JP2015521201A - Novel compounds and compositions for the treatment of respiratory control disorders or respiratory control disorders - Google Patents

Abstract

The present invention includes compositions useful for the treatment of respiratory control disorders or disorders in a subject in need thereof. The invention also includes a method of treating a respiratory disease or disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the invention. The present invention is further a method of preventing or stabilizing respiratory rhythm instability in a subject in need thereof, wherein a therapeutically effective amount of a pharmaceutical formulation of the present invention is administered to the subject Including methods, including steps.

Description

This application claims priority from U.S. Patent Application No. 13 / 482,837 filed May 29, 2012, which is dated November 29, 2011. This is a continuation-in-part of U.S. Patent Application No. 13 / 306,349, which claims priority, and U.S. Patent Application No. 13 / 306,349 includes a US provisional application filed on Priority is granted under 35 U.S.C. 119 (e) of patent application 61 / 417,777 and U.S. provisional patent application 61 / 494,268 filed June 7, 2011, both of which are The entirety of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION Normal control of respiration is a complex process that partially involves the body's interpretation and response to levels of chemical stimuli such as carbon dioxide, pH and oxygen in the blood, tissue and brain. Respiratory control is also affected by other factors such as wakefulness (ie whether the patient is awake or asleep), emotion, posture and vocalization. The respiratory control center that exists in the cerebral medulla interprets various feedforward and feedback signals that affect respiration and issues commands to the muscles that perform the breathing work. Major muscle groups are located in the abdomen, diaphragm, pharynx and chest. The centrally and peripherally located sensors then provide inputs to the central respiratory control area of the brain that allow responses to changing metabolic requirements.

For example, sufficient ventilation to meet the body's metabolic needs is maintained primarily by the body's rapid response to changes in carbon dioxide levels (CO ₂ ). An increase in CO ₂ level signals the body to increase the rate and depth of respiration, which increases blood oxygen levels and subsequently decreases blood CO ₂ levels. Conversely, low CO ₂ levels may result in periods of hypopnea (respiratory decline) or, in extreme cases, apnea (no breathing), as stimulation to breathing is reduced. This is what happens when an individual becomes hyperventilated.

In many diseases, loss of normal respiratory control is a primary or secondary feature of the disease. Examples of diseases with a primary loss of respiratory control include apnea (central, mixed or obstructive; breathing is interrupted repeatedly for 10-60 seconds) and congenital central hypoventilation syndrome. Secondary loss of respiratory control includes chronic cardiopulmonary disease (e.g. heart failure, chronic bronchitis, emphysema and impending respiratory failure), overweight (e.g. obesity hypoventilation syndrome), certain drugs (e.g. anesthetics, sedatives, anti Anxiety drugs, sleeping pills, alcohol and narcotic analgesics), and / or factors affecting the nervous system (eg, stroke, tumors, trauma, radiation damage and ALS) may be the reason. In chronic obstructive pulmonary disease, where the body is chronically exposed to high levels of carbon dioxide, kidney-mediated retention of bicarbonate, which has the effect of partially neutralizing CO ₂ / pH respiratory stimuli, makes the body relatively Adapt to low pH. Thus, the patient cannot initiate a normal ventilation response to changes in metabolic demand.

  Sleep-disordered breathing is one example where abnormal breathing control leads to a serious common disease in humans. Sleep apnea is characterized by periods of frequent apneas or partial breaths. Major factors contributing to these apneas include anatomical factors (such as obesity), decreased hypercapnic and hypoxic ventilation responses (e.g. response to high carbon dioxide and hypoxia levels, respectively) Loss), as well as loss of “wakefulness” (ie drive of the pharyngeal open muscle). Apnea events result in hypoxia (and associated oxidative stress) and ultimately severe cardiovascular events (hypertension, stroke, heart attack).

  The estimated number of U.S. individuals suffering from impaired respiratory control is sleep apnea (15-20 million); obesity hypoventilation syndrome (5-10 million); chronic heart disease (500 Including chronic obstructive pulmonary disease (COPD) / chronic bronchitis (10 million); drug-induced hypoventilation (2 million to 5 million); and ventilatory withdrawal (500,000).

There is a need in the art for new compounds that can be used to repair all or part of the body's normal respiratory control system in response to changes in CO ₂ and / or oxygen with minimal side effects. Such compounds would be beneficial in reducing the incidence and severity of impaired respiratory control. The present invention addresses and meets these needs.

BRIEF SUMMARY OF THE INVENTION The present invention includes a composition comprising at least one compound selected from the group consisting of: N- (2,4-bis-n-propylamino) -N- (6-methylamino) )-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine (CLXXIII), N- (2,4, 6-Tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any combination thereof.

  In one aspect, the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate. In another embodiment, the composition further comprises at least one pharmaceutically acceptable carrier.

  The invention also includes a method of preventing or treating a respiratory control disorder or respiratory control disorder in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N- (2, 4-Bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1 , 3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any combinations thereof.

  In one aspect, the respiratory control disorder or respiratory control disorder is respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia Selected from the group consisting of symptoms. In another aspect, respiratory depression is caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol or narcotics. In yet another embodiment, the subject is further administered a composition comprising at least one additional compound useful for treating a respiratory control disorder or respiratory control disorder. In yet another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, aluminin, theophylline, caffeine, methylprogesterone, serotonin modulators, cannabinoids and ampakines. In yet another aspect, the formulation is administered in combination with the use of a ventilator or positive airway pressure device to the subject. In yet another aspect, the subject is a mammal. In yet another aspect, the mammal is a human. In yet another aspect, the formulation is administered by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. To be administered.

  The invention also includes a method of preventing or stabilizing respiratory rhythm instability in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N- (2, 4-Bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1 , 3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any combinations thereof.

  In one aspect, the destabilization consists of respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia It is associated with a more selected respiratory control disorder or respiratory control disorder. In another aspect, respiratory depression is caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol or narcotics. In yet another embodiment, the subject is further administered a composition comprising at least one additional compound useful for treating a respiratory control disorder or respiratory control disorder. In yet another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, aluminin, theophylline, caffeine, methylprogesterone, serotonin modulators, cannabinoids and ampakines. In yet another aspect, the formulation is administered in combination with the use of a ventilator or positive airway pressure device to the subject. In yet another aspect, the subject is a mammal. In yet another aspect, the mammal is a human. In yet another aspect, the formulation is administered by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. To be administered.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is equal to or about 1% (w / w) relative to (XXXV) or a salt thereof Including a composition that is present at a level of less than.

  In one aspect, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is about 0.5% (w / w) relative to (XXXV) or a salt thereof. Present at equal or lesser level. In another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is about 0.3% (w / w) based on (XXXV) or a salt thereof. Is present at a level less than or equal to In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is about 0.2% (w / w) relative to (XXXV) or a salt thereof. ) Is present at a level less than or equal to. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is about 0.15% (w / w) relative to (XXXV) or a salt thereof. ) Is present at a level less than or equal to. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is about 0.1% (w / w) relative to (XXXV) or a salt thereof. ) Is present at a level less than or equal to. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof, The composition further comprises a buffer and a liquid carrier.

  In one embodiment, the salt of (XXXV) is hydrogen sulfate (XXXVI). In another aspect, the composition further comprises citric acid. In yet another embodiment, the pH of the composition is adjusted with a base. In yet another aspect, the base comprises sodium hydroxide. In yet another aspect, the liquid carrier includes water. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 6. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 5. In yet another embodiment, the pH of the composition ranges from about 3 to about 4. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 1-10 mg / mL. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 5-10 mg / mL. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 10 mg / mL. In yet another embodiment, the composition comprises less than 0.5% (w / w) (CLXXVIII) relative to (XXXV). In yet another embodiment, less than 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (XXXV) CLXXVIII) is formed at 2-8 ° C. over a 6 month shelf life of the composition. In yet another embodiment, less than 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (XXXV) CLXXVIII) is formed at 2-8 ° C. over a 12 month shelf life of the composition. In yet another embodiment, less than 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (XXXV) CLXXVIII) is formed at 2-8 ° C. over a shelf life of 18 months. In yet another embodiment, less than 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (XXXV) CLXXVIII) is formed at 2-8 ° C. over a 24 month shelf life of the composition.

  The present invention also provides N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) having the XRPD spectrum of FIG. ) Crystalline free base form A.

  The present invention also provides N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -NO-dimethyl-hydroxylamine (XXXV) selected from the group consisting of: At least one crystalline salt of: crystalline hydrogen sulfate (XXXVI) form A having the XRPD spectrum of FIG. 14; crystalline comprising a mixture of form A and form B having the XRPD spectrum of FIG. Crystalline hydrogen sulfate (XXXVI) Form C with XRPD spectrum of Figure 25; Crystalline hydrogen sulfate (XXXVI) Form D with XRPD spectrum of Figure 25; XRPD spectrum of Figure 26 Crystalline hydrogen sulfate (XXXVI) comprising a mixture of Form A and Form D having a crystalline phosphate (CLXXX) form A having an XRPD spectrum of FIG. 27; a crystal having an XRPD spectrum of FIG. Phosphate (CLXXX) Form C; Crystalline Phosphate (CLXXX) containing a mixture of Form A and Form B with the XRPD spectrum of Figure 29; XRPD of Figure 30 Crystalline phosphate (CLXXX) comprising a mixture of Form C and Form D having a cuttle; Crystalline phosphate (CLXXX) comprising a mixture of Form C and Form E having the XRPD spectrum of FIG. 31; And any mixture of them.

  The present invention also includes a salt of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XXXV) containing about 1 molar equivalent of sulfuric acid. . In one aspect, the salt further comprises 1 molar equivalent of water.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -NO-dimethyl-hydroxylamine (XXXV) containing at least 1 molar equivalent of phosphoric acid. ) Salt. In one aspect, the salt comprises about 1 molar equivalent of phosphoric acid.

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;R⁴はH、アルキルまたは置換アルキルであり;R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;R⁶はH、アルキル、置換アルキルまたはアルケニルであり;Xは結合、OまたはNR⁴であり;YはN、CR⁶またはCであり;ここで
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;
YがCである場合、結合b¹は単結合であり、かつ(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 The invention also includes a method of reducing or minimizing the open channel portion of a potassium maxi-K or BK channel in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forms a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R ³ is H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -NR 1 R 2, -C (} O) OR 1, acyl also Aryl; R ⁴ is an H, alkyl or substituted alkyl; R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -OR 1, -NR 1 R 2} , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ^{5 taken} together to form 3,6,9-trioxa Forming a biradical selected from the group consisting of -undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ⁶ is H, alkyl, substituted alkyl or alkenyl; X is Bond, O or NR ⁴ ; Y is N, CR ⁶ or C; where
When Y is N or CR ⁶ , bond b ¹ is not present and (i) Z is H, bond b ² is a single bond and A is CH; or (ii) Z is absent, bond b ² is absent and A is a single bond;
When Y is C, bond b ¹ is a single bond, and (i) Z is CH ₂ , bond b ² is a single bond, and A is CH; or (ii) Z Is CH, bond b ² is a double bond, and A is C.

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;R⁴はH、アルキルまたは置換アルキルであり;R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;R⁶はH、アルキル、置換アルキルまたはアルケニルであり;Xは結合、OまたはNR⁴であり;YはN、CR⁶またはCであり; ここで
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;
YがCである場合、結合b¹は単結合であり、かつ(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 The invention also includes a method of inhibiting a TASK-1 (KCNK3) channel in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forms a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R ³ is H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -NR 1 R 2, -C (} O) OR 1, acyl also Aryl; R ⁴ is an H, alkyl or substituted alkyl; R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -OR 1, -NR 1 R 2} , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ^{5 taken} together to form 3,6,9-trioxa Forming a biradical selected from the group consisting of -undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ⁶ is H, alkyl, substituted alkyl or alkenyl; X is A bond, O or NR ⁴ ; Y is N, CR ⁶ or C; where
When Y is N or CR ⁶ , bond b ¹ is not present and (i) Z is H, bond b ² is a single bond and A is CH; or (ii) Z is absent, bond b ² is absent and A is a single bond;
When Y is C, bond b ¹ is a single bond, and (i) Z is CH ₂ , bond b ² is a single bond, and A is CH; or (ii) Z Is CH, bond b ² is a double bond, and A is C.

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;R⁴はH、アルキルまたは置換アルキルであり;R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;R⁶はH、アルキル、置換アルキルまたはアルケニルであり;Xは結合、OまたはNR⁴であり;YはN、CR⁶またはCであり; ここで
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;
YがCである場合、結合b¹は単結合であり、かつ(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 The invention also includes a method of increasing minute ventilation in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forms a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R ³ is H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -NR 1 R 2, -C (} O) OR 1, acyl also Aryl; R ⁴ is an H, alkyl or substituted alkyl; R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -OR 1, -NR 1 R 2} , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ^{5 taken} together to form 3,6,9-trioxa Forming a biradical selected from the group consisting of -undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ⁶ is H, alkyl, substituted alkyl or alkenyl; X is A bond, O or NR ⁴ ; Y is N, CR ⁶ or C; where
When Y is N or CR ⁶ , bond b ¹ is not present and (i) Z is H, bond b ² is a single bond and A is CH; or (ii) Z is absent, bond b ² is absent and A is a single bond;
When Y is C, bond b ¹ is a single bond, and (i) Z is CH ₂ , bond b ² is a single bond, and A is CH; or (ii) Z Is CH, bond b ² is a double bond, and A is C.

In one embodiment, the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N, O— Dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropylmethyl)- N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6-n-propyl Amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4,6-bis -n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4-diamine, N- (4 , 6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [ 1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N- Isopropyl-hydroxy Ruamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5 ] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino- [ 1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl ) -O-isobutyl-N-methyl-hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4 -Diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N- (4,6 -Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1, 3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6- N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazol-2-yl) -methyl Amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2-dimethylamino) Ethyl) amino)-[ 1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl) -N, O- Dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis-n-propylamino -[1,3,5] Triazin-2-yl) -N-methyl-N'-methyl Hydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethylamino-7-methyl -Pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n-propylamino)- Pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino-7-methyl- Pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N -Methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n-propylamino-7 -Methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine, N- (2,4- Scan -n- propylamino) -N- (6-i- propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.

  In one embodiment, the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl) -O-methyl -Hydroxylamine, N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (2,4-bis-n -Propylamino) -N- (6-methylamino)-[1,3,5] triazine, N-[(2,6-bis-n-propylamino) -pyrimidin-4-yl] -N, O- Dimethyl-hydroxylamine, N, N-dimethyl-N ′-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, its salts, and mixtures thereof.

  In one embodiment, the compound of formula (I) is N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine or a salt thereof It is.

  In one aspect, the pharmaceutical formulation is administered by intravenous infusion. In another embodiment, the infusion rate of the pharmaceutical formulation is at least about 0.016 mg / kg / min. In yet another embodiment, the dosage of the pharmaceutical formulation is about 0.016 mg / kg / min. In yet another embodiment, the infusion amount of the pharmaceutical composition results in a plasma concentration of at least about 726 ng / mL in the subject. In yet another aspect, the subject is a mammal. In yet another aspect, the mammal is a human.

  For the purpose of illustrating the invention, certain aspects of the invention are shown in the drawings. However, the present invention is not limited to the exact arrangement and configuration of the embodiments shown in the drawings.

It is a graph which shows the result of the plethysmography experiment which monitored the minute ventilation of the opioid treatment rat at the time of administration of compound (XXXVI) [it shows as a compound (A)]. The arterial blood gas analysis result regarding administration of the compound (XXXVI) [it shows with a compound (A)] in an opioid treatment rat is shown. -PaCO ₂ (mmHg). The arterial blood gas analysis result regarding administration of the compound (XXXVI) [it shows with a compound (A)] in an opioid treatment rat is shown. -SaO ₂ (%). It is a graph which shows the result of the plethysmography experiment which monitored the minute ventilation of the rat at the time of the administration of the compound (XXXVI) [it shows as a compound (A)] under hypoxic conditions. ₂ is a graph showing end-tidal CO ₂ and minute ventilation of opioid-treated monkeys at the time of administration of compound (XXXVI) [labeled as compound (A)]. FIG. 6 is a graph showing the dose-dependent effects of Compound (XXXVI) [labeled as Compound (A)] and Compound (L) [labeled as Compound (B)] on maximal peak response on minute ventilation in rats. FIG. 2 is a graph showing the dose-dependent effects of Compound (XXXVI) [labeled as Compound (A)] and Compound (CXXI) [labelled as Compound (C)] on maximal peak response on minute ventilation in rats. Figure 2 shows the dose-dependent effect of compound (L) [labelled as compound (B)] on blood gas and pH in opioid-treated rats. -pH. Figure 2 shows the dose-dependent effect of compound (L) [labelled as compound (B)] on blood gas and pH in opioid-treated rats. - SaO _2. Figure 2 shows the dose-dependent effect of compound (L) [labelled as compound (B)] on blood gas and pH in opioid-treated rats. -pO ₂ . Figure 2 shows the dose-dependent effect of compound (L) [labelled as compound (B)] on blood gas and pH in opioid-treated rats. -pCO ₂ . Figure 2 shows the dose-dependent effect of compound (CXLII) [labelled as compound (D)] on blood gas and pH in opioid-treated rats. -pO ₂ . Figure 2 shows the dose-dependent effect of compound (CXLII) [labelled as compound (D)] on blood gas and pH in opioid-treated rats. - SaO _2. Figure 2 shows the dose-dependent effect of compound (CXLII) [labelled as compound (D)] on blood gas and pH in opioid-treated rats. -pCO ₂ . Figure 2 shows the dose-dependent effect of compound (CXLII) [labelled as compound (D)] on blood gas and pH in opioid-treated rats. -pH. It is a graph which shows the effect of the compound (CXLII) [it shows with a compound (D)] in the minute ventilation of an opioid treatment rat. ¹ shows the ¹ H-NMR spectrum of compound (XXXVI) in DMSO-d ₆ at 25 ° C. FIG. FIG. ¹³ shows a ¹³ C-NMR spectrum of compound (XXXVI) in DMSO-d ₆ at 25 ° C. FIG. 3 shows an FTIR spectrum of compound (XXXVI). 2 shows a thermal analysis by DSC of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogen sulfate (XXXVI). 2 shows an X-ray diffraction spectrum of Compound (XXXVI) Form A (hydrogen sulfate form A). 2 is a graph showing the effect of compound (XXXVI) in reversing the effect of midazolam on rat minute ventilation (MV). 2 is a graph showing the effect of compound (XXXVI) in reversing the effect of midazolam on tidal volume (TV) in rats. FIG. 2 is a graph showing the effect of compound (XXXVI) in reversing the effect of midazolam on rat respiratory rate (f). Acute high compound to the minute ventilation response to carbon dioxide hyperinsulinemia _{(3% CO 2) (XXXVI} ) is a graph showing the effect of injection. 2 is a graph showing the effect of pH on the water solubility of compound (XXXV) at ambient temperature. 2 is a graph showing the effect of pH on the water solubility of compound (XXXV) at ambient temperature. It is a graph which shows the effect of pH with respect to decomposition | disassembly of compound (XXXV) in pH 2-6. 2 is a graph showing the effect of pH on the degradation of compound (XXXV) at pH 2 to 3.6. It is a graph which shows the formation rate of the compound (CLXXVIII) from the compound (XXXV) in a 2-8 degreeC and pH 3-4 solution. 2 is a graph showing an X-ray powder diffraction pattern of a free base of compound (XXXV). 2 is a graph showing an X-ray powder diffraction spectrum of a mixture of Compound (XXXVI) Form A and Compound (XXXVI) Form B. 2 is a graph showing an X-ray powder diffraction spectrum of Compound (XXXVI) Form C. 2 is a graph showing an X-ray powder diffraction spectrum of Compound (XXXVI) Form D. 2 is a graph showing an X-ray powder diffraction spectrum of a mixture of Compound (XXXVI) Form A and Compound (XXXVI) Form D. 2 is a graph showing an X-ray powder diffraction spectrum of Compound (CLXXX) Form A. 2 is a graph showing an X-ray powder diffraction spectrum of Compound (CLXXX) Form C. 2 is a graph showing an X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form A and Compound (CLXXX) Form B. 2 is a graph showing an X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form C and Compound (CLXXX) Form D. 2 is a graph showing an X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form C and Compound (CLXXX) Form E. It is a graph which shows the effect of a compound (XLII) with respect to the respiration rate in a rat. It is a graph which shows the effect of the compound (XLII) with respect to the tidal volume in a rat. It is a graph which shows the effect of the compound (XLII) with respect to the minute ventilation in a rat. It is a graph which shows the effect of a compound (XLII) with respect to the 5-minute average of the change of the minute ventilation in a rat. It is a graph which shows the effect of a compound (CLXXII) with respect to the respiration rate in a rat. It is a graph which shows the effect of the compound (CLXXII) with respect to the tidal volume in a rat. It is a graph which shows the effect of the compound (CLXXII) with respect to the minute ventilation in a rat. It is a graph which shows the effect of a compound (CLXXII) with respect to the 5-minute average of the change of the minute ventilation in a rat. 34A-34C, including the effect of BK channel activity in response to a concentration of 1 μM compound (XXXV). FIG. 34A: Sample recording of channel activity at control conditions and 1 μM (XXXV). The arrow is closed. Figure 34B: All-point histogram obtained from 1 minute recording in control condition. FIG. 34C: All point histograms obtained by 1 minute recording at 1 μM (XXXV). Patch ID: C 05 SP 101008_0000. The design of test GAL-021-101 is shown, ie, the test duration and infusion rate and duration per group (cohort). Dose levels pooled for PD analysis are described on the left. It is an exemplary design drawing of the respiratory depression concept proof test (GAL-021-104). It is a graph which shows the tidal volume for the first 2 hours after the start of infusion. 38A-38D, including minute ventilation (Figure 38A), end-tidal CO2 (Figure 38B), respiratory rate (Figure 38C) and tidal volume (GAL-021-101) in the first clinical trial (GAL-021-101) FIG. 38D is a set of graphs showing the percent integrated change from baseline for the first hour (0-1 hour) and the first 2 hours (0-2 hours) after the start of infusion for FIG. 38D). Data from the first hour of period 9 (0.96 mg / kg / hr) was pooled with data from subjects with similar infusion rates in groups 6 and 7 for the 0-1 hour assessment. 39A-39D, including minute ventilation (Figure 39A), end-tidal CO2 (Figure 39B), respiratory rate (Figure 39C) and tidal volume (Figure 39A) in the second clinical trial (GAL-021-102) FIG. 39D is a set of graphs showing percent integrated change from baseline for the first 1 hour (0-1 hour) and the first 2 hours (0-2 hours) after the start of infusion for FIG. 39D). It is a graph which shows percutaneous hemoglobin oxygen saturation (GAL-021-102). The results of Part I of the GAL-021-104 clinical trial, ie the percent cumulative change from baseline for the last 10 minutes for each segment in terms of minute ventilation, are shown. The duration of the segment was 30 minutes, except for the segment indicated as (XXXVI) high, with a duration of 40 minutes due to the initial loading dose of 20 minutes. The end-expiratory end was clamped during the study and remained almost unchanged. The results of Part I of the GAL-021-104 clinical trial, i.e. the percent cumulative change from baseline for the last 10 minutes for each segment in relation to tidal volume, are shown. The duration of the segment was 30 minutes, except for the segment indicated as (XXXVI) high, with a duration of 40 minutes due to the initial loading dose of 20 minutes. The end-expiratory end was clamped during the study and remained almost unchanged. Shown are the results of Part I of the GAL-021-104 clinical trial, ie the percent cumulative change from baseline for the last 10 minutes for each segment in terms of respiratory rate. The duration of the segment was 30 minutes, except for the segment indicated as (XXXVI) high, with a duration of 40 minutes due to the initial loading dose of 20 minutes. The end-expiratory end was clamped during the study and remained almost unchanged. FIG. 6 is a graph showing the percentage of current change (n = 8) at the start of pain from Part 2 of the GAL-021-104 study, ie, a TENS device placed on the anterior tibial region. The results of Part 2 of the GAL-021-104 study are shown, ie the percentage change from baseline in the last 10 minutes for each segment with respect to minute ventilation. The results of Part 2 of the GAL-021-104 study, ie, the percent cumulative change from baseline for the last 10 minutes of each segment for end expiratory CO ₂ are shown. The results of Part 2 of the GAL-021-104 study, i.e. the percent cumulative change from baseline for the last 10 minutes of each segment in relation to respiratory rate, are shown. The results of Part 2 of the GAL-021-104 study are shown, ie the percentage change from baseline in the last 10 minutes for each segment with respect to tidal volume. N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl- after IV infusion for healthy volunteers during the first trial in humans 1 shows the mean plasma concentration-time profile of hydroxylamine hydrogen sulfate (XXXVI). N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl after IV infusion in healthy volunteers during the second trial in humans -Shows mean plasma concentration-time profile of hydroxylamine hydrogensulfate (XXXVI).

DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to the unexpected discovery that the compounds of the present invention are respiratory stimulants and are useful in the treatment of respiratory control disorders or respiratory control disorders.

Definitions As used herein, each of the following terms has the meaning associated with it in this section.

  Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and experimental techniques in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well known and commonly used in the art.

  As used herein, the articles “one” and “a” mean that the grammatical object of the article is one or more (ie, at least one). By way of example, “an element” means one element or more than one element.

  The term “about” as used herein is understood by one of ordinary skill in the art and will vary to some extent on the context in which it is used. The term “about” as used herein when referring to measurable values such as amount, duration, etc., is ± 20% or ± 10%, more preferably ± 5%, more preferably from a particular value. Is a variation of ± 1%, more preferably ± 0.1%, and is intended to encompass variations that are appropriate in performing the disclosed methods.

  A “subject” as used herein can be a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cows, pigs, dogs, cats and mouse mammals. Preferably, the subject is a human.

In a non-limiting embodiment, the following terminology used to report blood gas measurements is well known to those skilled in the art and can be defined as follows: Minute ventilation (MV) is a measure of respiratory volume per unit time and is indicated herein as mL / min. pCO ₂ is the partial pressure of carbon dioxide (gas) in blood (arterial blood) and is measured in mmHg (millimeter Hg). pO ₂ is the partial pressure of oxygen (gas) in blood (arterial blood) and is measured in mmHg (millimeter Hg). SaO ₂ is the proportion of hemoglobin in the form of oxyhemoglobin in the blood; end-tidal CO ₂ is a measure of exhaled carbon dioxide gas detected using colorimetry or capnometry.

As used herein, the term ED ₅₀ means an effective amount of a formulation that produces a given effect in 50% of the subjects to which the formulation is administered.

  As used herein, a “disease” is an animal health condition in which the animal cannot maintain homeostasis and the animal's health continues to deteriorate unless the disease is in remission.

  As used herein, an “disorder” of an animal is a health condition in which the animal is capable of maintaining homeostasis, but the health condition of the animal is less favorable than in the absence of the disorder. Even if left untreated, the disorder does not necessarily cause a further decline in the animal's health.

  As used herein, an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” of a compound is an amount of the compound sufficient to provide a beneficial effect to the subject to which the compound is administered. That is. As used herein, the term “treating” means reducing the frequency with which a patient or subject experiences symptoms, or administering a drug or compound to reduce the severity of experiencing the symptoms. To do.

  The term “pharmaceutically acceptable” as used herein refers to a carrier or diluent that does not abrogate the biological activity or properties of the compounds useful within the scope of the invention and is relatively non-toxic. I.e. the material is administered to an individual without causing an undesirable biological effect or without causing a harmful interaction with any of its components contained in the composition. can do.

  The term “salt” as used herein means an addition salt of a free acid or free base that is useful within the scope of the method of the invention. The term “salt” also means a mixture of a salt and its corresponding free acid or free base in isolated form (eg, as a solid) or in solution.

  As used herein, the phrase “pharmaceutically acceptable salts” refers to administered compounds prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases. Salts, solvates, hydrates and clathrates thereof.

  The term “composition” or “pharmaceutical composition” as used herein refers to a mixture of at least one compound useful within the scope of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

  As used herein, the term “pharmaceutically acceptable carrier” refers to a compound useful within or within the subject, such that a compound useful within the scope of the invention can perform its intended function. Pharmaceutically acceptable, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents or encapsulating materials involved in transportation or transportation Means a material, composition or carrier. Typically, such constructs are transported or transported from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation comprising the compound useful within the scope of the invention and not injurious to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate Derivatives; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; glycerin Polyols such as sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; magnesium hydroxide and aluminum hydroxide Buffers; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and substances which are compatible with other non-toxic to be used in pharmaceutical formulations and the like. As used herein, a “pharmaceutically acceptable carrier” is any coating, antimicrobial, compatible with the activity of the compounds useful within the scope of the present invention and physiologically acceptable to the subject. And antifungal agents, absorption delaying agents, and the like. Supplementary active compounds can also be incorporated into the compositions. A “pharmaceutically acceptable carrier” can further include a pharmaceutically acceptable salt of a compound useful within the scope of the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present invention are known in the art, eg, Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing, incorporated herein by reference). Co., 1985, Easton, PA).

  As used herein, the phrase “process-related impurities” refers to pharmaceuticals that result from exposing any starting materials, intermediates, reactants, solvents, and the pharmaceutically active ingredient itself to the conditions of the synthetic process. Means impurities formed during the process of producing the active ingredient.

  As used herein, “treating a disease or disorder” means reducing the frequency with which a subject experiences symptoms of a disease or disorder. In the present specification, disease and disorder are used interchangeably.

  As used herein, the term “specifically binds” means that a first molecule binds preferentially to a second molecule (eg, a particular receptor or enzyme), but not necessarily that second molecule. It means that it doesn't bind only to.

As used herein, the term "alkyl" or as part of another substituent alone, unless otherwise specified, a (i.e. C ₁ -C ₁₀ having a number of carbon atoms designated Means a straight-chain or branched hydrocarbon (meaning 1 to 10 carbon atoms) and includes a straight-chain, branched or cyclic substituent. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl and cyclopropylmethyl. Most preferred is (C ₁ -C ₆ ) alkyl, including but not limited to ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

As used herein, the term “cycloalkyl”, alone or as part of another substituent, has the specified number of carbon atoms (ie, C ₃ -C _6), unless otherwise specified. Means a cyclic hydrocarbon group (which means a cyclic group containing a cyclic group consisting of 3 to 6 carbon atoms), and includes a linear, branched or cyclic substituent. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Most preferred is (C ₃ -C ₆ ) cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “alkenyl” used alone or in combination with other terms, unless otherwise specified, is a stable monounsaturated or diunsaturated having the number of carbon atoms specified. It means a saturated linear or branched hydrocarbon group. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. A functional group representing an alkene is exemplified by —CH ₂ —CH═CH ₂ .

  As used herein, the term “alkynyl” used alone or in combination with other terms, unless otherwise specified, is stable with a triple carbon-carbon bond having the number of carbon atoms specified. A straight or branched hydrocarbon group. Examples include ethynyl and propynyl, and higher homologs and isomers.

As used herein, the terms “substituted alkyl”, “substituted cycloalkyl”, “substituted alkenyl” or “substituted alkynyl” are halogen, —OH, alkoxy, tetrahydro-2-H-pyranyl, —NH ₂ , _{-N (CH 3) 2, (} 1- methyl - imidazol-2-yl) pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C (= O) OH, trifluoromethyl, -C≡N, -C (= O) O (C 1 ~C 4) _{alkyl, -C (= O) NH 2} , -C (= O) NH (C 1 ~C 4) alkyl, -C (= 1, 2 or 3 substitutions selected from the group consisting of O) N ((C ₁ -C ₄ ) alkyl) ₂ , -SO ₂ NH ₂ , -C (= NH) NH ₂ and -NO ₂ Substituted with a group, preferably selected from halogen, —OH, alkoxy, —NH ₂ , trifluoromethyl, —N (CH ₃ ) ₂ and —C (═O) OH, more preferably halogen, alkoxy and — Containing one or two substituents selected from OH, as defined above Alkyl refers to a cycloalkyl, alkenyl or alkynyl. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

As used herein, the term “alkoxy” used alone or in combination with other terms, unless otherwise specified, is designated as connected to the rest of the molecule via an oxygen atom. It means an alkyl group as defined above having the number of carbon atoms, for example methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. (C ₁ -C ₃ ) alkoxy is preferred, including but not limited to ethoxy and methoxy.

  As used herein, the term “halo” or “halogen”, alone or as part of another substituent, unless otherwise stated, is a fluorine, chlorine, bromine or iodine atom, preferably fluorine, It means chlorine or bromine, more preferably fluorine or chlorine.

As used herein, the term “heteroalkyl”, alone or in combination with another term, unless specified otherwise, comes from the group consisting of the specified number of carbon atoms and O, N, and S. A stable linear or branched alkyl consisting of one or two selected heteroatoms, wherein the nitrogen and sulfur atoms may be oxidized and the nitrogen heteroatoms may be quaternized Means group. A heteroatom can be placed at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, and is attached to the most distal carbon atom of the heteroalkyl group. sell. Examples are -O-CH ₂ -CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -OH, -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ And —CH ₂ CH ₂ —S (═O) —CH ₃ . Up to two heteroatoms can be consecutive, such as, for example, —CH ₂ —NH—OCH ₃ or —CH ₂ —CH ₂ —SS—CH ₃ .

As used herein, the term "heteroalkenyl", alone or in combination with another term, unless specified otherwise, comes from the group consisting of the specified number of carbon atoms and O, N, and S. A stable straight or branched chain consisting of one or two selected heteroatoms, wherein the nitrogen and sulfur atoms may be oxidized and the nitrogen heteroatoms may be quaternized. An unsaturated or diunsaturated alkyl group is meant. A maximum of 2 heteroatoms can be arranged sequentially. Examples include -CH = CH-O-CH ₃ , -CH = CH-CH ₂ -OH, -CH ₂ -CH = N-OCH ₃ , -CH = CH-N (CH ₃ ) -CH ₃ and -CH ₂ -CH = CH-CH ₂ -SH.

  As used herein, the term “aromatic” refers to (4n + 2) delocalizations having one or more polyunsaturated rings and having aromaticity, i.e., n is an integer. A carbocyclic or heterocyclic ring having a π (pi) electron.

  As used herein, the term `` aryl '' used alone or in combination with other terms, unless stated otherwise, refers to one or more rings (typically 1, 2 or Means a carbocyclic aromatic system containing 3 rings), such rings can be linked together pendant like biphenyl or fused like naphthalene. Examples include phenyl, anthracyl and naphthyl. Phenyl and naphthyl are preferred and phenyl is most preferred.

The term “aryl- (C ₁ -C ₃ ) alkyl” as used herein refers to a functional group in which an alkylene chain having 1 to 3 carbon atoms is bonded to an aryl group, such as —CH ₂ CH ₂ -phenyl. or -CH ₂ - means phenyl (benzyl). Aryl-CH ₂ -and aryl-CH (CH ₃ )-are preferred. The term “substituted aryl- (C ₁ -C ₃ ) alkyl” refers to an aryl- (C ₁ -C ₃ ) alkyl functional group substituted with an aryl group. Substituted aryl (CH ₂ ) — is preferred. Similarly, the term “heteroaryl- (C ₁ -C ₃ ) alkyl” as used herein refers to a functional group in which an alkylene chain having 1 to 3 carbon atoms is bonded to a heteroaryl group, such as —CH 2. ₂ CH ₂ means pyridyl. Heteroaryl- (CH ₂ )-is preferred. The term “substituted heteroaryl- (C ₁ -C ₃ ) alkyl” refers to a heteroaryl- (C ₁ -C ₃ ) alkyl functional group substituted with a heteroaryl group. Substituted heteroaryl- (CH ₂ )-is preferred.

  As used herein, the term “heterocycle” or “heterocyclyl” or “heterocyclic”, alone or as part of another substituent, unless otherwise specified, includes carbon atoms and N, O And at least one heteroatom selected from the group consisting of S, nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen atom may be quaternized, unsubstituted or substituted stable Means a monocyclic or polycyclic heterocyclic ring system. Heterocyclic systems can be attached at any heteroatom or carbon atom that results in a stable structure, unless otherwise specified. Heterocycles can be aromatic or non-aromatic. In one aspect, the heterocycle is heteroaryl.

  The term “heteroaryl” or “heteroaromatic” as used herein refers to a heterocycle having aromatic character. A polycyclic heteroaryl may contain one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

  Examples of non-aromatic heterocycles include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, Thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3- Monocyclic groups such as dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin and hexamethylene oxide.

  Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including but not limited to 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3, 4-oxadiazolyl is mentioned.

  Examples of polycyclic heterocycles include indolyl (including but not limited to 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (1- and 5- Such as but not limited to isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including but not limited to 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8- Naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including but not limited to 3-, 4-, 5-, 6- and 7-benzofuryl), 2, 3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (including but not limited to 3-, 4-, 5-, 6- and 7-benzothienyl), benzoxazolyl, Examples include benzothiazolyl (including but not limited to 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolididinyl and quinolizidinyl.

  The above list of heterocyclyl and heteroaryl moieties is intended to be representative rather than limiting.

  The term “substituted” as used herein means that an atom or group of atoms has replaced a hydrogen as a substituent attached to another group.

For aryl groups, aryl- (C ₁ -C ₃ ) alkyl groups and heterocyclyl groups, the term “substituted” as applied to the ring of these groups refers to any permissible level of substitution, ie mono-substitution, Means disubstituted, trisubstituted, tetrasubstituted or pentasubstituted. The substituents are independently selected, and the substitution can be at any chemically accessible position. In one embodiment, the number of substituents varies from 1 to 4. In another embodiment, the number of substituents varies from 1 to 3. In yet another embodiment, the number of substituents varies from 1 to 2. In yet another embodiment, the substituents are independently selected from the group consisting of C _1-6 alkyl, —OH, C _1-6 alkoxy, halo, amino, acetamide and nitro. When the substituent used in the present specification is an alkyl group or an alkoxy group, the carbon chain may be branched, linear or cyclic, and is preferably linear.

