Cyclic pyrazinoylguanidine sodium channel blockers

This application claims priority under US Patent Provisional Application No. 60/495720, filed August 18, 2003, which is incorporated herein by reference.

The present invention relates to sodium channel blockers. The present invention further includes various therapeutic methods using these inventive sodium channel blockers.

The mucosal surface, located at the interface between the surroundings and the body, develops some "congenital defenses", or protective mechanisms. The main form of such innate defense is the use of liquids to clean these surfaces. Usually, the amount of liquid layer present on the mucosal surface is often the anion (Cl) that is bound to water (and the cation counterion).^-And / or HCO₃^-) And often water and counterions (Cl)^-And / or HCO₃^-) And Na⁺It reflects the balance with epithelial fluid absorption, which reflects absorption. Many diseases of mucosal surfaces are induced by too little protective fluid on these mucosal surfaces, which results from an imbalance between secretion (too little) and absorption (relatively too much). The protective salt transport processes that characterize these mucosal dysfunctions belong to the epithelial layer on the mucosal surface.

One technique for replenishing the protective fluid layer located on the mucosal surface is Na⁺It is to "rebalance" this system by blocking channels and liquid absorption. Na⁺Epithelial proteins that mediate the rate-determining step and fluid absorption of epithelial Na⁺Channel (ENaC). ENaC is located on the tip surface of the epithelium, i.e. the mucosal surface-peripheral interface. Therefore, Na mediated by ENaC⁺And in order to inhibit fluid absorption, it is necessary to transport the ENaC blocker of the amylolide group (which blocks ENaC from the extracellular space) to the mucosal surface, which is important to achieve the therapeutic effect. To do so, hold it in that position. The present invention provides for diseases characterized by too little fluid on the mucosal surface as well as the high potency, low mucosal absorption and slow dissociation from ENaC (unbound or detachment) required to treat these diseases. Describe a "local" sodium channel blocker designed as shown.

Cystic fibrosis (CF), a chronic bronchitis that includes the most common fatal genetic form of chronic bronchitis (CB), reflects the inability of the body to normally remove mucus from the lungs. It is a disease that ultimately leads to chronic airway inflammation. In normal lungs, primary protection against chronic intrapulmonary airway infections (chronic bronchitis) is mediated by continuous removal of mucus from the surface of the bronchial respiratory tract. If healthy, this function effectively removes toxins and pathogens that may be harmful from the lungs. Recent data indicate that the initial problem with both CB and CF, the "basic defect," is the inability to remove mucus from the airway surface. The inability to remove mucus reflects an imbalance between the amount of liquid located on the surface of the airways and mucin. This "airway surface fluid" (ASL) consists primarily of plasma-like proportions of salt and water (ie, isotonic). Mucin macromolecules organize a well-defined "mucous layer," which normally traps inhaled bacteria and "periciliary." It is carried out of the lungs through the action of pili that strike a watery, low-viscosity solution called "liquid)" (PCL). In the diseased state, there is an imbalance in the amount of mucus as ASL on the surface of the airways. This results in a relative reduction in ASL, which results in mucus concentration, reduced PCL lubricant activity and failure to remove mucus into the mouth via pili activity. Decreased mechanical removal of mucus from the lungs results in chronic bacterial colonization of mucus adhering to the airway surface. Chronic retention of bacteria, the inability of local antibacterial substances to eradicate bacteria trapped in mucus in the long term, and the body's continuous chronic inflammatory response to this type of surface infection are the syndromes of CB and CF. Bring.

The currently afflicted population in the United States is 12,000,000 patients with an acquired form of chronic bronchitis (mainly due to exposure to cigarette smoke) and approximately 30,000 with a genetic form of cystic fibrosis. I am a patient. Almost the same number of both populations exist in Europe. In Asia, CF is low, but as in the world and elsewhere, the incidence of CB is high and increasing.

Currently, there is a great unmet medical need for products that specifically treat CB and CF at the level of the underlying defect that results in these diseases. Current treatments for chronic bronchitis and cystic fibrosis focus on treating the symptoms and / or late effects of these diseases. Therefore, in chronic bronchitis, β-agonists, inhaled steroids, anticholinergic agents and oral theophylline and phosphodiesterase inhibitors are all being developed. However, none of these drugs effectively treat the fundamental problem of inability to remove mucus from the lungs. Similarly, in cystic fibrosis, the same spectrum of pharmacological agents is used. These strategies have recently been designed to remove DNA deposited in the lungs from CF lungs by neutrophils making futile attempts to eradicate bacteria growing in adherent mucous material. Strategy ("Pulmozyme"; Genentech) is further complemented by inhaled antibiotics ("TOBI") designed to increase the eradication mechanism of the lung itself, which removes bacterial adherent mucous plaques. .. In the normal principle of the body, in the case of mucus retention / occlusion, if the initiating lesion is not treated, the bacterial infection becomes chronic and resistant to antibacterial treatment. Therefore, the main unsatisfied therapeutic requirement for both CB and CF lung disease is rehydration of airway mucus (ie, recovery / expansion of ASL capacity) and its removal from the lungs (along with bacteria). ) Is an effective means of promoting.

RC Boucher (US Pat. No. 6,264,975) states that a pyrazinoylguanidine sodium channel blocker is used to hydrate the mucous surface. This compound, which is usually the well-known diuretics amylolide, benzamyl and phenamil, is effective. However, these compounds are (1) relatively impotent (this is important because the amount of drug that can be inhaled into the lungs is limited); (2) rapidly absorbed ( The half-life of the drug on the mucous surface is limited); (3) It has the great drawback of being able to dissociate freely from ENaC. All of these shortcomings manifested by these well-known diuretics result in compounds that have insufficient potency and / or effective half-life on the mucous surface to obtain the therapeutic benefit of hydrating the mucous surface. There is.

Obviously, more effective drugs are needed to restore mucus removal from the lungs of patients with CB / CF. The value of these new therapies will be reflected in improving quality of life and longevity in both the CF and CB populations.

Other mucosal surfaces in and above the body show subtle differences in the normal physiology of protective surface fluids on that surface, but the pathological physiology of the disease has a common theme: too little protective surface fluid. It reflects. For example, in xerostomia (xerostomia), continuous Na⁺Despite fluid absorption from the oral cavity mediated by (ENaC) transport, the oral cavity is depleted of fluid due to the inability of the parotid, sublingual and submandibular glands to secrete fluid. Similarly, keratoconjunctivitis sicca (dry eye) is a continuous Na on the contact surface.⁺Despite dependent fluid absorption, it is triggered by the inability of the lacrimal glands to secrete fluid. In nasal sinusitis, as with CB, there is an imbalance between mucus secretion and relative ASL depletion. Finally, in the gastrointestinal tract, Cl- (and fluid) is not secreted in the proximal small intestine, and high Na in the lower ileum.⁺Combined with (and liquid) absorption, distal bowel obstruction syndrome (DIOS) occurs. Excess Na in the descending colon in older patients⁺(And volume) absorption results in constipation and diverticulitis.

500 million Americans and hundreds of millions of others around the world suffer from hypertension, the subsequent sequelae of which lead to congestive heart failure and increased mortality. It is a leading cause of death in Western Europe and new medicines are needed to treat these diseases. Thus, in addition, some of the novel sodium channel blockers of the invention can be designed to target the kidneys, which can be used as is for hypertension, congestive heart failure (CHF) and other cardiovascular diseases. It can be used as a diuretic for treatment. These novel agents can be used alone or in combination with beta blockers, ACE inhibitors, HMGCoA reductase inhibitors, calcium channel blockers and other cardiovascular agents.<patcit num="1"><text>U.S. Patent Application No. 60/495720</text></patcit><patcit num="2"><text>U.S. Pat. No. 6,264,975</text></patcit><patcit num="3"><text>U.S. Pat. No. 5,656,256</text></patcit><patcit num="4"><text>U.S. Pat. No. 5292498</text></patcit><patcit num="5"><text>U.S. Pat. No. 5,899,391</text></patcit><patcit num="6"><text>U.S. Pat. No. 5,740,794</text></patcit><patcit num="7"><text>U.S. Pat. No. 5,654,007</text></patcit><patcit num="8"><text>U.S. Pat. No. 5,458 135</text></patcit><patcit num="9"><text>U.S. Pat. No. 5,775,320</text></patcit><patcit num="10"><text>U.S. Pat. No. 5785049</text></patcit><patcit num="11"><text>U.S. Pat. No. 5,622,166</text></patcit><patcit num="12"><text>U.S. Pat. No. 5577497</text></patcit><patcit num="13"><text>U.S. Pat. No. 5645051</text></patcit><patcit num="14"><text>U.S. Pat. No. 5,492,112</text></patcit><patcit num="15"><text>U.S. Pat. No. 5,826,570</text></patcit><patcit num="16"><text>U.S. Pat. No. 5813397</text></patcit><patcit num="17"><text>U.S. Pat. No. 5819726</text></patcit><patcit num="18"><text>U.S. Pat. No. 5,655,516</text></patcit><patcit num="19"><text>U.S. Pat. No. 4501729</text></patcit><nplcit num="1"><text>J. Nairn, Solutions, Emulsions, Suspensions and Extracts, in Remington: The Science and Practice of Pharmacy, chap. 86 (19thed. 1995)</text></nplcit><patcit num="20"><text>U.S. Pat. No. 4,389,393</text></patcit><patcit num="21"><text>U.S. Pat. No. 5,707,644</text></patcit><patcit num="22"><text>U.S. Pat. No. 4,294,829</text></patcit><patcit num="23"><text>U.S. Pat. No. 4,835,142</text></patcit><patcit num="24"><text>U.S. Pat. No. 5,656,256</text></patcit><nplcit num="2"><text>EJ Cragoe, "The Synthesis of Amiloride and Its Analogs" (Chapter 3) in Amiloride and Its Analogs, PP. 25-36</text></nplcit><patcit num="25"><text>U.S. Pat. No. 3313813</text></patcit><patcit num="26"><text>U.S. Pat. No. 229929</text></patcit><patcit num="27"><text>U.S. Pat. No. 233377</text></patcit><patcit num="28"><text>U.S. Pat. No. 234105</text></patcit><nplcit num="3"><text>Sabater et al, Journal of Applied Physiology, 1999, pp. 2191-2196</text></nplcit>

<p> It is an object of the present invention to provide compounds that are more potent than known compounds and / or are absorbed from the mucous surface later and / or less reversible than them.</p><p> Other aspects of the invention are compounds that are more potent than compounds such as amilorde, benzamil and phenamil, and / or are absorbed on the mucous surface later and / or exhibit less reversibility. To provide (I). Therefore, compounds of formula (I) will exhibit a longer pharmacodynamic half-life than known compounds on the mucosal surface.</p><p> Another object of the present invention is (1) to be absorbed from the mucosal surface, especially the airway surface, later than known compounds; (2) to block sodium channels when absorbed from the mucosal surface after being administered to the mucosal surface. In doing so, it is to provide a compound of formula (I) that changes in vivo to its metabolic derivative, which has a lower potency than the administered parent compound.</p><p> Another object of the present invention is to provide compounds of formula (I) that are more potent than compounds such as amylolide, benzamil and phenamil, and / or are absorbed later and / or exhibit lower reversibility. To provide. Therefore, a compound of formula (I) will exhibit a longer pharmacodynamic half-life on the mucosal surface than the preceding compound.</p><p> Another object of the present invention is to provide a compound of formula (I) that targets the kidney for use in treating cardiovascular disease.</p><p> Another object of the present invention is to provide a therapeutic method utilizing the above-mentioned properties.</p>

