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WO1997033583A1 - Methodes de traitement ou de prevention de la cystite interstitielle - Google Patents

Methodes de traitement ou de prevention de la cystite interstitielle Download PDF

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Publication number
WO1997033583A1
WO1997033583A1 PCT/US1997/003555 US9703555W WO9733583A1 WO 1997033583 A1 WO1997033583 A1 WO 1997033583A1 US 9703555 W US9703555 W US 9703555W WO 9733583 A1 WO9733583 A1 WO 9733583A1
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WIPO (PCT)
Prior art keywords
added
piperidin
mol
mixture
methoxybenzyl
Prior art date
Application number
PCT/US1997/003555
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English (en)
Inventor
Smriti Iyengar
Mark A. Muhlhauser
Karl B. Thor
Original Assignee
Eli Lilly And Company
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Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to JP9532693A priority Critical patent/JP2000506527A/ja
Priority to EP97908927A priority patent/EP0932406A4/fr
Priority to US09/125,952 priority patent/US6017930A/en
Priority to AU20714/97A priority patent/AU2071497A/en
Publication of WO1997033583A1 publication Critical patent/WO1997033583A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • NK-1 The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is believed in er »! ⁇ « to be involved in the neurotxansmission of pain sensations, including the pain associated with migraine headaches and with arthritis.
  • These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see. e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108:11- 20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, £ aL, British Journal of Pharmacology. 112:920-924 (1994).
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • Interstitial cystitis is a chronic debilitating inflammatory disorder of the bladder.
  • the disease is most common in women ranging in age from about thirty to sixty with onset of the condition typically occurring at about forty years of age. It is characterized by a number of urinary difficulties, such as suprapubic pressure and pain, with bladder filling, urinary frequency, nocturia, dysuria, urgency adn irritative voiding associated with morphological and histological changes in the bladder.
  • the condition is characterized as "interstitial cystitis" because it is believed the condition does not affect the surface of the bladder, but instead involves the spaces between the cells, namely the interstices, in the lining of the bladder.
  • Urethral syndrome is a related painful voiding disorder of unknown etiology affecting women exhibiting many of the conditions set forth above.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of R 1 and R 2 can be hydrogen;
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and Ci- C 6 alkyl;
  • Ci-C ⁇ alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • the term "Ci-C ⁇ alkyl” includes within its definition the term “C1-C3 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • haloformate refers to an ester of a haloformic acid, this compound having the formula 0 II
  • X is halo
  • R d is Ci-C ⁇ alkyl.
  • Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein R d is C3-C6 alkyl are especially preferred. Most preferred is isobutylchloroformate.
  • the compounds prepared in the processes of the present invention have an asymmetric center.
  • the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • D is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the term “treating” (or “treat”) as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
  • Patent Cooperation Treaty PubHcation WO 95/14017 published May 26, 1995, teaches, inter alia, a series of tachykinin receptor antagonists of Formula II
  • n are independently 0-6;
  • Z is -(CHR ⁇ p ⁇ CHR ⁇ q-, where,
  • p is 0 or 1;
  • R 4 and R 6 are independently selected from the group consisting of hydrogen and C 1 -C3 alkyl
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and Ci-
  • R 1 and R 2 are independently hydrogen, halo, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, nitro, trifluoromethyl, or Ci- C ⁇ alkyl;
  • Particularly preferred compounds are those of Formula IT in which m and n are both 1; R 1 and R 2 are independently hydrogen, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, methyl, and ethyl; Z is methylene; and Y, when combined with the heterocyclic group to which it is attached, forms 4-(piperidin-l-yl)piperidin-l-yl, 4- (cyclohexyl)piperazin-l-yl, 4-(phenyl)piperazin-l-yl, or 4- (phenyl)piperidin- 1 -yl.
  • Tr wherein "Tr” refers to a trityl group, and “NMM” refers to N- methylmorpholine.
  • Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D-tryptophan (100.0 g, 0.490 mol) in anhydrous methylene chloride (800 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours. Triethylamine (147.0 ml, 1.055 mol) was added, followed by the addition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mol) in methylene chloride (400 ml) using an addition funnel. The mixture was stirred at room temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched by the addition of methanol (500 ml).
  • the solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work-up involving a 5% citric acid solution (2X) and brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization.
  • the mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours.
