WO2005067537A2 - Muscarinic acetylcholine receptor antagonists - Google Patents

Muscarinic acetylcholine receptor antagonists Download PDF

Info

Publication number
WO2005067537A2
WO2005067537A2 PCT/US2005/001333 US2005001333W WO2005067537A2 WO 2005067537 A2 WO2005067537 A2 WO 2005067537A2 US 2005001333 W US2005001333 W US 2005001333W WO 2005067537 A2 WO2005067537 A2 WO 2005067537A2
Authority
WO
WIPO (PCT)
Prior art keywords
biphenylyl
chloro
azabicyclo
methyl
oct
Prior art date
Application number
PCT/US2005/001333
Other languages
French (fr)
Other versions
WO2005067537A3 (en
Inventor
Dramane I. Laine
Michael R. Palovich
Alexander G. Preston
Anthony William James Cooper
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to US10/585,830 priority Critical patent/US20080249127A1/en
Priority to BRPI0506777-4A priority patent/BRPI0506777A/en
Priority to EP05711495A priority patent/EP1711183A4/en
Priority to JP2006549649A priority patent/JP2007518740A/en
Priority to CA002552880A priority patent/CA2552880A1/en
Priority to AU2005204935A priority patent/AU2005204935A1/en
Publication of WO2005067537A2 publication Critical patent/WO2005067537A2/en
Publication of WO2005067537A3 publication Critical patent/WO2005067537A3/en
Priority to IL176775A priority patent/IL176775A0/en
Priority to NO20063636A priority patent/NO20063636L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • This invention relates to the olefinic derivatives of novel biphenyl 8- azoniabicyclo [3.2.1] octane compounds, pharmaceutical compositions, and use thereof in treating muscarinic acetylcholine receptor mediated diseases of the respiratory tract.
  • BACKGROUND OF THE INVENTION Acetylcholine released from cholinergic neurons in the peripheral and central nervous systems affects many different biological processes through interaction with two major classes of acetylcholine receptors - the nicotinic and the muscarinic acetylcholine receptors.
  • Muscarinic acetylcholine receptors mAChRs
  • mAChRs belong to the superfamily of G-protein coupled receptors that have seven transmembrane domains.
  • M1-M5 There are five subtypes of mAChRs, termed M1-M5, and each is the product of a distinct gene. Each of these five subtypes displays unique pharmacological properties. Muscarinic acetylcholine receptors are widely distributed in vertebrate organs where they mediate many of the vital functions. Muscarinic receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, M3 mAChRs mediate contractile responses. For review, please see Caulfield (1993 Pharmac. Ther. 58:319-79).
  • mAChRs have been localized to smooth muscle in the trachea and bronchi, the submucosal glands, and the parasympathetic ganglia. Muscarinic receptor density is greatest in parasympathetic ganglia and then decreases in density from the submucosal glands to tracheal and then bronchial smooth muscle. Muscarinic receptors are nearly absent from the alveoli.
  • Mi M 2 and M 3 mAChRs.
  • the M 3 mAChRs located on airway smooth muscle, mediate muscle contraction. Stimulation of M 3 mAChRs activates the enzyme phospholipase C via binding of the stimulatory G protein Gq/11 (Gs), leading to liberation of phosphatidyl inositol-4,5-bisphosphate, resulting in phosphorylation of contractile proteins.
  • Gq/11 stimulatory G protein
  • M 3 mAChRs are also found on pulmonary submucosal glands. Stimulation of this population of M 3 mAChRs results in mucus secretion.
  • M 2 mAChRs make up approximately 50-80% of the cholinergic receptor population on airway smooth muscles.
  • Neuronal M 2 mAChRs are located on , postganglionic parasympathetic nerves. Under normal physiologic conditions, neuronal M mAChRs provide tight control of acetylcholine release from parasympathetic nerves. Inhibitory M 2 mAChRs have also been demonstrated on sympathetic nerves in the lungs of some species. These receptors inhibit release of noradrenaline, thus decreasing sympathetic input to the lungs. Mi mAChRs are found in the pulmonary parasympathetic ganglia where they function to enhance neurotransmission.
