WO2003008387A1 - Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur - Google Patents

Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur Download PDF

Info

Publication number
WO2003008387A1
WO2003008387A1 PCT/FI2002/000643 FI0200643W WO03008387A1 WO 2003008387 A1 WO2003008387 A1 WO 2003008387A1 FI 0200643 W FI0200643 W FI 0200643W WO 03008387 A1 WO03008387 A1 WO 03008387A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethylpyrimidin
benzenesulfonamide
amino
compound
carbon atoms
Prior art date
Application number
PCT/FI2002/000643
Other languages
English (en)
Inventor
Topi Joutsamo
Andrei Yurievitch Tauber
Harri Salo
Anna-Marja Hoffrén
Siegfried Wurster
Original Assignee
Oy Juvantia Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FI20011560A external-priority patent/FI116940B/fi
Application filed by Oy Juvantia Pharma Ltd filed Critical Oy Juvantia Pharma Ltd
Priority to CA002454187A priority Critical patent/CA2454187A1/fr
Priority to HU0401076A priority patent/HUP0401076A2/hu
Priority to MXPA04000615A priority patent/MXPA04000615A/es
Priority to NZ530366A priority patent/NZ530366A/en
Priority to EP02748902A priority patent/EP1417182A1/fr
Priority to KR10-2004-7001043A priority patent/KR20040030850A/ko
Priority to JP2003513947A priority patent/JP2004535467A/ja
Priority to IL15951102A priority patent/IL159511A0/xx
Publication of WO2003008387A1 publication Critical patent/WO2003008387A1/fr
Priority to NO20040237A priority patent/NO20040237L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the use of selective alpha-2B-adrenoceptor antagonists for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of diseases mediated by the alpha-2B-adrenoceptor in mammals.
  • alpha-2B-adrenoceptors mediate vascular contractions. Therefore, alpha-2B-antagonists are useful in the treatment or prevention of diseases involving vascular contraction. It has also been found that certain individuals have a genetic polymorphism in the alpha-2B-adrenoceptor gene. It has been observed that the alpha-2B-adrenoceptor protein in some subjects has a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide (WO 01/29082; Heinonen et al., 1999).
  • An object of this invention is to provide compounds useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal.
  • Ri , R 2 , R 3 , R 4 and R 5 are independently of each other H , a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
  • X is H , a straight or branched alkyl chain with 1 to 4 carbon atoms, phenyl or -OH;
  • Z is H , acetyl, -CH 2 -Ph-0-CF 3 or -CH 2 -Ph-CF 3 , where Ph is phenyl;
  • Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is
  • phenyl optionally mono- or disubstituted and each substituent is independently selected from the group consisting of a halogen, a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, a nitrile, an amide, amino, or a nitro group;
  • 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl wherein one N optionally has a substituent that is a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, or benzyl; and wherein the 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
  • pyridinyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen
  • naphthyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen.
  • N-(4,6-dimethylpyrimidin-2-yl)-4-[(l -methyl- 1H- benzimidazol-2-ylmefhyl)-amino] -benzenesulfonamide No 653716, ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego CA 92127
  • N-(4,6-dimethylpyri ⁇ udin-2-yl)-4-[(l-ethyl-lH-benzimidazol-2-ylmethyl)-amino]- benzenesulfonamide No AE-848/34956037, SPECS and BioSPECS B.
