EP1149103A1 - Thienylbenzoylbenzazepine als vasopressinantagonisten - Google Patents

Thienylbenzoylbenzazepine als vasopressinantagonisten

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Publication number
EP1149103A1
EP1149103A1 EP00904244A EP00904244A EP1149103A1 EP 1149103 A1 EP1149103 A1 EP 1149103A1 EP 00904244 A EP00904244 A EP 00904244A EP 00904244 A EP00904244 A EP 00904244A EP 1149103 A1 EP1149103 A1 EP 1149103A1
Authority
EP
European Patent Office
Prior art keywords
chloro
benzodiazepin
methanone
dihydro
phenyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00904244A
Other languages
English (en)
French (fr)
Inventor
Amedeo Arturo Failli
David Kent Williams
Thomas Joseph Caggiano
Jay Scott Shumsky
Mark Anthony Ashwell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth
Original Assignee
American Home Products Corp
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
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP1149103A1 publication Critical patent/EP1149103A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention concerns tricyclic arylthiophene compounds which act as vasopressin V 2 agonists, as well as methods of treatment and pharmaceutical compositions utilizing these compounds.
  • Vasopressin antidiuretic hormone, ADH
  • ADH vascular endothelial growth factor
  • vasopressin Upon sensing an increase in plasma osmolality by brain osmoreceptors or a decrease in blood volume or blood pressure (detected by the baroreceptors and volume receptors), vasopressin is released into the blood circulation and activates vasopressin V la receptors on blood vessels causing vasoconstriction to raise blood pressure; and vasopressin V 2 receptors of the nephron of the kidney causing reabsorption mainly of water and to a lesser degree electrolytes, to expand the blood volume (Cervoni and Chan, Diuretic Agents, in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th ed., Wiley, Volume 8, 398-432, (1993)).
  • vasopressin in the pituitary was known as early as 1895 (Oliver and Schaefer, J Physiol. (London), 18, 277-279, (1895)). The determination of the structure and the total synthesis of vasopressin were accomplished by du Vigneaud and coworkers in 1954 (du Vigneaud, Gish and Katsoyannis, J. Am. Chem. Soc, 76, 4751-4752, (1954)).
  • vasopressin V la receptors The actions of vasopressin V la receptors are mediated through the phosphatidylinositol pathway. Activation of vasopressin V la receptors causes contraction of the smooth muscle of the blood vessels to raise blood pressure.
  • the actions of the vasopressin V 2 receptors are mediated through activation of the adenylate cyclase system and elevation of intracellular levels of cAMP.
  • the activation of vasopressin V 2 receptors by vasopressin or vasopressin-like (peptidic or non-peptidic) compounds increases water permeability of the collecting ducts of the nephron and permits the reabsorption of a large quantity of free water. The end result is the formation and excretion of a concentrated urine, with a decrease in urine volume and an increase in urinary osmolality.
  • Vasopressin plays a vital role in the conservation of water by concentrating the urine at the site of the collecting ducts of the kidney.
  • the collecting ducts of the kidney are relatively impermeable to water without the presence of vasopressin at the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the proximal convoluted tubule, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine.
  • vasopressin is released from the brain and activates the vasopressin V 2 receptors in the collecting ducts of the kidney rendering the ducts very permeable to water; hence water is reabsorbed and a concentrated urine is excreted.
  • the synthesis of vasopressin in the brain is defective and therefore, they produce very little or no vasopressin, but their vasopressin receptors in the kidneys are normal. Because they cannot concentrate the urine, they may produce as much as 10 times the urine volumes of their healthy counterparts and they are very sensitive to the action of vasopressin and vasopressin V 2 agonists.
  • Vasopressin and desmopressin which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus.
  • Vasopressin V 2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary delay of urination whenever desirable.
  • Vasopressin through activation of its V la receptors, exerts vasoconstricting effects so as to raise blood pressure.
  • a vasopressin V la receptor antagonist will counteract this effect.
  • Vasopressin and vasopressin-like agonists release factor VIII and von Willebrand factor so they are useful for the treatment of bleeding disorders, such as hemophilia.
  • Vasopressin and vasopressin-like agonists also release tissue-type plasminogen activator (t-PA) into the blood circulation so they are useful in dissolving blood clots such as in patients with myocardial infarction and other thromboembolic disorders (Jackson, "Vasopressin and other agents affecting the renal conservation of water", in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th ed., Hadman, Limbird, Molinoff, Ruddon and Gilman Eds., McGraw-Hill, New York, pp. 715-731 (1996); Lethagen, Ann. Hematol. 69, 173-180 (1994); Cash et al., Brit. J. Haematol, 27, 363-364 (1974); David, Regulatory Peptides, 45, 311-317 (1993); Burggraaf et al., CH. Sci., 86, 497-503 (1994)).
  • t-PA tissue-type plasminogen
  • Non-peptidic vasopressin antagonists have recently been disclosed.
  • Albright et al. describe tricyclic azepines as vasopressin antagonists or vasopressin and oxytocin antagonists in U.S. Patent 5,516,774 (1996), U.S.Patent 5,532,235 (1996), U.S. Patent
  • Patent 5,747,487 (1998), U.S.Patent 5,753,648 (1998), U.S. Patent 5,760,031 (1998), U.S. Patent 5,780,471 (1998); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in J.P. 0801460-A (1996); Ogawa et al., disclose benzoheterocyclic derivatives as vasopressin and oxytocin antagonists, and as vasopressin agonists in WO 9534540-A; and Venkatesan et al., disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Patent 5,521,173 (1996).
  • desmopressin l-desamino-8-D-arginine vasopressin
  • desmopressin is a vasopressin agonist.
  • the compound is a synthetic peptide with variable bioavailability.
  • An intranasal route is poorly tolerated and an oral formulation for nocturnal enuresis requires a 10-20 fold greater dose than the intranasal administration.
  • K 1 is CH; X is S; R 5 is hydrogen; R 7 is hydrogen; and the moiety:
  • Albright et al. broadly disclose a subset of tricyclic pyrrolo and pyrido benzodiazepines, part of the present application, as V, and/or V, vasopressin receptor antagonists and oxytocin receptor antagonists in WO 96/22282 Al (1996), inter alia.
  • Compounds of general structure 61b in Scheme 12 of the above application are claimed by Albright et al. to possess antagonist activity at V] and/or V 2 receptors and exhibit in vivo vasopressin antagonist activity, as well as antagonist activity at oxytocin receptors.
