WO2001058880A1 - Derives de triazole - Google Patents

Derives de triazole Download PDF

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Publication number
WO2001058880A1
WO2001058880A1 PCT/JP2000/000668 JP0000668W WO0158880A1 WO 2001058880 A1 WO2001058880 A1 WO 2001058880A1 JP 0000668 W JP0000668 W JP 0000668W WO 0158880 A1 WO0158880 A1 WO 0158880A1
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Prior art keywords
group
lower alkyl
methyl
biphenyl
optionally substituted
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PCT/JP2000/000668
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English (en)
Japanese (ja)
Inventor
Takeshi Suzuki
Takahiko Tobe
Takeshi Murakami
Atsuo Tahara
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to PCT/JP2000/000668 priority Critical patent/WO2001058880A1/fr
Priority to AU2000223275A priority patent/AU2000223275A1/en
Publication of WO2001058880A1 publication Critical patent/WO2001058880A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the present invention relates to a medicament, particularly a novel triazole derivative or a pharmaceutically acceptable salt thereof, and an arginine vasopressin A receptor antagonist containing the same as an active ingredient.
  • Diabetic nephropathy is one of the three major complications of diabetes, clinically showing signs of microalbuminuria, proteinuria, renal dysfunction, hypertension and edema, and eventually renal failure There are many. It is said that this diabetic nephropathy progresses relatively slowly in the early stage, and that the lesion is also reversible.However, in the overt period when proteinuria is positive, the disease becomes irreversible and rapidly It is said that severe renal function decline causes end-stage renal failure. At present, pathological diagnosis can be made before proteinuria becomes positive by measurement of microalbuminuria, etc.Aggressive treatment should be implemented as early as possible with reversible lesions as a measure to prevent progression of nephropathy It is believed that.
  • AVP plasma arginine vasopressin
  • V 1A receptor selective antagonists have also been made (Arzneim. Forsch. 46 (1996), 875-878). Based on the above, V 1A receptor antagonist Is expected to be an effective prophylactic and therapeutic agent for diabetic nephropathy.
  • AVP is a vascular permeability enhancer via V1A receptor expressed in vascular smooth muscle.
  • V1A receptor antagonists are useful for preventing and treating vascular diseases in various diseases.
  • V 2 receptor antagonists are known to have a water diuretic, preferably compounds having antagonistic activity against V 1A and v 2 both receptors on renal diseases involving edema, as this
  • benzazepine derivatives described in International Publications WO95 / 03305 and WO95 / 06035 are known.
  • diseases without edema or the like, in such as diabetic nephropathy with symptoms such as mouth thirst Ya polyuria considered more preferable selective V 1A receptor antagonist.
  • amino acid sequence is very similar to AVP, and also in the hypothalamus-pituitary system
  • AVP receptor antagonists also antagonize this oxytocin receptor and cause inhibition of physiological actions such as uterine contraction and milking.
  • blood vessel diseases such as in diabetic nephropathy or various diseases, for edema accompanied such have diseases, V 1A receptor selective for v 2 receptor and Okishitoshin receptors, and more powerful Compounds having significant antagonistic activity are expected to be good therapeutic agents.
  • the inventors of the present invention have proceeded with screening of compounds having selective and high affinity for the V1A receptor, and as a result, have found that certain specific triazole derivatives Found that the above conditions were satisfied, and completed the present invention.
  • the present invention is a pharmaceutical composition
  • Ring A a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or a group represented by —X—R 4 , or
  • R 1 is a hydrogen atom or a lower alkyl group
  • R 2 a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, an optionally substituted lower alkynyl group, or an optionally substituted amino Base ''
  • R 3 hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, —0-lower alkyl group,
  • R 4 aryl group optionally substituted with lower alkyl or aryl group; 5- or 6-membered heteroaryl group optionally substituted with lower alkyl group; optionally substituted with lower alkyl group 3 to 8 membered saturated heterocyclic group;
  • the present invention also relates to a triazole derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
  • a triazole derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
  • Ring A a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or a group represented by —X—R 4 , or
  • R 1 is a hydrogen atom or a lower alkyl group
  • R 2 a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, an optionally substituted lower alkynyl group, or an optionally substituted amino Base
  • R 3 hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyl group,
  • X single bond, — NH—CO—, — CO—NH—, — NH—CO—NH—, one NH—CS—NH—, one (CH 2 ) k — 0—, or one-one (CH 2 ) k — group 4: aryl group optionally substituted by lower alkyl or aryl group; 5- or 6-membered heteroaryl group optionally substituted by lower alkyl group; optionally substituted by lower alkyl group Good 3-8 membered saturated heterocyclic groups;
  • k integer from 0 to 5
  • R 1 groups are methyl groups in ring A Bifue two Le group, Y is CH, m is 1, R 3 groups are water atom, and, except for the compound R 2 groups are methoxy groups.
