EP2150543A2 - Composés hétérocycliques avec affinité des récepteurs muscariniques - Google Patents

Composés hétérocycliques avec affinité des récepteurs muscariniques

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Publication number
EP2150543A2
EP2150543A2 EP08759382A EP08759382A EP2150543A2 EP 2150543 A2 EP2150543 A2 EP 2150543A2 EP 08759382 A EP08759382 A EP 08759382A EP 08759382 A EP08759382 A EP 08759382A EP 2150543 A2 EP2150543 A2 EP 2150543A2
Authority
EP
European Patent Office
Prior art keywords
pyrazol
compound
tetrahydro
methylpyridine
alkoxy
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Withdrawn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
EP08759382A
Other languages
German (de)
English (en)
Inventor
Axel Stoit
Hein K.A.C. Coolen
Cornelis G. Kruse
Louise Heir Of Reinders Jan H. Terwel (Deceased)
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.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
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 Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to EP08759382A priority Critical patent/EP2150543A2/fr
Publication of EP2150543A2 publication Critical patent/EP2150543A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • C07D471/08—Bridged systems

Definitions

  • This invention relates to new heterocyclic compounds having affinity to muscarinic receptors, a pharmaceutical composition containing said compounds, as well as the use of said compounds for the preparation of a medicament for treating, alleviating or preventing muscarinic receptor mediated diseases and conditions.
  • Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems.
  • Muscarinic receptors comprise five distinct subtypes, denoted as muscarinic M1 , M2, M3, M4 and M5 receptors. Each subtype has a unique distribution in the central and peripheral nervous systems.
  • the M1 receptor is predominantly expressed in the cerebral cortex and is believed to be involved in the control of higher cognitive functions; the M2 receptor is the predominant subtype found in heart and is involved in the control of heart rate; the M3 receptor is widely expressed in many peripheral tissues and is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; the M4 receptor is present in the brain and may be involved in locomotion and antipsychotic effects; the M5 receptor is located in the brain and may be involved in compound addition and in psychotic conditions such as schizophrenia.
  • extensive efforts have been made to generate new compounds showing selective agonistic or antagonistic properties (see for example EP 0296721 ; EP 0316718; Sauerberg, P.
  • M1/M4 preferring muscarinic receptor agonist is the thiadiazole compound xanomeline which in preclinical studies has a desirable profile, however, in clinical studies displays a unfavourable side effects (see for example the review by Eglen, R.M., Progress in Medicinal Chemistry, 2005, 43, p.105-136 and US 5,376,668), which seem to be related to M2 receptor mediated activity (e.g. heart rate effects).
  • xanomeline has a relatively low (in vitro) metabolic stability.
  • Xanomeline related compounds are further disclosed in US 5,527,813. However, representative compounds display unfavourable side effects which seem to be related to M2 and M3 receptor mediated activity (e.g. heart rate effects and salivation, respectively).
  • the heterocycle comprises two double bonds which may be present at several positions, represented by the dashed lines ( — );
  • the heterocycle contains two heteroatoms, - W being N or NH;
  • - Y being CH, O or NH, wherein if Y is O, Xi is CH and X 2 is the residue C-Z-R2 or C-R3, wherein Z is NH, O, or S; and if Y is CH or NH, one of Xi and X2 is CH or N, the other being the residue C-Z-R2 or C-R3, wherein Z is NH or S;
  • - R1 is selected from the structures (a), (b) and (c):
  • R2 is selected from (Ci-Ci O )alkyl, (C 2 -Ci 0 )alkenyl and (C 2 -Ci 0 )alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, oxo, (Ci-C 6 )alkoxy, (Ci-C 6 )alkylthio, (CrC 6 )alkenyloxy, (Ci-C 6 )alkenylthio, (Ci-C 4 )alkoxy(Ci-C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen; or - R2 is an unbranched (C 2 -C 8 )alkyl substituted
  • R1 a representing identical symbols and substituents, respectively, as the symbols W, Y and Z and the substituent R1 in the other part of the structure of formula (I);
  • R3 is selected from (C 4 -Ci 0 )alkyl, (C 2 -Ci 0 )alkenyl and (C 2 -Ci 0 )alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, (CrC 6 )alkoxy, (CrC 6 )alkylthio, (CrC 6 )alkenyloxy,
  • the compounds of the invention are useful for treating, alleviating and preventing muscarinic receptor mediated diseases and conditions.