As used herein, the term “AcOH” refers to acetic acid, the term “nBuOH” refers to n-butanol, and the term “CH ₂ Cl ₂ ” refers to dichloromethane (also known as methylene dichloride). The term `` DMSO '' means dimethyl sulfoxide, the term `` EtOAc '' means ethyl acetate, the term `` EtOH '' means ethanol, the term `` HCl '' means hydrochloric acid or hydrochloride Meaning `` HPLC '' means high pressure liquid chromatography, the term `` H ₂ SO ₄ '' means sulfuric acid, the term `` LCMS '' means liquid chromatography mass spectrometry, and `` MS '' The term means mass spectrometry, the term “MeOH” means methanol, the term “NaCl” means sodium chloride, the term “NaHCO ₃ ” means sodium bicarbonate, “Na The term `` OH '' means sodium hydroxide, the term `` Na ₂ SO ₄ '' means sodium sulfate, the term `` mpk '' means mg / kg, the term `` NMR '' means nuclear magnetic resonance. The term `` PE '' or `` pet ether '' means petroleum ether, the term `` POCl <sub>3</sub> '' means phosphorus oxychloride, the term `` ppm '' means parts per million, and `` xphos The term “” means 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the term “dba” means trans, trans-dibenzylideneacetone.

  As used herein, the term “explanatory material” refers to a publication, record, chart or any other that can be used to convey the utility of the compositions and / or compounds of the invention in a kit. Including expression media. The instructional material for the kit can be attached, for example, to a container containing the compound and / or composition of the present invention, or can be shipped with the container containing the compound and / or composition. Alternatively, the explanatory material can be shipped separately from the container with the intention that the recipient uses the explanatory material and the compound together. Delivery of the explanatory material may be, for example, by physical transport of a publication or other expression medium that conveys the usefulness of the kit, or, for example, electronic transmission by computer, eg, e-mail, or download from a website It may be realized by.

Compounds and Compositions of the Invention The present invention includes compounds of the invention and any composition comprising such compounds.

  The present invention includes at least one compound selected from the group consisting of: N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] Triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), salts thereof, and them Any combination of.

  In one aspect, the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate. In another embodiment, at least one compound is formulated with at least one pharmaceutically acceptable carrier.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to or less than about 1% (w / w) relative to (XXXV) or a salt thereof Including a composition present in

  In one aspect, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to or less than about 0.5% (w / w) relative to (XXXV) or a salt thereof. Exists at less than levels. In another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to about 0.3% (w / w) relative to (XXXV) or a salt thereof, or It exists at a lower level. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to about 0.2% (w / w) relative to (XXXV) or a salt thereof. Or exist at a level below that. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to about 0.15% (w / w) relative to (XXXV) or a salt thereof. Or exist at a level below that. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is equal to about 0.1% (w / w) relative to (XXXV) or a salt thereof. Or exist at a level below that. In yet another embodiment, 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol is essentially absent from the composition.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof, The composition further comprises a buffer and a liquid carrier.

  In one embodiment, the salt of (XXXV) is hydrogen sulfate (XXXVI). In another aspect, the composition further comprises citric acid. In yet another embodiment, the pH of the composition is adjusted with a base. In yet another aspect, the base comprises sodium hydroxide. In yet another aspect, the liquid carrier includes water. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 6. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 5. In yet another embodiment, the pH of the composition ranges from about 3 to about 4. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 1-10 mg / mL. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 5-10 mg / mL. In yet another embodiment, the concentration of (XXXV) or salt thereof in the composition is about 10 mg / mL. In yet another embodiment, the composition comprises less than about 0.5% (w / w) 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol relative to (XXXV) (CLXXVIII) is included. In yet another embodiment, less than about 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol relative to (XXXV) (CLXXVIII) is formed at 2-8 ° C over the shelf life of the composition for at least 6 months. In yet another embodiment, less than about 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol relative to (XXXV) (CLXXVIII) is formed at 2-8 ° C. over the shelf life of the composition for at least 12 months. In yet another embodiment, less than about 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol relative to (XXXV) (CLXXVIII) is formed at 2-8 ° C. over the shelf life of the composition for at least 18 months. In yet another embodiment, less than about 0.5% (w / w) N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol relative to (XXXV) (CLXXVIII) is formed at 2-8 ° C. over the shelf life of the composition for at least 24 months.

  The present invention also provides N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) having the XRPD spectrum of FIG. ) Crystalline free base form A.

  The present invention also provides N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -NO-dimethyl-hydroxylamine (XXXV) selected from the group consisting of: At least one crystalline salt of: crystalline hydrogen sulfate (XXXVI) form A having the XRPD spectrum of FIG. 14; crystalline comprising a mixture of form A and form B having the XRPD spectrum of FIG. Crystalline hydrogen sulfate (XXXVI) Form C with XRPD spectrum of Figure 25; Crystalline hydrogen sulfate (XXXVI) Form D with XRPD spectrum of Figure 25; XRPD spectrum of Figure 26 Crystalline hydrogen sulfate (XXXVI) comprising a mixture of Form A and Form D having a crystalline phosphate (CLXXX) form A having an XRPD spectrum of FIG. 27; a crystal having an XRPD spectrum of FIG. Phosphate (CLXXX) Form C; Crystalline Phosphate (CLXXX) containing a mixture of Form A and Form B with the XRPD spectrum of Figure 29; XRPD of Figure 30 Crystalline phosphate (CLXXX) comprising a mixture of Form C and Form D having a cuttle; Crystalline phosphate (CLXXX) comprising a mixture of Form C and Form E having the XRPD spectrum of FIG. 31; And any mixture of them.

  The present invention also includes a salt of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XXXV) containing about 1 molar equivalent of sulfuric acid. . In one aspect, the salt further comprises 1 molar equivalent of water.

  The present invention also includes N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -NO-dimethyl-hydroxylamine (XXXV) containing at least 1 molar equivalent of phosphoric acid. ) Salt. In one aspect, the salt comprises about 1 molar equivalent of phosphoric acid.

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;
R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;
R⁴はH、アルキルまたは置換アルキルであり;
R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;
R⁶はH、アルキル、置換アルキルまたはアルケニルであり;
Xは結合、OまたはNR⁴であり;かつ
YはN、CR⁶またはCであり;ここで、
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ
(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;かつ
YがCである場合、結合b¹は単結合であり、かつ
(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 The present invention also includes a compound of formula (I) or a salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forming a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
R ³ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR ¹ R ² , —C (O) OR ¹ , acyl or aryl;
R ⁴ is H, alkyl or substituted alkyl;
R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR ¹ , -NR ¹ R ² , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, Are substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ⁵ together are 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane Forming a biradical selected from the group consisting of -1,8-diyl;
R ⁶ is H, alkyl, substituted alkyl or alkenyl;
X is a bond, O or NR ⁴ ; and
Y is N, CR ⁶ or C; where
If Y is N or CR ⁶ then there is no bond b ¹ and
(i) Z is H, bond b ² is a single bond, and A is CH; or (ii) Z is not present, bond b ² is not present, and A is a single bond And; and
When Y is C, the bond b ¹ is a single bond, and
(i) Z is CH ₂ and bond b ² is a single bond and A is CH; or (ii) Z is CH, bond b ² is a double bond and A Is C.

In one aspect, R ³ is H, alkyl, substituted alkyl, alkenyl, cycloalkyl, substituted cycloalkyl or substituted alkenyl. In another embodiment, R ⁵ is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, acyl, cycloalkyl or substituted cycloalkyl.

In one embodiment, Y is N, bond b ¹ is absent, Z is H, bond b ² is a single bond, A is CH, and the compounds of the invention have the formula (II-a) 1,3,5-triazine or a salt thereof.

In one embodiment, Y is N, bond b ¹ is not present, Z is not present, bond b ² is not present, A is a bond, and the compounds of the invention have the formula (II-b) 1,3,5-triazine or a salt thereof.

In one aspect, Y is CR ⁶ , bond b ¹ is absent, Z is H, bond b ² is a single bond, A is CH, and the compounds of the invention have the formula (III-a ) Pyrimidine or a salt thereof.

In one aspect, Y is CR ⁶ , bond b ¹ is not present, Z is not present, bond b ² is not present, A is a bond, and the compounds of the present invention have the formula (III-b) Pyrimidine or a salt thereof.

In one embodiment, Y is C, bond b ¹ is a single bond, Z is CH ₂ , bond b ² is a single bond, A is CH, and the compounds of the invention have the formula (IV) Pyrrolidinopyrimidine or a salt thereof.

In one embodiment, Y is C, bond b ¹ is a single bond, Z is CH, bond b ² is a double bond, A is C, and the compounds of the invention have the formula (V) Of pyrrolopyrimidine or its salt.

In one embodiment, the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N, O— Dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropylmethyl)- N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6-n-propyl Amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4,6-bis -n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4-diamine, N- (4 , 6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [ 1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N- Isopropyl-hydroxy Ruamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5 ] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino- [ 1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl ) -O-isobutyl-N-methyl-hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4 -Diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N- (4,6 -Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1, 3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6- N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazol-2-yl) -methyl Amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2-dimethylamino) Ethyl) amino)-[ 1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl) -N, O- Dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis-n-propylamino -[1,3,5] Triazin-2-yl) -N-methyl-N'-methyl Hydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethylamino-7-methyl -Pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n-propylamino)- Pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino-7-methyl- Pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N -Methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n-propylamino-7 -Methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine, N- (2,4- Scan -n- propylamino) -N- (6-i- propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.

  In one embodiment, the at least one compound is 2,6-bis- (N-n-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine or a salt thereof. In another embodiment, the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.

  In one embodiment, the at least one compound is selected from the group consisting of: 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVI ), 2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVIII), 2- (n-propyl) amino-4-methylamino-7-methyl -Pyrrolidino [2,3-d] pyrimidine (CXXXI), 2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine (CXXXVI) 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine (CXLIX), 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine (CLII), 8- (7-methyl-2- (propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] Octane-3-ol (CLV), salts thereof, and mixtures thereof In another embodiment, the salt is sulfated water. Basic salt, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.

  In one embodiment, the at least one compound is selected from the group consisting of: N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -O, N-dimethyl-hydroxylamine ( CXLI), N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLVIII), N- (2 -(Propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (CLX), N- (2-n-propylamino-7-methyl -Pyrrolo [2,3d] pyrimidin-4-yl) -O, N-dimethyl-hydroxylamine (CLXII), N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4- Yl) -O-methyl-hydroxylamine (CLXIV), N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVI), N-methyl-N -(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVIII), N , N-dimethyl-N ′-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXX), its salts, and mixtures thereof. In another embodiment, the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.

  In one aspect, the compound is formulated with at least one pharmaceutically acceptable carrier.

Preparation of the Compounds of the Invention The compounds of the invention can be prepared according to the general methodology illustrated in the synthetic schemes described below. The reagents and conditions described herein can be modified to allow for the preparation of the compounds of the invention, and such modifications are known to those skilled in the art. The schemes contained herein are intended to illustrate rather than limit the chemical reactions and methodologies that can be used by those skilled in the art to make the compounds of the present invention.

In one aspect, the compound of formula (I) is converted to a suitably chlorinated intermediate (VI) with (i) a primary amine, (ii) N-alkoxy-N--, as shown in Scheme 1 below. It can be prepared by sequential addition of an alkylamine or (iii) an appropriately substituted hydrazine (H ₂ N—NHR ² or R ¹ HN—NHR ² ).

In another aspect, compounds of formula (IV) or (V) can be prepared by reductive alkylation of suitably chlorinated amino-pyrrolidino-pyrimidines or amino-pyrrolo-pyrimidines, respectively (Scheme 2) .

In yet another aspect, the triazine compound of formula (II) is converted to a suitably chlorinated triazine with a primary amine and (i) N-alkoxy-N-alkylamine, (ii) hydrazine H ₂ N-NHR ² Or (iii) It can be prepared by adding hydrazine R ¹ HN-NHR ² sequentially. Under appropriate conditions, the reaction may allow one or two amine substituents to be added to the triazine ring. Alternatively, the N-alkoxy-N-alkylamine, hydrazine H ₂ N—NHR ² or hydrazine R ¹ HN—NHR ² can be added to the triazine first, followed by the amine.

  In a non-limiting example, a solution of primary amine (VII) is added to a solution of 2,4,6-trichlorotriazine in a suitable aprotic or protic solvent containing an inorganic or organic base and the reaction Is allowed to proceed at ambient temperature or heated to isolate the mono-amine adduct (VIII) or bis-amine adduct (IX).

In the subsequent reaction, the asymmetric monochloro-bis-amino-triazine adduct (XI) is obtained by reacting the mono-amine adduct (VIII) with another primary amine or secondary amine (X). In subsequent reactions, the monochloro-bis-amino-triazine adduct (XI) is converted to (i) N-alkoxy-N-alkylamine, (ii) in a suitable aprotic or protic solvent containing an inorganic or organic base. Reaction with hydrazine H ₂ N—NHR ² or (iii) hydrazine R ¹ HN—NHR ² yields the desired compound of formula (II) (Scheme 3).

Alternatively, in a subsequent reaction, the bis-amine adduct (IX) is converted to (i) N-alkoxy-N-alkylamine, (ii) hydrazine in a suitable aprotic or protic solvent containing an inorganic or organic base. H ₂ N—NHR ² or (iii) Reaction with hydrazine R ¹ HN—NHR ² yields the desired compound of formula (II) where R ³ CH ₂ is R ⁵ (Scheme 4).

In yet another aspect, the pyrimidine compound of formula (III) is converted to a suitably chlorinated pyrimidine with a primary amine and (i) N-alkoxy-N-alkylamine, (ii) hydrazine H ₂ N-NHR ² Or (iii) It can be prepared by adding hydrazine R ¹ HN-NHR ² sequentially.

In a non-limiting example, a solution of primary amine (VII) is added to a solution of 2,4,6-trichloropyrimidine (XII) in a suitable aprotic or protic solvent containing an inorganic or organic base. In addition, the reaction proceeds at ambient temperature or is heated to give the bis-amine adduct (XIII). In the subsequent reaction, the bis-amine adduct (XIII) is converted to (i) N-alkoxy-N-alkylamine, (ii) hydrazine H _{2 in} a suitable aprotic or protic solvent containing an inorganic base or an organic base. Reaction with N-NHR ² or (iii) hydrazine R ¹ HN-NHR ² yields the desired compound of formula (III) (Scheme 5).

  In yet another aspect, a pyrrolidino-pyrimidine of formula (IV) or a pyrrolo-pyrimidine compound of formula (V) can be prepared from an appropriately chlorinated aminopyrrolidinopyrimidine or aminopyrrolopyrimidine intermediate, respectively.

In a non-limiting example, a cycloadduct is obtained by adding 2-chloroacetaldehyde to a polar protic solvent solution of 2,6-diamino-4-hydroxy-1,3-pyrimidine (XIV) at ambient temperature or under heating. (XV) can be obtained. Subsequent treatment with a chlorinating agent, such as but not limited to phosphorus oxychloride, produces the chloro intermediate (XVI). Subjecting the intermediate (XVI) to a reductive alkylation with an aldehyde at ambient or elevated temperature in a protic solvent in the presence of a reducing agent such as borohydride (non-limiting example cyanoborohydride). An amino-substituted adduct (XVII) can be generated with In subsequent reactions, the amino-substituted adduct (XVII) is converted to (i) N-alkoxy-N-alkylamine, (ii) hydrazine H ₂ N in a suitable aprotic or protic solvent containing an inorganic base or an organic base. -NHR ² or (iii) Reaction with hydrazine R ¹ HN-NHR ² yields the desired compound of formula (V) where R ³ and R ⁴ are H (Scheme 6).

  In a non-limiting example, a pyrrolidinopyrimidine compound of formula (IV) can be prepared from the corresponding pyrrolopyrimidine analog via reduction (Scheme 7).

The manufacture of active pharmaceutical ingredients (APIs) can introduce or generate impurities in intermediates or final active pharmaceutical compounds. These impurities include trace metals, processing aid residues (eg, silica, cellulose fibers), or solvents derived from purchased starting materials. Other impurities can be formed as a result of the conditions that the starting material, process intermediate, or active ingredient itself is exposed to. These impurities can be problematic in that they affect the overall manufacturing process, and in particular the active ingredient (eg its purity and crystallinity, and its isolation and crystallization conditions). Such impurities often enter the isolated API.

  Process-related impurities derived from decomposition or side reactions involving starting materials, intermediates, reactants, solvents or APIs are often related to the structure of the API itself. Regulatory guidance (e.g., IQC Q3b R3) sets a tolerance limit at which such species that may be structurally related may be present in the active ingredient at the maximum, and if such impurities exceed it A threshold level to be identified or to be identified and restricted is provided along with toxicology data. In some instances, the presence of a given impurity within acceptable levels may still affect the behavior of the active ingredient as a drug formulated for testing or approved medical use . For example, process impurities present in the active ingredient within acceptable levels from a regulatory point of view may form unacceptable precipitates in parenteral formulations.

  Under certain conditions where the compounds of the invention and their synthetic intermediates are exposed to an acidic or alkaline aqueous environment, the bond between the aromatic heterocycle and the ring substituent may be prone to hydrolytic cleavage. is there. For example, in an intermediate of a compound of formula (II-a), the halo substituent at the 2-position (Schemes 3 and 4) is replaced by a hydroxyl group by hydrolysis, which results in N- (4,6-bis (n-propyl) Amino) -1,3,5-triazin-2-ol (CLXXVIII) can be formed, as well as the amine substituent of the compound of formula (II-a) may be replaced by a hydroxyl group, which is bound by theory. While not wishing to be able to do this, a series of chemical changes, such as the prior oxidation of additional amine side chains, occur with the hydrolytic replacement by hydroxyl as the final transformation, allowing this substitution. As a non-limiting example, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) N, O-dimethylhydroxylamino substituents partially with hydroxyl during processing in the presence of water In some cases, (CLXXVIII) may be formed as a process impurity by being replaced, (CLXXVIII) has not been reported, exhibits very low solubility in most organic solvents, and is sparingly soluble in aqueous environments Surprisingly, it was observed that (CLXXVIII) is very insoluble compared to the active ingredient even at high temperatures, so trace amounts of this compound in the API can be problematic in liquid formulations. In an embodiment, the solution of the active ingredient as the free base is filtered at high temperature to remove (CLXXVIII) formed during processing from the system, residual levels of impurities present after such filtration are the mother liquor and the final Purge during solid product isolation in the product wash.In one aspect, the level of (CLXXVIII) in the isolation (XXXVI) is 1% (w / w) relative to (XXXVI) In yet another embodiment, the level of (CLXXVIII) in isolation (XXXVI) Is less than 0.5% (w / w) relative to (XXXVI) In yet another embodiment, the level of (CLXXVIII) in the isolated (XXXVI) is 0.3% (w / w) relative to (XXXVI) In yet another embodiment, the level of (CLXXVIII) in the isolation (XXXVI) is less than 0.2% (w / w) relative to (XXXVI) In yet another embodiment, the isolation (XXXVI The level of (CLXXVIII) in () is less than 0.15% (w / w) relative to (XXXVI) In yet another embodiment, the level of (CLXXVIII) in (XXXVI) is relative to (XXXVI) Less than 0.1% (w / w). In yet another embodiment, the isolated (XXXVI) is essentially free of 4,6-bis (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII).

Formulation and drug stability
Extensive experiments were conducted to devise a suitable liquid formulation of (XXXVI). The experiment showed that the pKa of (XXXVI) is about 5.6. To evaluate the feasibility of formulating (XXXVI) for IV formulations as a simple buffer solution with appropriate pH, a pH solubility test was performed. Solubility was evaluated for (XXXV) alone (FIG. 19A) or (XXXV) (FIG. 19B) when mixed with citric acid and adjusted to pH 3-5.5 with 6N sodium hydroxide. From the data obtained (Table 12A, FIG. 19B), the solubility of (XXXV) was calculated to be 10 mg / mL at pH about 3.86, 25 mg / mL at pH about 3.46, and 50 mg / mL at pH about 3.16. Water solubility tests suggested that solubility at pH above about 3.6 could be inadequate to allow useful concentrations. Formulations below pH 3.6 may be acceptable if the formulated drug is diluted prior to administration, but drug stability may be an issue at such low pH.

  To further evaluate the potential of fully aqueous formulations, test stability of (XXXV) as a function of pH to minimize drug precipitation and avoid buffer-catalyzed drug degradation in the presence of buffer Special attention was paid to drug and buffer concentrations (Figure 20A, Table 12B). Water (XXXVI) (1 mg / mL) is mixed with a solution of citric acid and glycine (10 mM each), the mixture is adjusted to pH 2-5, 40 ° C., 60 ° C., 25 ° C. (control) and −70 ° C. ( Control) and evaluated for physical appearance, pH, assay and related substances after 1 week, 2 weeks and 4 weeks of storage. At 40 ° C and 60 ° C, degradation levels at pH 2 were about 10 times higher than at pH 3-6, but at pH 3-6, an increase in impurities to levels above 0.2 is still generally observed. It was. Due to the limited solubility of (XXXV) above pH 3.6, stability was evaluated in the pH range 2 to 3.6 using a methodology similar to that used for pH 2 to 5 (Figure 20B, Table 12C). The assay and sample pH showed little change, but an increase in impurities occurred over this range, and the impurity level at pH 2 was more than 10 times higher than that at pH 3.6.

  As another option, formulations containing a co-solvent matrix may be useful in achieving good solubility of the salt and free base forms at a suitable pH. (XXXV) and (XXXVI) solubility, including 0.9% NaCl, 5% dextrose, ethanol, methanol, acetonitrile, 30% PEG 400, 70% PEG 400 and 100% PEG 400, 5% Tween 80, and propylene glycol Evaluated in various solvents and standard IV solutions (Table 12D). Solubility of (XXXVI) exceeds 90 mg / mL in water (> 400 mg / mL), IV solution (0.9% saline and 5% dextrose), ethanol and methanol, and 30%, 70% and 100% propylene glycol It was. Its solubility in 100% PEG-400 was about 36 mg / mL, but in 30% and 70% PEG-400 it was over 90 mg / mL. The saturated solubility of (XXXV) in water was about 0.21 mg / mL, which was consistent with the predicted value from the pH solubility test. Solubility in ethanol, methanol and acetonitrile was greater than 90 mg / mL. Solubility in PEG-400 and propylene glycol systems improved with increasing cosolvent levels.

  The effect of buffer strength on stability was tested using a mixture of (XXXV) and 10-250 mmol of citrate at pH 3 (Table 12F). Impurity levels increased significantly at the highest buffer concentration, but there was no effect of buffer strength at 40 ° C. within the buffer concentration range appropriate for the formulation (approximately 10-50 mM).

  A total of nine (XXXVI) prototype formulations including simple buffer solution, co-solvent system and non-aqueous solution were prepared (Table 12G). The solution was prepared at 25 mg / mL (XXXV) as the free base corresponding to 35 mg / mL (XXXVI). Prototypes 6, 7 and 8 caused significant precipitation during preparation and were not evaluated further. The remaining prototypes were stored in serum vials at 2-8 ° C, room temperature, 40 ° C and 60 ° C. Samples stored at 2-8 ° C. and room temperature were analyzed at selected time points for stability (Table 12G.1 to Table 12G.6).

  This study suggested that (XXXV) buffered aqueous formulations near pH 3 were stable under refrigerated or 25 ° C conditions (Table 12G.1). Based on the data used to create Figure 19B, halving the concentration of (XXXV) increases the pH of the formulation by about 0.3 units, and as can be seen in Table 12C, a pH increase of 0.3 units increases the formulation's pH. Stability was substantially improved. Therefore, the concentration of (XXXV) in the formulation according to the first row of Table 12G decreases from 25 mg / mL to 10 mg / mL, the pH increases from 3.0 to 3.2, and the buffer concentration decreases proportionally from 50 mM to 20 mM. did. The final formulation is shown in Table 12H.

  Batches of clinically formulated (XXXVI) were placed under formal GMP stability (Table 20I.1 and Table 12I.2). The data obtained indicates that a single degradation product has formed over time. The degradation product was identified as N- (4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII) .The results of the GMP stability test showed that the degradation product was at least 2 years old. It was shown that it could be expected to stay below 0.5% (Figure 21, Table 12J).

  In one aspect, hydrolyzable degradation products may be observed over time as the compounds of the present invention are partially or fully dissolved in water or an aqueous mixture containing a suitable organic solvent. For example, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) is decomposed in an aqueous formulation to yield 4 , 6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII). As pH decreased below the value of 3, degradation became more pronounced (FIGS. 20A and 20B). For (XXXV), solubility was high below pH 3.5 and decreased rapidly from about pH 3.5 to about 4.4 (FIGS. 19A and 19B).

  In another aspect, the pH of the mixture containing (XXXV) is adjusted to a specific range to balance solubility and hydrolysis stability at any selected temperature. The degradation rate of (XXXV) was highest in the pH range where the solubility of (XXXV) reached clinically useful levels. In one aspect, the clinically useful concentration of (XXXV) in the liquid carrier is about 1-10 mg / mL. In another embodiment, the clinically useful concentration of (XXXV) in the liquid carrier is about 5-10 mg / mL. In addition, the decomposition of (XXXV) in an aqueous environment was very temperature dependent, and cold temperature delayed the decomposition.

  In one embodiment, (XXXV) as hydrogen sulfate (XXXVI) in a liquid carrier is mixed with an agent to adjust the pH to optimize solubility and minimize degradation. In another embodiment, (XXXV) as hydrogen sulfate (XXXVI) in a liquid carrier is mixed with a buffering aid. Suitable buffering aids include, but are not limited to, citric acid, ascorbic acid, monobasic phosphate and lactic acid. In one aspect, the buffering aid is citric acid. In another embodiment, (XXXV) as bisulfate (XXXVI) is mixed with citric acid and a base to adjust the pH as needed to optimize solubility and minimize hydrolytic degradation. To do. Suitable bases include but are not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide and dibasic potassium hydrogen phosphate. In one embodiment, the pH is adjusted with sodium hydroxide. In another aspect, the liquid carrier is a mixture of water and a suitable organic cosolvent. Suitable organic cosolvents include, but are not limited to glycerin, propylene glycol, polyethylene glycol 400, ethanol, 1,4-butanediol and dimethyl sulfoxide. In another aspect, the liquid carrier is water.

  In one embodiment, a mixture comprising (XXXV) as sulfate (XXXVI), citric acid and sodium hydroxide in water is adjusted to a pH of about 2.5-6. In another embodiment, the mixture is adjusted to a pH of about 3-5. In yet another embodiment, the mixture is adjusted to a pH of about 3-4.

  In one aspect, a mixture comprising (XXXV) as a hydrogen sulfate salt can be stored at a low temperature that retards the degradation rate of the compound. In another embodiment, the temperature can range from about 0-15 ° C. In yet another embodiment, the cold temperature can range from 2-8 ° C. In yet another embodiment, a mixture comprising (XXXV) as hydrogen sulfate (XXXVI) and citric acid and sodium hydroxide is adjusted to a pH of about 3-4 and stored at about 2-8 ° C. The rate of degradation was slow at 2-8 ° C and much faster above 25 ° C. As shown in FIG. 21, the level of (CLXXVIII) formed when formulating (XXXVI) for parenteral administration (non-limiting conditions: aqueous medium at pH 3-4) is 2-8 ° C. The formulation can be stored and maintained below 0.5% for over 2 years (Figure 21).

  The present invention optimizes drug solubility and maintains hydrolyzable degradation products within acceptable levels for formulations comprising active ingredients, salt formers, mixed buffering aids, mixed base pH, and liquid carrier. Including with necessary storage conditions.

Compounds described salts herein can form a salt with an acid, such salts are included in the present invention. In one aspect, the salt is a pharmaceutically acceptable salt. The term “salt” encompasses the free acid addition salts useful within the method of the invention. The term “pharmaceutically acceptable salt” means a salt having a toxicity profile within a range that confers utility in pharmaceutical applications. Salts that are not pharmaceutically acceptable despite having utility in the practice of the invention, for example, in the process of synthesis, purification, or formulation of compounds useful within the methods of the invention are highly crystalline, etc. May have the following characteristics.

  Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). It is done. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids such as formic acid, acetic acid, propionic acid, succinic acid. Acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, Phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexyl Aminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, sari Le acid, galactaric and galacturonic acid.

  Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, alkali metal salts, alkaline earth metal salts and transition metal salts such as calcium salts, magnesium salts, potassium salts, sodium salts and zinc salts. And metal salts containing. Examples of pharmaceutically acceptable base addition salts are made from basic amines such as N, N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Also included are organic salts. All these salts can be prepared from the corresponding compound, for example by reacting the compound with the appropriate acid or base.

Combination Therapy In one aspect, the compounds of the invention are useful in combination with at least one additional compound that is useful for treating respiratory control disorders in the methods of the invention. These additional compounds may include other compounds such as compounds of the present invention or commercially available compounds known to treat, prevent or reduce symptoms of respiratory disorders. In one aspect, the combination of at least one compound of the invention or a salt thereof and at least one additional compound useful for treating respiratory disorders is an additive effect in the treatment of respiratory disorders and the treatment of sleep-related respiratory disorders, Shows complementary or synergistic effects.

  In a non-limiting example, a compound of the present invention or salt thereof can be used in combination with one or more of the following drugs: acetazolamide, aluminthrin, theophylline, caffeine, methylprogesterone and related compounds, Serotonergic modulators, cannabinoids (including but not limited to dronabinol), and compounds known as ampakines. Non-limiting examples of ampakines include pyrrolidine derivative racetam drugs such as piracetam and aniracetam; CX-516 (6- (piperidin-1-yl-carbonyl) quinoxaline), CX-546 (2,3-dihydro-1, 4-benzodioxin-7-yl- (1-piperidyl) -methanone), CX-614 (2H, 3H, 6aH-pyrrolidino (2,1-3 ', 2')-1,3-oxazino- (6 ' , 5'-5,4) benzo (e) 1,4-dioxane-10-one), CX-691 (2,1,3-benzooxadiazol-6-yl-piperidin-1-yl-methanone) CX-series drugs including a series of benzoylpiperidine and benzoylpyrrolidine structures such as CX-717, CX-701, CX-1739, CX-1763 and CX-1837; cyclothiazide and IDRA-21 (7- Benzothiazide derivatives such as chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide); LY-392,098, LY-404,187 (N- [2- ( 4'-Cyanobiphenyl-4-yl) propyl] propane-2-sulf Amide), LY-451,646 and LY-503,430 (4 ′-{(1S) -1-fluoro-2-[(isopropylsulfonyl) amino] -1-methylethyl} -N-methylbiphenyl-4-carboxamide) There are biarylpropylsulfonamides.

Synergistic effects include, for example, sigmoid-E _max equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), Loewe additive equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313 -326) and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). By applying each equation mentioned above to the experimental data, a correspondence graph useful for evaluating the effect of the drug combination can be created. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Methods of the Invention The present invention includes methods for preventing or treating respiratory control disorders or respiratory control disorders in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N- (2, 4-Bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1 , 3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any combinations thereof.

  The invention also includes a method of preventing or stabilizing respiratory rhythm instability in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N- (2, 4-Bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1 , 3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any combinations thereof.

  In one aspect, the respiratory control disorder or respiratory control disorder is respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia Selected from the group consisting of symptoms. In another aspect, respiratory depression is caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol or narcotics. In yet another embodiment, the subject is further administered a composition comprising at least one additional compound useful for treating a respiratory control disorder or respiratory control disorder. In yet another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, aluminin, theophylline, caffeine, methylprogesterone, serotonin modulators, cannabinoids and ampakines. In yet another aspect, the formulation is administered in combination with the use of a ventilator or positive airway pressure device to the subject. In yet another aspect, the subject is a mammal. In yet another aspect, the mammal is a human. In yet another embodiment, the formulation is administered to the subject by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

  The invention also includes a method of reducing or minimizing the open channel portion of a potassium maxi-K or BK channel in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I).

  The invention also includes a method of inhibiting a TASK-1 (KCNK3) channel in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I).

  The invention also includes a method of increasing minute ventilation in a subject in need thereof. The method comprises administering to the subject an effective amount of an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I).

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;R⁴はH、アルキルまたは置換アルキルであり;R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;R⁶はH、アルキル、置換アルキルまたはアルケニルであり;Xは結合、OまたはNR⁴であり;YはN、CR⁶またはCであり; ここで
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;
YがCである場合、結合b¹は単結合であり、かつ(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 In one aspect, the compound of formula (I) is of the formula:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forms a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R ³ is H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -NR 1 R 2, -C (} O) OR 1, acyl also Aryl; R ⁴ is an H, alkyl or substituted alkyl; R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -OR 1, -NR 1 R 2} , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ^{5 taken} together to form 3,6,9-trioxa Forming a biradical selected from the group consisting of -undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ⁶ is H, alkyl, substituted alkyl or alkenyl; X is A bond, O or NR ⁴ ; Y is N, CR ⁶ or C; where
When Y is N or CR ⁶ , bond b ¹ is not present and (i) Z is H, bond b ² is a single bond and A is CH; or (ii) Z is absent, bond b ² is absent and A is a single bond;
When Y is C, bond b ¹ is a single bond, and (i) Z is CH ₂ , bond b ² is a single bond, and A is CH; or (ii) Z Is CH, bond b ² is a double bond, and A is C.

In another embodiment, the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N, O -Dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6-n- Propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3,5 ] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine , N- (4,6-bi Su-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino ) -1,3,5-Triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxyl Amine, O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4-diamine, N- ( 4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N -Isopropyl-hydro Silamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5 ] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino- [ 1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl ) -O-isobutyl-N-methyl-hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine- 2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N- ( 4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) ) Amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino -6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazol-2-yl) ) -Methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2 -Dimethylaminoethyl) amino )-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1,3 , 5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazine-2 -Yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl- Hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis-n -Propylamino- [1,3,5] triazin-2-yl) -N-methyl-N'-me Ruhydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethylamino-7- Methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4 -(i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine, 2 -(n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n-propylamino) -Pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4- Yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidine-4- Yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino-7-methyl- Pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N -Methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n-propylamino-7 -Methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine, N- (2, 4-Bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine, its salts, and mixtures thereof. In another embodiment, the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl) -O- Methyl-hydroxylamine, N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (2,4-bis- n-propylamino) -N- (6-methylamino)-[1,3,5] triazine, N-[(2,6-bis-n-propylamino) -pyrimidin-4-yl] -N, O -Dimethyl-hydroxylamine, N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, its salts, and mixtures thereof. In yet another aspect,

  In one aspect, the subject is a mammal. In another aspect, the mammal is a human. The compound of formula (I) is N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine or a salt thereof.

  In one aspect, the pharmaceutical formulation is administered by intravenous infusion. In another embodiment, the infusion rate of the pharmaceutical formulation is at least about 0.016 mg / kg / min. In yet another embodiment, the dosage of the pharmaceutical formulation is about 0.016 mg / kg / min. In yet another embodiment, the infusion amount of the pharmaceutical composition results in a plasma concentration of at least about 726 ng / mL in the subject. In yet another embodiment, the infusion amount of the pharmaceutical composition results in a plasma concentration of at least about 726 ng / mL in the mammal.

式中、
R¹およびR²は独立してH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、フェニル、置換フェニル、フェニルアルキル、置換フェニルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ヘテロアリールまたは置換ヘテロアリールであるか; あるいは、R¹およびR²は一緒になって、3-ヒドロキシ-ペンタン-1,5-ジイル、6-ヒドロキシ-シクロヘプタン-1,4-ジイル、プロパン-1,3-ジイル、ブタン-1,4-ジイルおよびペンタン-1,5-ジイルからなる群より選択されるビラジカルを形成し;R³はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-NR¹R²、-C(O)OR¹、アシルまたはアリールであり;R⁴はH、アルキルまたは置換アルキルであり;R⁵はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アルケニル、置換アルケニル、-OR¹、-NR¹R²、-C(O)OR¹、アシル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環または置換複素環であるか; あるいは、R³およびR⁵は一緒になって、3,6,9-トリオキサ-ウンデカン-1,11-ジイルおよび3,6-ジオキサ-オクタン-1,8-ジイルからなる群より選択されるビラジカルを形成し;R⁶はH、アルキル、置換アルキルまたはアルケニルであり;Xは結合、OまたはNR⁴であり;YはN、CR⁶またはCであり; ここで
YがNまたはCR⁶である場合、結合b¹は存在せず、かつ(i) ZはHであり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) Zは存在せず、結合b²は存在せず、かつAは単結合であり;
YがCである場合、結合b¹は単結合であり、かつ(i) ZはCH₂であり、結合b²は単結合であり、かつAはCHであるか; あるいは、(ii) ZはCHであり、結合b²は二重結合であり、かつAはCである。 The invention also includes a method of preventing or treating a respiratory control disorder or respiratory control disorder in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forms a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R ³ is H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -NR 1 R 2, -C (} O) OR 1, acyl also Aryl; R ⁴ is an H, alkyl or substituted alkyl; R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted ^{alkenyl, -OR 1, -NR 1 R 2} , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ^{5 taken} together to form 3,6,9-trioxa Forming a biradical selected from the group consisting of -undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ⁶ is H, alkyl, substituted alkyl or alkenyl; X is A bond, O or NR ⁴ ; Y is N, CR ⁶ or C; where
When Y is N or CR ⁶ , bond b ¹ is not present and (i) Z is H, bond b ² is a single bond and A is CH; or (ii) Z is absent, bond b ² is absent and A is a single bond;
When Y is C, bond b ¹ is a single bond, and (i) Z is CH ₂ , bond b ² is a single bond, and A is CH; or (ii) Z Is CH, bond b ² is a double bond, and A is C.

  The invention also includes a method of preventing or stabilizing respiratory rhythm instability in a subject in need thereof. The method includes administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or salt thereof.

  In one aspect, administering the formulation of the present invention stabilizes the subject's respiratory rhythm. In another aspect, administering the formulation of the present invention increases the subject's minute ventilation.

  In one aspect, the destabilization is associated with a respiratory control disorder or respiratory control disorder.

  In one aspect, the respiratory disorder or disorder is narcotic-induced respiratory depression, anesthetic-induced respiratory depression, sedation-induced respiratory depression, anxiolytic-induced respiratory depression, hypnotic-induced respiratory depression, alcohol-induced breathing Suppression, analgesic-induced respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstruction Selected from the group consisting of congenital lung disease (COPD). In another aspect, respiratory depression is caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol or narcotics.