  • Preferred compounds in the present invention are those represented by the above general formulas (I) and (1).
  • R 2 is
  • R 5 100 (CH 2 ) P _R 5 , -NH- (CH 2 ) p — R 5 , -CO- (CH 2 ) P — R 5 , -CO-O- (CH 2 ) an alkoxy, lower alkyl or lower alkynyl group having a substituent selected from the group represented by p —R 5 and —CO—NH— (CH 2 ) p— R 5 ;
  • R 5 represents i) a hydrogen atom, or ii) an aryl, a 5- to 6-membered heteroaryl or a 3- to 8-membered saturated heterocyclic group (these ring groups may further be a halogen atom, amino, nitro , Cyano, lower alkyl, —0—lower alkyl, one COO—lower alkyl, one CO—3- to 8-membered saturated heterocycle, one CO—3- to 8-membered saturated heterocycle, one- to three- to 8-membered saturated heterocycle 1-CO--3- to 8-membered saturated heterocyclic ring-lower alkyl, aryl, 5- or 6-membered heteroaryl, or 3- to 8-membered saturated heterocyclic group which may be substituted with a lower alkyl group
  • p is an integer of 0 to 4];
  • X is CH—R 6 , N—R 6 , O or S, where R 6 is lower alkyl, 1 O—lower alkyl, 1 COO—lower alkyl, —CO—3 to 8 member saturated Ring-lower alkyl, aryl, 5- to 6-membered heteroaryl or 3- to 8-membered saturated heterocyclic group, and Q and r are integers of 1 to 3);
  • the A ring has the formula
  • R 7 is a hydrogen atom, a halogen atom, a nitroamino or a lower alkyl group
  • a triazole derivative or a pharmaceutically acceptable salt thereof which is a group represented by the formula:
  • Y is CH and the R 2 group is represented by the following formula: And a pharmaceutically acceptable salt thereof.
  • the most preferred compound in the present invention is a triazole derivative or a pharmaceutical thereof, wherein the A ring is a 4-biphenyl ring, R 1 is a methyl group, and 2 is a group represented by —0— (CH 2 ) n —R 5. It is a chemically acceptable salt, and specific examples include the following compounds. 8.
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
  • a “lower alkyl group” is an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl group, or an isopropyl group, or the like. And is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl or ethyl group.
  • “Lower alkynyl group” is an alkynyl group having 2 to 6 carbon atoms, specifically, ethynyl group, 1-propenyl group, 1-l-pentynyl group, 1-l-pentynyl group, 1-l-hexynyl group Or a structural isomer such as a 1-methyl-2-propynyl group, preferably an ethenyl group.
  • alkoxyl group is an alkoxyl group having 1 to 12 carbon atoms. Specifically, it is a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a heptanoxy group, an octanoxy group. Group, nonanoxy group, decanoxy group, pendecanoxy group, dodecanoloxy group, or the same carbon number Having a branched alkoxyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and a fluoride atom.
  • Aryl is an aromatic ring having 6 to 14 carbon atoms and may have a substituent, and specific examples thereof include benzene, naphthalene, anthracene, and phenanthrene group, and preferably benzene. .
  • 5- to 6-membered heteroaryl refers to a 5- or 6-membered aromatic ring having 1 to 4 N, 0 or S atoms, which may have a substituent, specifically, furan, Examples include pyrrol, thiophene, imidazole, pyrazole, oxazole, thiazole, triazole, pyridine, pyrazine, pyrimidine, tetrazole and the like.