<p> The object of the present invention can be achieved by using the pyrazinoylguanidine compound group represented by the formula (I):</p><p><chemistry num="1"><img file="JP2007502829A_D0001.tif" /></chemistry></p><p>[In the above formula, X is hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-sulfonyl or phenyl-lower alkyl-sulfonyl. Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkylthio, halogen, lower alkyl, unsubstituted or substituted mononuclear aryl or -N (R)²)₂Is; R¹Is hydrogen or lower alkyl; R²Are independent, -R⁷,-(CH₂)_m-OR⁸,-(CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰,-(CH₂)_n-Z_g-R⁷,-(CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷Or</p><p><chemistry num="2"><img file="JP2007502829A_D0002.tif" /></chemistry></p><p>Is; R³And R⁴Are independently hydrogen, group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl) -lower alkyl, lower- (alkylphenyl alkyl), lower (alkoxyphenyl). )-Lower alkyl, naphthyl-Lower alkyl or pyridyl-Lower alkyl, but R³And R⁴At least one of the equations (A)<chemistry num="3"><img file="JP2007502829A_D0003.tif" /></chemistry>Is a group represented by; R^LAre independent, -R⁷,-(CH₂)_n-OR⁸, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸, -O- (CH₂CH₂O)_mR⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_m-(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_m-CO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,</p><p><chemistry num="4"><img file="JP2007502829A_D0004.tif" /></chemistry></p><p>; O is an integer from 0 to 10 independently, and p is an integer from 0 to 10, respectively; however, the sum of o and p in the adjacent chains is 1 to 10. Yes; x is independent of O, NR¹⁰, C (= O), CHOH, C (= NR)¹⁰), CHNR⁷R¹⁰Or represents a single bond; R⁵Are independent, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸, -O- (CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_m-(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_mCO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,</p><p><chemistry num="5"><img file="JP2007502829A_D0005.tif" /></chemistry></p><p> R⁵Are independent,-(CH₂)_n-NR¹²R¹², -O- (CH₂)_m-NR¹²R¹², -O- (CH₂)_n-NR¹²R¹², -O- (CH₂)_m(Z)_gR¹²,-(CH₂)_nNR¹¹R¹¹, -O- (CH₂)_mNR¹¹R¹¹,-(CH₂)_n-N⁺-(R¹¹)₃, -O- (CH₂)_m-N⁺-(R¹¹)₃,-(CH₂)_n-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰, -O- (CH₂)_m-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰,-(CH₂CH₂O)_m-CH₂CH₂NR¹²R¹², -O- (CH₂CH₂O)_m-CH₂CH₂NR¹²R¹²,-(CH₂)_n-(C = O) NR¹²R¹², -O- (CH₂)_m-(C = O) NR¹²R¹², -O- (CH₂)_m-(CHOR⁸)_mCH₂NR¹⁰-(Z)_g-R¹⁰,-(CH₂)_n-(CHOR⁸)_mCH₂-NR¹⁰-(Z)_g-R¹⁰,-(CH₂)_nNR¹⁰-O (CH₂)_m(CHOR⁸)_n-CH₂NR¹⁰-(Z)_g-R¹⁰, -O (CH)₂)_m-NR¹⁰-(CH₂)_m-(CHOR⁸)_nCH₂NR¹⁰-(Z)_g-R¹⁰,-(Het)-(CH₂)_m-OR⁸,-(Het)-(CH₂)_m-NR⁷R¹⁰,-(Het)-(CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(Het)-(CH₂CH₂O)_m-R⁸,-(Het)-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(Het)-(CH₂)_m-C (= O) NR⁷R¹⁰,-(Het)-(CH₂)_m-(Z)_g-R⁷,-(Het)-(CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(Het)-(CH₂)_m-CO₂R⁷,-(Het)-(CH₂)_m-NR¹²R¹²,-(Het)-(CH₂)_n-NR¹²R¹²,-(Het)-(CH₂)_m-(Z)_gR¹²,-(Het)-(CH₂)_mNR¹¹R¹¹,-(Het)-(CH₂)_m-N⁺-(R¹¹)₃,-(Het)-(CH₂)_m-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰,-(Het)-(CH₂CH₂O)_m-CH₂CH₂NR¹²R¹²,-(Het)-(CH₂)_m-(C = O) NR¹²R¹²,-(Het)-(CH₂)_m-(CHOR⁸)_mCH₂NR¹⁰-(Z)_g-R¹⁰,-(Het)-(CH₂)_m-NR¹⁰-(CH₂)_m-(CHOR⁸)_nCH₂NR¹⁰-(Z)_g-R¹⁰It may be, in this case, two -CHs₂OR⁸R if they are located 1,2- or 1,3- relative to each other⁸The groups are bonded and mono- or di-substituted cyclic 1,3-dioxane or 1,3-dioxolane,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane) -O- (CH)₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane)-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane), or -O- (CH)₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸The groups combine to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane), forming R⁵Are independent of each other, Link- (CH₂)_n-CAP, Link- (CH₂)_n(CHOR⁸) (CHOR⁸)_n-CAP, Link- (CH₂CH₂O)_m-CH₂-CAP, Link- (CH₂CH₂O)_m-CH₂CH₂-CAP, Link- (CH₂)_n-(Z)_g-CAP, Link- (CH₂)_n(Z)_g(CH₂)_m-CAP, Link- (CH₂)_n-NR¹³-CH₂(CHOR⁸) (CHOR⁸)_n-CAP, Link- (CH₂), (CHOR⁸)_mCH₂-NR¹³-(Z)_g-CAP, Link- (CH₂)_nNR¹³-(CH₂)_m(CHOR⁸)_nCH₂NR¹³-(Z)_g-CAP, Link- (CH₂)_m-(Z)_g-(CH₂)_m-CAP, Link-NH-C (= O) -NH- (CH₂)_m-CAP, Link- (CH₂)_m-C (= O) NR¹³-(CH₂)_m-C (= O) NR¹⁰R¹⁰, Link- (CH₂)_m-C (= O) NR¹³-(CH₂)_m-CAP, Link- (CH₂)_m-C (= O) NR¹¹R¹¹, Link- (CH₂)_m-C (= O) NR¹²R¹², Link- (CH₂)_n-(Z)_g-(CH₂)_m-(Z)_g-CAP, Link-Z_g-(CH₂)_m-Het- (CH₂)_m-Can be CAP; Links are independent, -O-,-(CH₂)_n-, -O (CH₂)_m-, -NR¹³-C (= O) -NR¹³, -NR¹³-C (= O)-(CH₂)_m-, -C (= O) NR¹³-(CH₂)_m,-(CH₂)_n-Z_g-(CH₂)_n, -S-, -SO-, -SO₂-,-SO₂NR⁷-,-SO₂NR¹⁰-Or -Het-; CAPs are independently thiazolidinedione, oxazolidinedione, heteroaryl-C (= O) NR¹³R¹³, -Heteroaryl-W, -CN, -OC (= S) NR¹³R¹³, -Z_gR¹³, -CR¹⁰(Z_gR¹³) (Z_gR¹³), -C (= O) OAr, -C (= O) NR¹³Ar, imidazoline, tetrazole, tetrazolamide, -SO₂NHR¹³, -SO₂NH-C (R¹³R¹³)-(Z)_g-R¹³, Cyclic sugar or oligosaccharide, Cyclic amino sugar or oligosaccharide,</p><p><chemistry num="6"><img file="JP2007502829A_D0006.tif" /></chemistry></p><p>Ar is phenyl and substituted phenyl, respectively, where the substituents of the substituted phenyl are OH and OCH.₃, NR¹³R¹³, Cl, F and CH₃Or 1 to 3 substituents independently selected from the group consisting of heteroaryl; W is thiazolidinedione, oxazolidinedione, heteroaryl-C (= O) NR, respectively.¹³R¹³, -CN, -OC (= S) NR¹³R¹³, -Z_gR¹³, -CR¹⁰(Z_gR¹³) (Z_gR¹³), -C (= O) OAr, -C (= O) NR¹³Ar, imidazoline, tetrazole, tetrazolamide, -SO₂NHR¹³, -SO₂NH-C (R¹³R¹³)-(Z)_g-R¹³, Cyclic sugar or oligosaccharide, Cyclic amino sugar or oligosaccharide,</p><p><chemistry num="7"><img file="JP2007502829A_D0007.tif" /></chemistry></p><p>Is; R⁶Are independent, -R⁵, -R⁷, -OR⁸, -N (R)⁷)₂,-(CH₂)_m-OR⁸, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸, -O- (CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_m-(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_mNR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_m-CO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,</p><p><chemistry num="8"><img file="JP2007502829A_D0008.tif" /></chemistry></p><p>And here are two -CHs₂OR⁸R if they are located 1,2- or 1,3- relative to each other⁸The groups combine to form a mono- or di-substituted cyclic 1,3-dioxane or 1,3-dioxolane; R⁷Are independently hydrogen, lower alkyl, phenyl, substituted phenyl or -CH₂(CHOR)⁸_m-R¹⁰Is; R⁸Are independent of hydrogen, lower alkyl, -C (= O) -R¹¹, Glucuronide, 2-tetrahydropyranyl, or</p><p><chemistry num="9"><img file="JP2007502829A_D0009.tif" /></chemistry></p><p>Is; R⁹Are independent, -CO₂R¹³, -CON (R¹³)₂, -SO₂CH₂R¹³Or -C (= O) R¹³Is; R¹⁰Are independent, -H, -SO₂CH₃, -CO₂R¹³, -C (= O) NR¹³R¹³, -C (= O) R¹³Or-(CH₂)_m-(CHOH)_n-CH₂OH; Z is CHOH, C (= O),-(CH, respectively)₂)_n-,-CHNR¹³R¹³, C = NR¹³Or NR¹³Is; R¹¹Are each independently lower alkyl; R¹²Are independent, -SO₂CH₃, -CO₂R¹³, -C (= O) NR¹³R¹³, -C (= O) R¹³Or-CH₂-(CHOH)_n-CH₂OH; R¹³Are independent of hydrogen and R⁷, R¹⁰,-(CH₂)_m-NR¹³R¹³, +-(CH₂)_m-NR¹³R¹³R¹³,-(CH₂)_m-(CHOR⁸)_m-(CH₂)_mNR¹³R¹³,-(CH₂)_m-NR¹⁰R¹⁰ +-(CH₂)_m-(CHOR⁸)_m-(CH₂)_mNR¹³R¹³R¹³、 </p><p><chemistry num="10"><img file="JP2007502829A_D0010.tif" /></chemistry></p><p>However, NR¹³R¹³Combined itself below:</p><p><chemistry num="11"><img file="JP2007502829A_D0011.tif" /></chemistry></p><p>You may form a ring containing any of the; Het independently, -NR¹³-, -S-, -SO-, -SO₂-, -O-, -SO₂NR¹³-,-NHSO₂-, -NR¹³CO- or -CONR¹³-And g is an integer from 1 to 6 independently; m is an integer from 1 to 7 independently; n is an integer from 0 to 7 independently; Q is an independent integer To, -CR⁶R⁵, -CR⁶R⁶, -NR¹⁰, -NR⁷, -NR⁵, -S-, -SO-, or -SO₂-And; up to 3 Qs in the ring contain heteroatoms and at least 1 Q is -CR⁵R⁶Or NR⁵Must; each V is independent,-(CH₂)_m-NR⁷R¹⁰,-(CH₂)_mNR⁷R⁷,-(CH₂)_m-+ NR¹¹R¹¹R¹¹,-(CH₂)_n-(CHOR⁸)_m-(CH₂)_mNR⁷R¹⁰,-(CH₂)_n-NR¹⁰R¹⁰, +-(CH₂)_n-(CHOR⁸)_m-(CH₂)_mNR⁷R⁷,-(CH₂)_n-(CHOR⁸)_m-(CH₂)_mNR¹¹R¹¹R¹¹However, if V is directly bonded to the nitrogen atom, V is independently R.⁷, R¹⁰Or (R¹¹)₂May be; however, two -CHs₂OR⁸R if the groups are located 1,2- or 1,3- relative to each other⁸The groups may be combined to form a mono- or di-substituted cyclic 1,3-dioxane or 1,3-dioxolane; any of the above compounds may be pharmaceutically acceptable salts thereof. , Said compounds include all enantiomers, diastereoisomers and racemic mixtures thereof].</p><p> In a preferred embodiment,-(CH₂)_n-(Z)_g-R⁷Are within the above-mentioned structure, respectively, and independently,-(CH₂)_n-(C = N) -NH₂,-(CH₂)_n-NH-C (= NH) NH₂,-(CH₂)_n-CONHCH₂(CHOH)_n-CH₂OH or -NH-C (= O) -CH₂-(CHOH)_nCH₂OH.</p><p> In another preferred embodiment, -O- (CH)₂)_m-(Z)_g-R⁷Are within the above-mentioned structure, respectively, and independently, -O- (CH)₂)_M-NH-C (= NH) -N (R)⁷)₂Or -O- (CH₂)_m-CHNH₂-CO₂NR⁷R¹⁰Is.</p><p> In another preferred embodiment, R⁵Are within the above-mentioned structure, respectively, and independently, -O-CH₂CHOHCH₂O-glucuronide, -OCH₂CHOHCH₃, -OCH₂CH₂NH₂, -OCH₂CH₂NHCO (CH₃)₃, -CH₂CH₂OH, -OCH₂CH₂OH, -O- (CH₂)_m-Boc,-(CH₂)_m-Boc, -OCH₂CH₂OH, -OCH₂CO₂H, -O- (CH₂)_m-NH-C (= NH) -N (R)⁷)₂,-(CH₂)_n-NH-C (= NH) -N (R)⁷)₂, -NHCH₂(CHOH)₂-CH₂OH, -O-CH₂CO₂Et, -NHSO₂CH₃,-(CH₂)_m-NH-C (= O) -OR⁷, -O- (CH₂)_m-NH-C (= O) -OR⁷,-(CH₂)_n-NH-C (= O) -R¹¹, -O- (CH₂)_m-NH-C (= O) -R¹¹, -O-CH₂C (= O) NH₂, -CH₂NH₂, -NHCO₂Et, -OCH₂CH₂CH₂CH₂OH, -CH₂NHSO₂CH₃, -OCH₂CH₂CHOHCH₂OH, -OCH₂CH₂NHCO₂Et, -NH-C (= NH2) -NH₂, -OCH₂-(α-CHOH)₂-CH₂OH-OCH₂CHOHCH₂NH₂、 </p><p><chemistry num="12"><img file="JP2007502829A_D0012.tif" /></chemistry></p><p>-(CH₂)_m-CHOH-CH₂-NHBoc, -O- (CH₂)_m-CHOH-CH₂-NHBoc,-(CH₂)_m-NHC (O) OR⁷, -O- (CH₂)_m-NHC (O) OR⁷, -O-CH₂CH₂CH₂NH₂, -OCH₂CH₂NHCH₂(CHOH)₂CH₂OH, -OCH₂CH₂NH (CH)₂[(CHOH)₂CH₂OH)]₂,-(CH₂)₄-NHBoc,-(CH₂)₄-NH₂,-(CH₂)₄-OH, -OCH₂CH₂NHSO₂CH₃, -O- (CH₂)_m-C (= NH) -N (R)⁷)₂,-(CH₂)_n-C (= NH) -N (R)⁷)₂,-(CH₂)₃-NH Boc,-(CH₂)₃NH₂, -O- (CH₂)_m-NH-NH-C (= NH) -N (R)⁷)₂,-(CH₂)_n-NH-NH-C (= NH) -N (R)⁷)₂, Or -O-CH₂-CHOH-CH₂-NH-C (= NH) -N (R)⁷)₂;.</p><p> R in the above embodiment⁵A preferred example of: -N (SO)₂CH₃)₂, -CH₂-CHNHBocCO₂CH₃(α), -O-CH₂-CHNH₂CO₂H (α), -O-CH₂-CHNH₂CO₂CH₃(α), -O- (CH₂)₂-N⁺(CH₃)₃, -C (= O) NH- (CH₂)₂-NH₂, And -C (= O) NH- (CH₂)₂-NH-C (= NH) -NH₂Is included.</p><p> R⁵A preferred example of: -N (SO)₂CH₃)₂, -CH₂-CHNHBocCO₂CH₃(α), -O-CH₂-CHNH₂CO₂H (α), -O-CH₂-CHNH₂CO₂CH₃(α), -O- (CH₂)₂-N⁺(CH₃)₃, -C (= O) NH- (CH₂)₂NH₂, -C (= O) NH- (CH₂)₂-NH-C (= NH) -NH₂,and</p><p><chemistry num="13"><img file="JP2007502829A_D0013.tif" /></chemistry></p><p>Is included.</p><p> The present invention further provides a drug composition containing the above compounds.</p><p> The present invention further provides a method of facilitating hydration of the mucosal surface, which comprises administering an effective amount of a compound represented by the formula (I) to the mucosal surface of a subject.</p><p> The present invention further provides a method of restoring mucosal defense, which comprises topically administering an effective amount of a compound represented by formula (I) to the mucosal surface of a subject in need thereof.</p><p> The present invention further provides a method of blocking ENaC, which comprises contacting a sodium channel with an effective amount of a compound represented by formula (I).</p><p> The present invention further provides a method of facilitating mucus removal on the mucosal surface, which comprises topically administering an effective amount of the compound represented by formula (I) to the mucosal surface of the examiner.</p><p> The present invention further provides a method of treating chronic bronchitis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating cystic fibrosis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating sinusitis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating nasal dryness, which comprises administering an effective amount of a compound represented by formula (I) to the nasal passages of the subject in need thereof.</p><p> In a particular embodiment, nasal dryness is caused by administration of dry oxygen to the subject.</p><p> The present invention further provides a method of treating sinusitis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating pneumonia, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of preventing mechanical ventilation-induced pneumonia, which comprises administering an effective amount of a compound represented by formula (I) to a subject with mechanical ventilation.</p><p> The present invention further provides a method of treating asthma, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating primary ciliary dyskinesia, which comprises administering an effective amount of a compound represented by the formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating otitis media, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of inducing sputum for diagnosis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating chronic obstructive pulmonary disease, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating emphysema, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating dry eye syndrome, which comprises administering an effective amount of a compound represented by formula (I) to the eye of a subject in need thereof.</p><p> The present invention further provides a method of facilitating eye hydration, which comprises administering to the subject's eye an effective amount of a compound represented by formula (I).</p><p> The present invention further provides a method of facilitating corneal hydration, which comprises administering to the eye of a subject an effective amount of a compound represented by formula (I).</p><p> The present invention further provides a method of treating Sjogren's syndrome, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating a dry vagina, which comprises administering an effective amount of a compound represented by formula (I) to the vaginal canal of a subject in need thereof.</p><p> The present invention further provides a method of treating dry skin, which comprises administering an effective amount of a compound represented by formula (I) to the skin of a subject in need thereof.</p><p> The present invention further provides a method of treating dry mouth (xerostomia), which comprises administering an effective amount of a compound represented by the formula (I) to the oral cavity of a subject in need thereof.</p><p> The present invention further provides a method of treating distal ileus syndrome, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating esophagitis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating constipation, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof. In one embodiment of the method, the compound is administered orally or via a suppository or enema.</p><p> The present invention further provides a method of treating chronic diverticulitis, which comprises administering an effective amount of a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating hypertension, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of lowering blood pressure, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of treating edema, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of promoting diuresis, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of promoting natriuresis, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p><p> The present invention further provides a method of promoting salt diuresis, which comprises administering a compound represented by formula (I) to a subject in need thereof.</p>

