TW200418831A - Sulfonamides - Google Patents

Abstract

The present invention relates to sulfonamides, pharmaceutical compositions containing them, and their use as antagonists of urotensin II.

Description

200418831 92564 A7 B7 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (1) Division of the invention-the model of the present invention _ The present invention is related to the bribery, the pharmaceutical filaments containing it and its use as a urethral astringent II antagonist Use of the agent. BACKGROUND OF THE INVENTION Complete control of cardiovascular homeostasis is achieved through a combination of direct neural unit control and systemic neurofluidic activation. Although the products of contraction and relaxation factors are usually released under urgent regulation, confusion in such conditions can lead to impaired cardiac blood flow dysfunction with pathological consequences. The main vascular affecting factors in mammals include this neurofluid axis, that is, angiotensin-II, endothelin-II, or adrenaline. All functions interact with each other through receptors (GPCRs) coupled to specific G-proteins. effect. Urinary tractin represents a novel member of this neurofluidic axon. In fish, the peptide has significant blood flow and endocrine effects in different end-systems and tissues: ♦ Smooth muscle contraction Vascular and non-vascular sources include smooth muscle preparations from the gastrointestinal tract and genitourinary tract. The activity of both hypertensive and hypotensive has been demonstrated when systemically administering exogenous peptides. ♦ Osmotic regulation: Various effects include regulation of epithelial ion (Na +, Cl ·) transport. Although the effects of diuresis have been described, benefits like this are estimated to be secondary to direct renal vascular effects (increased GFR). ♦ Metabolism: In fish, urethral tightening factor-II affects prolactin secretion and decomposes. The paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) -----. 200418831 92564 A7 ____B7 V. Description of the invention ( 2) Fat effect (activation of diglycerol enzymes and movement of non-g free fatty acids) (Symposium of the National Academy of Sciences (Pearson, USA) 1980, 77, 5021; Journal of Experimental Zoology, Kang Long et al. 1996 , 275, 226). In the study of human urethral tightening factor-II, it was found that: ♦ It is a highly effective and effective vasoconstrictor drug ♦ It exhibits continuous contractile activity and is not easy to wash off ♦ It has adverse effects on cardiac performance (myocardial contraction) The effect human urinary tractin-II is evaluated using the contractile activity of isolated mouse aorta and is shown to be the most potent contractile antagonist identified to date. Based on the in vitro pharmacology of human urinary tractin-II and the state of blood flow in vivo, it plays a pathological role in cardiovascular disease characterized by excessive or abnormal vascular tightening and myocardial contraction. (Nature of Amis et al., 1999, 401, 282; Cardiovascular Medicine Trends of Douglas and Ostan (2001); 10th Edition: Fu Zizhong) Compounds that can fight urethral astringin-II receptor are available for treatment of congestive Heart Failure, Stroke, Heart Disease (Angina Pectoris, Myocardial Ischemia), Arrhythmia, Hypertension (Spontaneous and Pulmonary), COPD, Fibrotic Diseases (eg Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, such as lung fiber Degeneration), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Lutman MA, Douglas SA: 2000, Pharmacological Journal · 131; 10-12) Neuroinflammation and metabolism Vascular vascular disease, all of which have abnormal vascular contraction and myocardial contraction characteristics. In addition to lowering blood pressure, urethral tightening hormone antagonists provide ultimate protection for allergic groups. -4- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200418831 92564 A7 ___ B7 V. Description of the invention (3) Because both U-II and GPR14 are expressed in the mammalian CNS (( 1 Ke, Shi et al. 1999, 401, 282), which can also be used to treat upper pain, rice schizophrenia, cognitive diseases / Alzheimer's disease, (Gatlon, psychopharmacological phase 1J (Bell ) June 2001; 155 (4) · 426-33), impulsivity, anxiety, stress, depression, pain, migraine, nerve and muscle function, Parkinson's disease, dyskinesia, sleep · wake cycle, and Stimulative induction (Clark et al. Brain Research 923 (2001) 120-127. The functional IMI receptor system can be characterized by tumors in the cell line of transverse leiomyomas. Therefore, urethral tightening hormone can also be used in various metabolic diseases, For example, diabetes (Natural Cell Biology of Amis et al. 1999, 401, 282, # Sak et al. Natural Cell Biology 1 · 383-385, 1999) and various gastrointestinal diseases, bone, cartilage, and joint diseases (eg , Arthritis and osteoporosis), and reproductive-urinary diseases. Therefore, these compounds can be used for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence. SUMMARY OF THE INVENTION In a first aspect, the present invention provides sulfonamides and pharmaceuticals containing the same. Composition. The second view is printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The present invention provides the use of sulfonamides as antagonists of urinary tractin Η and inhibitors of urethrin Η. Another view, The present invention provides the use of sulfonamides for the treatment of conditions associated with urinary tractin II balance deficiency. In another aspect, the present invention provides sulfonamides for the treatment of congestive heart failure, stroke, and ischemic heart Illness (angina pectoris, partial lack of myocardium) The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 92564 92564 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 Invention description (4) ~ --- blood ), Arrhythmia, palladium ^ > blood pressure (spontaneous and pulmonary), kidney disease (acute and amphipathic renal failure / kidney material) and peripheral vascular disease ( Erectile function hinders diabetic retinopathy, intermittent trekking / ischemic limb disease) and J bloody: hemorrhagic stroke, CQPD, restenosis, asthma, neuropathy ^ partial ^ pain ^ radioactive vascular disease, bone / cartilage / Joint diseases, arthritis and other inflammatory diseases' fibrotic diseases (eg, pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disease / Alzheimer's disease, Impulse, anxiety, oppression, suppression of 'Parkinson's' movement disorder, sleep-wake cycle, stimulus-induced 'pain' nerve and muscle function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases. The urinary tractin antagonist can be administered alone or in combination with one or more other treatments. The agent is selected from the group consisting of an endothelin receptor antagonist, an angiotensin converting enzyme (ACE) antagonist, and an a-π receptor antagonist. Agents, vasocapeptide inhibitors, diuretics, digitonin, and dual non-selective β-adrenergic receptors and 0cr adrenergic receptor antagonists. Other viewpoints and advantages of the present invention are further described in the following detailed description of its preferred specific examples. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I):