  • Preferred compounds are M1 and M4 receptor agonists and may be used in the treatment of muscarinic M1/M4 mediated diseases and conditions, e.g. -but not limited to- Alzheimer's disease, cognitive impairment, Sjogren's disease, Schizophrenia and antinociception.
  • the compounds of the present invention may be used to treat, alleviate or prevent cognitive impairment and psychotic disorders.
  • the compounds have formula (I) wherein wherein R2 is selected from (C r Ci 0 )alkyl, (C 2 -Ci 0 )alkenyl and (C 2 -Ci 0 )alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, oxo, (Ci-C 3 )alkoxy, (C- ⁇ -C 6 )alkylthio, (d-C 6 )alkenyloxy, (CrC 6 )alkenylthio, (CrC 4 )alkoxy(Ci-C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy and phenylthio, wherein the phenyl group is optionally substituted with halogen.
  • R2 is selected from (C r Ci 0
  • R2 is selected from (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl, optionally independently substituted with one or more substituents selected from halogen, hydroxy, cyano, oxo, (Ci-C6)alkoxy, (Ci-C4)alkoxy(Ci-C4)alkoxy, (C 5 -C 7 )cycloalkyl, tetrahydrofuranyl and phenyl, wherein the phenyl group is optionally substituted with halogen.
  • R2 is selected from (d-Cs)alkyl, (C 2 -C 8 )alkenyl : optionally substituted with one or more halogen or (d-di)alkoxy.
  • R3 is selected from (C 4 -Cio)alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 10 )alkynyl, optionally substituted with a substituent selected from (C 5 -C 7 )cycloalkyl or phenyl, wherein the phenyl group is optionally substituted with halogen.
  • R1 has the structure (a) or (b), in particular (a).
  • the compounds have formula (I) wherein W is N and Y is NH, in particular when X 1 is CH and X 2 is the residue C-Z-R2 or C-R3, and Z is O or S and preferably X 2 is the residue C-Z-R2.
  • Z preferably is S.
  • Y is O and Z is O or S, and preferably Z is S.
  • halogen refers to fluoro, chloro, bromo, or iodo. Preferred is fluoro.
  • (Ci-Ci O )alkyl means a branched or unbranched alkyl group having 1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, n-pentyl, sec-pentyl, hexyl, octyl.
  • unsubstituted n- pentyl is a preferred alkyl group.
  • Preferred substituted R2 alkyl groups are ethoxyethyl, when Z is O or S, and -(CH 2 ) 3 CF 3 when Z is S.
  • (d-C 6 )alkoxy means an alkoxy group having 1 -6 carbon atoms, wherein the alkyl moiety is as defined above.
  • (d-C 6 )alkylthio has a similar meaning.
  • (d-C 4 )alkoxy(d-C 4 )alkoxy means a (Crd)alkoxy group, the alkyl moiety of which is in turn substituted with (d-d)alkoxy.
  • (C 2 -C 8 )alkenyl means a branched or unbranched alkenyl group having 2-8 carbon atoms wherein the double bond(s) may be present at different parts of the group, for example vinyl, allyl, butenyl, n-pentenyl, sec-pentenyl, hexenyl, octenyl, etc.
  • a preferred alkenyl group is 4-pentenyl and a preferred substituted alkenyl group is 4,4-difluoro-but-3-enyl.
  • (Ci-C 6 )alkenyloxy means an alkenyloxy group having 1-6 carbon atoms, wherein the alkenyl moiety is as defined above.
  • (Ci-C 6 )alkenylthio has a similar meaning.
  • (C2-C ⁇ )alkynyl means a branched or unbranched alkynyl group having 2-8 carbon atoms wherein the triple bond(s) may be present at different parts of the group, for example ethynyl, propargyl, 1-butynyl, 2-butynyl, etc.
  • (C 5 -C 7 )cycloalkyl means a cyclic alkyl group having 5-7 carbon atoms, thus cyclopentyl, cyclohexyl, cyclopheptyl or cyclooctyl.