  • the mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% dtric add solution (2X), saturated sodium bicarbonate solution (2X), and brine (2X) was performed.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator.
  • the desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
  • RED-AL ® ' [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • Cydohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
  • the organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine.
  • the organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cydohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cydohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cydohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cydohexyl)piperazin-l-yl)acetate as a yellowish
  • the title compound was prepared by first cooling 2-((4- cydohexyl)piperazin-l-yl)acetic add potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric add, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin- l-yl)piperidin-l-yl)acetate.
  • the title compound was prepared by first admixing (R)-2- amino-3-(lH-indol-3-yl)- l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
  • reaction mixture was removed from the ice bath and allowed to warm to 15-20°C and the reaction was quenched by the addition of 200 ml of water.
  • the pH of the solution was adjusted to 2.3- 2.7 by the additon of IN sulfuric add.
  • the layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
  • N-trityl-D-tryptophan N-methylmopholine salt 108.0 g, 0.196 mol
  • acetonitrile 800 ml
  • 2-chloro-4,6-dimethoxy-l,3,5-triazine 38.63 g, 0.22 mol
  • N-methylmorpholine 29.1 ml
  • the resulting mixture was stirred at ambient temperature until homogeneous (about ten minutes). After about one hour, 2-methoxybenzylamine (29 ml) was added. The resulting mixture was heated to 35°C and maintained at that temperature overnight.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • Cydohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
  • the organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine.
  • the organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cydohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2- ((4-cydohexyl)piperazin-l-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C. Analysis for C12H21KN2O2 • 1.5 H2O:
  • the title compound was prepared by first cooling 2-((4- cydohexyl)piperazin-l-yl)acetic add potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric add, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • reaction mixture was then cooled to -35°C and solid (R)- 2-am o-3-(lH-mdol-3-yl)-l-[N-(2-methoxybenzyl)amino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C.
  • the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C.
  • the reaction was quenched by the addition of deionized water (7.5 L).
  • the reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide.
  • the aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was suffident 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
  • the two aqueous fractions were combined, back-extracted with methylene chloride (1.5 L) and then discarded.
  • the organic fractions were combined and washed with deionized water (4 x 3.5 L). These extracts were combined, back-extracted with methylene chloride (1.5 L), and then discarded.
  • the two organic layers were combined and washed with a saturated sodium chloride solution (3.7 L).
  • the organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator.
  • the mixed anhydride process will work in a number of organic solvents, in addition to the anhydrous N,N-dimethylformamide depicted above.
  • Representative examples of solvents which may be employed indude acetonitrile, tetrahydrofuran, dichloromethane.
  • the mixed anhydride process can be performed at temperatures below 0°C.
  • the oxalate can be isolated from ethyl acetate as well as from other solvents, probably induding acetone, acetonitrile, and 2-butyl methyl ether.
  • the use of oxalic add is, however, very important for the predpitation as a large number of adds do not give a predpitate.
  • the organic fraction was transferred to a jacketed round bottom flask and a solvent exchange was performed using about 23 volumes of acetone. Portions of the acetone were added to the product solution and the amount added was distilled away. The progress of the solvent exchange was monitored by NMR. The amount of desired product was monitored by high performance liquid chromatography.
  • Enough water was added to bring the water concentration to eleven percent and the resulting mixture was heated to 55°C.
  • Enough concentrated hydrochloric add was added to lower the pH to 2.0 and the reaction mixture was then permitted to cool to 37°C over 45 minutes.
  • the product solution was seeded and permitted to stir for 10- 30 minutes.
  • the product solution was cooled to 19°C over two hours and acetone (ten equivalent volumes) was added over three hours, after which time the reaction mixture was stirred for one to three hours, maintaining the temperature at 19°C.
  • the product solution was filtered and the residue was washed with 6.67 equivalents of acetone. The residue was then dried in a vacuum oven at 42°C to give the desired title product.
