JP2002535369A - Compositions and methods for treating diabetes - Google Patents

Abstract

(57) Abstract: A pharmaceutical composition for the treatment of diabetes, comprising a compound of formula (I) in excess of 600 mg (here, Y is O, R NHCONR ⁴ R ⁵ or ^{N = C (NR 4 R 5} ) is _2). Another pharmaceutical composition for treating another diabetes comprises a compound selected from the group consisting of compounds of formula (I) wherein Y is O and R is OH. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to compositions and methods for treating diabetes. BACKGROUND DISCUSSION: Diabetes has been defined as "a clinical syndrome characterized by relative or insufficient deficiency of insulin or resistance to the action of insulin" (Ratn
er RE: Management of Diabetes Mellitu
s: Perspectives of Care Across the Li
fespan. 1992, Mosby. ). This definition defines insulin-dependent diabetes (IDDM), which requires administration of insulin to address insulin loss or insufficient production of insulin by pancreatic beta cells.
Dent diabetes mellitus) or a form of diabetes that may be referred to as type I.

[0002] In non-insulin dependent diabetes mellitus (NIDDM) or type II patients, insulin production is often increased or slightly depleted, depending on the duration of NIDDM. Regardless of the patient's blood insulin levels, the hypoglycemic response to insulin is usually impaired. Patients therefore exhibit hyperglycemia after meals, and often during fasting, despite sometimes elevated levels of insulin. Of 1300-15 million diabetics in the United States,
It has been estimated that up to 90% of patients have NIDDM. By using a survey aimed at elucidating their distribution, half of these NIDDM patients have not been diagnosed and therefore have not been treated (Harris
MI: Undiagnosed NIDDM: Clinical and Pu
blic Health Issues. Diabetes Care 19
93; 16: 642-652). It is uncertain whether insulin production is sufficient to control glycemia with proper diet and / or drug therapy.

[0003] Two determinants that have a significant effect on cell membrane insulin resistance to glucose influx are (1) the availability of cell membrane insulin receptors, the number and activation of which are insulin dependent; (2) free fatty acids (FF) obtained from the lipolysis of food and / or stored triglycerides (mainly in adipose tissue);
A) Plasma levels.

[0004] Lipid degradation induced by hormones such as norepinephrine increases blood levels of FFA that can be used as a continuous energy source, especially for muscles. As blood levels of FFA increase, the resistance of the cell membrane to glucose uptake (insulin resistance) increases. Conversely, an increase in blood insulin levels induced by the endogenous development of hyperglucoseemia or a high glucose diet (eg, a glucose tolerance test) inhibits lipolysis, thereby increasing serum FFA levels and cellular FFA inhibition of glucose uptake can be suppressed. In healthy non-diabetic individuals, this variable balance of normal ranges of blood glucose, insulin blood levels, and FFA lipemia can result in exertion, sustained physical exertion over hours or days between meals. Activities and consciousness can be formed.

[0005] NIDDM individuals have poor ability to maintain a balance of dietary variability in glycemia, insulin, and FFA levels. With proper dietary intake of carbohydrates, fats, and protein, some can approach normal metabolic balance. motion,
A well-balanced lifestyle and adaptation to or relief from stress, along with diet, contribute as a basic therapy for these patients. Weight loss can be an important point in this behavioral pattern, as overweight and hypertension are common features of NIDDM diabetes.

This form of treatment of diet, exercise, and adaptation to stress is insufficient to regulate blood sugar to an appropriate range, and sulfonylurea drugs lower blood glucose levels to normal levels. Can be achieved. These drugs have been reported to stimulate the release of insulin from pancreatic β cells and increase insulin sensitivity on the cell surface. They are usually taken just before one or more meals. 25-
In 30% of patients, the initial (primary) response to the sulfonylurea may not be sufficient. Over time, an additional 5-10% of patients develop resistance to these drugs (Ilarde A, Tuck M: Treatment of no.
n-insulin-dependent diabetes mellitu
s and it's combinations. Drugs-Aging 1
994; 4: 470-492. ).

[0007] Sulfonylureas are not antihypertensives and do not reduce the levels of hyperlipidemia.
Therefore, in order to reduce the high risk of cardiovascular attacks such as atherosclerosis and coronary heart disease, the most common causes of death in these patients, supplemental anti-hypertensive and anti-hyperlipidemic Symptom therapy is needed.

