WO2006095822A1 - Compose sulfonamide et produit pharmaceutique le contenant - Google Patents

Compose sulfonamide et produit pharmaceutique le contenant Download PDF

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WO2006095822A1
WO2006095822A1 PCT/JP2006/304623 JP2006304623W WO2006095822A1 WO 2006095822 A1 WO2006095822 A1 WO 2006095822A1 JP 2006304623 W JP2006304623 W JP 2006304623W WO 2006095822 A1 WO2006095822 A1 WO 2006095822A1
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PCT/JP2006/304623
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Hiromu Egashira
Eiji Nishiyama
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Ono Pharmaceutical Co., Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached

Definitions

  • the present invention relates to a sulfonamide compound useful as a pharmaceutical product.
  • 11 ⁇ -Hydroxysteroid dehydrogenase (hereinafter abbreviated as 11 j8—HSD) is an enzyme that regulates the glucocorticoid corticosteroid and activates inactive glucocorticoids (cortisone in humans). Enzyme that converts glucocorticoid type (cortisol in humans) is called 11 ⁇ HSD1, and enzyme that converts activated glucocorticoid to inactive glucocorticoid is called 11 ⁇ HSD2.
  • Cortisol plays an important role in the body, having physiological actions such as gluconeogenesis, glucose uptake by insulin and inhibition of glycolysis, adipose differentiation, angiotensinogen production or bone formation inhibition.
  • excessive cortisol is known to cause various pathologies caused by abnormal glucose tolerance, abnormal lipid metabolism, inhibition of bone formation, excessive production of adipocyte-derived physiologically active substances, and the like.
  • diseases caused by excessive production of corticosteroids such as cortisol include metabolic diseases (eg, diabetes (eg, type 2 diabetes)), impaired glucose tolerance, hyperglycemia, insulin resistance, hyperinsulinemia.
  • 11 j8-HSD2 knockout mice have been reported to die within 48 hours after birth, or cause severe hypertension, hypokalemia, and the like. Based on the above, it is conceivable that a compound that selectively inhibits 11 18 HSD1 suppresses overproduction of cortisol and can be a preventive and Z or therapeutic agent for the above-mentioned diseases with few side effects.
  • T a represents a heteroaryl ring, Ariru ring or to, R la represents a hydrogen atom or a C 1-6 alkyl group, X a represents a CH or CO, Y a is CH CO or a bond
  • B a represents a hydrogen atom, C 1-6 alkyl or dimethylaminomethyl
  • R 2 a represents a C 16 alkyl group, azido, allylthio, or the like.
  • T b represents an aryl ring or a heteroaryl ring
  • R lb represents a hydrogen atom or a C 1-6 alkyl group
  • a lb and A 2b represent a nitrogen atom or C—Z b
  • Z b Represents an aryl ring, heteroaryl ring or X b — Y b — R 2b
  • X b represents CH or CO.
  • ring represents aryl or heteroaryl
  • R lc represents a mouthpiece, nitro, sheared hydroxyl, etc.
  • nc represents 0 3
  • R 2 R 3 R 4c and R 5c are each independently Represents a hydrogen atom, a hydroxyl group, amino, etc.
  • x e and Z e are each independently —SO
  • pc represents 0 or 1
  • sc represents 0 or 1
  • ring B e represents a carbocyclic or heterocyclic ring
  • R 6c represents a mouthpiece, nitro, sheared hydroxy, etc.
  • mc represents 0 3 .
  • R ld represents an aliphatic hydrocarbon group which may have a substituent
  • the ring A d is R ld except substituents may further have at least one nitrogen atom
  • Ring B d represents a cyclic group which may have a substituent, is bonded to ring A d by a bond
  • G d is 1 to 4 atoms of the bond or main chain.
  • J d is a spacer containing a hydrogen bond accepting group which may have a substituent (one SO NR 2d
  • R 2d represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group or an optionally substituted cyclic group;
  • K d represents the number of bonds or main chain atoms. represents one to four spacers one, representing the ring D d i to form a connexion ring such with substituents you d, i also, cyclic group which may have a substituent. ), Salts thereof, N-oxides thereof, solvates thereof, or prodrug chemokine receptor antagonists thereof (see Patent Document 4).
  • Patent Document 1 International Publication No. 01Z090090 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 03Z044000
  • Patent Document 3 International Publication No.04Z011410 Pamphlet
  • Patent Document 4 International Publication No.04Z092136 Pamphlet
  • Preventive and Z or therapeutic agents for type II diabetes and the like are useful as pharmaceuticals, and development of safe 11 ⁇ -HSD1 inhibitors is eagerly desired.
  • ring A represents an optionally substituted cyclic group
  • X and Y each independently represent a bond or a spacer having 1 to 8 atoms in the main chain
  • R 2 and R 3 each independently represents a hydrogen atom, a cyclic group which may have a substituent, or a hydrocarbon group which may have a substituent.
  • the substituent on the spacer of 1 to 8 atoms in the main chain represented by Y is a nitrogen-containing group that may have a substituent together with R 2 and the atom to which they are bonded.
  • a heterocycle may be formed.
  • ring A may be benzene, has a substituent, may have pyridazine, or may have a substituent, and may be piperidine.
  • ring Alpha 2 represents an optionally pyridazine ring which may have a substituent, and other symbols.
  • X is methylene, ethylene, propylene, butylene, pentylene, hexylene,
  • the compound is 3-methyl-N- [6- (3-phenylpropyoxy) pyridazine-3-yl] benzenesulfonamide, N— ⁇ 6 -— [3- (benzyloxy) propoxy] pyridazine 3-yl ⁇ 3-methyl Benzenesulfonamide, 3-methyl-N— (6— ⁇ 2— [Methyl (phenyl) amino] ethoxy ⁇ pyridazine-3-yl) benzenesulfonamide, N— (3— ⁇ 1— [(3 methyl Chain 2-yl) methyl] piperidine-4-yl ⁇ benzyl) -4-propylbenzenesulfonamide or N— ⁇ 3-— 1- (4-chlorobenzyl) piperidine mono 4-yl] benzyl ⁇ 4 methoxy
  • a pharmaceutical composition comprising a compound represented by the general formula (I) according to 1 above, a salt or solvate thereof, or a prodrug thereof,
  • composition according to the above 11 which is a preventive and epilepsy or therapeutic agent for diseases caused by excessive production of corticosteroids
  • a pharmaceutical comprising a combination of one or more
  • An adrenal gland in a mammal characterized by administering an effective amount of a compound represented by the general formula (I), a salt thereof or a solvate thereof, or a prodrug thereof according to the above 1 to the mammal.
  • a method for preventing and Z or treating diseases caused by cortical hormone overproduction 18.
  • a compound represented by the general formula (I), a salt thereof, or a solvent thereof for producing a ⁇ 11 HSD1 inhibitor It relates to the use of Japanese products or prodrugs thereof.
  • the compound of the present invention has an 11 ⁇ HSD1 inhibitory effect, it is useful as a preventive and epilepsy or therapeutic agent for diseases caused by excessive production of corticosteroids.
  • the “hydrocarbon group” in the “hydrocarbon group having a substituent” may be, for example, a linear or branched C1— 8 Aliphatic hydrocarbon groups and the like.
  • Examples of the "linear or branched C1-8 aliphatic hydrocarbon group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert butyl, pentyl, hexyl, heptyl Or a C 1-8 alkyl group such as an octyl group, for example, vinyl, probe, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butaenyl, pentageninore, hexageninore, heptageninore, octageninore, hexatrienole, C2-8 alkyl group such as heptatriol or otatriaryl group, or for example ethininole, propininole, butyninole, pentininore, hexininore, heptininore
  • Ring A, in R 2 and R 3 examples of the cyclic group in the “cyclic group having a substituent” may include, for example, a carbocycle or a heterocycle.
  • Carbocycle includes “unsaturated carbocycle” or “saturated carbocycle”.
  • saturated carbon ring examples include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • 3-15 membered cycloalkanes for example perhydropentalene, perhydroazulene, perhydroindene, Perhydronaphthalene, perhydroheptalene, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane, bicyclo [2.2.2] “3-15-membered saturated carbocycles” such as 7-15-membered bicyclic or tricyclic saturated carbocycles such as octane, adamantane, noradamantane and the like.
  • “Unsaturated carbocycle” includes, for example, 3- to 8-membered cycloanolene such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentagen, cyclohexagen, cyclohexabutadiene, cyclooctagen, etc .; for example, benzene, azulene, naphthalene Aromatic carbocycles such as pentalene, indene, indane, dihydronaphthalene, tetrahydronaphthalene, heptalene, biphenylene, as-indacene, s-indacene, acetnaphthene, acenenaphthylene, fluorene, phenalene, bicyclo [ 2.2.1] Hepter 2—Yen, Bicyclo [3.1.1] Hepter 2—Yen, Bicyclo [2.2.2] 7-15 Membere
  • the "heterocycle” includes, for example, a nitrogen atom, an oxygen atom, and sulfur nuclear power and optionally selected 1 to 7 heteroatoms, and may represent a monocyclic or polycyclic heterocycle .
  • Examples of the “heterocycle” include “3-15-membered unsaturated monocyclic or polycyclic heterocycle”, “3-15-membered saturated monocyclic or polycyclic heterocycle” and the like.
