Isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid or at least one effective salt thereof. A method of inhibiting TNF-α, which comprises administering (7) cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- for producing a TNF-α inhibitor. [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-
Methanesulfonylamino) pyrimidin-5-yl]-
Use of a compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or a salt thereof, and (8) cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S)
-7- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-
The present invention relates to a method for suppressing TNF-α, which comprises administering at least one compound selected from 6 (E) -heptenoic acid or a salt thereof at 2.5 to 1000 μg / kg / day.

[0005] Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4-] used in the present invention.
(4-fluorophenyl) -6-isopropyl-2-
(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid can be obtained by a commercially available compound or a known method, for example, (+)-( 3R, 5S) -7- [4-
(4-fluorophenyl) -6-isopropyl-2-
(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid can be produced by the method described in EP-521471. Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-
Methanesulfonylamino) pyrimidin-5-yl]-
As the salt of 3,5-dihydroxy-6 (E) -heptenoic acid, pharmacologically acceptable salts, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, and salts with organic acids And salts with basic or acidic amino acids. Preferable examples of salts with inorganic bases include, for example, salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and aluminum, ammonium and the like. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

The TNF-α inhibitor of the present invention has excellent TN
It has an inhibitory effect on F-α, prevents mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.) from preventing diseases associated with TNF-α. It is used safely as a therapeutic agent. Where TNF
A disease involving -α (induced by TNF-α) is a disease that develops due to the presence of TNF-α and is treated via the inhibitory effect of TNF-α. Such diseases include, for example, inflammatory diseases (eg, retinopathy, nephropathy, neuropathy, diabetic complications such as macrovascular disease; rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis,
Arthritis such as periosteitis; low back pain; gout; inflammation after surgery and trauma;
Remission of swelling; neuralgia; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; meningitis; inflammatory eye diseases; pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis Inflammatory lung diseases, etc.], cardiovascular diseases (eg, angina pectoris, myocardial infarction, congestive heart failure, generalized intravascular coagulation syndrome, etc.), diabetic nephropathy, asthma, allergic diseases, chronic obstructive Pulmonary disease, systemic lupus erythematosus, Crohn's disease, autoimmune hemolytic anemia, psoriasis, neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system disorders (eg, Cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, spinal injury, cerebral edema, multiple sclerosis, etc., toxicemia (eg, sepsis, septic shock, endotoxin shock, gram negative sepsis, toxin shock) Syndrome, etc. , Addison's disease, Creutzfeldt - Jakob disease, virus infection (e.g., cytomegalovirus, influenza virus, viral infections such as herpes virus), the suppression of rejection during transplantation, and dialysis hypotension.

[0007] The TNF-α inhibitors of the present invention may be used alone for therapy, or other lipid-lowering or cholesterol-lowering drugs, cardioprotective drugs, drugs for coronary artery disease, drugs for diabetes, thyroid gland. It may be used together with other pharmaceutical ingredients including a therapeutic agent for reducing function, a therapeutic agent for nephrotic syndrome or a therapeutic agent for chronic renal failure, in which case, in addition to parenteral administration, these compounds are preferably administered as oral preparations It may also be administered in the form of suppositories as a rectal preparation, if necessary. Further, as the possible combination components in this case, for example, the following drugs can be mentioned. Antidiabetic: Kinedak, Benfil, Humulin, Oygurcon, Glymicron, Daoneil, Novolin, Monotard, Insulins, Glucobay, Dimerin, Rustinone, Basilcon, Deamelin S, Isgilin; Hypothyroidism: Dry Thyroid (Thyroid ),
Levothyroxine sodium (Tyrazine S), liothyronidine sodium (thyronine, thyromin); Nephrotic syndrome drug: Prednisolone (prednin), prednisolone sodium succinate, methyl succinate are commonly used as first-line steroid therapy Prednisolone sodium (Sol Medrol),
Betamethasone (Rinderon) or the like is used. For anticoagulant therapy, dipyridamole (versantin), dilazep hydrochloride (comerian), tilopidine, clovidogrel, Xa
Antiplatelet drugs such as inhibitors are used; drugs for treating chronic renal failure: diuretics (eg, furosemide (Lasix), bumetanide (Lunetron), azosemide (Diaart)), antihypertensive drugs (eg, ACE inhibitors, (maleic acid) When administered in combination with enalapril (lenibase)) and Ca antagonists (manidipine), alpha receptor blockers and the like, it can be preferably used orally.