  • 5-membered unsaturated heterocycle in the definition of R2 means a heterocycle containing 5 atoms, wherein at least one atom is a heteroatom selected from O, N and S, the other atoms being carbon atoms, wherein the heterocycle further at least contains one double bond. Examples are furanyl and pyrrollyl groups. With reference to substituents, the term “independently” means that the substituents may be the same or different from each other.
  • the compounds of the invention may suitably be prepared by methods available in the art, and as illustrated in the experimental section of this description. Some novel and useful intermediates have been found for the preparation of the compounds of this invention.
  • Another embodiment of the invention is a heterocyclic compound of the formula ("I)
  • the heterocycle comprises two double bonds which may be present at several positions, represented by the dashed lines ( — );
  • the heterocycle comprises two heteroatoms, - W * being N, NH or N-2-(trimethylsilyl)ethoxymethyl; - Y * being CH, O, N or NR4, wherein R4 is selected from H, 2-(trimethylsilyl)- ethoxymethyl, -SO 2 N(CH 3 ) 2 and -S0 2 phenyl; wherein if Y * is O, Xi * is CH and X 2 * is the residue C-Z * -R2 * or C-R3 * , wherein Z * is NH 1 O, or S; and if Y * is CH or NH, one of Xi * and X 2 * is CH or N, the other being the residue
  • R2 * is selected from (d-C 8 )alkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl, optionally independently substituted with one or more: halogen, hydroxy, cyano, oxo, (CrC 6 )alkoxy, (C r C 6 )alkylthio, (CrC 6 )alkenyloxy, (CrC 6 )alkenylthio, (Ci-C 4 )alkoxy(Ci-C 4 )alkoxy, (C 5 -C 7 )cycloalkyl, a 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy or phenylthio, wherein the phenyl group is optionally substituted with halogen; or
  • R2 * is an unbranched (C 2 -C 8 )alkyl substituted at the Z * a-symbol of a group with the formula (Ha)
  • R5 is H and R6 is Br, or R5 is -Si(CH 3 ) 3 and R6 is Br or -Si(CH 3 ) 3 , which compound is useful in the preparation of compounds of formula (I) wherein R1 has the structure (a).
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • Compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • Isotopically-labeled compound of formula (I) or pharmaceutically acceptable salts thereof including compounds of formula (I) isotopically-labeled to be detectable by PET or SPECT, also fall within the scope of the invention.
  • pharmaceutically acceptable salt refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
  • the compounds of the invention may be administered enterally or parenterally.
  • the exact dose and regimen of these compounds and compositions thereof will be dependent on the biological activity of the compound per se, the age, weight and sex of the patient, the needs of the individual subject to whom the medicament is administered, the degree of affliction or need and the judgment of the medical practitioner.
  • parenteral administration requires lower dosages than other methods of administration which are more dependent upon adsorption.
  • the dosages for humans are preferably 0.001 - 10 mg per kg body weight, more preferably 0.01 - 1 mg per kg body weight.
  • enteral and parenteral dosages will be in the range of 0.1 to 1 ,000 mg per day of total active ingredients.
  • the medicament manufactured with the compounds of this invention may also be used as adjuvant in therapy.
  • the medicament or is administered in a combination treatment with other compounds useful in treating such disease states.
  • pharmaceutical combination preparations comprising at least one compound of the present invention and at least one other pharmacologically active substance are considered in this respect.
  • pharmaceutically suitable auxiliaries e.g. as described in the standard reference "Remington, The Science and Practice of Pharmacy” (21 st edition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing) the compounds may be compressed into solid dosage units, such as pills or tablets, or be processed into capsules or suppositories.
  • the compounds can also be applied in the form of a solution, suspension or emulsion.
  • dosage units e.g. tablets
  • conventional additives such as fillers, colorants, polymeric binders and the like
  • any pharmaceutically suitable additive which does not interfere with the function of the active compounds can be used.
  • Suitable carriers with which the compounds of the invention can be administered include for instance lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • Compositions for intravenous administration may for example be solutions of the compounds of the invention in sterile isotonic aqueous buffer. Where necessary, the intravenous compositions may include for instance solubilizing agents, stabilizing agents and/or a local anesthetic to ease the pain at the site of the injection.
  • compositions of the invention may be formulated for any route of administration and comprise at least one compound of the present invention and pharmaceutically acceptable salts thereof, with any pharmaceutically suitable ingredient, excipient, carrier, adjuvant or vehicle.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more pharmaceutical compositions of the invention.