  • the “3- to 8-membered saturated heterocycle” is a 3- to 8-membered saturated monocyclic ring having 1 to 3 N atoms which may contain 0 or S atoms, specifically, for example, azepine, Examples include piperidine, piperidine, piperazine, and morpholine.
  • substituent of the “optionally substituted alkoxyl group”, the “optionally substituted alkyl group” and the “optionally substituted alkynyl group” of R 2 include aryl and 5 to 6 members. Terroaryl or a 3- to 8-membered saturated heterocyclic group, or these ring groups are —O— (CH 2 ) p —, —NH— (CH 2 ) p —, —CO— (CH 2 ) p —, —CO — O— (CH 2 ) p —, —CO-NH— (CH 2 ) p — group (p is an integer of 0 to 4), and other substituents, such as halogen atom, amino, cyano, and nitrite Mouth, — OH, 1 O—lower alkyl, 1 NH—lower alkyl, 1 N—di—lower alkyl, — CO—lower alkyl, — COOH, 1 COO—lower alky
  • the aryl, the 5- or 6-membered heteroaryl, and the 3- or 8-membered saturated heterocyclic group may further have a substituent. Any substituent can be used as the substituent for these ring groups, as long as it is a commonly used substituent.
  • lower alkyl (the lower alkyl is a halogen atom, 10-lower alkyl, one COOH, amino, one NH-lower alkyl) And may be substituted with 1 to 4 substituents selected from the group consisting of N-di-lower alkyl group), halogen atom, amino, nitro, cyano, 10H, — ⁇ lower alkyl , One C ⁇ H, one COO—lower alkyl, one CO—3NO To 8-membered saturated heterocyclic ring, _C ⁇ 3 to 8 membered saturated heterocyclic ring 1 to 3 to 8 membered saturated heterocyclic ring, 1 CO-3 to 8 membered saturated heterocyclic ring, lower alkyl, —NH-lower alkyl, - N- Gee lower alkyl, one S- lower alkyl, -SO- lower alkyl, -S0 2 - lower alkyl, one C_ ⁇ _NH 2 one CONH - lower alkyl,
  • Preferred substituents for the “optionally substituted alkoxyl group”, the “optionally substituted alkyl group J” and the “optionally substituted alkynyl group” are those represented by the formula —R 5 , 10— (CH 2 ) p — R 5 , — NH— (CH 2 ) p — R 5 , —CO— (CH 2 ) P — R 5 , — CO— O— (CH 2 ) p — R 5 or one CO—NH— (CH 2 ) p — is a group represented by R 5 .
  • R 5 is i) a hydrogen atom, or ii) an aryl, a 5- to 6-membered heteroaryl or a 3- to 8-membered saturated heterocyclic group (these ring groups are further halogen atoms, amino, nitro, cyano , Lower alkyl, —O—lower alkyl, —COO—lower alkyl, —CO—3- to 8-membered saturated heterocycle, 1-CO—3- to 8-membered saturated heterocycle, _3- to 8-membered saturated heterocycle, _CO — 3- to 8-membered saturated heterocyclic ring-lower alkyl, aryl, 5- or 6-membered heteroaryl, or 3- to 8-membered saturated heterocyclic group which may be substituted by lower alkyl group Good) and p is an integer from 0 to 4)
  • an “optionally substituted alkoxyl group” include the following. Phenylalkoxy group, (4-alkylpiperazin-1-ylcarbonyl) phenylalkoxy group, (4-piperidinopiperidinocarbonyl) phenylalkoxy group, (piperidinocarbonyl) phenylalkoxy group, (4-alkylpyridinyl) Razine-1-ylcarbonyl) alkoxy group, (4-piperidinopiperidinocarbonyl) alkoxy group, (piperidinocarbonyl) alkoxy group, (morpholino-capillon) alkoxy group, (alkoxy-caprolponyl) alkoxy group, ( (Hydroxycarbonyl) alkoxy group, [(4-alkylpyrazine-111-Tyl) alkylaminocarbonyl] alkoxy group, [4- (pyrimidin-2-yl) pyrazine-1-1yl] alkoxy Group
  • the “optionally substituted amino group” of R 2 may be an amino group substituted with a lower alkyl group, or may form a saturated heterocycle containing an N atom together with the substituent.