[0008] Commonly used anti-hypertensive agents, such as thiazide and beta-adrenergic blockers,
Affects glucose and lipid metabolism in NIDDM patients. Not all,
Many calcium channel blockers are less likely to have an adverse effect in this regard. Angiotensin converting enzyme inhibitors do not inhibit either hyperglycemia or hyperlipidemia. Their antihypertensive effect is their ancillary role for these diabetics. Inhibitors of hydroxymethylglutaryl CoA reduction of cholesterol synthesis are
The effect of reducing hyperlipidemia derived from triglyceride synthesis or lipolysis which often occurs is relatively small.

Nicotinic acid inhibits the hydrolysis of triglycerides to FFA and glycerol, but is reported to be contraindicated in diabetes (Molnar GD, Berg)
e KG, Rosever JW, McGuckin WF, Achor R
WP: The effect of Nicotinic acid ind
iabetes mellitus. Metabolism 1964; 13;
181-190). Amiloride (2,4,5-tripolar substituted pyrazinone acid derivative)
Is commonly used in formulations with thiazide (hydrochlorothiazide) to compensate for thiazide-induced potassiumuria due to its potassium-retaining properties. However, amiloride or its combination with thiazide should be avoided in diabetics because it can induce hyperkalemia as well as hyperglycemia and hyperuricemia.

[0010] Therefore, blood levels of hyperglycemia, insulin, free fatty acids and triglycerides,
And there is a need for compounds that can safely meet these multiple needs of NIDDM patients for the control and regulation of essential (adrenergic) hypertension.

[0011] When studying pyrazinoylguanidines and their 3-amino analogs as inhibitors of urea and salt reabsorption by the kidneys (ie, as micturition enhancers and salt excretors) (Beyer KH, Gelarden RT, Vesell ES
： Inhibition of urea transport cross
renal tubes by pyrazinoylguanidin
e and analogs. Pharmacology 1992; 44: 1.
24-138), in addition to lowering blood urea levels and reducing hypertension (Chambers CE, Vesell ES, Heim C, Passan
anti GT, Beyer KH: Pyrazinoylguanidine
: Antihypertensive, hypocholesterolemi
can and rennin effects. J. Clin. Pharmacol
. 1992; 32: 1128-1134), these compounds, especially the representative pyrazinoylguanidine (PZG), reduced serum concentrations of triglycerides and cholesterol (Beyer KH, Ward TD, Vary JE, Ge.
larden RT, Knutson DW, Vesell ES: Contr
asting effects of pyrazinoylguanidin
e and hydrochlorothiazide in patient
s with regular insufficiency. J. Clin. Ph
armacol. 1993; 33: 554-561). In addition, PZG has no effect on normal glucose serum concentrations, but has an oral glucose tolerance test (
GTT) was able to block the increase in serum glucose and insulin levels normally induced by hydrochlorothiazide (Vesell ES, C
hambers CE, Passananti GT, Demers LM, B
eyer KH: Effects of pyrazinoylguanidi
ne on the glucose-fatity acid cycle i
n normal subjects and patients with
non-insulin-dependent diabetes melli
tus. J. Clin. Pharmacol. 1993; 33: 823-83.
1. ). These results indicate that administration of pyrazinoylguanidine (600 mg, 2
, Oral drug therapy) from a study on the effect 3 weeks after (
See Vesell et al. , J. et al. Clin. Pharmacol. 34:12
34-1245, 1994; U.S. Pat. No. 5,801,177).

[0012] Accordingly, it is an object of the present invention to provide compositions and methods for treating persons with NIDDM.

[0013] Another object of the present invention is to provide compositions and methods for reducing and / or regulating blood glucose levels in NIDDM subjects.

[0014] It is another object of the present invention to provide compositions and methods that reduce and / or regulate blood levels of FFA and triglycerides in NIDDM subjects.

[0015] These and other objects have been achieved by providing more than 600 mg of a compound of formula (I):

Embedded image

(Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or Branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or it is selected from the group consisting of _{C 1-10} alkyl) branched; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl Selected from the group consisting of alkyl, amino, and mono- or di-substituted amino, wherein the substituents are straight or branched C _1-10 alkyl, C _3-8 cycloalkyl ( However, ^{R 1} and ^{R 2} are simultaneously amino Must not be amino) substituted in; R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is) or formulation form of a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof Provided by the thing.

These compounds may be collectively referred to as “guanidines of the formula (I)”.

These and other objects are also achieved by a single dose of a composition comprising at least 600 mg of at least one of the above guanidines to a NIDDM patient.