In the present invention, compounds of formula (I) are more potent and / or later absorbed from mucosal surfaces, especially airway surfaces, and / or with ENaC than compounds such as amylolide, benzamil and phenamil. Based on the finding that reversibility from the interaction is low. Therefore, the compounds of formula (I) have a longer half-life on the mucosal surface than these compounds.

In the compound represented by the formula (I), X is hydrogen, halogen, trifluoromethyl, lower alkyl, lower cycloalkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl-. It may be sulfonyl or phenyl-lower alkyl-sulfonyl. Halogen is preferred.

Examples of halogens include fluorine, chlorine, bromine and iodine. Chlorine and bromine are the preferred halogens. Chlorine is particularly preferred. This statement applies to the term "halogen" as used throughout this disclosure.

As used herein, the term "lower alkyl" means an alkyl group having less than eight carbon atoms. This range includes the specific values of carbon atoms and all of the subranges in between, for example 1, 2, 3, 4, 5, 6 and 7 carbon atoms. The term "alkyl" includes all types of such groups, such as straight chain, branched chain and cyclic alkyl groups. This statement applies to the term "lower alkyl" as used throughout this disclosure. Examples of suitable lower alkyls include methyl, ethyl, propyl, cyclopropyl, butyl, isobutyl and the like.

Substituents with phenyl groups include halogens. Particularly preferred halogen substituents are chlorine and bromine.

Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen, lower alkyl, lower cycloalkyl, mononuclear aryl or -N (R)²)₂May be. The alkyl component of the lower alkoxy group is the same component as described above. Examples of mononuclear aryls include phenyl groups. The phenyl group may be unsubstituted or substituted as described above. Y's preferred identity is -N (R)²)₂Is. R²Compounds in which each is hydrogen are particularly preferable.

R¹May be hydrogen or lower alkyl. Hydrogen is R¹Is preferable.

R²Are independent, -R⁷,-(CH₂)_m-OR⁸,-(CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰,-(CH₂)_n-Z_g-R⁷,-(CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷Or

<chemistry num="14"><img file="JP2007502829A_D0014.tif" /></chemistry>

Is.

Hydrogen and lower alkyl, especially C₁~ C₃Alkyl is R²Is preferable. Hydrogen is particularly preferred.

R³And R⁴Are independently hydrogen, group represented by formula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-lower alkyl, (halophenyl) -lower alkyl, lower- (alkylphenyl alkyl), lower (alkoxyphenyl). )-Lower alkyl, naphthyl-Lower alkyl or pyridyl-Lower alkyl, provided that R³And R⁴At least one of is a group represented by the formula (A).

The preferred compound is R³And R⁴One is hydrogen and the other is a compound represented by the formula (A).

In equation (A),-(C (R)^L)₂)_O-x-(C (R)^L)₂)_P-Ingredients define an alkylene group attached to the interstructure. The variables o and p can be integers from 0 to 10, respectively, provided that the sum of o and p in the chain is from 1 to 10. Therefore, o and p may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, respectively. Preferably, the sum of o and p is 2 to 6. In a particularly preferred embodiment, the sum of o and p is 4.

Crosslinking groups x in the alkylene chain are independently O, NR¹⁰, C (= O), CHOH, C (= NR)¹⁰), CHNR⁷R¹⁰Or represents a single bond.

Therefore, when x is a single bond, the alkylene chain attached to the ring is-(C (R).^L)₂)_{O + p}Represented by-where the sum of o + p is 1 to 10.

R^LAre independent, -R⁷,-(CH₂)_n-OR⁸, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_mR⁸, -O- (CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_m-(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_m-CO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,

<chemistry num="15"><img file="JP2007502829A_D0015.tif" /></chemistry>

May be.

Preferred R^LBased on -H, -OH, -N (R⁷)₂Includes, where R⁷Are hydrogen, respectively.

One R bonded to a carbon atom in the alkylene chain in formula (A)^LIf the group is other than hydrogen, the other R attached to the carbon atom^LThe group is hydrogen, i.e. -CHR^L-Preferably. In addition, up to 2 Rs in the alkylene chain^LOther Rs in the chain if the group is non-hydrogen^LThe group is preferably hydrogen. More preferably, only one R in the alkylene chain^LOther Rs in the chain if the group is non-hydrogen^LThe group is hydrogen. In these embodiments, x preferably represents a single bond.

In another particular embodiment of the invention, R in the alkylene chain^LThe groups are all hydrogen. In these embodiments, the alkylene chain has the formula:-(CH₂)_{o o}-x- (CH₂)_pRepresented by-.

R⁵Are independent, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸, -O- (CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_n-(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_mNR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_m-CO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,

<chemistry num="16"><img file="JP2007502829A_D0016.tif" /></chemistry>

May be.

In addition, R⁵Are independent,-(CH₂)_n-NR¹²R¹², -O- (CH₂)_m-NR¹²R¹², -O- (CH₂)_n-NR¹²R¹², -O- (CH₂)_m-(Z)_gR¹²,-(CH₂)_n-NR¹¹R¹¹, -O- (CH₂)_mNR¹¹R¹¹,-(CH₂)_n-N⁺-(R¹¹)₃, -O- (CH₂)_m-N⁺-(R¹¹)₃,-(CH₂)_n-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰, -O- (CH₂)_m-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰,-(CH₂CH₂O)_m-CH₂CH₂NR¹²R¹², -O- (CH₂CH₂O)_m-CH₂CH₂NR¹²R¹²,-(CH₂)_n-(C = O) NR¹²R¹², -O- (CH₂)_m-(C = O) NR¹²R¹², -O- (CH₂)_m-(CHOR⁸)_mCH₂NR¹⁰-(Z)_g-R¹⁰,-(CH₂)_n-(CHOR⁸)_mCH₂-NR¹⁰-(Z)_g-R¹⁰,-(CH₂)_nNR¹⁰-O (CH₂)_m(CHOR⁸)_nCH₂NR¹⁰-(Z)_g-R¹⁰, -O (CH)₂)_m-NR¹⁰-(CH₂)_m-(CHOR⁸)_nCH₂NR¹⁰-(Z)_g-R¹⁰,-(Het)-(CH₂)_m-OR⁸,-(Het)-(CH₂)_m-NR⁷R¹⁰,-(Het)-(CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(Het)-(CH₂CH₂O)_m-R⁸,-(Het)-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(Het)-(CH₂)_m-C (= O) NR⁷R¹⁰,-(Het)-(CH₂)_m-(Z)_g-R⁷,-(Het)-(CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(Het)-(CH₂)_m-CO₂R⁷,-(Het)-(CH₂)_m-NR¹²R¹²,-(Het)-(CH₂)_n-NR¹²R¹²,-(Het)-(CH₂)_m-(Z)_gR¹²,-(Het)-(CH₂)_mNR¹¹R¹¹,-(Het)-(CH₂)_m-N⁺-(R¹¹)₃,-(Het)-(CH₂)_m-(Z)_g-(CH₂)_m-NR¹⁰R¹⁰,-(Het)-(CH₂CH₂O)_m-CH₂CH₂NR¹²R¹²,-(Het)-(CH₂)_m-(C = O) NR¹²R¹²,-(Het)-(CH₂)_m-(CHOR⁸)_mCH₂NR¹⁰-(Z)_g-R¹⁰,-(Het)-(CH₂)_m-NR¹⁰-(CH₂)_m-(CHOR⁸)_nCH₂NR¹⁰-(Z)_g-R¹⁰, And at this time, two -CHs₂OR⁸R if they are located 1,2- or 1,3- relative to each other⁸The groups are bonded and mono- or di-substituted cyclic 1,3-dioxane or 1,3-dioxolane,-(CH₂)_n(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane) -O- (CH)₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane)-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸Groups bind to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane) -O- (CH)₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸(However, at least two -CHs₂OR⁸When are located adjacent to each other, R⁸The groups combine to form mono- or di-substituted 1,3-dioxane or 1,3-dioxolane), and in addition, R⁵Are independent of each other, Link- (CH₂)_n-CAP, Link- (CH₂)_n(CHOR⁸) (CHOR⁸)_n-CAP, Link- (CH₂CH₂O)_m-CH₂-CAP, Link- (CH₂CH₂O)_m-CH₂CH₂-CAP, Link- (CH₂)_n-(Z)_g-CAP, Link- (CH₂)_n(Z)_g-(CH₂)_m-CAP, Link- (CH₂)_n-NR¹³-CH₂(CHOR⁸) (CHOR⁸)_n-CAP, Link- (CH₂)_n-(CHOR⁸)_mCH₂-NR¹³-(Z)_g-CAP, Link- (CH₂)_nNR¹³-(CH₂)_m(CHOR⁸)_nCH₂NR¹³-(Z)_g-CAP, Link- (CH₂)_m-(Z)_g-(CH₂)_m-CAP, Link-NH-C (= O) -NH- (CH₂)_m-CAP, Link- (CH₂)_m-C (= O) NR¹³-(CH₂)_m-C (= O) NR¹⁰R¹⁰, Link- (CH₂)_m-C (= O) NR¹³-(CH₂)_m-CAP, Link- (CH₂)_m-C (= O) NR¹¹R¹¹, Link- (CH₂)_m-C (= O) NR¹²R¹², Link- (CH₂)_n-(Z)_g-(CH₂)_m-(Z)_g-CAP, Link-Z_g-(CH₂)_m-Het- (CH₂)_m-Can be CAP.