  • This invention further concerns use of compound of formula (I)
  • Ri , R 2 , R 3 , R 4 and R 5 are independently of each other ⁇ , a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
  • Z is ⁇ , acetyl, -C ⁇ 2 -Ph-0-CF 3 or -CH 2 -Ph-CF 3 , where Ph is phenyl;
  • Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is
  • phenyl optionally mono- or disubstitued and each substituent is independently selected from the group consisting of a halogen, a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, an acetyl, a nitrile, an amide, amino, or a nitro group;
  • 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
  • pyridinyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen; or
  • naphthyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen.
  • Preferred compounds of the invention are compounds of formula (I)
  • X is H
  • Y is a phenyl optionally mono- or disubstituted with a straight or branched alkoxy group
  • Z is H.
  • Compounds fulfilling all of the aforementioned characteristics and wherein said phenyl is substituted and said alkoxy substituent is methoxy are 4-(2,4-dimethoxybenzylanMno)-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfon- amide, N-(4,6-dimefhylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfon- amide, 4-(3,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)- benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2- yl)-benzene
  • X is H
  • Y is a phenyl optionally mono- or disubstituted with a straight or branched alkyl and/or a halogen
  • Z is H.
  • These comprise compounds such as 4-benzylamino-N-(4,6-dimefhylpyrimidin-2- yl)-benzenesulfonamide, N-(4,6-dimefhylpyrimidin-2-yl)-4-(2-methylbenzyl- amino)-benzenesulfonamide, 4-(2,4-dimethylbenzylamino)-N-(4,6-dimethyl- pyrimidin-2-yl)-benzenesulfonamide, N-(4,6-dimefhylpyrimidin-2-yl)-4-(3-methyl- benzylamino)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(4-methyl- benzylamin
  • N-(4,6-dimethylpyrimidin-2-yl)-4-[(l-ethyl-lH- indol-3-ylmethyl)-amino] -benzenesulfonamide N-(4,6-dimethylpyrimidin-2-yl)-4- [(l-isobutyl-lH-benzimidazol-2-ylmethyl) -amino] -benzenesulfonamide
  • N-(4,6- dimemylpyrimidin-2-yl)-4-[2-(2-mefhoxyphenyl)-efhylamino]-benzenesulfon- amide N-(4,6-dimethylpyrimidin-2-yl)-4-[(naphthalen-2-ylmefhyl)-amino]
  • the compound is N-(4-methyl-2- pyrimidinyl)-4- [ [( 1 -methyl- 1 ⁇ -benzimidazol-2-yl)-methyl] amino] -benzenesulfonamide.
  • the invention also relates to the use of selective alpha-2B-adrenoceptor antagonists of formula (I)
  • Ri and R 3 are typically methyl and R 2 , R 4 and R 5 are typically H.
  • X is H
  • Y is a phenyl optionally mono- or disubstituted with a straight or branched alkoxy group and Z is H.
  • Especially preferable for use are compounds in which said phenyl is substituted and said alkoxy substituent is methoxy.
  • Such compound comprise 4-(2,4- dimethoxybenzylamino)-N-(4,6-dimefhylpyrimidin-2-yl)-benzenesulfonamide, N- (4,6-dimethylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfonamide, 4- (3,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)- benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-N-(4,6-dimethylpyrimidin-2- yl)-benzenesulfonamide and N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzyl- amino)-benzenesulf onamide .
  • X is H
  • Y is a phenyl optionally mono- or disubstituted with a straight or branched alkyl and/or a halogen and Z is H.
