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WO1993021185A1 - 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 Download PDF

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Publication number
WO1993021185A1
WO1993021185A1 PCT/US1993/003391 US9303391W WO9321185A1 WO 1993021185 A1 WO1993021185 A1 WO 1993021185A1 US 9303391 W US9303391 W US 9303391W WO 9321185 A1 WO9321185 A1 WO 9321185A1
Authority
WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/US1993/003391
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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
Priority to EP93909506A priority Critical patent/EP0636132A1/fr
Priority to JP5518520A priority patent/JPH07507772A/ja
Publication of WO1993021185A1 publication Critical patent/WO1993021185A1/fr
Anticipated expiration legal-status Critical
Ceased 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
  • 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. 86, 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., 313, 7, 1985).
  • Recent treatment strategies for neurodegenerative diseases include vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers” like ergoloid
  • 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.
  • 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:
  • This reference disclosed hydrazides and does not suggest alkyl or arly substituted amides.
  • 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.
  • 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;
  • Z is O, S, N-NH- 2 , 2 hydrogen atoms, or H and OH; and one of Het 1 or Het 2 is 2, 3, or 4-pyridyl, or 2, 4, or 5- pyrimidinyl and the other is selected from the group including: 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, 3- or
  • 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.
  • Z is 0 or 2 hydrogen atoms
  • More preferred compounds of this invention are those of the- above mentioned formula wherein, together or independently: X and Y are taken together to form, or
  • Het 1 and Het 2 are independently:
  • Specifically preferred compounds of the present invention are: 1'-PHENYL-2,6-BIS(4-PYRIDINYL)-SPIRO((CYCLOHEXANE-L ,3 ⁇ -((3H)-INDOLE))-2 ⁇ (1 ⁇ )-ONE;
  • the Michael Reaction described in Scheme 1 is a classic synthetic reaction and is well known by the skilled artisan. See, for example, H. O. 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:
  • protic solvents include C 1 -C 14 alcohols.
  • the choice of solvent 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 first reaction shown in Scheme 2 is reduction of the carbonyl carbon atom to a methylene group.
  • Two typical methods are the Clemmensen reduction in which a carbonyl compound is reduced with Zn/HCl or Pb/sulfuric acid and the Wolf-Kishner Reduction in which a carbonyl compound is reduced with hydrazine.
  • the Wolf-Kishner Reduction is the preferred method.
  • the reduction reaction is typically carried out in ethylene glycol using an excess of hydrazine and a suitable base.
  • the compound of formula (I) is treated with excess hydrazine at 25 °C.
  • a base sodium hydroxide
  • the reaction is monitored by thin layer chromatography and when complete is cooled to room
  • 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 CH 2 .
  • This well known reaction has been reviewed by H. O. 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
  • 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. O. House,
  • THF Tetrahydrofuran
  • Example 8 2,6-BIS(4-PYRIDINYL)-SPIRO((CYCLOHEXANE-1,5'- ((5H))CYCLOPENTA((2,1-B:3,4:B'))DIPYRIDINE Reaction carried out under an atmosphere of dry nitrogen.
  • the cyclohexanone from Example 1 (50 mg) in 2 ml diglyme was treated with hydrazine (0.2 ml) in one portion. Then sodium hydroxide was added (20 mg) and the reaction was heated to 175 °C for 2 h.
  • Example 1 Using the procedure of Example 1 the title compound was prepared from 1,5-diphenyl-1,4-pentadienone in a yield of 80% as an amorphous solid.
  • the compounds of examples 1-9, and other compounds which can be prepared by the above methods, are illustrated by the structures represented in Table 1. The table is intended to illustrate the invention, but not to limit its breadth.
  • 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.
  • Rats 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. Slices, 0.3 mm thick, from parietal cortex were prepared manually using a recessed Lucite guide and subsequently cut into squares (0.25 ⁇ 0.25 mm, average weight 100 mg).
  • the slices were washed 3 times with non-radioactive KR-medium and transferred to a superfusion apparatus to measure the drug effects on ACh release.
  • the superfusion apparatus consisted of 10
  • thermostated glass columns of 5 mm diameter provided with GF/F glass fiber filters to support the slices
  • Drug was added to the medium by 100-fold dilution of appropriate concentrations (in 0.9% NaCl/H 2 O) 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
  • 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, 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 continuous release of medication over a period of hours. 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.
  • powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, 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 continuous release of medication over a period of hours. 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 dis
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient
  • parenteral solutions In general, 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)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (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.
PCT/US1993/003391 1992-04-16 1993-04-15 Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs Ceased WO1993021185A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93909506A EP0636132A1 (fr) 1992-04-16 1993-04-15 Composes spiro contenant de l'azote substitue utilises pour traiter des deficits cognitifs
JP5518520A JPH07507772A (ja) 1992-04-16 1993-04-15 認識欠損治療用の置換された窒素含有スピロ化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86916392A 1992-04-16 1992-04-16
US07/869,163 1992-04-16

Publications (1)

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WO1993021185A1 true WO1993021185A1 (fr) 1993-10-28

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

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9527816B2 (en) 2005-05-10 2016-12-27 Intermune, Inc. Method of modulating stress-activated protein kinase system
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760083A (en) * 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines
EP0311010A2 (fr) * 1987-10-06 1989-04-12 The Du Pont Merck Pharmaceutical Company Composés aromatiques et hétéro-aromatiques alpha, alpha-disubstitués pour l'amélioration de la mémoire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760083A (en) * 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines
EP0311010A2 (fr) * 1987-10-06 1989-04-12 The Du Pont Merck Pharmaceutical Company Composés aromatiques et hétéro-aromatiques alpha, alpha-disubstitués pour l'amélioration de la mémoire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 86, 1977, Columbus, Ohio, US; abstract no. 43538z, PROSTAKOV, N. S. ET AL. 'Formation of spiran structure ...' *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9527816B2 (en) 2005-05-10 2016-12-27 Intermune, Inc. Method of modulating stress-activated protein kinase system
US10010536B2 (en) 2005-05-10 2018-07-03 Intermune, Inc. Method of modulating stress-activated protein kinase system
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 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

Also Published As

Publication number Publication date
CA2118212A1 (fr) 1993-10-28
JPH07507772A (ja) 1995-08-31
AU4027693A (en) 1993-11-18
EP0636132A1 (fr) 1995-02-01

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