  • container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
  • Nuclear magnetic resonance spectra ( 1 H NMR and 13 C NMR, APT) were determined in the indicated solvent using a Bruker ARX 400 ( 1 H: 400 MHz, 13 C: 100 MHz) at 300 K, unless indicated otherwise.
  • 19 F NMR and 13 C NMR experiments were carried out on a Varian Inova 500 spectrometer operating at 1 1.74 T (499.9 MHz for 1 H; 125.7 MHz for 13 C; 50.7 Mhz, 470.4 MHz for 19 F) using a 5 mm SW probe.
  • the spectra were determined in deuterated chloroform or dichloromethane obtained from Cambridge Isotope Laboratories Ltd.
  • Flash chromatography refers to purification using the indicated eluent and silica gel (either Acros: 0.030-0.075 mm or Merck silica gel 60: 0.040-0.063 mm).
  • Mass spectra were recorded on a Micromass QTOF-2 instrument with MassLynx application software for acquisition and reconstruction of the data. Exact mass measurement was done of the quasimolecular ion [M+H] + . Accurate mass measurements were performed using a JEOL JMS-SX/SX 102 A Tandem Mass Spectrometer using Fast Atom Bombardement (FAB). A resolving power of 10,000 (10% valley definition) for high resolution FAB mass spectrometry was used.
  • FAB Fast Atom Bombardement
  • Reactions were monitored by using thin-layer chromatography (TLC) on silica coated plastic sheets (Merck precoated silica gel 60 F254) with the indicated eluent. Spots were visualised by UV light (254 nm) or I 2 .
  • TLC thin-layer chromatography
  • the LC-MS system consists of 2 Perkin elmer series 200 micro pumps.
  • the pumps are connected to each other by a 50 ⁇ l tee mixer, connected to a Gilson 215 auto sampler.
  • the method is as follows:
  • step total time flow (ul/min) A(%) B(%)
  • the auto sampler has a 2 ⁇ l injection loop.
  • the auto sampler is connected to a Waters Atlantis C18 30 * 4.6 mm column with 3 ⁇ m particles.
  • the column is thermo stated in a Perkin Elmer series 200 column oven at 40° C.
  • the column is connected to a Perkin Elmer series 200 UV meter with a 2.7 ⁇ l flowcel.
  • the wavelength is set to 254 nm.
  • the UV meter is connected to a Sciex API 150EX mass spectrometer.
  • the mass spectrometer has the following parameters:
  • Scanrange 150-900 a.m.u.; polarity: positive; scan mode: profile ; resolution Q1 : UNIT ; step size: 0.10 a.m.u.; time per scan: 0.500 sec; NEB: 10; CUR: 10 IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.
  • the light scattering detector is connected to the Sciex API 150.
  • the light scattering detector is a Sedere Sedex 55 operating at 50° C and 3 bar N 2 .
  • the complete system is controlled by a G3 powermac.
  • the LC-MS system consists of an Agilent series 1100 system consisting of the following components:
  • the pumps are connected to a G1313A ALS auto sampler.
  • the method is as follows:
  • the auto sampler is connected to a Zorbax Extend C18 column 150x4.6 mm with 3.5 urn particles.
  • the column is thermo stated in a G1316A Colcomm column oven at 35° C.
  • the column is connected to a G1315B DAD diode array detector.
  • the wavelength range is set from 220 to 320 nm.
  • the UV meter is connected to G1946D MSD mass spectrometer, operating in electron spray mode.
  • the mass spectrometer has the following parameters:
  • An Alltech ELSD 2000 detector is connected parallel with the MSD. The flow is split after the DAD.
  • the ELSD has the following parameters: Drying gas: Nitrogen
  • PE petroleum ether 40-65 oC
  • the selection of the particular method depends on factors such as the compatibility of functional groups with the reagent used, the possibility to use protecting groups, catalysts, activating and coupling reagents and the ultimate structural features present in the final compound being prepared.
  • nicotinoyl chloride hydrochloride (1 ) is converted to the N-methyl-N-methoxyamide (2) in the presence of a base and reacted with hexyl-lithium (J. Med. Chem., 35, 1992, 2392-2406) to produce 1 - pyridin-3-yl-heptan-1 -one (3).
