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  • 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
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • 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.

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