  • Muscarinic acetylcholine receptor dysfunction in the lungs has been noted in a variety of different pathophysiological states.
  • COPD chronic obstructive pulmonary disease
  • inflammatory conditions lead to loss of inhibitory M2 muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle, causing increased acetylcholine release following vagal nerve stimulation (Fryer et al. 1999 Life Sci 64 (6-7) 449- 55).
  • COPD chronic bronchitis, chronic bronchiolitis and emphysema
  • Smoking is the major risk factor for the development of COPD; nearly 50 million people in the U.S. alone smoke cigarettes, and an estimated 3,000 people take up the habit daily.
  • Combivent® in combination with albuterol
  • This invention provides for a method of treating a muscarinic acetylcholine receptor (mAChR) mediated disease, wherein acetylcholine binds to an mAChR and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • mAChR muscarinic acetylcholine receptor
  • This invention also relates to a method of inhibiting the binding of acetylcholine to its receptors in a mammal in need thereof which comprises administering to aforementioned mammal an effective amount of a compound of Formula (I).
  • the present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
  • n 0 or 1 ;
  • Ha is an hydrogen atom in the exo postion
  • Rl and R2 are, independently, selected from the group consisting of a bond, hydrogen and methyl;
  • R3 is selected from the group consisting of hydrogen and Cl-4 alkyl
  • R4 and R5 are independently selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, C2-4 alkenyl, halo substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted C 1 -4 alkyl, and (CR9R9)qNC(O)Ra
  • R6, R7 and R8 are, independently, selected from the group consisting of hydrogen, halogen, cyano, Cl-4 alkyl, C2-4 alkenyl, Cl-4 alkoxy, halo-substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted Cl-4 alkyl, and (CR9R9)qNC(O)Ra; or two of either R6, R7 or R8 moieties together may form a 5 to 6 membered saturated or unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
  • Ra is selected form the group consisting of hydrogen, Cl-4 alkyl, and halo substituted Cl-4 alkyl;
  • R9 is hydrogen or C 1 -4 alkyl q is 0, or an integer having a value of 1 to 4;
  • X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
  • anion such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
  • aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below.
  • the term "the aryl, heteroaryl, and heterocyclic containing moieties” refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings.
  • the term “moieties” and “rings” may be interchangeably used throughout.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted C ⁇ _ ⁇ oalkyl
  • C ⁇ _ ⁇ o alkoxy such as methoxy or ethoxy
  • S(O) m ' C ⁇ _ ⁇ o alkyl wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl
  • NRioRll group NHC(O)R9; C(O)NR ⁇ oRli; C(O)OH; S(O) 2 NR ⁇ oRli;
  • Ci-io alkyl such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted C ⁇ _io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O) m 'C ⁇ -io alkyl; amino, mono & di-substituted alkyl amino, such as in the NRh)Rl 1 group; Ci-io alkyl,
  • halo all halogens, that is chloro, fluoro, bromo and iodo.
  • C ⁇ _ ⁇ o lkyl or “alkyl” - both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, r ⁇ -propyl, zso-propyl, «-butyl, sec-butyl, iso-butyl, tert- butyl, ⁇ -pentyl and the like.
  • cycloalkyl is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • aryl - phenyl and naphthyl; • “heteroaryl” (on its own or in any combination, such as “heteroaryloxy", or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine.
  • sulfur may be optionally oxidized to the sulfone or the sulfoxide.
  • arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Cl-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • sulfinyl - the oxide S (O) of the corresponding sulfide
  • thio refers to the sulfide
  • sulfonyl refers to the fully oxidized S(O)2 moiety.
  • Illustrative compounds of the present invention include Examples 1 through 140, disclosed on pages 24 - 62 of the specification hereinafter.
  • Preferred compounds of Formula (I) include:
  • More preferred compounds Formula (I) useful in the present invention include:
  • Particularly preferred compounds of the present invention include: (3-endo)-3-( ⁇ [(3'-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl ⁇ oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide; and
  • the desired compounds of Formula (I) can be prepared via the Curtius reaction of a suitable biphenyl acid 1 with the suitably protected [3.2.1] bicyclic alcohol 2 using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent. Removal of the protecting group using standard conditions such as treatment with p-toluenesulfonic acid in acetonitrile gives the compound of Formula (I).