  • Examples of the "3-15 membered unsaturated monocyclic or polycyclic heterocyclic ring” include a 5-15 membered aromatic heterocyclic ring or a 3-15 membered unsaturated non-aromatic heterocyclic ring.
  • Examples of the “5- to 15-membered aromatic heterocyclic ring” include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, thiphene, oxazole, isoxazole, thiazole, iso 5- or 6-membered monocyclic aromatic heterocycles such as thiazole, furazane, oxadiazole, thiadiazole ring; for example, indole, isoindole, benzofuran, isobenzofuran, benzothiphene, isobenzothiphene, indazole, quinoline, isoquinoline, purine , Phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazonole, benzothiazonole, benzoy
  • Examples of the “3- to 15-membered unsaturated non-aromatic heterocycle” include azepine, diazepine, pyran, oxepin, thiopyran, chepin, oxazine, oxazidine, oxazepine, oxadiazepine, thiazine, thiadiazine, thiazepine, thiadiazepine, and indidine.
  • Dithianaphthalene Dithianaphthalene, quinolidine, chromene, benzoxepin, benzoxazepine, benzoxazizepine, benzochepine, benzothiazepine, benzothiadiazepine, benzozezepine, benzodiazepine, xanthene, phenothiazine, phenoxazine, phenoxathiin, thianthrene, pyrroline, iminezo 2, 3-dihydro- 1H-pyrazole, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydrovirazine, Toluhydrovirazine, dihydropyrimidine, tetrahydropyrimidine, dihydric oral pyridazine, tetrahydropyridazine, tetrahydrotriazine, dihydroazepine, tetrahydroazepin
  • Examples of the “3-15 membered saturated monocyclic or polycyclic heterocyclic ring” include, for example, aziridine, azetidine, pyrrolidine, imidazolidine, triazolidine, tetrazolidine, virazolidine, piperidine, piperazine, perhydropyrimidine, Hydropyridazine, perhydroazepine, perhydrodiazepine, perhydroazocine, oxsilane, oxetane, tetrahydrofuran, tetrahydropyran, perhydrooxepin, thiirane, chetan, tetrahydrothiophene, tetrahydrothiopyran, perhydrochepi Pin, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydr isothiazole (
  • a hydrocarbon group (the “hydrocarbon group” has the same meaning as the above-mentioned “hydrocarbon group”), (2) It has a substituent.
  • An optionally substituted carbocyclic group (the “carbocycle” has the same meaning as the above-mentioned “carbocycle”), (3) an optionally substituted heterocyclic group (the “heterocycle” "Has the same meaning as the above-mentioned” heterocycle "), (4) an amino group, (5) a substituent, and a C1-10 acylamino group (for example, acetylamino-containing propio-lamino) ), (6) Primary or secondary amino group substituted with a substituent (for example, methylamino, ethylamine-containing n-propylamino-containing isopropylamino-containing butylami-containing dimethylamino-containing cyclohexylamino-containing 1-strength rubermo
  • a substituent
  • a phenylsulfuramine group (9) has a substituent! / May be a C1-8 alkylsulfol group (for example, methylsulfol, ethylsulfol, etc.), (10 ) Phenylsulfol group which may have a substituent, (11) Halogen atom (fluorine, chlorine, bromine, iodine), (12) Carboxyl group, (13) Cyano group, (14) Nitro group , (15) oxo group, (16) thixo group, (17) hydroxyl group, (18) having a substituent, C 1-8 alkoxy group, (19) having a substituent!
  • C3-8 cycloalkoxy group (20) a phenoxy group optionally having a substituent, (21) a mercapto group, or (22) a substituent.
  • C1-8 alkylthio group for example, methylthio, ethylthio, propylthio, isopropylthio group, butylthio, tert-butylthio, etc.
  • (23) a phenylthio group optionally having a substituent for example, 4 -Ruthio, etc.
  • (24) force rumomoyl group (25) amino-substituted carbonyl group substituted with substituents (eg, N-butylaminocarbonyl, N-cyclohexylmethylaminocarbonyl, N-butyl-N cyclohexyl) Methylaminocarbol, N cyclohexylaminocarbol, phenylaminocarbonyl,
  • C1-8 alkylsulfier group (36) with substituent! /, C1-10 acyl group, (37) hydroxyimino group, (38) C1-8 alkyloxymino A group (eg methyloxyethyloxymino).
  • (1) may have a substituent, may have a hydrocarbon group, (2) may have a substituent, may have! / May have a substituent, or may have a hydrocarbon ring group, and (3) has a substituent.
  • An optionally substituted heterocyclic group (5) an optionally substituted C1-6 acylamino group, (7) an optionally substituted! /, Or a C 1-8 alkylsulfo-lumino group Group, (8) phenylsulfolumino group optionally having substituent (s), (9) V having substituent (s), and C1-8 alkylsulfol group, (10) substituent Have it!
  • a phenylsulfonyl group (18) an optionally substituted C18 alkoxy group, and (19) a substituent! / Take it! /, C3-8 cycloalkoxy group, (20) with substituents! /, May! /, A phenoxy group, (22) an optionally substituted C1-8 alkylthio group, (23) an optionally substituted phenylthio group, and (28) a substituted group. !
  • a substituent for example, a C18 alkyl group (the “C18 alkyl group” has the same meaning as described above), a phenyl group, an amino group, a C1-4 alkyl group (for example, methyl, ethyl, propyl).
  • the substituents listed in the second group may be substituted at 1 to 5 substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different. . “Substitution” in (6) the first or second amino group substituted with the substituent, (25) the aminocarbonyl group substituted with the substituent, and (27) the aminosulfol group substituted with the substituent. Examples of the “group” include (1) the hydrocarbon group which may have a substituent, (2) the substituent, which may have a carbocyclic group or (3) a substituent. ! / May be a heterocyclic group, and these substituents may be substituted with 1 or 2 hydrogen atoms of an amino group. When two substituents are present, each group may be the same or different.
  • (C) -10-acyl group in the C5-10-acylamino group and (36) the optionally substituted C1-10-acyl group C1 10 alkanols such as formyl, acetyl, propanoyl, butanol, pentanoyl, hexanol, heptanol, otatanyl or bivaloyl, for example C6-10 fragrance such as benzoyl, phenylmethyl carboyl or 2 phenol carboyl Group carbocyclic carbonyl and the like.
  • C1 10 alkanols such as formyl, acetyl, propanoyl, butanol, pentanoyl, hexanol, heptanol, otatanyl or bivaloyl
  • C6-10 fragrance such as benzoyl, phenylmethyl carboyl or 2 phenol carboyl Group carbocyclic carbonyl and the like.
  • C18 alkylsulfoamino group which may have a substituent (9) C1-8 alkylsulfo group which may have a substituent, (22) C1-8 alkylthio group, which may have a substituent, (35) C1-8 alkylsulfyl group, which has (35) a substituent, and (38) C1 —
  • the “C1 8 alkyl” in the 8 alkyloxymino group has the same meaning as the “C1 8 alkyl group” in the “linear or branched C1 8 aliphatic hydrocarbon group”.
  • the (18) C18 alkoxy group which may have a substituent, and (28) the C1-8 alkoxy group in the C1-8 alkoxycarbo group may have a substituent.
  • C3-8 cycloalkoxy group in the C3-8 cycloalkoxy group includes, for example, cyclopropyloxy, cyclobutyloxy , Cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclocyclohexyl, and the like.
  • the "cyclic group" in ring A preferably includes, for example, a 6-8-membered cyclic group (for example, a 6-8-membered carbon ring or a 6-8-membered heterocyclic ring), and more preferably, , Benzene, pyridazine, piperidine and the like 6-membered carbon ring or 6-membered heterocycle.
  • R 1 preferably has, for example, a substituent, and examples thereof include a 5- to 8-membered cyclic group, and more preferably, for example, a 5-membered or 6-membered cyclic group (which may have a substituent) ( For example, a 5-membered or 6-membered carbocyclic ring, or a 5-membered or 6-membered heterocyclic ring). More preferable examples of the “5-membered or 6-membered cyclic group” include cyclopentane, cyclohexane, benzene, pyridine, and thiophene ring.
  • R 2 is preferably a hydrogen atom or a C1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), and more preferably a hydrogen atom.
  • R 3 is preferably, for example, a C1-4 alkyl group (for example, methyl, ethyl, tert-butyl, trifluoromethyl, optionally substituted) (for example, the substituents listed in the second group).
  • Benzyl, 7,7 dimethyl-2-oxobicyclo [2.2.1] heptyl-1-ylmethyl, etc. optionally having a substituent (for example, the substituents mentioned in the second group) C1 4 Having a group (for example, a fluorine group), a substituent (for example, the substituents mentioned in the first group)!
  • aromatic ring groups for example, aromatic carbon A ring or an aromatic heterocycle
  • aromatic cyclic group More preferable examples of the “aromatic cyclic group” include benzene, naphthalene, thiophene, benzothiophene, pyridine, pyrrole, imidazole, triazole, pyrazole, oxazole, isoxazole, oxadiazole and thiadiazole rings.
  • Spacer with 1 to 8 main chain atoms represented by X or Y is 1 to 8 atoms in the main chain. It means the interval that is connected.