These and other objects are to provide compounds of formula (I):

Embedded image

(Where Y is O; R is OH; R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl , Amino, and mono- or di-substituted amino, wherein the substituents are straight or branched C _1-10 alkyl, C _3-8 cycloalkyl, with the proviso that , R ¹ and R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, Compounds selected from the group consisting of salts and amides (excluding compounds wherein R ¹ is amino and R ² and R ³ are hydrogen) and their esters, anhydrides, salts and amides Compound The present invention is also achieved by a pharmaceutical composition for treating diabetes, comprising a compound of the formula (excluding compounds wherein R ¹ is amino and R ² and R ³ are hydrogen).

These compounds may be collectively referred to as “acids of formula (I)”.

[0022] These and other objects are attained by providing a composition comprising at least one of the aforementioned acids as a NID
It is also achieved by administration to DM patients.

Aryl may also include other aromatic ring systems, typically referring to a six membered aromatic ring.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the guanidine of formula (I), preferably, R ¹ and R ² are each independently hydrogen,
Selected from the group consisting of amino, and mono- or disubstituted amino, wherein the substituents are C _1-10 alkyl, linear or branched C _3-8 cycloalkyl.

The most preferred compounds of the formula (I) are the compounds of the formula (I) wherein Y is O, one of R ¹ and R ² is hydrogen and R ³ is hydrogen. It is. Particularly preferred compounds among the guanidines of the formula (I) are the following pyrazinoylguanidines (PZG) and 3-aminopyrazinoylguanidines.

In the acids of formula (I), preferably, R ¹ is hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, and mono- or disubstituted amino (wherein The substituents are selected from the group consisting of straight or branched C _1-10 alkyl, C _3-8 cycloalkyl.

In the acids of the formula (I), preferably, R ² is hydrogen, straight or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, and mono- or disubstituted amino ( Wherein the substituents are C _1-10 alkyl, linear or branched C _3-8 cycloalkyl).

In the acids of formula (I), more preferably, R ¹ is hydrogen and mono- or disubstituted amino, wherein the substituents are linear or branched C _1-10 alkyl, _3-8 cycloalkyl).

In the acids of formula (I), more preferably, R ² is hydrogen, amino, and mono- or disubstituted amino, wherein the substituent is a linear or branched C _1-10 alkyl. it is selected from the group consisting of _{C 3 -8} cycloalkyl).

The most preferred compounds of the formula (I) are those in which one of R ¹ and R ² is hydrogen and R ³ is hydrogen. Particularly preferred compounds among the acids of the formula (I) are the following pyrazinoic acid (PZA) and 3-aminopyrazinoic acid.

The compounds of formula (I) used in the present invention can be prepared by well-known procedures, for example, US Pat.
No. 4,313,813; 4,962,111; 5,643,912; and the references cited herein, all of which are incorporated herein by reference. It can be prepared according to the procedure.

As should be apparent from the structure of the preferred compounds of the present invention, the compounds of the present invention are distinguished from amiloride by the low level of substitution. Amiloride has two amino substituents, one chloro substituent, and one CONHC (= NH
) Having an NH ₂ substituent; For example, multipolar amiloride-like compounds, including their 5-fluoro analogs, have in common the potassium-retaining hyperkalemia property, which makes other drugs such as thiazide unlikely. Amiloride was not commonly available, except for preparations to counteract the potassiumuria effect. In a preferred embodiment of the invention, potassium is not retained or excreted in excess.

Recognizing that these are pharmaceutical compounds, it is possible that one or more of the metabolites of these compounds may be directly involved in all or part of the observed effects. There must be.

The guanidines of the formula (I) can be used in the form of salts derived from inorganic or organic acids. Such salts include: adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate , Cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate, hexanoate,
Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
Lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, Includes pivalate, propionate, succinate, tartrate, thiocyanate, toxylate, and undecanoate.

The combinations of the present invention may be administered orally, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. The term parenteral as used herein includes subcutaneous injections, intravenous or intramuscular injections, or infusion techniques. The present invention relates to the treatment of non-insulin-dependent diabetes, the treatment of pre-diabetic hypertensive patients, and the elevation of glycemia, hyperlipidemia and hypertension with Syndrome X (peripheral and coronary disease). (A risk factor for small or large cardiovascular injuries that can induce lipolysis).

Pharmaceutical compositions containing the active ingredient are suitable for oral use, for example as tablets, granules, hard or soft capsules prepared according to methods known in the art for the manufacture of pharmaceutical compositions. Such compositions, which may be in form, may also contain flavoring, coloring and / or preservatives to give pharmaceutically elegant and palatable preparations.