  • DPP A diphenylphosphoryl azide
  • the required [3.2.1] bicyclic alcohol 2 is not commercially available but can be prepared from compound 6 which has been previously described in the literature (T. Momone et al, J.C.S. Perkin. Trans. 1, 9, 1997. 1307-14).
  • compound 7 was prepared by the Wittig reaction of compound 6 using standard reagents such as methyltriphenyl phosphonium bromide and potassium tert- butoxide. Hydroboration of alkene 7 with disiamylborane followed by oxidation produced the alcohol 8. Subsequent removal of the benzylic moiety of 8 under hydrogenation conditions followed by protection of the ring nitrogen with a BOC group using standard conditions such as treatment with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide gave the desired alcohol 2.
  • the desired compounds of Formula (I) can also be prepared as outlined in Scheme 3.
  • a suitable carboxylic acid 3 can be reacted with the suitably protected [3.2.1] bicyclic alcohol 2 via the Curtius reaction using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent.
  • the intermediate 4 thus formed can be coupled to a suitable boronic acid 5 using standard methods well known in the art such as the Suzuki coupling with catalytic tetrakis(triphenylphosphino)palladium (0) in dimethylformamide and water in a presence of a base such as sodium carbonate or triethylamine. Removal of the protecting group on 4 using standard conditions such as treatment with p- toluenesulfonic acid in acetonitrile gives the compound of Formula (I).
  • a suitable alkylating reagent such as methyl bromide or methyl iodide
  • a base such as potassium carbonate
  • an inert solvent such as dimethylformamide
  • alkylation of the carbonate nitrogen may also occur.
  • a representative example is shown in Scheme 5.
  • the compounds of general formula (I) may also be prepared as depicted in Scheme 6.
  • a suitable carboxylic acid 3 can be reacted with the commercially available bicyclic alcohol 9 via the Curtius reaction using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent.
  • MDAP Mass Directed Automated Preparative
  • the preparative column used was a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5m)
  • the preparative column used was a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5m)
  • Step a Preparation of 3-methylidene-8-(phenylmethyl)-8-azabicyclo[3.2.11octane
  • a 500 ml flask with side arm, stirring bar, N 2 inlet, and septum stopper was charged with a solution of potassium tert-butoxide in THF (82 ml, 1M ) and methyltriphenyl phosphonium bromide (29.2 g, 82 mmol). It was cooled to 0 °C under dry N 2 , and anhydrous THF (140 ml) was added via syringe at 0 °C. The ylid solution was stirred for 20 min.
  • Step b Preparation of (3-ere oV8-(phenylmethyl)-8-azabicyclor3.2.1 " loct-3- yll methanol
  • a solution of disiamylborane was prepared by addition of 1.0 M borane in THF (20 ml, 20 mmol) to a 2.0 M solution of 2-methyl-2-butene in THF (20 ml, 40 mmol) at
  • Step c Removal of the benzyl group and protection with a BOC group
  • a solution of (3-erc ⁇ i ⁇ )-8-(phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]methanol (1.16 g) (Schneider et al, Arch. Pharm., 1975, 308-365) in exhanol (20 ml) and 6N HC1 (1 ml) containing palladium hydroxide on carbon (Pearlman's catalyst, 2.27 g, 22% (w/w)) was hydrogenated (55 psi H 2 ) at room temperature for 2 days. The catalyst was filtered off over Celite and the filtrate was evaporated under vacuum.
  • a mixture of methyl 4- [(phenylmethyl)oxy]-2- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ benzoate (390mg) and 3- chloroboronic acid (231mg) were added and the vessel was sealed.
  • the resulting mixture was heated in a microwave (Smith Creator, 150°C, 10 minutes). After cooling, the reaction mixture was diluted with dichloromethane (5ml), filtered through Hyflo and evaporated.
  • Example 1 (3-g « ⁇ fo " )-8-Azabicyclof3.2.1]oct-3-ylmethyl [3'-(trifluoromethyl)-2- biphenylyll carbamate
  • Example 3 (3-g «rfQV8-azabicyclof3.2.11oct-3-vImethyl-3',4'-bis(methyloxy)-2- biphenylyl] carbamate.