  • tachykinin receptor antagonists The biological efficacy of a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g.. J. Jukic, eLaL, T.ifo ficjejlfi . g 49:1463-1469 (1991); N. Kucharczyk, ejjal., Journal of Medicinal Chemistry. 36:1654-1661 (1993); N. Rouissi, £ a , Biochemical and Bionhvsical Research Communications. 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al.. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4°C.
  • the IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g.. Annals of the New York Academy Of S ⁇ ence, 190: 221-234 (1972); Nature ( LondonV 251:443-444 (1974); Proceedings of the National Academy ofSdenc.es MSA). 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/ml gentamidn sulfate and 10% fetal calf serum.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.
  • the CHO-hNK-2R cells a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemist y 265:20455-20462 (1990).
  • Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a
  • CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/ml chymostatin. A 200 ⁇ l volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive ligand was [ 125 I]iodol ⁇ istidyl-neurokinin A (New England Nudear,
  • NEX-252 2200 Ci/mmol.
  • the ligand was prepared in assay buffer at 20 nCi per 100 ⁇ l; the final concentration in the assay was 20 pM.
  • Non-specific binding was determined using 1 ⁇ M eledoisin.
  • Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
  • DMSO dimethylsulfoxide
  • IC50 IC50 determinations.
  • the order of additions for incubation was 190 or 195 ⁇ l assay buffer, 200 ⁇ l homogenate, 10 or 5 ⁇ l sample in DMSO, 100 ⁇ l radioactive ligand.
  • the samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter.
  • the method of the present invention is effective in treating mammals, particularly middle-aged women, exhibiting symptoms of interstitial cystitis and/or urethral syndrome.
  • the clinical and local immune response to the compounds of the present invention is investigated in an open trail with 10 female interstitial cystitis patients, whose disease is diagnosed according to the consensus criteria developed in 1987 at a National
  • a compound of the present invention is administered as a single daily dose determined by a dose-titration test.
  • Urinary interleukin-2 inhibitory activity IL-2-IN
  • IL-2-IN Urinary interleukin-2 inhibitory activity
  • Urinary IL-2-IN activity before therapy confirms the presence of cell-mediated inflammation: after 4 months of therapy IL-2-IN activity is normal in most of the patients, regardless of the severity of symptoms, which indicates that the compounds of Formula I exerts an immunosuppressive effect.
  • the data suggests that the compounds of Formula I can be an efficadous, well-tolerated, convenient oral medication for the treatment of interstitial cystitis.
  • Example 2 the present inventors also observes similar responses in regard to the treatment of urethral syndrome.
  • the test data dearly indicates that the compounds employed in the present invention can be effective therapeutic agents for the treatment of interstitial cystitis and or urethral syndrome.
  • compounds of Formula I are particularly well-suited for the treatment of interstitial cystitis and/or urethral syndrome because they not only provide effective relief, are available for oral administration, and are relatively inexpensive. It has been discovered that patients receiving the compounds of Formula I substantially reduce the pathological conditions exhibited by these two painful bladder disorders, and are able to carry on their daily activities in a relatively normal existence in comparison with their pre-treatment state.
  • Hunner's Ulcer (if present, less than 18 years old automatic indusion) benign or malignant tumors radiation, tuberculous, bacterial
  • Positive Factors at least 2 or cydophosphamide cystitis required for indusion: vaginitis duration of symptoms ⁇ 1 year suprapubic, pelvic, urethral, gynecologic cancer vaginal or perinea! pain urethral diverticulum, bladder or lower ureteral calculi glomerulations at cystoscopy active herpes (HSV II) after bladder distension waking frequency ⁇ 5 in 12 hrs.
  • HSV II cystoscopy active herpes
  • nocturia ⁇ 2 neurogenic bladder dysfunction decreased compliance on waking capadty > 400 ml, cystometrogram absence of urgency with bladder filling symptoms relieved by antibiotics, urinary pain on bladder filling urinary analgesics or relieved by emptying antiseptics
  • Cystometrics are performed after cessation of other modes of therapy andprior to institution of therapy: all patients had a waking bladder capadty of less than 350 ml (range 150 ml to 340 ml).
  • Symptom Evaluation The symptom scores (total score range: 0 to 10) form the basis for the evaluation of treatment efficacy. The severity of each symptom is assigned a numerical value, as follows:
  • Urgency urge to void equal to actual 0 frequency urge to void exceeds actual 1 requency constant urge to void 2
  • any patient who falls within the parameters of the indusion of exdusion descriptors of the NTH workshop consensus criteria will score at least a "4" on this survey (frequency ⁇ 1; urgency ⁇ 1; nocturia ⁇ 1; and either dysuria or suprapubic pain ⁇ 1).
  • Urine Collection Urine specimens are collected from all patients before and during therapy. Voided urine is centrifuged at 1000 x g for 10 minutes at 4°C and the supernatant separated from the sediment. The urine supernatant is subjected to 0. 2 ⁇ filtration (celluloseacetate) at 4°C to remove any bacteria and debris, and a 1 ml aliquot is removed for creatinine measurement (CREATININE H ANALYZERTM, Beckman Instruments, Inc., Brea, California). The supernatant is ultrafiltered against 3 x volume in phosphate-buffered saline (PBS) with 0.1 ⁇ g/ml albumin (Sigma, St.