  • R 2 may be an amino group substituted with a lower alkyl group, or may form a saturated heterocycle containing an N atom together with the substituent.
  • R 6 is lower alkyl, lower alkyl-1 O—, lower alkyl 1-1 CO 1, lower alkyl 1- to 8-membered saturated heterocycle CO—, aryl, 5- to 6-membered heteroaryl or 3 to It is an 8-membered saturated heterocyclic group, and Q and r are integers of 1 to 3.
  • cycloalkyl group formed by combining the R 2 group and the R 3 group include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • ring A is a phenyl group substituted with the group represented by X—R 4 include the following.
  • the compound of the present invention can form a salt with an inorganic acid or an organic acid, and these salts also have an action inhibiting effect.
  • Suitable salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid Salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, sodium, potassium, magnesium, calcium, aluminum And the like, salts with organic bases such as methylamine, ethylamine and ethanolamine, and salts with basic amino acids such as lysine and orditin.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic
  • a quaternary ammonium salt can be formed by reaction with a lower alkyl halide, lower alkyl triflate, lower alkyl tosylate, benzyl halide, or the like, but quaternary ammonium salts include methyl iodide or benzyl chloride. Are preferred.
  • the compound of the present invention may have an optical isomer based on an asymmetric carbon atom and a geometric isomer based on a double bond ⁇ cyclohexan ring, and when the compound has two or more asymmetric carbon atoms, In addition, diastereoisomers exist.
  • the present invention includes isolated ones of these various isomers and a mixture of these isomers.
  • the compounds of the present invention also include hydrates, various solvates, tautomers and the like. Further, some of the compounds of the present invention have a crystalline polymorph, and the compounds of the present invention include all such crystalline forms.
  • the compound which is an active ingredient of the medicament according to the present invention is a compound represented by the formula (I), wherein the A ring group is a 4-biphenyl group, R 1 is a methyl group, Y is CH, m is 1, R 3 is a hydrogen atom. And R 2 is new except for those having a methoxy group.
  • the Labtest GmbH (Freiberg, Germany) This product is available on request from Rabotest.
  • the 3,4-diaryl-substituted-5-substituted-1,2,4-triazole derivative (7) which is the basic skeleton, can be usually produced by the following two methods.
  • an aromatic carboxylic acid (1) is condensed in an inert solvent such as tetrahydrofuran diacetonitrile as an aromatic sulfonic acid chloride activated with thionyl chloride or the like.
  • an acid hydrazide (4) obtained by reacting an aromatic sulfonic acid ester with 10 equivalents of hydrazine in an alcohol, in the presence of an acylating agent such as acetic anhydride and an organic base such as pyridine. Condensation, or by reacting the aromatic carboxylic acid chloride (2) directly with the acid hydrazide to obtain diacylhydrazine (5), and the diacylhydrazine (5) thus obtained is converted to phosphorus pentoxide or the like.
  • the cyclization reaction is carried out in the presence of a dehydrating agent to give 1,3,4-oxazole (6), which is heated with an aniline derivative without solvent, or acid-catalyzed with tosylic acid or the like.
  • 1 can be obtained the target by the presence of heating to reflux in a solvent such as toluene, 2, 4 one Toriazo Ichiru derivative (7).
  • the acid catalyst used for the heating and refluxing besides tosylic acid, mesylic acid, sulfonic acid and the like can be used, and as the solvent, xylene, mono or dichlorobenzene other than toluene can be used.
  • an aniline derivative (8) is condensed with an acylating agent such as acetic anhydride in an organic solvent such as tetrahydrofuran to obtain anilide (9), which is then dissolved in toluene or the like.
  • Thioamide (10) is obtained by thioamidation using phosphorus pentasulfide in an organic solvent, and the thioamide (10) thus obtained is converted to S-methylthioimidate (11) with methyl iodide, and this is converted to acid hydrazide (4).
  • DMF dimethylformaldehyde
  • —Alkylimidate (12) which can be reacted with acid hydrazide (4) in the same manner as above to give 1,2,4-triazole derivative (7).