  • the “number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • the number of atoms of 1,2 cyclopentylene is 2, and the number of atoms of 1,3 cyclopentylene is 3.
  • One group isotonic force A divalent group having 1 to 8 atoms in the main chain, which can be arbitrarily selected from 1 to 8 combinatorial forces.
  • the “divalent aliphatic hydrocarbon group” include a C1-8 alkylene group (for example, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, etc.), a C2-8 alkylene group (for example, , Etylene, propenylene, butenylene, butagenylene, pentenylene, pentagenylene, hexylene, hexagenylene, heptenylene, heptagelenylene, octylene, octajylene, etc.) or C2-8 alkylene Groups (e.g., ethylene, propynylene, butylene, butazinylene, pentynylene, pent
  • Carbocycle and “heterocycle” have the same meanings as “carbocycle” and “heterocycle”, respectively.
  • a divalent aliphatic hydrocarbon group which may have a substituent, a substituent, a carbocycle, a substituent, or a “substituent” in a heterocycle Examples of the substituent include the substituents mentioned in the first group. Even if it has a substituent, the “substituent” in the nitrogen atom may be a hydrocarbon group having (1) a substituent in the first group, or (2) having a substituent. And may be a carbocyclic group or (3) a substituent and V may be a heterocyclic group.
  • the substituent on the spacer of 1 to 8 atoms in the main chain represented by Y has a substituent, together with R 2 and the atom to which they are bonded, and may contain nitrogen. Heterocycles may be formed. Examples of the “nitrogen-containing heterocycle” include a 5- to 8-membered monocyclic nitrogen-containing heterocycle.
  • Examples of the “5- to 8-membered monocyclic nitrogen-containing heterocycle” include pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, pyrroline, imidazoline, triazoline, tetrazoline, pyrazoline, dihydropyridine, tetrahydropyridine, dihydrovillar.
  • the “nitrogen-containing heterocycle” may have 1 to 5 substituents at substitutable positions. When the number of substituents is 2 or more, each substituent is the same or different. May be. Examples of the substituent include the above-mentioned first group of substituents.
  • X is preferably selected from, for example, a bond, a divalent aliphatic hydrocarbon group which may have a substituent, a substituent, or a nitrogen atom and an O group.
  • examples thereof include a divalent group having 1 to 6 atoms in the main chain, which has a combination force of ⁇ 6.
  • the divalent group having 1 to 6 atoms in the main chain specifically, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene,
  • Y is, for example, a bond or a divalent aliphatic hydrocarbon group which may have a substituent, a nitrogen atom which may have a substituent, and (having a substituent. And a divalent group having 1 to 6 atoms in the main chain and having a combination force of 1 to 6 arbitrarily selected from one group or the like. More preferably, a bond,
  • preferred compounds include those represented by the general formula (I).
  • ring A 1 further has a 6- to 8-membered cyclic group which may have a substituent
  • ring B further has a substituent, and may have a 5- to 8-membered cyclic group.
  • D may further have a substituent, and may represent an aromatic cyclic group, and other symbols have the same meaning as described above.
  • ring E is an optionally substituted 5- to 8-membered saturated monocyclic nitrogen-containing heterocycle
  • W represents a carbon atom or a nitrogen atom
  • the other symbols have the same meanings as described above.
  • ring B 1 represents a piperidine ring which may further have a substituent.
  • the substituent may be bonded to the NH nitrogen atom of ring B 1 . Represents the same meaning as described above.) And the like.
  • X 1 is a bond, or a divalent aliphatic hydrocarbon group which may have a substituent, a nitrogen atom which may have a substituent, and an O group, etc.
  • 1-6 A divalent group having 1 to 6 atoms in the main chain, which can also be combined, and the other symbols have the same meaning as described above.
  • the "6- to 8-membered cyclic group" in the "having a substituent, which may have 6- to 8-membered cyclic group" for ring A 1 is a 6- to 8-membered carbocyclic ring or a 6- to 8-membered heterocyclic group A ring, preferably, for example, cyclohexane, benzene, pyridine, pyrazine, pyrimidine, pyridazine, piperidine or piperazine ring. More preferred are benzene, pyridazine, piperidine and the like.
  • the “5-8-membered cyclic group” in the “having a substituent may be a 5--8-membered cyclic group” of ring B, the 5- to 8-membered carbocycle or 5- to 8-membered heterocyclic ring
  • the "aromatic cyclic group" in the "having a substituent! / ⁇ may be! / ⁇ aromatic cyclic group” represented by ring D includes an aromatic carbocyclic ring or an aromatic heterocyclic ring.
  • aromatic carbocyclic ring or an aromatic heterocyclic ring Preferably, for example, benzene, naphthalene, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazonole, thiazol, indole, isoindole, benzofuran, benzothiophene, etc. It is possible. More preferably, benzene, naphthalene, thiophene, benzothiophene, pyridine, etc. are mentioned.
  • the substituent on the spacer having 1 to 8 atoms in the main chain represented by ⁇ is R 2 and they are bonded.
  • Ring A 1 Ring A 2 , Ring A 3 , Ring B, Ring, Ring D, Ring D 1 or Ring E has 1 to 5 substituents selected from the first group. If the number of the substituents is 2 or more, each substituent may be the same or different.
  • a preferable example of the substituent for the ring A 3 is a strong rubamoyl group.
  • Specific preferred compounds of the present invention include, for example, 1-[(2,4-dichloro-3-methylphenol) sulfol] -4 mono (4-fluorophenol) piperazine (CAS registration) Number: 325812—17—7), 1— [4-Tro-2- (trifluoromethyl) phenol] —4— (phenylsulfol) piperazine (CAS Registry Number: 346459—18—5) ), 1— (2—Black mouth — 6— -Trophele) —4— [(4-Methylphenol) sulfol] piperazine (CAS registration number: 333425—22— 2), 4— [4— (2 naphthylsulfoyl) piperazine 1 yl] — 1H—indole (CAS registration number: 256458—67—0), 1— (2 black mouth—4 2 trophyl) —4— [ (4-Methylfurol) sulfol] piperazine (CAS registration)
  • preferred compounds include 3-methyl-N- [6- (3-phenolpropoxy) pyridazine-3yl] benzenesulfonamide (Compound 2), N- ⁇ 6- (Benzyloxy) propoxy] pyridazine 3-yl ⁇ 3-methylbenzenesulfonamide (compound 2-1), 3 methyl N- (6— ⁇ 2 [methyl (phenyl) amino] ethoxy ⁇ pyridazine 3 ) Benzenesulfonamide (compound 2-2), N- (3— ⁇ 1 [(3 methyl chain 2 yl) methyl] piperidine — 4 yl ⁇ ) -4 propylbenzenesulfonamide ( Compound 12—12), ⁇ — ⁇ 3— [1— (4-Clorobenzyl) piperidine 4-yl] benzyl ⁇ —4-methoxybenzenesulfonamide (Compound 12—71), 1— ( 2 Fluorophenol)
  • the compound names used in this specification are generally computer programs, ACD / Name (registered trademark, manufactured by Advanced Chemistry Development Inc.) or ACD / Name batch (named in accordance with IUPAC rules). Registered trademark, Advanced Chemistry Development
  • the compound represented by the formula was named 3-methyl-N- [6- (3-phenylpropoxy) pyridazine-3-yl] benzenesulfonamide.
  • Examples of the -len group, alkylene group, acyl group and acyloxy group include straight-chain and branched-chain groups.
  • isomers in double bonds, rings and condensed rings (E-form, Z-form, cis-form, trans-form), isomers due to the presence of asymmetric carbon (R-form, S-form, ⁇ -configuration, j8-configuration, enantiomers) , Diastereomers), optically active substances having optical activity (D, L, d, 1), polar substances (high polarity, low polarity) by chromatographic separation, equilibrium compounds, rotational isomerism Bodies, and mixtures of these in any proportion, racemic mixtures are all included in the present invention. In the present invention, all isomers of tautomers are also included.
  • optically active compound in the present invention is not only 100% pure but 50% It may contain less than other optical isomers.
  • the salts of the compound represented by the general formula (I) include all pharmacologically acceptable salts.
  • the pharmacologically acceptable salt is preferably water-soluble with little toxicity.
  • Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethyl ammonium salts, tetraptyl).
  • Ammonium salts, etc. organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine , N-methyl-D-dalkamine, etc.), acid adduct salts (inorganic acid salts (hydrochloric acid salts, hydrofluoric acid salts, hydroiodic acid salts, sulfuric acid salts, phosphates, nitrates, etc.) or organic acids Salt (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate Kuen salt, methanesulfonate, ethanesulfonate, benzenesulfonate Hong, toluenesulfonate, isethionate, glucuronate, Darukon salt
  • the salt includes quaternary ammonium salt.
  • a quaternary ammonium salt refers to a compound in which the nitrogen atom of the compound represented by the general formula (I) is quaternized with an R group.
  • the R group represents a C18 alkyl group or a C18 alkyl group substituted by a phenyl group.
  • suitable solvates of the compound represented by the general formula (I) include solvates such as water and alcohol solvents (eg, methanol, ethanol, etc.). The solvate is preferably non-toxic and water-soluble.
  • the solvates of the compounds of the present invention also include solvates of the above-mentioned alkali (earth) metal salts, ammonium salts, organic amine salts, and acid adduct salts of the compounds of the present invention.