This paper size applies to the national standard (CNS) A4 specification (210x297 public love) 200418831 92564 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 Invention Note (5) Among them,

Ar is phenyl, which is unsubstituted or substituted with one or two of the following: halogen, CN, S (Ci-6 alkyl), CF3, OCF3, SCF3, Ch alkyl, Ci-6 alkoxy, CO / Ch alkyl), or No 2; Y is 0 or s; Z is hydrogen, halogen, or Cm alkyl R 2 is argon, halogen, CN, or Cw alkyl;

R1 is murine or Cl-6 alkyl, or a pharmaceutically acceptable salt thereof. As used herein, the term "alkyl" includes all linear or branched isomers. Representative examples include: fluorenyl, ethyl, n-propyl, iso-propyl, n-butyl'di-butyl'iso-butyl'second-butyl, n-pentyl, and n- Jiji. The terms "halogen" and "halo" as used herein include fluorine, gas, bromine and iodine, and fluorine, chloro, bromo and iodo, respectively.

Preferred Ar substituents are halogen or alkoxy. Z is preferably halogen or hydrogen. R > 2 is preferably halogen or hydrogen.

R1 should be Ci_3. Particularly preferred compounds are: 5-bromo-N- (4-chloro-3-{[(3R) -l-methyl-3-tetrahydro.pyrrolyl] oxy} phenyl) -6-[( 2,3-dichlorophenyl) thio] -3-pyridinesulfonamide; 5-bromo-N · (4-gas-3-{[(3R) -1-methyl-3-tetrahydro. Ratio Pyryl] oxy} phenyl) -6- This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200418831 92564 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs, A7 B7 Invention Description (6) [( 3,5-Difluorophenyl) sulfanyl] -3-carboxamidinesulfonamide; 6-{[3,4-bis (methyloxy) phenyl] sulfanyl 5-bromo-N- (4 -Chloro-3-{[((3R) -l-fluorenyl-3-tetrahydropyrrolyl] oxy} phenyl) -3-tonimidinesulfonamide; 5-bromo-N- (4-chloro-3 -{[((3R) -l-methyl-3-tetrahydrotyrrolyl] oxy} phenyl) -6-[(3,5-dichlorophenyl) oxy] -3-carbinsulfonium Amine; 5-> odor-N- (4-chloro-3 · {[(3R) -1 -fluorenyl-3-tetrazolium carbonyl group] oxy} benzyl) -6_ [(3,5 -Difluorophenyl) oxy] -3-carboxidinesulfonamide; 6- {[3,4-bis (methyloxy) phenyl] oxy} -5-bromo-N- (4-chloro -3-{[((3R) -l-methyl-3-tetrahydropyrrolyl] oxy} phenyl) -3-pyridazolamide; 5-bromo-N- (4-chloro-3- { [(3R) -l-methyl-3-tetrahydro.pyrrolyl] Yl) phenyl) -6- {P- (methyloxy) phenyl] oxy} -3-carboxolsulfonamide; 5- > odor-N- (4-chloro-3-{[( 3 Ι) _1-methyl-3_tetrazine ° to 0 groups of each group] oxy} phenyl) -6_ {[4- (methyloxy) phenyl] oxy} -3-carboxolsulfonamide; 5-bromo-N- (4-chloro-3 _ {[((3R) _1-fluorenyl-3-tetrahydrogenyl] oxy} phenyl) -6) [(3,4-difluorophenyl) oxy ] -3-pyridinesulfonamide; and 5-bromo-N_ (4-air-3-{[((3R) -1-l-fluorenyl-3-tetrahydroσpyrrolyl] oxy} phenyl)- 6-[(2,3-dichlorophenyl) oxy] -3-carboxidinesulfonamide; The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in a racemic and selective active form. All such compounds and their diastereoisomeric forms are considered within the scope of the present invention. Compounds of formula (I) can be prepared as outlined in Scheme 1. The starting compounds can be prepared as outlined in WO0289793, which is incorporated herein by reference. Figure 1 This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200418831 92564 A7 B7 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics Invention description (7) αΆ ^ oAo | χχ: α