  • Such compound comprise 4-benzylamino-N-(4,6-dimethylpyrimidin-2-yl)-benzene- sulfonamide, N-(4,6-dimefhylpyrimidin-2-yl)-4-(2-methylbenzylamino)-benzene- sulfonamide, 4-(2,4-dimethylbenzylamino)-N-(4,6-dimethylpyrimidin-2-yl)- benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(3-methylbenzylamino)- benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(4-methylbenzylamino)- benzenes
  • Further preferred compounds to be used comprise 4-[(lH-benzimidazol- 2-ylmemyl)-amino]-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-(4,6- dimefhylpyrimidin-2-yl)-4-[( 1 -ethyl- lH-indol-3-ylmethyl)-amino] -benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4- [( 1 -isobutyl- lH-benz- imidazol-2-ylmethyl)-amino] -benzenesulfonamide, N-(4,6-dimethylpyrimidin-2- yl)-4-( 1 -phenylethylamino)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)- 4- [2-(2-methoxypheny
  • Alpha-2B-adrenoceptor antagonists are useful in the treatment and/or prevention of many diseases.
  • D/D genotype Individuals having a deletion in the alpha-2B-adrenoceptor protein (WO 01/29082; ⁇ einonen et al., 1999), particularly the deletion/deletion genotype (D/D genotype) is an important target group, which benefits from administration of selective alpha-2B-adrenoceptor antagonists. These individuals have a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide.
  • alpha-2B-adrenoceptors are believed to be involved in the pathogenesis of a significant fraction of all cases of AMI, especially in subjects with the D/D genotype, but also in I/D and I/I subjects (I means "insertion” and stands for the "normal” allele).
  • the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be particularly useful in the treatment or prevention of coronary heart diseases. As examples can be mentioned
  • alpha-2B-adrenoceptor dependent vasoconstriction is a causative factor in some cases of AMI, then antagonism of these receptors should restore coronary circulation and reduce the ischemic myocardial damage.
  • An alpha-2B-adrenoceptor antagonist will relieve the vasoconstrictive component in the sustained ischemic episode, thus alleviating the symptoms and preventing AMI.
  • An alpha-2B -adrenoceptor antagonist will help to alleviate the vasoconstrictive component in all types of CHD, providing both symptomatic relief and protection from AMI.
  • a general reduction in vascular tone will contribute to this by reducing venous return, cardiac workload and oxygen consumption (a nitrate-type effect; see below).
  • alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of essential hypertension, especially in subjects with increased sympathetic activity and a hyperdynamic circulatory system.
  • alpha-2B-adrenoceptor agonists In transgenic mice with targeted inactivation of the alpha-2B -adrenoceptor gene, intravenously administered alpha-2-adrenoceptor agonists fail to induce the characteristic blood pressure elevation, which is seen in normal animals and also in humans after large doses of such drugs (Link et al., 1996). The hypotensive effect of these drugs was markedly accentuated. This demonstrates that alpha- 2B- adrenoceptors mediate vascular contraction. Thus, an antagonist should reduce blood pressure. This effect has not been seen with alpha-2B-non-selective alpha-2- adrenoceptor antagonists, because antagonism of alpha-2A-adrenoceptors increases sympathetic outflow, cardiac output and blood pressure. In mice with dysfunctional alpha-2A-adrenoceptors, alpha-2-adrenoceptor agonists caused an accentuated hypertensive response and no hypotension (MacMillan
  • an alpha-2B -adrenoceptor antagonist is postulated to have favourable effects in hypertensive subjects through their effects on renal function, muscle blood flow, and also on vascular resistance in other vascular beds.