  • the compound represented by the general formula (I) can be converted into the above salt, the above N-oxide, and the above solvate by a known method.
  • a prodrug of the compound represented by the general formula (I) is a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body.
  • Shown by general formula (I) As a prodrug of the compound, for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, The amino group of the compound represented by the general formula (I) is converted to eicosanolation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolene-4-yl) methoxycarbonylation, and tetrahydrofullylation.
  • the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated, Alkylated, phosphorylated, borated compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, bivalylated, Diylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); when the compound represented by the general formula (I) has a carboxy group, the carboxy group is esterified or amidated.
  • the carboxy group of the compound represented by the general formula (I) is converted into ethyl ester, phenol ester, carboxymethyl ester, dimethylaminomethyl ester, bivalyloxymethyl ester, ethoxycarbo -Luoxetyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3 dioxolene-4-yl) methyl ester, cyclohexyloxycarbo-ruethyl esterification, methylamidated compounds, etc. ) And the like. These compounds can be produced by a method known per se.
  • the prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate.
  • the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten 1990, “Development of Drugs”, Vol. 7, “Molecular Design”, pages 163-198.
  • the compound may be changed to the compound represented by (I).
  • the compound represented by the general formula (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 1 etc.).
  • the compounds of the present invention represented by the general formula (I) can be prepared by known methods, for example, the methods shown below, an implementation sequence, and the like, and the omprehensive Organic Transformations: A uuide to Functional Group. It can be produced by combining the methods described in Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999). In each of the following production methods, the raw material mixture may be used as a salt. As such a salt, those described as the salt of the compound represented by the general formula (I) are used.
  • the compound represented by the general formula (I) is, for example, the general formula (II)
  • T 1 represents a hydroxyl group or a halogen atom
  • R 3 has the same meaning as described above.
  • a carboxyl group, a hydroxyl group, an amino group, or a mercapto group that can be contained in T 1 or R 3 needs to be protected.
  • it can be produced by subjecting the compound represented by (2) to sulfonamidation and, if necessary, deprotecting the protecting group.
  • sulfonamido reaction is well known.
  • sulfonic acid can be used in an organic solvent (such as chloroform, dichloromethane, dichloroethane, jetyl ether, tetrahydrofuran, methyl tert-butyl ether) or without solvent.
  • Reaction with a noride oxalyl chloride, thioyl chloride, phosphorus pentachloride, phosphorus trichloride, etc.
  • a base diisopropylethylamine
  • the deprotection reaction of the protecting group is carried out by a method known per se, such as TWGreene, It is carried out by a method described in Groups in Organic Synthesis, Wiley, New York, 1999 or a method according to these methods.
  • the deprotection reaction of a protecting group of a carboxy group, a hydroxyl group, an amino group, or a thiol group is well known.
  • (1) deprotection reaction by alkali hydrolysis, (2) under acidic conditions Deprotection reaction, (3) Deprotection reaction by hydrogenolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reaction using metal, or (6) Deprotection reaction using metal complex, etc. Can be mentioned.
  • the deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) in an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, water, Lithium oxide, etc.), alkaline earth metal hydroxides (barium hydroxide, potassium hydroxide, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof or mixtures thereof, Performed at a temperature of ⁇ 40 ° C.
  • an organic solvent methanol, tetrahydrofuran, dioxane, etc.
  • an alkali metal hydroxide sodium hydroxide, potassium hydroxide, water, Lithium oxide, etc.
  • alkaline earth metal hydroxides barium hydroxide, potassium hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • the deprotection reaction under acid conditions can be carried out, for example, by using an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p— in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.). Tosilic acid, etc.), or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide, Z acetic acid, etc.) at a temperature of about 0-100 ° C.
  • organic acid acetic acid, trifluoroacetic acid, methanesulfonic acid, p—
  • organic solvent dichloromethane, chloroform, dioxane, ethyl acetate, azole, etc.
  • Tosilic acid, etc. or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide, Z acetic
  • Deprotection reaction by hydrogenolysis includes, for example, solvent (ether type (tetrahydrofuran, dioxane, dimethoxyethane, jetyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type (benzene, toluene, etc.) ), Ketones (acetone, methylethylketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, catalyst (palladium) — In the presence of carbon, nodular black, palladium hydroxide, platinum oxide, Raney nickel, etc.) in a hydrogen atmosphere under normal or caloric pressure or in the presence of ammonium formate at a temperature of about 0 to 200 ° C. Done.
  • solvent ether type (tetrahydrofuran, dioxane, dime
  • the deprotection reaction of the silyl group is carried out at a temperature of about 0 to 40 ° C. using tetraptyl ammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.).
  • the deprotection reaction using a metal is carried out, for example, by using an acidic solvent (acetic acid, In a liquid or a mixture of these solutions and an organic solvent such as tetrahydrofuran) in the presence of powdered zinc and, if necessary, at a temperature of about 0 to 40 ° C. while applying ultrasonic waves.
  • an acidic solvent acetic acid, In a liquid or a mixture of these solutions and an organic solvent such as tetrahydrofuran
  • the deprotection reaction using a metal complex is carried out, for example, by using a trap reagent (tryptyltin hydride hydride) in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water or a mixed solvent thereof.
  • a trap reagent tryptyltin hydride hydride
  • organic solvent dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.
  • Triethylsilan dimedone, morpholine, jetylamine, pyrrolidine, etc.
  • organic acids acetic acid, formic acid, 2-ethylhexanoic acid, etc.
  • Z or organic acid salts sodium 2-ethylhexanoate, 2-ethylhexane
  • Metal complexes tetrakistriphenylphosphine palladium (0), bis (triphosphinephosphine) palladium dichloride) ( ⁇ ) in the presence or absence of phosphine reagents (triphenylphosphine, etc.) ), Palladium acetate ( ⁇ ), tris chloride (triphenylphosphine) Using palladium (I), etc.) at a temperature of about 0-40 ° C.
  • the desired compound of the present invention can be easily produced by using and separating these deprotection reactions.
  • Examples of the protecting group for the carboxy group include a methyl group, an ethyl group, an allyl group, a t-butyl group, a trichloroethyl group, a benzyl (Bn) group, and a phenacyl group.
  • Examples of hydroxyl protecting groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), and 2-tetrahydrovinyl (THP).
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • acetyl (Ac) group pivaloyl group
  • benzoyl group benzyl (Bn) group
  • p Examples thereof include a methoxybenzyl group, an aryloxy group (Alloc) group, and a 2,2,2-trichloro-ethoxy group (Troc) group.
  • protecting groups for amino groups include benzyloxycarbonyl group, tert-oxycarbonyl group, allyloxycarboxyl (Alloc) group, 1-methyl-1 (4-biphenyl) ethoxycarbol. (Bpoc) group, trifluoroacetyl group, 9 fluoromethylmethoxy group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group or 2- (trimethylsilyl) ethoxymethyl ( SEM) group and the like.
  • protecting groups for mercapto groups include benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydrovinyl (THP), diphenylmethyl or acetylene. And (Ac) group.
  • the protecting group for the carboxy group, hydroxyl group, amino group, or mercapto group is not particularly limited as long as it is a group that can be easily and selectively removed other than those described above.
  • For column f those described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.
  • X 1 and X 2 each independently represent a bond or a spacer having 1 to 7 atoms in the main chain, but the main chain of the spacer represented by X 1 and X 2 The sum of the number of atoms is not more than 7.
  • the other symbols have the same meaning as described above, except that the carboxyl group, hydroxyl group, amino group or mercapto group contained in each group is protected when protection is required.
  • T 2 represents a hydroxyl group or a leaving group (halogen atom, ⁇ toluenesulfonyloxy group, methanesulfo-loxy group, trifluoromethanesulfo-oxy group, etc.), and other symbols have the same meanings as described above.
  • a carboxyl group, a hydroxyl group, an amino group or a mercapto group, which may be contained in each group, is protected when protection is required.
  • It is produced by subjecting to a deprotection reaction if desired.
  • This etherification reaction is known, for example, an alkali metal hydroxide (dimethylformamide, dimethyl sulfoxide, black form, dichloromethane, jetyl ether, tetrahydrofuran, methyl t-butyl ether, etc.)
  • an alkali metal hydroxide dimethylformamide, dimethyl sulfoxide, black form, dichloromethane, jetyl ether, tetrahydrofuran, methyl t-butyl ether, etc.
  • alkaline earth metal hydroxides barium hydroxide, calcium hydroxide, etc.
  • carbonates sodium carbonate, potassium carbonate, etc.
  • an organic solvent dichloromethane, jetyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.
  • an azo compound jetyl carbonate diethyl (DEAD), azodicarboxylate diisopropyl, 1, 1 '(azodicarbol) dipiperidine 1, 1, -azobis (N, N-dimethylformamide, etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.) It is carried out by reacting at ⁇ 60 ° C.
  • the deprotection reaction is performed by the method described above.
  • This reaction is known, for example, an alkali metal hydroxide (dimethylformamide, dimethylsulfoxide, chloroform, formaldehyde, dichloromethane, jetyl ether, tetrahydrofuran, methyl t-butyl ether, etc.)
