WO1999006403A1 - Tricyclic vasopressin agonists - Google Patents
Tricyclic vasopressin agonists Download PDFInfo
- Publication number
- WO1999006403A1 WO1999006403A1 PCT/US1998/015487 US9815487W WO9906403A1 WO 1999006403 A1 WO1999006403 A1 WO 1999006403A1 US 9815487 W US9815487 W US 9815487W WO 9906403 A1 WO9906403 A1 WO 9906403A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- formula
- compound
- methyl
- chain alkyl
- Prior art date
Links
- 0 C[n]1nc(*)c(*)c1* Chemical compound C[n]1nc(*)c(*)c1* 0.000 description 17
- OXHNLMTVIGZXSG-UHFFFAOYSA-N C[n]1cccc1 Chemical compound C[n]1cccc1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- MWZDIEIXRBWPLG-UHFFFAOYSA-N C[n]1ncnc1 Chemical compound C[n]1ncnc1 MWZDIEIXRBWPLG-UHFFFAOYSA-N 0.000 description 1
- JWAWEQBUZOGIBZ-UHFFFAOYSA-N C[n]1nncc1 Chemical compound C[n]1nncc1 JWAWEQBUZOGIBZ-UHFFFAOYSA-N 0.000 description 1
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
Definitions
- This invention concerns tricyclic pyrido compounds, or pharmaceutical salts thereof, which act as vasopressin agonists, as well as methods of treatment and pharmaceutical compositions utilizing the 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 it activates V la receptors on blood vessels causing vasoconstriction to raise blood pressure and vasopressin V 2 receptors of the nephron of the kidney causing retention 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.
- 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 la 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.
- t-PA tissue-type plasminogen activator
- Non-peptidic vasopressin antagonists have recently been disclosed.
- Albright et al. describe tricyclic diazepines as vasopressin and oxytocin antagonists in U.S. Patent 5,516,774 (1996); 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; Albright et al., disclose tricyclic benzazepine derivatives as vasopressin antagonists in U.S. Patent 5,512,563 (1996); 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
- vasopressin agonist 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.
- the compounds of this invention are non-peptidic and have a good oral bioavailability. They are selective vasopressin V 2 agonists, and have no V la agonist effects so they do not raise blood pressure. In contrast, the prior art compounds (except some in WO 9534540-A) are vasopressin antagonists.
- This invention relates to novel compounds selected from those of Formula (I):
- W is O, or NR 6
- a and B are, independently, carbon or nitrogen; — 9
- R , R and R are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
- R 4 is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, optionally substituted aralkyl of 7 to 12 carbon atoms, or an acyl substituent selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, arylalkanoyl having an alkane chain of from 1 to 6 carbon atoms, aroyl or heteroaroyl of 7 to 13 carbon atoms;
- R is hydrogen, acyl of 2 to 6 carbon atoms, straight chain alkyl of 1 to 6 carbon atoms, or branched chain alkyl of 3 to 7 carbon atoms;
- X and Y are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, halogen, straight or branched chain alkoxy of 1 to 6 carbon atoms, hydroxy, CF , or perfluoroalkyl of 2 to 6 carbons;
- Z is hydrogen or a straight chain alkyl group of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen, alkoxyalkyl of 2 to 7 carbons, or hydroxyalkyl of 1 to 6 carbons, or CH 2 NR 7 R 8 ;
- R and R are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, aryl, or arylalkyl; or taken together with the nitrogen they form a five or six membered ring optionally containing one or more additional heteroatoms, preferably selected from N, S or O, such as
- R 9 is independently, hydrogen, a silyl containing group, or a lower alkyl of 1 to 6 carbons.
- R is a straight chain alkyl of 1 to 6 carbon atoms
- R is preferably a moiety selected from:
- R and R is hydrogen and the other is a straight chain alkyl of 1 to 6 carbon atoms or branched chain alkyl of 3 to 7 carbon atoms, more preferably it is methyl,
- R is hydrogen and R is a straight chain alkyl of 1 to 6 carbon atoms or branched chain alkyl of 3 to 7 carbon atoms, more preferably it is methyl.
- R , R and R are each preferably hydrogen, a straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms or perfluoroalkyl of 1 to 6 carbons, more preferably hydrogen, methyl, t-butyl or trifluoromethyl.
- Preferred embodiments are those wherein two of R , R and R are hydrogen and the third is a straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms or perfluoroalkyl of 1 to 6 carbons, more preferably where the third is selected from methyl, t-butyl and trifluoromethyl.
- R is preferably hydrogen, a straight chain alkyl of 1 to 6 carbon atoms or a branched chain alkyl of 3 to 7 carbon atoms, more preferably hydrogen or methyl.
- R is preferably hydrogen or a straight chain alkyl of 1 to 6 carbon atoms, more preferably hydrogen or methyl.
- X and Y are each preferably hydrogen, halogen, perfluoroalkyl of 2 to 6 carbons, straight chain alkyl of 1 to 6 carbon atoms or a branched chain alkyl of 3 to 7 carbon atoms, more preferably hydrogen, chloro, bromo, fluoro, trifluoromethyl, or methyl.
- X and Y is hydrogen, more preferably X is hydrogen.
- Z is preferably hydrogen.
- R and R are each preferably hydrogen or a straight chain alkyl of 1 to 6 carbon atoms, more preferably hydrogen or methyl.
- W is O and A, B, X, Y, Z and R -R , 10 are as defined above; and W is NR and A, B, X, Y, Z and R -R are as defined above.
- R is alkanoyl of 2 to 7 carbon atoms or a moiety selected from the group of:
- R 2 , R 3 and R 5 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
- R 4 is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, optionally substituted aralkyl of 7 to 12 carbon atoms, or an acyl substituent selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl or heteroaroyl of 7 to 12 carbon atoms, optionally substituted with one or two alkyl groups of 1 to 6 carbon atoms, or arylalkanoyl of 1 to 6 carbon atoms;
- R is hydrogen, acyl of 2 to 6 carbon atoms, straight chain alkyl of 1 to 6 carbon atoms, or branched chain alkyl of 3 to 7 carbon atoms;
- X and Y are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, halogen (including chlorine, bromine, fluorine, and iodine), straight chain or branched chain alkoxy of 1 to 6 carbons, hydroxy, CF 3 , or perfluoroalkyl of 2 to 6 carbons;
- Z is hydrogen or a straight chain alkyl group of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen, alkoxyalkyl of 2 to 7 carbons, hydroxyalkyl of 1 to 6 carbons, or CH 2 NR 7 R 8 ;
- R 7 and R 8 are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, aryl or arylalkyl; or taken together with the nitrogen they form a five or six membered ring optionally containing one or more additional heteroatoms, preferably selected from N, S or O, most preferably selected from N or O, such as
- R 10 is a straight chain alkyl of 1 to 6 carbon atoms
- alkyl as a moiety or part of a moiety e.g. alkoxy, - includes straight and branched chain alkyl groups e.g. methyl, ethyl, propyl, i-propy, n-butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl and heptyl groups.