  • PBS phosphate-buffered saline
  • the bioassay for IL-2-IN is modified from the method for measuring IL-2 activity described by Gillis and assodates. S. Gillis, fiLaL T-Cell Growth Factor: Parameters Of Production And A Quantitative Microassay For Activity, Journal of Immunology. 120:2027, (1978).
  • the murine IL-2-dependent cytotoxic T- cell line (CTLL-N) is derived fromthe CT-6 cell line. J. Kusugami, et al.. "Intestinal Immune Reactivity To Interleukin-2 Differs Among Crohn's Disease, Ulcerative Colitis And Controls", Gastroenterologv. 97:1 (1989).
  • CTLL-Ns are maintained in liquid culture using a 1: 1 mixture of Roswell Park Memorial Institute (RPMI) 1640 and Dulbecco's Modified Eagles Medium (DMEM; 4.5 g/L glucose) media supplemented with 2.9 mg/ml glucose, 9.4 mM HEPES buffer, 1.9 mg/ml glutamine, 289 ⁇ g/ml arginine, 0.12 M non-essential amino adds, 5 x 10" 5 M 2-mercaptoethanol, 4.5% fetal bovine serum, 90 units/ml penicillin, 90 ⁇ g/ml streptomycin, 22 ⁇ g/ml fungizone, 0.45 mg/ml gentamicin and 20 units/ml of human recombinant IL-2.
  • RPMI Roswell Park Memorial Institute
  • DMEM Dulbecco's Modified Eagles Medium
  • CTLL-Ns are washed and suspended at a concentration of 10"&/ml in the culture media. Assays are performed in triplicate, as follows: a serial dilution of the sample aliquot (50 ⁇ l), a 1:10 dilution of the human recombinant IL-2 standard and 10 -4 CTLL-Ns (100 ⁇ l) are placed in microliter wells. The microliter plates are incubated in a humidified 6% CO2 atmosphere at 37°C. for 24 hrs, and the cells are pulsed at the 19th hour with 1 ⁇ Ci well of methyl-tritiated thymidine (specific activity 6.7 Ci/mM, New England NudearJ. E. Dupont, Boston, Massachusetts).
  • the cells are collected onto glass filter paper discs.
  • the discs are placed in scintillation fluid and thymidine uptake is measured by liquid scintillation spectrophotometry.
  • IL-2 inhibitory activity is calculated by modified probit analysis.
  • the proliferation "maximum” is the tritiated thymidine uptake caused by the amount of exogenous IL-2 activity in the control microliter wells, assessed in quadruplicate for each assay.
  • the proliferation "minimum” is derived from lowest amount of tritiated thymidine uptake caused by the IL-2 inhibitor standard.
  • the probit calculation corrected for minor interassay variations of thymidine uptake in control wells, and permitted interassay comparisons of inhibitor activity among the urine samples. By this treatment of the data, the calculated value of IL-2 inhibitory activity in lyophilized urine samples varies less than 10% from assay to assay.
  • IL-2-IN activity is expressed in units/mg urine creatinine (U/mg u.c).
  • IL-2-IN activity is less than 0.05 U/mg u.c. inthe urine of healthy adults.
  • Patient Monitoring Patients are interviewed and blood pressure measured twice monthly during the first 2 months of therapy, during the first 2 months after a dose escalation, and then once monthly thereafter. The symptom severity score at each interview is based on the patient's experiences during tiie previous 24 hours.
  • compositions comprising a pharmaceutically acceptable exdpient and at least one active ingredient.
  • These compositions can be administered by a variety of routes induding oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the active ingredient is usually mixed with an exdpient, diluted by an exdpient or endosed within such a carrier which can be in the form of a capsule, sachet, paper or otiier container.
  • a carrier which can be in the form of a capsule, sachet, paper or otiier container.
  • the exdpient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehide, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to ⁇ nj]l the active compound to provide the appropriate pupe size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a mincee size of less than 200 mesh. If the active compound is substantially water soluble, the moussee size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • ex ⁇ pients indude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acada, caldum phosphate, alginates, tragacanth, gelatin, caldum silicate, microciystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally indude: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in assodation with a suitable pharmaceutical exdpient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is espedally preferred.
  • the amount of the compound actually administered will be determined by a physidan, in the light of the relevant circumstances, induding the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of ti e aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • Quantity Ingredient (mg/tahleti
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient(s) is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty add glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capadty and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Suffident water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium dtrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra- arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