  • Sodium hydroxide, lithium hydroxide, lithium hydroxide, etc. alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), alkali metal hydrides (sodium hydride, etc.), or carbonates (Natrium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof, and the reaction is carried out at about 0 to 1 oo ° C.
  • the deprotection reaction is performed by the method described above.
  • R 1_1 has a hydrogen atom, a group selected from the second group force, or a substituent selected from the second group! /, Or may be a C1 7 aliphatic hydrocarbon group. And other symbols have the same meaning as described above.
  • R 3 represents the same meaning as described above, provided that a carboxyl group, a hydroxyl group, an amino group or a mercapto group contained in R 3 is protected when protection is required.
  • R 1_1 are as defined above. However, a carboxyl group which may be contained in R 1 _1, a hydroxyl group, an amino group or a mercapto group is assumed to be protected when protection is required.)
  • the compound represented by the above formula is prepared by subjecting it to a reductive amination reaction and, if desired, a deprotection reaction.
  • the reductive amination reaction is known.
  • a reducing agent sodium triacetoxyborohydride, sodium cyanoborohydride
  • an organic solvent diichloroethane, dichloromethane, dimethylformamide, acetic acid, and a mixture thereof.
  • sodium borohydride, etc. at a temperature of about 0-40 ° C.
  • the deprotection reaction is performed by the method described above.
  • reaction involving heating can be performed using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.
  • a solid-phase-supported reagent supported on a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • a high-molecular polymer for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.
  • the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by scavenger resin or column chromatography, or by washing, recrystallization and the like. Purification may be performed for each reaction or after completion of several reactions.
  • a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin. It can be purified by scavenger resin or column chromatography, or by washing, recrystallization and the like. Purification may be performed for each reaction or after completion of several reactions.
  • the compound represented by the general formula (I), a salt thereof or a solvate thereof, or a prodrug thereof (hereinafter sometimes referred to as the compound of the present invention) has very low toxicity and is used as a medicine. Safe enough to do.
  • the compound of the present invention Since the compound of the present invention has an 11 ⁇ HSD1 inhibitory effect, it is a disease caused by excessive production of corticosteroids such as metabolic diseases (eg, diabetes (eg, type II diabetes)), impaired glucose tolerance, hyperglycemia, Insulin resistance, hyperinsulinemia, dyslipidemia, fatty liver, dyslipidemia, hyperlipidemia, hypertriglyceridemia, high LDL cholesterolemia, low HDL cholesterolemia, obesity, atherosclerotic artery Sclerosis, syndrome X, metabolic syndrome, Cushing syndrome, osteoporosis, etc.), hypertension, cognitive impairment, memory It is considered useful for prevention and Z or treatment of disorders, depression, anxiety, dementia, Alzheimer's disease, glaucoma, immune diseases, etc.
  • corticosteroids such as metabolic diseases (eg, diabetes (eg, type II diabetes)), impaired glucose tolerance, hyperglycemia, Insulin resistance, hyperinsulinemia, dyslipidemia, fatty liver, dyslipidemia, hyperlipidemia, hypertriglycerid
  • mice Male ob / ob mice (B6.VL mark; b Zj) are received at 7 weeks of age and then pre-bred for 1 to 5 weeks in individual cages. During the pre-breeding and testing period, solid feed and tap water can be ad libitum from the water bottle. The day before the start of medication (DayO), the body weight is measured, blood is collected from the tail vein, and the blood glucose level is measured. Divide into groups by stratified randomization based on blood glucose level and body weight, and assign 5 to 6 animals per group. The next day (Dayl) force will also start the test compound injection.
  • Dosing is carried out, for example, by suspending or dissolving the test compound in a vehicle and then administering it by gavage, diet, or intraperitoneal cavity.
  • a control group receives vehicle.
  • the dose and number of doses should be adjusted according to the strength of the test compound.
  • the efficacy evaluation in this diabetes model is conducted using body weight, blood glucose level, insulin level and blood triglyceride as indices. For example, measure these indicators 4 days after the start of medication (Day 4) and 7 days after (Day 7), and evaluate the effectiveness of this model.
  • the compound of the present invention comprises 1) complementation and Z or enhancement of the preventive and Z or therapeutic effects of the compound of the present invention, 2) kinetics / absorption improvement of the compound of the present invention, dose reduction, and 3) To reduce the side effects of the compound of the present invention, combine with other drugs and administer as a concomitant drug.
  • the concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be in the form of separate preparations.
  • simultaneous administration and administration by time difference are included.
  • administration by time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug is administered first and the compound of the present invention is administered later.
  • Each administration method is the same or different.
  • the other drug may be a low molecular compound or a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, RNA interference, decoy, antibody. Or a vaccine or the like.
  • the dose of the other drug can be appropriately selected based on the clinically used dose.
  • the combination ratio of the compound of the present invention and other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination and the like. For example, 0.01 to 100 parts by weight of another drug may be used per 1 part by weight of the compound of the present invention.
  • one or two or more selected arbitrarily from the following homogeneous groups and heterogeneous groups may be administered in appropriate proportions.
  • the disease that exerts preventive and Z or therapeutic effects by the above-mentioned concomitant drug is not particularly limited as long as it is a disease that complements and enhances or enhances the preventive and Z or therapeutic effects of the compound of the present invention.
  • Examples of those used for the prevention and Z or treatment of diabetes include sulfourine hypoglycemic drugs, biguanides, oc darcosidase inhibitors, fast-acting insulin secretagogues, insulin drugs, DPP Peptidyl peptidase) 4 inhibitor, GLP-1 (glucagon-like peptide 1) receptor agonist, ⁇ 3 adrenergic receptor agonist, PPAR (.peroxisome proliferator-activated receptor) agonist, fibfu , JNK (c-jun N-terminal kinase) inhibitors or diabetic complications.
  • Examples of the sulfo-urea hypoglycemic agent include acetohexamide, darribenclamide, daliclazide, glycloviramide, chlorpropamide, tolazamide, tolptamide, glimepiride and the like.
  • Examples of biguanide drugs include pformin hydrochloride or metformin hydrochloride.
  • Examples of the a-darcosidase inhibitor include akalbose or voglibose.
  • Examples of fast-acting insulin secretagogues include nateglinide or repaglinide.
  • Examples of the DPP4 inhibitor include NVP-DPP728A or MK-431.
  • Examples of GLP-1 receptor agonists include exendin 4 and the like.
  • Examples of the ⁇ 3 adrenergic receptor agonist include AJ-9677, BMS-210285, CP-331679, KUL-1248, LY-362884, L-750335, and ⁇ CP-331648.
  • Examples of the PPAR agonist include pioglitazone hydrochloride, troglitazone, rosiglitazone maleate, and the like.
  • Fibrate drugs include gemfib mouth gill, clofibrate, Examples include bezafibrate, fenofibrate, clinofibrate or symfibrate.
  • Examples of the therapeutic agent for diabetic complications include epalrestat, zenarestat, fidarestat, zopolrestat, AS-3201 or SG-210.
  • Examples for use in the prevention and Z or treatment of hyperlipidemia include, for example, MTP (Microsomal Triglyceride Transfer Protein) inhibitor ⁇ , HMLr-CoA (Hydromethylglutaryl coenzyme A) reductase inhibitor, squalene synthetase Inhibitors, fibrates (fibric acid derivatives), ACAT (facil CoA: cholesterol O-acyltransferase) inhibitors, 5-lipoxygenase inhibitors, cholesterol absorption inhibitors, bile acid absorption inhibitors, ileal Na + / bile acids Co-transporter (ileal NaVbile acid transporter; IBAT) inhibitor, L DL receptor activator, expression enhancer, spleen lipase inhibitor, probucol preparation, nicotinic acid preparation, cholesterol ester transfer protein (CETP) inhibitor, PPAR action Drugs and other anti-hypercholesterolemia drugs.
  • MTP Mericrosomal Triglyceride Transfer Protein
  • Examples of the MTP inhibitor include BMS-201038, BMS-212122, BMS-200 150, GW-328713 or R-103757.
  • Examples of the HMG-CoA reductase inhibitor include atorvastatin, flupastatin, oral pastatin, pitavastatin, pravastatin, rospastatin, sympastatin, and the like.
  • Examples of the ACAT inhibitor include F-12511, F-1394, CI-1011 and melinamide.
  • Examples of the squalene synthetase inhibitor include TAK-475 and the like.
  • Examples of the fibrate include gemfib mouth-zil, clofibrate, bezafibrate, fienofibrate, clinofibrate or symfibrate.
  • Examples of the ACAT inhibitor include C1 1011, FCE27677, RP73163, and the like.
  • Examples of the cholesterol absorption inhibitor include ezetimibe or soisterol.
  • Examples of bile acid absorption inhibitors include cholestyramine, colesevelam, or colestimide.
  • Examples of the LDL receptor activator 'expression enhancer include MD-700 and LY295427.
  • Examples of spleen lipase inhibitors include orlistat.
  • Examples of the PPAR agonist include pioglitazone hydrochloride, troglitazone, rosiglitazone maleate, and the like.
  • Examples for use in the prevention and Z or treatment of obesity include, for example, appetite suppressants, spleen Pase inhibitors, ⁇ 3 adrenergic receptor agonists, PPAR agonists, serotonin / norepinephrine'dopamine reuptake inhibitors or cannapinoid receptor antagonists.