  • dimethylacetoamide, DMSO, 1-methyl-2-pyrrolidone and the like are suitably used as a solvent in addition to DMF.
  • Examples of the method for converting the side chain include the method shown in the following formula. That is, benzyloxy PT / JP00 / 00668 De-benzylation of the derivative (7) by catalytic reduction to obtain the phenol derivative compound (13), which is then subjected to a Mitsunobu reaction with an alkyl halide, alkyl sulfonate or alcohol to form an alkyl group To obtain an alkoxyphenyltriazole derivative (14).
  • an alkylenedihalide is reacted with a phenol derivative compound (13) to obtain an octogenoalkoxyphenyltriazole derivative, which is subjected to a substitution reaction with an amine to obtain an aminoalkoxyphenyltriazole derivative.
  • the iodine element (1 5) subjected to Sonogashira reaction (P dC 1 2 (PPh 3 ) 2, Cu I, PPh 3, acetylene / E t 3 N-pyridine), alkylene induction body (16) , And subjected to catalytic reduction to obtain an alkylphenyltriazole derivative (17).
  • isomers such as a racemate, an optically active substance, and a diastereomer may exist alone or as a mixture.
  • the racemic compound is stereochemically prepared by using an appropriate starting compound or by a general racemic resolution method (for example, a method of optically resolving a diastereomeric salt with a general optically active acid (tartaric acid, etc.)).
  • a general racemic resolution method for example, a method of optically resolving a diastereomeric salt with a general optically active acid (tartaric acid, etc.
  • the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.
  • V IA receptor has selective antagonistic activity in the body, such as vasodilatory, hypotensive, cardiac hypertrophy, cardiomyocyte hypertrophy, vascular smooth muscle cell contraction / proliferation / hypertrophy, kidney mesangial cell contraction It has an inhibitory action on growth / hypertrophy, an inhibitory action on extracellular matrix accumulation in the kidney, an inhibitory action on platelet aggregation, and an inhibitory action on vascular permeability factor (vascular endothelial growth factor) production.
  • vasodilatory, hypotensive, cardiac hypertrophy, cardiomyocyte hypertrophy, vascular smooth muscle cell contraction / proliferation / hypertrophy, kidney mesangial cell contraction It has an inhibitory action on growth / hypertrophy, an inhibitory action on extracellular matrix accumulation in the kidney, an inhibitory action on platelet aggregation, and an inhibitory action on vascular permeability factor (vascular endothelial growth factor) production.
  • V 1A receptors AVP is present use in the treatment of various diseases involving, for example, vasodilators, antihypertensive agents, anti-heart failure agent, an anti-renal failure agent, anti-platelet aggregation inhibitor, a useful Yes, high blood pressure, heart failure, renal disease, cerebrovascular disease, diabetes, diabetic nephropathy, diabetic retinopathy, various ischemic diseases, circulatory failure, arteriosclerosis, dysmenorrhea, gastric ulcer, nausea, vomiting, fainting, It is effective for the prevention and treatment of malignant tumors, cancer, renal dysfunction, etc. In particular, it is useful for the prevention and treatment of diabetic nephropathy.
  • the compound of the present invention has excellent oral absorbability, is hardly metabolized in vivo, and has good sustainability.
  • the cells are subjected to suction filtration using a cell harvester and passed through a glass filter (GF / B) to remove the free ligand and excess buffer, and the labeled ligand bound to the membrane sample is removed from the glass filter. Trapped. After the glass filter was sufficiently dried, it was mixed with a liquid scintillation cocktail, and the radioactivity was measured with a liquid scintillation counter. 50% inhibition of specific binding of [ 3 H] AVP to membrane preparation of test drug Concentration (IC 5 o value) was determined from regression analysis of the displacement curve of the test drug.
  • the example compounds of the invention showed good affinity for the human V 1A receptor in the range of pKi values from 6.0 to 9.1.
  • rat liver membrane preparation was performed according to the method of Nakamura et al. (J. Biol. Cem. 258 (1983), 9283-9289).