  • 3-(4-bromo-1 H-pyrazol- 3-yl)-pyridine (20A) or its iodo analog (20B) (Bioorganic & Medicinal Chemistry, 4, 1996, 227-237) is used as precursor for the synthesis of compounds of the general formula I.
  • the dimethylsulfonamide group as Directing Metalation Group (DMG) in the reposition of 3-pyridin-3-yl-pyrazole-1 -sulfonic acid dimethylamide (23) enables the lithiation of the 5-position and thereby its functionalisation (Chem. Ber., 124, 1991 , 1639-1650).
  • 3-(4-iodo-1 H-pyrazol-3-yl)-pyridine (2OB, scheme 5) is employed as starting material for compounds of the present invention illustrated in formula I.
  • Alkylation of the 4-hydroxy derivate 30 can be accomplished using methods well known in the art, for example, by reacting compound 30 with K 2 CO 3 in DMF in the presence of a variety of (aryl)alkyl halides, for example (3-bromo-propyl)-benzene, to generate compound 31A (one isomer given). Subsequent removal of the SEM group resulted in 3-[4-(3- phenyl-propoxy)-1 H-pyrazol-3-yl]-pyridine (32A), which was converted to the 1 ,2,5,6- tetrahydro-1-methylpyridine derivate 33A according to the two step sequence shown in scheme 1.
  • Scheme 6 illustrates two alternative methods of preparing 3-(4-alkoxy-1 H-pyrazol-3- yl)-1 ,2,5,6-tetrahydro-1-methylpyridine compounds.
  • C-O bond formation can be accomplished using the aforementioned Cul/1 ,10-phenanthroline catalyzed cross- coupling methodology to generate compound 31 G.
  • the synthesis of compound 33G has been illustrated in scheme 6, according to the procedures illustrated in scheme 5.
  • One aspect of the invention relates to bis 3-(4-alkylsulfanyl-1 H-pyrazol-3-yl)-1 ,2,5,6- tetrahydro-1-methylpyridine derivatives (for example compound 22C, scheme 7) that bind to and can activate muscarinic receptors (J. Med. Chem., 44, 2001 , 4563-4576).
  • lntrodution of the phenylsulfonyl as protective group starting from 20A was accomplished regio-selectively to generate 3-(1-phenylsulfonyl-4-bromo-1 H-pyrazol- 3-yl)-pyridine (36A from 20A).
  • the cross-coupling of aliphatic and aromatic thiols and aryl bromides can be mediated by a Pd 2 (dba) 3 /Xantphos catalytic system in refluxing xylene to afford the corresponding aryl thioethers (Organic Lettters, 6, 2004, 4587-4590, Tetrahedron, 61 , 2005, 5253-5259).
  • 36A was converted to the protected bis-alkylsulfanyl-pyrazol derivative 37. Removal of the Nrphenylsulfonyl group can be accomplished using methods well known to those skilled in the art, for example, optionally reacting compound 37 with potassium hydroxide in diethylene glycol in the presence of hydrazine.
  • Scheme 7 illustrates an alternative method for preparing 3-(4-alkylsulfanyl-1 H- pyrazol-3-yl)-1 ,2,5,6-tetrahydro-1-methylpyridine derivatives, so can be used to synthezise compounds presented in scheme 3 & 4 (22A and 22B respectively), the main feature being the availability of the parent thiol.
  • Scheme 9 illustrates the preparation of 3-(4-alkynyl (and alkenyl)-1 H-pyrazol-3-yl)- 1 ,2,5,6-tetrahydro-1 -methylpyridine derivatives as compounds of the formula I.
  • 3-(1 -Phenylsulfonyl-4-bromo-1 H-pyrazol-3-yl)-pyridine (36A, scheme 7) or its iodo analog 36B (scheme 9) are excellent substrates for Sonogashira couplings with terminal acetylenes (Tetrahedron Letters, 38, 1997, 7835-7838., Eur J. Org. Chem., 2006, 3283-3307).
  • 3-(4-iodo-1 H-pyrazol-3-yl)-1 -azabicyclo[2.2.2]octane (48, Bioorganic & Medicinal Chemistry 8, 2000, 449-454) is employed as starting material for compounds of the present invention of formula I (scheme 10).