The tablets and granules may be uncoated or may have complete or partial delay in disintegration and absorption, to delay or prolong the action lasting longer,
It may be coated by a known method (sustained release composition). Dispensable powders and granules suitable for preparation of an aqueous suspension for immediate oral consumption include dispersing or wetting agents, suspending agents, one or more preservatives, coloring agents and / or Provides the active ingredient mixed with a flavoring agent. Dried and filled with non-toxic dispersing agents and solubilizing agents suitable for immediate solubilization in aqueous solutions, such as normal saline for immediate subcutaneous, intramuscular, or intravenous injection. (Filled
For packaging in a form, sterile preparations for injectable solutions can also be prepared. The formulation of the present invention involves mixing the drug in a suitable non-irritating, non-wetting excipient that is solid at normal temperatures such as cocoa butter or polyethylene glycol, but melts and remains liquid at rectal temperatures. May be administered in the form of suppositories for rectal administration prepared by the Pharmaceuticals, Inc. The compounds of formula (I) used in the present invention are active not only when administered parenterally, but also when administered orally.

For the acids of formula (I), 10 to 2400 mg, preferably 50 to 1200 m
g, more preferably 200-600 mg, most preferably 300-600 mg /
Daily dose levels (including all values therebetween) are suitably administered once a day (eg, before a meal) or in two or three divided doses. The compounds may be used alone or in combination with other therapies. A single dose of the acid of formula (I) is at least 200 mg, including 200-1000 mg, preferably 300 mg.
Preferred is an acute dosage of at least 300 mg, including ８００800 mg. Such acute dosing is 200, 250, 300, 350, 400, 450, 500, 5
Includes single doses of 50, 600, 650, 700, 750, 800, 850, 900, 950, and 1000 mg. The unit dosage can be 10-2400 mg, but is preferably at least 200 mg, including 200-1000 mg, more preferably at least 300 mg, including 300-800 mg. Such unit dosages include 200, 250, 300, 350, 400, 450, 500, 5
Single dosages of 50, 600, 650, 700, 750, 800, 850, 900, 950, and 1000 mg are included. Unit dosage forms include pills, tablets, suppositories,
A pre-measured solution, a pre-measured suspension, or other form of a drug specially prepared to be taken as a single dose.

The acids of formula (I) can cause a vasomotor response similar to nicotinic acid. The vasomotor response of varying degrees and times, especially in the flush area of the head and neck, is usually not dangerous. This unwanted side effect can be, for example,
Reduction by co-administration of an inhibitor of prostaglandin synthesis such as indomethacin or aspirin or even a guanidine of formula (I) such as PZG,
May be inhibited or eliminated. Dosage levels can be in amounts sufficient to inhibit prostaglandin synthesis. If a guanidine of the formula (I) is used, the dosage level may be the same as that of the guanidine of the formula (I) when used alone according to the invention. Preferred compositions containing the acids of formula (I) contain at least one of these synthetic inhibitors in order to inhibit the overall arachidone-plastanoid reaction.

For the guanidines of formula (I), a single dose can exceed from 600 to 300 per day
More than 600 mg containing 0 mg, preferably at least 700 mg containing 700-2400 mg, more preferably at least 750 mg, even more preferably 800-400 mg.
Acute dosages of at least 800 mg, including 1200 mg, are preferred and are suitably administered once a day (eg, before a meal) or in two or three divided doses. Most preferably, it is at least 850 mg, including 850-1200 mg, and 900-1200 mg, or at least 900 mg. Such acute dosing is 650
, 700, 750, 800, 850, 900, 950, 1000, 1100, 1
200, 1300, 1400, 1500, 1600, 1700, 1800, 19
Includes single doses of 00, 2000, 2100, 2200, 2300, and 2400 mg. A unit dosage may be greater than 600 mg to 2400 mg, but is preferably at least 700 mg, including 700 to 2400 mg, more preferably at least 750 mg, even more preferably at least 800 mg including 800 to 1200 mg. Most preferably, the unit dosage is between 850 and 1200 mg,
At least 850 mg, including at least 900 and 1200-1200 mg, or at least 900
mg. Such unit dosages are 650, 700, 750, 800, 85
0, 900, 950, 1000, 1100, 1200, 1300, 1400, 1
500, 1600, 1700, 1800, 1900, 2000, 2100, 22
Includes unit dosages of 00, 2300, and 2400 mg. Unit dosage forms are pills, tablets, suppositories, pre-measured solutions, pre-measured suspensions, or other forms of the drug specially prepared to be taken as a single dose.