Links are independent, -O-,-(CH₂)_n-, -O (CH₂)_m-, -NR¹³-C (= O) -NR¹³, -NR¹³-C (= O)-(CH₂)_m-, -C (= O) NR¹³-(CH₂)_m,-(CH₂)_n-Z_g-(CH₂)_n, -S-, -SO-, -SO₂-,-SO₂NR⁷-,-SO₂NR¹⁰-Or -Het-; CAPs are independently thiazolidinedione, oxazolidinedione, heteroaryl-C (= O) NR¹³R¹³, Heteroaryl-W, -CN, -OC (= S) NR¹³R¹³, -Z_gR¹³, -CR¹⁰(Z_gR¹³) (Z_gR¹³), -C (= O) OAr, -C (= O) NR¹³Ar, imidazoline, tetrazole, tetrazolamide, -SO₂NHR¹³, -SO₂NH-C (R¹³R¹³)-(Z)_g-R¹³, Cyclic sugar or oligosaccharide, Cyclic amino sugar or oligosaccharide,

<chemistry num="17"><img file="JP2007502829A_D0017.tif" /></chemistry>

Is.

Ar is independently phenyl and substituted phenyl, where the substituents of the substituted phenyl are OH and OCH.₃, NR¹³R¹³, Cl, F and CH₃Alternatively, it is 1 to 3 substituents independently selected from the group consisting of heteroaryl.

W is independent of thiazolidinedione, oxazolidinedione, heteroaryl-C (= O) NR¹³R¹³, -CN, -OC (= S) NR¹³R¹³, -Z_gR¹³, -CR¹⁰(Z_gR¹³) (Z_gR¹³), -C (= O) OAr, -C (= O) NR¹³Ar, imidazoline, tetrazole, tetrazolamide, -SO₂NHR¹³, -SO₂NH-C (R¹³R¹³)-(Z)_g-R¹³, Cyclic sugar or oligosaccharide, Cyclic amino sugar or oligosaccharide,

<chemistry num="18"><img file="JP2007502829A_D0018.tif" /></chemistry>

Is.

Examples of heteroaryls include pyridyl, pyrazil, tinadyl, frills, furfuryl, thienyl, tetradil, thiazolidinedioneyl and imidazole, pyrrolyl, flanyl, thiophenyl, quinolyl, indrill, adenyl, pyrazolyl, thiazolyl, isooxazolyl, indrill, benzimidazole, Includes prynyl, quinolinyl, isoquinolinyl, pyridadyl, pyrimidyl, pyrazil, 1,2,3-triadyl, 1,2,4-triadyl, 1,3,5-triadyl, synolyl, phthalazyl, quinazolyl, quinoxalyl or pterdyl groups.

In the above group, two -CH₂OR⁸R if they are located 1,2- or 1,3- relative to each other⁸The groups may be combined to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.

In one preferred embodiment,-(CH₂)_n-(Z)_g-R⁷Are within the above-mentioned structure, respectively, and independently,-(CH₂)_n-(C = N) -NH₂,-(CH₂)_n-NH-C (= NH) NH₂,-(CH₂)_n-CONHCH₂(CHOH)_n-CH₂OH, or -NH-C (= O) -CH₂-(CHOH)_nCH₂OH.

In another preferred embodiment, -O- (CH)₂)_m-(Z)_g-R⁷Are within the above-mentioned structure, respectively, and independently, -O- (CH)₂)_M-NH-C (= NH) -N (R)⁷)₂, Or -O- (CH₂)_m-CHNH₂-CO₂NR⁷R¹⁰Is.

In another preferred embodiment, R⁵Within the range of the groups mentioned above;-O-CH₂CHOHCH₂O-glucuronide, -OCH₂CHOHCH₃, -OCH₂CH₂NH₂, -OCH₂CH₂NHCO (CH₃)₃, -CH₂CH₂OH, -OCH₂CH₂OH, -O- (CH₂)_m-Boc,-(CH₂)_m-Boc, -OCH₂CH₂OH, -OCH₂CO₂H, -O- (CH₂)_m-NH-C (= NH) -N (R)⁷)₂,-(CH₂)_n-NH-C (= NH) -N (R)⁷)₂, -NHCH₂(CHOH)₂-CH₂OH, -OCH₂CO₂Et, -NHSO₂CH₃,-(CH₂)_m-NH-C (= O) -OR⁷, -O- (CH₂)_m-NH-C (= O) -OR⁷,-(CH₂)_n-NH-C (= O) -R¹¹, -O- (CH₂)_m-NH-C (= O) -R¹¹, -O-CH₂C (= O) NH₂, -CH₂NH₂, -NHCO₂Et, -OCH₂CH₂CH₂CH₂OH, -CH₂NHSO₂CH₃, -OCH₂CH₂CHOHCH₂OH, -OCH₂CH₂NHCO₂Et, -NH-C (= NH2) -NH₂, OCH₂-(α-CHOH)₂-CH₂OH-OCH₂CHOHCH₂NH₂、

<chemistry num="19"><img file="JP2007502829A_D0019.tif" /></chemistry>

-(CH₂)_m-CHOH-CH₂-NHBoc, -O- (CH₂)_m-CHOH-CH₂-NHBoc,-(CH₂)_m-NHC (O) OR⁷, -O- (CH₂)_m-NHC (O) OR⁷, -OCH₂CH₂CH₂NH₂, -OCH₂CH₂NHCH₂(CHOH)₂CH₂OH, -OCH₂CH₂NH (CH)₂[(CHOH)₂CH₂OH])₂,-(CH₂)₄-NHBoc,-(CH₂)₄-NH₂,-(CH₂)₄-OH, -OCH₂CH₂NHSO₂CH₃, -O- (CH₂)_m-C (= NH) -N (R)⁷)₂,-(CH₂)_n-C (= NH) -N (R)⁷)₂,-(CH₂)₃-NH Boc,-(CH₂)₃NH₂, -O- (CH₂)_m-NH-NH-C (= NH) -N (R)⁷)₂,-(CH₂)_n-NH-NH-C (= NH) -N (R)⁷)₂, Or -O-CH₂-CHOH-CH₂-NH-C (= NH) -N (R)⁷)₂It can be ;.

R⁶Are independent, -R⁷, -OR¹¹, -N (R)⁷)₂,-(CH₂)_m-OR⁸, -O- (CH₂)_m-OR⁸,-(CH₂)_n-NR⁷R¹⁰, -O- (CH₂)_m-NR⁷R¹⁰,-(CH₂)_n-(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂CH₂O)_m-R⁸, -O- (CH₂CH₂O)_m-R⁸,-(CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰, -O- (CH₂CH₂O)_m-CH₂CH₂NR⁷R¹⁰,-(CH₂)_n-C (= O) NR⁷R¹⁰, -O- (CH₂)_m-C (= O) NR⁷R¹⁰,-(CH₂)_n-(Z)_g-R⁷, -O- (CH₂)_m(Z)_g-R⁷,-(CH₂)_n-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸, -O- (CH₂)_m-NR¹⁰-CH₂(CHOR⁸) (CHOR⁸)_n-CH₂OR⁸,-(CH₂)_n-CO₂R⁷, -O- (CH₂)_m-CO₂R⁷, -OSO₃H, -O-glucuronide, -O-glucose,

<chemistry num="20"><img file="JP2007502829A_D0020.tif" /></chemistry>

Is.

In addition, one or more R⁶The group is the above-mentioned R⁶R that fits the broad definition of⁵It may be one of the groups.

As discussed above, R⁶May be hydrogen. Therefore, 1, 2, 3, or 4 Rs⁶The group may be other than hydrogen. Preferably up to 3 R⁶The group is other than hydrogen.

g is an integer from 1 to 6 independently. Therefore, g may be 1, 2, 3, 4, 5 or 6, respectively.

m is an integer from 1 to 7 independently. Therefore, g may be 1, 2, 3, 4, 5, 6 or 7, respectively.

n is an integer from 0 to 7 independently. Therefore, n may be 0, 1, 2, 3, 4, 5, 6 or 7, respectively.

Q is independent, -CR⁶R⁵, -CR⁶R⁶, -NR¹⁰, -NR⁷, -NR⁵, -S-, -SO-, or -SO₂-And; up to 3 Qs in the ring contain heteroatoms and at least 1 Q is -CR⁵R⁶Or NR⁵Must.

Thus, there may be one, two, or three nitrogen atoms in between. Preferably, up to two Q's are nitrogen atoms.

In a preferred embodiment of the invention, Y is -NH.₂Is.

In another preferred embodiment, R²Is hydrogen.

In another preferred embodiment, R¹Is hydrogen.

In another preferred embodiment, X is chlorine.

In another preferred embodiment, R³Is hydrogen.

In another preferred embodiment, R^LIs hydrogen.

In another preferred embodiment, o is 4.

In another preferred embodiment, p is 0.

In another preferred embodiment, the sum of o and p is 4.

In another preferred embodiment, x represents a single bond.

In another preferred embodiment, R⁶Is hydrogen.

In another preferred embodiment, up to two Q's are nitrogen atoms.

In another preferred embodiment, up to one Q is a nitrogen atom.

In another preferred embodiment, Q is also a nitrogen atom.

In another preferred embodiment of the invention, X is a halogen; Y is -N (R).⁷)₂Is; R¹Is hydrogen or C₁~ C₃Alkyl; R²Is -R⁷, -OR⁷, CH₂O⁷Or-CO₂R⁷Is; R³Is a group represented by equation (A); R⁴Is hydrogen, a group represented by the formula (A) or a lower alkyl.

In another preferred embodiment of the invention: X is chloro or bromo; Y is -N (R).⁷)₂Is; R²Is hydrogen or C₁~ C₃Alkyl; up to 3 Rs⁶Is non-hydrogen as mentioned above; up to 3 Rs^LIs non-hydrogen, as mentioned above; and up to two Q's are nitrogen atoms.

In another preferred embodiment of the invention: Y is -NH.₂Is.

In another preferred embodiment of the invention: R⁴Is hydrogen; up to 1 R^LIs non-hydrogen as mentioned above; up to 2 Rs⁶Is non-hydrogen as mentioned above; and up to one Q is a nitrogen atom.

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="21"><img file="JP2007502829A_D0021.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="22"><img file="JP2007502829A_D0022.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="23"><img file="JP2007502829A_D0023.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="24"><img file="JP2007502829A_D0024.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="25"><img file="JP2007502829A_D0025.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="26"><img file="JP2007502829A_D0026.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="27"><img file="JP2007502829A_D0027.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="28"><img file="JP2007502829A_D0028.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="29"><img file="JP2007502829A_D0029.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="30"><img file="JP2007502829A_D0030.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="31"><img file="JP2007502829A_D0031.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="32"><img file="JP2007502829A_D0032.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="33"><img file="JP2007502829A_D0033.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="34"><img file="JP2007502829A_D0034.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="35"><img file="JP2007502829A_D0035.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="36"><img file="JP2007502829A_D0036.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="37"><img file="JP2007502829A_D0037.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="38"><img file="JP2007502829A_D0038.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="39"><img file="JP2007502829A_D0039.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="40"><img file="JP2007502829A_D0040.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="41"><img file="JP2007502829A_D0041.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="42"><img file="JP2007502829A_D0042.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="43"><img file="JP2007502829A_D0043.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="44"><img file="JP2007502829A_D0044.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="45"><img file="JP2007502829A_D0045.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="46"><img file="JP2007502829A_D0046.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="47"><img file="JP2007502829A_D0047.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="48"><img file="JP2007502829A_D0048.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="49"><img file="JP2007502829A_D0049.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="50"><img file="JP2007502829A_D0050.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="51"><img file="JP2007502829A_D0051.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="52"><img file="JP2007502829A_D0052.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="53"><img file="JP2007502829A_D0053.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="54"><img file="JP2007502829A_D0054.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="55"><img file="JP2007502829A_D0055.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="56"><img file="JP2007502829A_D0056.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="57"><img file="JP2007502829A_D0057.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="58"><img file="JP2007502829A_D0058.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="59"><img file="JP2007502829A_D0059.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="60"><img file="JP2007502829A_D0060.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="61"><img file="JP2007502829A_D0061.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="62"><img file="JP2007502829A_D0062.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="63"><img file="JP2007502829A_D0063.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="64"><img file="JP2007502829A_D0064.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="65"><img file="JP2007502829A_D0065.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="66"><img file="JP2007502829A_D0066.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="67"><img file="JP2007502829A_D0067.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="68"><img file="JP2007502829A_D0068.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="69"><img file="JP2007502829A_D0069.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="70"><img file="JP2007502829A_D0070.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="71"><img file="JP2007502829A_D0071.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="72"><img file="JP2007502829A_D0072.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="73"><img file="JP2007502829A_D0073.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="74"><img file="JP2007502829A_D0074.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="75"><img file="JP2007502829A_D0075.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="76"><img file="JP2007502829A_D0076.tif" /></chemistry>

In another preferred embodiment of the invention, the compound of formula (1) is represented by the following formula:

<chemistry num="77"><img file="JP2007502829A_D0077.tif" /></chemistry>

The compound of formula (I) can be prepared and used as a free base. Alternatively, the compound can be prepared and used as a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is one that retains or enhances the desired bioactivity of the parent compound and does not add unwanted toxic effects. Examples of such salts are (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitrate, etc .; (b) organic acids such as acetic acid, oxalic acid. , Tartrate acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, methane sulfonic acid, p-toluene sulfon Salts formed with acids, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, etc.; and ( c) Element Anion, for example a salt formed from chlorine, bromine and iodine.