  • [ 3 H] AVP (0.5 nM) and rat liver membrane specimens were mixed with various concentrations of the test drugs and incubated.
  • the cells were subjected to suction filtration using a cell harvester, and free ligand and excess buffer were removed by passing through a glass filter (GF / B) to bind to the membrane sample at the glass filter. Labeled ligand was trapped. After the glass filter was sufficiently dried, it was mixed with a cocktail for liquid scintillation, and the radioactivity was measured with a liquid scintillation counter. The concentration (IC 50 value) that inhibits the specific binding of [ 3 H] AVP by 50% to the membrane preparation of the test drug was determined by regression analysis of the displacement curve of the test drug.
  • IC 50 value concentration that inhibits the specific binding of [ 3 H] AVP by 50% to the membrane preparation of the test drug was determined by regression analysis of the displacement curve of the test drug.
  • the negative logarithm of the Ki value calculated above was taken as the pKi value.
  • the example compounds of the present invention showed good affinity for rat V1A receptor.
  • Rats Male Wistar rats were anesthetized with pentobarbital sodium (60 mg / kg intraperitoneally), and a polyethylene tube for blood pressure measurement was introduced into the left common carotid artery. Rats were housed in individual cages and used for experiments after a 1-2 day recovery period. Blood pressure was measured from an arterial tube via a pressure transducer under anesthesia and unrestrained. To rats AVP (30 mU / kg) was administered intravenously, and the increase in blood pressure at that time was measured. The test drug was suspended orally in a 0.5% methylcellulose solution, and the pressor response due to AVP was measured. The pressor response by AVP before administration of the test drug was defined as 100%, and the suppression rate of the pressor response by AVP after administration of the test drug was observed over time to determine the V1A receptor antagonism.
  • compositions containing one or more of the compounds represented by the general formulas (I) and (1) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient are commonly used. Tablets, powders, granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches with the use of carriers, excipients and other additives Etc. and administered orally or parenterally.
  • the clinical dose of the compound of the present invention for humans is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, weight, etc. of the patient to which the compound is applied. 5500 mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above range may be sufficient.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicone. It is mixed with magnesium acid aluminate.
  • inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicone. It is mixed with magnesium acid aluminate.
  • the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid.
  • lubricants such as magnesium stearate
  • disintegrants such as calcium cellulose glycolate
  • stabilizers such as lactose
  • glutamic acid Alternatively, a solubilizing or solubilizing agent such as aspartic acid may be contained.
  • the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as Contains purified water and ethyl alcohol.
  • the composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous diluents and suspension diluents include distilled water for injections and physiological saline.
  • Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and surfactants such as polysorbate 80 (trade name). Agents.
  • compositions may further include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents (eg, glutamic acid, aspartic acid). May contain various additives. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.
  • Acetic anhydride (20 ml) was added to a solution of 2-aminophenol (10.91 g) in ethyl acetate (100 ml) at room temperature, and the mixture was stirred for 30 minutes. After concentrating the reaction solution, ethyl acetate was added to the residue, and the crystals were collected by filtration. A mixture of the crystals, benzyl bromide (18.8 g), and potassium carbonate (30.0 g) in acetonitrile (300 ml) was stirred at 70 ° C. overnight. After filtering the reaction solution, ethyl acetate was added to the residue, which was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography 1 to give 22.64 g (94%) of the title compound as a white solid. Its physical properties are as follows.
  • N- (2-benzyloxyphenyl) -S-methylacetothioimidate N- (2-benzyloxyphenyl) acetamide (22.5 5 g), phosphorus pentasulfide (23.0 g )) (300 ml) was stirred at 70 ° C. for 2 hours.
  • the supernatant of the reaction solution was separated and concentrated, and the residue was purified by silica gel column chromatography to obtain 11.51 g of N- (2-benzyloxyphenyl) thioacetamide as a brown liquid. .
  • Tables 1 to 8 show the structural formulas of typical compounds of the novel triazole compounds according to the present invention, including the compounds obtained in the above Examples, together with their physical properties. Further, among the compounds other than the compounds described in the examples, the NMR data of the compounds whose physical properties are indicated as amorphous crystals are also shown in Tables 9 to 11.