  • R 1 and R 2 are selected from hydrogen, (C J -C J ) lower alkyl, (C J -C J ) lower alkoxy and halogen; and the moiety
  • O represents an optionally substituted phenyl, a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, or a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom.
  • the compounds of this invention are non-peptidic and have a good oral bioavailability. They are vasopressin V 2 receptor agonists, and as such they promote reabsorption of water. They have no vasopressin V la receptor agonist effects so they do not raise blood pressure. In contrast, the prior art compounds are described as vasopressin antagonists at both the V la and V 2 receptors.
  • This invention relates to novel and known compounds selected from those of formula (I):
  • Y is a moiety selected independently, from NH or -(CH 2 ) n - wherein n is 1 ; m is an integer from 1 to 2;
  • R 1 , R 2 , R 5 and R 6 are independently, selected from hydrogen, lower alkyl (C, C 6 ), lower alkoxy (C,-C 6 ), halogen, and CF 3 ;
  • R 3 and R 4 are independently, selected from the group comprising hydrogen, lower alkyl (C,-C 6 ), halogen, amino, (C,-C 6 ) lower alkoxy, or (C,-C 6 ) lower alkylamino; and the moiety
  • Preferred compounds of this invention include:
  • R 1 , R 2 , R 3 , and R 4 may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers.
  • the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the indicated activity.
  • Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof which possess the indicated activity. Such regioisomers may be obtained in pure form by standard separation procedures known to those skilled in the art.
  • a method of treating or preventing disorders which are remedied or alleviated by vasopressin receptor agonist includes, but are not limited to, methods of treating, alleviating or preventing diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, and temporary delay of urination whenever desirable in humans or other mammals, which comprises administering to a human or other mammal an effective amount of a compound or a pharmaceutical composition of the invention.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients suffering from coagulation disorders.
  • a composition of the invention is in the form of a unit dose.
  • Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
  • Such unit dose forms may contain from 0.1 to 1000 mg of a compound of the invention and preferably from 2 to 50 mg.
  • Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
  • the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and ⁇ -blocking agents.
  • an acylating agent such as a haloaroyl halide, preferably a bromoaroyl (iodoaroyl) chloride of
  • the acylating species can be a mixed anhydride of the corresponding carboxylic acid, such as that prepared treating said acid with 2,4,6- trichlorobenzoyl chloride in an aprotic organic solvent such as dichloromethane according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979).
  • an aprotic organic solvent such as dichloromethane according to the procedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979).
  • Treatment of said mixed anhydride of general formula (2) with the tricyclic benzodiazepine of formula (1) in a solvent such as dichloromethane and in the presence of an organic base at temperatures ranging from 0°C to the reflux temperatures of the solvent yields the intermediate acylated derivative (3) of Scheme (I).
  • the acylating intermediate of formula (2) is ultimately chosen on the basis of its compatibility with the R 1 , R 2 , R 3 and R 4 groups, and its reactivity with the tricyclic benzodiazepine of formula (1).
  • the desired compounds of formula (I) of Scheme I can be alternatively, prepared by the process shown in Scheme IV.
  • the compounds of formula (I) that are 5-substituted 2-alkylthiophenes can be conveniently prepared as shown in Scheme VI, by reaction of the intermediate bromide of formula (3) with a 2-alkyl thiophene of formula H in the presence of a palladium(O) catalyst, potassium acetate and a solvent such as N,N-dimethyacetamide in a Carius tube at temperatures up to 150°C, essentially according to the procedure of Ohta et al., Heterocycles, 31, 1951 (1990).
  • R2 H
  • R 1 alkyl
  • the subject compounds of the present invention were tested for biological activity according to the following procedures.
  • Vasopressin V 2 Agonist Effects of Test Compounds in Normal Conscious Water- Loaded Rats:
  • mice Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Springfield, NY) of 350-500 g body weight were supplied with standard rodent diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with devices to separate the feces from the urine and containers for collection of urine. A test compound or a reference agent was given at an oral dose of 10 mg/Kg in a volume of 10 mL/Kg. The vehicle used was 20% dimethylsulfoxide (DMSO) in 2.5% preboiled corn starch.
  • DMSO dimethylsulfoxide
  • Step A (4-Bromo-2-chloro-phenyl)-(5H,llH-pyrrolo [2,l-c][l,4] benzodiazepin- 10-yl)-meth anone
  • N,N-dimethylformamide (1 drop) was added to a solution of 4-bromo-2- chlorobenzoic acid (2.30 g) in anhydrous tetrahydrofuran (20 mL).
  • Oxalyl chloride (1.46 g) was added and the mixture was warmed to reflux.
  • the resultant solution was cooled to ambient temperature before beeing evaporated to dryness to give crude 4- bromo-2-chlorobenzoyl chloride as a gold, viscous liquid, which was used without further purification.
  • the reaction mixture was heated to reflux for 17 hours, cooled to ambient temperature, stirred for an additional 26 hours and filtered through Celite, which was then rinsed with ethyl acetate.
  • the combined filtrate was diluted to 140 mL with water/ ethyl acetate (1:1).
  • the ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.
  • the residue (brown foam) was flash chromatographed on silica gel Merck-60 (eluant: hexane-ethyl acetate 4:1) to yield an off-white foam, which was redissolved in dichloromethane. Addition of hexane provided the title compound as a white powder, m.p.
  • the resulting solution was purged with nitrogen for 10 minutes, and then tetrakis (triphenylphosphine) palladium(O) catalyst (0.18 g, 0.16 mmol) was added.
  • the solution was heated at reflux for 41 hours, cooled to ambient temperature and filtered through Celite, which was rinsed with ethyl acetate.
  • the combined filtrate was diluted to 140 mL with water/ ethyl acetate (1:1), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.
  • Step A (4-Bromo-2-methyl-phenyl)-(5,ll-dihydro-pyrido [2,3-b][l,5] benzodiazepin-6-yl)-methanone
  • Step B (2-Methyl-4-thiophen-2-yl-phenyl)-(5,l l-dihydro-pyrido[2,3-b] [1,5] benzodiazepin-10-yl)-methanone
  • Step A (4-Bromo-2-chloro-phenyl)-(5,l 1-dihydro-pyrido [2,3-b][l,5] benzodiazepin-10-yl)-methanone
  • Step B [2-Chloro-4-(5-chloro-thiphen-2-yl)-phenyl]-(5,l 1-dihydro-pyrido [2,3- b][l,5] benzodiazepin-10-yl)-methanone 0.28 solvate with hexane