Various other treatments may be administered simultaneously with the guanidine of formula (I) or the acid of formula (I). Examples of these other treatments include lovastatin, glyburide, tolbutamide, glipizide, verapamil, diltiazem, propranolol, atenolol,
Dietary therapy is included, in addition to drugs such as nadolol, captopril, enalapril, and chlorpropamide. A fully effective amount of a compound of formula (I) is quickly added to complement other NIDDM therapies without causing undesired hypoglycemia, hyperglycemia, or abnormal changes in lipid or blood pressure measurements. Or pause.

The unique features of the compounds of formula (I) associated with reduced blood urea levels, reduced hypertension, and hyperlipidemia in patients with hypernitremia are described in prior patents (US Pat. No. 4,594,941). 34
No. 9, No. 4,663,322; No. 4,920,123; No. 4,952,58
2, No. 5,110,817) and the more general literature cited therein, the present invention provides compounds of formula (I) that contribute to the reduction and regulation of hyperglycemia.
All of these features of each of the compounds focus on a single clinical entity, which in turn translates clinical NIDDM into a pre-NIDDM patient, based on family history and clinical chemistry. It could be a few years ahead. Genetic screening for NIDDM allows these pre-NIDDM patients to be identified much more accurately. Thus, in addition to its use and safety in modulating or complementing the treatment of NIDDM, more than as indicated in studies of the treatment of anti-hypertension, anti-triglyceridemia, and anti-hypercholesterolemia, A single compound, such as a preferred embodiment of the examples of formula (I), as well as its general side effects and mortality,
It can be used as a prophylactic treatment for DDM.

EXAMPLE To compare and contrast the metabolic effects of a single dose of PZG and PZA, a single oral dose of placebo followed by 900 mg of pyrazinoylguanidine (PZG)
For one week, followed by 300 mg of pyrazinoic acid (PZA) for three weeks, with normal male subjects participating. The purpose of this study was to determine whether the metabolic effects observed in patients with kidney disease or diabetes 3 and 21 days after PZG administration also occurred after a single oral dose.

Blood analysis performed 0, 2, and 4 hours after administration of PZG and PZA showed that
The mean values of serum glucose, insulin, C-peptide, triglycerides, and free fatty acids were shown to decrease. PZG also significantly reduced very low density lipoproteins. Previously, it was not recognized that acute dosing of PZG and PZA could result in such rapid metabolic changes. Usually, metabolic changes require subchronic or chronic administration of the compound. For example, a sulfonylurea is
Several doses are required before they show a metabolic effect. Administration of an antithyroid compound can take as long as 2-3 weeks before any metabolic effects are observed. This is also true for many antidepressant treatments.

The details of this study are shown below. Subjects Eight non-smoking men aged 24-32 years old participated as subjects. Their medical history, physical examination, and general blood and urine tests were normal. No one was chronically taking any drug, and no one was chronically drinking alcoholic beverages.

Study Design This study was a single-blind, three-phase crossover study initiated at 8:00 am after a 10-hour fast, with the first venipuncture performed at time zero (control). did. In phase I, venipuncture was performed 2 and 4 hours after oral administration of three lactose capsules. In phase II, one week later, a control blood sample was collected at 8:00 am, PZG (900 mg) was administered orally, and blood samples were collected two and four hours later. In phase III, three weeks later, a control blood sample was taken at 8 am and PZA
(300 mg) was orally administered, and blood samples were collected 2 and 4 hours later.

Each phase consisted of three capsule doses each containing 300 mg. I
In phase three capsules are all lactose capsules; in phase II all three are PZG and in phase III two capsules are lactose and one is PZA
Met. All capsules are indistinguishable from the appearance,
Swallowed with water in the presence of the observer.

The doses of PZG (900 mg) and PZA (300 mg) were based on previous pharmacokinetic studies (Passantanti et al., Pharmacology 199).
2: 45: 129-141) to obtain equivalent blood concentrations.

Immediately after collection, a blood sample was centrifuged. Refrigerated serum or plasma glucose, insulin, red blood cells, blood urea nitrogen, creatinine, liver function tests, triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol,
Low density lipoprotein (LDL) cholesterol, very low density lipoprotein (V
(LDL) cholesterol, free fatty acids, and fibrinogen were analyzed within 24 hours.

Statistics Using a repeated-measures analysis of variance, placebo, PZG, and PZ
Phase A was compared. Two-tailed Student's t-test was performed between groups. All results are
It is expressed as the mean ± SD. Statistically significant when p <0.05. The results are shown in Tables 1 to 4.