  • Scheme 10 illustrates an alternative - but also general - method of preparing 3-(4- alkylsulfanyl-1 H-pyrazol-3-yl)-1-azabicyclo[2.2.2]octane derivatives.
  • compound 48 could be converted by the Pd 2 (dba) 3 /Xantphos catalytic system (analogous to scheme 7, but in DMF at 12O 0 C) yielding the corresponding aryl thioether 49B, in a single step without protection.
  • the mixture of readily available SEM protected pyrazoles 50 (one isomer given) was converted to a mixture of 51 A by the Cul/1 ,10-phenanthroline catalyzed cross- coupling methodology as described in scheme 6, however using different conditions. Subsequent deprotection of 51 A yields the corresponding 3-(4-butoxy-1 H-pyrazol-3- yl)-1-azabicyclo[2.2.2]-octane 52A.
  • 3-pyridinealdoxime (61 ) is converted to its chlorohydroxyimino derivative (US 2004/0157900) which is converted to nicotinonitrile oxide (Tetrahedron, 61 , 2005, 4363-4371 ) "in situ" and reacted with 1 ,2-bis-trimethylsilanyl-ethyne (Chem. Ber., 107, 1974, 3717-3722) to afford the 1 ,3- dipolar cycloaddition product 3-(4,5-bis-trimethylsilanyl-isoxazol-3-yl)-pyridine (62).
  • Halogen-induced ipso desilylation resulted in the 4-bromo-5-trimethylsilanyl derivative (63).
  • Subsequent desilylation with NH 4 OH (Chem. Ber., 112, 1979, 2829- 2836) generates 3-(4-bromo-isoxazol-3-yl)-pyridine (64).
  • the isoxazole-pyridine derivatives 62, 63 and 64 are new compounds and, as such, embodiments of the present invention.
  • Scheme 13 illustrates the preparation of 3-(4-alkynyl (and alkenyl)-isoxazol-3-yl)- 1 ,2,5,6-tetrahydro-1 -methylpyridine derivatives as compounds of the formula I.
  • 3-(4-Bromo-isoxazol-3-yl)-pyridine (64) is an excellent substrate for Sonogashira couplings with (terminal) acetylenes using an analog of the methodology described in scheme 9.
  • Nicotinoyl chloride hydrochloride (compound 1 ) (10 g, 56 mmol) and 6.28 g of N, O- dimethyl-hydroxylamine.HCI (72.8 mmol) were combined in 200 ml dichloromethane. To this mixture was added 18.14 ml of pyridine (in 15 minutes at O 0 C). The reaction mixture was subsequently stirred for 4 hours at room temperature. The reaction was concentrated in vacuo. The resulting residue was taken up in dichloromethane and H 2 O (O 0 C), washed with a 2N NaOH solution followed by brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Compound 21 D was prepared following the procedure as described for the synthesis of compound 21 A (see Scheme 3) using ethyldisulfanyl-ethane as the disulfide and 3-(4-bromo-1 H-pyrazol-3-yl)-pyridine (compound 20A).
  • Compound 21 F was prepared following the procedure as described for the synthesis of compound 21 A (see Scheme 3) using 1 -butyldisulfanyl-butane as the disulfide and 3-(4-iodo-1 H-pyrazol-3-yl)-pyridine (compound 20B). (flash chromatography conditions ethyl acetate/diethyl ether 3/1 ). Yield : 18.4%. (oil).
  • Compound 21 M was prepared following the procedure as described for the synthesis of compound 21 A (see scheme 3) using difurfuryl-disulfide and 3-(4-iodo-1 H-pyrazol- 3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield : 54%. (oil).
  • Compound 21 R was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-(2-cyano-ethyldisulfanyl)-propionitrile as the disulfide and 3-(4-iodo-1 H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield : 62%. (oil).
  • the temperature of the reaction mixture was lowered to -1 O 0 C and 2.2 ml (1.5 eq) of acetic acid was added. Subsequently, 1.1 eq of a 30% H 2 O 2 solution (2.93 ml) was added dropwise, while keeping the temperature ⁇ -5 0 C. The mixture was allowed to warm to ambient temperature and stirred for another 4 hours. To the reaction mixture was added 10 ml of H 2 O and subsequently ethyl acetate (500 ml). The organic layer was washed with a 5% NaHCO 3 solution, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • reaction mixture was subsequently treated with 38.4 mmol (6.74 ml) of 2- chloromethoxy-ethyl-trimethylsilane (SEM-CI). The resulting mixture was stirred for 20 hours at room temperature. Because of partial quarternization of the desired product (50), TBAF (1 M solution in THF, 45 ml, 45 mmol) was added and the mixture was stirred for 20 hours at room temperature.