- cycloalkyl includes saturated and unsaturated cyclic groups, e.g.
- cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclpropenyl, cyclobutenes, cyclopentenes, cyclohexenes and cycloheptenes.
- Saturated cycloalkyl groups are preferred.
- aryl groups include, for example, phenyl and naphthyl which can be substituted, independently, with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF 3 , or phenyl, the phenyl substituent being further optionally substituted with one or more substituents selected from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbons, branched chain alkyl of 3 to 7 carbons, or CF 3 .
- the preferred aryl groups herein are phenyl, biphenyl, and naphthyl, substituted or unsubstituted.
- aroyl groups include, for example, benzoyl and naphthoyl which can be substituted, independently, with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF 3 , or phenyl, the phenyl substituent being further optionally substituted with one or more substituents selected from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbons, branched chain alkyl of 3 to 7 carbons, or CF 3 .
- the preferred aroyl groups herein are benzoyl, (phenyl)benzoyl and napthoyl, substituted or unsubstituted.
- heteroaroyl refers to a five or six membered heterocyclic ring directly bonded to a carbonyl radical, and containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, for example thiophene carbonyl or pyridine carbonyl.
- the heteroaryl herein can be substituted, independently, with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbons, or CF 3 .
- arylalkanoyl refers to groups such as benzyl carbonyl or naphthylmethyl carbonyl containing an alkyl group of 1 to 6 carbon atoms directly bonded to a carbonyl radical, wherein the alkyl group is terminally substituted by an aryl, and the aryl group is as defined hereinbefore.
- aralkyl or arylalkyl refers to groups such as benzyl or naphthylmethyl containing an alkyl residue, preferably a lower alkyl residue of from 1 to 6 carbon atoms, most preferably from 1 to 3 carbon atoms, terminally substituted by an aryl, wherein the aryl group is as defined hereinbefore.
- halogen is meant to include chlorine, bromine, fluorine and iodine.
- the preferred compounds of this invention include:
- R , R , X, Y, and Z 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; as well as other mixtures of the 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.
- a method of treating diseases, conditions or disorders in which vasopressin agonist activity is desired comprising administering to a human or other mammal in need thereof an effective amount of a compound or a pharmaceutical composition of this invention.
- the present methods of treatment include those for diseases, conditions or disorders which make it desirable to release factor VIII and von Willebrand factor into the circulatory system, release tissue-type plasminogen activator (t-PA) in the blood circulation, or affect the renal conservation of water and urine concentration.
- Such methods of treatment include, but are not limited to, treatments for diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, or bleeding and coagulation disorders in humans or other mammals.
- the methods herein include facilitation in humans or other mammals of temporary delay of urination, which may also be described as controlling or treating the inability to temporarily delay urination, whenever desirable.
- This method is understood to include treatments facilitating the temporary delay of urination which are separate from and not included in the treatment of the conditions known as nocturnal enuresis and nocturia.
- 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 or excipient.
- 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 heart failure.
- 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.
- compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
- the 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.
- the compounds of the present invention may be prepared according to one of the general processes outlined below.
- the compounds of general formula (I) wherein W is oxygen or NR and R 6 is hydrogen, can be conveniently prepared as shown in Scheme I.
- an inorganic base such as potassium carbonate
- a polar, aprotic solvent such as dimethylformamide
- an organic base such as 4-dimethylaminopyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures
- 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).
- a compound of formula (3) is then treated with the sodium (potassium or lithium) salt of an appropriately substituted heterocycle of formula (4, wherein R is selected from the a, b, c, d, 1, n, or o group of heterocycles defined above) in an aprotic organic solvent such as dimethylformamide (or tetrahydrofuran) at temperatures ranging from ambient to the reflux temperature of the solvent, to yield a compound of general formula (I), wherein W is oxygen or NH, and A, B, X, Y, Z, R 2 , R 3 , and R 5 are as defined above, R is hydrogen, and R 1 is an heterocyclic moiety selected from the a, b, c, d, 1, n or o group of heterocycles defined above and illustrated below.
- an aprotic organic solvent such as dimethylformamide (or tetrahydrofuran
- the sodium (potassium or lithium) salts of the heterocycle of formula (4, wherein R is selected from the a, b, c, d, 1, n or o group of heterocycles defined above) of Scheme I are prepared by treatment of said heterocycle with a strong base such as sodium, potassium or lithium hydride or a metal alkoxide at temperatures ranging from -40°C to ambient in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran.
- a strong base such as sodium, potassium or lithium hydride or a metal alkoxide
- an appropriately substituted fluoroaryl or fluoro(chloro)heteroaryl carboxylic acid of formula (5) is esterified using methods known in the art, such as treatment with oxalyl chloride or thionyl chloride in an alcohol solvent such as methanol, in the presence of a catalytic amount of dimethylformamide; or by condensation with an alcohol such as methanol, in the presence of an acid catalyst such as para-toluenesulfonic acid at temperatures ranging from ambient to reflux temperature of the solvent.
- the resulting ester of formula (6) is reacted with the sodium (potassium or lithium) salt of an appropriately substituted heterocycle of formula (4, wherein R is selected from the a, b, c, d, l, n or o group of heterocycles defined above) in a polar aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to reflux temperature of the solvent, to yield an intermediate ester of general formula (7).
- a polar aprotic organic solvent such as dimethylformamide
- the intermediate carboxylic acid (8) is then converted into an acylating agent, preferably an acid chloride or a mixed anhydride of general formula (9) using any of the procedures described hereinbefore.
- an acylating agent preferably an acid chloride or a mixed anhydride of general formula (9) using any of the procedures described hereinbefore.
- a fluoroaryl or fluoro(chloro)heteroaryl nitrile of formula ( 10) is reacted with the sodium (potassium or lithium) salt of an appropriately substituted heterocycle of formula (4, wherein R is selected from the a, b, c, d, 1, n or o group of heterocycles defined above) in a polar aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to the reflux temperature of the solvent, to yield an intermediate of general formula (11).
- Condensation of (10) with the intermediate (4) leads to a variable ratio of regioisomers of general formula (11) which are separated by means of chromatography and/or crystallization.
- Hydrolysis of the intermediate nitrile of formula (11, wherein Y is not CF 3 ) is preferentially carried out with an inorganic acid such as dilute sulfuric acid, at temperatures ranging from ambient to 60°C.
- hydrolysis of the nitrile (11) can be carried out by heating in the presence of a strong alkaline base such as sodium hydroxide in an alcohol solvent such as ethanol, with or without a phase transfer catalyst such as benzyldimethyltetradecyl ammonium chloride.