  In one aspect, at least one additional compound useful for treating a respiratory disorder or disorder is further administered to the subject. In another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, alumintrine, theophylline, caffeine, methylprogesterone and related compounds, serotonergic modulators, cannabinoids and ampakines. In yet another aspect, the formulation is administered to the subject in combination with the use of a mechanical ventilator or a positive airway pressure device. In one aspect, the formulation is administered to the subject by inhalation, topical, oral, buccal, rectal, intravaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route. In another aspect, the subject is a mammal, including but not limited to mice, rats, ferrets, guinea pigs, monkeys, dogs, cats, horses, cows, pigs and other domestic animals.

In one aspect, the subject is a human. In another embodiment, the at least one compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclo Propylmethyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6 -n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1, 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazine-2- Yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl -Hydroxyl Amine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino ) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 -Yl) -O-methyl-hydroxylamine, O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4 , 6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine- 2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4, 6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5 ] Triazin-2-yl) -N-iso Lopyl-hydroxylamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n -Propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1, 3,5] triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl- Hydroxylamine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propyl Amino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine- 2-yl) -O-isobutyl-N-methyl-hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ² , N ⁴ -dipropyl- 1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N- Methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6 -Bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino- 6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazole-2 -Yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1- N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6 -Bis- (N- (2-dimethylamino Noethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[ 1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl ) -N, O-dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19 ), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O -Dimethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6- Bis-n-propylamino- [1,3,5] triazine-2-y ) -N-methyl-N'-methylhydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) Amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2 -(n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [ 2,3-d] pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl -2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2 , 3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl)- O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n- Propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidine-4 -Yl) -hydrazine, N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2 -n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[ 1,3,5] triazine, N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1,3- Rimijin, N-(2,4-bis -n- propylamino) -N- (6-i- propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.

Pharmaceutical Compositions and Formulations The present invention also encompasses the use of a pharmaceutical composition of at least one compound of the present invention or a salt thereof for practicing the methods of the present invention.

  Such a pharmaceutical composition may consist of at least one compound of the invention or a salt thereof in a form suitable for administration to a subject, or the pharmaceutical composition comprises at least one compound of the invention Or a salt thereof and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination thereof. As is well known in the art, at least one compound of the invention is present in a pharmaceutical composition, for example in the form of a physiologically acceptable salt in combination with a physiologically acceptable cation or anion. sell.

  In one aspect, a pharmaceutical composition useful for performing the methods of the invention can be administered to deliver a dose of 1 ng / kg / day to 100 mg / kg / day. In another embodiment, a pharmaceutical composition useful for practicing the present invention can be administered to deliver a dose of 1 ng / kg / day to 500 mg / kg / day.

  The relative amounts of the active ingredient, pharmaceutically acceptable carrier and any further ingredients in the pharmaceutical composition of the invention are determined by the identity, size and condition of the subject being treated, as well as the composition to be administered. It varies depending on the route. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

  Pharmaceutical compositions useful in the methods of the present invention include inhalation, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ocular, intrathecal, intravenous or It can be suitably developed for other administration routes. Compositions useful within the methods of the invention can be administered directly to the mammalian brain, brainstem, or any other part of the central nervous system. Other contemplated formulations include projected nanoparticles, liposome preparations, re-encapsulated red blood cells containing the active ingredient, and immunologically based formulations. The route of administration will be readily apparent to those skilled in the art and will depend on any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.

  Formulations of the pharmaceutical compositions described herein can be prepared by any method known or later developed in the pharmacology field. In general, such preparative methods include the step of bringing into association the active ingredient with the carrier or one or more other accessory ingredients and then, when necessary or desirable, the product into the desired single dose or multiple dose units. Forming or packaging.

  As used herein, a “unit dose” is a discrete amount of a pharmaceutical composition that contains a predetermined amount of an active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient administered to the subject, or a convenient fraction of such a dose, for example one half or one third of such a dose. The unit dosage form can be for a single daily dose or one of multiple daily doses (eg, about 1 to 4 times or more per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

  While the description of pharmaceutical compositions presented herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, those skilled in the art will recognize that such compositions are suitable for all types of animals. It will be understood that it is generally suitable for administration. It is well understood to modify a pharmaceutical composition suitable for administration to humans to provide a composition suitable for administration to various animals, and veterinary scientists with ordinary knowledge will be able to make such modifications. Even if it is based on an experiment, it can be designed and implemented by a normal experiment. Subjects envisaged for administration of the pharmaceutical composition of the present invention include mammals including humans and other primates, commercially relevant mammals such as cattle, pigs, horses, sheep, cats and dogs. But is not limited thereto.

  In one aspect, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one aspect, the pharmaceutical composition of the invention comprises a therapeutically effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier. Useful pharmaceutically acceptable carriers include, but are not limited to, glycerin, water, saline, ethanol, and solutions of other pharmaceutically acceptable salts such as phosphates and organic acid salts. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

  The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Prevention of the action of microorganisms can be achieved with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. In one aspect, the pharmaceutically acceptable carrier is not DMSO alone.

  The formulations are conventional excipients suitable for oral, parenteral, nasal, inhalation, intravenous, subcutaneous, transdermal, enteral, or any other suitable mode of administration known in the art, That is, it can be used as a mixture with pharmaceutically acceptable organic or inorganic carrier materials. The pharmaceutical preparation may be sterilized and, if desired, adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to influence osmotic pressure, buffers, coloring substances Further, it may be mixed with a flavor substance and / or a fragrance substance. If desired, they may be combined with other active agents, such as other analgesics. As used herein, “further ingredients” include, but are not limited to, one or more ingredients that can be used as a pharmaceutical carrier.

  The composition of the present invention may comprise preservatives of about 0.005% to 2.0% of the total weight of the composition. Preservatives are used to prevent damage in the event of exposure to environmental pollutants. Examples of preservatives useful according to the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, paraben, imidourea, and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

  The composition preferably contains an antioxidant and a chelating agent that inhibit the degradation of the compound. Preferred antioxidants for some compounds are preferred ranges of about 0.01% to 0.3% BHT, BHA, α-tocopherol and ascorbic acid, more preferably 0.03% to 0.1% by weight of the total weight of the composition. BHT in the range. Preferably, the chelating agent is present in an amount from 0.01% to 0.5% by weight of the total weight of the composition. Particularly preferred chelating agents include edetate (e.g. disodium edetate) and citric acid in a weight range of about 0.01% to 0.20% by weight, more preferably 0.02% to 0.10% by weight of the total weight of the composition. Examples include acids. Chelating agents are useful for chelating metal ions in compositions that can be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelators, respectively, for some compounds, but may be replaced by other suitable and equivalent antioxidants and chelators known to those skilled in the art. Good.

  A suspension of the active ingredient in an aqueous or oily medium can be obtained by preparing a liquid suspension using conventional methods. Examples of the aqueous medium include water and isotonic saline. Examples of the oily medium include almond oil, oily ester, ethyl alcohol, peanut oil, olive oil, sesame oil or coconut oil, and other vegetable oils, rectified vegetable oil, and mineral oil such as liquid paraffin. Liquid suspensions include one or more additional agents including but not limited to suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffering agents, salts, flavoring agents, coloring agents and sweetening agents. Ingredients may further be included. The oily suspension may further contain a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hardened edible fat, sodium alginate, polyvinylpyrrolidone, tragacanth gum, gum arabic, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersants or wetting agents include natural phosphatides such as lecithin, condensation of alkylene oxides with fatty acids, long chain fatty alcohols, partial esters derived from fatty acids and hexitol, or partial esters derived from fatty acids and anhydrous hexitol. Products such as, but not limited to, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate and polyoxyethylene sorbitan monooleate, respectively. Known emulsifiers include but are not limited to lecithin and gum arabic. Known preservatives include, but are not limited to, methyl para-hydroxybenzoate, ethyl or n-propyl, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerin, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin and cetyl alcohol.

  Liquid solutions of the active ingredient in aqueous or oily solvents can be prepared in substantially the same way as liquid suspensions, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. It is. As used herein, an “oily” liquid is a liquid that contains carbon-containing liquid molecules and exhibits a lower polarity than water. It will be understood that a liquid solution of the pharmaceutical composition of the present invention may contain each of the ingredients described with respect to the liquid suspension, and that the suspending agent does not necessarily help dissolve the active ingredient in the solvent. . Examples of the aqueous solvent include water and isotonic saline. Examples of the oily solvent include almond oil, oily ester, ethyl alcohol, peanut oil, vegetable oil such as olive oil, sesame oil or coconut oil, rectified vegetable oil, and mineral oil such as liquid paraffin.

  Powder formulations and granule formulations of the pharmaceutical preparation of the present invention can be prepared using known methods. Such formulations can also be administered directly to a subject, for example to form an aqueous or oily solution or suspension, for example, to form tablets, to fill capsules, or to add aqueous or oily media thereto. It can also be used to prepare. Each of these formulations may further comprise one or more of a dispersing or wetting agent, suspending agent, and preservative. Additional ingredients such as fillers and sweetening, flavoring or coloring agents may also be included in these formulations.

  The pharmaceutical compositions of the invention may be prepared, packaged or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a mixture of these. Such compositions include esters or partial esters derived from combinations of fatty acids and anhydrous hexitol, such as natural gums such as gum arabic or tragacanth, natural phosphatides such as soy or lecithin phosphatide, sorbitan monooleate, And one or more emulsifiers such as condensates of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may contain further ingredients including, for example, sweetening or flavoring agents.

  Methods for impregnating a material with a chemical composition or coating a material with a chemical composition are known in the art and include methods for depositing or bonding a chemical composition on a surface, synthesis of materials (i.e., e.g., A method of incorporating a chemical composition into the structure of the material (by a physiologically degradable material) and a method of absorbing an aqueous or oily solution or suspension into the absorbent material with or without subsequent drying. But not limited to.

Dosing / dosing regimens can affect what constitutes an effective amount. The therapeutic formulation can be administered to the patient either before or after the onset of a respiratory disorder event. In addition, several divided and staggered dosages may be administered daily or sequentially, or doses may be continuously infused or bolus injected. Furthermore, the dosage of the therapeutic formulation can be increased or decreased proportionally as indicated by an impending treatment or prevention situation.

  Administration of the composition of the present invention to a patient, preferably a mammal or a bird, more preferably a human, is carried out using known techniques at a dosage and for a period effective to treat a disorder of respiratory control in the patient. Can do. The effective amount of therapeutic compound required to obtain a therapeutic effect is the activity of the particular compound used; administration time; rate of compound excretion; duration of treatment; other drugs, compounds used in combination with the compound Or material; it can vary depending on factors such as the condition, age, sex, weight, condition, general health and history of the patient or disease being treated, and similar factors well known in the medical field. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be reduced proportionally as indicated by an impending treatment situation. A non-limiting example of an effective range of therapeutic compounds of the present invention is about 0.01 mg / kg to 50 mg / kg body weight / day. One skilled in the art will be able to review the relevant factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation.

  The compound can be administered to the animal several times a day, or less frequently, for example once a day, once a week, once every two weeks, once a month, or even less frequently, For example, it can be administered once every few months, even once a year or less. It will be understood that the daily dosage of the compound may be administered daily, every other day, every 2 days, every 3 days, every 4 days or every 5 days in non-limiting examples. For example, with alternate day administration, a 5 mg per day dosing may be started on Monday, a first subsequent 5 mg dose per day administered on Wednesday, and a second subsequent 5 mg per day dose administered on Friday. The frequency of dosing will be readily apparent to those skilled in the art and will depend on any number of factors, including but not limited to, the type and severity of the disease being treated, the type and age of the animal.

  The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is not toxic to the patient to achieve the desired therapeutic response, desired composition and desired mode of administration for the particular patient. It can be varied to obtain an effective amount of active ingredient.

  A physician having ordinary knowledge in the art, such as a physician or veterinarian, can readily determine and prescribe the desired effective amount of the pharmaceutical composition. For example, a physician or veterinarian can begin dosing a compound of the invention used in a pharmaceutical composition at a level lower than that required to obtain the desired therapeutic effect, until the desired effect is obtained. The dosage can be increased gradually.

  In certain embodiments, it is particularly advantageous to formulate the compound in unit dosage form for ease of administration and uniformity of dosage. As used herein, a unit dosage form means a physically discrete unit suitable as a unit dosage for the patient being treated, each unit being in association with the required pharmaceutical carrier as desired. Contains a predetermined amount of the therapeutic compound calculated to produce a therapeutic effect. The unit dosage forms of the present invention formulate / formulate (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be realized, and (b) the treatment of respiratory disorders in the patient. Is determined by and directly dependent on the limitations inherent in the technical field.

  In one aspect, the compositions of the invention are administered to a patient at dosages ranging from 1 to 5 times or more per day. In another embodiment, the composition of the present invention comprises a patient in a dosage range including, but not limited to, once a day, once every two days, once every three days to once a week, and once every two weeks. To be administered. Those skilled in the art will appreciate that the frequency of administration of the various combination compositions of the present invention depends on a number of factors including, but not limited to, age, the disease or disorder to be treated, gender, general health, and other factors. It will be readily apparent that this is different. Thus, the present invention should not be construed as limited to any particular dosage regime, and the exact dosage and composition administered to any patient will allow the attending physician to consider all other factors associated with the patient. Put in and decide.

  The compounds of the invention for administration are from about 1 μg to about 7,500 mg, from about 20 μg to about 7,000 mg, from about 40 μg to about 6,500 mg, from about 80 μg to about 6,000 mg, from about 100 μg to about 5,500 mg, from about 200 μg to about 5,000 mg About 400 μg to about 4,000 mg, about 800 μg to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg To about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any integer or partial increment range between them .

  In some embodiments, the dose of a compound of the invention is from about 0.5 μg to about 5,000 mg. In some embodiments, the dose of a compound of the invention used in the compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or about Less than 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or about 300 mg. Less than, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or about 5 mg. Less than, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any integer or partial increment thereof.

  In one aspect, the invention includes a container that holds a therapeutically effective amount of a compound of the invention alone or in combination with a second pharmaceutical agent; treating, preventing, or one or more symptoms of breathing disorder in a patient And a packaged pharmaceutical composition comprising instructions for using the compound to reduce

  The term “container” includes any container for holding a pharmaceutical composition. For example, in one aspect, the container is a package that contains the pharmaceutical composition. In other embodiments, the container is not a package containing the pharmaceutical composition, i.e., the container is a packaged pharmaceutical composition or an unpackaged pharmaceutical composition and instructions for using the pharmaceutical composition. And a container such as a box or a vial. In addition, packaging techniques are well known in the art. It should be understood that instructions for use of the pharmaceutical composition can be included on the package containing the pharmaceutical composition, thus increasing the functional relationship between the instruction and the packaged product. However, it is to be understood that the instructions may include information regarding the ability of the compound to perform its intended function, for example, the ability to treat, prevent or reduce respiratory impairment in a subject.

Route of administration Any route of administration of the composition of the present invention includes inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g. sublingual, translingual, (trans) buccal, (trans ) Urethra, intravaginal (e.g. transvaginal and perivaginal), nasal cavity (inner) and (trans) rectal), intravesical, intrapulmonary, duodenum, intragastric, intrathecal, subcutaneous, intramuscular, intradermal Intraarterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrapleural, and topical administration.

  Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches. , Gel, powder, pellet, magma, electuary, cream, paste, plaster, lotion, disc, suppository, liquid spray for nasal or oral administration, dry powder formulation or aerosol formulation for inhalation And compositions and preparations for intravesical administration. It should be understood that formulations and compositions that would be useful in the present invention are not limited to the specific formulations and compositions described herein.

Oral administration For oral application, tablets, dragees, solutions, drops, suppositories, or capsules, caplets and gel capsules are particularly suitable. Other formulations suitable for oral administration include powder or granule formulations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpastes, mouth washes, coatings, oral rinses, or emulsions. However, it is not limited to that. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions are inert and non-toxic pharmaceutical formulations suitable for the manufacture of tablets. It may contain one or more agents selected from the group consisting of dosage forms. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate.

  The tablets may be uncoated or they may be coated using known methods to achieve sustained release and absorption of the active ingredient by providing delayed disintegration in the subject's gastrointestinal tract. Good. By way of example, materials such as glyceryl monostearate or glyceryl distearate can be used to coat tablets. By way of further example, osmotic controlled release tablets can be formed by coating the tablets using the methods described in US Pat. Nos. 4,256,108; 4,160,452; and 4,265,874. Tablets may further comprise sweetening, flavoring, coloring, preserving, or some combination of these to give a pharmaceutically elegant and palatable preparation.

  Hard capsules containing the active ingredient can be made using a physiologically degradable composition such as gelatin. Such hard capsules contain the active ingredient and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin.

  Soft gelatin capsules containing the active ingredients can be made using a physiologically degradable composition such as gelatin. Such soft capsules contain an active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

  For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders; fillers; lubricants; disintegrants; or wetting agents. It can be. If desired, tablets can be prepared using suitable methods and coating materials such as the OPADRYTM film coating system available from Colorcon, West Point, Pa. (E.g. OPADRYTM OY, OYC, organic enteric OY-P Type, aqueous enteric OY-A type, OY-PM type, and OPADRY ™ White, 32K18400).

  Liquid preparations for oral administration can be in the form of solutions, syrups or suspensions. Liquid preparations include suspending agents (e.g. sorbitol syrup, methylcellulose or hardened edible fat); emulsifiers (e.g. lecithin or gum arabic); non-aqueous media (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. Can be prepared by conventional means with pharmaceutically acceptable additives such as methyl or propyl para-hydroxybenzoate, or sorbic acid). Liquid formulations of the pharmaceutical composition of the present invention suitable for oral administration are prepared and packaged either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable medium prior to use. Or can be sold.

  A tablet containing the active ingredient may be made, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets favor active ingredients in free-flowing form such as powder or granule preparations optionally mixed with one or more of binders, lubricants, excipients, surfactants and dispersants Can be prepared by compression in a simple apparatus. Molded tablets can be prepared by molding in a suitable apparatus a mixture of the active ingredient, a pharmaceutically acceptable carrier and at least a liquid sufficient to wet the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binders, and lubricants. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, crystalline cellulose, calcium phosphate, calcium hydrogen phosphate and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binders include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinyl pyrrolidone and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica and talc.

  Granulation techniques for modifying the active ingredient starting powders or other particulate materials are well known in the pharmaceutical arts. Typically, the powder is mixed with a binder material into larger permanent free-flowing aggregates or granules called “granulates”. For example, a “wet” granulation process that uses a solvent involves combining the powder with a binder material, moistening with water or an organic solvent under conditions that result in the formation of a wet granulation mass, and then always starting from the granulation mass. It is generally characterized by evaporating the solvent.

  Melt granulation is generally solid or semi-solid at room temperature (i.e., relative to facilitate granulation of powdered materials or other materials in the absence of the addition of water or other liquid solvent in nature. The use of materials with a low softening point or melting point range. The low melting point solid liquefies when heated to a temperature in the melting range and acts as a binder or granulation medium. The liquefied solid diffuses onto the surface of the powder material it contacts and upon cooling forms a solid agglomerate with the initial materials bound together. The resulting melt granulate can then be subjected to a tablet press or encapsulated to prepare an oral dosage form. Melt granulation improves the dissolution rate and bioavailability of the active ingredient (ie drug) by forming a solid dispersion or solid solution.

  US Pat. No. 5,169,645 discloses directly compressible wax-containing granules having improved flowability. Granules are obtained when the wax is mixed with certain flow enhancing additives in the melt and then the mixture is cooled and granulated. In certain embodiments, only the wax itself melts in the melt combination of wax and additive, and in other cases both the wax and additive melt.

  The present invention also provides a layer that provides delayed release of one or more compounds useful within the method of the present invention and an immediate release of one or more compounds useful within the method of the present invention. Including multi-layer tablets, including additional layers. A wax / pH sensitive polymer mixture can be used to obtain a gastric insoluble composition that encapsulates the active ingredient to ensure its delayed release.

Parenteral Administration As used herein, “parenteral administration” of a pharmaceutical composition is characterized by the administration of the pharmaceutical composition through a physical opening into the tissue of interest and through the opening in the tissue. Including any route of administration. Accordingly, parenteral administration includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, application of the composition through a surgical incision, application of the composition through a tissue penetrating non-surgical wound, and the like. Not. In particular, parenteral administration is envisioned including but not limited to subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and renal dialysis infusion techniques.

  A formulation of a pharmaceutical composition suitable for parenteral administration comprises a combination of the active ingredient with a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline. Such formulations can be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable preparations can be prepared, packaged, or sold in unit dosage forms, for example, in ampoules or in multi-dose containers containing preservatives. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous media, pastes, and implantable sustained release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including but not limited to suspending, stabilizing or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (ie, powder or granule) form that is reconstituted with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. .

  The pharmaceutical compositions can be prepared, packaged or sold in the form of a sterile injectable aqueous or oleaginous suspension or solution. This suspension or solution can be formulated according to known techniques and can contain, in addition to the active ingredient, further ingredients such as dispersing, wetting or suspending agents described herein. Such sterile injectable formulations can be prepared using a non-toxic parenterally acceptable diluent or solvent such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and non-volatile oils such as synthetic monoglycerides or diglycerides. Other parentally-administrable formulations that are useful include formulations that contain the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Sustained release or embedding compositions can include pharmaceutically acceptable polymeric or hydrophobic materials such as emulsions, ion exchange resins, sparingly soluble polymers or sparingly soluble salts.

Topical administration The barrier to local administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids and various other lipids and includes keratinocytes and living cells. One factor that limits the penetration rate (flow rate) of a compound through the stratum corneum is the amount of active substance that can be added or applied to the skin surface. The greater the amount of active substance applied per unit area of skin, the greater the concentration gradient between the skin surface and the lower layer of the skin, and thus the greater the diffusivity of the active substance through the skin. Thus, a formulation containing a relatively large concentration of active substance will penetrate more active substance through the skin at a more consistent rate than a formulation with a relatively small concentration but all the same Probability is high.

  Formulations suitable for topical administration include oil-in-water or water-in-oil emulsions such as liniments, lotions, creams, ointments or pastes, and liquid or semi-liquid preparations such as solutions or suspensions. However, it is not limited to that. Topically administrable formulations may contain, for example, about 1% to about 10% (w / w) active ingredient, although the active ingredient concentration may be the same as the solubility limit of the active ingredient in the solvent . Formulations for topical administration can further comprise one or more additional ingredients as described herein.

  Penetration enhancers can be used. These materials increase the penetration rate of the drug through the skin. Typical accelerators in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, and the like. Other accelerators include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acid, dimethyl sulfoxide, polar lipids or N-methyl-2-pyrrolidone.

  One vehicle acceptable for topical delivery of some compositions of the invention may contain liposomes. The composition of liposomes and their use are known in the art (see, eg, US Pat. No. 6,323,219 to Constanza).

  In alternative embodiments, the topically active pharmaceutical composition may include other adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, thickeners, buffers, preservatives, and the like. You may combine with an ingredient. In another embodiment, a penetration enhancer is included in the composition and is effective in improving transdermal penetration of the active ingredient into and through the stratum corneum relative to a composition lacking the penetration enhancer. is there. Various penetration enhancers are known to those skilled in the art including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acid, dimethyl sulfoxide, polar lipids or N-methyl-2-pyrrolidone. In another aspect, the composition may further comprise a hydrophile, which functions to increase the structural disorder of the stratum corneum, thus allowing for increased transport through the stratum corneum. . Various hydrophobizing agents are known to those skilled in the art, such as isopropyl alcohol, propylene glycol or sodium xylene sulfonate.

  Topically active pharmaceutical compositions should be applied in an amount effective to effect the desired change. As used herein, “effective amount” shall mean an amount sufficient to cover the area of the skin surface where a change is desired. The active compound should be present in an amount of about 0.0001% to about 15% by weight of the composition. More preferably, it should be present in an amount of about 0.0005% to about 5% of the composition, and most preferably it should be present in an amount of about 0.001% to about 1% of the composition. Such compounds may be synthetic or natural.

Buccal administration The pharmaceutical composition of the invention can be prepared, packaged or sold as a formulation suitable for buccal administration. Such formulations can be, for example, in the form of tablets or electuary made using conventional methods, such as those containing 0.1-20% (w / w) active ingredient. The remainder comprises an orally soluble or degradable composition, and optionally one or more additional ingredients as described herein. Alternatively, formulations suitable for buccal administration can include powders or aerosolized or atomized solutions or suspensions containing the active ingredients. Such a powder, aerosolized or aerosolized formulation preferably exhibits an average particle size or droplet size in the range of about 0.1 to about 200 nanometers when dispersed, and one or more of the additional ones described herein Ingredients may further be included. The examples of formulations described herein are not exhaustive and it is understood that the present invention includes further modifications of these and other formulations not described herein but known to those of skill in the art. Like.

Rectal Administration The pharmaceutical composition of the present invention can be prepared, packaged or sold as a formulation suitable for rectal administration. Such compositions can be in the form of, for example, suppositories, retention enemas, and rectal or colonic lavage solutions.

  Suppository formulations are non-irritating pharmaceutically acceptable active ingredients and solids at normal room temperature (ie about 20 ° C) and liquid at the subject's rectal temperature (ie about 37 ° C in healthy humans) It can produce by combining with an excipient | filler. Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycol and various glycerides. Suppository formulations may further comprise a variety of additional ingredients including, but not limited to, antioxidants and preservatives.

  A retention enema formulation or rectal or colonic irrigation solution can be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema formulations can be administered and packaged within a delivery device adapted to the subject's rectal anatomy. Enema formulations can further include a variety of additional ingredients including, but not limited to, antioxidants and preservatives.

Additional Dosage Forms Additional dosage forms of the present invention include the dosage forms described in US Pat. Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837 and 5,007,790. Further dosage forms of the present invention include those described in US Patent Application Publication Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688 and 20020051820. Further dosage forms of the present invention include PCT applications WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416 No., WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755 and WO 90/11757 Mention may also be made of the dosage forms described.

Controlled Release Formulations and Drug Delivery Systems Controlled or sustained release formulations of the pharmaceutical compositions of the invention can be made using conventional techniques. In some cases, the dosage forms used can be hydropropyl methylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multilayer coatings, microparticles, liposomes or microspheres, or a variety that provides the desired release profile. Combinations thereof in proportions can be provided as a slow or controlled release of one or more active ingredients in the dosage form, eg, used. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use in the pharmaceutical compositions of the present invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules and caplets, adapted for controlled release are encompassed by the present invention.

  Most pharmaceutical controlled release products have a common goal of improving drug treatment compared to drug treatment achieved by their uncontrolled counterparts. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by the minimal drug substance used to cure or control the condition with the least amount of time. Advantages of controlled release formulations include prolonged drug activity, reduced dosage frequency, and increased patient compliance. In addition, controlled release formulations can be used to affect other properties such as the time of onset of action, or the blood level of the drug, and thus can affect the appearance of side effects.

  Most controlled-release formulations gradually release other doses that maintain this level of therapeutic effect over an extended period of time, with the initial release of the drug that rapidly produces the desired therapeutic effect. Designed to release. In order to maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.

  Controlled release of the active ingredient can be stimulated by various inducers such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled release component” in the context of the present invention includes compounds, including but not limited to polymers, polymer matrices, gels, osmotic membranes, liposomes or microspheres, or combinations thereof that facilitate controlled release of active ingredients. As defined herein.

  In certain embodiments, the formulations of the present invention can be, but are not limited to, short release, rapid offset, and controlled release, such as sustained release, delayed release and pulsed release formulations.

  The term sustained release is used in its normal sense to gradually release a drug over a long period of time and, if not necessarily, result in a substantially constant blood level of the drug over a long period of time. Means a drug formulation. The period can be as long as one month or longer and should be a longer release than the same amount of drug administered in bolus form.

  For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that imparts sustained release to the compound. Thus, the compounds used in the method of the invention can be administered in the form of microparticles, for example by injection or by implantation in the form of an oblate or disc.

  In a preferred embodiment of the invention, sustained release formulations are used to administer the compound of the invention to the patient alone or in combination with another pharmaceutical agent.

  The term delayed release is used herein in its ordinary sense to release the drug for the first time after any delay following drug administration and not necessarily from about 10 minutes up to about 12 hours. Means a drug formulation that can contain

  The term pulsed release is used in its normal sense and refers to a drug formulation that releases drug so as to produce a pulsed plasma profile after drug administration.

  The term immediate release is used in its normal sense and refers to a drug formulation that releases drug immediately after drug administration.

  As used herein, short term refers to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes after drug administration, Means any period up to and including about 20 minutes or about 10 minutes and any integer or partial increments thereof.

  As used herein, rapid offset is about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes after drug administration. , About 20 minutes or about 10 minutes, and any period up to that including any integer or partial increments thereof.

In one aspect of the present invention, a method of treating a patient lacking normal breathing and normal breathing control comprises administering a composition described herein that is useful within the scope of the present invention, and Further treating the patient using a device for treatment of lack of normal breathing. Such devices include, but are not limited to, ventilators, CPAP and BiPAP devices.

  Mechanical ventilation is a method that mechanically assists or substitutes for spontaneous breathing. Mechanical ventilation is typically used after invasive intubation, which is a technique for inserting an endotracheal tube or tracheostomy tube into the airway. It is usually used for a short time during surgery, medical procedures, or serious illnesses in serious situations such as operating rooms or ICUs. It may be used at home or in a nursing or rehabilitation facility if the patient has a chronic illness that requires long-term ventilation support. The main form of mechanical ventilation is positive pressure ventilation, which works by pushing air into the lungs by increasing the pressure of the patient's airways. Negative pressure ventilators (eg, “iron lungs”) that draw air into the lungs by creating a negative pressure environment around the patient's chest are less common today. Mechanical ventilation is often a lifesaving intervention, but it has many potential complications, including pneumothorax, airway damage, alveolar damage, and ventilator-associated pneumonia. For this reason, the pressure and volume of the gas used are strictly controlled and reduced as quickly as possible. The types of mechanical ventilation include normal ventilation, high frequency ventilation, non-invasive ventilation (non-invasive positive pressure ventilation or NIPPV), proportional assisted ventilation (PAV), adaptive assisted ventilation (ASV) and neuromodulated assisted ventilation ( NAVA).

Non-invasive ventilation means any mode that assists ventilation without the use of endotracheal tubes. Non-invasive ventilation is primarily aimed at minimizing patient discomfort and complications associated with invasive ventilation, often in heart disease, exacerbation of chronic lung disease, sleep apnea and nerves. Used in muscle disease. Non-invasive ventilation relates only to the patient interface and not to the type of ventilation used. The mode may include a spontaneous mode or a control mode, and may be a mode related to either pressure or volume. Some commonly used NIPPV formats include the following.
(a) Continuous Positive Airway Pressure (CPAP): This type of machine has been used primarily by patients for the treatment of sleep apnea at home, but is now one of the forms of ventilation in the intensive care unit. As widely used. CPAP machine delivers a flow of compressed air via a hose to a nasal pillow, nasal mask or full face mask that secures the airway to allow non-occlusive breathing (holds it open under air pressure) To stop upper airway obstruction and reduce and / or prevent apnea and hypopnea. If the machine is turned on before placing the mask over the head, air flow will pass through the mask. After placing the mask over the head, it closes the face and the air stops flowing. At this point, only atmospheric pressure achieves the desired result. This has the added benefit of reducing or eliminating the very large snoring that sometimes accompanies sleep apnea.
(b) Bi-level positive airway pressure (BIPAP): The pressure alternates between positive inspiratory airway pressure (IPAP) and lower positive expiratory airway pressure (EPAP) depending on patient effort. For many such devices, a backup rate can be set that delivers IPAP pressure even if the patient is unable to begin breathing.
(c) Intermittent positive pressure ventilation (IPPV) through mouthpiece or mask.

  Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific techniques, aspects, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims appended hereto. For example, reaction times, reaction sizes / scales, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions such as nitrogen atmospheres, and reaction conditions including but not limited to reducing / oxidizing agents are recognized in the art. It is to be considered within the scope of this application to modify by means of alternatives and simply using routine experimentation.

  In all places in this specification that indicate values and ranges, the description in the form of ranges is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention. You should understand that. Accordingly, all values and ranges encompassed by these values and ranges are intended to be included within the scope of the present invention. In addition, all values within these ranges, and the upper or lower limits of the range of values are also contemplated by this application. A range description should be considered to have specifically disclosed all the possible subranges, as well as individual numerical values within that range, and, where appropriate, subintegers of the numerical values within the range. For example, a description relating to a range such as 1 to 6 includes subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, as well as individual numbers within the range, for example 1, 2, 2.7, 3, 4, 5, 5.3 and 6 should be considered as specifically disclosed. This is true regardless of the range width.

  The following examples further illustrate aspects of the present invention. However, they are in no way intended to limit the teaching or disclosure relating to the invention described herein.

  The invention will now be described with reference to the following examples. These examples are given for illustrative purposes only, and the invention is not limited to these examples, but rather encompasses all variations apparent as a result of the teachings presented herein.

Materials Unless otherwise stated, all remaining starting materials were obtained from commercial suppliers and used without purification. Unless otherwise stated, the final product is typically isolated as a hydrochloric acid addition salt.

Example 1:
N- (4,6-Bis-methylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XX)

2-Chloro-N- (4,6-bis-methylamino)-[1,3,5] triazine (XIX)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was dissolved in acetone (35 mL) and poured into ice water (50 mL) to form a very fine suspension. . A solution of N-methylamine hydrochloride (3.66 g, 54 mmol) in water (20 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added dropwise 2N NaOH (54 mL, 108 mmol) so as to keep the temperature between 0 ° C and 5 ° C. The mixture was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. The precipitate was filtered and washed with water (3 × 25 mL). After high vacuum drying with anhydrous calcium chloride, 2-chloro-N- (4,6-bis-methylamino)-[1,3,5] triazine (XIX) as a white powder (4.2 g, 89% yield) Isolated. LCMS (ESI) m / z = 174 (M + H) ⁺ .

N- (4,6-Bis-methylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XX)
2-Chloro-N- (4,6-bis-methylamino)-[1,3,5] triazine (XIX) (1.74 g, 10 mmol), N, O-dimethylhydroxylamine hydrochloride (3.88 g, 40 mmol) And a mixture of DIPEA (7.74 g, 60 mmol) in EtOH (200 mL) was heated at 100 ° C. for 16 h before the solvent was removed in vacuo. The residue was dissolved in EtOAc (150 mL), washed with water (100 mL) and brine solution (100 mL), then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1 → 5/3) to give 899 mg (23%) of the desired product. The isolated free amine (380 mg, 2 mmol) was taken up in H ₂ O (10 mL) and 0.5 M aqueous HCl (6 mL) was added. The resulting solution is lyophilized to give the desired product N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XX) was obtained as a white solid (468 mg).

Example 2:
N- (4,6-Bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXII)

2-Chloro-N- (4,6-bis-ethylamino)-[1,3,5] triazine (XXI)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was dissolved in acetone (35 mL) and poured into ice water (50 mL) to form a very fine suspension. . A solution of ethylamine (2.43 g, 54 mmol) in water (20 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added 2N NaOH (27 mL, 54 mmol) dropwise so as to keep the temperature between 0 ° C and 5 ° C. The mixture was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). After drying in anhydrous calcium chloride under high vacuum, 2-chloro-N- (4,6-bis-ethylamino)-[1,3,5] triazine (XXI) as a white powder (5.0 g, yield 92%) Isolated. LCMS (ESI) m / z = 202 (M + H) ⁺ .

N- (4,6-Bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXII)
2-Chloro-N- (4,6-bis-ethylamino)-[1,3,5] triazine (XXI) (4.03 g, 20 mmol), N, O-dimethylhydroxylamine hydrochloride (9.7 g, 100 mmol) And a mixture of DIPEA (1.806 g, 140 mmol) in EtOH (200 mL) was heated at 100 ° C. for 16 h. Thereafter, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL) and washed with water (100 mL) and brine solution (100 mL), then dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1 → 5/2) to give 811 mg (18%) of the desired product. The isolated free amine (811 mg, 3.58 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M HCl solution in H ₂ O (7.2 mL) was added. The resulting solution was lyophilized to give the desired product N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride ( XXII) was obtained as a white solid (938 mg).

Example 3:
N- (4-Cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXV)

2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (20 g, 109 mmol) was dissolved in acetone (100 mL) and poured into ice water (50 mL) to form a very fine suspension. A solution of propan-1-amine (7.1 g, 120 mmol) in water (20 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added 2N NaOH (60 mL, 120 mmol) dropwise so as to keep the temperature between -5 ° C and 0 ° C. The mixture was stirred at 0 ° C. for 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). 2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII) isolated as a white powder (18 g, 80% yield) after high vacuum drying with calcium chloride did. LCMS (ESI) m / z = 208 (M + H) ⁺ .

2-Chloro-N- (4-cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazine (XXIV)
2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII) (18 g, 87 mmol) was dissolved in acetone (100 mL) and poured into ice water (50 mL) to A fine suspension was formed. A solution of cyclopropylmethanamine (6.7 g, 95 mmol) in acetone (30 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added 2N NaOH (44 mL, 88 mmol) dropwise so as to keep the temperature between 0 ° C and 5 ° C. The mixture was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). After high vacuum drying with anhydrous calcium chloride, 2-chloro-N- (4-cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazine (XXIV) was added to a white powder (12 g, Isolated as 57% yield). LCMS (ESI) m / z = 242 (M + H) ⁺ .

N- (4-Cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXV)
2-Chloro-N- (4-cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazine (XXIV) (1.5 g, 6.2 mmol), N, O-dimethylhydroxylamine After a mixture of hydrochloride (3.0 g, 31.0 mmol) and DIPEA (6.5 g, 49.6 mmol) in EtOH (50 mL) was heated at 100 ° C. for 16 h, the solvent was removed in vacuo. The residue was dissolved in EtOAc (400 mL), washed with water (100 mL) then brine solution (100 mL) and dried over Na ₂ SO ₄ . The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1 → 5/2). The solvent was removed in vacuo to give 500 mg (26%) of the desired product. The isolated free amine (500 mg, 1.88 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (4.0 mL) was added. The resulting solution is lyophilized to give the desired product N- (4-cyclopropylmethyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXV, 520 mg) was obtained as a brown oil.