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Abstract

L'invention concerne des méthodes de traitement ou de prévention de la cystite interstitielle ou le syndrome urétral chez un mammifère. Ces méthodes consistent à administrer à un mammifère une dose efficace d'un composé présentant la formule (I) dans laquelle R1 et R2 sont indépendamment sélectionnés dans le groupe constitué par hydrogène, méthyle, méthoxy, chloro et trifluorométhyle, à condition qu'un seul élément entre R1 et R2 puisse représenter hydrogène; et Y est égal à (1), (2), (3), (4), (5), (6), N-Ra, ou CH-NR?bRc où Ra, Rb et Rc¿ sont indépendamment sélectionnés dans le groupe constitué par hydrogène et alkyle C¿1?-C6; ou un sel ou un solvate pharmaceutiquement acceptables de ces derniers.
PCT/US1997/003555 1996-03-11 1997-03-07 Methodes de traitement ou de prevention de la cystite interstitielle WO1997033583A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9532693A JP2000506527A (ja) 1996-03-11 1997-03-07 間質性膀胱炎の治療または予防方法
EP97908927A EP0932406A4 (fr) 1996-03-11 1997-03-07 Methodes de traitement ou de prevention de la cystite interstitielle
US09/125,952 US6017930A (en) 1996-03-11 1997-03-07 Methods of treating or preventing interstitial cystitis
AU20714/97A AU2071497A (en) 1996-03-11 1997-03-07 Methods of treating or preventing interstitial cystitis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1313096P 1996-03-11 1996-03-11
US60/013,130 1996-03-11

Publications (1)

Publication Number Publication Date
WO1997033583A1 true WO1997033583A1 (fr) 1997-09-18

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PCT/US1997/003555 WO1997033583A1 (fr) 1996-03-11 1997-03-07 Methodes de traitement ou de prevention de la cystite interstitielle

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EP (1) EP0932406A4 (fr)
JP (1) JP2000506527A (fr)
AU (1) AU2071497A (fr)
CA (1) CA2247822A1 (fr)
WO (1) WO1997033583A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP0932406A4 *
THE JOURNAL OF UROLOGY, Vol. 153, May 1995, ZENG et al., "Characterization of Tachykinin NK2 Receptors in Human Urinary Bladder", pages 1688-1692. *

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EP0932406A4 (fr) 2000-07-05
EP0932406A1 (fr) 1999-08-04
CA2247822A1 (fr) 1997-09-18
JP2000506527A (ja) 2000-05-30

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