- a strong alkaline base such as sodium hydroxide in an alcohol solvent such as ethanol
- a phase transfer catalyst such as benzyldimethyltetradecyl ammonium chloride.
- the intermediate substituted carboxylic acids of formula (8, wherein R 1 is not b or d) of Scheme II can be prepared according to the process described in Scheme IV by sequential treatment of a nitrile of formula (11, wherein A and B are carbon, and R is an heterocyclic moiety selected from the a, c, e, 1, n and o, but not b or d group of heterocycles defined above) with basic hydrogen peroxide in dimethylsulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949 (1989); followed by hydrolysis of the resulting amides of formula (12) preferably by treatment with dilute sulfuric acid and sodium nitrite according to the procedure of Hales et al, Tetrahedron, 51, 7403 (1995).
- R 1 a,c,e,l,n,o but not b or d)
- a base such as sodium (or potassium) hydride and an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide)
- an aprotic solvent such as dimethylformamide or tetrahydrofuran
- NR and R is an alkyl or acyl residue
- A, B, X, Y, Z, R , R , and R are as defined above, and R is an heterocyclic moiety selected from the group consisting of a, b, c, d, 1, n or o, defined above and illustrated below.
- R 6 alkyl or acyl residue
- a fluoroaryl or fluoro(chloro)heteroaryl intermediate of formula (3) of Scheme I (wherein W is NH) is reacted with the sodium (potassium or lithium) salt of an appropriately substituted heterocycle of formula (4, wherein R 1 is selected from the a, b, c, d, I, n or o group of heterocycles defined above) in a polar aprotic organic solvent such as dimethylformamide at temperatures ranging from ambient to the reflux temperature of the solvent, generating an intermediate of general formula (I, wherein W is NH) which without prior isolation, is further alkylated (or acylated) using the reaction conditions described hereinbefore to provide the desired compound of formula (I, wherein W is NR , and R is an alkyl or acyl residue).
- a polar aprotic organic solvent such as dimethylformamide
- This process leads also to a variable ratio of regioisomers of general formula (I), wherein W is NR 6 , and R 6 is an alkyl or acyl residue; A, B, X, Y, Z, R 2 , R 3 , R 4 and R are as defined above, and R is an heterocyclic moiety defined as in Scheme VI.
- the regioisomers of formula (I) can be separated by means of chromatography and/or crystallization.
- an appropriately substituted haloaryl carboxylic acid ester preferably a bromo (or iodo)phenyl methylester of formula (17, wherein A and B are carbon
- a dialkylamino propyne in the presence of a catalyst such as bis(triphenylphosphine) palladium (II) chloride and copper (I) iodide in an organic base such as triethylamine as the solvent, and at temperatures ranging from ambient to 80°C essentially according to the procedures of Alami et al., Tetrahedron Lett., 34, 6403 (1993), and of Sanogashira et al., Tetrahedron Lett., 4467 (1975), to provide the substituted acetylene intermediate of general formula (18).
- the intermediate (18) is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (see Albini, Synthesis, 263, (1993)) or with a dioxirane reagent (see Murray, Chem. Rev. , 1187 (1989)) in an aprotic organic solvent such as dichloromethane at temperatures below ambient.
- the intermediate N-oxide is not isolated but is rearranged in situ to an enone of general formula (19) by heating in a hydroxylic solvent such as methanol or by using any of the procedures of Dushin et al.
- This procedure provides a novel synthesis of enaminone compounds from propargylic amines (or their N-oxides) in hydroxylic solvents, which influence the ultimate outcome of the reaction.
- This new method of enaminone synthesis provides a convenient alternative to existing methods and further extends the range of starting materials that can be converted into enaminone products.
- the intermediate (22) is then converted into an acylating species, preferably an acid chloride (bromide or iodide) or a mixed anhydride of formula (23) by procedures analogous to those described hereinbefore.
- the acylating agent (23) is then used to acylate a pyridobenzodiazepine (or benzoxazepine) of formula (1) by any of the procedures described hereinbefore to yield the desired compound of formula (I), wherein W is O or NH, A and B are carbon, X, Y, Z, and R are as defined
- R is hydrogen, and R is an heterocyclic moiety selected from the g group of heterocycles defined above and illustrated below.
- R is hydrogen, and R is an heterocyclic moiety selected from the f group of heterocycles defined above.
- the intermediate ester of formula (24, wherein R is H, A and B are carbon) is 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 dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C to 80°C to yield a mixture of regioisomers of formulas (20) and (21) in a variable ratio.
- a base such as sodium or potassium hydride
- an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic solvent such as dimethylformamide or tetrahydrofuran
- the major regioisomer of formula (21) is separated by chromatography and/or crystallization and is subsequently hydrolyzed to the desired carboxylic acid of formula (25), which is then converted to an acylating agent, preferably an acid chloride or a mixed anhydride by procedures analogous to those described hereinbefore.
- the acylating species of formula (26) is then used to acylate a pyridobenzodiazepine (or benzoxazepine) of formula (1) to yield the desired compound of formula (I), wherein W is O or NH, A and B are carbon, X, Y, Z, and R are as defined above, R is hydrogen, and R is an heterocyclic moiety selected from the f group of heterocycles defined above and illustrated below.
- An appropriately substituted malondialdehyde of formula (27) is treated first with a hydrazine in acetic acid at temperatures ranging from ambient to the reflux temperature of the solvent and the intermediate pyrazole is oxidized preferably with potassium permanganate in a basic aqueous solution at temperatures ranging from ambient to the reflux temperature of the solvent to yield a carboxylic acid intermediate of formula (28).
- the acid (28) is converted into an acylating agent, preferably an acid chloride (bromide or iodide) or a mixed anhydride by procedures analogous to those described hereinbefore.
- the acylating agent of formula (29) is finally reacted with a pyridobenzodiazepine (or benzoxazepine) of formula (1) to yield compounds of general formula (I) wherein W is O or NH, A and B are carbon, X, Y, Z, and R 4 are as defined above, and R 1 is an heterocyclic moiety selected from the h group of heterocycles defined above and illustrated below.
- Scheme X are either available commercially, or are known in the art, or can be readily prepared by procedures analogous to those in the literature for known compounds, such as those of Knorr et al., J. Org. Chem., 49, 1288 (1984) and
- organotin reagent of formula (31) is reacted in a Stille coupling reaction with an appropriately substituted aryl(heteroaryl) halide, preferably a bromide (or iodide) of formula (3 4 ) in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium (0) and copper (I) iodide in an organic aprotic solvent such as dimethylformamide at temperatures ranging from ambient to 150°C, essentially according to procedures analogous to those of Farina et al., J. Org. Chem., 59, 5905 (1994).