  • Example 4 (3-en o)-8-Azabicyclo[3.2.11oct-3-ylmethyl (4'-butyl-2- biphenylyDcarbamate
  • the title compound was prepared from 4'-butyl-2-biphenylcarboxylic acid according to the procedure outlined in example 1.
  • Example 5 (3-g «rfoV8-Azabicyclof3.2.11oct-3-ylmethyl[5-chloro-4'- (trifluoromethyI)-2-biphenylyricarbamate
  • the title compound was prepared from 5-chloro-4'-(trifluoromethyl)-2- biphenylcarboxylic acid according to the procedure outlined in example 1.
  • Example 6 (3-gw ⁇ fo)-8-Azabicvclo[3.2.11oct-3-ylmethyl[6-chloro-4'- (trifluoromethyf)-2-biphenylvHcarbamate
  • Example 8 (3-gw ⁇ foV8-Azabievclo[3.2.11oct-3-ylmethyl (4'-hydroxy-2- biphenylvDcarbamate
  • the title compound was prepared from 4'-hydroxy-2-biphenylcarboxylic acid according to the procedure outlined in example 1.
  • Example 16 (3-gH ⁇ foV8-azabicvclo[3.2.11oct-3-vImethyl (2',5'-dimethyl-2- biphenylvDcarbamate According to the procedure outlined in example 10, 2,5-dimethylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[( ⁇ [(2- bromophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R T 2.49 mins MH + 365.
  • Example 17 (3-g « ⁇ / ⁇ )-8-azabicyclo[3.2.11oct-3-ylmethyl (4 t -fluoro-3'-methyl-2- biphenylyDcarbamate
  • Example 20 (3-g « ⁇ /oV8-azabicyclo[3.2. ⁇ oct-3-ylmethyl [2-(2- naphthalenvDphenyll carbamate
  • Example 22 (3-g/ ⁇ fo)-8-azabieyclo [3.2.11 oct-3-ylmethyl (3'- [(trifluoromethv oxyl -2-biphenylyl) carbamate According to the procedure outlined in example 10, ⁇ 3-
  • Example 25 (3-g/iffoV8-azabicvclor3.2.11oct-3-ylmethyl [2'-(trifluoromethvD-2- biphenylyll carbamate According to the procedure outlined in example 10, (2-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( ⁇ [(2-bromophenyl)amino] carbonyl ⁇ oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound.
  • Example 26 (3-g «*fo -8-azabieyclo[3.2.11oct-3-ylmethyl [4'-(l.l-dimethylethvP- 2-biphenylvH carbamate
  • Example 31 (3-g « ⁇ fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-fluoro-2- biphenylyPcarbamate
  • (3-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)-[( ⁇ [(2-bromophenyl)amino] carbonyl ⁇ oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound.
  • Example 34 (3-g « ⁇ /o)-8-azabicyclo[3.2.11oct-3-ylmethyl [4'-(methyloxy)-2- biphenylyll carbamate According to the procedure outlined in example 10, [4-(methyloxy)phenyl]boronic acid and 1,1-dimethylethyl (3-endo)-[( ⁇ [(2- bromophenyl)amino] carbonyl ⁇ oxy)methyl] -8 -azabicyclo [3.2.1] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI R T 2.29 mins MH + 367.
  • Example 37 (3-g/ ⁇ / ⁇ )-8-azabicyclof3.2.11oct-3-yImethyl [2'-(methyloxy)-2- biphenylyll carbamate
  • Example 40 (3-g « ⁇ / ⁇ -8-azabicyclo[3.2.11oct-3-ylmethyI (3'-chloro-4'-fluoro-2- biphenylvPcarbamate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e « ⁇ ⁇ )-[( ⁇ [(2-bromophenyl)amino]carbonyl ⁇ oxy)methyl]- 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R ⁇ 2.42 mins MH ⁇ 389.
  • Example 43 (3-gn ⁇ o)-8-azabicyclof3.2.11oct-3-ylmethyl [3'-chIoro-4'-fluoro-5,6- bis(methyloxy)-2-biphenylyl1carbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e ⁇ io)- ⁇ [( ⁇ [2-bromo-3,4- bis(methyloxy)phenyl]amino ⁇ carbonyl)oxy]methyl ⁇ -8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI R 2.56 mins MH + 449.