Example 4:
N- (4-Ethylamino) -N- (6-n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXVII)

2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (20 g, 109 mmol) was dissolved in acetone (100 mL) and poured into ice water (50 mL) to form a very fine suspension. A solution of propan-1-amine (7.1 g, 120 mmol) in water (20 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added 2N NaOH (60 mL, 120 mmol) dropwise so as to keep the temperature between -5 ° C and 0 ° C. The mixture was then stirred at 0 ° C. for 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). After drying in anhydrous calcium chloride under high vacuum, 2,4-dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII) was obtained as a white powder (18 g, 80% yield). Released. LCMS (ESI) m / z = 208 (M + H) ⁺ .

2-Chloro-N- (4-ethylamino) -N- (6-n-propylamino)-[1,3,5] triazine (XXVI)
2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII) (4.0 g, 19.5 mmol) is dissolved in acetone (40 mL) and poured into ice water (40 mL). A very fine suspension was formed. A solution of ethanamine hydrochloride (1.91 g, 23.4 mmol) in water (10 mL) was added and the temperature was maintained at about 0 ° C. A solution of NaOH (2.34 g, 58.5 mmol) in water (10 mL) was added dropwise to keep the temperature between 0 ° C and 5 ° C. The mixture was then stirred at room temperature for 40 minutes and concentrated. The precipitate was filtered off and washed with water (3 × 25 mL). After high vacuum drying with calcium chloride, the desired product 2-chloro-N- (4-ethylamino) -N- (6-n-propylamino)-[1,3,5] triazine (XXVI) is white powder Isolated as (3.89 g, 92% yield). LCMS (ESI) m / z = 216 (M + H) ⁺ .

N- (4-Ethylamino) -N- (6-n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXVII)
2-Chloro-N- (4-ethylamino) -N- (6-n-propylamino)-[1,3,5] triazine (XXVI) (2 g, 9.3 mmol), N, O-dimethylhydroxylamine hydrochloride After a mixture of salt (4.5 g, 46.5 mmol) and DIPEA (8.4 g, 65.1 mmol) in EtOH (20 mL) was heated at 100 ° C. for 16 h, the solvent was removed in vacuo. The residue was dissolved in EtOAc (150 mL), washed with water (100 mL), washed with brine solution (100 mL) and then dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 10/1 → 2/1) to give the desired product (820 mg, 37%). The isolated free amine (820 mg, 3.42 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (11 mL) was added. The resulting solution is lyophilized to give the desired product N- (4-ethylamino) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O -Dimethyl-hydroxylamine hydrochloride (XXVII) was obtained as a colorless oil (944 mg).

Example 5:
N- (bis-4,6- (2-methylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXIX)

2-Chloro-N- (4,6-bis- (2-methylpropylamino)-[1,3,5] triazine (XXVIII)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (5.0 g, 27 mmol) was dissolved in acetone (35 mL) and poured into ice water (50 mL) to form a very fine suspension. . A solution of 2-methylpropan-1-amine (4.0 g, 54 mmol) in acetone (20 mL) was added and the temperature was maintained at about 0 ° C. To this mixture was added 2N NaOH (27 mL, 54 mmol) dropwise so as to keep the temperature between 0 ° C and 5 ° C. The mixture was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). After drying in anhydrous calcium chloride under high vacuum, 2-chloro-N- (4,6-bis- (2-methylpropylamino)-[1,3,5] triazine (XXVIII) was white powder (6.0 g, yield) 87%) LCMS (ESI) m / z = 258 (M + H) ⁺ .

N- (bis-4,6- (2-methylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXIX)
2-Chloro-N- (4,6-bis- (2-methylpropylamino)-[1,3,5] triazine (XXVIII) (2.57 g, 10 mmol), N, O-dimethylhydroxylamine hydrochloride (1.94 g, 20 mmol) and DIPEA (5.16 g, 40 mmol) in EtOH (100 mL) was heated at 100 ° C. for 16 h, and then the solvent was removed in vacuo.The residue was dissolved in EtOAc (200 mL) and washed with water (2 × 100 mL). Washed and washed with brine solution (100 mL), then dried over Na ₂ SO _4. Solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1) The isolated free amine (920 mg, 3.3 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (6.6 mL) was added. The solution is subjected to lyophilization to the desired product N- (bis-4,6- (2-methylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine The hydrochloride salt (XXIX) was obtained as a white solid (1.0 g).

Example 6:
N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXXI)

N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (30 g, 163 mmol) was dissolved in acetone (300 mL) and N, O-dimethylhydroxylamine hydrochloride (15.8 g, 163 mmol) and DIPEA ( 42 g, 326 mmol) was added and the mixture was stirred at 0 ° C. for 1 h. The solution was concentrated, the residue was treated with EtOAc (750 mL), washed with water (100 mL), and the organic layer was dried over Na ₂ SO ₄ . Volatiles were removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 50/1 → 10/1) to give the desired product N- (4,6-dichloro [1,3,5 ] Triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) was obtained as a white solid (25 g, 73% yield). LCMS (ESI) m / z = 210 (M + H) ⁺ .

N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXI)
N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (1 g, 4.78 mmol), 2,2-dimethylpropan-1-amine After a mixture of (832.5 mg, 9.57 mmol) and DIPEA (1.85 g, 14.34 mmol) in EtOH (20 mL) was heated at 100 ° C. for 16 h, the solvent was removed in vacuo. The residue was dissolved in EtOAc (40 mL), washed with water (20 mL) and brine solution (20 mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 20/1 → 5/1) to give the desired product (1.4 g, 95%). The isolated free amine (1.4 g, 4.52 mmol) is dissolved in H ₂ O (10 mL), 0.5 M HCl solution in H ₂ O (14.5 mL) is added and the resulting solution is subjected to lyophilization to the desired The product N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride was converted to a white solid (1.67 g).

Example 7:
4,6-Bis-N-cyclopropylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXXIII)

2-Chloro-N- (4,6-bis- (cyclopropylamino)-[1,3,5] triazine (XXXII)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (40 g, 217 mmol) was dissolved in 200 mL of acetone and poured into ice water (250 mL) to form a very fine suspension. A solution of cyclopropanamine (24.8 g, 435 mmol) was added at 0 ° C. with stirring. To this mixture was added 2N NaOH (218 mL, 435 mmol) dropwise at a rate to keep the temperature between 0 ° C and 5 ° C. The resulting mixture was stirred at ambient temperature for 30 minutes and then at 50 ° C. for an additional 60 minutes. The precipitate was filtered off and washed with water (3 × 100 mL). Isolation of chloro-N- (4,6-bis- (cyclopropylamino)-[1,3,5] triazine (XXXII) as white powder (46 g, 93% yield) after high vacuum drying with calcium chloride LCMS (ESI) m / z = 226 (M + H) ⁺ .

4,6-Bis-N-cyclopropylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXIII)
Chloro-N- (4,6-bis- (cyclopropylamino)-[1,3,5] triazine (XXXII) (2.25 g, 10 mmol), N, O-dimethylhydroxylamine hydrochloride (1.94 g, 20 mmol) And a mixture of DIPEA (5.16 g, 40 mmol) in EtOH (100 mL) was heated at 100 ° C. for 16 h, then the solvent was removed under reduced pressure, the residue was dissolved in EtOAc (200 mL), water (2 × 100 mL) and brine (100 mL) And then dried over Na ₂ SO _{4. The} solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 3/1) to give 1.0 g (40% of the desired product). The isolated free amine (1.0 g, 4.0 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (8 mL), and then the solution was lyophilized to give N- (4,6 -Bis-cyclopropylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (XXXIII) was obtained as a white solid (1.05 g).

Example 8A:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV)
Example 9A:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI)

2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV)
Suspension of 2,4,6-trichloro-1,3,5-triazine (XVIII) (15.00 g, 81.34 mmol) and n-propylamine (13.4 mL, 162.68 mmol) in acetone (300 mL) and water (15 mL) To the solution was added 2M NaOH solution (82 mL, 162.68 mmol) dropwise at 0 ° C. The reaction mixture was heated at 50 ° C. for 3 hours and then cooled. Water (100 mL) was added to the reaction mixture and the resulting precipitate was filtered, washed with water, ethyl ether and dried to give 2-chloro-N- (4,6-bis- (n-propylamino)- [1,3,5] triazine (XXXIV) (15.88 g, 85% yield) was obtained.

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) (10.00 g, 43.53 mmol), N, O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06mmol) and NaOH (3.13 g, was heated for 6 hours at 1,4-dioxane (120 mL) and water (30 mL) in a mixture of 78.35mmol) 60 ℃, volatiles were removed under reduced pressure. saturated NaHCO ₃ Solution (500 mL) was added to the residue and the mixture was extracted with EtOAc (3 × 200 mL) The combined organic extracts were washed with water (300 mL) then brine solution (300 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the resulting residue was filtered through silica gel using eluent CH ₂ Cl ₂ / EtOH (9/1 v / v) to give N- (4,6-bis-n- Propylamino [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) (9.96 g, 90% yield) was obtained.

融点: 134〜135℃。 N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI)
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV, 3.24 g, 12.74 mmol) of 1,4- Concentrated (95%) H ₂ SO ₄ (0.72 mL, 12.74 mmol) was added dropwise at 0 ° C. to a dioxane (100 mL) solution. The mixture was stirred at room temperature for 0.5 hour and volatiles were removed in vacuo. The residue was coevaporated with dry toluene (3 × 25 mL). The resulting white residue was crystallized from ethanol / ethyl ether to give N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine Hydrogen sulfate (XXXVI, 3.86 g, 86% yield) was obtained as a white solid.

Melting point: 134-135 ° C.

Example 8B:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV)
Example 9B:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI)

Step 1: 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV)
Summary: Di-chloro substitution with 2 equivalents of n-propylamine. In one embodiment, 2 equivalents or more of n-propylamine produced only the starting bis-propylamine derivative. When the progress of the reaction was monitored by HPLC, a desired intermediate (2-chloro-4,6-bis-n-propylamino-s-triazine) was precipitated. In-process QC inspection was performed.

  To a suitable glass reactor equipped with a mechanical stirrer, thermocouple, condenser, addition funnel and temperature control mantle was added 8 L acetone followed by 1 kg (5.42 mol) cyanuric chloride. The stirred mixture was pre-cooled to 15 ° C and n-propylamine (at ambient temperature) was added slowly via an addition funnel to maintain the temperature below 45 ° C. A 2M NaOH solution was prepared and added to the mixture at a rate that maintained the temperature below 45 ° C. The pH of the mixture was acidic (and pH = 4) and the pH was adjusted to 8-9 by adding 6N NaOH. The mixture was stirred at 40-50 ° C. for 0.5 h and reaction completion was monitored by IPC HPLC analysis. The reaction was considered complete when the detection of cyanuric chloride was less than 2%. The analysis was repeated every hour until the reaction was complete.

  After the reaction was complete, WFI (sterile water) was slowly added to maintain the temperature below 50 ° C. The resulting suspension was cooled to room temperature overnight with stirring. The solid was filtered through a polypropylene filter cloth and washed with acetone / water (1: 2) followed by 1.5 L MTBE. The solid was dried on the filter (vacuum assist) and then placed in a vacuum oven (45 ± 5 ° C.,> 29 "Hg) for a minimum of 6 hours, showing a weight loss change of less than 0.5%. Collected for analytical inspection (QC HPLC analysis and Karl Fischer analysis) and 2 g was collected for QA retention The product produced in Step 1 was a white solid. It was transferred to a double-bag plastic bag, placed in a fiber drum, labeled for quarantine storage and subjected to QA.

Step 2, Step 1: N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV)
Summary: Chloro substitution with 1 equivalent of N-methoxymethylamine. The progress of the reaction was monitored by HPLC, and precipitation of the desired product free base was achieved by adding water and cooling. In-process QC inspection was performed. The free base was converted to the corresponding sulfate salt by crystallization and the final product was subjected to vacuum oven drying. In-process QC inspection and final product QC inspection were performed.

In a suitable round bottom flask equipped with a mechanical stirrer, thermocouple, condenser and heating mantle, N, N-dimethylacetamide (DMA) 6L followed by 6-chloro-N, N-dipropyl- [1,3,5] -1 kg (4.35 mol) of triazine-2,4-diamine (stage 1 product) was added. To this stirred mixture was added K ₂ CO ₃ (1.2 kg, 6.53 mol, 2 eq) at room temperature, rinsing with a small amount of additional DMA. To this, N, O-dimethylhydroxylamine hydrochloride (0.637 kg, 8.71 mol, 1.5 eq) is added in small portions over about 5-10 minutes to reduce foaming (and keep the temperature below 60 ° C). Added while rinsing using a small amount of additional DMA. The mixture was heated to 75-80 ° C. and stirred for a minimum of 0.5 hours. The reaction completion was monitored by HPLC once at 75-80 ° C. The mixture was cooled below 65 ° C. and water (12 L) was added. The resulting suspension was cooled to room temperature overnight (18 hours) with stirring. The resulting solid was filtered and washed with 1.2 L of water. The filter cake was air-dried for 1 hour to obtain a sample for OVI amine GC analysis. The remaining solid was vacuum oven dried (45 ° C.,> 29 "Hg) for a minimum of 6 hours (NMT 1% weight change). The desired product (free base (XXXV)) was a dense white solid. An IPC sample was obtained.

Crystalline N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine free base (XXXV)
(XXXV) The free base in methylene chloride was quickly evaporated to dryness. The resulting solid was dried under reduced pressure at about 25 ° C. for about 45 minutes (XXXV free base form A). DSC: Sharp endotherm at about 95.2 ℃. XRPD: Figure 22.

Step 2, Step 2: N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) salt Methyl ethyl ketone (20 L) was added to 2,800 g (12.2 mol) of formation and crystallization substrate free base (XXXV). The mixture is stirred and heated to 40 ° C., then finish filtered through a medium porosity sintered glass funnel and placed in a 72 L reactor to give a clear solution and fluffy white residue (12 g, 0.43 wt. %). The mixture was warmed to 45 ° C. and concentrated H ₂ SO ₄ (12.8 mol, 1.05 equivalents to prefiltered weight) was added slowly via addition funnel over 1 hour. The mixture was stirred overnight (18 hours) with cooling (a solid precipitate started to form at about 36 ° C .; final temperature = 27 ° C.).

The mixture was further cooled to 15 ° C., stirred for 0.5 h and filtered. The solid product cake is washed with methyl ethyl ketone (6 L), air dried on a Buchner funnel for 4 hours (assisted vacuum), then placed in a vacuum oven (over 29 '' Hg, 50-55 ° C.) and dried for at least 6 hours. N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) 3,252 g (84%) Obtained as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 0.88 (pentet, 6 H), 1.41-1.63 (m, 4 H), 3.16-3.40 (m, 7 H), 3.69-3.83 (m, 3 H), 7.50-8.56 (m, 2 H). In-process purity (HPLC (AUC) at 210 nm) = 99.81%. Filtration residue: ¹ H NMR (400 MHz, methanol-d ₄ ) 3.27-3.35 (m), 1.55-1.65 (q) 0.90-0.95 (t). MS m / z: 212 [M + H], consistent with the data of N- (4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII) (see Comparative Example 1). The isolated title compound contained no detectable (CLXXVIII).

Stage 1:
IPC inspection 1: Temperature chart recording during addition −
Maintains temperature control specified in the process
IPC test 2: IPC HPLC analysis
The reaction is complete when the detection of cyanuric chloride is less than 2%.
The analysis is repeated every hour until the reaction is complete.
If the reaction is not complete after the third sampling, contact your supervisor.
Stage 1 product QC inspection:
QC HPLC analysis −
Recorded results of cyanuric chloride and 2-chloro-4,6-bis-n-propylamino-s-triazine assay Karl Fischer −
Record result

Stage 2:
Step 1: reaction:
IPC inspection 1: Temperature chart recording during addition −
Maintains temperature control specified in the process
IPC inspection 2: IPC HPLC analysis −
The reaction is complete when the detection of 2-chloro-4,6-bis-n-propylamino-s-triazine is less than 2%.
The analysis is repeated every hour until the reaction is complete.
If the reaction is not complete after the third sampling, contact your supervisor.
IPC inspection 3: Residual amine analysis (by GC) −
n-Propylamine and N, O-dimethylhydroxylamine levels NMT 0.1%
IPC inspection 4: Weight change during drying −
NMT 1%
IPC test 5: IPC HPLC analysis −
Purity recording results by HPLC (AUC) Step 2: Salt formation and crystallization
IPC inspection 1: Temperature chart recording during addition of concentrated sulfuric acid −
Maintains temperature control specified in the process
IPC inspection 2: GC MEK and DMAc OVI −
NMT 800ppm each
IPC inspection 4: Weight change during drying −
NMT 1%

Proton nuclear magnetic resonance (NMR) spectroscopy
¹ H NMR data of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) at 400 MHz Obtained as a solution in DMSO-d ₆ . This is presented in FIG. Shift attribution is presented in Table 1.

(Table 1) ¹ H chemical shift assignment of (XXXVI) in DMSO-d ₆ at 25 ° C

Carbon-13 NMR spectroscopy
¹³ C NMR data of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) at 100 MHz Obtained as a solution in DMSO-d ₆ . This is presented in FIG. Shift attribution is presented in Table 2.

(Table 2) Assignment of ¹³ C chemical shift at 25 ° C in (XXXVI) in DMSO-d ₆

Fourier transform infrared (FTIR) spectroscopy
The FTIR spectrum of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogen sulfate (XXXVI) is shown in Table 3 and Fig. Presented in 12.

(Table 3) FTIR spectrum of (XXXVI)

The mass obtained from high resolution and low resolution mass spectrometry liquid chromatography mass spectrometry (LCMS) was 254 amu. This is consistent with the theoretical mass of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI). I'm doing it. The high resolution results obtained through direct injection are presented in Table 4.

(Table 4) Mass spectrometry result of (XXXVI)

Chromatographic purity
The HPLC chromatographic purity of RS was determined to be 100.0 area% and no related material was detected.

Determination of water content The water content was determined to be 0.04% by Karl Fischer titration.

Elemental analysis
Elemental analysis of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was obtained. Presented in Table 5.

(Table 5) Elemental analysis results of (XXXVI)

Thermal analysis by differential scanning calorimetry (DSC)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was added to cUSP <891> / EP Analysis from 25 ° C to 250 ° C at a rate of 10 ° C per minute according to 2.2.34 showed endotherms at 90.19 ° C, 126.38 ° C and 138.30 ° C (Figure 13).

X-ray powder diffraction
XRPD diffraction pattern of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogen sulfate (XXXVI) was obtained. , Consistent with form A. Presented in FIG.

Counter ion content
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogen sulfate (XXXVI) contains 27.13% sulfate ions It was found by titration to have a quantity.

PH of aqueous solution
A 1% aqueous solution of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) has a pH of 1.89. Was generated.

Physical description
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) is a white crystalline solid It has been determined.

Example 10: N- (4- (methoxy (methyl) amino) -6- (propylamino) -1,3,5-triazin-2-yl) propionamide (XL)

6-Amino-2,4-dichloro- [1,3,5] triazine (XXXVII)
2,4,6-Trichloro-1,3,5-triazine (XVIII) (10.0 g, 55 mmol) was dissolved in acetone (80 mL) and poured into ice water (80 mL) to form a very fine suspension. . To this mixture was added 1N ammonium hydroxide solution (108 mL, 109.4 mmol) at 0 ° C. The reaction was stirred at ambient temperature for 30 minutes and at 25 ° C. for an additional 60 minutes. The precipitate was filtered off and washed with water (3 × 25 mL). After high vacuum drying with calcium chloride, 6-amino-2,4-dichloro- [1,3,5] triazine (XXXVII) was isolated as a white powder (7.4 g, 82% yield). LCMS (ESI) m / z = 165 (M + H) ⁺ .

6-Amino-2-chloro-4-n-propylamino- [1,3,5] triazine (XXXVIII)
6-Amino-2,4-dichloro- [1,3,5] triazine (XXXVII) (30.0 g, 187 mmol) dissolved in acetone (100 mL) and poured into ice water (100 mL) to form a very fine suspension Formed. To this mixture was added propan-1-amine (11.0 g, 187 mmol) in acetone (20 mL) at 0 ° C. 2N NaOH (94 mL, 187 mmol) was added dropwise to the reaction at a rate that maintained the temperature between 0 ° C. and 5 ° C. The mixture was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. After concentrating the mixture, the precipitate was filtered off and washed with water (3 × 100 mL). After high vacuum drying with calcium chloride, 6-amino-2-chloro-4-n-propylamino- [1,3,5] triazine (XXXVIII) was isolated as a white powder (35 g, 100% yield). LCMS (ESI) m / z = 188 (M + H) ⁺ .

N- (6-Amino-4-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXIX)
6-amino-2-chloro-4-n-propylamino- [1,3,5] triazine (XXXVIII) (5 g, 26.65 mmol), N, O-dimethylhydroxylamine hydrochloride (13 g, 133.24 mmol) and DIPEA After a mixture of (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at 100 ° C. for 16 h, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL), washed with water (200 mL), then brine solution (200 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give N- (6-amino-4-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXIX) as a white solid (5 g Yield 89%). LCMS (ESI) m / z = 213 (M + H) ⁺ .

N- (4- (methoxy (methyl) amino) -6- (propylamino) -1,3,5-triazin-2-yl) propionamide (XL)
N- (6-amino-4-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXIX) (5 g, 23.58 mmol) in THF (50 mL) Dissolved in. Propionyl chloride (3.25 g, 35.38 mmol) and DIPEA (5.47 g, 42.44 mmol) were added at 0 ° C. The resulting mixture was stirred at ambient temperature for 10 minutes and then stirred at 70 ° C. for 16 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL) and the extract was washed with water (80 mL) then brine solution (80 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1 → 2/1) to give 930 mg (15%) of the desired product. The isolated free amine (930 mg, 3.47 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M HCl solution in H ₂ O (10.4 mL), then the solution was lyophilized to give N- (4- ( Methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide (XL) was obtained as a colorless oil (1.06 g).

Example 11:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine (XLI)
Example 12:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine hydrochloride (XLII)

2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV)
Suspension of 2,4,6-trichloro-1,3,5-triazine (XVIII) (30.0 g, 162.68 mmol) and n-propylamine (26.8 mL, 325.36 mmol) in acetone (600 mL) and water (30 mL) To the solution was added 2M NaOH solution (163 mL, 325.36 mmol) dropwise at 0 ° C. (water-ice / NaCl bath). The ice bath was removed and the reaction mixture was heated at 50 ° C. for 3 hours and then cooled. Water (200 mL) is added to the reaction mixture, the precipitate is filtered, washed with water (200 mL), dried with P ₂ O _{5 at} 40 ° C. for 20 hours and 2-chloro-N- (4,6-bis- (n-Propylamino)-[1,3,5] triazine (XXXIV, 33.6 g, yield 90%) was obtained.

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine (XLI)
6-chloro-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine (XXXIV) (2.30 g, 10.01 mmol), O-methyl-hydroxylamine hydrochloride (1.67 g, 20.02 mmol) ) And NaOH (0.72 g, 18.00 mmol) in 1,4-dioxane (30 mL) and water (6 mL) were heated at 60 ° C. for 3 h. After this time NaOH (0.72 g, 18.00 mmol) was added and the reaction mixture was heated for an additional 3 hours. Volatiles were removed in vacuo. Saturated NaHCO ₃ solution (100 mL) was added to the residue and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the crude product was purified by flash column chromatography using gradient elution from CH ₂ Cl ₂ / EtOH (99: 1) to CH ₂ Cl ₂ / EtOH (95: 5) to give N- 2.17 g (90%) of (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine (XLI) was obtained. ESI-MS (m / z): 241 [M + H] ⁺

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine hydrochloride (XLII)
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxylamine (XLI) (2.17 g, 9.03 mmol) of 1,4-dioxane To the (5 mL) solution was added 2M HCl / ethyl ether (4.5 mL, 9.00 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 h, volatiles were removed in vacuo and N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-methyl-hydroxyl Amine hydrochloride (XLII) was obtained in quantitative yield.

Example 13:
O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XLIII)
Example 14
O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine hydrochloride (XLIV)

O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) (2.00 g, 8.71 mmol), O-allyl-hydroxylamine hydrochloride (1.91 g , 17.42mmol) and NaOH (0.70g, 17.42mmol) in 1,4-dioxane (25 mL) and water (5 mL) in a mixture was heated for 4 hours at 60 ° C.. volatiles were removed under reduced pressure. saturated NaHCO ₃ solution ( 100 mL) was added to the residue and the mixture was extracted with EtOAc (3 × 25 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na ₂ SO _{4. The} solvent was removed under reduced pressure. The crude product was purified by flash column chromatography using gradient elution from CH ₂ Cl ₂ / EtOH (99: 1) to CH ₂ Cl ₂ / EtOH (95: 5) to give O-allyl-N- Obtained (4,6-bis-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XLIII, 2.05 g, 88% yield) ESI-MS (m / z) 267 [M + H] ⁺ .

融点: 130〜132℃。 O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine hydrochloride As described in Example 12, O-allyl-N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XLIII) and 2M HCl / ethyl ether to O-allyl-N- (4,6-bis -n-Propylamino- [1,3,5] triazin-2-yl) -hydroxylamine hydrochloride (XLIV) was prepared.

Melting point: 130-132 ° C.

実施例13に記載のように2-クロロ-N-(4,6-ビス-(n-プロピルアミノ)-[1,3,5]トリアジン(XXXIV)およびヒドロキシルアミン塩酸塩からN-(4,6-ビス-n-プロピルアミノ-[1,3,5]トリアジン-2-イル)-ヒドロキシルアミン(XLV)を調製した(収率99%)。

融点: 138〜141℃。 Example 15:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XLV)

From 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and hydroxylamine hydrochloride as described in Example 13, N- (4, 6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XLV) was prepared (99% yield).

Melting point: 138-141 ° C.

Example 16
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine (XLVI)
From 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and N, N-dimethylhydrazine as described in Example 19, N- ( 4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ′, N′-dimethylhydrazine (XLVI) can be prepared.

実施例10に記載のように6-アミノ-2-クロロ-4-n-プロピルアミノ-[1,3,5]トリアジン(XXXVIII)およびN,O-ジメチルヒドロキシルアミンから6-(メトキシ(メチル)アミノ)-N2-プロピル-1,3,5-トリアジン-2,4-ジアミン(XLVII)を調製することができる。 Example 17
6- (Methoxy (methyl) amino) -N2-propyl-1,3,5-triazine-2,4-diamine (XLVII)

From 6-amino-2-chloro-4-n-propylamino- [1,3,5] triazine (XXXVIII) and N, O-dimethylhydroxylamine as described in Example 10, 6- (methoxy (methyl) Amino) -N2-propyl-1,3,5-triazine-2,4-diamine (XLVII) can be prepared.

実施例13に記載のように2-クロロ-N-(4,6-ビス-(n-プロピルアミノ)-[1,3,5]トリアジン(XXXIV)およびN-メチル-ヒドロキシルアミン塩酸塩からN-(4,6-ビス-n-プロピルアミノ-[1,3,5]トリアジン-2-イル)-N-メチル-ヒドロキシルアミン(XLVIII)を調製した(収率90%)。

Example 18:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (XLVIII)

From 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and N-methyl-hydroxylamine hydrochloride as described in Example 13 -(4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (XLVIII) was prepared (yield 90%).

Example 19:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N'-dimethyl-hydrazine (XLIX)
Example 20
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N'-dimethyl-hydrazine hydrogensulfate (L)

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N'-dimethyl-hydrazine (XLIX)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) (2.50 g, 10.88 mmol), N, N′-dimethyl-hydrazine dihydrochloride A mixture of (2.89 g, 21.76 mmol) and NaOH (2.18 g, 54.40 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated for 18 h at 60 ° C. The volatiles were removed in vacuo. _Three solutions (100 mL) were added to the residue and the mixture was extracted with EtOAc (3 × 50 mL) The combined organic extracts were washed with water (75 mL), brine (75 mL) and dried over Na ₂ SO ₄ . Was removed in vacuo and the crude product was purified by flash column chromatography using gradient elution (CH ₂ Cl ₂ / EtOH (99: 1) to CH ₂ Cl ₂ / EtOH (95: 5)) to give N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N′-dimethyl-hydrazine (1.17 g, 42%) was obtained.

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N'-dimethyl-hydrazine hydrogensulfate_ (L)
6- (N, N′-Dimethyl-hydrazino) -N, N′-dipropyl- [1,3,5] triazine-2,4-diamine (XLIX) (1.17 g, 4.62 mmol) of 1,4-dioxane To the (10 mL) solution, 95% H ₂ SO ₄ (0.26 mL, 4.62 mmol) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 0.5 hour and volatiles were removed in vacuo. The residue was coevaporated with dry toluene (3x25mL) to give N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, N'-dimethyl-hydrazine hydrogen sulfate Salt (L) was obtained in quantitative yield.

Example 21:
O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (LIII)
Example 22:
O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine hydrogensulfate (LIV)

Formaldehyde O-benzyl-oxime (LI)
O- benzyl - hydroxylamine hydrochloride (5.00g, 31.32mmol) and formaldehyde (H ₂ O in about 37 wt.%) (2.3mL, 31.32mmol) NaOH in toluene (40 mL) in a mixture of (1.25g, 31.32mmol) Of water (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After this time, the organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 30 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo to give formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%).

O-Benzyl-N-methyl-hydroxylamine (LII)
To a solution of formaldehyde O-benzyl-oxime (3.85 g, 28.48 mmol) in EtOH was added 1M HCl / EtOH solution (50 mL) dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour and volatiles were removed in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO ₃ solution (75 mL), water (75 mL) and dried over Na ₂ SO ₄ . The product was purified by flash column chromatography using gradient elution from petroleum ether / EtOAc (9: 1) to petroleum ether / EtOAc (7: 1) to give O-benzyl-N-methyl-hydroxylamine (1.72 g 44%).

O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (LIII)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-benzyl-N-methyl-hydroxylamine as described in Example 13 (LII) to react with O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (LIII) ( Yield 29%) was obtained.

O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine hydrogensulfate (LIV)
O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine (LIII) as described in Example 20 O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine sulfate reacted with 95% H ₂ SO ₄ Hydrogen salt (LIV) was obtained in quantitative yield.

Example 23:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine (LV)
Example 24:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine hydrogensulfate (LVI)

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine (LV)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and N-isopropyl-hydroxylamine hydrochloride as described in Example 13 The reaction yielded N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine (LV) (61% yield). ESI-MS (m / z): 269 [M + H] ⁺ .

融点: 154〜156℃。 N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine hydrogensulfate (LVI)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine (LV) and 95% H ₂ as described in Example 20 N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-isopropyl-hydroxylamine hydrogensulfate (LVI) was prepared from SO ₄ (yield 95 %).

Melting point: 154-156 ° C.

Example 25:
6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine (LVII)
Example 26:
6- [1,2] oxazinan-2-yl-N, N'-di-n-propyl- [1,3,5] triazine-2,4-diamine hydrogensulfate (LVIII)

6- [1,2] oxazinan-2-yl-N, N'-di- n- propyl- [1,3,5] triazine-2,4-diamine (LVII)
An ACE® pressure tube was charged with 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) (1.50 g, 6.53 mmol), N-ethyl Diisopropylamine (19.59 mmol), 1,2-oxazinane hydrochloride (1.61 g, 13.06 mmol) and tetrahydrofuran were added and the reaction mixture was heated at 100 ° C. for 2 hours, then cooled and poured into saturated NaHCO ₃ solution (50 mL). The suspension was extracted with EtOAc (3 × 25 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na ₂ SO _{4. The} solvent was removed under reduced pressure, The crude product was purified by flash column chromatography using gradient elution from CH ₂ Cl ₂ / EtOH (99: 1) to CH ₂ Cl ₂ / EtOH (95: 5) to give 6- [1,2] oxazinane. -2-yl-N, N′-di- n- propyl- [1,3,5] triazine-2,4-diamine (LVII) (1.63 g, 89%) was obtained.ESI-MS (m / z): 281 [M + H] ⁺ .

融点: 134〜137℃。 6- [1,2] oxazinan-2-yl-N, N'-di- n- propyl- [1,3,5] triazine-2,4-diamine hydrogensulfate (LVIII)
6- [1,2] oxazinan-2-yl-N, N′-di- n- propyl- [1,3,5] triazine-2,4-diamine (LVII) and as described in Example 20 95% H ₂ SO ₄ to 6- [1,2] oxazinan-2-yl-N, N'-di- n- propyl- [1,3,5] triazine-2,4-diamine hydrogensulfate (LVIII ) Was prepared. A quantitative yield was isolated.

Melting point: 134-137 ° C.

Example 27:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine (LXIV)
Example 28:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine hydrogen sulfate (LXV)

2-Isopropoxy-isoindole-1,3-dione (LIX)
To a stirred suspension of propan-2-ol (4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol) and N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL) was added diethyl azodicarboxylate. (14.5 mL, 73.56 mmol) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 20 hours and evaporated to dryness. The product was purified by flash column chromatography using gradient elution from petroleum ether / EtOAc (9: 1) to petroleum ether / EtOAc (5: 1) to give 2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%).

O-isopropyl-hydroxylamine hydrochloride (LX)
A mixture of 2-isopropoxy-isoindole-1,3-dione (LIX, 10.78 g, 52.50 mmol) and hydrazine monohydrate (5.1 mL, 105.00 mmol) in CH ₂ Cl ₂ (60 mL) at room temperature for 20 hours. Stir. The reaction mixture was filtered. The filtrate was washed with water (70 mL), brine (70 mL) and dried over Na ₂ SO ₄ . After the desiccant was filtered off, 4M HCl / 1,4-dioxane (13.8 mL, 55.00 mmol) was added, the volatiles were removed under reduced pressure and O-isopropyl-hydroxylamine hydrochloride (LX, 3.91 g, yield 67). %).

O-Benzyl-N-isopropoxycarbamate (LXI)
To a precooled (0 ° C.) solution of O-isopropyl-hydroxylamine hydrochloride (3.89 g, 34.87 mmol) in CH ₂ Cl ₂ (150 mL) was added N, N-diisopropyl-ethylamine (14.4 mL, 87.18 mmol) and benzyl chloroformate. (5.0 mL, 34.87 mmol) was added. The resulting solution was stirred at room temperature for 5 hours. At this point, the solution was washed twice with saturated aqueous NaHCO ₃ (30 mL) and dried over Na ₂ SO ₄ . The product was purified by flash column chromatography using gradient elution from petroleum ether / EtOAc (95: 5) to petroleum ether / EtOAc (6: 1) to give O-benzyl-N-isopropoxycarbamate (LXI, 4.98 g, 68%).

O-Benzyl-N-methyl-N-isopropoxycarbamate (LXII)
Add benzylisopropoxycarbamate (4.98 g, 23.80 mmol), anhydrous K ₂ CO ₃ (4.94 g, 35.70 mmol), methyl iodide (6.7 mL, 107.10) and anhydrous acetone (30 mL) to an ACE® pressure tube. It was. The reaction mixture was heated at 70 ° C. for 24 hours. The reaction mixture was filtered and the acetone was evaporated. The resulting slurry was dissolved in EtOAc, washed with water (3 × 50 mL), dried (Na ₂ SO ₄ ) and filtered. Removal of the solvent gave benzylisopropoxy (methyl) carbamate (4.96 g, 93%).

O-isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII)
O-Benzyl-N-methyl-N isopropoxycarbamate (4.96 g, 22.22 mmol) and 33% HBr / AcOH (45 mL) were stirred at room temperature for 20 minutes. Saturated NaHCO ₃ solution (400 mL) was added and the suspension was extracted with CH ₂ Cl ₂ (3 × 150 mL). The combined organic extracts were dried with Na ₂ SO ₄ . After the desiccant was filtered off, 4M HCl / 1,4-dioxane (6.7 mL, 26.65 mmol) was added, the volatiles were removed in vacuo and O-isopropyl-N-methyl-hydroxylamine hydrochloride (2.09 g, 75 %).

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine (LXIV)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) (1.65 g, 16.61 mmol), O-isopropyl-N-methyl-hydroxylamine hydrochloride A mixture of salt (LXIII, 2.09 g, 16.61 mmol) and NaOH (0.66 g, 16.61 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated for 16 h at 100 ° C. The volatiles were then reduced in vacuo. Saturated NaHCO ₃ solution (50 mL) was added to the residue and the mixture was extracted with EtOAc (3 × 50 mL) The combined organic extracts were washed with water (50 mL), brine (50 mL) and Na ₂ SO ₄ . dried solvent was removed in _{vacuo, CH 2 Cl 2 / EtOH (} 99: 1) from _{CH 2 Cl 2 / EtOH (95} : 5) until the crude product is purified by flash column chromatography using a gradient elution of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 95%) ESI-MS (m / z): 283 [M + H] ⁺ .

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine hydrogen sulfate (LXV)
1,-(4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 6.83 mmol) To a solution of 4-dioxane (6 mL), 95% H ₂ SO ₄ (0.36 mL, 6.83 mmol) was added dropwise at 0 ° C. After the mixture was stirred at room temperature for 0.5 h, volatiles were removed under reduced pressure. The residue was coevaporated with dry toluene (3 × 25 mL) to give N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine Hydrogen sulfate (almost quantitative yield) was obtained.

Example 29:
O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine (LXVIII)
Example 30:
O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine hydrogensulfate (LXIX)

O-Benzyl-N-vinyl-hydroxylamine (LXVI)
Acetaldehyde (24.7 mL, 44.2 mmol) was added dropwise to a cooled solution (0 ° C.) of O-benzyl-hydroxylamine hydrochloride (7.00 g, 43.85 mmol) in water (100 mL) and MeOH (20 mL). The reaction mixture was stirred for 16 hours. Volatiles were removed in vacuo and the aqueous suspension was extracted with EtOAc (2 × 75 mL). The combined organic extracts were washed with brine, then dried over Na ₂ SO ₄ and evaporated to give O-benzyl-N-vinyl-hydroxylamine (LXVI) in quantitative yield.