- a catalyst such as tetrakis(triphenylphosphine) palladium (0) and copper (I) iodide
- organic aprotic solvent such as dimethylformamide
- organotin reagents of formula (31) of Scheme XI wherein R is preferably an alkyl group are conveniently prepared by metallation of a 4-bromo-N- alkylpyrazole of formula (30) with a trialkyltin halide, preferably a tributyltin chloride (or bromide) in the presence of a metallating agent such as n-butyl lithium in an aprotic organic solvent such as diethyl ether at temperatures ranging from -40° C to ambient according to procedures analogous to those found in Martina et al., Synthesis, 8, 613 (1991).
- a metallating agent such as n-butyl lithium
- aprotic organic solvent such as diethyl ether
- N-alkyl substituted pyrazoles of formula (30) of Scheme XI are conveniently prepared from a 4-bromopyrazole by alkylation with an alkyl halide, preferably an alkyl chloride (bromide or iodide) in the presence of a base such as
- alkylation of the 4-bromopyrazole can be carried out with an alkylating agent mentioned above, and a strong alkaline base such as sodium hydroxide in the presence of a phase transfer catalyst, such as benzyldimethyltetradecyl ammonium chloride or benzyltrimethylammonium chloride (see Jones, Aldrichimica Acta, 9, 35 (1976)).
- a phase transfer catalyst such as benzyldimethyltetradecyl ammonium chloride or benzyltrimethylammonium chloride (see Jones, Aldrichimica Acta, 9, 35 (1976)).
- the preferred aryl (heteroaryl) iodides of formula (34) of Scheme XI are conveniently prepared by diazotization of the corresponding substituted anilines of formula (33) followed by reaction of the corresponding diazonium salt with iodine and potassium iodide in aqueous acidic medium essentially according to the procedures of Street et al., J. Med. Chem., 36, 1529 (1993) and of Coffen et al., J. Org. Chem., 49, 296 (1984).
- the compounds of general formula (I) may be prepared also according to one of the general processes outlined below.
- the preferred substituted acetylaroyl (heteroaroyl)chlorides of formula (37) of Scheme XII are conveniently prepared by treating the corresponding carboxylic acids with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0°C to 40°C.
- dialkylamide dialkylacetals of formula (39) of Scheme XII are either available commercially, or are known in the literature, or can be conveniently prepared according to procedures analogous to those in the literature for the known compounds (see Kantlehner, Chem. Ber., 105, 1340 (1972).
- a pyridobenzodiazepine (or benzoxazepine) of formula (1) is treated with an appropriately substituted bromoaroyl(heteroaroyl) halide, preferably a bromoaroyl(heteroaroyl) chloride of formula (42) according to any of the procedures described hereinbefore, to yield the acylated intermediate of formula (43).
- the intermediate (43) is subsequently coupled with a monosubstituted acetylene of formula (53, wherein R is preferably trimethylsilyl or lower alkyl of 1 to 6 carbon atoms) in the presence of pyridine and a catalyst such as bis(triphenylphosphine) palladium (II) chloride and copper (I) iodide in an organic base such as triethylamine as the solvent, in a sealed pressure tube at temperatures ranging from ambient to 100°C essentially according to the procedure of Martinez et al., J. Med. Chem., 52, 3491 (1987).
- a catalyst such as bis(triphenylphosphine) palladium (II) chloride and copper (I) iodide in an organic base such as triethylamine as the solvent
- acetylene intermediate of formula (44) is then hydrated by treatment with 1% sulfuric acid in an aprotic organic solvent such as tetrahydrofuran saturated with mercury (II) sulfate at ambient temperature essentially according to the procedure of Reed et al, J. Org. Chem., 52, 3491 (1987) to provide the desired acyl compound of formula (38) wherein W is O or NH, and A, B, X, Y, and Z are as defined above, and R is hydrogen or lower alkyl of 1 to 6 carbon atoms.
- compound (44) where R 9 is trimethylsilyl is treated with n- tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran, to afford compound (44) where R 9 is hydrogen. .
- the preferred acylating agents of formula (42) of Scheme XIII are conveniently prepared by treating an appropriately substituted aryl(heteroaryl) carboxylic acid of formula (41) with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0°C to 40°C.
- the intermediate acetyl compounds (38) of Scheme XII can be prepared also by the Stille coupling of a bromo aryl (heteroaryl) compound of formula (43) of Scheme XIII with an ( ⁇ -alkoxyvinyl)trialkyltin preferably an ( ⁇ -ethoxyvinyl)tributyltin of formula (45), in the presence of a catalytic amount of bis(triphenylphosphine) palladium (II) chloride in an aprotic organic solvent such as toluene at temperatures ranging from ambient to the reflux temperature of the solvent, essentially according to the procedure of Kosugi et al., Bull. Chem. Soc. Jpn., 60, 767 (1987).
- the preparation of the acetyl compound (38) can also be accomplished via the palladium-catalyzed arylation of a vinyl alkylether such as vinyl butylether, with the aryl halide intermediate of formula (43) according to the procedure of Cabri et al., Tetrahedron Lett., 32, 1753 (1991).
- a pyridobenzodiazepine (or benzoxazepine) of formula (1) is treated with an appropriately substituted cyanoaroyl (heteroaroyl) halide, preferably a cyanoaroyl(heteroaroyl) chloride of formula (46) according to any of the procedures described hereinbefore, to yield an intermediate nitrile of formula (54) which in turn, is converted to an amide intermediate of general formula (47) by treatment with an inorganic acid such as sulfuric acid at temperatures ranging from ambient to 50°C.
- an inorganic acid such as sulfuric acid
- Scheme XVI Another preferred process for the preparation of the intermediate amide of formula (47, where A, B are carbon) of Scheme XV is outlined in Scheme XVI.
- An appropriately substituted aryl nitrile of formula (49, A and B are carbon) is hydrated with basic hydrogen peroxide in dimethyl sulfoxide essentially according to the procedure of Katritzky et al., Synthesis, 949 (1989), to provide the intermediate amide (50).
- Subsequent hydrolysis of the ester moiety gives the carboxylic acid intermediate (51) which is then converted into the acylating species of formula (52) by using any of the procedures described hereinbefore.
- Treatment of a pyridobenzazepine (or benzoxazepine) of formula (1) with (52) using any of the procedures described hereinbefore provides the desired intermediate amide (47, where A and B are carbon).
- an appropriately substituted amide of formula (50) of Scheme XVI is treated with a dialkylamide dialkylacetal such as a dimethylamide dimethylacetal of formula (39, where alkyl is CH 3 ) at temperatures ranging from 0°C to 100°C to provide the intermediate of formula (55).
- a dialkylamide dialkylacetal such as a dimethylamide dimethylacetal of formula (39, where alkyl is CH 3
- a substituted hydrazine of formula (36) in acetic acid at temperatures ranging from ambient to reflux, yields the desired intermediate triazole ester of formula (56).