Abstract

L'invention concerne des dérivés de triazole de formule générale (I) ou leurs sels pharmaceutiquement acceptables. L'invention concerne également des antagonistes du récepteur de vasopressine arginine V1A dans lesquels ces dérivés ou leurs sels tiennent lieu de principe actif. Dans ladite formule, A est benzène éventuellement substitué ou une chaîne thiophène; Y est N ou CH; R1 est hydrogène ou alkyle; et R2 et R3 sont chacun hydrogène, halogéno, amino ou autre substituant.
PCT/JP2000/000668 2000-02-08 2000-02-08 Derives de triazole WO2001058880A1 (fr)

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WO2003053437A1 (fr) * 2001-12-20 2003-07-03 Applied Research Systems Ars Holding N.V. Triazoles utilises comme antagonistes de l'oxytocine
WO2004037809A1 (fr) * 2002-10-25 2004-05-06 Pfizer Limited Composes triazole pour le traitement de la dysmenorrhee
WO2005006899A1 (fr) * 2003-07-23 2005-01-27 Pfizer Limited Traitement des dysfonctionnements sexuels chez l'homme
WO2005028452A1 (fr) * 2003-09-22 2005-03-31 Pfizer Limited Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine
WO2005063754A1 (fr) * 2003-12-22 2005-07-14 Pfizer Limited Derives de triazole utiles comme antagonistes de la vasopressine
WO2005068466A1 (fr) * 2004-01-13 2005-07-28 Pfizer Limited Composes utiles en therapie
WO2005079808A1 (fr) * 2004-01-22 2005-09-01 Pfizer Limited Derives de triazole inhibant l'activite antagoniste de la vasopressine
WO2005082866A2 (fr) * 2004-02-20 2005-09-09 Pfizer Limited Derives de triazole substitues utilises en tant qu'antagonistes de l'oxytocine
WO2005105779A1 (fr) * 2004-04-28 2005-11-10 Pfizer Limited Derives 3-heterocyclyl-4-phenyl-triazole comme inhibiteurs de la vasopressine par recepteur
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US7084164B2 (en) 2000-05-19 2006-08-01 Astellas Pharma, Inc. Triazole derivative
US7084145B2 (en) 2002-10-25 2006-08-01 Pfizer Inc. Triazole compounds useful in therapy
WO2006100588A1 (fr) * 2005-03-21 2006-09-28 Pfizer Limited Derives de triazole substitues utilises en tant qu'antagonistes d'oxytocine
US7119088B2 (en) 2003-02-19 2006-10-10 Pfizer Inc. Triazole compounds useful in therapy
WO2006123242A1 (fr) * 2005-05-18 2006-11-23 Pfizer Limited Derives de 1, 2, 4-triazole en tant qu'antagonistes de la vasopressine
JP2008533192A (ja) * 2005-03-21 2008-08-21 ファイザー・リミテッド オキシトシンアンタゴニストとしての置換されたトリアゾール誘導体
US7649003B2 (en) * 2003-09-22 2010-01-19 Pfizer Inc. Substituted triazole derivatives as oxytocin antagonists
US7745630B2 (en) 2003-12-22 2010-06-29 Justin Stephen Bryans Triazolyl piperidine arginine vasopressin receptor modulators
EP2716638A1 (fr) * 2012-10-08 2014-04-09 Université de Strasbourg Ligands marqués du récepteur oxytocin

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US7034047B2 (en) * 2000-05-19 2006-04-25 Astellas Pharma, Inc. Triazole derivative
US7084164B2 (en) 2000-05-19 2006-08-01 Astellas Pharma, Inc. Triazole derivative
JP2005517662A (ja) * 2001-12-20 2005-06-16 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ オキシトシン・アンタゴニストとしてのトリアゾール類
US7468385B2 (en) 2001-12-20 2008-12-23 Laboratoires Serono Sa Triazoles as oxytocin antagonists