  • Example 45 (3-gwrf )-8-azabicycIo[3.2.11oct-3-ylmethyl [3'-chloro-4'-fluoro-4- (methyloxyV2-biphenylyl]carbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-er ⁇ do)- ⁇ [( ⁇ [2-bromo-5- (methyloxy)phenyl]amino ⁇ carbonyl)oxy]methyl ⁇ -8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.71 mins Mt 419.
  • Example 46 (3-g « ⁇ foV8-azabievclo[3.2.11oct-3-ylmethyI [4-(methyloxy -2- biphenylyll carbamate
  • Example 47 (3-g « ⁇ foV8-azabicvclo [3.2.11 oct-3-ylmethyl (3'-chloro-5-methyl-2- biphenylyPcarbamate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( ⁇ [(2-bromo-4-methylphenyl)amino]carbonyloxy) methyl]-8 ⁇ azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R ⁇ 2.72 ins MH " 385.
  • Example 48 (3-g/f ⁇ fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-4'-fluoro-5- methyl-2-biphenylyPcarbamate
  • Example 49 (3-g «rfoV8-azabicvclo [3.2.11 oct-3-ylmethyl (5-methyl-2- biphenylvPcarbamate According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3 -endo)- [( ⁇ [(2-bromo-4-methylphenyl)amino] carbonyl ⁇ oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound.
  • Example 50 (3-g « ⁇ foV8-azabicyclo [3.2.11 oct-3-ylmethyl (3'-chloro-3-methyl-2- biphenylvPcarbamate
  • Example 51 (3-g/ ⁇ / ⁇ V8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-4-fh ⁇ oro-2- biphenylvPcarbamate
  • Example 53 (3-gfi ⁇ fo)-8-azabicvclo[3.2.11oct-3-ylmethyI (3 , -chIoro-4',6-difluoro- 2-biphenylvPcarbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e « o)-[( ⁇ [(2-bromo-3- fluorophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R 2.72 mins MH + 407.
  • Example 54 (3-gM ⁇ fo)-8-azabicvclo[3.2.11oct-3-ylmethyl (6-fluoro-2- biphenylvPcarbamate
  • Example 55 (3-g «rfo)-8-azabicvclo[3.2.11oct-3-ylmethyl (3 , -chloro-4',5-difluoro- 2-biphenylvPcarbamate
  • Example 56 (3-g « ⁇ fo)-8-azabicvclo[3.2.11oct-3-ylmethyl [3'-chloro-4- (methyloxy -2-biphenylyll carbamate trifluoroacetate
  • Example 59 (3-g» ⁇ /o)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-5-fluoro-2- biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e « ⁇ )-[( ⁇ [(2-bromo-4-fluorophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R ⁇ 2.50 mins MH + 389.
  • Example 60 (3-g/f ⁇ o -8-azabicyclo[3.2.11oct-3-ylmethyl (3'-fluoro-4-methyl-2- biphenylyPcarbamate trifluoroacetate
  • Example 64 (3-g « ⁇ foy8-azabicvclo[3.2.11oct-3-ylmethyl (3',4-difluoro-2- biphenylyPcarbamate trifluoroacetate
  • Example 66 (3-g « ⁇ foV8-azabicvelor3.2.11oct-3-ylmethyl (4'-fluoro-3',4- dimethyl-2-biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluoro-3 -methy Iphenyl) boronic acid and 1,1-dimethylethyl (3-en ⁇ )-[( ⁇ [(2-bromo-5-methylpheny ⁇ ) amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1 ] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI R ⁇ 2.73 mins MH + 383.
  • Example 70 (3-g « ⁇ foV8-azabicvclo[3.2.11oct-3-ylmethyl (4,4'-difluoro-3'- methyl-2-biphenylvPcarbamate trifluoroacetate
  • Example 71 (3-g «rfo)-8-azabicyclo[3.2.11oct-3-ylmethyl (4',5-difluoro-3'- methyl-2-biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluoro-3- methylphenyl)boronic acid and 1,1-dimethylethyl (3-e « o)-[( ⁇ [(2-bromo-4- fluorophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R T 2.65 mins MH + 387.