O-Benzyl-N-ethyl-hydroxylamine (LXVII)
To a solution of O-benzyl-N-vinyl-hydroxylamine (LXVI, 6.52 g, 43.70 mmol) in AcOH (10 mL) was added NaCNBH ₃ (11.00 g, 175.05 mmol) little by little. The reaction mixture was stirred at room temperature for 1 hour. The mixture was neutralized with 1N NaOH (pH 7) and extracted with EtOAc (3 × 75 mL). The combined organic extracts were washed with saturated NaHCO ₃ solution (2 × 100 mL), dried over Na ₂ SO ₄ and flash column chromatography (eluent: petroleum ether / EtOAc (9: 1) → petroleum ether / EtOAc (1 : 4)) to give O-benzyl-N-ethyl-hydroxylamine (LXVII, 2.10 g, 32%).

O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine (LXVIII)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-benzyl-N-ethyl-hydroxylamine as described in Example 13 (LXVII) to react with O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine (LXVIII, yield) Rate 38%).

O-Benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine hydrogensulfate (LXIX)
O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-hydroxylamine (LXVIII) as described in Example 9 O-benzyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine sulfate reacted with 95% H ₂ SO ₄ Hydrogen salt (LXIX) was obtained in quantitative yield.

Example 31:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine (LXX)
Example 32:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine hydrogensulfate (LXXI)

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine (LXX)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-isopropyl-hydroxylamine hydrochloride as described in Example 13 Reaction (80% yield) ESI-MS (m / z): 269 [M + H] ⁺ .

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine hydrogensulfate (LXXI)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxylamine (LXX) and 95% H ₂ as described in Example 20. Reaction with SO ₄ (quantitative yield).

実施例13に例示のように2-クロロ-N-(4,6-ビス-(n-プロピルアミノ)-[1,3,5]トリアジン(XXXIV)とO-ベンジル-N-イソプロピル-ヒドロキシルアミンとを反応させて6-((ベンジルオキシ)(イソプロピル)アミノ)-N²,N⁴-ジプロピル-1,3,5-トリアジン-2,4-ジアミン(LXXII)を調製した。実施例20に記載のように対応する硫酸水素塩(LXXIII)を調製した。 Example 33:
6-((Benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine (LXXII)
Example 34:
6-((Benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine hydrogensulfate (LXXIII)

As illustrated in Example 13, 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-benzyl-N-isopropyl-hydroxylamine To produce 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine (LXXII). The corresponding hydrogen sulfate (LXXIII) was prepared as described.

Example 35:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine (LXXVI)
Example 36:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine hydrogensulfate (LXXVII)

O-Benzyl-N-ethyl-N-isopropoxy-carbamate (LXXIV)
ACE® pressure tube was charged with benzylisopropoxycarbamate (4.08 g, 19.50 mmol), anhydrous K ₂ CO ₃ (4.04 g, 29.25 mmol), ethyl iodide (7.0 mL, 87.75 mmol) and anhydrous acetone (30 mL). added. The reaction mixture was heated at 70 ° C. for 24 hours. Ethyl iodide (7.0 mL, 87.75 mmol) and K ₂ CO ₃ (4.04 g, 29.25 mmol) were added and the reaction mixture was heated for 24 hours. The reaction mixture was filtered and the acetone was evaporated. The resulting slurry was dissolved in EtOAc (150 mL), washed with water (3 × 50 mL), dried (Na ₂ SO ₄ ) and filtered. The solvent was removed to give O-benzyl-N-ethyl-N-isopropoxy-carbamate (3.86 g, 83%).

N-ethyl-O-isopropyl-hydroxylamine hydrochloride (LXXV)
O-benzyl-N-ethyl-N-isopropoxy-carbamate and HBr / AcOH were reacted as described in Example 27 for the preparation of compound LXIII (71% yield).

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine (LXXVI)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and N-ethyl-O-isopropyl-hydroxylamine as described in Example 13 Reaction with hydrochloride (LXXV) to give N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine (LXXVI (Yield 88%) ESI-MS (m / z): 297 [M + H] ⁺ .

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine hydrogensulfate (LXXVII)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine (LXXVI) as described in Example 20 95% H ₂ SO ₄ was reacted (quantitative yield).

Example 37:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isobutyl-N-methyl-hydroxylamine (LXXXII)
Example 38:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isobutyl-N-methyl-hydroxylamine hydrogensulfate (LXXXIII)

O-Benzyl-N-isobutoxycarbamate (LXXIX)
For the preparation of compound LXI, O-isobutyl-hydroxylamine hydrochloride (LXXVIII) was reacted with benzyl chloroformate as described in Example 27 to give O-benzyl-N-isobutoxycarbamate (LXXIX) (87% yield). )

O-Benzyl-N-methyl-N-isobutoxycarbamate (LXXX)
For the preparation of compound LXII, O-benzyl-N-isobutoxycarbamate was reacted with methyl iodide as described in Example 27 to yield O-benzyl-N-methyl-N-isobutoxycarbamate in 78% yield. Obtained.

O-isobutyl-N-methyl-hydroxylamine hydrochloride (LXXXI)
O-benzyl-N-methyl-N-isobutoxycarbamate and HBr / AcOH were reacted as described in Example 27 for the preparation of compound LXIII (38% yield).

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isobutyl-N-methyl-hydroxylamine (LXXXII)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-isobutyl-N-methyl-hydroxylamine as described in Example 13 Reaction with hydrochloride gave LXXXII in 82% yield, ESI-MS (m / z) 297 [M + H] ⁺ .

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isobutyl-N-methyl-hydroxylamine hydrogensulfate (LXXXIII)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isobutyl-N-methyl-hydroxylamine (LXXXII) as described in Example 20 95% H ₂ SO ₄ was reacted (quantitative yield).

実施例13に例示のように2-クロロ-N-(4,6-ビス-(n-プロピルアミノ)-[1,3,5]トリアジン(XXXIV)とO-(チオフェン-2-イル-メチル)-N-メチル-ヒドロキシルアミンとを反応させて6-(メチル(チオフェン-2-イルメトキシ)アミノ)-N²,N⁴-ジ-n-プロピル-1,3,5-トリアジン-2,4-ジアミン(LXXXIV)を調製することができる。 Example 39:
6- (methyl (thiophen-2-ylmethoxy) amino) -N ^2, N ⁴ - di -n- propyl-1,3,5-triazine-2,4-diamine (LXXXIV)
Example 40:
6- (methyl (thiophen-2-ylmethoxy) amino) -N ^2, N ⁴ - di -n- propyl-1,3,5-triazine-2,4-diamine hydrogen sulfate (LXXXV)

As illustrated in Example 13, 2-chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O- (thiophen-2-yl-methyl) ) -N-methyl-hydroxylamine to react with 6- (methyl (thiophen-2-ylmethoxy) amino) -N ² , N ⁴ -di-n-propyl-1,3,5-triazine-2,4 -Diamine (LXXXIV) can be prepared.

Example 41:
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI)
Example 42:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine hydrogensulfate (XCII)

2-Cyclopropylmethoxy-isoindole-1,3-dione (LXXXVI)
Compound LIX was reacted with N-hydroxyphthalimide and cyclopropyl-methanol as described in Example 27 to give LXXXVI in 87% yield.

O-cyclopropylmethyl-hydroxylamine hydrochloride (LXXXVII)
Compound LX was reacted with 2-cyclopropylmethoxy-isoindole-1,3-dione and hydrazine as described in Example 27 (LXXXVII, 67% yield).

O-Benzyl-N-cyclopropylmethoxycarbamate (LXXXVIII)
Compound LXI was reacted with O-cyclopropylmethyl-hydroxylamine hydrochloride and benzyl chloroformate as described in Example 27 (LXXXVIII, 88% yield).

O-Benzyl-N-methyl-N-cyclopropylmethoxy-carbamate (LXXXIX)
Compound LXII was reacted with O-benzyl N-cyclopropylmethoxycarbamate and methyl iodide as described in Example 27 (LXXXIX, 95% yield).

O-cyclopropylmethyl-N-methyl-hydroxylamine hydrochloride (XC)
Compound LXIII was reacted with O-benzyl-N-methyl-N-cyclopropylmethoxycarbamate and HBr / AcOH as described in Example 27 to give XC in 77% yield.

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-cyclopropylmethyl-N-methyl- as described in Example 13 Reaction with hydroxylamine hydrochloride (XC) gave (XCI) in 99% yield.

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine hydrogensulfate (XCII)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI) as described in Example 20 ) And 95% H ₂ SO ₄ were reacted to give (XCII) in quantitative yield.

Example 43:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine (XCVI)
Example 44:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine hydrogensulfate (XCVII)

tert-Butylethoxycarbamate (XCIII)
To a solution of O-ethyl-hydroxylamine (1.76 g, 18.0 mmol) and di-tert-butyl dicarbonate (5.13 g, 23.67 mmol) in dichloromethane (45.0 mL), saturated Na ₂ CO ₃ solution (45.0 mL) was added dropwise at room temperature. And stirred for 24 hours. Water was added and the pH of the mixture was adjusted to 2 by the addition of 6N HCl and the resulting system was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated. The crude product was purified by flash column chromatography using gradient elution from petroleum ether / EtOAc (98: 2) to petroleum ether / EtOAc (95: 5) to give tert-butylethoxycarbamate (XCIII) (2.62 g, 90%) was obtained.

tert-Butylethoxy (methyl) carbamate (XCIV)
To a suspension of 60% sodium hydride (0.66 g, 16.92 mmol) in DMF (5 mL), a solution of tert-butylethoxycarbamate (XCIII, 2.48 g, 15.38 mmol) in DMF (10 mL) was added dropwise at 0 ° C. After 30 minutes, methyl iodide (1.95 mL, 31.32 mmol) in DMF (10 mL) was added and the reaction mixture was stirred at room temperature for 24 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (3 × 50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give tert-butylethoxy (methyl) carbamate (XCIV, 2.34 g, 87%). It was.

O-ethyl-N-methyl-hydroxylamine hydrochloride (XCV)
To tert-butylethoxy (methyl) carbamate (XCIV, 2.34 g, 13.35 mmol), 4M HCl / 1,4-dioxane solution (25 mL) was added in portions at 0 ° C. The mixture was stirred at room temperature for 4 hours. Volatiles were removed in vacuo and the residue was triturated with ethyl ether and filtered to give a solid (O-ethyl-N-methyl-hydroxylamine hydrochloride, XCV, 1.35 g, 91%).

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine (XCVI)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O-ethyl-N-methyl-hydroxylamine as described in Example 13 Reaction with hydrochloride gave XCVI in 93% yield, ESI-MS (m / z) 269 [M + H] ⁺ .

融点: 84〜86℃。 N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine hydrogensulfate (XCVII)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine (XCVI) as described in Example 20 Reaction with 95% H ₂ SO ₄ gave (XCVII) in 91% yield.

Melting point: 84-86 ° C.

Example 45:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine (C)
Example 46:
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine hydrogensulfate (CI)

2- (2,2-Difluoro-ethoxy) -isoindole-1,3-dione (XCVIII)
Compound LXI was reacted with N-hydroxyphthalimide and 2,2-difluoro-ethanol as described in Example 27 to give XCVIII in 52% yield.

O- (2,2-difluoro-ethyl) -hydroxylamine hydrochloride (XCIX)
Compound LX was reacted with 2- (2,2-difluoro-ethoxy) -isoindole-1,3-dione and hydrazine as described in Example 27 to give XCIX in 73% yield.

N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine (C)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5] triazine (XXXIV) and O- (2,2-difluoro-ethyl) as described in Example 13 ) -Hydroxylamine hydrochloride to give C in 59% yield.

融点: 91〜93℃。 N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine hydrogensulfate (CI)
N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine (C, 1.02 g, 3.51 mmol ) And 95% H ₂ SO ₄ (0.19 mL, 3.51 mmol) were reacted in diethyl ether (3 mL) at 0 ° C. 2 drops of EtOH are added and the resulting crystals are filtered, washed with diethyl ether and dried to give N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine hydrogensulfate (CI) (1.26 g, 93%) was obtained.

Melting point: 91-93 ° C.

Example 47:
4-N- (2-Dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CIII)
Example 48:
4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CIV )

2-Chloro-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CII)
2,4-Dichloro-N- (6-n-propylamino)-[1,3,5] triazine (XXIII) (18 g, 87 mmol) was dissolved in acetone (100 mL) and poured into ice water (50 mL) to A fine suspension was formed. A solution of N, O-dimethylhydroxylamine hydrochloride (9.3 g, 95 mmol) in water (30 mL) was added while maintaining the temperature at 0 ° C. (ice bath). To this mixture was added 2N NaOH (44 mL, 88 mmol) dropwise at a rate adjusted to maintain the temperature between 0 ° C and 5 ° C. The reaction was stirred at ambient temperature for 30 minutes and at 50 ° C. for an additional 60 minutes. The resulting precipitate was filtered off and washed with water (3 × 25 mL). After high vacuum drying with calcium chloride, 2-chloro-N- (6-n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CII, 12 g, 60%) was isolated as a white powder. LCMS (ESI) m / z = 232 (M + H) ⁺ .

4-N- (2-Dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CIII)
2-Chloro-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CII, 1.5 g, 6.5 mmol), N, N A mixture of -dimethylethane-1,2-diamine (3.5 g, 39 mmol) and DIPEA (2.5 g, 20 mmol) in EtOH (30 mL) was heated at 100 ° C. for 16 h. The solvent was then removed under reduced pressure. The residue was dissolved in EtOAc (80 mL), washed with water (2 × 50 mL), then brine solution (50 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 20/1 → 5/1) to give 4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1, 3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine (620 mg, 33%) was obtained.

4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CIV )
4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (610 mg, 2.1 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (6.6 mL) and the solution was lyophilized to give 4-N- (2-dimethylaminoethyl) amino-6-N- (n-propyl) Amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CIV, 630 mg) was obtained as a colorless oil. LCMS (ESI) m / z = 284 (M + H) ⁺ .

Example 49:
4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine (CV)
Example 50:
4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine hydrochloride (CVI)

4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine (CV)
2-Chloro-6-N- (n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CII) (400 mg, 2.9 in EtOH (50 mL)) mmol), DIPEA (5.16 g, 40 mmol) and 3- (1-methyl-1H-imidazol-2-yl) propan-1-amine (J. Heterocyclic Chem., 2005, 42: 1011-15) (732 mg, 3.2 mmol) was heated at 100 ° C. for 16 h. Thereafter, the solvent was removed under reduced pressure. The residue was dissolved in DCM / MeOH (400 mL / 200 mL), washed with water (50 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH = 50/1 → 10/1) to give 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino- 6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CV, 210 mg, 22%) was obtained.

4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine hydrochloride (CVI)
4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine (CV) (210 mg, 0.63 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (1.3 mL) and the solution was lyophilized to give 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxyl Amine hydrochloride (CVI, 210 mg) was obtained as a yellow oil.

Example 51:
4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl -Hydroxylamine (CVII)
Example 52:
4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl -Hydroxylamine hydrochloride (CVIII)

4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl -Hydroxylamine (CVII)
2-Chloro-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CII) (1 g, 4.5) in EtOH (50 mL) mmol), (1-methyl-1H-imidazol-2-yl) methanamine (600 mg, 5.4 mmol) and K ₂ CO ₃ (1.24 g, 9 mmol) were heated at 100 ° C. for 16 h. The reaction mixture was filtered and volatiles were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (30 mL), then brine solution (30 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH = 20/1 → 8/1) to give 4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- ( n-Propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CVII, 650 mg, 47%) was obtained.

4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl -Hydroxylamine hydrochloride (CVIII)
4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl - dissolved hydroxylamine (CVII, 650mg, 2.1mmol) in a H ₂ O (10mL) and 0.5M HCl aqueous solution (6.3 mL). The resulting solution was subjected to lyophilization to give 4-N- (1-N-methylimidazol-2-yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazine- 2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CVIII, 389 mg) was obtained as a colorless oil.

Example 53:
4,6-Bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CIX)
Example 54:
4,6-Bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CX)

4,6-Bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CIX)
N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (7 g, 33.5 mmol), N, N- in THF (250 mL) Dimethyl-ethane-1,2-diamine (6.05 g, 68.7 mmol) and K ₂ CO ₃ (10.2 g, 73.7 mmol) were heated at 70 ° C. for 5 hours, and then the solvent was removed under reduced pressure. The residue was purified by reverse phase flash column chromatography to give 4,6-bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl -Obtained hydroxylamine (270 mg, 3%).

4,6-Bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CX)
4,6-bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (270 mg, 0.86 mmol) in H ₂ Dissolve in O (10 mL) and 0.5 M aqueous HCl (2 mL) and lyophilize the resulting solution to 4,6-bis- (N- (2-dimethylaminoethyl) amino)-[1,3,5 Triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (290 mg) was obtained as a colorless oil.

Example 55:
4,6-Bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXI)
Example 56:
4,6-Bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXII)

4,6-Bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXI)
N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (1 g, 4.78 mmol), pyridine-4-in EtOH (80 mL) After ilmethamineamine (1.14, 10.52 mmol) and DIPEA (1.85 g, 14.34 mmol) were heated at 100 ° C. for 16 hours, the solvent was removed under reduced pressure. The crude product was filtered by flash chromatography and 4,6-bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl- Hydroxylamine (CXI) (450 mg, 27%) was obtained.

4,6-Bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXII)
4,6-bis- (N- (pyridin-4-ylmethyl) amino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXI) (450 mg, 1.28 mmol) Is dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (3.84 mL), and the resulting solution is lyophilized to give 4,6-bis- (N- (pyridin-4-ylmethyl) amino)-[1 , 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine_hydrochloride (497 mg) was obtained as a yellow solid.

Example 57:
4,6-Bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXIII)
Example 58:
4,6-Bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXIV)

4,6-Bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXIII)
N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (1 g, 4.78 mmol), 3-methoxypropane in EtOH (50 mL) After 1-amine (936 mg, 10.52 mmol) and DIPEA (1.85 g, 14.34 mmol) were heated at 100 ° C. for 16 hours, the solvent was removed in vacuo. The residue was dissolved in EtOAc (200 mL), washed with water (50 mL), then brine solution (50 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 5/1 → 1/2) to give 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1 , 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXIII) (1.4 g, 93%) was obtained.

4,6-Bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXIV)
4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXIII, 1.4 g, 4.46 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (13.4 mL) and the resulting solution was lyophilized to give 4,6-bis- [N- (3-methoxy-n-propyl) amino. ]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (1.56 g) was obtained as a colorless oil.

Example 59:
4,6-Bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXV)
Example 60:
4,6-Bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXVI)

4,6-Bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXV)
N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (1 g, 4.78 mmol), (tetrahydro-2H) in EtOH (50 mL) After -pyran-4-yl) methanamine (1.21 g, 10.52 mmol) and DIPEA (1.85 g, 14.34 mmol) were heated at 100 ° C. for 16 hours, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with water (50 mL), then brine solution (50 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (PE / EA = 5/1 → 1/1) to give 4,6-bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3, 5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXV) (1.5 g, 85%) was obtained.

4,6-Bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXVI)
4,6-Bis- [N- (tetrahydropyran-4-ylmethyl) amino]-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (CXV) (1.5 g, 4.1 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (12.3 mL) and the resulting solution was lyophilized to give 4,6-bis- [N- (tetrahydropyran-4-ylmethyl) amino] -[1,3,5] Triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXVI) (1.65 g) was obtained as a white solid.

Example 61:
N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -triene-17- Yl) -N, O-dimethylhydroxylamine (CXVII)
Example 62:
N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -triene-17- Yl) -N, O-dimethylhydroxylamine hydrochloride (CXVIII)

N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -triene-17- Yl) -N, O-dimethylhydroxylamine (CXVII)
2,2 ′-(2,2′-oxybis (ethane-2,1-diyl) bis (oxy)) dietanamine (Org. Biomol. Chem. 2005, 3: 2255-61) (1.5 g, 7.8 mmol) and DIPEA (2.01 g, 15.6 mmol) to N- (4,6-dichloro [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXX) (1.63 g) in EtOH (100 mL) 7.8 mmol). The reaction solution was heated at 100 ° C. for 3 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with water (2 × 100 mL), then brine solution (100 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (DCM / MeOH = 50/1 → 20/1) to give N- (5,8,11-trioxa-2,14,16,18,19- Pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -trien-17-yl) -N, O-dimethylhydroxylamine (CXVII) (700 mg) was obtained as a colorless oil ( Yield 27%).

N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -triene-17- Yl) -N, O-dimethylhydroxylamine hydrochloride (CXVIII)
N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -triene-17- Yl) -N, O-dimethylhydroxylamine (CXVII) (700 mg, 2.1 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (4.3 mL), and the resulting solution was lyophilized to give N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -trien-17-yl) -N, O-dimethylhydroxylamine hydrochloride (CXVIII) (750 mg) was obtained as a colorless oil.

Example 63:
2,6-Bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CXX)
Example 64:
2,6-Bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (CXXI)

4-Chloro-2,6-bis- [Nn-propylamino] -1,3-pyrimidine (CXIX)
2,4,6-Trichloro-pyrimidine (5.00 g, 27.26 mmol) and n-propylamine (13.5 mL, 163.56 mmol) in EtOH were heated at 60 ° C. for 24 hours and then cooled. Volatiles were removed in vacuo. Water (100 mL) was added and the resulting suspension was extracted with CH ₂ Cl ₂ (3 × 75 mL). The combined organic extracts were washed with water (150 mL) then brine solution (100 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 4-chloro-2,6-bis- [Nn-propylamino] -1,3-pyrimidine (CXIX) (5.78 g, 93%).

(2,6-Bis-N- [n-propylamino] -pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CXX)
4-chloro-2,6-bis- [Nn-propylamino] -1,3-pyrimidine (CXIX) (5.78 g, 25.27 mmol) in 1,4-dioxane (400 mL) and water (20 mL), N, O-dimethylhydroxylamine hydrochloride (4.93 g, 50.54 mmol) and NaOH (2.02 g, 50.54 mmol) were heated at 60 ° C. for 24 hours. N, O-dimethylhydroxylamine hydrochloride (4.93 g, 50.54 mmol) and NaOH (3.03 g, 75.81 mmol) were added to the reaction mixture and heating was continued at 110 ° C. for 3 days. Volatiles were removed in vacuo. Saturated NaHCO ₃ solution (50 mL) was added to the residue and the mixture was extracted with CH ₂ Cl ₂ (3 × 75 mL). The combined organic extracts were washed with water (150 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (CH ₂ Cl ₂ / EtOH (25/1)) to give (2,6-bis-N- [n-propylamino] -pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine (CXX) (1.2 g, 19%) was obtained.

融点: 123〜126℃。 (2,6-Bis-N- [n-propylamino] -pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (CXXI)
(2,6-Bis-N- [n-propylamino] -pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (1.20 g, 4.74 mmol) in 1,4-dioxane (15 mL) was added to 0. Treated dropwise at 95 ° C. with 95% H ₂ SO ₄ (0.27 mL, 4.74 mmol). After the mixture was stirred at room temperature for 0.5 h, volatiles were removed under reduced pressure. The resulting residue was coevaporated with dry toluene (3 × 5 mL) to give (2,6-bis-N- [n-propylamino] -pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate ( CXXI) was obtained in quantitative yield.

Melting point: 123-126 ° C.

Example 65:
2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVI)
Example 66:
2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXVII)

2- (t-Butyl-dimethylsilyl) amino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (CXXII)
Et ₃ N (26 g, 260 mmol) was added to a solution of 2-amino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (8.7 g, 52 mmol) in dichloromethane (100 mL) and the mixture was stirred at −30 ° C. did. After this time, TBDMSOTf (15.1 g, 57.2 mmol) was slowly added dropwise and the resulting reaction was stirred at ambient temperature for 1.5 hours. The observed solid material was completely dissolved to form a light brown solution. The mixture was then quenched with 1N NaOH (100 mL) and extracted with DCM (250 mL). The organic layer was washed with H ₂ O (150 mL) then brine solution (150 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (PE / EtOAc = 10/1 → 5/1) to give 2- (t-butyl-dimethylsilyl) amino-4-chloro-7H-pyrrolo [2 , 3-d] pyrimidine (CXXII, 11.4 g, 79%) was obtained as a pale yellow solid. LCMS: (ESI) m / z = 283 (M + H) ⁺ .

2- (t-Butyl-dimethylsilyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIII)
2- (t-Butyl-dimethylsilyl) amino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (CXXII) (700 mg, 2.5 mmol), 0.18 mL of methyl iodide (3.5 mL) in DMF (10 mL) mmol) and K ₂ CO ₃ (552 mg, 4 mmol) were reacted at ambient temperature for 15 hours. After adding H ₂ O (10 mL), the reaction was extracted with EtOAc (100 mL) and the organic layer was washed with brine solution (10 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (PE / EtOAc = 10/1 → 5/1) to give 2- (t-butyl-dimethylsilyl) amino-4-chloro-7-methyl-pyrrolo. [2,3-d] pyrimidine (CXXIII) (750 mg, 100%) was obtained as a pale yellow oil. LCMS (ESI) m / z = 297 (M + H) ⁺ .

2- (n-propyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIV)
2- (t-Butyl-dimethylsilyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIII, 5.0 g, 17 mmol) and 1-iodopropane (4.3 g, under nitrogen atmosphere) 25 mmol) was dissolved in DMF (20 mL). After the reaction mixture was cooled to 0 ° C. with vigorous stirring, NaH (1 g of a 60% dispersion in mineral oil, 21 mmol) was added. The mixture was stirred for 10 minutes and water (50 mL) was added slowly to quench the reaction. The aqueous solution was extracted with EtOAc (200 mL) and the organic layer was washed with water (50 mL) and brine solution (50 mL) and finally dried over anhydrous Na ₂ SO ₄ . After evaporation of the volatiles, a yellow oily residue (5.7 g) was isolated. The residue was dissolved in Et ₂ O (50 mL) and concentrated hydrochloric acid (10 mL) was added at 0 ° C. with stirring. The mixture was allowed to react for an additional 10 minutes. After this time, the solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed with H ₂ O (150 mL) then brine solution (150 mL) and finally dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography (PE / EtOAc = 10/1 → 5/1) to give the desired product 2- (n-propyl) amino-4-chloro-7. -Methyl-pyrrolo [2,3-d] pyrimidine (3.78 g, 100%) was obtained as a yellow solid. LCMS: (ESI) m / z = 225 (M + H) ⁺ .

2- (n-propyl) amino-4- (i-propyl) amino-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXV)
To a solution of 2- (n-propyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (1.6 g, 7.1 mmol) in n-butanol (10 mL) was added potassium carbonate (4.9 g, 35.5 mmol). ) Followed by propan-2-amine (632 mg, 10.7 mmol). The mixture was stirred at 140 ° C. for 16 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water, then with a brine solution, and finally dried over anhydrous Na ₂ SO ₄ . Volatiles were removed under reduced pressure and the residue was purified by flash column chromatography (PE / EtOAc = 3/1) to give 2- (n-propyl) amino-4- (i-propyl) amino-7-methyl-pyrrolo [ 2,3-d] pyrimidine (1.2 g, 75%) was obtained as a yellow solid. LCMS: (ESI) m / z = 248 (M + H) ^<+> .

2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVI)
2- (n-propyl) amino-4- (i-propyl) amino-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXV, 1.0 g, 4 mmol) in EtOAc (50 mL) in 10% Pd / C (1.0 g) and AcOH (2.43 g, 40 mmol) were added. The mixture was attached to a hydrogenator and the system was evacuated and refilled with hydrogen. The reaction was stirred at ambient temperature for 48 hours. After this time, the mixture was filtered over 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (DCM / MeOH = 50/1 → 10/1) to give 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVI, 500 mg, 50%) was obtained as a yellow solid.

2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXVII)
The isolated free amine (CXXVI, 500 mg, 2 mmol) was dissolved in H ₂ O (10 mL) and 0.5 M aqueous HCl (4 mL) and the solution was lyophilized to give 2- (n-propyl) amino-4- (i -Propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXVII, 525 mg) was obtained as a brown solid.

Example 67:
2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVIII)
Example 68:
2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXIX)

2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXVII)
2- (n-propyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (1.0 g, 4.5 mmol) (CXXIV) in n-butanol (20 mL) to potassium carbonate (3.7 g, 27 mmol) and dimethylamine hydrochloride (1.0 g, 22 mmol) were added. The mixture was stirred at 120 ° C. for 16 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water then brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (PE / EtOAc = 6/1) to give 2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolo [2,3-d ] Pyrimidine (CXXVII, 800 mg, 76%) was obtained as a yellow solid. LCMS (ESI) m / z = 234 (M + H) ⁺ .

2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVIII)
2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXVII, 800 mg, 3.4 mmol) in EtOAc (30 mL) in 10% Pd / C (1.0 g ) And AcOH (3 mL) were added and the mixture was attached to a hydrogenator. The system was evacuated and then refilled with hydrogen. The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (EtOAc / MeOH = 25/1) to give 2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] Pyrimidine (CXXVIII, 600 mg, 75%) was obtained as a yellow solid.

2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXIX)
2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXVIII, 600 mg, 2.6 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (5.2 mL ) And lyophilized the solution to give 2- (n-propyl) amino-4-dimethylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXIX, 600 mg) as a yellow solid It was.

Example 69:
2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXXI)
Example 70:
2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXXII)

2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXXI)
2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXX) (2.0 g, 9.13 mmol) in EtOAc (50 mL) in 10% Pd / C ( 2.1 g) and AcOH (8 mL) were added and the mixture was attached to a hydrogenator. The system was evacuated and refilled with hydrogen. The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (DCM / MeOH = 60/1 → 10/1) to give 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2, 3-d] pyrimidine (CXXXI, 700 mg, 43%) was obtained as a yellow solid.

2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXXII)
2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (CXXX, 700 mg, 3.2 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (7 mL) And the solution was lyophilized to give 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine (717 mg) as a brown solid.

Example 71:
2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine (CXXXVI)
Example 72:
2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXXVII)

2- (t-Butyl-dimethylsilyl) amino-4-chloro-7-i-propyl-pyrrolo [2,3-d] pyrimidine (CXXXIII)
2- (t-Butyl-dimethylsilanyl) amino-4-chloro-7H-pyrrolo [2,3-d] pyrimidine (CXXII) (5 g, 17.7 mmol), 2-iodopropane (4.5) in DMF (20 mL). g, 26.6 mmol) and K ₂ CO ₃ (4.3 g, 26.6 mmol) were reacted at ambient temperature for 15 hours. After adding H ₂ O (50 mL) to the reaction mixture, the aqueous solution was extracted with EtOAc (300 mL) and the organic layer was washed with brine solution (50 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / EtOAc = 10/1 → 5/1) to give 2- (t-butyl-dimethylsilyl) amino-4-chloro-7-i- Propyl-pyrrolo [2,3-d] pyrimidine (CXXXIII, 5.7 g, 100%) was obtained as a pale yellow oil. LCMS: (ESI) m / z = 325 (M + H) ⁺ .

2- (n-propyl) amino-4-chloro-7-i-propyl-pyrrolo [2,3-d] pyrimidine (CXXXIV)
2- (t-butyl-dimethylsilanyl) amino-4-chloro-7-i-propyl-pyrrolo [2,3-d] pyrimidine (5.7 g, 17.6 mmol) and 1-iodopropane (4.5) under nitrogen atmosphere g, 26.4 mmol) was dissolved in DMF (20 mL). The reaction mixture was cooled to 0 ° C. with vigorous stirring and NaH (60% dispersion in mineral oil 1.06 g, 26.4 mmol) (60%) was added. After the mixture was stirred for 10 minutes, water (50 mL) was slowly added to quench the reaction. The mixture was extracted with EtOAc (300 mL) and the organic layer was washed with water (50 mL) then brine solution (50 mL) and finally dried over anhydrous Na ₂ SO ₄ . After evaporation of the solvent, a yellow oily residue was isolated (6.5 g). The residue was dissolved in Et ₂ O (50 mL), concentrated hydrochloric acid (10 mL) was added at 0 ° C. with stirring, and the mixture was stirred for an additional 10 minutes. After the reaction was complete, the solution was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was washed with H ₂ O (150 mL) then brine solution (150 mL) and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography (PE / EtOAc = 10/1 → 5/1) to give 2- (n-propyl) amino-4-chloro-7-i-propyl-pyrrolo [ 2,3-d] pyrimidine (CXXXIV, 4.5 g, 100%) was obtained as a yellow solid. LCMS (ESI) m / z = 253 (M + H) ⁺ .

2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolo [2,3-d] pyrimidine (CXXXV)
2- (n-Propyl) amino-4-chloro-7-i-propyl-pyrrolo [2,3-d] pyrimidine (CXXXIV, 3.0 g, 12 mmol) in n-butanol (10 mL) to propan-2-amine ( 1.05 g, 18 mmol) and potassium carbonate (2.5 g, 18 mmol) were added. The resulting mixture in an autoclave equipped with a stirrer was stirred at 140 ° C. for 16 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water then brine solution and dried over anhydrous Na ₂ SO ₄ . After removing the solvent under reduced pressure, the residue was purified by flash column chromatography (PE / EtOAc = 5/1 → 3/1) to give 2- (n-propyl) amino-4- (i-propyl) amino-7- i-Propyl-pyrrolo [2,3-d] pyrimidine (CXXXV, 1.2 g, 36%) was obtained as a yellow solid. LCMS: (ESI) m / z = 276 (M + H) ⁺ .

2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine (CXXXVI)
2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolo [2,3-d] pyrimidine (1.0 g, 3.6 mmol) in EtOAc (10 mL) in 10% Pd / C (1.0 g) and AcOH (2.43 g, 40 mmol) were added. The mixture was attached to a hydrogenator. The system was evacuated and refilled with hydrogen gas. The mixture was stirred at ambient temperature for 48 hours and filtered through 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (DCM / MeOH = 100/1 → 20/1) to give 2- (n-propyl) amino-4- (i-propyl) amino-7-i- Propyl-pyrrolidino [2,3-d] pyrimidine (CXXXVI) (800 mg, 79%) was obtained as a yellow solid.

2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CXXXVII)
2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolo [2,3-d] pyrimidine (200 mg, 0.72 mmol) in H ₂ O (10 mL) and 0.5 M HCl Dissolve in aqueous solution (1.5 mL) and then freeze-dry the solution to give 2- (n-propyl) amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine The hydrochloride salt (225 mg, 95%) was obtained as a yellow solid.

Example 73: N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CXLI)
Example 74: N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXLII)

2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo [2,3d] pyrimidine (CXXXVIII)
To a solution of 2,4-diamino-6-hydroxypyrimidine (50 g, 397 mmol) in H ₂ O (750 mL) was added 2-chloroacetaldehyde (40% in H ₂ O, 85 g, 437 mmol) dropwise at 0 ° C. The mixture was stirred at 65 ° C. for 2 hours and then heated at 100 ° C. until the reaction was complete. The resulting solid was filtered and the residue was heated to reflux in EtOH (750 mL). Further solids were filtered and the mother liquor was concentrated to give 2-amino-4-oxo-4,7-dihydro-3H-pyrrolo [2,3d] pyrimidine (CXXXVIII) as a yellow solid 40 g (about 67%, purity about 70% ). LCMS (ESI) m / z = 151 (M + H) ⁺ .

2-Amino-4-chloro-7H-pyrrolo [2,3d] pyrimidine (CXXXIX)
2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo [2,3d] pyrimidine (CXXXVIII, 25 g, 167 mmol) was suspended in POCl ₃ (200 mL) and cooled in an ice bath. The mixture was allowed to warm slowly and heated to 120 ° C. for 3 hours. After this time, volatiles (excess POCl ₃ ) were evaporated under reduced pressure. Ice water (200 mL) was added to the residue, and the resulting solid was filtered to give 2-amino-4-chloro-7H-pyrrolo [2,3d] pyrimidine (CXXXIX) as a yellow solid (20 g, about 71%, purity about 75%). LCMS (ESI) m / z = 169 (M + H) ⁺ .

4-Chloro-2-n-propylamino-7H-pyrrolo [2,3d] pyrimidine (CXL)
AcOH (50 mL) was added to a solution of 2-amino-4-chloro-7H-pyrrolo [2,3d] pyrimidine (CXXXIX, 26 g, 155 mmol) and n-propionaldehyde (27 g, 464 mmol) in MeOH (600 mL). The reaction was stirred at ambient temperature for 30 minutes. After this time, NaBH ₃ CN (49 g, 775 mmol) was added in portions at −20 ° C. for 30 minutes. The resulting mixture was stirred at 80 ° C. for 3 hours to remove volatiles. The resulting residue was extracted with EtOAc (3 × 300 mL) and the combined organics were washed with brine solution (2 × 100 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc (5/1)) to give 4-chloro-2-n-propylamino-7H-pyrrolo [2, 3d] pyrimidine (CXL) was obtained as a yellow solid (6 g, 18%). LCMS (ESI) m / z = 211 (M + H) ⁺ .

N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CXLI)
4-Chloro-2-n-propylamino-7H-pyrrolo [2,3d] pyrimidine (CXL, 1.0 g, 4.8 mmol) in n-BuOH (5 mL) was added potassium carbonate (3.3 g, 5.0 eq) and N, O-dimethylhydroxylamine hydrochloride (1.1 g, 4.0 eq) was added. The mixture was stirred at 100 ° C. for 8 hours in an autoclave equipped with a stirrer. After cooling to ambient temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water then brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 5/1) to give N- (2-n-propylamino-7H-pyrrolo [2,3d] pyrimidine-4. -Yl) -N, O-dimethyl-hydroxylamine (CXLI, 500 mg, 45%) was obtained.

N- (2-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CXLII)
N- (2-n-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CXLI, 500 mg, 2.1 mmol) with H ₂ O (10 mL) and 0.5 Dissolved in M HCl aqueous solution (5 mL). The solution was then lyophilized to give N- (2-n-propylamino-7H-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride as a white solid (CXLII, 550 mg).

Example 75: 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine (CXLIX)
Example 76: 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine hydrochloride (CL)

5-Allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII)
To cold anhydrous EtOH (200 mL) and NaOEt (30% in ethanol) (200 mL) was added guanidine hydrochloride (27 g, 0.28 mol) and the mixture was stirred at 0 ° C. for 10 min. This was followed by the addition of diethyl allylmalonate (55 g, 0.28 mol). The reaction mixture was then stirred at room temperature for 18 hours. Acidification with 3N HCl precipitated the crude product (pH = 6). The solid was collected by filtration and washed with ethanol. Recrystallization from water gave 29 g (62%) of pure 5-allyl-2-amino-4,6-dihydroxypyrimidine (CXLIII). LCMS (ESI) m / z = 168 (M + H) ⁺ .