- the ester (56) is subsequently hydrolyzed to the carboxylic acid of formula (57, wherein R 1 is an heterocyclic moiety selected from the e or i group of heterocycles defined above, and R is not hydrogen) which is then converted to an acylating agent, preferably an acid chloride or a mixed anhydride of formula (58) by procedures analogous to those described hereinbefore.
- an acylating agent preferably an acid chloride or a mixed anhydride of formula (58) by procedures analogous to those described hereinbefore.
- the acylating species (58) is used to acylate a pyridobenzodiazepine (or benzoxazepine) of formula (1) to yield the desired compound of formula (I) wherein W is O or NH, A, B, X, Y, Z and R 2 are as defined above, R 1 is an heterocyclic moiety selected from the e and i group of heterocycles defined above and illustrated below, and R is not hydrogen.
- the acylating agent (62) is used to acylate a pyridobenzodiazepine (or benzoxazepine) of formula (1) to yield the desired compound of formula (I) wherein W is O or NH, X, Y, Z, A, B and R are as defined above, R is a heterocyclic moiety selected from the e or i group of heterocycles defined above, and R is not hydrogen.
- a compound of general formula (I) of Scheme XV wherein W is O or NH, A, B, X, Y, Z and R 2 are as defined above, R 1 is an heterocyclic moiety selected from the e and i group of heterocycles defined above and illustrated below, and R is hydrogen, can be conveniently prepared from a compound of formula (I) of Scheme XVIII wherein R is an optionally substituted aralkyl group, preferably a p-methoxybenzyl group by using a number of procedures which include hydrogenolysis or treatment with a strong acid such as trifluoroacetic acid at temperatures ranging from 0°C to reflux temperature, essentially according to the procedure of Buckle et al., J. Chem. Soc. Perkin Trans. 1, 627 (1982).
- the compounds of general formula (I) wherein R is an heterocyclic moiety selected from the group e, f, g, h, i, j, or k, and W is NR 6 and R is other than hydrogen, can be preferably prepared by alkylation or acylation of a compound of formula (I, W is NH) of Schemes VIII, IX, X, XII, and XV, as outlined in Scheme XX. SCHEME XX
- a base such as sodium (or potassium) hydride
- an alkylating agent such as an alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C to 80°C
- a nitrile of formula (54, W is NH) of Scheme XV can be 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 dimethylformamide or tetrahydrofuran at temperatures ranging from
- Conversely (54) can be 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 (63, W is NR and R is
- R alkyl or acyl, and R is selected from the group m of heterocycles defined in
- the subject compounds of the present invention were tested for biological activity according to the following procedures.
- 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
- the urinary osmolality should increase proportionally.
- two rats were used for each compound. If the difference in the urine volume of the two rats was greater than 50%, a third rat was used. The results of this study are shown in Table I, below. Table 1
- Diborane dimethylsulfide complex 35 mL was added via syringe to a suspension of 6,11 -dihydro-5H-pyrido[2,3-b][l,5]benzodiazepin-5-one 1: 1 salt with hydrochloric acid of Step A (25 g, 0.1 mole) in dioxane (230 mL) under nitrogen.
- the mixture was sonicated overnight at room temperature and then evaporated to dryness in vacuo.
- the green residue was treated with cold 2N hydrochloric acid and diethyl ether.
- the cold aqueous layer was basified with 50% aqueous sodium hydroxide (to pH 9) and the basic layer extracted with ethyl acetate.
- the organic extracts were dried over anhydrous potassium carbonate, and evaporated to dryness to yield a burgundy solid (24.35 g, 61.4%).
- This crude material was purified by trituration with diethyl ether. The solid was collected, washed and dried in vacuo.
- Step D (2-Chloro-4-fluorophenyl)-(5,ll-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone
- the crude material was purified by flash chromatography (on silica Merck-60, hexane- ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g).
- the pure material is an off-white crystalline solid, which is used as such in the next step.
- Step E [2-Chloro-4-(3-methyl-pyrazol-l-yl)-phenyl]-(5,ll-dihydro-pyrido [2,3- b] [1,5] benzodiazepin-6-yl)-methanone
- Step B [2-Bromo-4-fluorophenyl]-(5,ll-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone
- Step B (5.15 g, 26.1 mmol) in dimethylformamide (70 mL) under nitrogen was added potassium carbonate (7.95 g, 57.51 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-bromo-4-fluorobenzoyl chloride of Step A (31.37 mmol) in dimethylformamide (30 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give a brown solid foam. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column.
- the mixture was placed in an oil bath (preheated at 130°C) for 40 minutes, cooled and partitioned between water and ethyl acetate.
- the organic extracts were dried over magnesium sulfate and evaporated to dryness.
- the crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the less polar title compound (3.87 g) along with a mixture of 3- and 5- methylpyrazole regioisomers (0.860 g).
- the title compound (3.5 g, 51%) crystallized by sonication from hexane-ethanol, m.p. 208-209°C (dec).
- Step B (5,ll-Dihydro-pyrido[2,3-b] [l,5]benzodiazepin-6-yl)-(4-fluoro-2- trifluoromethyl-phenyl)-methanone
- Step B To a solution of 6,l l-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepine of Example 1, Step B (10.6 g, 53.8 mmol) in dimethylformamide (125 mL) under nitrogen was added potassium carbonate (22.4 g, 162 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-trifluoromethyl-4-fluorobenzoyl chloride of Step A (81 mmol) in dimethylformamide (25 mL). After stirring at room
- the aqueous layer was acidified with 2 N hydrochloric acid and the white solid was collected by filtration to give 7.5 g (29.3%) of the starting 4-fluoro-2- trifluoromethylbenzoic acid.
- Step B 4-(3-Methyl-pyrazol-l-yl)-2-trifluoromethyl benzoic acid methyl ester
- Step D (5,ll-Dihydro-pyrido[2,3-b][l,5]benzodiazepin-6-yl)-[4-(3-methyl- pyrazol-l-yl)-2-trifluoromethyl-phenyl]-methanone
- Step B (2,4-Difluoro-phenyl)-(5,ll-dihydro-pyrido[2,3-b][l,5]benzodiazepin-10- yl)-methanone
- Step B To a solution of 6,l l-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepine of Example 1, Step B (3.0 g, 15.2 mmol) in dimethylformamide (35 mL) under nitrogen was added potassium carbonate (6.3 g, 45.6 mmol) followed by a solution of the crude 2,4-difluorobenzoylchloride of Step A (22.8 mmol) in dimethylformamide (15 mL). After stirring at room temperature for 20 minutes, the reaction mixture was washed with water and stirred to give a solid which was collected by filtration. The solid was dissolved in chloroform and washed with 1 N sodium hydroxide and brine.
- Step C (5,ll-Dihydro-pyrido[2,3-b][l,5]benzodiazepin-10-yl)-[2-fluoro-4-(3- methyI-pyrazol-l-yl)-phenyl]-methanone 0.19 hydrate
- the mixture was placed in an oil bath (preheated at 130°C) for 1 hour, cooled and partitioned between water and ethyl acetate.