  • Examples of the appetite suppressant include leptin, mazindol, amphetamine, methane phetamine, and the like.
  • Examples of splenic lipase inhibitors include orlistat and the like.
  • Examples of the ⁇ 3 adrenergic receptor agonist include AJ-9677, BMS-210 285, CP-331679, KUL-1248, LY-362884, L-750335, CP-33 1648 and the like.
  • Examples of the PPAR agonist include pioglitazone hydrochloride, trodaritazone, rosiglitazone maleate, and the like.
  • Examples of serotonin 'norpinephrine' dominine reuptake inhibitors include sibutramine and the like.
  • Examples of cannapinoid receptor antagonists include rimonabant and the like.
  • composition comprising the compound of the present invention or a concomitant agent of the compound of the present invention and another drug for the above-mentioned purpose, it is usually systemically or locally, orally or parenterally. Is administered.
  • the dose varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but is usually from once to several times a day in the range of about 100 / zg to about lOOOmg per adult.
  • the dose varies depending on various conditions, and therefore, an amount smaller than the above dose may be sufficient, or administration beyond the range may be necessary.
  • a pharmaceutical composition comprising the compound of the present invention or a combination agent of the compound of the present invention and another drug is administered, for example, a solid preparation for internal use for oral administration, a liquid preparation for internal use, and a parenteral preparation Used as injections, external preparations, suppositories, eye drops, inhalants, etc. for administration.
  • Examples of solid preparations for internal use for oral administration include tablets, pills, capsules, powders or granules.
  • examples of capsules include node capsules and soft caps. A cell etc. are mentioned.
  • one or more active substances are left as they are, or excipients (for example, ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binding Agents (for example, hydroxypropylcellulose, polyburpi oral lydone, magnesium aluminate metasilicate), disintegrants (for example, calcium calcium glycolate), lubricants (for example, magnesium stearate), stabilizers, solubilizers It is mixed with an agent (for example, glutamic acid, aspartic acid, etc.), etc., and formulated into a conventional method for use.
  • excipients for example, ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.
  • binding Agents for example, hydroxypropylcellulose, polyburpi oral lydone, magnesium aluminate metasilicate
  • disintegrants for example, calcium calcium glycolate
  • lubricants for example, magnesium stearate
  • stabilizers solubil
  • a coating agent for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • a coating agent for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of a material that can be absorbed such as gelatin.
  • Liquid preparations for internal use for oral administration include, for example, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • a solution one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (eg, purified water, ethanol or a mixture thereof).
  • this solution may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • Examples of the dosage form of external preparations for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops. And nasal drops. These contain one or more active substances and are prepared by known methods or commonly used formulations.
  • the ointment is produced by a known or commonly used formulation. For example, it is prepared by mixing or melting one or more active substances in a base.
  • the ointment base may be selected from known or commonly used strengths. For example, higher fatty acid or higher fatty acid ester (for example, adipic acid, myristic acid, normitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.) Waxes (eg, beeswax, whale wax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphates, etc.) ), Higher alcohols (eg, cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (eg, dimethylpolysiloxane, etc.), hydrocarbons (eg, lyophilic petrolatum
  • the gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base.
  • the gel base may be selected from known or commonly used forces.
  • lower alcohols for example, ethanol, isopropyl alcohol, etc.
  • gelling agents for example, carboxymethylcellulose, hydroquine chinose resinose, hydroxypropino resinose, ethino resinose, etc.
  • neutralizer For example, triethanolamine, diisopropanolamine, etc.
  • surfactants eg, polyethylene glycol monostearate, etc.
  • gums water, absorption promoters, anti-rash agents, or a mixture of two or more.
  • a preservative, an antioxidant, a flavoring agent and the like may be included.
  • the cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers ( For example, polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, anti-rash agents, or a combination of two or more selected. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.
  • the poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support.
  • the poultice base is selected from known or commonly used ones. For example , Thickeners (eg, polyacrylic acid, polybutylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide) , Talc, calcium, magnesium, etc.), water
  • Solubilizers Solubilizers, tackifiers, anti-rash agents, or a combination of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support.
  • the base for patch is selected from known or commonly used ones. For example, one selected from high molecular weight bases, fats and oils, higher fatty acids, tackifiers, and rash prevention agents may be used alone or in admixture of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is produced by a known or commonly used formulation.
  • one or more actives may be selected from water, alcohol (eg, ethanol, polyethylene dallicol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent, etc. Prepared by dissolving, suspending or emulsifying. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • Sprays, inhalants, and sprays include buffers that provide isotonicity with stabilizers such as sodium bisulfite in addition to commonly used diluents, such as sodium chloride salt, kenic acid Is sodium, or contains isotonic agents such as citrate.
  • stabilizers such as sodium bisulfite
  • diluents such as sodium chloride salt, kenic acid Is sodium
  • isotonic agents such as citrate.
  • Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use.
  • An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used.
  • this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative and the like. .
  • a stabilizer for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.
  • an emulsifier for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.
  • an emulsifier for example, glutamic acid, aspartic acid, Polysorbate 80 (registered trademark), etc.
  • a suspending agent for example, glutamic acid, as
  • Eye drops for parenteral administration include ophthalmic solutions, suspension-type eye drops, emulsion-type eye drops, use-dissolving eye drops, and eye ointments.
  • eye drops are produced according to known methods.
  • one or more active substances are used by dissolving, suspending or emulsifying them in a solvent.
  • a solvent for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oil, etc.) and combinations thereof are used.
  • Eye drops include isotonic agents (eg, sodium chloride, concentrated glycerin, etc.), buffering agents (eg, sodium phosphate, sodium acetate, etc.), surfactants (eg, polysorbate 80 (trade name) ), Polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil, etc.), stabilizers (eg, sodium citrate, sodium edetate, etc.), preservatives (eg, salt benzalkol, parabens, etc.) Etc. may be appropriately selected as necessary. These are sterilized in the final step or prepared by aseptic manipulation. Alternatively, a sterile solid preparation such as a freeze-dried product can be produced and used by dissolving it in sterilized or sterile purified water or other solvent before use.
  • isotonic agents eg, sodium chloride, concentrated glycerin, etc.
  • buffering agents eg, sodium phosphate, sodium acetate, etc.
  • surfactants eg, polysorb
  • Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are dissolved or suspended in water or other suitable medium at the time of use.
  • the form to use may be sufficient.
  • preservatives eg, salt benzalcoum, parabens, etc.
  • coloring agents eg, coloring agents, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonicity
  • buffering agents eg, sodium phosphate, sodium acetate, etc.
  • isotonicity It is prepared by appropriately selecting an agent (for example, sodium chloride salt, concentrated glycerin, etc.), a thickener (for example, cariboxybule polymer, etc.), an absorption accelerator, and the like as necessary.
  • lubricants eg stearic acid and its salts
  • binders eg starch, dextrin etc.
  • excipients eg lactose, cellulose etc.
  • colorants eg antiseptics
  • An agent for example, salt benzalkonium, paraben, etc.
  • an absorption accelerator for example, freon, black mouth fluorocarbon, etc.
  • a propellant for example, freon, black mouth fluorocarbon, etc.
  • compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration that contain one or more active substances and are prescribed by conventional methods. .
  • MS used the ESI (electron spray ion) method to detect only positive ions (pos.).
  • HPLC conditions are as follows.
  • Solution A 0.1% trifluoroacetic acid aqueous solution
  • Liquid B 0.1% trifluoroacetic acid-acetonitrile solution
  • Example 1 ⁇ — (6 black mouth 1 pyridazine 1 3 yl) 4-methylbenzenesulfonamide (Compound 1 1)
  • Example 2 N- ⁇ 6- [3- (benzyloxy) propoxy] pyridazine 3-yl ⁇ 3 methylbenzenesulfonamide (compound 2-1)
  • Example 3 4-Methyl-N- [6- (2phenoxyethoxy) pyridazine-3-yl] benzenesulfonamide (Compound 3)
  • the filtered fat was washed three times with tetrahydrofuran (50 mL) and four times with methylene chloride (50 mL), and then dried overnight at room temperature under reduced pressure to obtain fat (4.02 g). Obtained rosin (300 mg) was washed with anhydrous 1,4 dioxane (5 mL) and then suspended in anhydrous 1,4 dioxane (5 mL). After adding 2 phenoxyethanol (0.647 mL) to this suspension, n-butyllithium (1.59 M hexane solution, 2.43 mL) was prepared at room temperature under an argon atmosphere. The reaction solution was stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature and then filtered.
  • the filtered koji was washed twice with 1,4 dioxane (5 mL), three times with methanol (5 mL), and four times with methylene chloride (5 mL).
  • the obtained rosin was suspended in trifluoroacetic acid (50% 1,2 dichloroethane solution, 5 mL). The suspension was stirred at room temperature for 1 hour and then filtered.
  • the filtered resin was washed with 1,2 dichloroethane (5 mL). The filtrate and washings were combined and concentrated to give the title compound (67 mg) having the following physical data.
  • Example 3 The same procedure as in Example 3 was carried out using Compound 1 1 or Compound 1 or Compound 1 2 or Compound 1 3 instead of 2-phenoxyethanol or an alcohol compound corresponding to the target product instead. To give the compounds shown below.