Further, the TNF-α inhibitor of the present invention is suitable for preventing and treating thrombus formation. They may be used alone or in combination with the following known therapeutic agents, preferably by oral administration. Antithrombotic drug: Anticoagulant (eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), Xa inhibitor), thrombolytic drug (eg,
tPA, urokinase], antiplatelet drugs [eg, aspirin, sulfinpyrazolo (anturane), dipyridamole (persantin), ticlopidine (panaldine),
Cilostazol (pletal), GPIIb / IIIa antagonist (Leopro)] Coronary vasodilators: nifedipine, diltiazem, nicorazil, moxa nitrate Cardioprotective agents: oral drugs for cardiac ATP-K, endothelin antagonists, urotensin antagonists The TNF-α inhibitor can be used orally or parenterally by injection, infusion, inhalation, rectal injection, or topical administration, and can be used as it is or as a pharmaceutical composition formulation (eg, powder, granule, Tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions and the like). For example, pharmaceutically acceptable carriers (adjuvants, excipients, excipients, and / or diluents, etc.) as necessary by combining or mixing the compounds of the active ingredients or the above compounds used in the present invention, if necessary. Can be used as a mixture.

[0009] The TNF-α inhibitor of the present invention can be formulated according to the means generally used for formulation. Such preparations can be usually produced by mixing / kneading the active ingredient with additives such as excipients, diluents and carriers.
In this specification, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration include the drug and suitable non-irritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at intestinal tract and melt in the rectum, Can be manufactured by mixing with a substance that emits.

The solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills and capsules. Formulations in such dosage form comprise an active ingredient compound and at least one additive, such as sucrose,
Lactose (lactose), cellulose sugar, mannitol (D
Mannitol), maltitol, dextran, starches (eg, corn starch), microcrystalline cellulose, agar, alginate, chitins, chitosans, pectins, tragacanth gums, gum arabic, gelatins,
It can be produced by mixing and / or kneading collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, antioxidants such as α-tocopherol and cysteine, disintegrants (eg, croscarmellose sodium), binders (eg, hydroxypropylcellulose),
Thickeners, buffering agents, sweeteners, flavoring agents, perfumes and the like can be mentioned. Tablets and pills can also be prepared with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which are inert diluents commonly used in the art, such as water and optionally It may contain additives. These oral liquid preparations can be manufactured according to a conventional method such as mixing an active ingredient compound, an inert diluent, and other additives as necessary. In the preparation of the present invention, although it depends on the dosage form, usually 0.01 to 99 W%, preferably 0.1 to 90 W%, usually 0.5 to 50 W%, of the active ingredient compound of the present invention is compounded. Good.

[0011] Dosage may include age, weight, general health,
Gender, diet, time of administration, method of administration, rate of excretion, combination of drugs, and the extent of the condition of the patient being treated at that time may be determined in consideration of these or other factors. The cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-) of the present invention.
Methanesulfonylamino) pyrimidin-5-yl]-
The daily dose of the TNF-α inhibitor containing at least one compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or a salt thereof depends on the condition and weight of the patient and the type of the compound. For example, when used as a preventive / therapeutic agent for hyperlipidemia, the daily dose for an adult (with a body weight of about 60 kg) is about 1 to 500 mg as an active ingredient in the case of an oral preparation. It is preferably about 10 to 200 mg, and in the case of a parenteral preparation, it is about 0.1 to 100 mg, preferably about 1 to 50 mg, usually about 1 to 20 mg as an active ingredient, and more specifically, as an oral preparation. Cerivastatin 0.15 to 0.30 mg, atorvastatin 10 to 60 mg, simvastatin 5 to 10 mg,
Pravastatin is 10 to 20 mg, itavastatin is 1 to
4 mg, and (+)-(3R, 5S) -7- [4- (4
-Fluorophenyl) -6-isopropyl-2- (N-
Methyl-N-methanesulfonylamino) pyrimidine-5
-Yl] -3,5-dihydroxy-6 (E) -heptenoic acid is from 1 to 40 mg. No toxicity is seen in this range.

When used as a TNF-α inhibitor, the daily dose for an adult (assuming a body weight of about 60 kg) is about 0.15 to 60 mg as an active ingredient in the case of an oral preparation.
(2.5-1000 μg / kg / day), preferably about 0.1
5 to 30 mg (2.5 to 500 μg / kg / day), and in the case of parenteral preparation, about 0.1 to 30 mg (1.6
~ 500 μg / kg / day), preferably about 0.1-20 mg
(1.6-333 μg / kg / day), usually about 0.1-10 mg
(1.6 to 166 μg / kg / day), and no toxicity is observed in this range. Examples of the TNF-α inhibitor include those used for the prevention and treatment of hyperlipidemia at a dose of less than 20 mg per day (assuming a body weight of about 60 kg). Used for the prevention and treatment of hyperemia, preferably for use in the prevention and treatment of hyperlipidemia at a dose of less than 5 mg, more preferably 1
Those used for the prevention / treatment of hyperlipidemia at a dose of less than mg are exemplified.

The TNF-α inhibitory effect of the compound of the present invention can be determined by, for example, a method known in the literature (The Journal of Pharmacol).
ogy and Experimental Therapeutics, 291 (2), 680-68
7, (1999)).

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Reference Examples, but these do not limit the present invention.