- the organic extracts were dried over sodium sulfate and evaporated to dryness.
- the crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate (gradient from 9:1 to 1: 1) provided the title compound along with the more polar 4-fluoro regioisomer of Example 10.
- the title compound (0.30 g, 12.7%) was obtained as a foam which crystallized by sonication from hexane-ethanol, m.p. 122-125°C.
- the title product was obtained along with its 2-fluoro regioisomer as described in Example 9.
- the material was further purified by preparative HPLC (Waters silica cartridge, 55:45 hexane-ethyl acetate as the eluant, flow rate 150 mL/min, detection at 254 nm) to give the pure title compound (0.25 g, 10.6%) as a foam which crystallized by sonication from hexane-ethanol, m.p. 180-181°C.
- Step A (2-Chloro-4-fluoro-phenyl)-(5-methyl-5,ll-dihydro-pyrido[2,3- b][l,5]benzodiazepin-10-yl)-methanone
- Methyl iodide (2.51 g, 17.7 mmol) was added in one portion to the yellow solution, and stirring was continued for 1 hour. The mixture was partitioned between 20% aqueous sodium chloride and dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with hexane-ethyl acetate gradient (from 95:5 to 85:15) provided the title product (4.55 g, 72%) as a white crystalline solid, m.p. 222-223°C.
- Step B [2-Chloro-4-(3-methyl-pyrazol-l-yl)-phenyl]-(5-methyl-5,ll-dihydro- pyrido[2,3-b][l,5]benzodiazepin-10-yl)-methanone
- Step B (5,ll-Dihydro-pyrido[2,3-b][l,5]benzodiazepin-6-yl)-(5-fluoro-2-methyl- phenyl)-methanone
- Step B To a solution of 6,l l-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepine of Example 1, Step B (2.0 g, 10.1 mmol) in dimethylformamide (15 mL) under nitrogen was added potassium carbonate (4.1 g, 29.7 mmol). The mixture was treated dropwise with a solution of crude 5-fluoro-2-methyl benzoyl chloride of Step A (15.0 mmol) in dimethylformamide (10 mL). After stirring at room temperature for 15 minutes, the mixture was diluted with water and stirred to give a solid mass which was collected by filtration. The solid was dissolved in chloroform and washed with 1
- Step C (5,ll-Dihydro-pyrido[2,3-b][l,5]benzodiazepin-10-yl)-[2-methyI-5-(3- methyl-pyrazol-l-yl)-phenyl]-methanone
- the mixture was placed in an oil bath (preheated at 130°C) for 30 minutes and then heated at reflux for 5 hours. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The crude residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 25% ethyl acetate in hexane provided the title product (0.23 g, 36.0%) as a foam which crystallized by trituration with hexane-ether, m.p. 136-140°C.
- lithium aluminum hydride (0.258 g, 6.877 mmol) was added portion wise under stirring to 6H-pyrido[2,3-b][l,5]benzoxazepin- 5-one (0.636 g, 3 mmol) in 25 mL of tetrahydrofuran. After heating at reflux for 3 hours, excess lithium aluminum hydride was decomposed by the stepwise addition of 0.3 mL of water, 0.3 mL of IN sodium hydroxide, 0.9 mL of water, and 3.8 g sodium sulfate. The solids were filtered and washed with ethyl acetate.
- Step B (2-Chloro-4-fluoro-phenyl)-(llH-5-oxa-4,10-diaza- dibenzo[a,d]cyclohepten-10-yl)-methanone
- the mixture was heated at 130°C for 3.5 hours, cooled and partitioned between ethyl acetate and brine. The organic phase was washed with water, dried over sodium sulfate and concentrated to dryness in vacuo.
- the crude product was purified by flash chromatography (on silica Merck 60, dichloromethane-ethyl acetate gradient from 19: 1 to 9:1) to give the title compound as a white solid (0.18 g, 21%), m.p. 220-222°C.
- Step B 2-Chloro-4-(3-dimethylamino-2-propen-l-yl)-benzoic acid methyl ester
- Step F [2-Chloro-4-(l-methyl-lH-pyrazol-3-yl)-phenyl]-(5,ll-dihydro- pyrido[2,3-bJLl,5]benzodiazepin-10-yl)-methanone
- Step C [2-Chloro-4-(3-methyl-pyrazol-l-yl)-phenyl]-(5,ll-dihydro-pyrido[2,3- b][l,5]benzodiazepin-6-yl)-methanone
- Step D employing 2-chloro-4-(3-mefhyl-lH- pyrazol-l-yl)-benzoic acid of Step B (0.971 g, 4.1 mmol), triethylamine (0.57 mL, 4.1 mmol), 1,3,5-trichlorobenzoylchloride (0.63 mL, 4.0 mmol), 6,l l-dihydro-5H- pyrido[2,3-b][l,5]benzodiazepine of Example 1, Step B (0.67 g, 3.4 mmol) and 4- dimethylamino pyridine (0,42 g, 3.4 mmol) in dichloromethane (20 mL), was obtained a compound identical to that of Example 1.
- Example 21 The title compound was prepared as described in Example 21, Step A and separated from the 3-methylpyrazole isomer of Example 21 by flash chromatography (on silica Merck-60, eluant: dichloromethane). It was obtained as a white solid (0.20 g, 7.5 %).
- Step B 2-Chloro N-(l-dimethylaminoethylidene)-terephthalamic acid methyl ester
- Step D 2. Chloro-4-[l-(4-methoxy-benzyl)-5-methyl-lH-[l,2,4]triazol-3-yl]- benzoic acid methyl ester 0.03 solvate with dichloromethane
- Step E 2-Chloro-4-[l-(4-methoxy-benzyI)-5-methyl-lH-[l,2,4]-triazol-3-yl]- benzoic acid 0.10 hydrate 0.04 solvate with ethyl acetate
- the aqueous layer was acidified with IN aqueous HCl.
- the precipitate was collected by filtration to provide the title compound (1.25 g, 81.2%) as a white solid, m.p. 154-
- Step F 2-Chloro-4-[l-(4-methoxy-benzyl)-5-methyl-lH-[l,2,4]-triazol-3-yl]- benzoyl chloride
- Step E A suspension of the acid of Step E (1 g, 2.8 mmol) in dichloromethane containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (0.30 mL, 3.4 mmol). After gas evolution subsided, the reaction mixture was refluxed for another 15 minutes and then evaporated to dryness in vacuo to provide the title compound which was used as such in the next step. Step G.