  • Example 3 4-Methyl N— (6— ⁇ 2— [Methyl (phenyl) amino] ethoxy ⁇ pyridazine 3 yl) benzenesulfonamide (Compound 3-1)
  • Example 3 3-Methyl-N— [6- (4 phenbutoxy) pyridazine 3 yl] benzenesulfonamide (Compound 3-14) HPLC retention time: 4.02 min; MS (ESI, Pos. 20 V): 398 (M + H) +.
  • Example 3 4-Methyl-N- [6- (2 Phenylethoxy) pyridazine-3-yl] Benzenesulfonamide (Compound 3-36)
  • Triphenyl phosphine resin (Argonaute Technologies, Catalog No. 800380, 1.8 g, 2.36 mmol) was added to a solution of Compound 6 (345 mg) in tetrasalt-carbon (100 mL) and heated to reflux. did. After 4 hours, the reaction solution was returned to room temperature, filtered, and the filtrate was concentrated. Sodium azide (230 mg) was added to a solution of the obtained residue (390 mg) in dimethylformamide (20 mL). The reaction solution was stirred at room temperature for 13 hours, and further stirred at 45 ° C for 3 hours. After returning the reaction solution to room temperature, tert butyl methyl ether was added to the reaction solution.
  • triphenyl-phosphine resin manufactured by Argonaut Technologies, catalog number: 800380, 500 mg, 0.87 mmol
  • the reaction solution was filtered, and the resin was washed with tetrahydrofuran (2.0 mL X 3). The filtrate and washings were combined, concentrated, and azeotroped with dioxane (0.5 mL ⁇ 4) to give the title compound (108 mg) having the following physical data.
  • Example 10 [4 — ( ⁇ 4— [3- (aminomethyl) phenol] —1-piveridyl ⁇ methyl) phenol] jetylamine (compound 10-1) )
  • Example 9 The title compound (1.20 g) having the following physical data was obtained by the same procedures as in Example 10. In the step corresponding to Example 9, 4 (jetylamino) benzaldehyde was used in place of 2-methyl-4-phenolpentanal.
  • Example 11 N— (3— ⁇ 1— [4 (Jetylamino) benzyl] piperidine 4-yl ⁇ benzyl) -1,1, -biferro-lu 4-sulfonamide hydrochloride (Compound 11) [Chemical 31]
  • Example 12 4 Chloro- ⁇ - ⁇ 3- [1- (2-methyl-4-phenolpentyl) piperidine 4-yl] benzyl ⁇ benzenesulfonamide (Compound 12-2)
  • Example 12 5 Chloro-3-methyl-N— ⁇ 3-— [1— (2-Methyl-4-phenolpentyl) piperidine-4-yl] benzyl benzothiophene 2-sulfonamide (Compound 12 -Four)
  • Example 12 4-Methoxy-N— (3- ⁇ 1 — [(3-methylchen-2-yl) methyl] piperidine 4-yl ⁇ benzyl) benzenesulfonamide (Compound 12-8)
  • Example 12 4 Chloro-N— (3— ⁇ 1 [(3 methylchen-2-yl) methyl] piperidine-4-yl ⁇ benzyl) benzenesulfonamide (compound 12-10)
  • Example 12 5 Chloro-3-methyl-N— (3-— ⁇ 1 -— ((3 methylchen-2-yl) methyl] piperidine-4-yl ⁇ benzyl) 1 benzothiophene 2 sulfonamide ( Compound 12—11)
  • Example 12 5 Chloro-N— (3— ⁇ 1 [(3 methylchen-2-yl) methyl] piperidine-4-yl ⁇ benzyl) thiophene-2-sulfonamide (compound 12— 14)
  • Example 12 5 Chloro-N— [3- (l-hexylbiperidine 4-yl) benzyl] — 3 Methyl 1 benzothiophene 2 sulfonamide (Compound 12-18) HPLC retention time: 3.76 min; MS (ESI, Pos .20 V): 519 (M + H) +.
  • Example 12 N— (4 ⁇ [(3— ⁇ 1 [4 (Jetylamino) benzyl] piperidine 4-yl ⁇ benzyl) amino] sulfol ⁇ phenol) acetoamide (Compound 12-25) HPLC retention time: 2.96 min; MS (ESI, Pos. 20 V): 549 (M + H) +.
  • Example 12 5 Chloro-N— (3— ⁇ 1 [4 (Jetylamino) benzyl] piberidin 4 yl ⁇ benzyl) -3 methyl 1 benzothiophene 1 2 sulfonamide (compound 12— 26)
  • Example 12 4-Butoxy? ⁇ -(3- ⁇ 1 [(1-Methyl-111-indole-3-yl) methyl] piperidine 4-yl ⁇ benzyl) benzenesulfonamide (Compound 12- 3 1)
  • Example 12 4-chloro? ⁇ -(3- ⁇ 1 [(1-Methyl-111-indole-3-yl) methyl] piperidine-4-yl ⁇ benzyl) benzenesulfonamide (Compound 12-32) HPLC retention time: 3.55 min; MS (ESI, Pos. 20 V): 508 (M + H) +.
  • Example 12 5 Chloro-3-methyl-N— (3-— ⁇ 1-[(1-Methyl-1H-Indo 1-Lu 3-yl) methyl] piperidine 1- 4-yl ⁇ benzyl) -1 benzothiophene 2-sulfonamide (compound 12—34)
  • Example 12 (35): ⁇ — (3— ⁇ 1— [(1 Methyl 1 H indole 3 yl) methyl] piperidine 4 yl ⁇ benzyl) 4 propylbenzenesulfonamide (Compound 12-3
  • Example 12 (36): ⁇ — (3— ⁇ 1— [(1 Methyl 1 H indole 3 yl) methyl] piperidine 1-4-yl ⁇ benzyl) 1, 1, 1 biphenol- 4-sulfonamide (Yi compound 12 -36)
  • Example 12 5 Chloro-N— (3-— ⁇ 1-[(1-methyl-1H-indole-3-yl) methyl] piperidine 4-yl ⁇ benzyl) thiophene 2 sulfonamide (compound 1
  • Example 12 N— (4 ⁇ [(3— ⁇ 1 [3— (4 tertbutylbutyl) 2-methylpropyl] piperidine-4-yl ⁇ benzyl) amino] sulfo -Le ⁇ phenol) acetamide (compound 12—41)
  • Example 12 N— (3— ⁇ 1 [3- (4-tert butylphenol) -2 methylpropyl] piperidine 4yl ⁇ benzyl) 4 propylbenzenesulfonamide (compound 1
  • Example 12 4 Chloro-N— ⁇ 3-— [1— (2-Clorobenzyl) piperidine-4-yl] benzyl ⁇ benzenesulfonamide (Compound 12-46)
  • Example 12 4-Butoxy N— ⁇ 3-— [1- (4 phenoxybenzyl) piperidine 4-yl] benzyl ⁇ benzenesulfonamide (Compound 12- 56) HPLC retention time: 3.83 min; MS (ESI, Pos. 20 V): 585 (M + H) +.
  • Example 12 (61): ⁇ — ⁇ 3— [1— (4 phenoxybenzyl) piperidine 4 yl] benzil ⁇ — 1, 1, bibi-luo 4-sulfonamide (compound) 12—61)
  • Example 12 5 Chloro-N— ⁇ 3 -— [1 (4-phenoxybenzyl) piperidine 4-yl] benzyl ⁇ thiophene 2-sulfonamide (compound 12-62)
  • Example 12 (4 Chloro-N— ⁇ 3 -— [1- (3 Chloro-4-methoxybenzyl) piperidine 4-yl] benzyl ⁇ benzenesulfonamide (Compound 12-65) HPLC retention time: 3.51 min; MS (ESI, Pos. 20 V): 519 (M + H) +.
  • Example 12 4 butoxy-N— ⁇ 3 -— [1 (4-chlorobenzyl) piperidine 4-yl] benzyl ⁇ benzenesulfonamide (Compound 12-72)
  • Example 12 N— ⁇ 4 [( ⁇ 3— [1 (4-chlorobenzyl) piperidine 4-yl] benzyl ⁇ amino) sulfol] phenol ⁇ acetamide (Compound 12— 74) HPLC retention time: 3.28 min; MS (ESI, Pos. 20 V): 512 (M + H) +.
  • Example 12 N— (3— ⁇ 1 — [(1,5 dimethyl-3-oxo-2 phenol-2,3-dihydro 1H pyrazole 4yl) methyl] piperidine 4yl ⁇ benzyl )-1, 1, 1 biferroe 4-sulfonamide (compound 12- 81)
  • 2-Dimethylaminonaphthalene-6-sulfochloride (4.9 mg) and pyridine (0.030 mL) were added to a solution of compound 10 (4.3 mg) in dichloromethane (0.3 mL), and the mixture was shaken for 23 hours.
  • Trisamine rosin (manufactured by Argonaut Technology, catalog number: 800229, 34 mg, 0.113 mmol) was added to the reaction solution, and the mixture was shaken at room temperature for 3 hours and filtered. The obtained filtrate was concentrated to give the title compound (5.8 mg) having the following physical data.
