EP0636132A1 - Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs - Google Patents

Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs

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Publication number
EP0636132A1
EP0636132A1 EP93909506A EP93909506A EP0636132A1 EP 0636132 A1 EP0636132 A1 EP 0636132A1 EP 93909506 A EP93909506 A EP 93909506A EP 93909506 A EP93909506 A EP 93909506A EP 0636132 A1 EP0636132 A1 EP 0636132A1
Authority
EP
European Patent Office
Prior art keywords
compound
mammal
effective amount
therapeutically effective
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93909506A
Other languages
German (de)
English (en)
Inventor
Matthew Mark Abelman
David Ross Brittelli
David Alan Nugiel
Matthew Ernst Voss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Publication of EP0636132A1 publication Critical patent/EP0636132A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D471/10—Spiro-condensed systems

Definitions

  • This invention relates to novel spirocyclic compounds, pharmaceutical compositions containing them and methods of using them in mammals to treat cognitive deficiencies and/or neurological dysfunction and/or mood disturbances as found, for example, in degenerative nervous system diseases .
  • Nervous system disorders cause cognitive and neurological deficiencies and are becoming more prevalent in today's society. Many of these disorders are age related and/or the direct result of degenerative changes in the nervous system. Specific neurological systems are often directly affected in the early stages of some diseases (e.g. cholinergic systems in Alzheimer's Disease and the dopamineregic system in Parkinson's Disease), while multiple neurotransmitter system deficiencies (acetylcholine, dopamine, seretonin, norepinephrine) are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, etc. This may explain the generally observed symptomology including cognitive, neurological and effective/psychotic components (see Gottfries, Psych ⁇ pharmacol. ££, 245, 1985) . Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et al, New England J. Med. r 313, 7, 1985) .
  • Recent treatment strategies for neurodegenerative diseases include vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers” like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like -DOPA, choline and 5-hydroxytryptamine; metabolizing enzyme inhibitors like physostigmine; and neuropeptides like ACTH and vasopressin-related peptides.
  • Another strategy is to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Such an enhancement might improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation. Cook, If .
  • DuP 996 may exhibit indirect action or may have an active metabolite, and that three metabolites have been identified, a mono-N-oxide, a bis-oxide and a C- dealkylated alcohol.
  • Chem._Abstracts 111(13) :108875p suggests that the following structure is one of the above named metabolites of Dup 996:
  • Patent WO 91/01/306, Feb. 7, 1991 discloses oxindole derivatives of formula:
  • EP415-102-A discloses a series of 1,3-dihydro-l- (pyridinylamino)-2H-indol-2-ones of formula:
  • spirocyclic compounds can enhance the stimulus-induced release of neurotransmitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an active avoidance task.
  • X and Y are taken together to form a saturated or unsaturated carbocylic or heterocyclic first ring and the shown carbon in said ring is ⁇ to at least one additional aromatic ring or heteroaromatic ring fused to the first ring;
  • Het 1 or Het 2 is 2, 3, or 4-pyridyl, or 2, 4, or 5- pyri idinyl and the other is selected from the group including: 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3- or
  • This invention also provides pharmaceutical compositions comprising a suitable pharmaceutical carrier and an effective amount of one..or more of the above- described compounds effective to treat cognitive or neurological dysfunction. Still further, this invention relates to a a method of treating cognitive or neurological dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of one or more of the above-described compounds.
  • Preferred compounds of this invention are those of the formula (I) wherein:
  • Z is 0 or 2 hydrogen atoms
  • Het 1 and Het 2 are independently:
  • More preferred compounds of this invention are those of the- above mentioned formula wherein, together or independently:
  • Z is 0 or 2 hydrogen atoms
  • Het 1 and Het 2 are independently:
  • Specifically preferred compounds of the present invention are:
  • the Michael Reaction described in Scheme 1 is a classic synthetic reaction and is well known by the skilled artisan. See, for example, H. 0. House, Modern Synthetic Reactions. 595-623 (2nd Edition 1972) and E. D. Bergmann et al., Organic Reactions, 10, 179 (1959) both of which are hereby incorporated by reference, which disclose numerous examples, reaction conditions, solvents, bases, and reactants.
  • the reaction is typically run by generating an anion at the methylene carbon of the core group represented by formula (II) with a suitable base and treating this anion with the desiredorgone. For example, treatment of diazafluorene with a suitable base generates an anion at the 9-position.
  • the reaction can be run in an aprotic or protic solvent.
  • Preferred aprotic solvents include: tetrahydrofuran, diethylether, dimethylsulfoxide, dimethylformamide, glyme and diglyme.
  • Preferred protic solvents include C1-C14 alcohols. The choice of solvent
  • S U BSTITUTESHEET will also determine the character of the base.
  • the ideal base is Triton B. Where this base is used and the diazafluorene core is used, the diazafluorene and the dienone are premixed before adding the base. If the cardone is not soluble in a protic solvent then an aprotic solvent like ether or tetrahydrofuran may be used. When this base is used and diazafluorene is the core group, the diazafluorene is pretreated with base and the cardone is then added to the resulting mixture.
  • the preferred base with aprotic solvents is sodium hydride.
  • the procedure of Scheme 1 is typically run over the temperature range -50 to 150 °C, under a inert atmosphere, and is usually complete within 10 minutes to 24 hours.
  • the preferred temperature range is 0 to 25 °C.
  • the preferred atmosphere is nitrogen or argon.
  • the preferred reaction time is 1-60 minutes.
  • the reaction can easily be monitored by thin layer chromatography.
  • the work up of the reaction generally involves pouring it into a saturated ammonium chloride solution and extracting the product with either chloroform or methylene chloride. The organic phase is then washed with brine, dried with an appropriate reagent (sodium sulfate, potassium carbonate or magnesium sulfate) and the solvent removed at reduced pressure to give a compound of formula (I) wherein Z is 0.
  • the compound of formula (I) thus obtained may be further purified using flash chromatography and recrystallization.