It is noted that all enantiomers, diastereoisomers and racemic compounds of the compounds within formula (I) are included in the present invention. All mixtures of such enantiomers and diastereoisomers are within the scope of the present invention.

Without being limited to a particular theory, compounds of formula (I) are thought to act as sodium channel blockers in vivo. By blocking the epithelial sodium channels present on the mucosal surface, the compound of formula (I) reduces the absorption of water by the mucosal surface. This action increases the volume of protective solution on the mucosal surface, rebalances the system and treats the disease.

Furthermore, the present invention provides a therapeutic method that utilizes the properties of the compound of formula (I) discussed above. Therefore, subjects that can be treated by the methods of the present invention include, but are not limited to, cystic fibrosis, primary hairy dyskinesia, chronic bronchitis, chronic obstructive airway disease, patients with ventilator, and acute. Includes patients with pneumonia. The present invention can be used to obtain a sputum sample from a patient by administering the active compound to at least one lung of the patient and then inducing or collecting sputum from that patient. Usually, the present invention is administered to the respiratory mucosal surface via an aerosol (liquid or dry powder) or lavage.

Subjects who can be treated by the methods of the invention are further nasally administered with auxiliary oxygen (a regime that tends to dry the airway surface); patients suffering from an allergic disease or response that affects the nasal airway surface ( Allergic response to, for example, pollen, dust, animal hair or particles, insects or insect particles); bacterial infections on the surface of the nasal respiratory tract, such as Stahirococcus infections such as Stahirococcus aureus infections, hemophilus influenza infections, streptococcus pneumoniae infections, Patients suffering from Pseudomonas aeruginosa infection, etc .; Patients suffering from inflammatory diseases affecting the surface of the nasal respiratory tract; One or more activators are administered to promote the excretion of mucous secretions that are stagnant in the sinus by administering an effective amount), or complex nasal sinusitis is included. Is done. The present invention can be administered to the sinus surface by topical transport, including aerosols and drops.

The present invention can also be used to hydrate mucosal surfaces other than the airway surface. Such other mucosal surfaces include the gastrointestinal surface, oral surface, reproductive-urethral surface, eyeball surface or eye surface, inner ear and middle ear. For example, the active compounds of the invention can be administered in effective amounts by appropriate means, including topical, oral or rectal.

The compounds of the present invention can also be used to treat various functions related to the cardiovascular system. Therefore, the compound of the present invention can be used as an antihypertensive agent. In addition, compounds can be used to lower blood pressure and treat edema. In addition, the compounds of the invention can be further used to promote diuresis, natriuresis and salt diuresis. The compounds can be used alone, beta blockers, ACE inhibitors, HMGCoA, reductase inhibitors, calcium channel blockers and other cardiovascular drugs to treat hypertension, congestive heart disease and reduce cardiovascular fat. It can also be used in combination with.

The compounds of the present invention can also be used to treat airborne infections. Examples of airborne infections include, for example, RSV. The compounds of the present invention can also be used to treat anthrax infections.

Although the present invention primarily relates to the treatment of human subjects, it can also be used to treat mammalian subjects such as dogs and cats for veterinary purposes.

As discussed above, the compounds used to prepare the compositions of the present invention may be in the form of pharmaceutically acceptable free bases. Since the free base of a compound is usually less soluble in aqueous solution than its salt, the free base composition can be used to result in a longer sustained release of the active agent into the lungs. The active agent, which is present in the lungs in the form of particles that are not dissolved in solution, does not provide a physiological response, but serves as a biologically available depot that gradually dissolves in solution.

Another aspect of the present invention is a pharmaceutical composition containing a compound of formula (I) in a pharmaceutically acceptable carrier (eg, an aqueous carrier solution). Usually, the compound of formula (I) is contained in the composition in an amount effective for inhibiting the reabsorption of water by the mucosal surface.

The compounds of the present invention can also be used with P2Y2 receptor agonists or pharmaceutically acceptable salts thereof (sometimes referred to as "active agents"). The composition may further contain a P2Y2 receptor agonist or a pharmaceutically acceptable salt thereof (sometimes referred to as an "active agent"). P2Y2 receptor agonists are usually included in amounts effective to stimulate chloride and water secretion by the airway surface, especially the nasal airway surface. Suitable P2Y2 receptor agonists are described in columns 9-10 of U.S. Pat. No. 6,264,975, U.S. Pat. No. 5,656,256 and U.S. Pat. No. 5292498, respectively, incorporated herein by reference. There is.

Bronchodilators can also be used in combination with the compounds of the invention. These bronchodilators include, but are not limited to, epinephrine, isoproterenol, phenotelol, albutereol, terbutaline, pyrubuterol, vitorterol, metaproterenol, iosetaline, salmeterol xinafoate. Includes β-adrenaline agonists, as well as, but not limited to, anticholinergic agents, including but not limited to ipratropium bromide, as well as compounds such as theophylline and aminophylline. These compounds can be administered prior to or at the same time as the active compounds described herein according to known techniques.

Another aspect of the invention is a drug formulation containing the active compound in a pharmaceutically acceptable carrier (eg, an aqueous carrier solution). Usually, the active compound is included in the composition in an amount effective for treating the mucosal surface, such as inhibiting the reabsorption of water by the mucosal surface, including the airways and other surfaces.

The active compounds disclosed herein can be administered to the mucosal surface by appropriate means, including topical, oral, rectal, transvaginal, eye and skin. For example, to treat constipation, the active compound can be administered orally or rectum to the gastrointestinal mucosal surface. With a pharmaceutically acceptable carrier in the appropriate form, such as as sterile physiological or diluted saline or topical solution, as droplets, tablets, etc. for oral administration, as suppositories for rectal or reproductive-urinary tract administration, etc. Can be combined. Excipients may be included in the formulation to enhance the solubility of the active compound as desired.

The active compounds disclosed herein are those of the patient by any suitable means, including spraying, mist or droplets of the active compound in a physiologically or pharmaceutically acceptable carrier such as dilute aqueous saline solution or distilled water. It can be administered to the surface of the airway. For example, the active compound can be prepared as a formulation and administered as is as described in US Pat. No. 5,789,391, granted to Jacobus, which is incorporated herein by reference.

Solid or liquid particle activators prepared to carry out the present invention include inhalable or non-inhalable sizes, as described above; i.e., for inhalable particles, the particle size is inhaled. For non-inhalable particles that are small enough to pass through the mouth and larynx and reach the bronchial and pulmonary alveolar, the particles pass through the larynx and reach the bronchial and pulmonary alveolar nasal airways. Large enough to stay in. Generally, particles in the size range of about 1 to 5 microns (preferably about 4.7 microns in size) are inhalable. Particles of non-inhalable size are larger than about 5 microns and up to the size of visible droplets. Therefore, for nasal administration, particle sizes in the range of 10-500 μm are used to ensure nasal retention.

In producing the formulations according to the invention, the active agent or a physiologically acceptable salt or free base thereof is usually mixed with a particularly acceptable carrier. Of course, the carrier must be compatible with the other ingredients in the formulation and must not be harmful to the patient. The carrier must be solid, liquid, or both, preferably formulated with the compound as a unit volume formulation that may contain 0.5% to 99% by weight of the active compound, eg, as a capsule. To. One or more active compounds can be introduced into the formulation of the invention, which formulation can be prepared by a well-known technique of pharmacy consisting primarily of mixing ingredients. it can.

The drying activator is ground using a mortar and pestle, and then the micronized composition is passed through a 400 mesh screen to break or separate large agglomerates so that the micronized activator is inhalable or non-inhalable. A composition containing various dry particles can be prepared.

The particulate active agent composition may optionally contain a dispersant that helps facilitate the formulation of the aerosol. A suitable dispersant is lactose, which can be blended with the activator in the appropriate ratio (eg, 1: 1 weight ratio).

The active compounds disclosed herein can be administered to the airway surface, including the patient's nasal passages, sinuses and lungs, by appropriate means known in the art such as nasal droplets, mist. it can. In one embodiment of the invention, the active compound of the invention is administered by transbronchoscopic lavage. In a preferred embodiment of the invention, the active compound of the invention is deposited on the surface of the pulmonary airways by administering an aerosol suspension of inhalable particles containing the active compound inhaled by the subject. The inhalable particles may be liquid or solid. Numerous inhalers are known for administering aerosol particles to a subject's lungs.

Not limited to these, US Pat. No. 5,740,794, incorporated herein by reference; US Pat. No. 5,654,007, US Pat. No. 5,458,135, US Pat. No. 5,775,320 and US Pat. Inhalers such as those developed by Inhale Therapeutic Systems, Palo Alto (California, USA), including those disclosed in No. 5785049, can be used. Applicants specifically intend that the disclosures of all patent references cited herein are incorporated herein by reference in their entirety. Not limited to these, but disclosed in U.S. Pat. No. 5,622,166; U.S. Pat. No. 5,574,977, U.S. Pat. No. 5645051, and U.S. Pat. No. 5,492,112, incorporated herein by reference. Dura, including those that are Inhalers such as those developed by Pharmaceuticals, Inc. (San Diego, CA, USA) can also be used. In addition, but not limited to, U.S. Pat. No. 5,826,570, incorporated herein by reference; U.S. Pat. No. 5813397, U.S. Pat. No. 5819726 and U.S. Pat. No. 5,655,516. Inhalers such as those developed by Aradigm Corp. (Hayward, CA, USA), including those disclosed in, can also be used. These devices are particularly suitable as dry particle inhalers.

Aerosols of liquid particles containing the active compound can be produced by suitable means such as using a pressure propulsion aerosol sprayer or an ultrasonic sprayer. See, for example, US Pat. No. 4,501,729, which is incorporated herein by reference. The atomizer is a commercially available device, which is a solution or suspension of the active ingredient by means of propelling compressed gas, usually air or oxygen, through a narrow Venturi opening, or by means of ultrasonic agitation. Turn the solution into a therapeutic aerosol mist. Formulations suitable for use in atomizers consist of the active ingredient in a liquid carrier, which accounts for up to 40% w / w of the formulation, preferably less than 20% w / w. .. The carrier is usually water (more preferably sterile pyrogen-free) or diluted alcohol aqueous solution. A perfluorocarbon carrier can also be used. If the formulation is not manufactured sterile, additional additives include preservatives such as methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffers and surfactants. ..

Aerosols of solid particles containing the active compound can also be generated using a solid particulate pharmaceutical aerosol generator. An aerosol generator for administering a solid particle drug to a subject results in inhalable particles as described above, producing a predetermined dose of the drug at a rate suitable for administration to a human. .. An example of a type of solid particulate aerosol generator is an injector. Formulations suitable for administration by infusion include finely ground powder, which can be transported by infusion or taken into the nasal cavity in the manner of an olfactory agent. In an injector, the powder (eg, a measured dose effective to perform the treatment described above) is usually contained in a gelatin or plastic capsule or cartridge, which can be perforated or opened on the fly. The powder is then transported by air drawn through the device during inhalation or by a manually operated pump. The powder used in the inhaler consists of the active ingredient alone or a powder blend containing the active ingredient, a suitable powder diluent such as lactose and an additional surfactant. The active ingredient usually accounts for 0.1 to 100% w / w of formulation. An example of a second type of aerosol generator comprises a measured dose inhaler. The measured dose inhaler is a pressurized aerosol dispenser, which typically comprises a suspension or solution formulation of the active ingredient in a liquefaction propellant. During use, these devices drain the formulation through a valve adjusted to deliver the measured volume, typically 10 to 150 μl, resulting in a particulate spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, such as surfactants such as ethanol, oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents.

Whether solid or liquid particles are produced, the aerosol generator allows the aerosol at a rate of about 10 to 150 liters per minute, preferably 30 to 150 liters per minute, more preferably about 60 liters per minute. Can be produced. Aerosols containing larger amounts of pharmaceuticals can also be administered more rapidly.

The dose of the active compound disclosed herein depends on the condition being treated and the condition of the subject, but is usually about 0.01, 0.03, 0.05, 0.1 to 1, 5, drugs deposited on the airway surface. It can be 10 or 20 mg. The daily dose can also be divided into single or multiple unit doses. The purpose is drug concentration 10 on the surface of the pulmonary airways^-9~10⁴To achieve M.

In other embodiments, they are administered by administering an aerosol suspension of inhalable or non-inhalable particles (preferably non-inhalable particles) containing an active compound that is inhaled by the subject through the nose. .. The inhalable or non-inhalable particles may be liquid or solid. The amount of activator contained is about 10 dissolved concentrations of activator on the surface of the airway of the subject.^-9、10^-8Or 10^-7From about 10^-3、10^-2、10^-1Mol / liter, more preferably about 10^-9From about 10^-4The amount may be sufficient to achieve mol / liter.

The dose of the active compound varies depending on the symptoms being treated and the patient's condition, but usually the dissolved concentration of the active compound on the nasal surface of the subject is about 10^-9、10^-8Or 10^-7From about 10^-3、10^-2、10^-1Mol / liter, more preferably about 10^-7From about 10^-4The amount may be sufficient to achieve mol / liter. The daily dose can be divided into single or multiple unit doses, depending on the solubility of the particular formulation of the active compound being administered. The daily dose by weight may range from about 0.01, 0.03, 0.1, 0.5 or 1.0 to 10 or 20 milligrams of activator particles in human subjects, depending on the subject's age and symptoms. Currently the preferred unit dose is about 0.5 milligrams of active agent administered in a regime of 2 to 10 doses per day. Doses can be provided as pre-packaged units by appropriate means (eg, encapsulated in gelatin capsules).