  • the anti-AMI effect of such a drug will be an additional benefit, as hypertension is a significant risk factor for AMI.
  • This protection is due to three factors: 1) a reduction in systemic blood pressure, 2) decreased risk of coronary vasoconstriction, and 3) a nitrate-like effect on venous return, myocardial workload and oxygen consumption.
  • the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of other vascular diseases. Specifically, benefits can be expected in the treatment or prevention of
  • alpha-2B-adrenoceptor antagonists disclosed in this invention are also useful in anaesthesia and analgesia to potentiate the clinical efficacy of alpha-2- adrenoceptor agonists, which are not selective for the alpha-2B-adrenoceptor subtype.
  • a simultaneously administered alpha-2B-adrenoceptor antagonist will allow the use of larger doses of said agonists, up to anaesthetic dose levels which have not previously been possible in man, only in veterinary anaesthetic practice.
  • the affinity of test compounds for the three human ⁇ 2 -adrenoceptor subtypes was determined in competition binding assays with H-rauwolscine.
  • the biological material for these experiments consisted of membranes from Shionogi SI 15 cells stably transfected with any of the three human 2 subtypes (Marjamaki et al. 1992). Membrane (5-10 ⁇ g of total protein per sample) and 1-2 nM 3 H-rauwolscine (specific activity 78 Ci/mmol) were incubated in 50 mM KH 2 P0 4 , pH 7.5 with 6 concentrations of the compounds. Each concentration was run in duplicate.
  • Non-specific binding was defined by 100 ⁇ M oxymetazoline and corresponded to 5-15% of total binding. After 30 min at room temperature, incubations were terminated by rapid vacuum filtration through GF/B glass fiber filter and three 5 ml washes with ice-cold incubation buffer. The filters were then dried, impregnated with scintillate and their radioactivity was measured by scintillation counting. The analysis of the experiments was carried out by nonlinear least square curve fitting. Experimentally determined IC50 values were converted to Ki's by making use of the Cheng-Prusoff equation (Cheng and Prusoff, 1973). Experiments were repeated a minimum of three times.
  • Table 1 Human 2 -adrenoceptor subtypes binding affinities. Data is presented as Ki's in nM (Mean ⁇ SEM).
  • Antagonist potencies were determined as the ability of test compounds to competitively inhibit epinephrine-stimulated S-GTP ⁇ S binding to G proteins (Tian et al., 1993; Wieland and Jakobs, 1994; Jasper et al., 1998) in membranes of CHO cells stably transfected with one of the three human 2 subtypes (Pohjanoksa et al., 1997; Marjamaki et al., 1998).
  • Membranes (2-6 ⁇ g of protein per sample) and 12 concentrations of test compound were preincubated for 30 min with a fixed concentration fo epinephrine (5 ⁇ M for ⁇ 2A originate 15 ⁇ M for 2B , 5 ⁇ M for 2 c) in 50 mM Tris, 5 mM MgCl 2 , 150 mM NaCl, 1 mM DTT, 1 mM EDTA, 10 ⁇ M GDP, 30 ⁇ M ascorbic acid, pH 7.4 at room temperature. Binding of radiolabel was started by the addition of trace amounts of 35 S-GTP ⁇ S (0.08-0.15 nM, specific activity 1250 Ci/mmol) to the incubation mixture.
  • the alpha-2B-adrenoceptor antagonist or its pharmaceutically acceptable salt can be administered by various routes.
  • the suitable administration forms include, for example, oral formulations; parenteral injections including intravenous, intramuscular, intradermal and subcutanous injections; transdermal or rectal administration forms.