[0051]

[Table 1]

[0052]

[Table 2]

[0053]

[Table 3]

Mean serum or plasma concentration ± S in placebo, PZG, and PZA phases for glucose, insulin, C-peptide, free fatty acids, and norepinephrine
A comparison of D is shown in Table 1. Triglyceride, VLDL, LDL, HDL
A comparison of mean serum or plasma concentrations ± SD in these three phases for total cholesterol, fibrinogen, and serum PZG and PZA concentrations is shown in Table 2. Serum PZG and P at 2 and 4 hours after administration of PZG and PZA
Note that the ZA concentrations are very consistent. Table 3 compares the mean serum or plasma concentrations ± SD of renin, angiotensin 1, aldosterone, potassium, urea, and uric acid in the three phases of the study. As in previous studies, PZ
G was well tolerated and no adverse reactions to PZG occurred. In a previous preliminary experiment to determine serum PZA concentration after giving different doses of PZA, unexpectedly, a single dose of 300 mg PZA orally was followed by a mild redness of about 90 minutes. A typical skin vasomotor response in his reddish area, including flushed and hot skin on the face, neck, and shoulders, occurred in the first subject (EV). 600
After a single oral dose of mg PZA, the second subject (KB) did not show any skin vasomotor response. Many male volunteers generally exhibited a vasomotor response of the skin, similar to EV. They exhibited various reactions such as hot redness or flushing of the head and neck, and pruritus (Table 4). These responses, graded from 6 (heaviest) to 0 (not observed), were 30 in 3 subjects.
Minutes, and lasted up to 4 hours in one subject. One of the eight subjects did not respond at all. None of the cutaneous vasomotor responses were severe enough to disqualify participation in the study. No significant correlation was found between the response score (effect + duration) and the peak blood concentration of PZA in the subject (r = 0.281) (Table 4). When the reaction occurred, its onset preceded the peak serum PZA concentration, as in the case of the skin reaction associated with nicotinic acid.

[0055]

[Table 4]

A comparison of the effects of PZG and PZA over 4 hours (Tables 1-3) was more appropriate to follow some of the parameters studied than the other parameters. In general, when PZG reduced factors associated with the glucose-fatty acid pathway, PZA showed almost the same effect. In this regard, PZG and PZA appear very similar. For example, at the same plasma PZG and PZA concentrations, insulin, C-peptide, free fatty acids (Table 1), and triglycerides (Table 2)
) Serum concentration was reduced.

It has long been known that PZA lowers serum triglycerides and increases uric acid levels in blood (Passananti T., Vesell).
E, Jeszenka E, Gelarden T, Beyer K. : Pha
rmakokinetics of Pyrazinolyguanidine
, 3-Aminopyrazinoylguanidine and Thei
r Corresponding Pyrazinoic Acid Meta
bolites in Humans and Dogs, Pharmacol
ogy 1992: 45: 129-141; Weiner IM, Tinker
JP: Pharmacology of Pyrazinamide: Met
abolic and Renal Function Studios Re
lated to the Mechanism of Drug-induce
d Urate Retention, J. et al. Pharmacol. Exp. Th
re. 1972: 180: 411-434; Ellard GA, Halsam.
RM: Observations on the Reduction of
theRenal Elimination of Urate in Ma
n Caused by the Administration of Py
razinamide, Tubercle 1976: 57: 97-103).
PZG usually does not alter plasma renin and aldosterone activity, or slightly reduces both (Chambers C, Vesell E, Helm).
C, Passantanti T, Beyer K: Pyrazinolygu
andine: Antihypertensive, Hypocholest
erolemic, and Renin Effects, J. Mol. Clin. P
Pharmacol. 1992: 32: 1128-1134). The slight but insignificant increase in plasma renin activity in this study may be due to a parallel elevation of plasma norepinephrine, depending on its role in counteracting the inhibition of hormone-controlled lipolysis by PZG (Table 1). In contrast, PZA did not increase plasma norepinephrine (Table 1). It is unclear whether the difference between PZG and PZA with respect to the plasma concentration of norepinephrine is biologically significant. In all cases, the effect was not statistically significant. VLDL was reduced by both PZG and PZA, but LDL, HDL, and total cholesterol did not change systemically during this time (Table 2). Blood potassium concentration is PZG or PZA
(Table 3). Plasma uric acid concentration was increased by PZA, but not by PZG (Table 3).