In one embodiment of the invention, the microparticulate activator composition comprises the free base of the activator and a pharmaceutically acceptable salt so as to provide both early and sustained release of the activator that dissolves in nasal mucous secretions. May contain both. Such compositions serve to provide the patient with both an early release and a sustained release over a period of time. By reducing the number of daily doses required, sustained release is expected to increase patient adaptation to the course of activator treatment.

Drug formulations suitable for airway administration include formulations of solutions, emulsions, suspensions and extracts. In general, J. Nairn, Solutions, Emulsions, Suspensions and Extracts, in Remington: The Science and Practice of Pharmacy, chap.86 (19), incorporated herein by reference.^thSee ed.1995). U.S. Pat. No. 4,389,393, affixed to Schor, the disclosure of which is incorporated herein by reference; U.S. Pat. No. 5,707,644, a specification of Illum; U.S. Pat. No. 4,294,829, granted to Suzuki. Drug formulations suitable for nasal administration can be prepared as described in US Pat. No. 4,835,142.

Any suitable means, such as a simple nasal spray with an active agent in a pharmaceutically acceptable aqueous carrier such as sterile saline or sterile water, may result in a mist or aerosol of liquid particles containing the active compound. it can. Administration can be performed using a pressure propulsion aerosol sprayer or an ultrasonic sprayer. See, for example, U.S. Pat. No. 4,501729 and U.S. Pat. No. 5,656,256, both incorporated herein by reference. Formulations suitable for use in nasal droplets or spray bottles or sprayers consist of the active ingredient in a liquid carrier, where the active ingredient is up to 40% w / w of the formulation, preferably 20. It occupies less than% w / w. The carrier is usually water (more preferably sterile pyrogen-free) or diluted alcohol aqueous solution, preferably produced in a 0.12% to 0.8% solution of sodium chloride. Additional additives include preservatives such as methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffers, osmotic activators (eg mannitol, etc.) unless the formulation is manufactured sterile. Xylitol, erythritol) and surfactants are included.

The drying activator is ground using a mortar and pestle, and then the micronized composition is passed through a 400 mesh screen to break or separate large agglomerates so that the micronized activator is inhalable or non-inhalable. A composition containing various dry particles can be prepared.

The particulate composition may optionally contain a dispersant that helps facilitate the formulation of the aerosol. A suitable dispersant is lactose, which can be blended with the activator in the appropriate ratio (eg, 1: 1 weight ratio).

Compounds of formula (I) can be synthesized according to procedures known in the art. An example of the synthesis procedure is shown in the scheme below:

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These procedures are described, for example, in EJ Cragoe, "The Synthesis of Amiloride and Its Analogs" (Chapter 3) in Amiloride and Its Analogs, PP. 25-36, incorporated herein by reference. Other methods of preparing the compounds are described, for example, in US Pat. No. 3313813, which is incorporated herein by reference. In particular, see methods A, B, C and D described in US Pat. No. 3313813. Other methods useful for preparing these compounds, in particular for preparing novel HNR3R4 fragments, are, for example, US Pat. No. 229929, US Pat. No. 233377, which is incorporated herein by reference. It is described in the specification and US Pat. No. 234105. Schemes 1-4 are examples of procedures used to prepare the sodium channel blockers described herein, but not limited to these.

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Several assays can be used to identify the compounds of the invention. Examples of assays are discussed below.

In vitro Measurement of Sodium Channel Blocking Activity and Reversibility One assay used to assess the mechanism of action and / or efficacy of the compounds of the invention uses an airway epithelial monolayer placed in a ushing chamber. , Short circuit current (I_sc) Includes measuring rumen drug inhibition of airway epithelial sodium currents measured below. Cells obtained from freshly resected human, canine, sheep or rodent airways are seeded in porous 0.4 micron Snapwell Inserts (CoStar) and hormones under gas-phase-liquid-phase interface (ALI) conditions. Incubate in a defined medium and sodium transport activity (I_sc), While soaking in a Krebs Bicarbonate Ringer (KBR) in a washing room. All study drugs were added to the lumen bath with a half-log dose addition protocol (1 x 10)^-11From 3x10^-5M), I_scCumulative change (inhibition) was recorded. All drugs in dimethyl sulfoxide, 1 x 10^-2It was prepared as a stock solution with a concentration of M and stored at -20 ° C. Eight formulations are usually treated in parallel, but two formulations per treatment include amyloid and / or benzamil as positive controls. Maximum concentration (5 x 10)^-5After administration of M), replace the lumen bath with a fresh drug-free KBR solution, resulting in I_scWas measured over approximately 5 minutes after each wash. Reversibility is defined as the percentage of recovery to baseline values for sodium current after 3 washes. All data from fixed voltage was collected via a computer interface and analyzed offline.

Consider the dose-effect relationship for all compounds and analyze with the Prism 3.0 program. I c₅₀Values, maximum effect concentrations and reversibility are calculated and compared to amylolide and benzamil as positive controls.

Pharmacological assay of absorption (1) Tip disappearance assay Bronchial cells (dog, human, sheep or rodent cells), 1.13 cm²0.25 × 10 on a porous Transwell-Col collagen coated membrane with a growing area of⁶/cm²The seeds were seeded at the same density and grown in a hormonally defined medium that promotes polarized epithelium at the gas-phase liquid-phase interface. After 12 to 20 days of developing the gas-liquid phase interface (ALI), the culture is expected to have&gt; 90% pilus and mucin accumulates in the cells. Transepithelial resistance (R), an indicator of integrity regarding the polarization properties of cultures, to ensure the integrity of primary airway epithelial cell preparations_t) And transepithelial potential difference (PD) are measured. Human cell lines are preferred for studying absorption rates from the tip surface. Under conditions that mimic a "thin" membrane (~ 25 μl) in vivo, a elimination assay is performed and an experimental sodium channel blocker or positive control (amylolide, benzamil, phenamil) is added to the tip surface at an initial concentration of 10 μM. Start with. Collect a series of samples (5 μl volume per sample) at various time points, including 0, 5, 20, 40, 90 and 240 minutes. Concentrations are measured by measuring the intrinsic fluorescence of each sodium channel blocker using a Fluorocount Microplate Flourometer or HPLC. Quantitative analysis uses a standard curve resulting from a reliable reference material with known concentrations and purity. Data analysis of disappearance rate is performed using non-linear regression and one-phase exponential decay (Prism V 3.0).

2. Confocal microscopy assay for amylolide homologue intake Almost all amylolide-like molecules fluoresce in the UV range. By using an xz confocal microscope, this property of these molecules can be used to directly measure cell uptake. A molar concentration of a positive control containing the experimental compound as well as amylolide and compounds exhibiting rapid ingestion into the cell chamber (benzamil and phenamil) is placed on the tip surface of the airway culture located on the stage of a confocal microscope. Over time, a series of xz images is obtained, the degree of fluorescence accumulated in the cell chamber is quantified, and plotted as a change in fluorescence over time.

3. In vitro assay of compound metabolism Airway epithelial cells have the ability to metabolize drugs during the process of transepithelial absorption. In addition, less certain, due to special extracellular enzyme activity, the drug can be metabolized on the surface of the airway epithelium. As an extracellular surface event, perhaps more certainly, the compound can be metabolized by an infectious secretion that occupies the airway lumen of a patient with lung disease, such as cystic fibrosis. Therefore, a series of assays will be performed to identify compound metabolism resulting from the interaction of the test compound with human airway epithelium and / or human airway epithelial lumen products.

In the first series of assays, the interaction of test compounds in KBR as an "ASL" stimulant was applied to the apical surface of human airway epithelial cells grown in a T-Col insertion system. Most compounds are metabolized by using high performance liquid chromatography (HPLC) to elucidate the species and the endogenous fluorescence properties of these compounds to estimate the relative amounts of test compounds and novel metabolites. Development of new species) was tested. In a conventional assay, a test solution (25 μl KBR containing 10 μM of test compound) is applied to the surface of the epithelial lumen. Obtain 10 μl of continuous sample 5 to 10 μl from the lumen and serosal chamber for HPLC analysis of (1) the amount of test compound permeating from the lumen into the serosal bath and (2) the possible formation of metabolites from the parent compound. Radiation-labeled compounds are used for these assays if the fluorescent properties of the test compounds are not suitable for such identification. From HPLC data, the rate of disappearance and / or formation of novel metabolite compounds on the lumen surface and appearance of test compounds and / or new metabolites in basolateral solutions is quantified. Data on chromatographic mobility of possible novel metabolites are also quantified with reference to the parent compound.

To analyze the metabolism of test compounds that may occur with CF sputum, a mixture of exhaled CF sputum "examples" (IRB approved) from 10 CF patients was collected. By vigorous vortexing, the sputum is dissolved in a 1: 5 mixture of KBR solution, then the mixture is divided into "neat" sputum aliquots and the aliquots are ultracentrifuged to give the "supernatant" aliquots. Obtained (original = cell; supernatant = liquid phase). The usual study of compound metabolism by CF sputum is to add a known amount of test compound to the "original" CF sputum, incubate an aliquot of CF sputum "supernatant" at 37 ° C, and then perform HPLC analysis as described above. It is necessary to continuously sample aliquots from each sputum type in order to identify compound stability / metabolism by. Then, as described above, analysis of compound disappearance, formation rate of new metabolites, and HPLC mobility of new metabolites is performed.

4. The in vivo model described in Sabater et al., Journal of Applied Physiology, 1999, pp. 2191-2196, which is incorporated herein by reference to the pharmacological action and mechanism of action of drugs in animals. It can be used to measure the action of compounds that enhance mucoid hair removal (MCC).

Method Animal Preparation: An adult female sheep (weight 25-35 kg) was restrained in an upright position in a special body harness tailored to a deformed shopping cart. The animal's head was fixed and local anesthesia of the nasal passages was induced with 2% lidocaine. The animal was then nasally intubated with an intratracheal intubation (ETT) with an inner diameter of 7.5 mm. The tip of the ETT (cuff) was placed just below the vocal cords and its position was confirmed with a flexible bronchoscope. After intubation, animals were equilibrated for approximately 20 minutes before starting measurement of mucous pili clearance.

Administration of radiant aerosol: Using the Raidrop Nebulizer, which produces droplets with a central aerodynamic diameter of 3.6 μm.^99mAn aerosol of Tc-human serum albumin (3.1 mg / ml; containing approximately 20 mCi) was produced. The atomizer was connected to a dosing system consisting of a solenoid valve and a source of compressed air (20 psi). The outlet of the atomizer is directly connected to the plastic T-connector; one end is connected to the endotracheal tube and the other is connected to the piston respirator. The system was activated for 1 second at the beginning of the inspiratory cycle of the respiratory system. Central airway deposition was maximized by setting the respiratory system to a single breath volume of 500 mL, an inspiratory-expiratory ratio of 1: 1 and a rate of 20 breaths per minute. The sheep breathed the radiolabeled aerosol for 5 minutes. From the airway using a gamma camera^99mRemoval of Tc-human serum albumin was measured. With a naturally upright sheep supported by a cart, the camera was placed on the animal's back and the image field was perpendicular to the animal's spinal cord. Externally radiolabeled markers were placed on the sheep to ensure accurate placement under the gamma camera. All images were saved on a computer integrated with a gamma camera. The area was traced with an image corresponding to the right lung of the sheep and the count was recorded. The count was corrected for attenuation and expressed as a percentage of the radioactivity initially present in the baseline image. The left lung was excluded from the analysis. This is because its contours overlap the stomach and the counts can be swallowed and enter the stomach as radiolabeled mucus.

Treatment protocol (activity assessment at t-0): Baseline deposition images were obtained immediately after administration of the radioactive aerosol. At time 0, after baseline images were obtained, vehicle controls (distilled water), positive controls (amylolide) or experimental compounds were aerosolly administered from a 4 ml volume to free-breathing animals using a Pari LC Jet Plus nebulizer. The atomizer was operated with compressed air with a flow rate of 8 liters per minute. The time to transport the solution was 10 to 12 minutes. Immediately after transporting the full dose, the animals were extubated to prevent the apologetic increase in count caused by inhaling excess radiotracer from the ETT. Continuous images of the lungs were taken every 15 minutes for the first 2 hours after dosing and every hour for the following 6 hours after dosing for a total of 8 hours of observation. A period of administration with another experimental drug was provided with a washout period of at least 7 days.

Treatment Protocol (Activity Assessment at t-4 Hours): After a single exposure to vehicle control (distilled water), positive control compound (amylolide or benzamil) or the agent of the invention using the following variations of the standard protocol: The response period was evaluated. At 0, a vehicle control (distilled water), a positive control (amyllide) or a compound of the invention was aerosolly administered from a 4 ml volume to a free breathing animal using a Pari LC Jet Plus nebulizer. The atomizer was operated with compressed air with a flow rate of 8 liters per minute. The time to transport the solution was 10 to 12 minutes. The animal was restrained in a special body harness in an upright position for 4 hours . At the end of 4 hours, the animal was made into a single volume aerosol from the Raindrop Nebulizer.^99mTc-human serum albumin (3.1 mg / ml; containing about 20 mCi) was administered. Animals were extubated immediately after transporting the full dose of radiotracer. Immediately after administration of the radioactive aerosol, baseline deposition images were obtained. Continuous images of the lungs are taken every 15 minutes for the first 2 hours after administration of the radiotracer (representing 4 to 6 hours after administration of the drug) and every hour for the next 2 hours after administration. Obtained over a 4-hour observation period. A period of administration with another experimental drug was provided with a washout period of at least 7 days.