  • the required dosage of the compounds of the alpha-2B -adrenoceptor antagonist will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being employed.
  • the suitable dose varies in the range 5 ⁇ g to 100 mg per kg body weight and day for an adult person.
  • Step I Alkylation o/2-hydroxymethylbenzimidazole
  • Step II Chlorination o/l-ethyl-2-hydroxymethylbenzimidazole
  • Step III Coupling reaction between l-ethyl-2-chloromethylbenzimidazole and sul/amethazine
  • reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) and 2:1 petrol ether: ethylacetate to obtain the title compound as white crystals with a yield of 10%. .
  • l-ethylindole-3-carboxaldehyde was prepared from alkylation reaction of indole-3- carboxaldehyde.
  • Indole-3-carboxaldehyde (900 mg, 6.2 mmol) was dissolved in 5 ml dimethylformamide, ethyl bromide (918 ⁇ l, 12 mmol) and sodium hydride (282.8 mg, 12 mmol) were added to the reaction mixture. Solution was stirred and refluxed for three hours. The reaction mixture was then evaporated to dryness and washed with water. Pale brown crystals were obtained with 80% yield.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Gynecology & Obstetrics (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés de formule (I) ou un sel pharmaceutiquement acceptable desdits composés. Dans cette formule, R1, R2, R3, R4 et R5, indépendamment les uns des autres, sont H, un groupe alkyle ou alcoxy linéaire ou ramifié avec 1 à 4 atomes de carbone, ou un halogène, X est H, une chaîne alkyle linéaire ou ramifié avec 1 à 4 atomes de carbone, phényle OH ou =O, Z est H, acétyle, -CH2-Ph-O-CF3 ou CH2-Ph-CF3, et Y est une structure cyclique éventuellement associée à la formule (I) avec une chaîne alkyle comprenant un ou deux atomes de carbone. L'invention concerne en outre l'utilisation de ces composés pour la fabrication d'une préparation pharmaceutique utile dans le traitement ou la prévention d'une maladie induite par l'alpha-2B-adrénorécepteur chez un mammifère.
PCT/FI2002/000643 2001-07-20 2002-07-22 Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur WO2003008387A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA002454187A CA2454187A1 (fr) 2001-07-20 2002-07-22 Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur
HU0401076A HUP0401076A2 (hu) 2001-07-20 2002-07-22 Alfa-2B-andrenoceptor antagonista vegyületek és alkalmazásuk gyógyszerkészítmények előállítására
MXPA04000615A MXPA04000615A (es) 2001-07-20 2002-07-22 Compuestos utiles para el tratamiento o la prevencion de enfermedades mediadas por alfa-2b-adrenoceptor.
NZ530366A NZ530366A (en) 2001-07-20 2002-07-22 Compounds useful for treatment or prevention of disease mediated by alpha-2B-adrenoceptor
EP02748902A EP1417182A1 (fr) 2001-07-20 2002-07-22 Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur
KR10-2004-7001043A KR20040030850A (ko) 2001-07-20 2002-07-22 알파-2비-아드레노셉터 매개 질병의 치료 및 예방에유용한 화합물
JP2003513947A JP2004535467A (ja) 2001-07-20 2002-07-22 α−２Ｂ−アドレナリン受容体が介在する疾患を治療又は予防するために有用な化合物
IL15951102A IL159511A0 (en) 2001-07-20 2002-07-22 Compounds useful for treatment or prevention of disease mediated by alpha-2b-adrenoceptor
NO20040237A NO20040237L (no) 2001-07-20 2004-01-19 Forbindelser anvendelige for behandling eller forbygging av sykdom overført via alfa-2B-adrenoceptor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US30644901P 2001-07-20 2001-07-20
US60/306,449 2001-07-20
FI20011560A FI116940B (fi) 2001-07-20 2001-07-20 Alfa-2B-adrenoseptorivälitteisen sairauden hoitoon tai ehkäisyyn käyttökelpoiset yhdisteet
FI20011560 2001-07-20

