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
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
• • 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

Definitions

• This invention concerns benzoheterocyclic carboxyamides, particularly pyridobenzodiazepine and pyridobenzoxazepine carboxyamides, 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)).
• 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.
• vasopressin V 2 receptors 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 no or very little 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 receptors, exerts vasoconstricting effects so as to raise blood pressure.
• a vasopressin V la receptor antagonist will counteract this effect.
• Vasopressin and vasopressin 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. Haematoi, 27, 363-364 (1974); David, Regulatory Peptides, 45, 311-317 (1993); Burggraaf et al., Cli. Sci., 86, 497-503 (1994)).
• t-PA tissue-type plasmin
• vasopressin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit partial agonist activity.
• Non-peptidic vasopressin antagonists have recently been disclosed. Albright et al. describe tricyclic azepines as vasopressin and oxytocin antagonists in U.S. Patent 5,516,774 (1996); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in J.P.
• 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.
• Albright et al. broadly disclose a subset of tricyclic pyrido benzodiazepine and pyridooxa/epine indole carboxyamides of the present application, as V, and/or V, vasopressin receptor antagonists and oxytocin receptor antagonists in U.S. Patent 5,512,563 (1996); U.S. Patent 5, 686.445 ( 1997); U.S. Patent 5.736,538 ( 1998); EP 640592 Al (1995); WO 97/47624 Al : and WO 97/47625 Al, inter alia.
• indolc carboxyamides of general structure 16b have been found unexpectedly to be vasopressin V, receptor agonists in vivo, and thus possess different biological profile and clinical utility from those originally disclosed.
• vasopressin V vasopressin V
• receptor agonists receptor agonists in vivo
• they unexpectedly cause reabsorption of water, i.e. they reduce urine volume and increase urine osmolality.
• 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 reabso ⁇ tion of water. They demonstrate no vasopressin V la receptor agonist effects and, thus, do not raise blood pressure. In contrast, the prior art compounds (except some in WO 9534540-A) are described as vasopressin antagonists at both the V ld and V 2 receptors.
• This invention relates to novel and known compounds selected from those of formula (I):
• X, Y and Z independently, are selected from a group consisting of O, S, CH, CH., N, or NR 4 ;
• W is NR 5 or O
• R, and R 2 are independently, hydrogen, straight chain alkyl (C,-C 6 ), branched chain alkyl (C 3 -C 7 ), cycloalkyl (C 3 -C 7 ), alkoxyalkyl (C 2 -C 7 ), halogen, straight or branched chain alkoxy (C,-C 6 ), hydroxy, CF 3 , or perfluoroalkyl (C 2 -C 6 );
• R 3 is hydrogen or a straight chain alkyl group (C r C 6 ), branched chain alkyl (C 3 -C 7 ), cycloalkyl (C 3 -C 7 ), alkoxyalkyl (C 2 -C 7 ), or hydroxyalkyl (C,-C 6 );
• R 4 is selected from hydrogen, or lower alkyl (C,-C 6 );
• R 5 is independently selected from hydrogen, acyl (C 2 -C 6 ), straight chain alkyl (C,-C 6 ), or branched chain alkyl (C 3 -C 7 );
• R 6 is selected from hydrogen or halogen; or a pharmaceutically acceptable salt thereof.
• R R 2 , R 3 , R 4 , and R 5 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.
• the pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: citric, lactic, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
• the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier or excipient.
• 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. Also according to the present invention there are provided processes for producing the compounds of the present invention.
• a pyridobenzodiazepine (benzoxazepine) of formula (3, wherein W is O or NR 5 , and R,, R 2 , R 3 , and n are as defined above) is treated with an appropriately activated heteroaryl carboxylic derivative of formula (2) to provide the desired compounds of formula (I) wherein R R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, Z, W and n are as defined above.
• an inorganic base such as potassium carbonate in a polar, aprotic solvent such as N,N- dimethylformamide
• an organic base such as 4-dimethylamino pyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from -40° C to 50°C.
• the acylating species of formula (2) can be a mixed anhydride of the corresponding carboxylic acid, such as that prepared by 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).
• the activation of the carboxylic acids of general formula (1) can be carried out by reacting said acids with other peptide coupling reagents known to those skilled in the art, in an organic aprotic solvent such as dichloromethane, tetrahydrofuran, N.N-dimethylformamide, or the like, at temperatures ranging from - 40° C to 120° C .
• the activating reagent for the carboxylic acids of formula (1) is ultimately chosen on the basis of its compatibility with the R 4 and R 5 groups, and its reactivity with the tricyclic pyridobenzodiazepine (benzoxazepine) of formula (3).
• W is NR 5 , and R 5 is other than hydrogen; and R.' R 2 , R 3 , X, Y, Z and n are as defined above, can be prepared by alkylation or acylation of a compound of formula (I, wherein W is NH, and R 4 is other than hydrogen ) of Scheme 1, as outlined in
• Scheme 1 are alkylated by treatment with a base such as sodium (or potassium) hydride and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic solvent such as N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C to 80°C to yield compounds of formula (I) wherein W is NR 5 and R 5 is alkyl, R 4 is other than hydrogen, and R R 2 , R 3 , X, Y, Z and n are as defined above.
• a base such as sodium (or potassium) hydride and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic solvent such as N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C to 80°C to yield compounds of formula (I) where
• the compounds of formula (I, W is NH, and R 4 is other than hydrogen) of Scheme 1 are acylated by treatment with a carboxylic acid halide or a carboxylic acid anhydride in the presence of an amine base such as pyridine or a trialkylamine such as triethylamine in an aprotic solvent such as dichloromethane or with no addition of solvent when pyridine is used as the base, at temperatures ranging from 40°C to ambient, to yield compounds of formula (1) wherein W is NR 5 and R 5 is acyl, R 4 is other than hydrogen, and R,, R,, R 3 , X, Y, Z and n are as defined above.
• the subject compounds of the present invention were tested for biological activity according to the following procedures.
• Vasopressin V 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
• Example 1 (5,11-Dihydro-pyrido r2,3-blfl,51 benzodiazepin-10-yl)-(l-methyl-lH-indol-5- yl)-methanone
• Step B l-Methyl-indole-5-carboxylic acid
• reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the solvent and flash-chromatography of the residue (on silica gel Merck- 60, hexane-ethyl acetate 4:1) provided the title compound as a white solid (0.260 g), m.p. 147-148°C, upon recrystallization from diethyl ether.

Landscapes

• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (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)
• Diabetes (AREA)
• Hematology (AREA)
• Endocrinology (AREA)
• Urology & Nephrology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=22923710

Family Applications (1)

Country Status (6)

Families Citing this family (3)

Family Cites Families (2)

• 2000
  • 2000-01-13 EP EP00906916A patent/EP1149097A2/de not_active Withdrawn
  • 2000-01-13 WO PCT/US2000/000886 patent/WO2000046225A2/en not_active Application Discontinuation
  • 2000-01-13 JP JP2000597295A patent/JP2002536375A/ja active Pending
  • 2000-01-13 AU AU28496/00A patent/AU2849600A/en not_active Abandoned
  • 2000-01-13 CN CN00803455A patent/CN1339035A/zh active Pending
  • 2000-01-13 CA CA002358895A patent/CA2358895A1/en not_active Abandoned

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events