- Example 1 Step B (0.55 g, 2.8 mmol) in dimethylformamide (10 mL) under nitrogen was added solid potassium carbonate (0.39 g, 2.8 mmol). The mixture was treated dropwise with a solution of the crude acid chloride (2.8 mmol) of Step F in dimethylformamide (10 mL). After stirring at room temperature for 90 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined and washed with IN aqueous sodium hydroxide, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed on a column of flash silica Merck-60.
- Step H [2-Chloro-4-(5-methyl-lH-[l,2,4]-triazol-3-yl)-phenyl]-(5,ll-dihydro- pyrido[2,3-b] [l,5]benzodiazepin-6-yl)-methanone
- the title compound may be prepared in a manner analogous to that of the 2- chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][l,5]benzoxazepine of Example 16, Step A, with 2-bromo-4-fluorobenzoyl chloride of Example 3, Step A. Subsequent reaction of the intermediate (2-bromo-4-fluoro-phenyl)-(l lH-5-oxa-4,10- diaza-dibenzo[a,d] cyclohepten- 10-yl)-methanone with the sodium salt of 3- methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
- the title compound may be prepared in a manner analogous to that of the 2- chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][l,5]benzoxazepine of Example 16, Step A with 2-trifluoromethyl-4-fluorobenzoyl chloride of Example 4, Step A. Subsequent reaction of the intermediate (4-fluoro-2-trifluoromethyl-phenyl)- (HH-5-oxa-4,10-diaza-dibenzo[a,d]cyclohepten-10-yl)-methanone with the sodium salt of 3 -methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
- the title compound may be prepared in a manner analogous to that of the 2- chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][l,5]benzoxazepine of
- the title compound may be prepared in a manner analogous to that of the pyrazole analog of Example 19, by reacting the intermediate 2-chloro-4-(l-methyl- lH-pyrazol-3-yl)-benzoylchloride of Example 19 with 6H-pyrido[2,3- b][l,5]benzoxazepine of Example 16, Step A.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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)
- 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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0003394A HUP0003394A3 (en) | 1997-07-30 | 1998-07-24 | Pyrido[2,3-b][1,5]benzodiazepine derivatives, their use, process for their preparation and pharmaceutical compositions containing them |
DK98937144T DK1000059T3 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
IL13378798A IL133787A0 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
NZ502448A NZ502448A (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists and medicaments containing these compounds |
DE69826677T DE69826677T2 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
JP2000505161A JP2001512120A (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonist |
BR9811559-6A BR9811559A (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
AU85925/98A AU8592598A (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
CA002297407A CA2297407A1 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
KR1020007000976A KR20010022397A (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
AT98937144T ATE277926T1 (en) | 1997-07-30 | 1998-07-24 | TRIZYCLIC VASOPRESSIN AGONISTS |
EP98937144A EP1000059B1 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
NO20000241A NO20000241L (en) | 1997-07-30 | 2000-01-18 | Tricyclic vasopressin agonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US94170797A | 1997-07-30 | 1997-07-30 | |
US90337097A | 1997-07-30 | 1997-07-30 | |
US08/941,707 | 1997-07-30 | ||
US08/903,370 | 1997-07-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999006403A1 true WO1999006403A1 (en) | 1999-02-11 |
Family
ID=27129361
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/015487 WO1999006403A1 (en) | 1997-07-30 | 1998-07-24 | Tricyclic vasopressin agonists |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1000059B1 (en) |
JP (1) | JP2001512120A (en) |
KR (1) | KR20010022397A (en) |
CN (1) | CN1162429C (en) |
AT (1) | ATE277926T1 (en) |
AU (1) | AU8592598A (en) |
BR (1) | BR9811559A (en) |
CA (1) | CA2297407A1 (en) |
DE (1) | DE69826677T2 (en) |
DK (1) | DK1000059T3 (en) |
ES (1) | ES2229523T3 (en) |
HU (1) | HUP0003394A3 (en) |
IL (1) | IL133787A0 (en) |
NO (1) | NO20000241L (en) |
NZ (1) | NZ502448A (en) |
PT (1) | PT1000059E (en) |
WO (1) | WO1999006403A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000046225A2 (en) * | 1999-02-04 | 2000-08-10 | American Home Products Corporation | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists |
WO2000046224A2 (en) * | 1999-02-04 | 2000-08-10 | American Home Products Corporation | Tricyclic pyridine n-oxides vasopressin agonists |
WO2001049682A1 (en) * | 2000-01-05 | 2001-07-12 | Ferring Bv | Condensed azepines as vasopressin agonists |
WO2002000626A1 (en) * | 2000-06-26 | 2002-01-03 | Ferring B.V. | Fused azepine derivatives and their use as antidiuretic agents |
US7183271B2 (en) | 2003-04-28 | 2007-02-27 | Astellas Pharma Inc. | 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine derivative or salt thereof |
US7326701B2 (en) | 2000-12-01 | 2008-02-05 | Ajinomoto Co., Inc. | Lactam compounds and pharmaceutical use thereof |
WO2011121308A1 (en) | 2010-04-01 | 2011-10-06 | Vantia Limited | New polymorph |
US9458110B2 (en) | 2013-02-28 | 2016-10-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors |
US9828345B2 (en) | 2013-02-28 | 2017-11-28 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR4999M (en) * | 1964-02-28 | 1967-04-17 | ||
US5420270A (en) * | 1993-10-07 | 1995-05-30 | G. D. Searle & Co. | Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use |
US5512563A (en) * | 1993-07-29 | 1996-04-30 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
WO1996022282A1 (en) * | 1995-01-17 | 1996-07-25 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
WO1997022591A1 (en) * | 1995-12-15 | 1997-06-26 | Otsuka Pharmaceutical Company, Limited | Benzazepine derivatives with vasopressin agonistic activity |
-
1998
- 1998-07-24 PT PT98937144T patent/PT1000059E/en unknown
- 1998-07-24 IL IL13378798A patent/IL133787A0/en unknown
- 1998-07-24 ES ES98937144T patent/ES2229523T3/en not_active Expired - Lifetime
- 1998-07-24 DE DE69826677T patent/DE69826677T2/en not_active Expired - Fee Related
- 1998-07-24 AT AT98937144T patent/ATE277926T1/en not_active IP Right Cessation
- 1998-07-24 NZ NZ502448A patent/NZ502448A/en unknown
- 1998-07-24 CA CA002297407A patent/CA2297407A1/en not_active Abandoned
- 1998-07-24 CN CNB988096420A patent/CN1162429C/en not_active Expired - Fee Related