dd) phenol or thiophene, NaH, DMF, heat; ee) phenol or thiophene NaH, Cs2C03, DMF, heat. Y, Z, R1, and R2 are as described in Formula I, and X is a substituent listed in Ar. Aniline B has been previously described in published application WO 2002089792 A1, which is incorporated herein by reference.

H.N

Aniline B Sulfonium chloride, when it is not commercially available, can be prepared by methods known in the art. · Bio-organic and medicinal chemistry of Salibo AB, etc. 2002, 10, 31; Journal of medicinal chemistry such as Russell PE, 1978 21,845; Han Cuisi et al. American Journal of Chemical Science 1941, 63, 3446; Hashimoto H. et al. Medicinal Chemistry Journal 2002, 45, 1511; O'Brien PM et al. Medicinal Chemistry Journal 2000, 43, 156; Cloth Lundy D.'s Journal of Medicinal Chemistry 1999, 22, 4584 〇 This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200418831 92564 A7

4

92564 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200418831 A7 V. Description of the Invention (9) Typical parenteral compositions include solutions or suspensions of compounds or salts in sterile aqueous or non-aqueous carriers, which optionally contain Acceptable oils for parenteral administration are, for example, polyethylene glycol, polyvinylpyrrolidone, and lecithin. Or Zhi Yan oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion, which can be administered in the form of a dry powder or aerosol, such as monochlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of formula VII or a pharmaceutically acceptable salt thereof, which is active when administered in this manner, and a binder and / or / portal / 3 刽 e.g., polyethylene glycol, gel , Coconut oil or other low melting point plant waxes or fats or their synthetic analogs. Typical transdermal formulations include conventional aqueous or non-aqueous carriers, such as emulsions, ointments, lotions or pastes or in the form of medicated plasters, patches or films. The composition should preferably be in a unit dosage form, such as a lozenge, capsule, or metered aerosol dose, so that the patient can take a single dose to himself. Each dosage unit for oral administration suitably contains, from 0.1 mg to 500 mg / kg, and preferably from 丨 mg to 100 mg / kg, based on free acid, and is administered parenterally. Each dosage unit suitably contains from 0.125 g to 100 g of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Each dosage unit for intranasal administration suitably contains P400 mg per person and ranges from 10 to 200 ¾ grams. The topical formulation suitably contains 0. to 1.0% of a compound of formula (I).