  • the tissues were exposed to a maximal concentration of the respective reference agonist to verify responsiveness and to obtain a control response. Following extensive washings and recovery of the initial state, the tissues were exposed to the test compounds or the same agonist.
  • the compounds were left in contact with the tissues until a stable response was obtained or for a maximum of 15 min. When several concentrations were tested, they were added cumulatively.
  • the M3 receptor assay the compounds were left in contact with the tissues for a time sufficient to obtain a peak response or for a maximum of 10 min, then washed out. When several concentrations were tested, they were added consecutively at 40-min intervals. Where an agonist-like response was obtained, the respective reference antagonist was tested against the highest concentration of the compounds to confirm the involvement of the receptor studied in this response.
  • the tissues were exposed to a submaximal concentration of the respective reference agonist to obtain a control response.
  • the test compounds or the reference antagonists were added after stabilization of the agonist- induced response then left in contact with the tissues until a stable effect was obtained or for a maximum of 15 min. When several concentrations were tested, they were added cumulatively.
  • the test compounds or the reference antagonist were added 30 min before re-exposure to the agonist which was added at 40-min intervals. Where it occurred, an inhibition of the agonist-induced response produced by the compounds indicated an antagonist activity at the receptor studied.
  • Each compound was investigated in the three assays for agonist and antagonist activities at one or several concentrations in three separate tissues. In each assay, the reference agonist and antagonist were tested at several concentrations in three separate tissues to obtain concentration-response curves.
  • the parameters measured were the maximum change in the amplitude of the electrically-evoked contractions (M1 and M2 receptor assays) or in tension (M3 receptor assay) induced by each compound concentration. The results are expressed as a percent of the control agonist-induced response.
  • the EC50 values of the reference agonists (concentration producing a half-maximum response) and IC50 values of the reference antagonists (concentration producing a half-maximum inhibition of the agonist-induced response) were calculated by linear regression analysis of their concentration-response curves.
  • the results are expressed as a percent of reference agonist values and blanks in the presence of the test compound, percent stimulation for agonist mode; for the antagonist mode (test compound in the presence of reference agonist) as percent inhibition.
  • the EC50 values concentration causing a half-maximal stimulation of control values
  • IC50 values concentration causing a half-maximal inhibition of control values
  • Test Substance Compounds were dissolved in DMSO (10 mM) and diluted in assay buffer to test concentration. Prime testing was at 10 ⁇ M; for actives (Pl, percent inhibition with respect to total and non-specific binding > 40%) testing was continued at lower concentrations in 10-fold dilutions: 1 ⁇ M, 0.1 ⁇ M, etc.
  • the receptor preparations were rapidly filtered under vacuum through glass fibre filters; the filters were washed extensively with an ice-cold buffer using a harvester. Bound radioactivity was measured by scintillation counting using a liquid scintillation cocktail.
  • the inhibition constants (Ki) were calculated from the Cheng-Prushoff equation Ki IC50/(1 +L/Kd), where L is the concentration of radioligand in the assay, and Kd the affinity of the radioligand for the receptor. Results were expressed as pKi's, means ⁇ SD of at least 2 separate experiments; i.e. outliers (outside +/- 1 std of mean) and discrepancies were excluded. Compounds with no significant affinity at concentrations of 10 ⁇ M and higher were concluded to be "inactive" denoted by pKi of " ⁇ 5.0".
  • PERALTA E. G., ASHKENAZI, A., WINSLOW, J. W., SMITH, D. H., RAMACHANDRAN, J. and CAPON, D. J. (1987) Distinct primary structures, ligand- binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO. J., 6: 3923-3929.

