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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
  • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P25/06—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
  • 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
  • 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.
• the present invention also relates to a method for the treatment or prevention of diseases mediated by the alpha-2B-adrenoceptor in mammals, by administering to said mammal said selective alpha-2B-adrenoceptor antagonist.
• the selective alpha- 2B-adrenocep tor antagonists shown in Scheme I below are all previously known.
• the inventors obtained the compounds A (ordering No AE- 848/34956037), C (ordering No AF-399/36012031) and D (ordering No AH- 034/34347043) from SPECS and BioSPECS B.V., Fleminglaan 16, 2289 CP Rijswijk, The Netherlands.
• the compounds B (ordering No 653716) and E (ordering No 569063) were supplied by ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego CA 92127.
• 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 there is a genetic polymorphism in the alpha-2B-adrenoceptor gene at certain individuals. It has been observed that the alpha-2B-adrenoceptor protein at some subjects has a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid trech of 17 amino acids, located in the third intracellular loop of the receptor polypeptide (Heinonen et al., 1999).
• this invention relates to the use of a selective alpha-2B-adrenoceptor antagonist for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of a disease mediated by the alpha-2B -adrenoceptor in a mammal.
• said antagonist is a compound selected from the group consisting of compound A, B, C, D and E disclosed in Scheme I, or a pharmaceutically acceptable salt of said compound.
• This invention relates also to a method for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal, said method comprising administering to said mammal an effective amount of a selective alpha-2B- adrenoceptor antagonist, wherein said antagonist is a compound selected from the group consisting of compound A, B, C, D and E disclosed in Scheme I, or a pharmaceutically acceptable salt of said compound.
• 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 (Heinonen 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.
• 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).
• 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.
• Vasoconstriction is a key factor in the pathogenesis of Prinzmetal's angina, and an alpha-2B- adrenoceptor antagonist may resolve and prevent attacks.
• 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).
• the 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- adrenoceptors mediate vascular contraction.
• an antagonist should reduce blood pressure.
• alpha-2B-nonselective alpha-2- adrenoceptor antagonists because antagonism of alpha-2A-adrenoceptors increases sympathetic outflow, cardiac output and blood pressure.
• alpha-2-adreoceptor agonists caused an accentuated hypertensive response and no hypotension (MacMillan et al., 1996).
• 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.
• 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 anesthesia 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 anesthetic dose levels which have not previously been possible in man, only in veterinary anesthetic 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 either of the three human ⁇ 2 subtypes (Marjamaki et al. 1992). Membrane (5-10 ⁇ g of total protein per sample) and 1 nM - 2 nM 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.
• Nonspecific 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 icecold 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.
• the affinity for rat neocortical ⁇ adrenoceptors was determined in competition binding assays with 3 H-prazosin.
• the biological material for these assays consisted of membranes from rat neocortex. Membrane suspensions (100-200 ⁇ g of total protein per sample) and 0.2 nM-0.25nM of ⁇ -prazosin (specific activity 74 Ci/mmol) were incubated with 6 concentrations of compounds in a total volume of 0.25 ml (50 mM Tris pH 7.7 at 25°C). Each concentration was run in duplicate. Nonspecific binding was defined by 10 ⁇ M phentolamine methanesulfonate and corresponded to 25-30 % of total binding.
• Antagonist potencies were determined as the ability of test compounds to competitively inhibit epinephrine-stimulated 35 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 assume 15 ⁇ M for 2B , 5 ⁇ M for 2C ) 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 nM- 0.15 nM, specific activity 1250 Ci/mmol) to the incubation mixture.
• the alpha-2B -adrenoceptor antagonist as disclosed in Scheme I 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.

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