11_ 200418831 92564

5. Description of the invention (10) The daily ingestion dose for oral administration is suitably about 001 mg / kg to 40 mg / kg of a compound of formula (I) or a pharmaceutically acceptable compound thereof. The appropriate daily ingestion dose for parenteral administration is suitably large: 0.1 grams of gram's to 40 mg / kg of the compound of formula (I) or its acceptable salt, calculated as free acid. The daily ingestion dose for intranasal and oral inhalation is suitably about 10 to about 5 mg / person. The active ingredient is sufficient to inhibit the desired activity from 1 to 6 times a day. These amines are useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina pectoris, myocardial ischemia), arrhythmia, blood pressure (spontaneous and pulmonary), kidney disease (acute and chronic Renal failure / end-stage kidney disease) and peripheral vascular disease (male erectile dysfunction, employee property cooperative printed by the Intellectual Property Office of the Ministry of Diabetes Economics, consumer reproductive disease, intermittent claudication / ischemic limb disease) and ischemic / hemorrhagic stroke COPD, restenosis, asthma, neuroinflammation, migraine, metabolic vascular disease, bone / cartilage / joint disease, arthritis and other inflammatory diseases' fibrotic disease (eg, pulmonary fibrosis), sepsis, atherosclerosis Sclerosis, dyslipidemia, addiction, schizophrenia, cognitive disease / Alzheimer's' impulsiveness, anxiety, oppression, depression, pain, hydroxy and muscle function, diabetes, gastric reflux, gastric motility disorders, ulcers And birth urinary diseases. Urinary tractin antagonists may be administered alone or in combination with one or more other therapeutic agents selected from the group consisting of: endothelin receptor antagonists, angiotensin converting enzyme (ACE) antagonists, A-II receptors Antagonist, -12- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200418831 92564 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (U) Angiopeptidase inhibition Agents, diuretics, digitalis, and dual non-selective beta: adrenergic receptors and adrenergic receptor antagonists. When the compounds of the present invention are administered according to the present invention, no unacceptable toxicological effects occur. The biological activity of the compound of formula (0) is illustrated by the following test: Radioligand binding: HEK_293 cell membrane containing stable, selective human and mouse GPR-14 (20 micrograms / analysis) was applied at 2000 pM [125I] h_U -n (200 ci / millimol 1 in the presence of increasing concentrations of test compounds in DMSO (01 nM to 10 μM) 'was incubated in a final culture volume of 200 μl (20 mM Tris-HCl, 5 mM MgCl2) Incubate at room temperature for 30 minutes and then filter by a GF / B filter with a Brand cell harvester. The 1251-labeled u-II binding is quantified by gamma-ray counting. Non-specific binding is at 10 ( ) In the presence of nM unlabeled human IMI, the combination is defined as υ4Ι. The analysis of the data is performed in accordance with nonlinear least squares.

Ca2-mobile. Ca2-mobile FLIPR analysis (Mole device, Sunnyvale, Gadotium-based microtiter plate for ligand-activated HEK-293 cells showing (stable) functional identification of recombinant GPR-14 .The next day of transfection, the cells were translated into a 96-well dark / bright dish coated with polyamic acid. After 18-24 hours, the medium was withdrawn and the fluorescent 3 AM-loaded cells were exposed to different concentrations of the test compound. Then hU-II. After the analysis is started, read the number of fluorescent lights per second for one minute, and then read one minute every 3 seconds. Calculate various executions. 13- This paper standard applies to China National Standard (CNS) A4 specifications ( 210x297 mm)