In the present study, 7 out of 8 subjects responded to PZA and showed a cutaneous vasomotor response as seen with nicotinic acid. The vasomotor response of varying degrees and duration, particularly in the red areas of the head and neck (Table 4), is not usually dangerous but cannot be combined with nicotinic acid prescribed in patient care This is so inconvenient that it can cause serious problems.

In summary, the metabolic effects of PZA are similar to those of nicotinic acid. PZA
Both Table 1 and nicotinic acid transiently irritate the red areas of the face, neck and shoulders, while reducing the plasma concentration of unesterified fatty acids. PZG is has anti-lipolytic effects as with PZA and nicotinic acid, inducibility of prostaglandin D ₂ Synthesis of PZA and nicotinic acid does not. These two effects of nicotinic acid are due to prostaglandin synthesis inhibitors (
Indomethacin and aspirin) can be terminated by pre-administration, but the lipolytic effect of nicotinic acid cannot be broken. PZG, like indomethacin and aspirin, can suppress the body's response to its major metabolite, PZA, by inhibiting the overall arachidone-plastanoid response to nicotinic acid.

Obviously, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that, within the scope of the following claims, the invention may be practiced differently from what is specifically described herein.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 241/24 C07D 241/24 241/28 241/28 241/32 241/32 (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM , AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU , CZ, DE, DK, DM, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZWF terms (reference) 4C084 AA02 AA19 MA02 NA14 ZC122 ZC351 ZC412 4C086 AA01 AA02 BC48 MA01 MA02 MA04 NA14 ZC12 ZC35 ZC41

Claims (40)