Publications (1)

Publication Number Publication Date
WO2003008387A1 true WO2003008387A1 (fr) 2003-01-30

Family

ID=26161203

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI2002/000643 WO2003008387A1 (fr) 2001-07-20 2002-07-22 Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur

Country Status (10)

Country Link
EP (1) EP1417182A1 (fr)
JP (1) JP2004535467A (fr)
CA (1) CA2454187A1 (fr)
HU (1) HUP0401076A2 (fr)
IL (1) IL159511A0 (fr)
MX (1) MXPA04000615A (fr)
NZ (1) NZ530366A (fr)
PL (1) PL367040A1 (fr)
RU (1) RU2004105035A (fr)
WO (1) WO2003008387A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068653A1 (fr) * 2004-01-15 2005-07-28 Oy Jurilab Ltd Methode de detection du risque de maladies cardio-vasculaires, telles qu'un infarctus du myocarde aigu et une coronaropathie par analyse de la defensine
WO2006100263A2 (fr) 2005-03-23 2006-09-28 Klat Pharma Animal Health Gmbh Utilisation d'amides non absorbants de sulfadimidine destinee au traitement de maladies intestinales
WO2019081353A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Imidazopyridinamides substituées et leur utilisation
WO2020216669A1 (fr) 2019-04-23 2020-10-29 Bayer Aktiengesellschaft Imidazopyridinamides substitués par un phényle et leur utilisation
CN116396236A (zh) * 2023-04-19 2023-07-07 河北科技大学 一种二芳基甲基磺胺类化合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) * 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
US6150389A (en) * 1994-07-11 2000-11-21 Allergan Sales, Inc. Comformationally rigid bicyclic and adamantane derivatives useful as α2 -adrenergic blocking agents
WO2001058454A1 (fr) * 2000-02-11 2001-08-16 Oy Juvantia Pharma Ltd Compose utile pour le traitement ou la prevention d'une maladie mediee par le recepteur adrenergique alpha 2b
WO2001083427A1 (fr) * 2000-04-28 2001-11-08 Sankyo Company, Limited MODULATEURS DE PPAR$g(g)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292740A (en) * 1991-06-13 1994-03-08 Hoffmann-La Roche Inc. Sulfonamides
US6150389A (en) * 1994-07-11 2000-11-21 Allergan Sales, Inc. Comformationally rigid bicyclic and adamantane derivatives useful as α2 -adrenergic blocking agents
WO2001058454A1 (fr) * 2000-02-11 2001-08-16 Oy Juvantia Pharma Ltd Compose utile pour le traitement ou la prevention d'une maladie mediee par le recepteur adrenergique alpha 2b
WO2001083427A1 (fr) * 2000-04-28 2001-11-08 Sankyo Company, Limited MODULATEURS DE PPAR$g(g)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CROAT. CHEM. ACTA., vol. 38, 1966, pages 309 - 311 *
DATABASE STN INTERNATIONAL [online] FILE CAPLUS; BEDENKO V. ET AL: "N4-acylsulfonamides. I. Derivatives of +-(2-ethoxybenzamido)benzenesulfonamide.", XP002902754, retrieved from CAPLUS accession no. 1967:411468 Database accession no. 67:11468 *
DATABASE STN INTERNATIONAL [online] FILE CAPLUS; SANKYO COMPANY LTD: "Preparation of nitrophenylcarboxamide derivatives as peroxisome proliferator-activated receptor (PPAR) gamma modulators.", XP002902751, retrieved from CAPLUS accession no. 2001:816614 Database accession no. 135:357944 *
DATABASE STN INTERNATIONAL [online] FILE CHEMCATS, order number AE-848/12530187; 1 July 2001 (2001-07-01), "Benzenesulfonamide, 4-[1(1-methyl-iH-benzimidazol-2-yl)methyl]amino]-N-(4-methyl-2-pyrimidinyl)-", XP002902752, retrieved from CHEMCATS accession no. 2002:1405436 *
RAJENDRA S. VARMA ET AL: "Potential biologically active agents. XII. Synthesis and antibacterial activity of substituted p-methylamino-benzenesulfonamides.", JOURNAL INDIAN CHEM. SOC., vol. 55, no. 7, July 1978 (1978-07-01), pages 716 - 718, XP002902753 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068653A1 (fr) * 2004-01-15 2005-07-28 Oy Jurilab Ltd Methode de detection du risque de maladies cardio-vasculaires, telles qu'un infarctus du myocarde aigu et une coronaropathie par analyse de la defensine
WO2006100263A2 (fr) 2005-03-23 2006-09-28 Klat Pharma Animal Health Gmbh Utilisation d'amides non absorbants de sulfadimidine destinee au traitement de maladies intestinales
WO2006100263A3 (fr) * 2005-03-23 2007-01-18 Klat Pharma Animal Health Gmbh Utilisation d'amides non absorbants de sulfadimidine destinee au traitement de maladies intestinales
WO2019081353A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Imidazopyridinamides substituées et leur utilisation
WO2020216669A1 (fr) 2019-04-23 2020-10-29 Bayer Aktiengesellschaft Imidazopyridinamides substitués par un phényle et leur utilisation
CN116396236A (zh) * 2023-04-19 2023-07-07 河北科技大学 一种二芳基甲基磺胺类化合物及其制备方法