200418831 92564 A7 V. Explanation of the Invention 12 The inhibitory concentration of the test compound printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs at 50% (IC50). Inositol phosphate analysis: HEK-293-GpR14 cells in a T150 flask were pre-labeled at 1 uCi myo- [3H] -inositol inositol-free Dubik's modified Eagei, s medium overnight. After labeling, the cells were washed twice with Dubic acid phosphate-buffered saline (DPBS) and then incubated at 37 r in DPBS containing 10 mM LiCl for 10 minutes. This experiment was initiated by continuously increasing the concentration of h-U-II (l pM to nM to 10 μM) into three test compounds in the presence or absence of three different concentrations and continued at 37. After another 5 minutes of incubation, the reaction was stopped by adding 10% (final concentration) trichloroacetic acid and centrifuged. The supernatant was neutralized with 100 microliters of 1M Tdzma base and the inositol phosphate was separated on an AG 1-X8 column (packed with 0.8 ml, 100-200 mesh) in the formate phase. The inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate. The combined di- and tri-fill salts were eluted with 4 ml of 1 M ammonium osmate / 0.1 M formic acid. The eluted fraction was counted in a beta liquid scintillation counter. Calculated based on the displacement of the control curve Kb. The activity range of the compounds of the present invention is from (radioligand binding analysis): Ki = 1 nM to 100 nM. The following examples are intended to illustrate, but not limit, specific examples of the invention. Example 1 Gas-3 {"(3R) -1-fluorenyl-3_tetrahydropyrrole 1oxy 1HV6_f (2,3-dioxybenzyl) thio 1_3_ ^ specific amine 14- This paper Standards apply to China National Standard (CNS) A4 specifications (210 x 297)

200418831 92564 V. Description of the invention A7 B7 13

Aniline B (1.2 g, 5.29 mmol) was dissolved in u ml of dichloromethane, 30 ml of carbon tetrachloride, and pyridine (0428 ml: | Chlorophyll. Biyadosulfonyl chloride (1.54 g, 5.29 mmol) was treated in a solution of 4 x dichloroform 5 * liters of tonified carbon and stirred vigorously at room temperature. The reaction mixture was maintained for 18 hours, and then The solvent was removed under reduced pressure. The residue was separated by silica gel chromatography (35 g of Redis 叩 column, silica, 40 um, 60 A, 35 ml / min, a:

MeOH, B: CH2C12, A: 20 minutes at 0%, 0% to 10% over 10 minutes, 10% at 20 minutes, 10% to 30% over 20 minutes, 30% at 15 minutes, 30% to 50% exceeded 2 minutes, 50% at 10 minutes; detected at 214 nm) and purified to give 1.14 g (45%) of the target compound as an orange solid. MS (ES) m / e 480 [M + H] + lb) 5_odor_N_ (4_ 气 -3 {"(3R) -1_methyl_3-tetraoxo." Base} benzene-15- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm)

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200418831 92564 A7 _____B7 V. Description of the invention (Η) The base m (2,3-a milk-benzyl) thio base 1-3- ^. It was confirmed that 2,1,1-chlorobenzenethiol (41.0 mg, 0.229 mmol) was dissolved in 1-litre anhydrous 1-fluorenyl-2-pyrrolidone and dispersed in NaH (60% in mineral oil). Medium, 10.0 mg, 0. 250 millimoles). After all bubbling ceased, the reaction was stirred for an additional 30 minutes and the solution was treated with 5-bromo-6-chloro-N- (4-chloro-3 {[(3R) -1-methyl-3-tetrahydropyrrolyl) oxy } Phenyl) pyridamidine (1000 mg, 0.208 mol) was treated in 1 ml of anhydrous methyl-2-pyrrolidone. The reaction was heated at 125 ° C for 18 hours, cooled to room temperature, filtered through a 0.2 micron Acrodisk, and preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 ml / min, A: Ethyl wax B: Water, A: 5% to 95% 15 minutes, cumulative measurement at 214 nm) to obtain 92.5 mg (71 ° / 0) of the target compound as a brown solid. MS (ES) m / e 624 [M + H] + Example 2 5 -Bromo-Nm_-3 {"(3R)-! Dif 棊 -3 -pyryl] air-based} benzyl V6_" (3.5-II Chlorobenzyl) 1-3-pyridinesulfonyl!