[Claims] 1. A pharmaceutical composition for treating diabetes, comprising 600 mg
Compounds of formula (I) exceeding: (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 2. A pharmaceutical composition in unit dosage form for treating diabetes, comprising more than 600 mg of a compound of formula (I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 3. A pharmaceutical composition for reducing blood glucose, serum triglycerides, or serum fatty acids, which comprises more than 600 mg of a compound of formula (I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 4. A pharmaceutical composition in unit dosage form for reducing blood glucose, serum triglycerides, or serum fatty acids, which comprises more than 600 mg of a compound of formula (I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 5. A pharmaceutical composition for preventing the development of NIDDM, which comprises:
More than 600 mg of the compound of formula (I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 6. A pharmaceutical composition in unit dosage form for preventing the development of NIDDM, comprising more than 600 mg of a compound of formula (I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or pharmaceutical composition comprising their pharmaceutically acceptable salts. 7. The pharmaceutical composition according to any one of claims 1 to 6, wherein
A pharmaceutical composition comprising 750-1200 mg of the compound. 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein
A pharmaceutical composition comprising at least 900 mg of the compound. 9. The pharmaceutical composition according to any one of claims 1 to 6, wherein
A pharmaceutical composition wherein R is N = C (NR ⁴ R ⁵ ) ₂ . 10. The pharmaceutical composition according to claim 1, wherein the compound is pyrazinoylguanidine. 11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the compound is 3-aminopyrazinoylguanidine. 12. A method for treating diabetes, comprising administering to a patient in need thereof a single dose of a compound of formula (I) in excess of 600 mg: (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ^3, the method comprising the administration of hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or their pharmaceutically acceptable salts. 13. A method for preventing the development of NIDDM, comprising administering to a patient in need thereof a single dose of a compound of formula (I) in excess of 600 mg: (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ^3, the method comprising the administration of hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or their pharmaceutically acceptable salts. 14. A method of reducing blood glucose, serum triglycerides, or serum fatty acids, comprising administering to a patient in need thereof a single dose of over 600 mg of the formula (
Compound of I): (Where Y is O; R is NHCONR ⁴ R ⁵ , or N ＝ C (NR ⁴ R ⁵ ) ₂ ; R ⁴ and R ⁵ are each independently hydrogen, linear or branched C _1-10 alkyl, aryl C _1-4 alkyl, and mono- or di-substituted aryl C _1-4 alkyl, wherein the substituent is fluoro, chloro, bromo, iodo, or linear or branched is selected from the group consisting of _{C 1-10} alkyl) of; ^{R 1} and ^{R 2} are each independently hydrogen, _{C 1-10} alkyl linear or _{branched, C 3-8} cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² are amino or substituted simultaneously Must not be amino); R ^3, the method comprising the administration of hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo is), or their pharmaceutically acceptable salts. 15. The method according to any one of claims 12 to 14, wherein said single dose is at least 900 mg of said compound. 16. The method according to any one of claims 12 to 14, wherein said single dose is at least 900 mg of said compound. 17. The method according to any one of claims 12 to 14, wherein R
Is N = C (NR ⁴ R ⁵ ) ₂ . 18. The method according to any one of claims 12 to 14, wherein the compound is pyrazinoylguanidine. 19. The method according to any one of claims 12 to 14, wherein the compound is 3-aminopyrazinoylguanidine. 20. A pharmaceutical composition for treating diabetes, comprising a compound of the formula (I)
Compound of the formula: (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 21. A pharmaceutical composition in unit dosage form for treating diabetes, comprising a compound of formula (I): (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising at least 100 mg of a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 22. A pharmaceutical composition for reducing blood glucose, serum triglycerides, or serum fatty acids, comprising a compound of formula (I): (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 23. A pharmaceutical composition in unit dosage form for reducing blood glucose, serum triglycerides, or serum fatty acids, comprising a compound of formula (I): (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising at least 100 mg of a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 24. A pharmaceutical composition for preventing the development of NIDDM, comprising a compound of formula (I): (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 25. A pharmaceutical composition in unit dosage form for preventing the development of NIDDM, comprising a compound of formula (I): (Where Y is O, R is OH and R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino, And a mono- or di-substituted amino, wherein the substituent is a linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, provided that R ¹ And R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, and A pharmaceutical composition comprising at least 100 mg of a compound selected from the group consisting of amides (excluding compounds where R ¹ is amino and R ² and R ³ are hydrogen). 26. A pharmaceutical composition according to any one of claims 21, 23 and 25, comprising 100 to 1000 mg of said compound. 27. A pharmaceutical composition according to any one of claims 21, 23 and 25, comprising at least 300 mg of said compound. 28. The pharmaceutical composition according to any one of claims 20 to 25, wherein R ¹ is hydrogen and mono- or di-substituted amino (substituents may be linear or branched. R ² is selected from the group consisting of C _1-10 alkyl, C _3-8 cycloalkyl), wherein R ² is hydrogen, amino, and a mono- or di-substituted amino group, wherein the substituent is a straight or branched chain; A C _1-10 alkyl, C _3-8 cycloalkyl). 29. The pharmaceutical composition according to any one of claims 20 to 25, wherein the compound is pyrazinoic acid. 30. The pharmaceutical composition according to any one of claims 20 to 25, wherein said compound is 3-aminopyrazinoic acid. 31. The pharmaceutical composition according to any one of claims 20 to 25, further comprising a prostaglandin synthesis inhibitor. 32. A method of treating diabetes, which comprises administering to a patient in need thereof a compound of formula (I): (Where Y is O, R is OH, R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are straight or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, And a compound selected from the group consisting of amides and amides (excluding compounds wherein R ¹ is amino and R ² and R ³ are hydrogen). 33. A method for reducing blood glucose, serum triglycerides, or serum fatty acids, which comprises administering to a patient in need thereof a compound of formula (I): (Where Y is O, R is OH, R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, And a compound selected from the group consisting of amides and amides (excluding compounds wherein R ¹ is amino and R ² and R ³ are hydrogen). 34. A method for preventing the development of NIDDM, comprising administering to a patient in need thereof a compound of formula (I): (Where Y is O, R is OH, R ¹ and R ² are each independently hydrogen, linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, amino And mono- or di-substituted amino, wherein the substituents are linear or branched C _1-10 alkyl, C _3-8 cycloalkyl, wherein R ¹ and R ² must not be simultaneously amino or substituted amino); R ³ is hydrogen, trifluoromethyl, fluoro, chloro, bromo, or iodo), and its esters, anhydrides, salts, And a compound selected from the group consisting of amides and amides (excluding compounds wherein R ¹ is amino and R ² and R ³ are hydrogen). 35. The method according to any one of claims 32 to 34, wherein
A method wherein a single dose of 00-1000 mg of the compound is administered. 36. The method according to any one of claims 32-34, wherein a single dose of at least 300 mg of the compound is administered. 37. The method according to any one of claims 32-34, wherein R ¹ is hydrogen and mono- or di-substituted amino (substituents are linear or branched C _1-10 alkyl is selected from the group consisting of C _3-8 cycloalkyl), R ² is hydrogen, amino, and mono- or di-substituted amino (wherein the substituents are straight-chain or branched Chain C _1-10 alkyl, C _3-8 cycloalkyl). 38. The method according to claim 32, wherein the compound is pyrazinoic acid. 39. The method according to any one of claims 32 to 34, wherein the compound is 3-aminopyrazinoic acid. 40. The method of any one of claims 32-34, further comprising administering a prostaglandin synthesis inhibitor.