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Abstract

La présente invention porte sur des composés hétérocycliques de formule (I) ou un sel pharmaceutiquement acceptable, un solvate ou un hydrate desdits composés. Dans ladite formule: 1) l'hétérocycle comprend deux doubles liaisons qui peuvent être présentes en plusieurs positions, représentées par des traits interrompus ( -- ); 2) l'hétérocycle contient deux hétéroatomes, W étant N ou NH, Y étant CH, O ou NH, où si Y est O, X1 représente CH et X2 est le C-Z-R2 ou C-R3 résiduel, où Z est NH, O ou S; et si Y est CH ou NH, X1 et X2 est CH ou N, l'autre étant le C-Z-R2 ou C-R3 résiduel, où Z représente NH ou S; 3) R1 est choisi parmi les structures (a), (b) et (c); 4) R2 est choisi parmi alkyle en C1-C10, alcényle enC2-C10 et alcynyle en C2-C10, facultativement substitué de façon indépendante par un ou plusieurs substituants choisis parmi halogène, hydroxy, cyano, oxo, alcoxy en C1-C6, alkylthio en C1-C6, alcényloxy en C1-C6, alcénylthio en C1-C6, alcoxy en C1-C4- alcoxy en C1-C4, cycloalkyle en C5-C7, un hétérocycle insaturé à 5 chaînons (facultativement substitué par halogène), phényle, phényloxy et phénylthio, où le groupe phényle est facultativement substitué par halogène; ou bien 5) R2 est un alkyle en C2-C8 non ramifié substitué sur le symbole Za d'un groupe ayant la formule (Ia) dans laquelle si X1 est CH ou N1, X1 est CH ou N et X2a est C-Za-, ou bien si X1 est C-Z-R2, X1a est C-Za- et X2a est CH ou N; et les symboles Wa, Ya et Za et le substituant R1a ont les mêmes significations que précédemment définies pour les symboles W, Y et Z et le substituant R1, et ne sont pas indépendamment choisis, chacun des symboles Wa, Ya et Za et le substituant R1a représentant respectivement des symboles et des substituants identiques, comme les symboles W, Y et Z et le substituant R1 dans l'autre partie de la structure de formule (I); 6) R3 est choisi parmi alkyle en C4-C10, alcényle en C2-C10 et alcynyle en C2-C10, facultativement indépendamment substitués par un ou plusieurs substituants choisis parmi halogène, hydroxy, cyano, alcoxy en C1C6, alkylthio en C1C6, alcényloxy en C1C6, alcénylthio en C1C6, alcoxy en C1-C4- alcoxy en C1-C4, cycloalkyle en C5-C7, un hétérocycle insaturé à 5 chaînons facultativement substitué par halogène, phényle, phényloxy et phénylthio, le groupe phényle étant facultativement substitué par halogène. Les composés de l'invention ont une affinité pour les récepteurs muscariniques et peuvent être utilisés dans le traitement, le soulagement ou la prévention de maladies et d'états à médiation par les récepteurs muscariniques.
EP08759382A 2007-04-24 2008-04-23 Composés hétérocycliques avec affinité des récepteurs muscariniques Withdrawn EP2150543A2 (fr)

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US8084473B2 (en) 2007-04-24 2011-12-27 Solvay Pharmaceuticals B.V. Heterocyclic compounds with affinity to muscarinic receptors
CN102459175A (zh) * 2009-05-07 2012-05-16 托蓝特医药公司 用于治疗糖尿病的哌啶衍生物
JP5996532B2 (ja) 2010-07-15 2016-09-21 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ 有害生物防除剤としての新規複素環式化合物
CA2880326A1 (fr) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibiteurs 3,4-disubstitue 1h-pyrazole et 4,5-disubstitue thiazole de syk
AR121893A1 (es) 2020-04-22 2022-07-20 Sumitomo Chemical Co Compuesto de fenilo y método para controlar enfermedades vegetales

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IL88156A (en) * 1987-11-13 1997-02-18 Novo Nordisk As Azacyclic compounds their preparation and pharmaceutical compositions containing them
WO1999062885A1 (fr) * 1998-06-05 1999-12-09 Boehringer Ingelheim Pharmaceuticals, Inc. 1-(4-aminophenyl) pyrazoles substitues et leur utilisation en tant qu'agents anti-inflammatoires
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JP2010525020A (ja) 2010-07-22
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CN101939311A (zh) 2011-01-05
MX2009011499A (es) 2009-11-09

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