This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200418831 92564 A7 B7 5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Br

Aniline B (1.2 g, 5.29 millimoles) was dissolved in 1 liter of dichloromethane '30 liters of tetracarbonated carbon 'and roar (0-428 ml, 529 millimoles) and used 5- > Stinky 6-chloro-3-role 12 Dingshihuang brewing gas (1.54 g, 5.29 mmol) was dissolved in 4 ml of mono-gas methyl charcoal and 5 liters of tetra-gas carbon solution and treated to the temperature Violently dial out. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure. The residue is separated by a silica gel layer (35g Redisep column, Shi Xishi, 40 um, 60A, 35ml / min, eight:

MeOH, B · CH2C12, A · 20 minutes at 0%, 0% to 10% over 10 minutes, 10% at 20 minutes, 10% to 30% over 20 minutes, 30% at 15 minutes, 30% to 50% over 2 minutes, 10 minutes at 50%; detection at 214 nm) purification gave 1.14 g (45%) of the target compound as an orange solid. MS (ES) m / e 480 [M + H] + 2b) 5-Bromo-N- (4-chloro-3fiY3RVl-methyl_3-tetrahydropyrrole, a dioxobenzenesulfonyl) hydropyridine Dichlorophenol (136.0 μg, 0.832 mmol) was dissolved in 1 mL of anhydrous 1-fluorenyl-2-pyrrolidone and dispersed in NaH (60% in Shiguang oil, 35.0 mg, 0.874 mmol) Ear) processing. After all bubbling has stopped, the reaction is searched for another 30 minutes and 5- > odor-6-gas-N- (4-chloro-3 丨 1-methyl-3-tetrahydrotolyl) oxy} Phenyl) -3-upyridinesulfonamide (1000 mg, 0.208 mmol) in 1.0 ml of anhydrous 1-methyl-2-pyrrolidine_ 中 -17- This paper applies Chinese national standards (CNS) A4 specification (210x297 mm) 200418831 92564 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ___ B7 V. Solution processing of invention description (16). The reaction was heated at 125 C for 18 hours, cooled at room temperature through a 0.2 micron Acrodisk, and filtered by preparative HPLC (YMC CombiPrep 0DS-A, 50 X 20 mm, 20 ml / min, A: acetonitrile B: water, A: 5% to 95% (15 minutes, detection at 214 nm) was purified to obtain 19.4 mg (15%) of the compound as a brown solid. MS (ES) m / e 606 [Μ + Η] + Examples 3 -10 The following compounds were prepared by a method similar to that described in Examples 1 and 2 using the appropriate phenol or thiol: Name__ m / z 3 αχτ5'ί \ η Y 5-bromochloro-3 {[(3R) -1-methyl-3-tetrahydro. 〇 various groups] oxy} phenyl) -6-[(3,5-dichlorophenyl) thio] -3-° specific σ amine 624 4 Me0rvsYS η 6-{[3,4- Bis (methyloxy) phenyl] thio} -5- > odor-N- (4-air-3 {[((3R) -1-methyl-3-tetrahydropyrrolyl] oxy} benzene Pyridinylsulfonamide 614 5 5-bromo-N- (4-chloro-3 {[((3R) -1-amidino-3-tetrahydro.pyrrolyl] oxy} phenyl) -6- [ (3,5-Difluorophenyl) oxy] -3-tonimidinesulfonamide 574 6-{[3,4-bis (methyloxy) jasmine This paper is sized for China National Standard (CNS) A4 (210x297 mm) 20 04 1 8 83 1 92564 A7 B7 17 V. Invention $ You Ming 6

BrMe0Y > r0YS η group] oxy}-5- > O-N- (4-chloro-3 {[(3R) -1-methyl-3-tetrahydropyrrolyl] oxy} phenyl) -3 ^ pyridazine 598 7

Br 5- > O-N- (4-Ga-3-{[((3R) -1 -methyl-3-tetrahydropyrrolyl] oxy} phenyl) -6-{[3- (methyl (Oxy) phenyl] oxy] -3-carboxidinesulfonamide 568 9

Brrr ° rS η MeO ^ N ^ Ss; N 0 0 5-bromo-N- (4-air-3-{[(3R) -l-methyl-3-tetrahydro-0-bicycloyl] oxy} benzene Yl) -6-{[4- (fluorenyloxy) phenyl] oxy} -3-carboxolsulfonamide 568

5-bromo-N- (4-chloro-3-{[((3R) -l-methyl-3-tetrahydropyrrolyl] oxy} phenyl) -6-[(3,4-dichlorobenzene (Oxy) oxy] -3-carbosulfanilamide 606 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 Ο