5-Allyl-2-amino-4,6-chloropyrimidine (CXLIV)
To a solution of PCl ₅ (6.6 g, 29.5 mmol) in POCl ₃ (180 mL), 5-allyl-2-amino-4,6-dihydroxypyrimidine (4.9 g, 28.0 mmol) was added little by little at 60 ° C., and diethylaniline (3 g ) Was added dropwise. The temperature was raised to 120 ° C. The reaction mixture was heated to reflux overnight and then evaporated to dryness. Hot water (100 ° C.) (100 mL) was slowly added to the residue and the resulting suspension was cooled and extracted with CH ₂ Cl ₂ ( ₂ × 100 mL). The combined organic layers were washed 3 times with cold water until the aqueous extract was above pH = 5. The organic layer was dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / petroleum ether = 1: 10) to give 5-allyl-2-amino-4,6-chloropyrimidine (CXLIV, 2.5 g, 42%). LCMS (ESI) m / z = 204 (M + H) ⁺ .

2- (2-Amino-4,6-chloropyrimidin-5-yl) ethanal (CXLV)
5-Allyl-2-amino-4,6-chloropyrimidine (1 g, 4.9 mmol) was dissolved in ethyl acetate (40 mL) and reacted with ozone gas at −78 ° C. for about 1 hour (rate about 1 L / min about 5 %ozone). The reaction was monitored by TLC (petroleum ether / AcOEt = 3/1 (v / v)) and when the starting material was consumed, the reaction mixture was flushed with oxygen for 10 minutes. At this point, NaI (3 g) and glacial acetic acid (3 mL) were added simultaneously to the cold reaction mixture and the temperature was raised to 20 ° C. over 60 minutes with continuous stirring. Sodium thiosulfate solution (67 g / H ₂ O 100 mL) was added to it until the reaction mixture became colorless. The resulting mixture was diluted with water (30 mL) and extracted with CH ₂ Cl ₂ (4 × 70 mL). The combined organic extracts were washed successively with H ₂ O (4 × 30 mL), saturated NaHCO ₃ solution (30 mL) and brine solution (30 mL) and finally dried over anhydrous Na ₂ SO ₄ . After filtration and evaporation, 2- (2-amino-4,6-chloropyrimidin-5-yl) ethanal (CXLV, 1.1 g, 87%) was isolated as a white solid with a purity of about 80%. LCMS (ESI) m / z = 207 (M + H) ⁺ .

2-Amino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] pyrimidine (CXLVI)
2- (2-amino-4,6-chloropyrimidin-5-yl) ethanal (CXLV, 1.2 g, 5.8 mmol) and para-methoxybenzylamine (PMBNH ₂ ) (1.6 g, 11.6 mmol) in THF (20 mL) And AcOH (2 mL) solution was stirred at ambient temperature for 30 min. To this mixture was added NaBH (OAc) ₃ (6.2 g, 29 mmol) little by little and the reaction was stirred overnight. The mixture was concentrated under reduced pressure and extracted with EtOAc (3 × 80 mL). The combined organic extracts were then washed with brine solution (2 × 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 10/1) to give 2-amino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] pyrimidine ( CXLVI, 950 mg, 52%) was obtained as a yellow solid (52%). LCMS (ESI) m / z = 291 (M + H) ⁺ .

2-n-propylamino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] pyrimidine (CXLVII)
2-Amino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] pyrimidine (CXLVI, 950 mg, 3.3 mmol) and propionaldehyde (575 mg) in MeOH (30 mL) and AcOH (3 mL) 16.5 mmol) at ambient temperature for 30 minutes. At this point, NaBH ₃ CN (1.0 g, 16.5 mmol) was added in portions and the reaction was heated at 85 ° C. for 16 hours. After cooling, the mixture was evaporated and extracted with EtOAc (2 × 50 mL). The combined organics were then washed with brine solution (2 × 50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (PE / EtOAc = 10/1) to give 2-n-propylamino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] Pyrimidine (CXLVII, 920 mg, 85%) was obtained. LCMS (ESI) m / z = 333 (M + H) ⁺ .

2-n-propylamino-4-chloro-7H-pyrrolidino [2,3-d] pyrimidine (CXLVIII)
A solution of 2-n-propylamino-4-chloro-7- (4-methoxy) benzyl-pyrrolidino [2,3-d] pyrimidine (CXLVII, 920 mg, 3.2 mmol) in TFA (5 mL) was heated at 85 ° C. for 3 hours did. After cooling, the mixture was evaporated and extracted with EtOAc (2 × 50 mL). The combined organics were washed with brine solution (2 × 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 5/1) to give 2-n-propylamino-4-chloro-7H-pyrrolidino [2,3-d] pyrimidine (CXLVIII, 500 mg, 85%) was obtained as a colorless solid. LCMS (ESI) m / z = 213 (M + H) ⁺ .

2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine (CXLIX)
2-n-propylamino-4-chloro-7H-pyrrolidino [2,3-d] pyrimidine (CXLVIII, 500 mg, 2.38 mmol) is dissolved in n-butanol (5 mL) and potassium carbonate (1.64 g, 5.0 eq) And propan-1-amine (923 mg, 4.0 eq) were added. The mixture was stirred at 100 ° C. for 72 hours in an autoclave equipped with a stirrer. After cooling to room temperature, 20 mL of water was added and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water and brine solution and dried over anhydrous Na ₂ SO ₄ . After removing the solvent under reduced pressure, the resulting residue was purified by preparative HPLC to give 2-n-propylamino-4-chloro-7H-pyrrolidino [2,3-d] pyrimidine (CXLIX, 210 mg, 37% yield) Got.

2,4-Bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine hydrochloride (CL)
2-n-propylamino-4-chloro-7H-pyrrolidino [2,3-d] pyrimidine (CXLIX, 210 mg, 0.89 mmol) was dissolved in H ₂ O (5 mL) and 0.5 M aqueous HCl (2.0 mL), The solution was lyophilized to give 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d] pyrimidine hydrochloride (CL, 242 mg, 95% yield) as an orange solid.

Example 77:
2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine (CLII)
Example 78:
2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CLIII)

2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolo [2,3-d] pyrimidine (CLI)
n-Butanol (10 mL) to 2- (n-propyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIV) (1.6 g, 7.1 mmol) followed by potassium carbonate (4.9 g, 35.5 mmol) and piperidin-4-ol hydrochloride (632 mg, 10.7 mmol) were added. The mixture was stirred at 130 ° C. for 16 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water then brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether / EtOAc = 3/1) to give 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7- Methyl-pyrrolo [2,3-d] pyrimidine (1.2 g, 75%) was obtained as a yellow solid. LCMS (ESI) m / z = 290 (M + H) ⁺ .

2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine (CLII)
To a solution of 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolo [2,3-d] pyrimidine (CLI, 1.0 g, 4 mmol) in EtOAc (50 mL) 10% Pd / C (1.0 g) and AcOH (2.43 g, 40 mmol) were added. The mixture was attached to a hydrogenator. The system was evacuated and refilled with hydrogen gas. The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (DCM / MeOH = 50/1 → 10/1) to give 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl)- 7-methyl-pyrrolidino [2,3-d] pyrimidine (CLII, 500 mg, 50% yield) was obtained as a yellow solid.

2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine hydrochloride (CLIII)
2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine (CLII, 500 mg, 2 mmol) in H ₂ O (10 mL), And 0.5M HCl solution in H ₂ O (4 mL) and the solution lyophilized to give 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [ 2,3-d] pyrimidine hydrochloride (525 mg) was obtained as a yellow solid.

Example 79
8- (7-Methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLV)
Example 80
8- (7-Methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol hydrochloride (CLVI)

8- (7-Methyl-2- (n-propylamino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLIV)
2- (n-propyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIV) (1.0 g, 4.5 mmol) in n-butanol (10 mL) in DIPEA (1.0 g, 7.8 mmol) and 8-aza-bicyclo [3.2.1] octan-3-ol hydrochloride (1.1 g, 6.7 mmol) were added. The mixture was stirred at 125 ° C. for 16 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water then brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 6/1) to give 8- (7-methyl-2- (n-propylamino) -7H-pyrrolo [2 , 3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLIV) (800 mg, 57% yield) was obtained as a yellow solid. LCMS (ESI) m / z = 316 (M + H) ⁺ .

8- (7-Methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLV)
2- (n-propyl) amino-4- (4-hydroxy-1-aza-bicyclo [3.2.1] octan-1-yl) -7-methyl-pyrrolo [2,3-d] pyrimidine (CLIV, 1.00 g, 3.2 mmol) in EtOAc (10 mL) was added 10% Pd / C (1.0 g) and AcOH (3 mL). The mixture was attached to a hydrogenator. The system was evacuated and refilled with hydrogen. The mixture was stirred at ambient temperature for 48 hours. The mixture was filtered through 10 g of silica gel on a glass filter. The filtrate was concentrated and the residue was purified by flash column chromatography (EtOAc / MeOH = 50/1) to give 8- (7-methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidine- 4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLV) (500 mg, 49% yield) was obtained as a yellow solid.

8- (7-Methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol hydrochloride (CLVI)
8- (7-Methyl-2- (n-propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol (CLV, 200 mg, 0.63 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (1.3 mL), and the solution was lyophilized to give 8- (7-methyl-2- (n-propylamino) -pyrrolidino [2,3- d] Pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol hydrochloride (CLVI) (224 mg) was obtained as a yellow solid.

Example 81:
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLVIII)
Example 82:
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CLIX)

2- (propen-2-yl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CLVII)
2- (t-Butyl-dimethylsilanyl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CXXIII) (7.5 g, 25 mmol) dissolved in DMF (100 ml) under nitrogen atmosphere 3-iodoprop-1-ene (6.38 g, 38 mmol) was added. After the mixture was cooled to 0 ° C. with vigorous stirring, NaH (60% dispersion in mineral oil 1.5 g, 38 mmol) was added. The mixture was stirred for 30 minutes and the reaction was quenched by the slow addition of water (50 mL). The aqueous mixture was extracted with EtOAc (300 mL) and the organic layer was washed with water (100 mL) then brine solution (100 mL) and dried over anhydrous Na ₂ SO ₄ . After evaporation, 8.6 g of a yellow oily residue was isolated. This material was dissolved in Et ₂ O (100 mL) and concentrated hydrochloric acid (20 mL) was added at 0 ° C. with stirring. The mixture was then stirred for an additional 10 minutes. The mixture was extracted with EtOAc (200 mL) and 1N NaOH (200 mL). The organic layer was separated, washed with H ₂ O (150 mL) and brine solution (150 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 10/1 → 5/1) to give 2- (propen-2-yl) amino-4-chloro-7- Methyl-pyrrolo [2,3-d] pyrimidine (6 g, 100% yield) was obtained as a yellow solid. LCMS: (ESI) m / z = 223 (M + H) ⁺ .

N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLVIII)
2- (propen-2-yl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CLVII, 500 mg, 2.38 mmol) to n-butanol (5 mL), potassium carbonate (1.64 g, 5.0 eq.) And N, O-dimethylhydroxylamine hydrochloride (923 mg, 4.0 eq.) Were added. The mixture was stirred at 100 ° C. for 8 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water and brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was then evaporated under reduced pressure and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 3/1) to give N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLVIII, 310 mg, 55% yield) was obtained.

N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CLIX)
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (310 mg, 1.32 mmol) was added to H ₂ O ( 5 mL) and 0.5 M aqueous HCl (2.7 mL), and the solution was lyophilized to give N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl ) -N, O-dimethyl-hydroxylamine hydrochloride (CLIX, 325 mg) was obtained as a white solid.

Example 83:
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (CLX)
Example 84:
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine hydrochloride (CLXI)

N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (CLX)
2- (2-propen-2-yl) amino-4-chloro-7-methyl-pyrrolo [2,3-d] pyrimidine (CLVII) (700 mg, 3.15 mmol) was dissolved in n-butanol and potassium carbonate ( 2.2 g, 5.0 eq) and O-methylhydroxylamine hydrochloride (768 mg, 4.0 eq) were added. The mixture was stirred at 100 ° C. for 12 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water and brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 5/1) to give N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2 , 3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (370 mg, 46% yield) was obtained.

N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine hydrochloride (CLXI)
N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (370 mg, 1.59 mmol) in H ₂ O (5 mL) And 0.5M HCl aqueous solution (2 mL) and the solution is lyophilized to give N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O -Methyl-hydroxylamine hydrochloride (383 mg) was obtained as a white solid.

Example 85:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLXII)
Example 86:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine hydrochloride (CLXIII)

N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine (CLXII)
The desired compound was prepared from 4-chloro-2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidine and N, O-dimethyl-hydroxylamine as described in Example 73.

Example 87:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (CLXIV)
Example 88:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine hydrochloride (CLXV)

N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine (CLXIV)
The desired compound was prepared from 4-chloro-2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidine and O-methyl-hydroxylamine as described in Example 73.

Example 89:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVI)
Example 90:
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXVII)

N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVI)
Hydrazine (14 mL) is added to a solution of 4-chloro-2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidine (CXXIV, 1.0 g, 4.5 mmol) in ethanol (70 mL) and the mixture is heated for 3 hours. Refluxed. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (CH ₂ Cl ₂ / MeOH = 30/1) to give N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVI, 1.0 g, yield 80%) was obtained.

N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXVII)
N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (460 mg, 2.0 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (4 mL) Upon dissolution, the solution was lyophilized to give N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (440 mg) as a brown solid.

Example 91:
N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVIII)
Example 92
N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXIX)

N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVIII)
4-Chloro-2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidine (CXXIV, 800 mg, 3.42 mmol) in n-butanol (5 mL) in potassium carbonate (2.36 g, 5.0 eq) and methyl Hydrazine (630 mg, 4.0 eq) was added. The mixture was stirred at 100 ° C. for 15 hours in an autoclave equipped with a stirrer. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water and brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (petroleum ether / EtOAc = 3/1 → DCM / MeOH = 10/1) to give N-methyl-N- (2-n-propylamino). -7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXVIII, 220 mg, 36% yield) was obtained.

N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXIX)
N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (220 mg, 0.94 mmol) in H ₂ O (10 mL) and 0.5 M aqueous HCl (2 mL) and the solution was lyophilized to give N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXIX, 238 mg) was obtained as a brown solid.

Example 93
N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXX)
Example 94:
N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXXI)

N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXX)
4-Chloro-2-n-propylamino-7-methyl-pyrrolo [2,3d] -pyrimidine (1.1 g, 5 mmol) and 1,1-dimethylhydrazine (450 mg, 7.5 mmol) in dioxane (30 mL) in xphos (622 mg, 1 mmol), Pd ₂ (dba) ₃ (458 mg, 0.5 mmol) and Cs ₂ CO ₃ (2.45 g, 7.5 mmo) were added. The solution was degassed by bubbling argon through the solution for 10 minutes using a syringe needle. The mixture was then stirred at 80 ° C. for 2 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water and brine solution and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography (DCM / MeOH = 30/1 → 5/1) to give N, N-dimethyl-N ′-(2-n-propylamino-7 -Methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (CLXX, 100 mg, yield 8%, purity about 85%) was obtained.

N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine hydrochloride (CLXXI)
N, N-dimethyl-N ′-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine (100 mg, 0.4 mmol) in H ₂ O (5 mL) and 0.5 Dissolve in aqueous M HCl (1 mL) and freeze-dry the solution to N, N-dimethyl-N '-(2-n-propylamino-7-methyl-pyrrolo [2,3-d] pyrimidin-4-yl ) -Hydrazine hydrochloride (110 mg) was obtained as a yellow oil.

圧力管に2-クロロ-N-(4,6-ビス-(n-プロピルアミノ)-[1,3,5-トリアジン(XXXIV)(1.50g、6.53mmol)、N,N-ジイソプロピルエチルアミン(5.4mL、32.65mmol)、メチルアミン塩酸塩(2.2g、32.65mmol)およびテトラヒドロフラン(20mL)を加えた。反応混合物を70℃で48時間加熱した。さらなる量のN,N-ジイソプロピルエチルアミン(5.4mL、32.65mmol)およびメチルアミン塩酸塩(2.2g、32.65mmol)を加え、反応混合物を70℃でさらに48時間加熱した。混合物を飽和NaHCO₃溶液(40mL)に注いだ。懸濁液をEtOAc(3x70mL)で抽出した。一緒にした有機抽出物を水(70mL)、次にブライン溶液(70mL)で洗浄し、最後に無水Na₂SO₄で乾燥させた。溶媒を減圧除去し、石油エーテル/EtOAc(9:1(v/v))から石油エーテル/EtOAc(1:4(v/v))までの勾配溶離を使用するフラッシュカラムクロマトグラフィーで粗生成物を精製してN-(2,4-ビス-n-プロピルアミノ)-N-(6-メチルアミノ)-[1,3,5]トリアジン(0.35g、24%)を得た。

Example 95:
N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII)

2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5-triazine (XXXIV) (1.50 g, 6.53 mmol), N, N-diisopropylethylamine (5.4 mL, 32.65 mmol), methylamine hydrochloride (2.2 g, 32.65 mmol) and tetrahydrofuran (20 mL) were added and the reaction mixture was heated for 48 hours at 70 ° C. An additional amount of N, N-diisopropylethylamine (5.4 mL, 32.65 mmol) and methylamine hydrochloride (2.2 g, 32.65 mmol) were added and the reaction mixture was heated for a further 48 hours at 70 ° C. The mixture was poured into saturated NaHCO ₃ solution (40 mL) The suspension was EtOAc (3 × 70 mL). The combined organic extracts were washed with water (70 mL), then brine solution (70 mL) and finally dried over anhydrous Na ₂ SO _{4. The} solvent was removed in vacuo and petroleum ether / EtOAc. The crude product was purified by flash column chromatography using gradient elution from (9: 1 (v / v)) to petroleum ether / EtOAc (1: 4 (v / v)) to give N- (2,4 -Bis-n- Ropiruamino)-N-(6- methylamino) - [1,3,5] triazine (0.35 g, to obtain a 24%).

Example 96:
N- (2,4,6-Tris-n-propylamino)-[1,3,5] triazine (CLXXIII)
Example 97
N- (2,4,6-Tris-n-propylamino)-[1,3,5] triazine hydrogensulfate (CLXXIV)

N- (2,4,6-Tris-n-propylamino)-[1,3,5] triazine (CLXXIII)
2-Chloro-N- (4,6-bis- (n-propylamino)-[1,3,5-triazine (XXXIV) (1.00 g, 4.35 mmol), NaOH (348 mg, 8.70 mmol) and n-propyl A mixture of amine (1.4 mL, 17.40 mmol) in 1,4-dioxane (40 mL) was heated for 4 h at 60 ° C. The volatiles were then removed under reduced pressure, water (50 mL) was added to the residue and the mixture was added EtOAc ( The combined organic extracts were washed with water (50 mL), then with brine solution (50 mL) and finally dried over anhydrous Na ₂ SO _{4. The} solvent was removed under reduced pressure and CH ₂ Cl _The residue was purified by flash column chromatography using gradient elution from ₂ / EtOH (99: 1 (v / v)) to CH ₂ Cl ₂ / EtOH (97: 3 (v / v)) to give N- ( 2,4,6-Tris-n-propylamino)-[1,3,5] triazine (790 mg, 72%) was obtained.

N- (2,4,6-Tris-n-propylamino)-[1,3,5] triazine hydrogensulfate (CLXXIV)
The title compound was obtained in quantitative yield from N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine and 95% H ₂ SO ₄ as described in Example 8A. Prepared.

Example 98:
N- (2,4,6-Tris-n-propylamino) -1,3-pyrimidine (CLXXIV)
Example 99:
N- (2,4,6-Tris-n-propylamino) -1,3-pyrimidine hydrogensulfate (CLXXVI)

N- (2,4,6-Tris-n-propylamino) -1,3-pyrimidine (CLXXIV)
4-Chloro-2,6-bis- (Nn-propylamino) -1,3-pyrimidine (CXIX) (1.53 g, 6.65 mmol), n-propylamine (2.7 mL, 33.25 mmol), N, N-diisopropylethylamine (2.3 mL, 13.30 mmol) and pyridine (15 mL) were added. The reaction mixture was heated at 130 ° C. for 48 hours. Volatiles were removed in vacuo. Water (50 mL) was added to the residue and the mixture was extracted with CH ₂ Cl ₂ (3 × 50 mL). The combined organic extracts were washed with water (100 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed in _{vacuo, CH 2 Cl 2 / EtOH (} 99: 1 (v / v)) from _{CH 2 Cl 2 / EtOH (95} : 5 (v / v)) to flash column chromatography using a gradient elution of The residue was purified by to give N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine (0.90 g, 54%).

N- (2,4,6-Tris-n-propylamino) -1,3-pyrimidine hydrogensulfate (CLXXVI)
The title compound was prepared in quantitative yield from N- (2,4,6-tris-n-propylamino) -1,3-pyrimidine and 95% H ₂ SO ₄ as described in Example 8A.

Example 100:
N- (4-i-propylamino) -N- (2,6-bis-n-propylamino) -1,3-pyrimidine (CLXXVII)
Example 101:
N- (4-i-propylamino) -N- (2,6-bis-n-propylamino) -1,3-pyrimidine hydrogensulfate (CLXXVIII)

N- (4-i-propylamino) -N- (2,6-bis-n-propylamino) -1,3-pyrimidine (CLXXVII)
The title compound was prepared from 4-chloro-2,6-bis- (Nn-propylamino) -1,3-pyrimidine (CXIX) and i-propylamine in 16% yield as described in Example 98. .

N- (4-i-propylamino) -N- (2,6-bis-n-propylamino) -1,3-pyrimidine hydrogensulfate (CLXXVIII)
Quantitatively from N- (4-i-propylamino) -N- (2,6-bis-n-propylamino) -1,3-pyrimidine and 95% H ₂ SO ₄ as described in Example 8A The title compound was prepared in yield.

N-(4,6-ビス(プロピルアミノ)-1,3,5-トリアジン-2-オール(CLXXVIII)
バイアルに6-クロロ-N²,N⁴-ジプロピル-1,3,5-トリアジン-2,4-ジアミン(XXXIV)(800mg、3.48mmol)、NaOH(696mg、17.40mmol)、水(3mL)および1,4-ジオキサン(3mL)を加えた。反応混合物をマイクロ波照射下にて140℃で30分間加熱した。混合物を1N HClでpH 5に酸性化し、析出物を濾過し、水で洗浄した。生成物を50%トリフルオロ酢酸(30mL)に溶解させ、未溶解残渣を濾去した。濾液を飽和NaHCO₃溶液で中和し、形成された析出物を濾過し、水、アセトンで洗浄し、乾燥させて4,6-ビス(プロピルアミノ)-1,3,5-トリアジン-2-オール(CLXXVIII)550mg(75%)を得た。

Comparative Example 1:

N- (4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII)
The vial 6-Chloro -N ^2, N ⁴ - dipropyl-1,3,5-triazine-2,4-diamine (XXXIV) (800mg, 3.48mmol) , NaOH (696mg, 17.40mmol), water (3 mL) and 1,4-Dioxane (3 mL) was added. The reaction mixture was heated at 140 ° C. for 30 minutes under microwave irradiation. The mixture was acidified with 1N HCl to pH 5 and the precipitate was filtered and washed with water. The product was dissolved in 50% trifluoroacetic acid (30 mL) and the undissolved residue was removed by filtration. The filtrate was neutralized with saturated NaHCO ₃ solution and the precipitate formed was filtered, washed with water, acetone and dried to give 4,6-bis (propylamino) -1,3,5-triazine-2- All (CLXXVIII) 550 mg (75%) was obtained.

主要断片(M+H) 170, 128, 86。 N- (4,6-bis (propylamino) -1,3,5-triazin-2-ol hydrogen sulfate (CLXXIX)
To a suspension of 4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII) (110 mg, 0.52 mmol) in 1,4-dioxane (2 mL) was added 95% H ₂ SO ₄ ( 28 μL, 0.52 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The resulting precipitate was filtered, washed with Et ₂ O and dried to quantitatively collect 4,6-bis (propylamino) -1,3,5-triazin-2-ol hydrogen sulfate (CLXXIX). Obtained at a rate.

Major fragment (M + H) 170, 128, 86.

Example 102:
(XXXVI) Preparation of salt form A (Figure 1) Method A:
A solution of 1 molar equivalent of concentrated sulfuric acid in ethanol (XXXV) (about 151 mg / mL, clear solution) in ethyl acetate at ambient temperature was added. The clear solution was stirred at ambient temperature for about 1 day (clear) and then 6 volume equivalents of isopropyl ether (relative to ethyl acetate) was added to give a turbid mixture. The mixture was stirred for 3 days and then filtered to obtain a solid product (hydrogen sulfate salt form A).

Method B:
1 molar equivalent of concentrated sulfuric acid was added in methyl ethyl ketone (about 104 mg / mL, clear solution) at about 65 ° C. Immediately formed precipitates were quickly redissolved. The mixture was stirred at about 65 ° C. for about 5 hours and slowly cooled to ambient temperature over about 1 hour. The mixture was stirred at ambient temperature for 1 day and then filtered to give a solid product (61% yield) (hydrogen sulfate salt form A).

Method C:
1 molar equivalent of concentrated sulfuric acid was added to (XXXV) (about 100 mg / mL, clear solution) in methyl ethyl ketone at about 65 ° C. Immediately formed precipitates were quickly redissolved. The mixture was stirred at about 65 ° C. for about 1 hour and slowly cooled to ambient temperature over 1 hour to give a solid in the form of a rod. The mixture was stirred at ambient temperature for about 4 hours. 1 volume equivalent of heptane (relative to methyl ethyl ketone) was added and the mixture was stirred at ambient temperature for 1 day and then filtered to give a solid product (81% yield) (hydrogen sulfate form A).

Method D:
1 molar equivalent of concentrated sulfuric acid was added to (XXXV) (about 200 mg / mL, clear solution) in methyl ethyl ketone at about 69 ° C. Immediately formed precipitates were quickly redissolved. The mixture was stirred at about 69 ° C. for about 1 hour, quenched to ambient temperature, and stirred for about 0.5 hour to give a thick paste. The mixture was stirred in an ice bath for about 45 minutes and then filtered to collect the solid product (bisulfate form A).

Method E:
1 molar equivalent of concentrated sulfuric acid was added to (XXXV) (about 101 mg / mL, clear solution) in methyl ethyl ketone at about 67 ° C. The mixture was stirred at about 67 ° C. for about 1 hour and allowed to cool slowly to ambient temperature. After the mixture was stirred at ambient temperature for about 1.5 hours, 1 volume equivalent of methyl tert-butyl ether (based on methyl ethyl ketone) was added and the mixture was stirred for 1 day before being filtered to obtain a solid product (76% yield) (sulfuric acid Hydrogen salt form A) was collected.

Method F:
A 1 mol equivalent of concentrated sulfuric acid was added to (XXXV) (about 199 mg / mL, clear solution) in acetone at about 50 ° C. to form a clear solution. The mixture was stirred at about 50 ° C. for about 1 hour and allowed to cool slowly to ambient temperature, at which point a solid formed. To the mixture was added about 2 volume equivalents (based on methyl ethyl ketone) of methyl tert-butyl ether. The mixture was stirred at ambient temperature for 1 day and then filtered to collect the solid product (yield 79%) (hydrogen sulfate salt form A).

Example 103:
Preparation of a mixture of (XXXVI) salt form A and (XXXVI) salt form B 1 mol equivalent of concentrated sulfuric acid was added to (XXXV) (99 mg / mL, clear solution) in ethyl acetate at about 65 ° C. Concentrated suspension with a small amount of sticky material within 5 minutes. The mixture is stirred at about 65 ° C. for about 5 hours, slowly cooled to ambient temperature, stirred for 4 days, then filtered to collect the solid product of FIG. 23 (hydrogen sulfate form A as a mixture with form B). did.

Example 104:
(XXXVI) Preparation of salt form C
(XXXVI) Form A samples were exposed to ambient humidity 97% at ambient temperature for 4 days. The resulting solid form was called bisulfate form C. The resulting material under thermogravimetric analysis lost 4.6% by weight at about 30-50 ° C., which was consistent with about 1 molar equivalent of water (FIG. 24).

Example 105:
(XXXVI) Preparation of Salt Form D One mole equivalent of concentrated sulfuric acid was added to (XXXV) (about 100 mg / mL) in ethyl acetate at about 65 ° C. The sticky material precipitated immediately and additional solids were observed after about 5 minutes. These small solid samples were removed with a pipette and filtered without cooling. These solids were called bisulfate form D (Figure 25).

Example 106:
Preparation of a mixture of (XXXVI) salt form A and (XXXVI) salt form D 1 mol equivalent of concentrated sulfuric acid was added as a solution in isopropyl acetate to (XXXV) (203 mg / mL, clear solution) in isopropyl acetate at about 80 ° C. . A precipitate was formed. The mixture was stirred at about 80 ° C. for about 45 minutes, then slowly cooled to ambient temperature, stirred for 1 day, then filtered to obtain a solid product (83% yield), ie as a mixture with hydrogen sulfate Form D. Hydrogen sulfate salt form A (FIG. 26) was obtained.

Example 107:
Preparation of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine phosphate (CLXXX) Form A Acetonitrile at ambient temperature 2 molar equivalents of phosphoric acid were added to (XXXV). After the mixture was stirred for 2 days, the solid formed was filtered off and dried on the filter under a stream of nitrogen (phosphate form A; FIG. 27).

Example 108:
Preparation of (CLXXX) Form C 1 molar equivalent of phosphoric acid was added to (XXXV) (clear solution) in methanol at ambient temperature to obtain a clear solution. The vial containing the solution was placed in a sealed chamber with an isopropyl ether vial and the vapor was diffused to form a solid that was collected by filtration (phosphate form C, FIG. 28).

Example 109:
Preparation of a mixture of (CLXXX) Form A and (CLXXX) Form B 1 molar equivalent of phosphoric acid was added to (XXXV) (slurry) in acetonitrile at ambient temperature. A thick slurry was formed. The slurry was sonicated at ambient temperature for 3 days and then filtered to collect the solid product (phosphate form A as a mixture with form B, FIG. 29).

Example 110:
Preparation of a mixture of (CLXXX) Form C and (CLXXX) Form D 2 molar equivalents of phosphoric acid as a solution in ethanol was added to (XXXV) (clear solution) in ethyl acetate. A precipitate was formed. The mixture was further diluted with ethyl acetate and stirred for 3 days, then filtered to collect the solid product (mixture of phosphate form C and phosphate form D, FIG. 30).

Example 111:
Preparation of a mixture of (CLXXX) Form C and (CLXXX) Form E 3 molar equivalents of phosphoric acid were added to (XXXV) (clear solution) in tetrahydrofuran at ambient temperature. A precipitate was formed. The mixture was stirred at ambient temperature for 3 days and then filtered to collect the solid product (mixture of phosphate form C and phosphate form E, FIG. 31).

Example 112:
Effect of compound (XXXVI) on opioid-induced respiratory depression in rats
Rats pre-cannulated in the jugular vein (for drug administration) were acclimated to the plethysmography room for a minimum of 60 minutes or until the animals were not disturbing. Each animal was dosed with morphine sulfate (10 mg / kg) (supplied by Baxter Healthcare Corporation) dissolved in sterile water at a concentration of 10 mg / mL via injection into the jugular vein catheter over 5-10 seconds.

  Compound (XXXVI) was dissolved in 20% hydroxypropyl β-cyclodextran (20% bcd on the graph) at a concentration of 0.45 mg / mL at pH 5. After 5 minutes, compound (XXXVI) labeled Compound (A) was administered via jugular vein infusion at a dose of 0.10 mg / kg / min for 20 minutes, then at a dose of 0.30 mg / kg / min for 20 minutes ( (For example, in 20 μL / min / 0.3 kg rats producing 0.03 mpk / min).

  After an infusion of 20 minutes at this dose, the infusion pump was stopped and all animals were allowed a 20 minute recovery period before a post-study analysis on rat health and behavior. Minute ventilation data shows that compound (XXXVI) significantly reversed opioid-induced respiratory depression in rats compared to vehicle. The results are shown in Figure 1.

Example 113:
Effects of morphine and compound (XXXVI) on blood gases in rats
Rats pre-cannulated into jugular vein and femoral artery catheters (to administer drugs and obtain blood samples, respectively) were obtained from Harlan laboratories and held at the Galleon Pharmaceuticals animal facility until experimental procedures. Each animal received morphine sulfate (10 mg / kg) dissolved in saline at a concentration of 10 mg / ml via a 20-second injection into the jugular vein with a 20-second washout with 0.9% NaCl saline. Dosed. Prior to morphine administration, two 250 μL arterial blood samples were aspirated from the femoral artery and placed in a pre-heparinized syringe. Samples were analyzed on a Radiometer ABL Flex 800 and pO ₂ , pCO ₂ , pH, SaO ₂ and other parameters were recorded. To prevent blood volume loss, the aspirated volume of arterial blood was replaced with room temperature sterile saline (approximately 300 μL), and the sterile saline was slowly flushed back into the rodent femoral artery catheter. Morphine was then administered and another blood sample was taken 2 minutes later.

  Five minutes after administration of morphine, compound (XXXVI), labeled as compound (A), was administered at doses of 0.1, 0.3 and 1.0 mg / kg / min (dissolved in PBS buffer) via jugular vein infusion. Administered. The infusion started at t = 15 minutes and ended at t = 35 minutes. Arterial blood gas analysis was performed at t = 12, 18, 25, 35, 40, 45 and 50 minutes. The data show that compound (XXXVI) significantly reverses opioid-induced respiratory depression in rats compared to vehicle. The results are shown in FIGS. 2a and 2b and the accompanying Table 6.

(Table 6)

Example 114:
Effects of compound (XXXVI) on hypoxic ventilation response (HVR) and HVR in rats
Rats pre-cannulated in the jugular vein (for drug administration) were acclimated to the plethysmography room for a minimum of 60 minutes or until the animals were not disturbing. Each animal was dosed with Compound (XXXVI) labeled Compound (A) at 0.03 mg / kg / min for 50 minutes via infusion into the jugular vein catheter. After 20 minutes, an isocarbonic low oxygen mixture (12% O ₂ , residual N ₂ ) was charged into the whole room for 20 minutes using a gas mixer (CWE inc. GSM-3 gas mixer). Thereafter, the gas mixer was stopped and normal air was sent into the room. Ten minutes later, the infusion pump was turned off and all animals were allowed a 20 minute recovery period, followed by a post-study analysis of rat health and behavior. Minute ventilation data shows that compound (XXXVI) significantly enhances hypoxic ventilation response in rats compared to vehicle. The results are shown in Figure 3.

Example 115:
Effect of compound (XXXVI) on opioid-induced respiratory depression in monkeys Young macaques (4-year-old cynomolgus monkeys, 2-5 kg, n = 13) were used in the study. Animal husbandry was conducted under USDA guidelines and the protocol was approved by the Institutional Animal Care and Use Committee at East Carolina University.

Anesthesia was induced with 5% isoflurane and then maintained with 1.5-2% isoflurane (100% O2, ₂ L / min). The forearm vein was cannulated. Animals were equipped with Vivometrics Lifeshirts (Ventura, CA) to monitor respiratory function by inductance plethysmography. Abdominal and thorax deflections are calibrated by a Qualitative Diagnostic Calibration (QDC) procedure, and tidal volume is normalized to 15 mL representing typical tidal volume of these animals already measured using normal techniques Turned into. Heart rate was continuously monitored with a 3-lead ECG.

ETCO ₂ was measured via a neonatal nasal cannula connected to a microstream CO ₂ sensor (Cardell monitor, model 9405). SpO ₂ and HR were monitored by pulse oximetry using a reflectance probe (Nelcor Max-Fast) positioned inside the upper arm. HR was also determined from an ECG that allowed measurements when animal activity compromised the integrity of the pulse oximetry signal. BP was measured in anesthetized animals using a cuff positioned at the ankle.

Compound (XXXVI) was dissolved in 20% hydroxypropyl β-cyclodextran (HPBCD) and sterile filtered through a 2 μ syringe filter. Next, compound (XXXVI) labeled Compound (A) was delivered at a rate of 0.20 mg / kg / min for 5 minutes, and then the infusion rate was reduced to 0.10 mg / kg / min for 10 minutes. Minute ventilation and end-tidal CO ₂ were monitored. Delivery of naloxone HCl (0.05 mg / kg iv) reversed the morphine effect and terminated the experiment. The data showed that Compound (A) produced a complete reversal of the end-tidal carbon dioxide increase caused by opioids and further increased minute ventilation (Figure 4).

Example 116:
Dose-dependent effects of compounds (XXXVI) and (L) on minute ventilation (MV) in untreated rats All surgical procedures were performed under medical anesthesia induced by 2% isoflurane in compressed medical air . The rat was placed in a supine position and a catheter was inserted into the right femoral vein using a polyethylene tube (PE-50). This catheter was used for fluid and drug administration. At the same time, a catheter was also inserted into the right femoral artery to monitor blood pressure. To measure respiratory parameters in spontaneously breathing rats, the trachea was intubated using a 13 gauge endotracheal tube (inner diameter 2.5 mm, Instech Solomon, PA).

After establishing a stable baseline with 1.5% isoflurane, cumulative dose-dependent (0.01, 0.03, 0.1, 0.3) for compounds (XXXVI) and (L) labeled as Compound (A) and Compound (B), respectively. , 1, 3, 10 mg / kg) ventilatory responses were generated from spontaneously breathing rats. Maximum peak minute ventilation (MV) values at each dose of the corresponding drug were calculated and used to generate ED ₅₀ values. The results are shown in FIG. Compound (XXXVI) and (L) are both increased minute ventilation in a dose-dependent manner, ED ₅₀ calculated values were, respectively, 0.14 and 0.13 mg / kg.

Example 117:
Effect of Compound (CXXI) on Dose-Dependent Minute Ventilation (MV) in Untreated Rats According to the above procedure, compound (CXXI) labeled Compound (C) increases minute ventilation in a dose-dependent manner It was shown that The results are shown in FIG.