Statistics: Data were analyzed using SYSTAT for Windows®, version 5. Data were analyzed using a two-way repeat ANOVA (to assess overall effect), followed by a pair-t-test to identify differences in a particular pair. Significance was observed when P was 0.05 or less. The slope value on the mean MCC curve (calculated from the data collected initially 45 minutes after administration at the t-0 rating) was calculated using linear least squares regression and the initial velocity in the rapid elimination phase. The difference was evaluated. The compounds can be further tested for efficacy in the canine bronchial epithelium using the in vitro assay described above. The results with the compounds of the present invention are reported as multipliers for amylolide.

(Examples) The present invention has been described in general, but unless otherwise specified, reference is made to certain specific examples shown solely for the sake of detail, without intending to limit the invention. Provides further understanding.

Preparation of sodium channel blockers Ingredients and methods. All reagents and solvents were purchased from Aldrich Chemical Corp. and used without further purification. NMR spectrum of Bruker WM360 (at 360MHz)¹At 1 H NMR and 90MHz¹³C NMR) or Bruker AC 300 (at 300MHz)¹At 1 H NMR and 75 MHz¹³Obtained by C NMR). Flash chromatography from the Elution Solution (PO Box 5147, Charlottesville, Virginia 22905) was performed on the Flash Elute system at 20 psi (N).₂) Was filled with a 90 g silica gel cartridge (40 M FSO-0110-040155, 32-63 μm). GC analysis was performed on a Shimadzu GC-17 with a Heliflex Capillary Column (Alltech); Phase: AT-1, length 10 meters, inner diameter: 0.53 mm, membrane: 0.25 micrometers. GC parameters: syringe 320 ° C, detector 320 ° C, FID gas flow: H at 40 ml / min₂, 400 ml / min with air. Carrier gas: split ratio 16: 1, N₂Flow 15 ml / min, N₂Speed 18 cm / sec. The temperature program is 70 ° C for 0 to 3 minutes, 70 to 300 ° C for 3 to 10 minutes, and 300 ° C for 10 to 15 minutes.

HPLC analysis was performed with a Microsorb MV C8 column, 100A, Gilson 322Pump with 25 cm, 360 nm detector UV / Vis-156. Mobile phase: Acetonitrile with A = 0.1% TFA, water with B = 0.1% TFA. Gradient program: 1 minute B: A = 95: 5, then 7 minutes B: A = 20:80, then 1 minute A100%, then A100% for 11 minutes, flow rate: 1 ml / min.

(Example 1) N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (2-hydroxyethyl) piperidine-4-yl] butyl} guanidine dihydrochloride Synthesis of (PSA25193)

<chemistry num="83"><img file="JP2007502829A_D0083.tif" /></chemistry>

A solution of 1 (2.00 g, 9.50 mmol) and chlorotrimethylsilane (2.30 g, 20.1 mmol) in 4- (piperidine-4-yl) butyrate methyl ester (2) methanol (30 mL) was stirred at room temperature overnight. (Scheme 1). The solvent is then removed under reduced pressure and the residue is purified by flash TM chromatography (BIOTAGE, Inc) (9: 1 dichloromethane / methanol, v / v) to a bright yellow solid of 2 (1.73 g, 98%). ) Was obtained. 1H NMR (300MHz, CD3OD) δ1.39 (m, 4H), 1.66 (m, 3H), 1.95 (d, 2H), 2.39 (m, 2H), 3.02 (m, 2H), 3.40 (m, 2H) , 3.69 (s, 3H). m / z (ESI): 186 [C10H19NO2 + H] +.

4- [1- (2-benzyloxyethyl) piperidine-4-yl] Methyl butyrate (3a) 2 (2.00 g, 108 mmol) in dichloromethane (30 mL), (2-bromoethoxymethyl) benzene (2.31 g, A solution of 10.8 mmol) and triethylamine (4.5 ml, 32.4 mmol) was stirred at room temperature overnight. Evaporate the solvent and flush the residue^TMPurification by chromatography (BIOTAGE, Inc) (9.3: 0.7 dichloromethane / methanol) gave 3a (1.3 g, 42%) as a yellow oil.¹1 H NMR (300MHz, CD₃OD) δ1.30 (m, 5H), 1.66 (m, 2H), 1.87 (d, 2H), 2.37 (m, 2H), 2.58 (m, 2H), 3.04 (m, 2H), 3.39 (m, 2H), 3.65 (s, 3H), 3.80 (m, 2H), 4.55 (s, 2H), 7.37 (m, 5H). m / z (ESI): 320 [C₁₉H₂₉NO₃⁺H] +.

4- [1- (2-benzyloxyethyl) piperidine-4-yl] butyramide (4a) compound 3a (1.30 g, 4.0 mmol) in methanol (25 mL) in a sealed tube at 7 N NH₃Dissolved in. The resulting solution was stirred at 50 ° C for 3 days. The solvent is then removed under vacuum and the residue is flushed.^TMPurification by chromatography (BIOTAGE, Inc) (9.5: 0.45: 0.05 dichloromethane / methanol / concentrated ammonium hydroxide, v / v) gave 4a (0.93 g, 78%) as a white solid.¹1 H NMR (300MHz, CD₃OD) δ1.27 (m, 5H), 1.65 (m, 4H), 2.11 (m, 4H), 2.65 (m, 2H), 2.96 (d, 2H), 3.62 (m, 2H), 4.51 (s, 2H), 7.37 (m, 5H). m / z (ESI): 305 [C₁₈H₂₈N₂O₂+ H]₊。

4- [1- (2-benzyloxyethyl) piperidine-4-yl] butylamine (5a) BH cooled to 0 ° C₃-Compound 4a (100 mg, 0.3 mmol) was added to a solution of THF (2.2 mL, 2.2 mmol). The purified mixture was stirred for 30 minutes, then warmed to room temperature and stirred overnight. Stop the reaction with water and Et₂Extracted with O. Organic solvent Na₂SO₄It was dried in, concentrated under vacuum to give 5a (85.2 mg, 89%) and used directly without further purification.¹1 H NMR (500MHz, CD₃OD) δ1.39 (m, 2H), 1.45 (m, 4H), 1.62 (m, 1H), 1.71 (m, 2H), 1.95 (m, 2H), 2.87 (m, 2H), 2.97 (m, 2H), 3.25 (m, 2H), 3.45 (d, 2H), 3.82 (m, 2H), 4.61 (s, 2H), 7.39 (m, 5H). m / z (ESI): 291 [C₁₈H₃₀N₂O + H]⁺。

2- [4- (4-Aminobutyl) piperidine-1-yl] ethanol (6a) 5a (0.3 g, 1.03 mmol) in methanol (25 mL) and catalyst (10% palladium on carbon, 0.8 g, 50%) w Wet) suspension was placed in a Parr shaker bottle. The system was evacuated and refluxed with nitrogen. This method was repeated 3 times. The mixture was then shaken overnight at room temperature under a 40 psi hydrogen atmosphere. The system was then evacuated again and refluxed with nitrogen. This method was repeated 3 times. The crystals were filtered under vacuum and washed with methanol (2 x 10 mL). The filtrate and washing solution were combined and concentrated under reduced pressure to give 6a (186 mg, 90%). The crude product was used directly without purification. m / z (ESI): 201 [C₁₁H₂₄N₂O + H]⁺。

N-(3,5-1) diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (2-hydroxyethyl) piperidin-4-yl] butyl} guanidine (7a, PSA25193) Hydrochloride 1- (3,5-diamino-6-chloropyrazine-2-carbonyl) -2-methylisothiourea (290 mg, 0.73 mmol) in ethanol (5 mL) with compound 6a (130 mg, 0.65 mmol) and It was added to a solution of DIPEA (0.34 mL 1.95 mmol). The reaction mixture was stirred at 65 ° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by semi-prepared HPLC (water / acetonitrile / 0.1% TFA). The purified product was dissolved in 5% aqueous HCL solution and stirred at room temperature for 30 minutes. The mixture was then concentrated and further dried under high pressure to give 7a (15 mg, 6%) as a bright yellow solid.¹1 H NMR (500MHz, CD₃OD) δ1.50 (m, 9H), 2.01 (m, 2H), 3.20 (m, 2H), 3.61 (m, 2H), 3.89 (s, 2H). m / z (ESI): 413 [C₁₇H₂₉CLN₈O₂+ H]⁺.. mp168-170 ° C

(Example 2) N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (3-hydroxypropyl) piperidine-4-yl] butyl} guanidine dihydrochloride Synthesis of (PSA25310)<chemistry num="84"><img file="JP2007502829A_D0084.tif" /></chemistry>

4- [1- (3-benzyloxypropyl) piperidine-4-yl] butyrate methyl ester (3b) According to the same method described for the preparation of compound 3a, compound 3b as a yellow oil from compound 2 to 40%. Was synthesized in the yield of.¹1 H NMR (300MHz, CD₃OD) δ1.21 (m, 4H), 1.49 (m, 2H), 1.83 (d, 2H), 1.93 (m, 2H), 2.31 (m, 2H), 2.69 (m, 2H), 2.99 (m, 2H), 3.35 (m, 2H), 3.60 (m, 5H), 4.50 (m, 2H), 7.28 (m, 5H). m / z (ESI): 334 [C₂₀H₃₁NO₃+ H]⁺。

4- [1- (3-benzyloxypropyl) piperidine-4-yl] butyramide (4b) Yield 69% from compound 3b with compound 4b as a yellow solid according to the same method described for the preparation of compound 4a. Synthesized at a rate.¹1 H NMR (500MHz, DMSO-d₆) δ1.25 (m, 5H), 1.49 (m, 2H), 1.68 (m, 2H), 1.85 (m, 2H), 2.014 (m, 2H), 2.40 (m, 2H), 2.75 (m, 2H) ), 3.13 (m, 3H), 3.45 (m, 3H), 4.47 (m, 2H), 7.37 (m, 5H). m / z (ESI): 319 [C₁₉H₃₀N₂O₂+ H]⁺。

4- [1- (3-benzyloxypropyl) piperidine-4-yl] butylamine (5b) According to the same method described for the preparation of compound 5a, compound 5b as a bright yellow solid from compound 4b to 70%. Synthesized in yield.¹1 H NMR (500MHz, CDCl₃) δ1.16 (m, 5H), 1.29 (m, 2H), 1.43 (m, 2H), 1.61 (m, 3H), 1.85 (m, 5H), 2.60 (m, 3H), 2.70 (m, 1H) ), 2.95 (m, 2H), 3.50 (m, 2H), 4.51 (s, 2H), 7.39 (m, 5H). m / z (ESI): 305 [C₁₉H₃₂N₂O + H]⁺。

3- [4- (4-Aminobutyl) Piperidine-1-yl] Propan-1-ol (6b) From compound 5b as compound 6b as a bright yellow solid according to the same method described for the preparation of compound 6a. Synthesized in 90% yield.¹1 H NMR (500MHz, CDCl₃) δ1.20 (m, 7H), 1.41 (m, 2H), 1.65 (m, 5H), 1.89 (m, 2H), 2.60 (m, 4H), 3.00 (m, 4H), 3.79 (m, 2H) ). m / z (ESI): 215 [C₁₂H₂₆N₂O + H]⁺。

N-(3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (3-hydroxypropyl) piperidine-4-yl] butyl} guanidine (7b, PSA25310) Compound 7b was synthesized from compound 6b in a yield of 40% as a yellow solid according to the same method described for preparing compound 7a.¹1 H NMR (500MHz, DMSO-d₆) δ1.25 (m, 5H), 1.52 (m, 5H), 1.85 (m, 4H), 2.85 (m, 2H), 3.00 (m, 2H), 3.15 (m, 1H), 3.31 (m, 2H) ), 3.45 (m, 4H), 7.41 (m, 3H), 8.90 (m, 2H), 9.40 (m, 1H). m / z (ESI): 427 [C₁₈H₃₁CLN₈O₂+ H]⁺.. mp165-16 7 ° C.