Cl Br 5-bromo-N- (4-chloro-3-{[(3R) -l-fluorenyl-3-tetrahydro0pyrrolyl] oxy} phenyl) -6-[(2,3- Diphenylphenyl) oxy] -3-sulfanimidine 606 19- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200418831 92564 Printed by A7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs B7 Description of the invention (18) Example 11 The pharmaceutical formulation incorporating the compound of the present invention can be made into various types and contains many excipients. Examples of these formulations are listed below: Tablets / components per tablet 1. Active ingredient 40 mg (Cpd of type I) 2. King rice starch 20 mg 3. Alginic acid 20 mg 4. Sodium alginate 20 mg 5. Preparation method of 1.3 mg and 2.3 mg magnesium stearate: Step 1: Mix No. 1, No. 2, No. 3 and No. 4 ingredients in an appropriate mixer / mixer. Step 2: Add sufficient water in portions to the mixture obtained from Step 1 and mix carefully after each addition. Add water and mix until the consistency of the lump can be converted into wet granules. Step 3: The wet mass is converted into granules by a sieve of a swing granulator using a No. 8 screen (2.38 mm). Step 4: The wet granules are then dried in an oven at 140 ° F (60 ° C) until dry. -20- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200418831 92564 A7 B7 V. Description of the invention (l9) Step 5: Lubricate the dry particles with No. 5 component. Step 6: Compress the lubricated granules on a suitable tablet press. Inhalation formulations A compound of formula (I) (1 mg to 100 mg) delivers the desired aerosol drug amount from a metered dose aspirator per use. Formulations for parenteral administration Pharmaceutical compositions for parenteral administration are prepared by dissolving a suitable amount of a compound of formula (I) in a polyethylene glycol while heating. This solution was then diluted with water for injection of Ph Eur. (To 100 ml). The solution was then sterilized by filtration through a 0.22 micron membrane filter and sealed in a sterile container. The foregoing description and examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the specific examples described above, but includes all changes thereof within the scope of the following patent applications. Various references cited in this article for journals, patent cases, and other public cases contain the current state of the arts and are incorporated herein by reference as if fully set forth. CNS) A4 size (210x297 mm)

Claims (1)