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP00904244A 1999-02-04 2000-01-07 Thienylbenzoylbenzazepine als vasopressinantagonisten Withdrawn EP1149103A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US24417999A 1999-02-04 1999-02-04
US244179 1999-02-04
PCT/US2000/000358 WO2000046227A1 (en) 1999-02-04 2000-01-07 Thienylbenzoylbenzazepines as vasopressin agonists

Publications (1)

Publication Number Publication Date
EP1149103A1 true EP1149103A1 (de) 2001-10-31

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EP00904244A Withdrawn EP1149103A1 (de) 1999-02-04 2000-01-07 Thienylbenzoylbenzazepine als vasopressinantagonisten

Country Status (7)

Country Link
EP (1) EP1149103A1 (de)
JP (1) JP2002536377A (de)
CN (1) CN1339036A (de)
AR (1) AR028470A1 (de)
AU (1) AU2603000A (de)
CA (1) CA2358891A1 (de)
WO (1) WO2000046227A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1216045A2 (de) * 1999-09-27 2002-06-26 American Cynamid Company Vasopressinagonist enthaltende arzneizubereitung und herstellungsverfahren
BR0208823A (pt) 2001-04-12 2004-03-09 Wyeth Corp Composto, método de tratamento de distúrbios que são remediados ou aliviados pela atividade de agonista de vasopressina em um mamìfero necessitando do mesmo, e, composição farmacêutica
GB201005623D0 (en) 2010-04-01 2010-05-19 Vantia Ltd New polymorph

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521173A (en) * 1995-01-17 1996-05-28 American Home Products Corporation Tricyclic benzazepine vasopressin antagonists
US5849735A (en) * 1995-01-17 1998-12-15 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0046227A1 *

Also Published As

Publication number Publication date
AU2603000A (en) 2000-08-25
WO2000046227A1 (en) 2000-08-10
AR028470A1 (es) 2003-05-14
CA2358891A1 (en) 2000-08-10
CN1339036A (zh) 2002-03-06
JP2002536377A (ja) 2002-10-29

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