- 1998-07-24 WO PCT/US1998/015487 patent/WO1999006403A1/en active IP Right Grant
- 1998-07-24 EP EP98937144A patent/EP1000059B1/en not_active Expired - Lifetime
- 1998-07-24 KR KR1020007000976A patent/KR20010022397A/en not_active Application Discontinuation
- 1998-07-24 BR BR9811559-6A patent/BR9811559A/en active Search and Examination
- 1998-07-24 HU HU0003394A patent/HUP0003394A3/en unknown
- 1998-07-24 DK DK98937144T patent/DK1000059T3/en active
- 1998-07-24 AU AU85925/98A patent/AU8592598A/en not_active Abandoned
- 1998-07-24 JP JP2000505161A patent/JP2001512120A/en active Pending
-
2000
- 2000-01-18 NO NO20000241A patent/NO20000241L/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR4999M (en) * | 1964-02-28 | 1967-04-17 | ||
US5512563A (en) * | 1993-07-29 | 1996-04-30 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
US5420270A (en) * | 1993-10-07 | 1995-05-30 | G. D. Searle & Co. | Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use |
WO1996022282A1 (en) * | 1995-01-17 | 1996-07-25 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
WO1997022591A1 (en) * | 1995-12-15 | 1997-06-26 | Otsuka Pharmaceutical Company, Limited | Benzazepine derivatives with vasopressin agonistic activity |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000046224A2 (en) * | 1999-02-04 | 2000-08-10 | American Home Products Corporation | Tricyclic pyridine n-oxides vasopressin agonists |
WO2000046224A3 (en) * | 1999-02-04 | 2000-12-07 | American Home Prod | Tricyclic pyridine n-oxides vasopressin agonists |
WO2000046225A3 (en) * | 1999-02-04 | 2000-12-14 | American Home Prod | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists |
WO2000046225A2 (en) * | 1999-02-04 | 2000-08-10 | American Home Products Corporation | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists |
US7560454B2 (en) | 2000-01-05 | 2009-07-14 | Vantia Limited | Condensed azepines as vasopressin agonists |
WO2001049682A1 (en) * | 2000-01-05 | 2001-07-12 | Ferring Bv | Condensed azepines as vasopressin agonists |
AU777538B2 (en) * | 2000-01-05 | 2004-10-21 | Vantia Limited | Condensed azepines as vasopressin agonists |
CZ303444B6 (en) * | 2000-01-05 | 2012-09-19 | Vantia Limited | Condensed azepines functioning as vasopressin agonists |
HRP20020481B1 (en) * | 2000-01-05 | 2009-03-31 | Vantia Limited | Condensed azepines as vasopressin agonists |
WO2002000626A1 (en) * | 2000-06-26 | 2002-01-03 | Ferring B.V. | Fused azepine derivatives and their use as antidiuretic agents |
US7176195B2 (en) | 2000-06-26 | 2007-02-13 | Ferring Bv | Fused azepine derivatives and their use as antidiuretic agents |
CN1308313C (en) * | 2000-06-26 | 2007-04-04 | 费林股份公司 | Fused azepine drivatives and their use as antidiuretic agents |
US7326701B2 (en) | 2000-12-01 | 2008-02-05 | Ajinomoto Co., Inc. | Lactam compounds and pharmaceutical use thereof |
US7632830B2 (en) | 2000-12-01 | 2009-12-15 | Ajinomoto Co., Inc. | Lactam compounds and pharmaceutical use thereof |
US7807664B2 (en) | 2003-04-28 | 2010-10-05 | Astella Pharma Inc. | 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative or salt thereof |
US7183271B2 (en) | 2003-04-28 | 2007-02-27 | Astellas Pharma Inc. | 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine derivative or salt thereof |
WO2011121308A1 (en) | 2010-04-01 | 2011-10-06 | Vantia Limited | New polymorph |
US9079881B2 (en) | 2010-04-01 | 2015-07-14 | Vantia Limited | Polymorph of 1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide |
US9458110B2 (en) | 2013-02-28 | 2016-10-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors |
US9828345B2 (en) | 2013-02-28 | 2017-11-28 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
DK1000059T3 (en) | 2005-01-10 |
CA2297407A1 (en) | 1999-02-11 |
CN1162429C (en) | 2004-08-18 |
NO20000241D0 (en) | 2000-01-18 |
ATE277926T1 (en) | 2004-10-15 |
HUP0003394A3 (en) | 2003-04-28 |
NO20000241L (en) | 2000-03-06 |
HUP0003394A2 (en) | 2001-08-28 |
BR9811559A (en) | 2000-09-12 |
CN1272110A (en) | 2000-11-01 |
ES2229523T3 (en) | 2005-04-16 |
IL133787A0 (en) | 2001-04-30 |
NZ502448A (en) | 2002-12-20 |
PT1000059E (en) | 2004-12-31 |
AU8592598A (en) | 1999-02-22 |
JP2001512120A (en) | 2001-08-21 |
KR20010022397A (en) | 2001-03-15 |
DE69826677D1 (en) | 2004-11-04 |
EP1000059B1 (en) | 2004-09-29 |
EP1000059A1 (en) | 2000-05-17 |
DE69826677T2 (en) | 2005-02-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6194407B1 (en) | Tricyclic pyrido vasopressin agonists | |
US6090803A (en) | Tricyclic vasopressin agonists | |
EP1000062B1 (en) | Tricyclic vasopressin agonists | |
US7329653B2 (en) | Cyclohexylphenyl vasopressin agonists | |
US6235900B1 (en) | Tricyclic pyridine N-oxides vasopressin agonists | |
EP1000059B1 (en) | Tricyclic vasopressin agonists | |
US6511974B1 (en) | Tricyclic vasopressin agonists | |
EP1021444B1 (en) | 3-CARBOXAMIDE DERIVATIVES OF 5H-PYRROLO[2,1-c][1,4]-BENZODIAZEPINES | |
US6268360B1 (en) | 1H-pyrido[2,3-b][1,5]benzodiazipine vasopressin agonists | |
US6344451B1 (en) | Pyrrolobenzodiazepine carboxyamide vasopressin agonists | |
EP1149096B1 (en) | Tricyclic pyridine n-oxides vasopressin agonists | |
WO1997049708A9 (en) | Tricyclic benzazepine vasopressin antagonists | |
US6620807B1 (en) | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists | |
EP1149103A1 (en) | Thienylbenzoylbenzazepines as vasopressin agonists | |
EP1149104B1 (en) | Pyrrolobenzodiazepine carboxyamide vasopressin agonists | |
MXPA01007917A (en) | Tricyclic pyridine n-oxides vasopressin agonists | |
EP1149097A2 (en) | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists | |
MXPA00000749A (en) | Tricyclic vasopressin agonists | |
MXPA01007916A (en) | Thienylbenzoylbenzazepines as vasopressin agonists | |
MXPA01007918A (en) | Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 133787 Country of ref document: IL Ref document number: 98809642.0 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 85925/98 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998937144 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2297407 Country of ref document: CA Ref document number: 2297407 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 502448 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2000/000749 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020007000976 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 1998937144 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: 1020007000976 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1020007000976 Country of ref document: KR |
|
WWG | Wipo information: grant in national office |
Ref document number: 1998937144 Country of ref document: EP |