200418831 92564 A8 B8 C8 D8 Patent application scope A compound with formula (I) Member of Intellectual Property Bureau of the Ministry of Economic Affairs, X Consumer Cooperative Technology, where Ar is phenyl, which is unsubstituted or replaced by one or two of the following: halogen 'CN' s (Cl-6 alkyl), CF3, 〇cf3 , scf3, Cn6 alkyl, Cl_6 alkyloxy 'C〇2 (Cl-6 alkyl), or No2; Y is 0 or s; z is hydrogen, halogen, or c1-6 alkyl; R2 is argon , Halogen, CN, or Cm alkyl; Ri is hydrogen or Ck alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to item 1 of the scope of patent application, wherein Ar is substituted with one or two halogen or alkoxy groups; Z is a halogen or hydrogen; R2 is a halogen or hydrogen; and I is a Cw alkyl group. 3 The compound according to item 1 of the scope of patent application is selected from the following: 5_ / odor-N_ (4-air-3-{[(3R) -1-methyl-3-tetrahydrosilyl] oxy} Phenyl) [(2,3-—Gabenzyl) thio] _3-Hou σ is a continuous amine; 5-ΊΝ- (4- 气 -3 _ {[(3R) -1-methyl-3-tetrakis Hydropyrrolyl] oxy} phenyl) 1 [[3,5-dichlorophenyl) thio] -3-pyridinesulfonamide; -22-" " ___ This paper size applies to Chinese national standards ( CNS) A4 specification (210x297 mm) " " noodle " '一 200418831 92564 A8 B8 C8 D8 Application scope of patent 6-{[3,4-bis (methyloxy) phenyl] thio-O-N -(4-chloro-3-{[(3R) -l-fluorenyl-3-tetrahydropyrrolyl] oxy} phenyl) -3-pyridinesulfonamide; 5-bromo-N- (4-chloro -3-{[((3R) Small methyl-3-tetrahydropyrrolyl] oxy} phenyl) -6-[(3,5-monophenyl) lactyl] -3-11 than hydration acid Amine, 5-bromo-N- (4-gas-3-{[((3R) -l-fluorenyl-3-tetrahydropyrrolyl] oxy} phenyl) -6-[(3,5-difluoro Phenyl) oxy] -3-yl. Diethylamine; 6- {[3,4-bis (methyloxy) phenyl] oxy} -5-bromo- ^ 1 " (4-chloro-3-{[(311) -1- 曱Methyl-3-tetrahydropyrrolyl] oxy} phenyl >3-pyridinesulfonamide; 5-bromo-N- (4-chloro_3 _ {[(3R) small methyl_3_tetrahydropyrrolyl ] Oxy} phenyl) -6-{[3 · (methyloxy) phenyl] oxy} -3-pyridinesulfonamide; 5-bromo-N- (4H {[(3R) -1-methyl 3--3-tetrahydropyrrolyl] oxy} phenyl) winter {[4_ (fluorenyloxy) phenyl] oxy} · 3 "than chlorite xanthoamine; 5-bromo-N- (4 _Chloro-3-{[((3R) berberyl-3-tetrahydropyrrolyl] oxy} phenyl) dong [(3,4-dichlorophenyl) oxy] _3-pyridylamine; And 5-bromo-N- (4-chloro-3-{[((3R) -1-methyl-3-tetrahydropyrrolyl] oxy} phenyl) -6-[(2,3-dichlorophenyl ) Oxy] _3-pyroxypyramine. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4 · A pharmaceutical composition containing a compound of formula (worker) and a pharmaceutically acceptable carrier Or an excipient. 5-A method for treating a condition related to a deficiency in urinary tractin-II balance by antagonizing the urinary tractin-n (Urotensin-II) receptor, which comprises applying patent application No. 1 The compound of the formula (I) is administered to a patient in need thereof. 6. The method according to item 5 of the scope of patent application, wherein the disease is congestive ~ visceral exhaustion, stroke, ischemic heart disease, angina pectoris, myocardial localization Miss-23-This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200418831 92564 A8 B8 C8 D8 Sixth Intellectual Property Bureau of the Ministry of Economy Employees' Cooperatives printed the scope of patent application for blood, arrhythmia, spontaneity and lung Hypertension, kidney disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication / ischemic limb disease, ischemic / hemorrhagic stroke, chronic obstructive Lung disease, restenosis, asthma, neuroinflammation 'migraine' metabolic vascular disease, bone / cartilage / joint disease, arthritis and other inflammatory diseases, fibrotic disease, pulmonary fibrosis, sepsis, atherosclerosis, Dyslipidemia, addiction, schizophrenia, cognitive disease, Alzheimer's disease, impulsivity, anxiety, stress, depression, Parkinson's Dyskinesia, dyskinesia, sleep-wake cycle, irritant induction, pain, nerve and muscle function, diabetes, gastric reflux, gastrokinetic disorders' ulcers and genitourinary diseases. 7 ·-a antagonizing urinary tractin-π receptor A method for treating a condition related to a deficiency of urethral astringent 41 balance in vivo, which comprises administering a compound of formula (I) of claim 3 to a patient in need thereof. 8. The method according to item 7 of the patent application, wherein the disease is congestive heart failure, stroke, ischemic heart disease, angina pectoris, myocardial ischemia 'arrhythmia, spontaneous and pulmonary hypertension, kidney disease, acute And chronic renal failure, end-stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication / ischemic limb disease, ischemic / haemorrhagic stroke, chronic obstructive pulmonary disease, restenosis, Asthma, neuroinflammation, migraine, metabolic vascular disease, bone / cartilage / joint disease, arthritis and other inflammatory diseases, fibrotic disease, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction ， Spirit score-24-This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200418831 92564 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 Six. Application for patent scope Rift disease, cognitive disease, Alzheimer's disease, impulsivity, anxiety, oppression, depression, Parkinson's disease, dyskinesia, sleep-wake cycle, Inducing a stimulated 'pain' nerve and muscle function 'diabetic' stomach countercurrent 'gastric motility disorders, ulcers and genitourinary diseases. 9. A pharmaceutical composition comprising a compound of formula (I) as claimed in item 3 of the patent application and a pharmaceutically acceptable carrier or excipient. 2 This paper size applies to China National Standard (CNS) A4 (210x297 mm)