WO2003053437A1 (fr) * 2001-12-20 2003-07-03 Applied Research Systems Ars Holding N.V. Triazoles utilises comme antagonistes de l'oxytocine
WO2004037809A1 (fr) * 2002-10-25 2004-05-06 Pfizer Limited Composes triazole pour le traitement de la dysmenorrhee
US7084145B2 (en) 2002-10-25 2006-08-01 Pfizer Inc. Triazole compounds useful in therapy
US7119088B2 (en) 2003-02-19 2006-10-10 Pfizer Inc. Triazole compounds useful in therapy
US7442795B2 (en) 2003-02-19 2008-10-28 Pfizer Inc. Triazole compounds useful in therapy
WO2005006899A1 (fr) * 2003-07-23 2005-01-27 Pfizer Limited Traitement des dysfonctionnements sexuels chez l'homme
WO2005028452A1 (fr) * 2003-09-22 2005-03-31 Pfizer Limited Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine
US7875615B2 (en) 2003-09-22 2011-01-25 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
JP2007505888A (ja) * 2003-09-22 2007-03-15 ファイザー インコーポレイテッド オキシトシン拮抗薬としての置換トリアゾール誘導体
US7649003B2 (en) * 2003-09-22 2010-01-19 Pfizer Inc. Substituted triazole derivatives as oxytocin antagonists
JP2007515468A (ja) * 2003-12-22 2007-06-14 ファイザー・インク バソプレシン・アンタゴニストとしてのトリアゾール誘導体
JP4698604B2 (ja) * 2003-12-22 2011-06-08 ファイザー・インク バソプレシン・アンタゴニストとしてのトリアゾール誘導体
AP2331A (en) * 2003-12-22 2011-12-05 Pfizer Triazole derivatives as vasopressin antagonists.
US8093400B2 (en) 2003-12-22 2012-01-10 Pfizer Inc. Compounds useful in therapy
EA010132B1 (ru) * 2003-12-22 2008-06-30 Пфайзер Инк. Производные триазола в качестве антагонистов вазопрессина
US7745630B2 (en) 2003-12-22 2010-06-29 Justin Stephen Bryans Triazolyl piperidine arginine vasopressin receptor modulators
KR100854872B1 (ko) * 2003-12-22 2008-08-28 화이자 인코포레이티드 바소프레신 길항제로서의 트리아졸 유도체
WO2005063754A1 (fr) * 2003-12-22 2005-07-14 Pfizer Limited Derives de triazole utiles comme antagonistes de la vasopressine
WO2005068466A1 (fr) * 2004-01-13 2005-07-28 Pfizer Limited Composes utiles en therapie
WO2005079808A1 (fr) * 2004-01-22 2005-09-01 Pfizer Limited Derives de triazole inhibant l'activite antagoniste de la vasopressine
US7449462B2 (en) * 2004-01-22 2008-11-11 Pfizer, Inc. Triazole derivatives which inhibit vasopressin antagonistic activity
WO2005082866A2 (fr) * 2004-02-20 2005-09-09 Pfizer Limited Derives de triazole substitues utilises en tant qu'antagonistes de l'oxytocine
WO2005082866A3 (fr) * 2004-02-20 2006-04-13 Pfizer Ltd Derives de triazole substitues utilises en tant qu'antagonistes de l'oxytocine
WO2005105779A1 (fr) * 2004-04-28 2005-11-10 Pfizer Limited Derives 3-heterocyclyl-4-phenyl-triazole comme inhibiteurs de la vasopressine par recepteur
US7618972B2 (en) 2005-03-21 2009-11-17 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
JP2008533192A (ja) * 2005-03-21 2008-08-21 ファイザー・リミテッド オキシトシンアンタゴニストとしての置換されたトリアゾール誘導体
WO2006100588A1 (fr) * 2005-03-21 2006-09-28 Pfizer Limited Derives de triazole substitues utilises en tant qu'antagonistes d'oxytocine
WO2006123242A1 (fr) * 2005-05-18 2006-11-23 Pfizer Limited Derives de 1, 2, 4-triazole en tant qu'antagonistes de la vasopressine
EP2716638A1 (fr) * 2012-10-08 2014-04-09 Université de Strasbourg Ligands marqués du récepteur oxytocin
WO2014056852A1 (fr) * 2012-10-08 2014-04-17 Universite De Strasbourg Ligands marqués du récepteur de l'ocytocine

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