  • Example 13 6- (dimethylamino) -N- (3- ⁇ 1 -— [(3-methylchen-2-yl) methyl] piperidine 4-yl ⁇ benzyl) naphthalene 2 sulfonamide (compound 13— 1)
  • Example 13 (11) N— ⁇ 3— [1— (4-Chronobenzyl) piperidine-4-yl] benzyl ⁇ — 6 (dimethylamino) naphthalene 2 sulfonamide (Compound 13-11)
  • Example 13 4- (2-methoxyphenoxy) N— (3- ⁇ 1 [(1-methyl-1H-indole-3-yl) methyl] piperidine-4-yl ⁇ benzyl) Benzenesulfonamide (compound 13-15)
  • Example 3 and Example 1 were prepared using the corresponding sulfamoylpyridazine compound in place of Compound 1-1, and 3-phenyl-1-propanol or 3-benzyloxy-1-propanol in place of 2-phenoxyethanol. The same operation was performed to obtain the following compounds.
  • Example 14 4-Methoxy-N— [6— (3 phenol-propoxy) -3pyridazil] benzenesulfonamide (compound 14-8) HPLC retention time: 3.86 min; MS (ESI, Pos. 20 V): 400 (M + H) +.
  • Example 14 (33) 1, 1, 1-trifluoro-N— [6— (3 phenolpropoxy) —3 pyridazil] methanesulfonamide (compound 14—33)
  • Example 14 N— [6— (3 phenol) 3 pyridazil] 3 (trifluoromethyl) benzenesulfonamide (Compound 14—36) HPLC retention time: 4.04 min; MS (ESI, Pos. 20 V): 438 (M + H) +.
  • Example 14 5 Black Mouth 3 Methyl N— [6— (3 Phenolpropoxy) 3—Pyridazil] 1 Benzothiophene 2 Sulfonamide (Compound 14-50) HPLC Retention Time: 4.27 min MS (ESI, Pos. 20 V): 474 (M + H) +.
  • Example 14 N— [5 — ( ⁇ [6— (3 phenylpropoxy) 3 pyridazil] amino ⁇ sulfol) 1 naphthyl] acetamide (compound 14—51 )
  • Example 14 5 chloro-2-methoxy N— ⁇ 2- [4 — ( ⁇ [6— (3-phenylpropoxy) —3-pyridazil] amino ⁇ sulfol) fur] Benzylamide Benzamide (Compound 14 54) HPLC retention time: 4.04 min; MS (ESI, Pos. 20 V): 581 (M + H) +.
  • Example 14 N- [6- (3phenolpropoxy) -3pyridazyl] -2,3 dihydro 1,4 benzodioxin 6 sulfonamide (compound 14-55)
  • Example 14 5— [(4 black mouth) thio] —N— [6— (3 mole propoxy) 1-3 pyridazil] 2 thiophenesulfonamide (14-56)
  • Example 14 N- ⁇ 6- [3- (benzyloxy) propoxy] 3 pyridazinyl ⁇ 2 Methyl-2-propanesulfonamide (Compound 14- 82)
  • the measurement method of the present invention is one in which the measurement accuracy is improved and the measurement sensitivity is improved in order to evaluate the compound of the present invention as follows.
  • the detailed experimental method is shown below.
  • Human 11 ⁇ - HSD1 recombinant enzyme was prepared by modifying the method of Elizabeth A. Walker et al. (THE JOUNAL OF BILOGICAL CHEMISTRY, Vol.276, No.24, p21343-21350, 2001; THE JOUNAL OF BILOGICAL CHEMISTRY, Vol.266, No.25, pl6 653-16658, 1991).
  • the human 11 ⁇ -HSD1 cDNA was obtained from the human liver cDNA library by PCR.
  • the fragment (23 amino acids deleted from the terminus and 3 amino acids, methionine, serine and alanine added) was amplified.
  • the transformed E. coli was cultured in LB medium (containing carbecillin 50 ⁇ g / mL) at 37 ° C with shaking (until the absorbance at 600 nm reached 0.5), then IPTG (isopropyl- ⁇ - D-thiogal actopyranoside) was added to ImM and cultured with shaking at 15 ° C for 16 hours. E. coli was recovered from the culture solution, and a soluble protein fraction was prepared using a solubilization buffer (Novagen, BugBuster TM, Cat. No. 70584) to obtain a recombinant enzyme. [0158] 1 2: Measurement of human 11 18- HSD1 inhibitory activity
  • Cortisol was quantified using cortisol enzyme immunoassay kit (Cortisol EIA kit (R & D)) after adding 100 ⁇ mol / L carbenoxolone-containing acetonitrile (50 ⁇ L / well). Cortisol was quantified by a method according to the package insert of the cortisol enzyme immunoassay kit. Using the obtained measured values, a calibration curve was prepared according to the package insert, and the 11 ⁇ -HSD1 inhibition rate of the compound of the present invention was calculated from the amount of cortisol when the compound of the present invention was added.
  • the 11 ⁇ HSD1 inhibitory activity of the compound of the present invention was measured.
  • the IC value of Compound 2 for 11 ⁇ -HSD1 was 250 ⁇ .
  • MSZMS MSZMS
  • the atmospheric pressure chemical ionic method APCI
  • the detection method used was a multiple reaction monitoring (MRM) method.
  • the primary ionization was m / z361 and the secondary ionization was m / zl63.
  • a calibration curve was created with the area value of the secondary ion amount obtained here, and the cortisone concentration in the sample was quantified.
  • the 11 ⁇ -HS D2 inhibition rate of this cortisone concentration power compound of the present invention was calculated.
  • cortisol can be detected by the same method, so the inhibitory activity of 11 18 HSD 1 was measured. It can also be applied to.
  • the compound of the present invention has 11 ⁇ HSD1 inhibitory activity, it is useful as a preventive and epilepsy or therapeutic agent for diseases caused by excessive production of corticosteroids. Therefore, this invention compound can be utilized as a pharmaceutical.

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  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention concerne un composé ayant le pouvoir d'inhiber la 11β-HSD1. Des composés de formule générale (I) (dans laquelle tous les caractères sont tels que définis dans la description), leurs sels ou leurs hydrates et des promédicaments les contenant présentent une capacité à inhiber la 11β-HSD1. Ils sont par conséquent utiles pour prévenir et/ou traiter les maladies dues à une surproduction d’hormone adrénocorticale, par exemple des maladies métaboliques (diabète sucré, dont le diabète de type II, etc., la baisse de tolérance au glucose, l’hyperglycémie, la résistance insulinique, les taux élevés d’insuline dans le plasma, les anomalies du métabolisme des lipides, la stéatose hépatique, la dyslipidémie, l’hyperlipidémie, l’hypertriglycéridémie, l’hyper-LDL-cholestérolémie, l’hypo-HDL-cholestérolémie, l’obésité, l’athérosclérose, le syndrome X, syndrome métabolique, le syndrome de Cushing, l’ostéoporose, etc.), l’hypertension, les défauts sensoriels, les troubles de la mémoire, la dépression, l’anxiété, la démence, la maladie d’Alzheimer, le glaucome, les maladies immunologiques, etc.
PCT/JP2006/304623 2005-03-11 2006-03-09 Compose sulfonamide et produit pharmaceutique le contenant WO2006095822A1 (fr)

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WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
WO2009071477A1 (fr) * 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridazine
US8153793B2 (en) 2005-09-27 2012-04-10 Shionogi & Co., Ltd. Sulfonamide derivative having PGD2 receptor antagonistic activity
WO2012124744A1 (fr) * 2011-03-14 2012-09-20 大正製薬株式会社 Composé hétérocyclique condensé contenant de l'azote
US8785435B2 (en) 2011-10-20 2014-07-22 Hoffmann-La Roche Inc. Solid forms

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8153793B2 (en) 2005-09-27 2012-04-10 Shionogi & Co., Ltd. Sulfonamide derivative having PGD2 receptor antagonistic activity
US8993763B2 (en) 2005-09-27 2015-03-31 Shionogi & Co., Ltd. Sulfonamide derivative having PGD2 receptor antagonistic activity
US9440938B2 (en) 2005-09-27 2016-09-13 Shionogi & Co., Ltd. Sulfonamide derivative having PGD2 receptor antagonistic activity
WO2007128761A2 (fr) 2006-05-04 2007-11-15 Boehringer Ingelheim International Gmbh Utilisations d'inhibiteurs de l'enzyme dpp iv
EP2351568A2 (fr) 2006-05-04 2011-08-03 Boehringer Ingelheim International GmbH Utilisations d'inhibiteurs de l'enzyme dpp iv
WO2009071477A1 (fr) * 2007-12-04 2009-06-11 F. Hoffmann-La Roche Ag Dérivés isoxazolo-pyridazine
JP2011505402A (ja) * 2007-12-04 2011-02-24 エフ．ホフマン−ラ ロシュ アーゲー イソオキサゾロ−ピリダジン誘導体
US7943619B2 (en) 2007-12-04 2011-05-17 Hoffmann-La Roche Inc. Isoxazolo-pyridazine derivatives
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WO2012124744A1 (fr) * 2011-03-14 2012-09-20 大正製薬株式会社 Composé hétérocyclique condensé contenant de l'azote
US9035059B2 (en) 2011-03-14 2015-05-19 Taisho Pharmaceutical Co., Ltd. Nitrogen-containing condensed heterocyclic compound
US8785435B2 (en) 2011-10-20 2014-07-22 Hoffmann-La Roche Inc. Solid forms

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