Example 118:
Effect of Compound (L) in Opioid Treated Rats According to the procedure of Example 6, compound (L), labeled as compound (B), increases pH, SaO ₂ and pO ₂ as shown in FIGS. 7A-7D And reducing pCO ₂ levels have been shown to reverse the effects of opioids on blood gas and pH in rats.

Example 119:
Effect of Compound (CXLII) in Opioid Treated Rats According to the procedure of Example 6, compound (CXLII), designated as compound (D), increases pO ₂ levels, as shown in FIGS. 8A-8D, (SaO ₂₎ increasing the oxygen saturation, by raising the and pH decrease the pCO ₂ levels were shown to reverse the effects of opioids on blood gases and pH in rats.

Example 120:
Effect of Compound (CXLII) on Opioid-Induced Respiratory Suppression in Rats According to the procedure of Example 5, compound (CXLII), designated as compound (D), was subject to minute ventilation (as determined by plethysmography) Increasing MV) has been shown to reverse opioid-induced respiratory depression in rats. The results are shown in FIG.

Example 121:
Effect of compounds on minute ventilation (MV) and cardiovascular parameters in untreated rats All surgical procedures were performed under anesthesia induced by 2% isoflurane in medical compressed air. The rat was placed in a supine position and a catheter was inserted into the right femoral vein using a polyethylene tube (PE-50). This catheter was used for fluid and drug administration. At the same time, the right femoral artery was also catheterized to monitor blood pressure and heart rate. To measure respiratory parameters in spontaneously breathing rats, the trachea was intubated using a 13 gauge endotracheal tube (inner diameter 2.5 mm, Instech Solomon, PA).

  After establishing a stable baseline with 1.5% isoflurane, the compound (typically a dose of 1 mpk) is administered intravenously and ventilation parameters from spontaneously breathing rats with cardiovascular output (mean arterial pressure (MAP) and heart rate). Created. Maximum peak minute ventilation (MV) response (MPR) was obtained as shown in the following table along with minute ventilation versus baseline change (DMV).

(Table 7)

(Table 8)

Example 122:
Effect of Compound (XXXVI) on Benzodiazepine-Induced Respiratory Inhibition (BIRD) It was.

Method:
Compound (XXXVI) dissolved in 20% hydroxypropyl-β-cyclodextran in sterile water and titrated to pH 4-8 using pH test paper and NaOH or HCl, clear and stable at a concentration of 1.5 mg / mL Solution was obtained. Other compounds: Morphine sulfate supplied as a 10 mg / ml solution (Baxter, Inc) and Midazolam supplied as a 5 mg / mL solution (Hospira, Inc.).

material:
Male Sprague-Dawley rats (Harlan, Inc.), 250-350 g upon dosing, prepared surgically using a jugular vein cannula with Harlan. Buxco, Inc.'s 12-chamber plethysmography system (PLY 3223; Buxco, Inc., Wilmington, NC, USA) with temperature / humidity compensation (Epstein et al., 1980, J. Apply Physiol. 49: 1107-1115) ). Biosystem XA software v2.11.1. Customized 12-site automatic injection system (Harvard device; Instech, Inc)

Method:
Minute ventilation and respiratory patterns were evaluated and quantified using rat whole body plethysmography. A respiratory waveform was created from the exchange of air between the animal and the room. This exchange constructed a breathing waveform by inducing a change in air volume, and this change was measured with a pressure transducer. In addition, atmospheric temperature and humidity were measured using a temperature and humidity probe that samples room conditions. The compensation factor is then determined and compensated for the respiratory condition by applying it to the respiratory waveform using a standardization algorithm (Epstein et al., 1980, J. Apply Physiol. 49: 1107-1115) and this is applied to the parameter COMP (See Appendix).

  All animals were acclimated to the plethysmography room for at least 1 hour, or before data collection (up to 2 hours) until the animals were no longer disturbing. Bolus intravenous (IV) dosing was performed at a rate of 5-10 seconds per dose and the catheter was flushed with 350 μL of sterile saline to ensure drug delivery was complete. All 12 animals (6 vehicle treatment; 6 drug treatment) were dosed simultaneously within 60 seconds. For intravenous infusion, vehicle or test compound was prepared as described in a 0.1 mg / mL stock and administered with a Harvard device infusion pump. Five minutes after midazolam bolus IV administration, compound (XXXVI) was administered via infusion to give a dose of 0.1 mg / kg / min over 30 minutes at a rate of 20 μL / min / 0.3 kg. None of the included studies were conducted blindly due to the logistics of multiple animals during co-medication. All plethysmographic data were recorded automatically by a Buxco instrument.

Statistical analysis:
Respiratory data was collected for each breath and averaged into 1 minute time bins for data analysis. For each specified acquisition period, which is the time between medications, respiratory rate (f), tidal volume (TV), cumulative volume (AV), minute ventilation (MV), inspiratory time (Ti), expiration time ( Te), peak inspiratory flow (PIF), peak expiratory flow (PEF), relaxation time (RT), end-inspiratory rest period (EIP), end-expiratory rest period (EEP), delta amount (DV), 50% on TV Multiple ventilations including expiratory flow (EF50), rejection index (Rinx), compensation (Comp), enhanced pause (Penh), rest period (PAU), PEF rate (Rpef), relative humidity (RH) and temperature (Temp) The percent change from pre-treatment baseline values for the parameters was calculated for each cohort.

  To calculate the percent difference, each parameter was compared to the media using the area under the curve (AUC) and peak response value for each specified acquisition period using a customized visual basic reconstruction analysis macro. In addition, the percent reversal of drug-induced respiratory depression by the compound was calculated using the mean respiratory depression derived from all vehicle (or untreated) animals, compared to the mean pretreatment baseline for all animals in the study. Calculated.

result:
Compound (XXXVI) (0.1 mg / kg / min) reversed BIRD-induced reduction of MV by 100 by the end of the infusion period (t = 38). Compound (XXXVI) showed the effect of reversing the effect of midazolam on MV (Figure 15), TV (Figure 16), AV, Te, PIF, PEF and EEP, but f (Figure 17), Ti, RT, There was no apparent effect on EIP, dv, EF50, Rinx, Comp, Penh, PAU, Rpef, RH and Temp. During IV bolus injection, a small increase in minute ventilation in all groups was often seen, which was considered an injection artifact due to animal arousal and showed no other apparent effect on ventilation.

  Potential adverse events were monitored, but no adverse effects on behavior were observed after administration of compound (XXXVI) at the test dose. The results of these experiments indicated that compound (XXXVI) appeared to reverse and be well tolerated with midazolam-induced respiratory depression at the test dose in rats.

Example 123:
Effect of Compound (XXXVI) on Hypercapnia In one aspect, the aim of this study is to evaluate the effect of compound (XXXVI) administered intravenously on hypercapnic ventilatory response (HCVR) in rats There was a thing.

  A medium which is 20% hydroxypropyl-β-cyclodextran in sterile water was added to the pre-weighed compound and mixed thoroughly to obtain a clear solution. An injection volume of 0.10 mg / kg / min was obtained by creating a 1.5 mg / mL stock. An injection volume of 0.03 mg / kg / min was obtained by creating another 0.45 mg / mL stock. All compound solutions and media were titrated to show pH 4-8 by titrating with NaOH or HCl solution using pH test paper.

Male Sprague-Dawley rats (Harlan, Inc.) 250-350 g at the time of dosing were surgically prepared by Harlan to include a jugular vein cannula. Buxco, Inc.'s 12-chamber plethysmography system (PLY 3223; Buxco, Inc., Wilmington, NC, USA) with temperature / humidity compensation (Epstein et al., 1980, J. Apply Physiol. 49: 1107-1115) ). Using Biosystem XA software v2.11.1 and a customized 12 site automatic injection system (Harvard instrument, Instech, Inc). A gas mixer (CWE Inc.) was used for this experiment to provide hypercapnic concentrations (3% CO ₂ , 21% O ₂ , balance nitrogen). Three tanks containing 100% O ₂ , CO ₂ and nitrogen were attached to the gas mixer and a customized gas mixture was fed to each plethysmograph at a rate of 2 L / min.

  Minute ventilation and respiratory patterns were evaluated and quantified using rat whole body plethysmography. A respiratory waveform was created from the exchange of air between the animal and the room. This exchange constructed a respiratory waveform by inducing a change in air volume, which was measured with a pressure transducer (Lomask M., 2005, "Respiration measurement in the whole body plethysmography," Buxco Inc., http: // Search from www.buxco.com/downloads/LomaskWBP.pdf). In addition, atmospheric temperature and humidity were measured using a temperature and humidity probe that samples room conditions. The compensation factor is then determined and compensated for the respiratory condition by applying it to the respiratory waveform using a standardization algorithm (Epstein et al., 1980, J. Apply Physiol. 49: 1107-1115) and this is applied to the parameter COMP As reported.

  All animals were acclimated to the plethysmography room for at least 1 hour or until the animals were not disturbing (up to 2 hours before data collection). Minute ventilation (MV) was calculated from the direct measurements of tidal volume (TV) and respiratory rate (f) using the formula MV = TV x f by Biosystem XA software. Minute ventilation (mL / min) is a common endpoint for assessing ventilation performance. The protocol included administration as a 20 minute infusion of compound (XXXVI) followed by a 20 minute exposure to 3% hypercapnia in addition to the compound (XXXVI) infusion. After 20 minutes of hypercapnia, compound (XXXVI) infusion was continued for another 10 minutes, resulting in a total compound (XXXVI) infusion time of 50 minutes. Each experiment included 6 animals dosed with test compound (XXXVI) (0.03 or 0.10 mg / kg / min) versus 6 animals dosed with vehicle, all of which were hypercapnic (3%). Exposed. Animals were continuously monitored and observed for adverse effects on behavior. Such findings were recorded in experimental notes for each test animal.

Statistical analysis Respiration data were collected for each breath and averaged into 1-minute time bins for data analysis. For each specified acquisition period, which is the time between medications, respiratory rate (f), tidal volume (TV), cumulative volume (AV), minute ventilation (MV), inspiratory time (Ti), expiration time ( Te), peak inspiratory flow (PIF), peak expiratory flow (PEF), relaxation time (RT), end inspiratory pause (EIP), end expiratory pause (EEP), delta volume (dV), 50% on TV Multiple ventilations including expiratory flow (EF50), rejection index (Rinx), compensation (Comp), enhanced pause (Penh), rest period (PAU), PEF rate (Rpef), relative humidity (RH) and temperature (Temp) The percent AUC change from the pre-treatment baseline value for the parameters was calculated for each cohort. To calculate the percent difference, each parameter was compared to the media using the area under the curve (AUC) and peak response value for each acquisition period using the customized visual basic reconstruction analysis macro (Lopotosky, S Galleon Buxco Restructure tool, v5.2, 2008). All data analysis of a single stand-alone study was performed using this reconstruction analysis macro (Lopotosky, S. Galleon Buxco Restructure tool, v5.2, 2008). In the hypercapnia study, all combined data analysis for both medications was performed with Graphpad Prism for MV, TV and f only. In addition, the percent increase over the cohort average just prior to hypercapnia exposure to the group peak response was calculated. In the combined hypercapnia study, t = 62 to t = 67 was used.

Results and Discussion:
Compound (XXXVI) administration stimulated respiration in untreated animals at 0.10 mg / kg / min, but had little or no effect at 0.03 mg / kg / min. Furthermore, when the animals were administered compound (XXXVI), exposure to hypercapnia (3% CO ₂ ) produced a dose-dependent increased MV response compared to vehicle treatment alone. Compound (XXXVI) at intravenous 0.03 or 0.1 mg / kg / min caused an increase in hypercapnic ventilatory response (HCVR) at relatively large doses of 0.10 mg / kg / min, but 0.03 mg No effect at / kg / min. The 0.03 mg / kg / min group and the vehicle group produced 60% acceleration of HCVR from t = 62 to t = 67. 0.10 mg / kg / min showed a 44% increase in MV during HCVR exposure at the same time, in addition to an increase in MV by compound (XXXVI) alone. Compound (XXXVI) at 0.03 mg / kg / min against HCVR has an effect on PIF only, f, TV, AV, MV, Ti, Te, PEF, RT, EIP, EEP, dv, EF50, No discernible change in Rinx, Comp, penh, PAU, Rpef, RH or Temp. Dose 0.10 mg / kg / min is effective against f, TV, AV, MV, Ti, Te, PIF, PEF, EIP, EF50, Comp and RH, EEP, dV, Rinx, Penh, PAU, Rpef And did not cause a discernable change in Temp. These data suggest that compound (XXXVI) administered as an infusion can facilitate ventilation during acute hypoxemia by enhancing the ventilation effect of hypercapnia . Furthermore, there were no adverse clinical findings associated with compound (XXXVI) at the test dose.

Example 124:
Effect of compound (XLII) on the 5-minute mean of respiratory rate, tidal volume, minute ventilation, and minute ventilation changes in rats General methods:
Adult male Sprague Dawley rats (weight 250-350 g; Harlan, Indianapolis, IN, USA) were anesthetized with isoflurane in oxygen. The femoral vein was cannulated to administer the compound. During the experiment, body temperature was maintained at 36.0-37.2 ° C. To measure tracheal airflow, a cannula was inserted into the neck of the trachea and a rat-sized respiratory flow meter was attached. After completion of the surgical instrument setup, isoflurane was slowly interrupted while urethane (1.8 g / kg) was administered intravenously over 10-15 minutes to maintain anesthesia. Rats breathed spontaneously and inhaled 100% of oxygen. At least 30-45 minutes after the interruption of isoflurane, baseline tracheal airflow was recorded for 20-30 minutes, followed by compound administration. The vehicle and test compound were administered intravenously at a constant volume (1 mL / kg) over 15-25 seconds. There was at least 15 minutes between each dose of compound. Tracheal airflow was continuously recorded before, during and after compound administration. The tidal volume was derived from the airflow integral and the respiratory rate was derived from the number of inspiratory cycles per minute. Minute ventilation was calculated as the product of tidal volume and respiratory rate (Figure 32).

result:
Compound (XLII) increased both respiratory rate and tidal volume, and their product, minute ventilation, relative to vehicle.

Example 125:
Effect of compound (CLXXII) on 5-minute average of respiratory rate, tidal volume, minute ventilation, and minute ventilation changes in rats General method: See Example 124 above

Results Compound (CLXXII) increased both respiratory rate and tidal volume, and their product, minute ventilation, relative to vehicle.

Example 126:
Effect of compound (XXXV) on BK potassium channel current in GH3 cells Experimental procedure Stock solutions of test articles were prepared in dimethyl sulfoxide (DMSO) and stored frozen. Stock solutions of the test compound concentration by diluting with physiological saline were freshly prepared daily (composition in _{mM): KCl, 125; CaCl 2} , 8.5; HEPES, 10; EGTA, 11.25; pH to 7.2 with KOH Adjust (prepare weekly until use and refrigerate). All test solutions contained 0.1% DMSO.

GH3 cells were grown in culture using standard techniques. The ionic current was measured from the inner and outer patch of GH3 cells. Channel activity was monitored at a holding potential of -60 mV under symmetric K ⁺ conditions. Activity before and in the presence of each concentration of test article was recorded over a period of 3 minutes each.

Data analysis
Data acquisition and analysis were performed using a suite of pCLAMP (Ver. 8.2) program (Sunnyvale, Calif., MDS-AT). The percent inhibition by the test article was calculated using the following formula: 100 * (NPo _control -NPo _test ) / NPo _control

Results Compound (XXXV) was evaluated at 1 and 10 μM, and positive control aluminumtrin was evaluated at 1 μM. The channel effect was estimated from the change in activity at steady state after application of the test article. The effects of compound (XXXV) are summarized in Table 9. Sample recordings before and after 1 μM (XXXV) and all point histograms are shown in FIG.

NPo: 総チャネル開口確率。
阻害(%) = 100*(NPo_対照 - NPo_試験)/NPo_対照
洗い出しはパッチC 05 SP 101007 0000に対して1μMアルミトリンの適用の前および後に行い、パッチB 05 SP 101012 000に対して10μM(XXXV)の適用後に行った。 Table 9: Effect of compound (XXXV) on single BK potassium channel expressed in GH3 cells recorded in medial exterior patch

NPo: Total channel opening probability.
Inhibition (%) = 100 * (NPo _control -NPo _test ) / NPo _control
Washing was performed before and after application of 1 μM aluminin for patch C 05 SP 101007 0000 and after application of 10 μM (XXXV) for patch B 05 SP 101012 000.

Overview and Conclusion As shown in FIG. 34, compound (XXXV) performed concentration-dependent inhibition of the native BK channel expressed in GH3 cells. At the highest test concentration (10 μM), compound (XXXV) reduced the total channel opening probability by 42%.

Example 127:
Effect of compounds on thallium flow through rat TASK-1 (KCNK1) and human TASK-3 (KCNK9) channels <br/> Experimental approach
(a) Cell seeding plate:
CHO cells expressing tetracycline-inducible recombinant rat KCNK3 / TASK-1 (KCNK3-CHO cells) at a density of 6,000 cells / well (50 μl / well of 120,000 cells / mL) in poly-D-lysine-coated 384-well plates And incubated for 72 hours at 30 ° C. in the presence of 5% CO ₂ and 1 μg / mL tetracycline. HEK cells expressing tetracycline-inducible recombinant human KCNK9 / TASK-3 (KCNK9-HEK cells) are plated at a density of 15,000 cells per well (50 μl / well, 300,000 cells / mL) and 1 μg / mL tetracycline Incubated overnight at 37 ° C. and 5% CO ₂ .

(b) Preparation of compound-containing plates:
Drug plates were prepared from 10 mM 100% DMSO mother plates. Compounds were transferred to 384 well drug plates and titrated in 1: 3 serial dilutions in 100% DMSO for a total of 9 dilutions. Dilution plates are made by taking 2.4 μl from the mother plate and adding to 17.6 μl of assay buffer to make a 12% DMSO dilution plate. Prepare the final daughter plate from the dilution plate by taking 1 μl of the dilution plate and adding to 40 μl of assay buffer to a final DMSO concentration of 0.3%. Each compound was evaluated in duplicate, and the concentration range evaluated was 3 nM to 30 μM.

Assay protocol:
When thallium was added to the extracellular solution along with a stimulus to open the channel, Tl ⁺ flowed down the concentration gradient into the cell. Channel activity was detected by the indicator dye FluxOR ™ that increases cytosolic fluorescence. FluxOR ™ indicator dye was added into the cells as a membrane permeable acetoxymethyl ester. On each assay day, a new FluxOR ™ assay buffer was made from Hanks Balanced Salt Solution (HBSS) buffered with 20 mM HEPES and adjusted to pH 7.4 with NaOH. The dye addition solution was prepared according to the manufacturer's instructions and 25 μl of dye solution was applied to each well with a multi-dropper after manually removing the plating medium from the cells. The dye was added for 90 minutes at room temperature in a dark room.

After 90 minutes of dye addition and subsequent manual dye removal, 24 μl of the drug daughter plate is transferred to the cell plate by the cybi-well system and then incubated for 20 minutes at room temperature to allow in-well equilibration did. Stimulation buffer containing 5 times the desired final assay concentration of 10 mM K ⁺ 2.8 mM Tl ⁺ was prepared from 5X chloride-free buffer, thallium and potassium sulfate. The cell plates were then transferred to a FDSS 6000 dynamic imaging plate reader (Hamamatsu). A baseline for the entire plate was established by measuring fluorescence at 525 nm (excitation 488 nm) at 1 Hz for 10 seconds. After establishing the baseline, 6 μl / well of stimulation buffer was added and the fluorescence signal was recorded for an additional 140 seconds.

Data analysis
Inhibitory concentration curves were plotted from the fluorescence signals in the absence and presence of Galleon compounds and IC ₅₀ values were estimated using a curve fitting algorithm.

Results The results are summarized in Table 10. When Tl ⁺ current was used as an indicator of the activity of rat TASK-1 and human TASK-3, some compounds showed rTASK-1 blockade.

Table 10: IC ₅₀ values for inhibition of rat TASK-1 and hTASK-3

Example 128:
Effect of Compound (XXXVI) on Ventilation in Human Volunteers N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl during two single-dose trials of similar design ) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was administered to humans.

The first study (GAL-021-101) was a dose escalation single dose study in healthy subjects. A mild / moderate burning sensation at the injection site was the only adverse event that differed between placebo and drug-treated subjects. At the highest dose (0.96 mg / kg / hr), stimulation of minute ventilation and a decrease in end-tidal CO ₂ (ETCO ₂ ) were observed.

  The second study (GAL-021-102) doubled the dose range investigated during the first study and established the maximum respiratory stimulating dose in healthy subjects without concurrent use of opioids or anesthetics . A similar change in minute ventilation was observed at 0.96 mg / kg / hour, with a greater effect at the highest dose (1.92 mg / kg / hour).

Phase I data
(a) Phase I clinical safety summary The first study (GAL-021-101) is a nine-period, double-blind, randomized placebo in three alternating cohorts of healthy subjects. Control dose escalation single dose study. Each of the 3 cohorts of 10 subjects was randomly divided into treatments with a 4: 1 ratio (treatment 8, placebo 2) in the rotating panel design (Figure 35). Subjects in the first cohort participated in dosing periods 1, 4, and 7, the second cohort participated in dosing periods 2, 5, and 8, and the third cohort participated in dosing periods 3, 6, and 9. Subjects who received placebo during the first dosing period also received placebo during the second and third dosing periods. Similarly, drug treatment subjects received the drug during all three dosing periods. After overnight fasting, the subject was treated with N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) or Placebo was infused intravenously and PD, PK and safety assessments were performed during the next 24 hours.

  Eight intravenous dose levels are administered, with the first seven doses being fixed rate infusions (0.1-0.96 mg / kg / hour) for 1, 2, 3 or 4 hours, and finally the loading dose (0.72 mg / kg / hour) 1 hour) followed by administration of a maintenance dose (0.36 mg / kg / hour for 3 hours).

  The second study (GAL-021-102) was a four-blind, randomized, placebo-controlled, dose escalating single dose study in an alternating cohort of healthy subjects. Two cohorts of 9 subjects were each randomized to treatment with a 2: 1 ratio (treatment 6, placebo 3) in a rotating panel design. Subjects in the first cohort participated in dosing periods 1 and 3, and the second cohort participated in dosing periods 2 and 4. Subjects received up to one placebo during the study. After overnight fasting, the subject was treated with N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) or Placebo was infused intravenously and PD, PK and safety assessments were performed during the next 24 hours.

Three intravenous dose levels were administered for 2 hours with a fixed rate infusion (0.96-1.92 mg / kg / hour). During the third treatment period, two subjects showed an increase in respiratory effort and a decrease in ETCO ₂ (lowest points: 22 and 29 mmHg), and the respiratory effort decreased rapidly when the infusion was stopped. The criteria for stopping further dose escalation were met. During the fourth and final treatment period, subjects were reassigned to two lower dose levels based on the previous treatment to increase the total number of subjects receiving these dose levels.

A third study, a two-part, four-treatment, cross-over, double-blind, placebo-controlled, step-by-step infusion study, N- (4,6-bis-) on respiratory drive in an opioid-induced respiratory depression model. The ventilation PD effect of n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was evaluated. Part 1 used dynamic end-expiratory CO ₂ forced technology. This is a progressive hypercapnia that produces a target minute ventilation of 20 L / min. Once achieved, PCO ₂ is maintained (clamped) at the same level throughout the remainder of the treatment period to eliminate the confounding effects of CO ₂ changes on minute ventilation.

  In each part, subjects were treated with two treatments (placebo or N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogen sulfate Salt (XXXVI)) and each subject received one treatment. In Part 2, the treatment sequence and opioid administration of Part 1 was repeated with the addition of ambient air conditions and pain assessment. All treatment periods were subdivided into 7 segments by design over time (treatment period details are shown in Figure 36). Two dose levels of alfentanil and two dose levels of (XXXVI) were included in each treatment period to make a preliminary assessment of dose response.

  In Part 2, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) is the opioid pain Pain was assessed using percutaneous electrical stimulation on the tibia to determine if it would prevent reduction.

23 subjects participated in the study. Twelve subjects completed both treatment periods in Part 1, and eight subjects who participated completed both treatment periods in Part 2. Three subjects completed one treatment period in Part 1. Of these subjects, 2 were discontinued after completing the first treatment period, and the third subject was discontinued before completing segment 2 of the second treatment period. One of these three subjects completed Part 2 successfully. Six subjects dropped out of the study between just before the start of the first segment and completion of segment 2. If segment 2 was completed, subject completed the remaining 5 segments of the treatment period. Main reason for dropping by these subjects (installation of e.g. arterial line, anxiety associated with mask) related reasons procedure, or hyperventilation additional intake CO ₂ is induced by hypercapnia induced It was difficult to adapt.

で示される各セグメントの終わりの10分間の評価期間にベースライン換気パラメータを評価した。セグメント2中、対象が分時換気量20L/分を達成するまでガス混合器を使用してCO₂濃度をゆっくりと増大させた。セグメント3において、呼気終末分時換気量の25〜35%減少、およびセグメント2の終わりと同じ呼気終末PCO₂を維持するように調整されたCO₂吸入量を達成するように、アルフェンタニルを用量設定した。残りのセグメントを通じて同様のCO₂調整を行った。セグメント4において、低用量N-(4,6-ビス-n-プロピルアミノ-[1,3,5]トリアジン-2-イル)-N,O-ジメチル-ヒドロキシルアミン硫酸水素塩(XXXVI)を、最初は急速注入(2.0mg/kg/分)で、次に維持注入(0.4mg/kg/時)で、低用量の定常状態濃度まで投与した。セグメント5において、2回目の急速注入(2.0mg/kg/時)およびより多量の維持注入(1.1mg/kg/時)を使用して、高定常状態濃度での一次エンドポイント(分時換気量)を評価した。その後(セグメント6)、個別化されたアルフェンタニルの負荷量および維持量を(セグメント3から)2倍にし、換気パラメータを評価した。最終セグメント7のはじめに、アルフェンタニルおよびN-(4,6-ビス-n-プロピルアミノ-[1,3,5]トリアジン-2-イル)-N,O-ジメチル-ヒドロキシルアミン硫酸水素塩(XXXVI)/プラセボの注入を停止し、対象を観察した。パート1のセグメント1において個々のアルフェンタニル用量を確立した後、パート1および2の残りすべてのセグメントで同じ注入量を使用した。パート2では、周囲空気を呼吸しながらCO2クランピング技術を使用せずに同じセグメント進行を使用した。パート2では、脛骨の上での経皮的電気刺激(TENS)を使用することで、疼痛の検出限界および最大忍容度を確立した。疼痛試験中、電流を漸進的に増大させ、対象は、ボタンを押すことで疼痛の開始および忍容可能な最大の疼痛を知らせ、その時点で電流を停止させた。セグメント1〜6中、疼痛評価を換気評価間隔の前に行う。 As shown in FIG. 36, during each study part, subjects were randomly selected during the first treatment period with N- (4,6-bis-n-propylamino- [1,3,5] triazine-2- Yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) or placebo and the other was administered during the second treatment period. All subjects were pretreated with ondansetron and metoclopramide because of severe nausea and vomiting in a pilot study following alfentanil administration. During segment 1 of part 1, after about 20 minutes free breathing of ambient air, blue inverted triangle

Baseline ventilation parameters were evaluated during the 10-minute evaluation period at the end of each segment. During segment 2, the CO ₂ concentration was slowly increased using a gas mixer until the subject achieved a minute ventilation of 20 L / min. In segment 3, dose alfentanil to achieve a 25-35% decrease in end-tidal minute ventilation and CO ₂ inhalation adjusted to maintain the same end-tidal PCO ₂ as the end of segment 2 Set. Similar CO ₂ adjustments were made throughout the remaining segments. In segment 4, low dose N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) The first dose was a rapid infusion (2.0 mg / kg / min) followed by a maintenance infusion (0.4 mg / kg / hr) to a low dose steady state concentration. In segment 5, using a second rapid infusion (2.0 mg / kg / hr) and a higher maintenance infusion (1.1 mg / kg / hr), the primary endpoint (minute ventilation) at a high steady-state concentration ) Was evaluated. Thereafter (segment 6), the loading and maintenance of individualized alfentanil was doubled (from segment 3) and ventilation parameters were evaluated. At the beginning of final segment 7, alfentanil and N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI ) / Placebo infusion was stopped and the subject was observed. After establishing individual alfentanil doses in segment 1 of part 1, the same infusion was used in all remaining segments of parts 1 and 2. In Part 2, the same segment progression was used without breathing ambient air and using CO2 clamping techniques. Part 2 established pain detection limits and maximum tolerance by using percutaneous electrical stimulation (TENS) on the tibia. During the pain test, the current was gradually increased and the subject was notified of the onset of pain and the maximum tolerable pain by pressing a button, at which point the current was stopped. During segments 1-6, pain assessment is performed before the ventilation assessment interval.

(b) Phase I Pharmacodynamic Overview Pharmacodynamic (PD) assessments included tidal volume, respiratory rate, minute ventilation, end-tidal CO ₂ and percutaneous hemoglobin oxygen saturation (SpO ₂ ). Baseline respiratory data was acquired 1 hour before dosing. The parameter average over that period of time after removal of the recording area includes an artificial result by a treatment-blind polysomnographic specialist before analysis. PD data was collected approximately 1 hour after completion of infusion. Percent time-weighted change from baseline was calculated for all respiratory parameters. Data for the first 2 hours of groups 6 and 7 (over 0.7 hours at 0.72 mg / kg / hour) were pooled for PD analysis. At all doses, the change in respiratory rate was small, usually less than 10%. The change in tidal volume was also small, with only a dose of 0.96 mg / kg / hour showing a consistent increase of less than 10% (Figure 37).

To further assess respiratory changes, responses were integrated over the first 2 hours after the start of infusion. When using a system based on the Drager respiratory flow meter, minute ventilation did not change significantly, although an increase of 7-16% was observed at the two highest infusion rates (FIG. 38A). End expiratory CO ₂ decreased in parallel with the increase in minute ventilation, and the cumulative decrease was approximately 6% (FIG. 38B). The onset of effects on minute ventilation and ETCO ₂ was rapid, with a half-maximum effect exceeding 7.5 minutes (at the first evaluation). A similar pattern of change in minute ventilation, tidal volume and respiratory rate (FIGS. 38C-38D) was observed by the system based on NOX-T3 inductance plethysmography, with minute ventilation increased by approximately 24%. Percutaneous hemoglobin O ₂ partial pressure was not significantly different from placebo, except that the mean change was + 0.85% vs. -0.05% at a dose of 0.96 mg / kg / hour (p <0.05).

A second study was conducted at the same clinical site as the first study and utilized similar PD assessments and equipment. The first dose had the same infusion rate (0.96 mg / kg / hour) as the first study with a long duration of 2 hours. Minute ventilation increased rapidly, with an average increase of 15.4% during the 2-hour infusion period, similar to the first study (16.1%). Medium dose showed a similar increase (13.6%), while higher dose showed a greater increase (24.3%). Changes in minute ventilation were statistically significant at all three dose levels (Figure 39A). The effects on tidal volume and respiratory rate, which are the basis for changes in minute ventilation, are more variable, with low doses being relative to tidal volume, medium doses being related to respiratory rate, and high doses being both The first effect was shown for the combination. End expiratory CO ₂ also decreased at all dose levels, with the highest dose showing an average decrease of over 8% over the infusion period (FIG. 39B). Changes in ETCO ₂ and tidal volume at low and high doses were statistically different from placebo. Minute ventilation, tidal volume and half-maximal effects of ETCO ₂ occurred before or immediately after the 5-minute evaluation (first measurement time point) (FIGS. 39B-39D). A rapid initial response was already observed at lower infusion rates in the first trial, but tended to decrease shortly thereafter. On the other hand, PD response was maintained at doses above 0.72 mg / kg / hour.

Similar to the maximum infusion rate (0.96 mg / kg / hr) in the first study, hemoglobin O ₂ saturation (SpO ₂ ) increases rapidly after the start of infusion, with statistically significant differences between low and high doses Was observed at 25-75 minutes (FIG. 40). The cumulative effect over the 2 hour infusion increased by 0.60% and 0.76% for placebo (0.13%, p <0.05) at low and high doses, respectively. Medium dose shows an increase in minute ventilation (17.2%) over the first hour (10.0%) in the 1-2 hour period, and a statistically significant increase in SpO ₂ relative to placebo (0.41%) Vs. -0.02%, p <0.05) was also shown.

During the respiratory suppression concept proof test (GAL-021-104), ventilation parameters were continuously captured and integrated as the primary endpoint over the final 10-minute interval, and segment 5 was the primary guess statistical comparison. The initial CO ₂ gradual increase (segment 2) was slowly performed so that the minute ventilation increased to 20 liters / minute (about 2.5 times the baseline) (FIG. 41A). Thereafter, alfentanil was dosed so that the increase in minute ventilation by CO ₂ stimulation was reduced by about 2/3 (absolute decrease 37%). When the minimum irritation (XXXVI) amount (0.4 mg / kg / hour) was added, the minute ventilation showed a tendency to deviate from the placebo (p <0.07), and was statistical at the maximum infusion rate (1.1 mg / kg / hour). Reached significant (p <0.0001). Doubled alfentanil loading and infusion rate in the sixth segment reduced minute ventilation for both GAL-021 and placebo, while the statistically significant divergence between the two treatments was Followed (p <0.005). Similar patterns of statistically significant differences were observed in tidal volume (Figure 41B) and respiratory rate (Figure 41C).

During Part 2 of the study, subjects received the same alfentanil loading and infusion rate as Part 1. Subjects were breathing ambient air and no attempt was made to regulate end-tidal CO ₂ or minute ventilation. Pain was also evaluated using a transcutaneous electrical nerve stimulator (TENS) placed over the anterior tibial area so that minimal muscle effects were generated. During the test, the current was gradually increased to generate a current threshold associated with the onset of pain and the maximum tolerable pain (FIG. 36). Administration of alfentanil increased the pain onset threshold (FIG. 42). Administration of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) initiates pain or persistence The maximum acceptable threshold did not decrease.

Minute ventilation decreased with the start of alfentanil infusion (FIG. 43A). Placebo-treated subjects remained stable until higher doses of alfentanil in segment 6, and minute ventilation was further reduced in segment 6. As in Part 1, minute ventilation was measured with placebo and low dose N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl- Deviation from hydroxylamine bisulfate (XXXVI) treatment reached statistical significance at higher doses in segment 5. In Part 1 (Segment 6), a high dose of alfentanil is N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine sulfate Although hydrogen salt (XXXVI) stimulation was reduced, there was no decrease in minute ventilation under room air conditions. Consistent with the known opioid effect, end-tidal CO ₂ was further increased by high-dose alfentanil administration (FIG. 43B). N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) is administered at end-tidal CO ₂ concentration There was a statistical significance with high-dose alfentanil (segment 6). There was no difference in respiratory rate (Figure 43C). Tidal volume is high dose N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N in both low and high dose alfentanil infusions. , O-dimethyl-hydroxylamine bisulfate (XXXVI) increased compared to placebo treatment (FIG. 43D).

Between Part 1 and Part 2, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) Showed a consistent and clinically and statistically significant effect compared to placebo at higher infusion rates (1.1 mg / kg / hr). This effect was independent of the presence of exogenous CO ₂ following opioid administration or endogenous CO ₂ retention. Minimal stimulating low dose of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) treated with placebo The change in minute ventilation reached statistical significance before the effect was achieved. Similar trends in low-dose N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) It was recognized in the test part. The increase in minute ventilation tended to be caused by the increase in tidal volume observed in both study parts. Changes in respiratory rate were observed only in Part 1. Overall, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was administered after opioid administration. Improved ventilation, consistent with previous observations in rats and non-human primates. The improvement in ventilation after administration of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) The analgesic effect of alfentanil was not impaired. This suggests that the current difficulty in balancing opioid analgesia and respiratory depression effects may be less when co-administering the two drugs.

(c) Phase I Pharmacokinetic Summary In general, the overall shape of the plasma concentration-time profile was similar in both studies. Plasma concentrations rose rapidly during the infusion, initially rapidly after the infusion and then gradually decreased. As shown in FIG. 44, the mean maximum plasma concentration (C _max ) was generally reached at the end of the infusion, or in the case of a biphasic infusion at the end of the loading dose infusion.

In the first study after the end of infusion, all plasma concentration-time profiles showed an apparent biexponential decay with a steep distribution phase and a slow elimination phase, with an average terminal half-life (t _{1 / 2} ) ranged from 4.3 to 6.5 hours (Figure 44A). The pharmacokinetics of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) in healthy volunteers Generally best described by a two-compartment model with a distribution half-life of less than 20 minutes. Mean systemic plasma clearance value (CL _p) was about half of liver blood flow in humans. Average steady-state distribution volume values (V _ss ) ranging from 1.7 to 2.5 L / kg were about 2 to 3 times the total water content in humans. This indicates that N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) is highly It is suggested that it was distributed. Plasma concentration C _1h at 1 hour after injection (range: 54.9-930 ng / mL) was dose proportional at all test infusion rates. Similarly, systemic exposure (AUC _0-∞ ) was dose proportional. C _1h and AUC met the statistical requirements for dose proportionality. In general, for t _1/2 , CL _p and V _ss , the variation within a subject is less than the variation between subjects.

^aデータは各パラメータの幾何平均値(変動係数%)であるが、但しT_maxは中央値(範囲)で表す。
^b6名の対象由来。
^**/60Kgの対象を想定する。
対象012は注入の中途終了のためコホート2、期間2 PKの分析に含めない Table 11A: N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) in human plasma Mean pharmacokinetic parameters

^{The a} data is the geometric mean value (variation coefficient%) of each parameter, where T _max is represented by the median value (range).
^{b From} 6 subjects.
^** Assumes target of / 60Kg.
Subject 012 is not included in Cohort 2, Period 2 PK analysis due to end of infusion

^aデータは各パラメータの幾何平均値(変動係数%)であるが、但しT_maxは中央値(範囲)で表す。
^b4名の対象から(対象107および109は注入の中途終了のため分析に含めない)。 Table 11B: N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) in human plasma Mean pharmacokinetic parameters (GAL-021-102) ^a

^{The a} data is the geometric mean value (variation coefficient%) of each parameter, where T _max is represented by the median value (range).
^{b From} 4 subjects (Subjects 107 and 109 are not included in the analysis due to the end of the infusion).