Also Published As

Publication number Publication date
RU2004105035A (ru) 2005-06-27
HUP0401076A2 (hu) 2004-09-28
NZ530366A (en) 2005-02-25
JP2004535467A (ja) 2004-11-25
MXPA04000615A (es) 2004-04-20
IL159511A0 (en) 2004-06-01
CA2454187A1 (fr) 2003-01-30
EP1417182A1 (fr) 2004-05-12
PL367040A1 (en) 2005-02-21

Similar Documents

Publication Publication Date Title
EP0748800B1 (fr) Dérivés de pyrimidine dione, pyrimidine trione, triazine dione comme antagonistes des récepteurs alpha-1-adrénergiques
US9579325B2 (en) Modulators of TNF-α signaling
FI93957B (fi) Menetelmä pyrimidiinien valmistamiseksi
US5859014A (en) Pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives as α1 -adrenergic receptor antagonists
CN1997640A (zh) 作为代谢调节剂的经取代芳基和杂芳基衍生物及其相关病症的预防和治疗
CZ295346B6 (cs) Pyrimidinové sloučeniny, způsob jejich přípravy, farmaceutická kompozice a jejich použití pro léčbu poruch souvisejících s ligandy dopaminu D3
NO316673B1 (no) Amidderivater eller salter derav
IL135488A (en) Reliable Cyclic History
BG63487B1 (bg) Използване на хетероциклени съединения
JP2722250B2 (ja) 新規なジアミン化合物及びこれを含有する脳機能障害改善剤
US5210086A (en) 2-aminopyrimidine-4-carboxamide derivatives, their preparation and their use in therapy
TW200407113A (en) Fluorinated di-aryl urea compounds
JP2515434B2 (ja) ２−アミノピリミジン−４−カルボキサミド誘導体、その製造法およびそれを含有する医薬
JPH0460596B2 (fr)
NZ232023A (en) 4-substituted piperidinyl(alkyl)guanidine, amidine and amine derivatives; preparatory processes and pharmaceutical compositions
PL179580B1 (pl) Srodek farmaceutyczny zawierajacy pochodne kwasów karboksylowych PL PL PL PL PL PL PL
AU2001259691A1 (en) Modulators of TNF-alpha signaling
US6767909B2 (en) Compounds useful for treatment or prevention of disease mediated by alpha-2B-adrenoceptor
EP1417182A1 (fr) Composes utiles pour le traitement ou la prevention d'une maladie induite par l'alpha-2b-adrenorecepteur
AU2002319331A1 (en) Compounds useful for treatment or prevention of disease mediated by alpha-2B-adrenoceptor
SK283489B6 (sk) Piperazinylalkyltiopyrimidínové deriváty, spôsob ich prípravy, farmaceutické kompozície s ich obsahom a ich použitie
JP3285421B2 (ja) ２−アミノ−ｎ−［［［４−（アミノカルボニル）ピリミジン−２−イル］アミノ］アルキル］ピリミジン−４−カルボキシアミド誘導体、その製造および医薬への応用
US7368462B1 (en) Melanin concentrating hormone antagonists
JPS59148780A (ja) 精神病治療性５−フルオロ−ピリミジン−２−イルピペラジン化合物
CA2399421A1 (fr) Compose utile pour le traitement ou la prevention d'une maladie mediee par le recepteur adrenergique alpha 2b

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ CZ DE DE DK DK DM DZ EC EE EE ES FI FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 159511

Country of ref document: IL

Ref document number: 2002319331

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 530366

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2454187

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2002814595X

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/000615

Country of ref document: MX

Ref document number: 2003513947

Country of ref document: JP

Ref document number: 112/CHENP/2004

Country of ref document: IN

Ref document number: 1020047001043

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2002748902

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2002748902

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 530366

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 530366

Country of ref document: NZ

WWW Wipo information: withdrawn in national office

Ref document number: 2002748902

Country of ref document: EP