(Example 3) N- {4- [1- (2-aminoethyl) piperidine-4-yl] butyl} -N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl) trihydrochloric acid Synthesis of guanidine (PSA25455)<chemistry num="85"><img file="JP2007502829A_D0085.tif" /></chemistry>

4- [1- (-tert-butoxycarbonylaminoethyl) piperidine-4-yl] butyrate methyl ester (3c) From compound 2 as compound 3c as a grayish white solid according to the same method described for the preparation of compound 3a. Synthesized.¹1 H NMR (300MHz, CD₃OD) δ1.18-1.35 (m, 7H), 1.41 (m, 9H), 1.59-1.84 (m, 5H), 2.29-2.37 (m, 2H), 2.41-2.52 (m, 2H), 2.86-3.02 (m, 2H), 3.13-3.24 (m, 2H), 3.67 (s, 3H). m / z (ESI): 329 [C₁₇H₃₂N₂O₄+ H]⁺。

{2- [4- (3-Carbamoylpropyl) Piperidine-1-yl] Ethyl} Carbamate tert-Butyl Ester (4c) Follow the same procedure described for the preparation of Compound 4a, as Compound 4c as a grayish white solid. Synthesized from compound 3c.¹1 H NMR (300MHz, CD₃OD) δ1.18-1.35 (m, 7H), 1.41 (m, 9H), 1.59-1.84 (m, 5H), 2.29-2.37 (m, 2H), 2.41-2.52 (m, 2H), 2.86-3.02 (m, 2H), 3.13-3.24 (m, 2H). m / z (ESI): 314 [C₁₆H₃₁N₃O₃+ H]⁺。

{2- [4- (4-Aminobutyl) piperidin-1-yl] ethyl} Carbamate tert-butyl ester (5c) Solution of compound 4c (250 mg, 0.80 mmol) in dichloromethane (10 mL) to 0 ° C. After cooling, DIBAI-H (7.4 mL, 7.4 mmol of 1 M in toluene) was added dropwise to the solution over 45 minutes. The mixture was stirred for 1 hour, then warmed to room temperature and stirred for 14 hours. The reaction was stopped with aqueous potassium sodium tartrate solution. The mixture was extracted with dichloromethane (3 x 10 mL). The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated under vacuum to give an oil. Purification by column chromatography (silica; 90: 10, v / v, dichloromethane / methanol, followed by 89: 10: 1 dichloromethane / methanol / ammonium hydroxide) yields the desired product 5c (54 mg, 23% non-optimized yield) Yield) was obtained as a clear, colorless oil.¹1 H NMR (500MHz, CDCl₃) δ1.21-1.26 (m, 8H), 1.42-1.46 (m, 11H), 1.64-1.67 (m, 3H), 1.91-1.99 (m, 2H), 2.41-2.48 (m, 2H), 2.67- 2.70 (m, 2H), 2.83-2.86 (m, 2H), 3.20-3.22 (m, 2H), 5.00 (br s, 1H). m / z (ESI): 300 [C₁₆H₃₃N₃O₂+ H]₊

。

[3- (4- {4- [N'-(3,5-diamino-6-chloropyrazine-2-carbonyl) guanidino] butyl} piperidine-1-yl) ethyl] carbamate tert-butyl ester (7c) Compound 7c was synthesized as a yellow solid in a yield of 54% from compound 5c according to the same method described for the preparation of compound 7a (Scheme 2).¹1 H NMR (500MHz, CDCl₃) δ1.21-1.26 (m, 8H), 1.41-1.46 (m, 11H), 1.64-1.67 (m, 7H), 1.91-1.99 (m, 2H), 2.41-2.48 (m, 2H), 2.83- 2.86 (m, 2H), 3.20-3.22 (m, 2H), 5.00 (br s, 2H). m / z (ESI): 512 [C₂₂H₃₈ClN₉O₃+ H]⁺。

N-{4- [1- (2-aminoethyl) piperidine-4-yl] butyl} -N'-(3,5-diamino-6-chloropyrazine-2-carbonyl) guanidine (8c, PSA25455) A solution of compound 7c (37 mg, 0.0723 mmol) dissolved in methanol (2 mL) was cooled to 0 ° C (Scheme 2). 1N HCl in diethyl ether (1 mL) was added dropwise to the stirred solution. The resulting mixture was stirred for 2 hours, then the solvent was removed under vacuum and the residue was dried under high pressure to give 8c (36 mg, quantitative) as a yellow solid: mp&gt; 200 ° C.¹1 H NMR (500MHz, DMSO-d₆) δ1.24-1.92 (m, 12H), 2.82-3.02 (m, 2H), 3.51-3.72 (m, 4H), 7.45-7.58 (m, 2H), 8.42 (br s, 3H), 8.75-9.09 (m, 2H), 9.29 (br s, 1H), 10.55 (br s, 1H), 10.75 (m, 1H). m / z (APCI): 412 [C₁₇H₃₀ClN₉O + H]⁺。

(Example 4) N- {4- [1- (3-aminopropyl) piperidine-4-yl] butyl} -N'-(3,5-diamino-6-chloropyrazine-2-carbonyl) guanidine trihydrochloric acid Synthesis of (PSA25510)<chemistry num="86"><img file="JP2007502829A_D0086.tif" /></chemistry>

4- [1- (3-tert-butoxycarbonylaminopropyl) piperidine-4-yl] butyrate methyl ester (3d) Following the same method described for the preparation of compound 3a, compound 3d as a yellow solid compound. Synthesized in yields of 2 to 64%.¹1 H NMR (500MHz, CDCl₃) δ1.30 (m, 3H), 1.41 (m, 2H), 1.65 (m, 3H), 1.78 (m, 2H), 1.95 (m, 2H), 2.25 (m, 3H), 2.75 (m, 1H) ), 3.17 (m, 4H), 3.67 (m, 3H), 4.98 (s, 1H). m / z (ESI): 343 [C₁₈H₃₄N₂O₄+ H]⁺。

{3- [4- (3-Carbamoylpropyl) piperidin-1-yl] propyl} carbamic acid tert-butyl ester (4c) Follow the same procedure described for the preparation of compound 4a, with compound 4d as a yellow solid. It was synthesized from compound 3d in a yield of 66%.¹1 H NMR (500MHz, CDCl₃) δ1.22 (m, 7H), 1.45 (s, 9H), 1.65 (m, 6H), 1.87 (m, 2H), 2.19 (m, 2H), 2.39 (m, 2H), 2.90 (d, 2H) ), 5.40 (s, 2H), 5.62 (s, 1H). m / z (ESI): 328 [C₁₇H₃₃N₃O₃+ H]⁺。

{3- [4- (4-Aminobutyl) Piperidine-1-yl] Propyl} Carbamic Acid tert-Butyl Ester (5d) Following the same method described for the preparation of Compound 5c, Compound 5d was made into a grayish white solid. Was synthesized from compound 4d in a yield of 82%.¹1 H NMR (500MHz, CDCl₃) δ1.20 (m, 5H), 1.35 (m, 3H), 1.46 (m, 12H), 1.65 (m, 2H), 1.84 (m, 2H), 2.46 (m, 2H), 2.68 (m, 1H) ), 2.87 (d, 2H), 3.18 (d, 2H), 3.45 (s, 1H), 5.65 (s, 2H), 7.49 (m, 1H). m / z (ESI): 314 [C₁₇H₃₅N₃O₂+ H]⁺。

[3- (4- {4- [N'-(3,5-diamino-6-chloropyrazine-2-carbonyl) guanidino] butyl} piperidine-1-yl) propyl] Carbamic acid tert-butyl ester (7d, PSA25452) Compound 7d was synthesized from compound 5d as a yellow solid according to the same method described for the preparation of compound 7c (Scheme 2).¹1 H NMR (500MHz, DMSO-d₆) δ1.12 (m, 6H), 1.31 (m, 11H), 1.47 (m, 4H), 1.60 (d, 2H), 1.77 (m, 2H), 2.20 (m, 2H), 2.79 (d, 2H) ), 2.91 (m, 2H), 3.10 (m, 3H), 6.55 (m, 3H), 6.79 (s, 2H), 9.05 (s, 1H). m / z (APCI): 527 [C₂₃H₄₀ClN₉O₃+ H]⁺.. mp98-10 2 ° C.

N-{4- [1- (3-aminopropyl) piperidine-4-yl] butyl} -N'-(3,5-diamino-6-chloropyrazine-2-carbonyl) guanidine (8d, PSA25510) Compound 8d was synthesized as a yellow solid in 91% yield from compound 7d according to the same method described for the preparation of compound 8c (Scheme 2).¹1 H NMR (500MHz, DMSO-d₆) δ1.30 (m, 4H), 1.55 (m, 5H), 1.85 (d, 2H), 2.07 (m, 2H), 2.85 (m, 3H), 3.12 (m, 2H), 3.31 (m, 2H) ), 3.44 (m, 2H), 7.45 (m, 2H), 8.19 (s, 3H), 8.90 (d, 2H), 9.35 (s, 1H), 10.55 (s, 1H), 10.75 (s, 1H) .. m / z (ESI): 426 [C₁₈H₃₂ClN₉O + H]⁺.. mp105-10 8 ° C.

(Example 5) N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (2,3-dihydroxypropyl) -piperidine-4-yl] butyl} Guanidine (PSA25456)<chemistry num="87"><img file="JP2007502829A_D0087.tif" /></chemistry>

4- [1- (2,3-dihydroxypropyl) piperidine-4-yl] butyramide (10) Compound 10 (263 mg, 71% yield, scheme, according to the same method described for the preparation of compound 4. 3) was prepared from compound 9 as a clear orange oil.¹1 H NMR (500MHz, CDCl₃) δ1.21-1.29 (m, 6H), 1.65-1.70 (m, 6H), 2.92-2.98 (m, 1H), 2.19-2.34 (m, 3H), 2.51-2.53 (m, 1H), 2.78- 2.82 (m, 1H), 2.96-3.02 (m, 1H), 3.45-3.75 (m, 3H), 5.28 (m, 2H). m / z (ESI): 245 [C₁₂H₂₄N₂O₃+ H]⁺。

3- [4- (4-Aminobutyl) piperidine-1-yl] propane-1,2-diol (11) Compound 10 (263 mg, 1.07 mmol) was dissolved in tetrahydrofuran (12 mL) under a nitrogen atmosphere. Lithium aluminum hydride (3.7 mL of 1 M solution in THF) was added dropwise for 20 minutes. The reaction was refluxed for 8 hours and then cooled to room temperature. It was stopped by the continuous addition of water (1 mL, droplets), 20% sodium hydroxide solution (1 mL), then 25% ammonium hydroxide solution (2 mL). The product mixture was stirred for 30 minutes and then filtered through diatomaceous earth. The filtrate was dried over sodium sulphate and concentrated under vacuum to give amine 11 (183 mg, 74% yield) as a red oil, which was carried out without further purification:¹1 H NMR (500MHz, CDCl₃) δ1.21-1.68 / (m, 12H), 1.88-1.95 (m, 3H), 2.20-2.33 (m, 4H), 2.49-2.53 (m, 1H), 2.66-2.70 (m, 1H), 2.78 -2.82 (m, 1H), 2.96-3.02 (m, 1H), 3.48-3.94 (m, 3H). m / z (ESI): 231 [C₁₂H₂₆N₂O₂+ H]⁺。

N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (2,3-dihydroxypropyl) -piperidine-4-yl] butyl} guanidine (12, PSA25453) ) Compound 12 was synthesized as a yellow solid in yields of compound 11 to 28% according to the same method described for the preparation of compound 7a. Mp188-19 1 ° C.¹1 H NMR (500MHz, DMSO-d₆) δ1.09-1.32 (m, 8H), 1.45-1.61 (m, 4H), 1.90 (br s, 2H), 2.20-2.30 (m, 2H), 3.75-3.92 (m, 2H), 3.11 (br s, 2H), 3.57 (br s, 1H), 4.31 (br s, 1H), 4.56-4.57 (m, 1H), 6.60 (br s, 3H), 9.06 (br s, 1H). m / z (APCI): 443 [C₁₈H₃₁ClN₈O₃+ H]⁺。

(Example 6) N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (3-guanidinopropyl) piperidine-4-yl] butyl} guanidine trihydrochloric acid Synthesis of (PSA25795)<chemistry num="88"><img file="JP2007502829A_D0088.tif" /></chemistry>

N- (3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1-(3- [N "N"'-bis-tert-butoxycarbonyl] guanidinopropyl) piperidine- 4-Il] butyl} guanidine (13, PSA25569) Goodman's reagent, (tert-butoxycarbonylamino-trifluoromethanesulfonyliminomethyl) carbamic acid tert-butyl ester (368 mg, 0.94 mmol), compound 8d in methanol (20 mL) It was added to a solution of (360 mg, 0.67 mmol) and DIPEA (0.47 mL, 2.69 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash gel chromatography (9: 0.9: 0.1 dichloromethane / methanol / concentrated ammonium hydroxide, v / v) to give 13 (327 mg, 73%) as a yellow solid. Obtained. mp122-125 ° C.¹1 H NMR (500MHz, DMSO-d₆) δ1.25 (m, 9H), 1.40 (m, 21H), 1.59 (m, 4H), 1.75 (m, 2H), 2.25 (m, 2H), 2.82 (m, 2H), 3.11 (m, 2H) ), 6.60 (m, 3H), 8.55 (s, 2H), 9.05 (s, 1H), 11.55 (s, 2H). m / z (ESI) 668 [C₂₉H₅₀ClN₁₁O₅+ H]⁺。

N-(3,5-diamino-6-chloropyrazine-2-carbonyl) -N'-{4- [1- (3-guanidinopropyl) piperidin-4-yl] butyl} guanidine (14, PSA25795) 12N HCl (2.5 mL) was added dropwise to a solution of compound 13 (250 mg, 0.37 mmol) in methanol (5 mL) cooled to 0 ° C. It was first stirred at 0 ° C for 0.5 hours and then warmed to room temperature. Stirring was continued for another 3 hours. Complete removal of the solvent under vacuum gave 14 (215 mg, 94%) as a yellow solid. mp176-178 ° C.¹1 H NMR (500MHz, DMSO-d₆) δ1.29 (m, 2H), 1.30 (m, 3H), 1.54 (m, 6H), 1.82 (m, 2H), 1.93 (m, 2H), 2.84 (m, 2H), 3.02 (m, 2H) ), 3.15 (s, 1H), 3.24 (m, 5H), 7.17 (m, 3H), 7.99 (s, 1H), 8.90 (d, 2H), 9.30 (s, 1H), 10.54 (s, 1H) , 10.62 (s, 1H). m / z (ESI) 468 [C₁₉H₃₄ClN₁₁O + H]⁺。

(Example 7) Sodium channel blocking activity of selected cyclic pyrazinoylguanidine

<tables num="1"><img file="JP2007502829A_D0089.tif" /></tables>

Of course, various modifications and modifications of the present invention are possible in view of the above teachings. Therefore, it will be understood that the present invention can be carried out by a method different from the specific description of the present application within the scope of the appended claims.