During the second test, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was 0.96. Infused at 1.44 and 1.92 mg / kg / hr for 2 hours. In general, plasma concentration-time profiles at higher doses were similar to those observed in first-in-human studies. In general, the mean maximum plasma concentration (C _max ) was reached at the end of the infusion, as shown in Table 11B and FIG. 44B. After the end of the infusion, all plasma concentration-time profiles show an apparent biexponential decay with a steep distribution phase and a slow elimination phase, with an average terminal half-life (t _1/2 ) of 5.2. It was in the range of ~ 8.1 hours.

Similar to the values observed in the first-in-human test, mean systemic plasma clearance values (CL _p ) ranging from 10.5 to 12.4 ml / min / kg were about half of the hepatic blood flow in humans. Mean steady-state volume distribution values (V _ss ) ranging from 1.8 to 2.5 L / kg were about 2 to 3 times the total water content in humans.

In general, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) Showed good pharmacokinetics when administered intravenously to healthy volunteers. The plasma concentration-time profile fits well in the two-compartment model with a short distribution half-life of less than 20 minutes. In the first study (0.1-0.96 mg / kg / hr) C _max and AUC _0-∞ are dose proportional, t _1/2 , CL _p and V _ss are dose independent, the second There was no clear deviation from the expected linearity during the test. As a result of linear pharmacokinetics, future dosing regimen adjustments may be simplified. The terminal half-life (t _1/2 approximately 6 hours) suggests that little accumulation occurs after 24 hours, which is consistent with low measurable plasma C _24h .

(d) Overall conclusion of Phase I clinical trial
N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) was tested during the first clinical trial. Good tolerability was observed and only mild / moderate burning sensation at the injection site was different from placebo. Minute ventilation increased at the two highest infusion rates (0.72 and 0.96 mg / kg / hr). During the second study, hyperventilation occurred at high doses (1.92 mg / kg / hr), establishing the PD maximum in healthy subjects untreated with respiratory inhibitors. Stimulation of minute ventilation at an infusion rate of 0.96 mg / kg / hour was similar in the two studies (approximately 16%), and the stimulation at the higher dose was greater (25%). The pharmacokinetic behavior of the drug was good, and the concentration increased rapidly during the initial infusion period and decreased rapidly with infusion cessation. This compound is dose proportional with respect to both AUC and _C1h , with little variation between and within subjects.

N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) in the presence of opioid-induced respiratory depression ) Administration was as well tolerated as placebo, with only a slight burning sensation at the injection site in several subjects. In the presence of clamped hypercapnia, minute ventilation, tidal volume, and respiratory rate increased to a statistically and clinically significant extent with a (XXXVI) dose of 1.1 mg / kg / hr. Similar ventilation improvements were noted for minute ventilation, end-tidal CO ₂ and tidal volume when room air was breathed. Overall, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine hydrogensulfate (XXXVI) Shows useful pharmacological effects in contextual stimulation and potential clinical utility in postoperative respiratory depression.

Example 129
Development of liquid preparation of (XXXVI)
A. Solubility of (XXXV) as a function of pH Methodology
A concentration of (XXXVI) at a concentration of about 10 ⁷ mg / mL in 100 mM citric acid at pH 2.5 was prepared. Approximately 150 μL aliquots of this solution were transferred to six separate glass HPLC vials. Each aliquot was titrated with 6N sodium hydroxide to different pH values ranging from 3 to 5.5 (Table 12A). All samples containing pH 2.5 solutions were shaken overnight at room temperature using a swirl shaker. After shaking, the samples were visually assessed for the presence of precipitates and then filtered through a 0.45 μm syringe tip filter (4 mm diameter) at 3,000 rpm for 20 minutes. The final pH value of the filtrate was measured. The filtrate was then diluted appropriately and analyzed using HPLC assay for (XXXV) concentration.

Results The pH value, appearance, and (XXXV) concentration of the sample before and after overnight shaking are shown in Table 12A. Solutions prepared with target pH values of 2.5, 3.0 and 3.5 are clear (no excess solids are present) and therefore the (XXXV) concentration values of these samples do not represent saturation solubility values. The pH solubility profile is shown in FIG. 19B. The black rhombus is the saturation solubility value, and the white rhombus is the measured concentration in the unsaturated sample (excess solid is not present). The dotted line represents the best-fit curve and was plotted using Equation 1. This equation is a simplified representation of the weak base solubility equilibrium and assumes that the total solubility is much greater than the solubility of the free base in the pH range of interest.
log S = log S ₀ + log (1 + 10 ^pKa-pH ) Equation 1
In the formula, “S” is the total solubility, and “S ₀ ” is the solubility of the free base.

  Equation 1 was fitted to an experimentally determined pH-solubility profile using the Microsoft Excel Solver function and a (XXXVI) pKa value of 5.6. Therefore, the calculated solubility of the free base was 0.18 mg / mL. Based on this formula, the solubility (expressed in free base) is expected to be 10 mg / mL at pH about 3.86, 25 mg / mL at pH about 3.46, and 50 mg / mL at about pH 3.16.

(Table 12A) pH solubility results

B. Stability of (XXXV) as a function of pH Methodology
A buffer solution containing approximately 10 mM each of citrate and glycine in the pH range 2-6 is titrated with 1N NaOH / 1N HCl to remove a 50 mL aliquot of the desired pH value, with a single stock of 250 mL containing both buffers. To prepare. For a 1 mg / mL XXXVI solution in a pH 2-5 buffer solution, adjust the pH to the target value by dissolving approximately 25 mg of XXXVI in approximately 23 mL of the given buffer and bring the volume to 25.0 mL in a volumetric flask. And prepared. A (XXXVI) solution at pH 6 was prepared in the same manner, but using 6.68 mg of (XXXVI), the drug concentration was lowered to 0.25 mg / mL.

  Each buffer XXXV solution was filtered through a 0.2 μm polyethersulfone syringe filter into a volumetric flask. The volumetric flask was rinsed beforehand with 70% ethanol and dried in a laminar flow hood. After filtration, each buffer (XXXV) solution was divided into 10 aliquots (9 aliquots of 2.5 mL each and 1 aliquot of 2 mL) and placed into 5 mL serum vials. The vial was previously rinsed with 70% ethanol and dried in a laminar flow hood. An aliquot was filtered and prepared in a laminar flow hood. A 2 mL aliquot of each buffer (XXXV) solution was subjected to TO analysis (HPLC assay and related materials).

  Of the 9 2.5 mL aliquots, each 3 aliquots were stored at 40 ° C. and 60 ° C., 2 aliquots were stored at 25 ° C. and 1 aliquot was stored at −70 ° C. Samples stored at 40 ° C. and 60 ° C. were evaluated for physical appearance, pH, assay, and related substances after 1 week, 2 weeks and 4 weeks storage. Samples at 25 ° C and -70 ° C served as controls to be analyzed as needed.

result
The pH stability data is shown in Table 12B. At both 40 ° C. and 60 ° C., all samples remained clear, colorless and particle free for up to 4 weeks of storage. At both storage temperatures, the pH value of all samples remained relatively constant for up to 4 weeks. Both assay and impurity data indicate that (XXXV) has a significantly lower stability at pH 2 compared to the rest of the pH rating. No specific trend was observed in the pH range 3-6. The pH stability profile at 60 ° C. is shown in FIG. 20A (% impurity).

n.d. = 検出せず (Table 12B) pH stability of (XXXV) at pH 2-5 (GAL 021)

nd = not detected

C. Stability of (XXXV) over a narrow pH (pH 2-3.6) Methodology
A buffer solution containing approximately 10 mM citrate and glycine each in the pH range 2 to 3.6 is titrated with 1N NaOH / 1N HCl to remove a 50 mL aliquot of the desired pH value from a single stock containing both buffers. To prepare. A 1 mg / mL (XXXVI) solution in buffer can be obtained by dissolving approximately 25 mg of (XXXVI) in approximately 23 mL of the given buffer, adjusting the pH to the target value, and adjusting the volume to 25.0 mL in a volumetric flask. Prepared. Each buffer (XXXV) solution was filtered through a 0.2 μm polyethersulfone syringe filter into a volumetric flask. The volumetric flask was rinsed beforehand with 70% ethanol and dried in a laminar flow hood. After filtration, each buffer (XXXV) solution was divided into 9 aliquots and placed in 5 mL serum vials. The vial was previously rinsed with 70% ethanol and dried in a laminar flow hood. An aliquot was filtered and prepared in a laminar flow hood. Of the 9 aliquots, 3 aliquots were stored at 40 ° C. and 60 ° C., 2 aliquots were stored at 25 ° C., and 1 aliquot was subjected to the T0 test. Samples were evaluated for pH, assay, and related substances at T0 and after 1 week, 2 weeks and 4 weeks storage at 40 ° C and 60 ° C. Samples stored at 25 ° C served as controls to be analyzed as needed.

Results Data are summarized in Table 12C and FIG. 20B. The most notable result of this test is that during storage at both 40 ° C. and 60 ° C., impurity levels decreased significantly with increasing pH over the entire pH range tested. This means that any increase in the pH of the formulation led to improved stability within the pH range suitable for aqueous formulations.

n.d. = 検出せず (Table 12C) pH stability of (XXXV) at pH 2 to 3.6

nd = not detected

D. Evaluation of solubility of (XXXV) in solvents and IV solutions Methodology
The solubility of (XXXVI) and XXXV was evaluated in various solvents and IV solutions. Solvents and target concentrations for solubility assessment are shown in Table 12D. Due to restrictions on API supply at the time of testing, most solvent systems were only evaluated to a level of 100 mg / mL, even if the solution was not saturated at that level. Attempts were made to reach saturation solubility only in water, regardless of how high its solubility was. The solubility of salt / free base in each solvent was evaluated in duplicate.

  To assess the solubility of (XXXVI) in 0.9% NaCl, 5% dextrose, ethanol, 30% PEG 400, 70% PEG 400 and 100% PEG 400 at a target value of 200 mg / mL, approximately 100 mg of drug in 500 μL of solvent It was done by adding. The remaining solubility, excluding water, was evaluated by adding approximately 50 mg of drug (XXXVI or XXXV) to 500 μL of solvent. For solubility in water, the drug was added under intermittent shaking to ensure that there was excess undissolved drug indicating saturation and clogging of the 13 mm PTFE 0.2 μm syringe filter. The filtrate was diluted appropriately and analyzed by HPLC for (XXXV) concentration.

Results Solubility results are shown in Table 12D.
(XXXVI): The solubility of (XXXVI) was greater than 400 mg / mLa in water and at least 200 mg / mL in IV solution (0.9% saline and 5% dextrose). During the evaluation of the solubility of (XXXV) salt in water, it was observed that about 350-400 mg of API was completely dissolved in 500 μL of water, but the sample formed a turbid gel after about 2 hours of shaking at room temperature, This was dissolved by the addition of water (about 80-250 μL). The clear solution was further shaken overnight at room temperature to form a turbid gel. The addition of another small aliquot of water (about 60-220 μL) gave a suspension that could be filtered and analyzed for (XXXV) concentration. The exact reason for this behavior of (XXXVI) in water has not been clarified, but may suggest the formation of a supersaturated solution. The salt was readily soluble in ethanol and methanol, and showed a saturated solubility in acetonitrile of about 68 mg / mL. Solubility in 30%, 70% and 100% propylene glycol was at least 90 mg / mL. Solubility in 100% PEG-400 reached saturation at about 36 mg / mL, but (XXXVI) was at least 90 mg / mL in 70% PEG-400 and up to about 198 mg / mL in 30% PEG-400 It was soluble.

  (XXXV): The saturated solubility of (XXV) in water was about 0.21 mg / mL, consistent with the predicted value from the pH-solubility curve detailed in Example 129A. The solubilities in ethanol, methanol and acetonitrile were about 92 mg / mL, about 102 mg / mL and about 45 mg / mL, respectively. The solubility of the free base in 5% Tween 80 dispersion was about 2.7 mg / mL. Solubility in PEG-400 and propylene glycol systems appears to increase with increasing cosolvent levels. The solubility of the free base was higher in propylene glycol (about 90 mg / mL) than in PEG-400 (about 73 mg / mL). The data suggests that at similar pH values, the solubility of XXXV free base in the propylene glycol system is higher than that in the PEG-400 system.

* NA = 該当なし。回収不能として列挙された試料は濾過の失敗により失われた。 (Table 12D) Solubility of (XXXV) in solvents and IV solutions

* NA = Not applicable. Samples listed as unrecoverable were lost due to filtration failure.

E. Stability of (XXXV) as a function of buffer strength Methodology
A 10 mg / mL solution of (XXXVI) in 100 mM citrate buffer at pH 3.0 and 500 mM citrate buffer at pH 3.0 was prepared. As shown in Table 12E, these two stock solutions were used to prepare 1 mg / mL solutions of (XXXVI) in various concentrations of citrate buffer ranging from 10 to 250 mM.

Table 12E: Solutions for evaluation of stability as a function of buffer strength

  Each of the above solutions was stored as approximately 2.5-3 mL aliquots (total of 7 aliquots) in 5 mL serum vials. Two aliquots of each were stored at 40 ° C, 60 ° C and 25 ° C. An aliquot stored at 25 ° C served as a control to be evaluated as needed. Samples were evaluated for pH, assay, and related substances at T0 and after 2 weeks storage at 40 ° C and 60 ° C.

Results The buffer effect test data are summarized in Table 12F. Impurity levels increased significantly at the highest buffer concentration, but there was no effect of buffer strength at 40 ° C. within the range of buffer concentrations suitable for the formulation.

n.d. = 検出せず Table 12F: Effect of buffer strength on (XXXV) stability

nd = not detected

F. Prototype formulation Methodology A total of nine (XXXV) prototypes were prepared including simple buffer solution, co-solvent system and non-aqueous solution. These are shown in Table 12G. Prototypes 6, 7 and 8 were not evaluated further as they caused significant precipitation during preparation. The remaining prototypes were stored in serum vials at 2-8 ° C, room temperature, 40 ° C and 60 ° C. Samples stored at 2-8 ° C. and room temperature were analyzed at selected time points.

Results The data collected so far is shown in Tables 12G.1 to 12G.6. The aqueous buffer formulation (Prototype No. 1) was found to be stable at room temperature and under refrigeration, but some degradation was observed under accelerated conditions. Of particular interest was the very small amount of precipitates described as one or two snowflake-like particles observed after 2 weeks at 60 ° C and after 8 weeks at 40 ° C. The appearance of this precipitate during storage at 60 ° C. was consistent with the actual decrease in the first impurity peak, thus examining the possibility that the degradation product is insoluble.

  (XXXV) was unstable in prototype number 2, ie 50% PEG / 50% water without pH adjustment. The instability was probably due to the low pH of this formulation. This drug was found to be much more stable in prototype number 3 (which has the same 50% PEG base but also contains enough sodium hydroxide to bring the apparent pH up to about 4.5). Similarly, good stability was seen in prototype number 9, ie 70% propylene glycol / 30% water with ammonium acetate buffer to bring the apparent pH to about 5.3. Even in simple solutions of this salt in PEG or propylene glycol, good stability was seen, probably because there was no water as a reactant.

(Table 12G) (XXXVI) prototype for stability evaluation

(Table 12G.1) (XXXV) Stability of prototype formulation number 1

(Table 12G.2) (XXXV) Prototype formulation number 2 stability

(Table 12G.3) (XXXV) Prototype formulation number 3 stability

(Table 12G.4) (XXXV) Prototype formulation number 4 stability

(Table 12G.5) (XXXV) Prototype formulation number 5 stability

(Table 12G.6) (XXXV) Stability of prototype formulation number 9

G. Final formulation and GMP drug stability data The final formulation is shown in Table 12H. The stability data for the drug formulations of Table 12H at 25 ° C / 60% relative humidity and 2-8 ° C are shown in Tables 12I.1 and 12I.2, respectively. The levels of N- (4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII) measured during the stability test are shown in Table 12J.

(Table 12H) Final formulation of (XXXV)

a. GMPバッチの包装成分: 50mL透明、20mm開口、USP 1型ガラス(Wheaton 223745); テフロン2でコーティングされた灰色ブチルをストッパーとする。4416/50(West 1014 4937); フリップオフシール、20mm、3766白、8-ブリッジ(West 5420 3028)。
b. 無色〜淡黄色の液体。透明および無粒子
c. 無色液体。透明および無粒子
d. バイアルにはひび割れなし、ストッパがしっかりと定位置にあり、漏洩の兆候なし
e. 両バイアルにはひび割れなし、ストッパがしっかりと定位置にあり、漏洩の兆候なし
f. 各容器について、10μm以上の粒子 NMT 6000個; 25μm以上の粒子 NMT 600個
^*(I) = 倒立; ^**(U) = 直立 (Table 12I.1) Long-term stability results for (XXXVI) formulation GMP lot number 041I0511 ^a (25 ° C./60% relative humidity)

GMP batch packaging ingredients: 50 mL clear, 20 mm aperture, USP type 1 glass (Wheaton 223745); gray butyl coated with Teflon 2 as a stopper. 4416/50 (West 1014 4937); flip-off seal, 20 mm, 3766 white, 8-bridge (West 5420 3028).
b. Colorless to pale yellow liquid. Transparent and particle free
c. Colorless liquid. Transparent and particle free
d. Vials are not cracked, stopper is firmly in place, no signs of leakage
e. No crack on both vials, stopper is firmly in place, no signs of leakage
f. For each container, 6000 particles NMT over 10μm; 600 particles NMT over 25μm
^* (I) = inverted; ^** (U) = upright

a. GMPバッチの包装成分: 50mL透明、20mm開口、USP 1型ガラス(Wheaton 223745); テフロン2でコーティングされた灰色ブチルをストッパーとする。4416/50(West 1014 4937); フリップオフシール、20mm、3766白、8-ブリッジ(West 5420 3028)。
b. 無色〜淡黄色の液体。透明および無粒子
c. 無色液体。透明および無粒子
d. バイアルにはひび割れなし、ストッパがしっかりと定位置にあり、漏洩の兆候なし
e. 両バイアルにはひび割れなし、ストッパがしっかりと定位置にあり、漏洩の兆候なし
f. 各容器について、10μm以上の粒子 NMT 6000個; 25μm以上の粒子 NMT 600個
^*(I) = 倒立; ^**(U) = 直立 (Table 12I.2) Long-term stability results for (XXXVI) formulation GMP lot number 041I0511 ^a (5 ° C / ambient)

GMP batch packaging ingredients: 50 mL clear, 20 mm aperture, USP type 1 glass (Wheaton 223745); gray butyl coated with Teflon 2 as a stopper. 4416/50 (West 1014 4937); flip-off seal, 20 mm, 3766 white, 8-bridge (West 5420 3028).
b. Colorless to pale yellow liquid. Transparent and particle free
c. Colorless liquid. Transparent and particle free
d. Vials are not cracked, stopper is firmly in place, no signs of leakage
e. No crack on both vials, stopper is firmly in place, no signs of leakage
f. For each container, 6000 particles NMT over 10μm; 600 particles NMT over 25μm
^* (I) = inverted; ^** (U) = upright

(Table 12J) Level of degradation product 4,6-bis (propylamino) -1,3,5-triazin-2-ol (CLXXVIII)
GMP stability test, lot number GMP lot number 041I0511

  The disclosures of all patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. While the invention has been disclosed with reference to particular embodiments, it will be apparent to those skilled in the art that other embodiments and variations of the invention can be devised without departing from the spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims (69)

  A composition comprising at least one compound selected from the group consisting of: N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine ( CLXXII), N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino) -1 , 3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and any of them Combination.   2. The composition of claim 1, wherein the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.   2. The composition of claim 1, further comprising at least one pharmaceutically acceptable carrier.   A method of preventing or treating a respiratory control disorder or respiratory control disorder in a subject in need thereof, comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: A method comprising administering to said subject an effective amount of a pharmaceutical formulation: N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine (CLXXIII), N- (2,4,6-tris-n-propylamino)- 1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), its salts, and their Any combination.   A group of respiratory control disorder or respiratory control disorder consisting of respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia 5. The method of claim 4, wherein the method is more selected.   6. The method of claim 5, wherein the respiratory depression is caused by an anesthetic, sedative, anxiolytic, sleeping pill, alcohol or narcotic.   5. The method of claim 4, wherein the subject is further administered a composition comprising at least one additional compound useful for treating a respiratory control disorder or respiratory control disorder.   8. The method of claim 7, wherein the at least one additional compound is selected from the group consisting of acetazolamide, alumintrin, theophylline, caffeine, methylprogesterone, serotonin modulators, cannabinoids and ampakines.   5. The method of claim 4, wherein the formulation is administered in combination with the use of a ventilator or a positive airway pressure device to the subject.   5. The method of claim 4, wherein the subject is a mammal.   11. The method of claim 10, wherein the mammal is a human.   The formulation is administered to a subject by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. 4. The method described.   A method of preventing or stabilizing respiratory rhythm instability in a subject in need thereof, wherein the respiratory rhythm is at least one selected from the group consisting of at least one pharmaceutically acceptable carrier and Administering to the subject an effective amount of a pharmaceutical formulation comprising one compound: N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1, 3,5] triazine (CLXXII), N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine (CLXXIII), N- (2,4,6-tris-n -Propylamino) -1,3-pyrimidine (CLXXIV), N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine (CLXXV), Salt, and any combination thereof.   Instability is selected from the group consisting of respiratory depression, sleep apnea, premature infant apnea, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia 14. The method of claim 13, wherein the method is associated with a respiratory control disorder or a respiratory control disorder.   15. The method of claim 14, wherein respiratory depression is caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol or narcotics.   16. The method of claim 15, further comprising administering to the subject a composition comprising at least one additional compound useful for treating a respiratory control disorder or respiratory control disorder.   17. The method of claim 16, wherein the at least one additional compound is selected from the group consisting of acetazolamide, alumintrin, theophylline, caffeine, methylprogesterone, a serotonin modulator, a cannabinoid and an ampakine.   14. The method of claim 13, wherein the formulation is administered in combination with the use of a ventilator or a positive airway pressure device to the subject.   14. The method of claim 13, wherein the subject is a mammal.   20. The method of claim 19, wherein the mammal is a human.   The formulation is administered to a subject by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. 13. The method according to 13.   N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof, -(n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or less than about 1% (w / w) relative to (XXXV) or a salt thereof The composition.   4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is less than or equal to about 0.5% (w / w) relative to (XXXV) or a salt thereof 23. The composition of claim 22, wherein the composition is present at a level of:   4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is less than or equal to about 0.3% (w / w) relative to (XXXV) or a salt thereof 24. The composition of claim 23, present at a level of:   4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is less than or equal to about 0.2% (w / w) relative to (XXXV) or a salt thereof 25. The composition of claim 24, present at a level of:   4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is less than or equal to about 0.15% (w / w) relative to (XXXV) or a salt thereof 26. The composition of claim 25, present at a level of:   4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is less than or equal to about 0.1% (w / w) relative to (XXXV) or a salt thereof 27. The composition of claim 26, present at a level of:   28. The composition of claim 27, wherein 4,6-bis- (n-propylamino) -1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition.   Buffer and liquid carrier comprising N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) or a salt thereof A composition further comprising:   30. The composition of claim 29, wherein the salt of (XXXV) is hydrogen sulfate (XXXVI).   30. The composition of claim 29, further comprising citric acid.   30. The composition of claim 29, wherein the pH of the composition is adjusted with a base.   35. The composition of claim 32, wherein the base comprises sodium hydroxide.   30. The composition of claim 29, wherein the liquid carrier comprises water.   30. The composition of claim 29, wherein the pH of the composition ranges from about 2.5 to about 6.   36. The composition of claim 35, wherein the pH of the composition ranges from about 2.5 to about 5.   38. The composition of claim 36, wherein the pH of the composition ranges from about 3 to about 4.   30. The composition of claim 29, wherein the concentration of (XXXV) or a salt thereof in the composition is about 1-10 mg / mL.   39. The composition of claim 38, wherein the concentration of (XXXV) or a salt thereof in the composition is about 5-10 mg / mL.   40. The composition of claim 39, wherein the concentration of (XXXV) or a salt thereof in the composition is about 10 mg / mL.   30. The composition of claim 29, comprising less than 0.5% (w / w) (CLXXVIII) relative to (XXXV).   Less than 0.5% (w / w) of N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (CLXXVIII) relative to (XXXV) is 2 to 42. The composition of claim 41, formed at 8 [deg.] C over a 6 month shelf life of the composition.   Less than 0.5% (w / w) of N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (CLXXVIII) relative to (XXXV) is 2 to 43. The composition of claim 42, formed at 8 [deg.] C over a 12 month shelf life of the composition.   Less than 0.5% (w / w) of N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (CLXXVIII) relative to (XXXV) is 2 to 44. The composition of claim 43, wherein the composition is formed at 8 [deg.] C over a shelf life of 18 months.   Less than 0.5% (w / w) of N- (4,6-bis-n-propylamino)-[1,3,5] -triazin-2-ol (CLXXVIII) relative to (XXXV) is 2 to 45. The composition of claim 44, wherein the composition is formed at 8 [deg.] C over a 24 month shelf life of the composition.   Crystalline release of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine (XXXV) with the XRPD spectrum of FIG. Base form A. At least one of N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -NO-dimethyl-hydroxylamine (XXXV), selected from the group consisting of Crystalline salt:
(i) crystalline hydrogen sulfate (XXXVI) Form A having the XRPD spectrum of FIG. 14;
(ii) crystalline hydrogen sulfate (XXXVI) comprising a mixture of Form A and Form B having the XRPD spectrum of FIG. 23;
(iii) crystalline hydrogen sulfate (XXXVI) Form C having the XRPD spectrum of FIG. 24;
(iv) Crystalline hydrogen sulfate (XXXVI) Form D having the XRPD spectrum of FIG. 25;
(v) crystalline hydrogen sulfate (XXXVI) comprising a mixture of Form A and Form D having the XRPD spectrum of FIG. 26;
(vi) Crystalline phosphate (CLXXX) form A, having the XRPD spectrum of FIG. 27;
(vii) Crystalline phosphate (CLXXX) Form C having the XRPD spectrum of FIG. 28;
(viii) crystalline phosphate (CLXXX) comprising a mixture of Form A and Form B having the XRPD spectrum of FIG. 29;
(ix) crystalline phosphate (CLXXX) comprising a mixture of Form C and Form D, having the XRPD spectrum of FIG. 30;
(x) crystalline phosphate (CLXXX) comprising a mixture of Form C and Form E having the XRPD spectrum of FIG. 31;
And any mixture of them.   N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine (XXXV) salt containing about 1 molar equivalent of sulfuric acid.   49. The salt of claim 48, further comprising 1 molar equivalent of water.   N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N.O-dimethyl-hydroxylamine (XXXV) salt containing at least 1 molar equivalent of phosphoric acid.   51. The salt of claim 50, comprising about 1 molar equivalent of phosphoric acid. A method of reducing or minimizing the open channel portion of a potassium maxi-K or BK channel in a subject in need thereof, comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or Administering to the subject an effective amount of a pharmaceutical formulation comprising the salt thereof:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forming a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
R ³ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR ¹ R ² , —C (O) OR ¹ , acyl or aryl;
R ⁴ is H, alkyl or substituted alkyl;
R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR ¹ , -NR ¹ R ² , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, Are substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ⁵ together are 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane Forming a biradical selected from the group consisting of -1,8-diyl;
R ⁶ is H, alkyl, substituted alkyl or alkenyl;
X is a bond, O or NR ⁴ ;
Y is N, CR ⁶ or C; where
If Y is N or CR ⁶ then there is no bond b ¹ and
(i) Z is H, the bond b ² is a single bond, and A is CH;
(ii) Z is absent, bond b ² is absent, and A is a single bond;
When Y is C, the bond b ¹ is a single bond, and
(i) Z is CH ₂ , bond b ² is a single bond, and A is CH;
(ii) Z is CH, bond b ² is a double bond, and A is C. 53. The method of claim 52, wherein the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropyl Methyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6- n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3 , 5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl ) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl- Hydroxylamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl)- O-methyl-hydroxylamine, O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis -n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4- Diamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis- n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 -Il) -N-isopropyl- Droxylamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n- Propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3 , 5] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxyl Amine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 - yl) -O- isobutyl -N- methyl - hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ^2, N ⁴ - dipropyl-1,3,5-tri Gin-2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N -(4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propyl Amino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n -Propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -Amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazole-2 -Yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2-dimethylaminoethyl) Mino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1, 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazine- 2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl -Hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis- n-Propylamino- [1,3,5] triazin-2-yl) -N-methyl -N'-methylhydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethyl Amino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) Amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d Pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n -Propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] Pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrim N-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl -Hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino- 7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -Hydrazine, N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n- Propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3 , 5] triazine, N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1, 3-pyrimidine , N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.   54. The method of claim 52, wherein the subject is a mammal.   55. The method of claim 54, wherein the mammal is a human. A method of inhibiting TASK-1 (KCNK3) channel in a subject in need thereof, comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof Administering to the subject an effective amount of a formulation:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forming a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
R ³ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR ¹ R ² , —C (O) OR ¹ , acyl or aryl;
R ⁴ is H, alkyl or substituted alkyl;
R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR ¹ , -NR ¹ R ² , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, Are substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ⁵ together are 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane Forming a biradical selected from the group consisting of -1,8-diyl;
R ⁶ is H, alkyl, substituted alkyl or alkenyl;
X is a bond, O or NR ⁴ ;
Y is N, CR ⁶ or C; where
If Y is N or CR ⁶ then there is no bond b ¹ and
(i) Z is H, the bond b ² is a single bond, and A is CH;
(ii) Z is absent, bond b ² is absent, and A is a single bond;
When Y is C, the bond b ¹ is a single bond, and
(i) Z is CH ₂ , bond b ² is a single bond, and A is CH;
(ii) Z is CH, bond b ² is a double bond, and A is C. 59. The method of claim 56, wherein the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropyl Methyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6- n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3 , 5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl ) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl- Hydroxylamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl)- O-methyl-hydroxylamine, O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis -n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4- Diamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis- n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 -Il) -N-isopropyl- Droxylamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n- Propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3 , 5] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxyl Amine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 - yl) -O- isobutyl -N- methyl - hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ^2, N ⁴ - dipropyl-1,3,5-tri Gin-2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N -(4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propyl Amino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n -Propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -Amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazole-2 -Yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2-dimethylaminoethyl) Mino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1, 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazine- 2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl -Hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis- n-Propylamino- [1,3,5] triazin-2-yl) -N-methyl -N'-methylhydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethyl Amino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) Amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d Pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n -Propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] Pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrim N-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl -Hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino- 7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -Hydrazine, N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n- Propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3 , 5] triazine, N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1, 3-pyrimidine , N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.   58. The method of claim 57, wherein the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl)- O-methyl-hydroxylamine, N- (4,6-bis-n-propylamino-1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (2,4- Bis-n-propylamino) -N- (6-methylamino)-[1,3,5] triazine, N-[(2,6-bis-n-propylamino) -pyrimidin-4-yl] -N , O-dimethyl-hydroxylamine, N, N-dimethyl-N ′-(2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, its salts, and their blend.   57. The method of claim 56, wherein the subject is a mammal.   60. The method of claim 59, wherein the mammal is a human. A method for increasing minute ventilation in a subject in need thereof, comprising: at least one pharmaceutically acceptable carrier and at least one compound of formula (I) or a salt thereof. Administering an amount to the subject comprising:

Where
R ¹ and R ² are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R ¹ and R ^{2 taken} together are 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- Forming a biradical selected from the group consisting of cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl;
R ³ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR ¹ R ² , —C (O) OR ¹ , acyl or aryl;
R ⁴ is H, alkyl or substituted alkyl;
R ⁵ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR ¹ , -NR ¹ R ² , -C (O) OR ¹ , acyl, aryl, substituted aryl, heteroaryl, Are substituted heteroaryl, heterocycle or substituted heterocycle; or R ³ and R ⁵ together are 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane Forming a biradical selected from the group consisting of -1,8-diyl;
R ⁶ is H, alkyl, substituted alkyl or alkenyl;
X is a bond, O or NR ⁴ ;
Y is N, CR ⁶ or C; where
If Y is N or CR ⁶ then there is no bond b ¹ and
(i) Z is H, the bond b ² is a single bond, and A is CH;
(ii) Z is absent, bond b ² is absent, and A is a single bond;
When Y is C, the bond b ¹ is a single bond, and
(i) Z is CH ₂ , bond b ² is a single bond, and A is CH;
(ii) Z is CH, bond b ² is a double bond, and A is C. 62. The method of claim 61, wherein the compound of formula (I) is selected from the group consisting of: N- (4,6-bis-methylamino- [1,3,5] triazin-2-yl) -N , O-dimethyl-hydroxylamine, N- (4,6-bis-ethylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-cyclopropyl Methyl) -N- (6-n-propylamino) [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4-ethylamino) -N- (6- n-propylamino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2-methylpropylamino)) [1,3 , 5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl ) -N, O-dimethyl-hydroxylamine, N- (bis-4,6- (2,2-dimethylpropylamino)) [1,3,5] triazin-2-yl) -N, O-dimethyl- Hydroxylamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, N- (4- (methoxy (methyl) amino) -6- (n-propylamino) -1,3,5-triazin-2-yl) propionamide, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl)- O-methyl-hydroxylamine, O-allyl-N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, N- (4,6-bis -n-propylamino- [1,3,5] triazin-2-yl) -hydroxylamine, 6- (methoxy (methyl) amino) -N ² -propyl-1,3,5-triazine-2,4- Diamine, N- (4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis- n-propylamino- [1,3,5] triazin-2-yl) -N-methyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 -Il) -N-isopropyl- Droxylamine, 6- [1,2] oxazinan-2-yl-N, N'-dipropyl- [1,3,5] triazine-2,4-diamine, N- (4,6-bis-n- Propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-N-methyl-hydroxylamine, O-benzyl-N- (4,6-bis-n-propylamino- [1,3 , 5] Triazin-2-yl) -N-ethyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-isopropyl-hydroxyl Amine, 6-((benzyloxy) (isopropyl) amino) -N ² , N ⁴ -dipropyl-1,3,5-triazine-2,4-diamine, N- (4,6-bis-n-propylamino -[1,3,5] triazin-2-yl) -N-ethyl-O-isopropyl-hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazine-2 - yl) -O- isobutyl -N- methyl - hydroxylamine, 6- (methyl (thiophen-2-ylmethoxy) amino) -N ^2, N ⁴ - dipropyl-1,3,5-tri Gin-2,4-diamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -O-cyclopropylmethyl-N-methyl-hydroxylamine, N -(4,6-Bis-n-propylamino- [1,3,5] triazin-2-yl) -O-ethyl-N-methyl-hydroxylamine, N- (4,6-bis-n-propyl Amino- [1,3,5] triazin-2-yl) -O- (2,2-difluoro-ethyl) -hydroxylamine, 4-N- (2-dimethylaminoethyl) amino-6-N- (n -Propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (3- (1-N-methylimidazol-2-yl) -propyl) -Amino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4-N- (1-N-methylimidazole-2 -Yl) -methylamino-6-N- (n-propyl) amino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (2-dimethylaminoethyl) Mino)-[1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- (N- (pyridin-4-yl-methyl) amino)-[1, 3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (3-methoxy-n-propyl) amino]-[1,3,5] triazine- 2-yl) -N, O-dimethyl-hydroxylamine, 4,6-bis- [N- (tetrahydropyran-4-yl-methyl) amino]-[1,3,5] triazin-2-yl)- N, O-dimethyl-hydroxylamine, N- (5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo [13.3.1] nonadeca-1 (18), 15 (19), 16 (17) -Trien-17-yl) -N, O-dimethylhydroxylamine, 2,6-bis- (Nn-propylamino)-[1,3] pyrimidin-4-yl) -N, O-dimethyl -Hydroxylamine, N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N ', N'-dimethylhydrazine, N- (4,6-bis- n-Propylamino- [1,3,5] triazin-2-yl) -N-methyl -N'-methylhydrazine, 2- (n-propyl) amino-4- (i-propylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-dimethyl Amino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) amino-4-methylamino-7-methyl-pyrrolidino [2,3-d] pyrimidine, 2- (n-propyl) Amino-4- (i-propyl) amino-7-i-propyl-pyrrolidino [2,3-d] pyrimidine, 2,4-bis- (n-propyl) amino-7H-pyrrolidino [2,3-d Pyrimidine, 2- (n-propyl) amino-4- (4-hydroxypiperidin-1-yl) -7-methyl-pyrrolidino [2,3-d] pyrimidine, 8- (7-methyl-2- (n -Propylamino) -pyrrolidino [2,3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] octan-3-ol, N- (2-propylamino-7H-pyrrolo [2,3d] Pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrim N-4-yl) -N, O-dimethyl-hydroxylamine, N- (2- (propen-2-yl) amino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl -Hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -N, O-dimethyl-hydroxylamine, N- (2-n-propylamino- 7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -O-methyl-hydroxylamine, N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -Hydrazine, N-methyl-N- (2-n-propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N, N-dimethyl-N '-(2-n- Propylamino-7-methyl-pyrrolo [2,3d] pyrimidin-4-yl) -hydrazine, N- (2,4-bis-n-propylamino) -N- (6-methylamino)-[1,3 , 5] triazine, N- (2,4,6-tris-n-propylamino)-[1,3,5] triazine, N- (2,4,6-tris-n-propylamino) -1, 3-pyrimidine , N- (2,4-bis-n-propylamino) -N- (6-i-propylamino) -1,3-pyrimidine, its salts, and mixtures thereof.   The compound of formula (I) is N- (4,6-bis-n-propylamino- [1,3,5] triazin-2-yl) -N, O-dimethyl-hydroxylamine or a salt thereof, Item 62. The method according to Item 62.   62. The method of claim 61, wherein the pharmaceutical formulation is administered by intravenous infusion.   65. The method of claim 64, wherein the injected dose of the pharmaceutical formulation is at least about 0.016 mg / kg / min.   66. The method of claim 65, wherein the injected dose of the pharmaceutical formulation is about 0.016 mg / kg / min.   62. The method of claim 61, wherein the infusion amount of the pharmaceutical composition results in a plasma concentration of at least about 726 ng / mL in the subject.   62. The method of claim 61, wherein the subject is a mammal.   69. The method of claim 68, wherein the mammal is a human.

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