EXAMPLES Reference Example 1 Cerivastatin 20.5 g, lactose 16160 g and carboxymethylcellulose calcium (carmellose calcium)
540 g is placed in a fluidized granulation dryer (manufactured by Powrex), preheated and mixed, and sprayed with 7500 g of an aqueous solution in which 450 g of hydroxypropylcellulose is dissolved to obtain a granulated powder. The obtained granulated powder (16820 g) is passed through a cutter mill (manufactured by Showa Kagaku Kikai Kosakusho) to give a sized powder. 16530 g of the obtained sized powder, 513 g of carmellose calcium and 57 g of magnesium stearate were mixed using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and 16800 g of the mixed powder was pressed using a tableting machine (manufactured by Kikusui Seisakusho). Tablets are obtained to give 140,000 tablets of the following composition containing 0.15 mg of cerivastatin per tablet.

Reference Example 2 In the same manner as in Reference Example 1, atorvastatin was administered per tablet.
140,000 tablets of the following composition containing 33.1 mg are obtained.

Reference Example 3 In the same manner as in Reference Example 2, 0.1 tablet of cerivastatin was added per tablet.
140,000 tablets containing 3 mg and having the following composition are obtained.

Experimental Example 1 Method for measuring TNF-α inhibitory action (in vitro) A method known in the literature (The Journal of Pharmacology and Ex
perimental Therapeutics, 291 (2), 680-687, (1999))
Perform according to. That is, peripheral blood of rats, mice, dogs, humans, and the like is collected by heparin, and then RPMI is centrifuged.
After washing several times using a culture medium such as I1640 medium,
Obtain peripheral mononuclear cells. The obtained peripheral mononuclear cells are suspended again in a culture medium containing fetal bovine serum so as to have an appropriate cell concentration, and cultured at 37 ° C. using a culture equipment such as a flat-bottom 96-well culture plate. At that time, cell culture without adding a compound is also performed. After 1 to 24 hours from the start of the culture, the culture supernatant is collected. TNF-α contained in these culture supernatants
By measuring the amount by an ELISA method or a bioassay method, the TNF-α inhibitory effect of the compound can be measured. In addition, this measurement can also be performed using a cell line that produces TNF-α, such as THP-1 cells.

Experimental Example 2 Method for measuring TNF-α inhibitory action (in vivo) A method known in the literature (The Journal of Pharmacology and Ex
perimental Therapeutics, 291 (2), 680-687, (1999))
Perform according to. That is, a compound is administered to experimental animals such as rats, mice, dogs and the like by any one of methods such as oral, subcutaneous, intraperitoneal or intravenous administration. After 30 minutes to 5 hours, a group to which an appropriate amount of lipopolysaccharide is administered subcutaneously, intraperitoneally or intravenously and a group to which no lipopolysaccharide is administered are prepared. After 30 minutes to 3 hours,
Plasma is collected by an appropriate method, and T contained in the plasma is collected.
By measuring the amount of NF-α by an ELISA method or a bioassay method, the TNF-α inhibitory action of the compound can be measured.

[0019]

The TNF-α inhibitor of the present invention has excellent T
It has an inhibitory effect on NF-α and is useful as a prophylactic / therapeutic agent for TNF-α-related diseases such as inflammatory diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/505 A61K 31/505 A61P 3/10 A61P 3/10 9/00 9/00 13/00 13 / 00 13/12 13/12 17/06 17/06 25/00 25/00 25/28 25/28 29/00 29/00 31/00 31/00 37/00 37/00 43/00 111 43/00 111 // C07D 207/34 C07D 207/34 213/55 213/55 215/14 215/14 239/42 239/42 Z 309/30 309/30 D (72) Inventor Kazumasa Ikeya Ikaruga, Ikoma-gun, Nara Machi Hattori 2-10-8 (72) Inventor Yoshiharu Suzuki 50-303 Yamada Minami B-303, Suita-shi, Osaka

Claims (8)

[Claims] Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl- N-
Methanesulfonylamino) pyrimidin-5-yl]-
A TNF-α inhibitor comprising at least one compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or a salt thereof. 2. The TNF-α inhibitor according to claim 1, wherein the compound is cerivastatin. 3. The compound according to claim 1, wherein the compound is atorvastatin.
The TNF-α inhibitor described. 4. The TNF-α inhibitor according to claim 1, which is a preventive or therapeutic agent for a disease associated with TNF-α. 5. The TNF-α according to claim 4, which is an anti-inflammatory agent.
Inhibitors. 6. Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl- N-
Methanesulfonylamino) pyrimidin-5-yl]-
A method for suppressing TNF-α, which comprises administering an effective amount of at least one compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or a salt thereof. 7. Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5) for producing a TNF-α inhibitor.
S) -7- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E)- Use of a compound selected from heptenoic acid or a salt thereof. 8. Cerivastatin, atorvastatin, simvastatin, pravastatin, itavastatin and (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl- N-
Methanesulfonylamino) pyrimidin-5-yl]-
A compound selected from 3,5-dihydroxy-6 (E) -heptenoic acid or at least one of its salts,
TNF-, characterized in that it is administered at a dose of 000 μg / kg / day.
α suppression method.