  • the compound of formula (I) is treated with excess hydrazine at 25 °C. Then a base (sodium hydroxide) is added and the reaction heated to 170-185 °C. The reaction is monitored by thin layer chromatography and when complete is cooled to room temperature and poured into water. Extraction with methylene chloride and work up provides a residue that is
  • the second reaction shown in Scheme 2 is the Wittig olefination reaction.
  • This reaction involves treating a compound of formula (I) wherein Z is 0 with a phosphonium ylide or a phosphinoxy carbanion to give a compound of formula (I) wherein Z is CH2-
  • This well known reaction has been reviewed by H. 0. House, Modern Synthetic Reactions, 682 (2nd Edition 1972) and G. Wittig and A. Hesse, Org.
  • the preferred method utilizes a phosphonium ylide and is run in an aprotic solvent such as tetrahydrofuran or benzene at 0 °C.
  • the reagent is generated from methyl triphenyl phosphonium bromide and a strong base such as potassium tert-butoxide although many bases can be used.
  • the carbonyl compound is then added to an excess of the reagent and the reaction monitored by thin layer chromatography. Reactions usually take from 5-30 in and are quenched with acetone, diluted with ether and worked up to provide a residue that can be purified by flash chromatography to afford a purified compound of formula (I) wherein Z is CH2.
  • the third reaction shown in Scheme 2 is treatment of a compound of formula (I) wherein Z is 0 with a reducing agent to afford a compound of formula (I) wherein Z is OH.
  • a reducing agent is LiAlH.4 and ' NaBH.4, • although others are available. This reaction has been extensively reviewed. See, for example, H. 0. House,
  • SUBSTtTUTESHEET The reducing agent is usually added in several portions and the reactions are usually fast. The reaction can be monitored by thin layer chromatography and upon completion the methanol is evaporated to facilitate isolation of the product. The residue is partitioned between aqueous dilute sodium hydroxide and ether or ethyl acetate. After usual workup, the residue can be purified by chromatography and recrystallization to afford a purified compound of formula (I) wherein Z is OH.
  • THF Tetrahydrofuran
  • Example 2 Using the procedure of Example 1 the title compound was prepared from 1, 5-diphenyl-l, -pentadienone in a yield of 80% as an amorphous solid.
  • Example 27 and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 2.
  • the table is intended to illustrate the invention, but not to limit its breadth.
  • Example 61 and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 3.
  • the table is intended to illustrate the invention, but not to limit its breadth.
  • the compounds of this invention and their pharmaceutically acceptable salts can enhance the stimulus- induced release of neurotransmitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an active avoidance task. These compounds are useful for treating cognitive deficiencies and/or neurological dysfunction and/or mood disturbances as found, for example, in degenerative nervous system diseases.
  • acetylcholine release was tested using a slice superfusion technique described by Miller et al, Brain Res . , 70, 372 (1974) , as modified according to Nickolson et al, Uaunyn Schmied. Arch. Pharmacol.. 212., 48, (1982) .
  • Male Wistar rats (Charles River) weighing 175-200 grams were used. They were housed for seven days before the experiment under a 12-12 hour light/dark cycle. They had ad lib access to standard rat chow (Purina) and deionized water. Rats were decapitated and brains were dissected immediately.
  • Ringer medium containing (mM) NaCI (116), C1 (3), CaCl2 (1.3), MgCl 2 (1.2), KH 2 P0 4 (1.2), Na 2 S0 4 (1.2), NaHC0 3 (25), glucose (11), to which 10 ⁇ Ci 3 H-Choline (spec. act. approx. 35 Ci/mmol; NEN) and 10 mmoles unlabeled choline had been added to give a final concentration of 10 ⁇ 6 M.
  • the superfusion apparatus consisted of 10 thermostated glass columns of 5 mm diameter provided with GF/F glass fiber filters to support the slices (approximately 10 mg tissue/column) .
  • Superfusion was carried out with KR-medium (0.3 ml/min) containing 10 -5 M hemicholinium-3 (HC-3) . This prevents choline uptake, formed during the superfusion from phospholipids and released ACh, which would be converted into unlabeled ACh and released in preference to the preformed, labelled ACh.
  • the medium was delivered by a 25-channel peristaltic pump and warmed to 37 °C in a thermostated stainless steel coil before entering the superfusion column.
  • Each column had a 4-way slider valve allowing rapid change of low to high K + - KR-medium and with two 10-channel, 3-way valves used to change from drug-free to drug-containing low and high K + - KR-medium. _
  • Drug was added to the medium by 100-fold dilution of appropriate concentrations (in 0.9% NaCl/H 2 0) with either low or high K + -KR-medium. All superfusion fractions were collected in liquid sintillation vials . After superfusion, slices were removed from the columns and extracted in 1 ml of 0.1 N HCl. To these fractions and extracts was added 12 ml Liquiscint counting fluid (NEN) and samples counted in a Packard Tricarb Liquid Scintillation Counter. No corrections made for quenching.
  • NNN Liquiscint counting fluid
  • Dosage forms (compositions) suitable for administration ordinarily will contain 0.5-95% by weight of the active ingredient based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, * starch, cellulose derivatives, magnesium stearate, stearic acid r and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for
  • Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Cette invention concerne de nouveaux composés spirocycliques de formule (I) ou leurs sels physiologiquement acceptables. Dans cette formule X et Y forment ensemble un premier cycle carbocyclique ou hétérocyclique saturé ou non saturé et l'atome de carbone représenté dans ledit cycle représente α pour au moins un autre cycle aromatique ou un cycle hétéroaromatique fusionné sur le premier composé; Z représente O, S, N-NH2, 2 atomes d'hydrogène, ou H et OH; un des deux composants Het?1 et Het2¿ représente 2-, 3-, ou 4-pyridyle, ou bien 2-, 4-, ou 5-pyrimidinyle tandis que l'autre est sélectionné dans le groupe formé par: 2-, 3-, ou 4-pyridyle, 2-, 4-, ou 5-pyrimidinyle, 2-pyrazinyle, 3- ou 4-pyridazinyle, 3- ou 4-pyrazolyle, 2- ou 3-tétrahydrofuranyle, et 3-thiényle. Cette invention concerne également des compositions pharmaceutiques renfermant ces composés ainsi qu'un procédé d'utilisation de ces derniers chez des mammifères pour traiter des déficits cognitifs et/ou des dysfonctionnements neurologiques et/ou des troubles de l'humeur tels que ceux qu'on a découverts par exemple dans les pathologies dégénératives du système nerveux.
EP93909506A 1992-04-16 1993-04-15 Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs Withdrawn EP0636132A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US86916392A 1992-04-16 1992-04-16
US869163 1992-04-16
PCT/US1993/003391 WO1993021185A1 (fr) 1992-04-16 1993-04-15 Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs

Publications (1)

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EP0636132A1 true EP0636132A1 (fr) 1995-02-01

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Country Status (5)

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EP (1) EP0636132A1 (fr)
JP (1) JPH07507772A (fr)
AU (1) AU4027693A (fr)
CA (1) CA2118212A1 (fr)
WO (1) WO1993021185A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007014114A (es) 2005-05-10 2008-03-14 Intermune Inc Derivados de piridona para modular el sistema de proteina cinasa activada por estres.
JP5627574B2 (ja) 2008-06-03 2014-11-19 インターミューン， インコーポレイテッド 炎症性および線維性疾患を治療するための化合物および方法
AR092742A1 (es) 2012-10-02 2015-04-29 Intermune Inc Piridinonas antifibroticas
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10343991B2 (en) 2016-11-02 2019-07-09 Council Of Scientific & Industrial Research C5, C6 substituted and/or fused oxindoles as anti-cancer agents and process for preparation thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5173489A (en) * 1986-04-10 1992-12-22 The Dupont Merck Pharmaceutical Co. α,α-disubstituted aromatics and heteroaromatics as cognition enhancers
US4760083A (en) * 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9321185A1 *

Also Published As

Publication number Publication date
JPH07507772A (ja) 1995-08-31
WO1993021185A1 (fr) 1993-10-28
AU4027693A (en) 1993-11-18
CA2118212A1 (fr) 1993-10-28

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