  • Example 72 (3-g « ⁇ fo)-8-azabicyclo[3.2.1]oct-3-yImethyl (3',4-dichloro-4 f -fluoro- 2-biphenyIvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (3-chloro-4-fluorophenyl) boronic acid and 1,1-dimethylethyl (3-e «cf ⁇ )-[( ⁇ [(2-bromo-5-chlorophenyl) amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R ⁇ 2.81 mins MH + 423.
  • Example 74 (3-g « ⁇ f ⁇ V8-azabicyclof3.2.11oct-3-ylmethyl (3'-chloro-4,4'-difluoro- 2-biphenylvPcarbamate trifluoroacetate
  • Example 76 (3-gw ⁇ /o)-8-azabicyclof3.2.11oct-3-yImethyI (4-chloro-2'-fluoro-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (2-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-ewfo)-[( ⁇ [(2-bromo-5- chlorophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.66 mins MET 1" 389.
  • Example 77 (3-g» ⁇ foV8-azabicvclo [3.2.11 oct-3-ylmethyl (2'-fluoro-5-methyl-2- biphenylyPcarbamate trifluoroacetate
  • Example 80 (3-g « ⁇ /o -8-azabicyclo[3.2.11oct-3-ylmethyl (4'-fluoro-4-methyl-2- biphenylyPcarbamate trifluoroacetate
  • Example 82 (3-gwrfoV8-azabicyclo [3.2.11 oct-3-ylmethyl (4'-fluoro-5-methyl-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e «t ⁇ )-[( ⁇ [(2-bromo-4- methylphenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI R T 2.62 mins
  • Example 84 (3-g « ⁇ fo)-8-azabicyclo [3.2.11 oct-3-ylmethyl (4,4'-difluoro-2- biphenylyPcarbamate trifluoroacetate
  • Example 88 (3-g « ⁇ fo)-8-azabicyclo[3.2.11oct-3-ylmethyI (3,3'-dimethyl-2- biphenylyPcarbamate trifluoroacetate
  • Example 90 (3-g»rfoV8-azabicvelof3.2.11oct-3-ylmethyl (5-fluoro-3'-methyl-2- biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-emfo)-[( ⁇ [(2-bromo-4- fluorophenyl)amino] carbonyl ⁇ oxy)methyl] -8-azabicyclo [3.2.1 ]octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI R T 2.62 mins MH + 369.
  • Example 92 (3-g «tfoV8-azabicyclo[3.2.11oct-3-ylmethyl (4-chloro-4 t -methyI-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-ewd ⁇ )-[( ⁇ [(2-bromo-5- chlorophenyl)amino]carbonyl ⁇ oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.79 mins MH 4" 385.
  • Example 93 (3-gf* ⁇ foy8-azabicvclo[3.2.11oct-3-ylmethyl (4',5-dimethyl-2- biphenylyPcarbamate trifluoroacetate
  • Example 99 (3-gw ⁇ foH(f r(3'-chloro-3-methyl-2- biphenylyPaminol carb ony 1 ⁇ oxy)methy 1] -8,8-dimethy 1-8- azoniabicyclo[3.2.11octane trifluoroacetate
  • the title compound was prepared from (3-e ⁇ i ⁇ )-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 -chloro-3 -methyl-2-bi ⁇ henylyl)carbamate according to the procedure outlined in example 97.
  • Example 100 ⁇ -gwffoH f ⁇ '-ehloro- ⁇ -fluoro ⁇ - biphenylyP(methyPaminolcarbonyl ⁇ oxy)methyn-8,8-dimethyl-8- azoniabicyclo [3.2.11 octane trifluoroacetate
  • Example 102 (3-g ⁇ o)-[( ⁇ [(3'-chloro-3-fluoro-2- biphenylyPfmethyPaminolcarbonyPoxy ⁇ methyll-S ⁇ -dimethyl-S- azoniabicyclo[3.2.11octane trifluoroacetate
  • Example 103 (3-gwrfoV[((f(3'-chloro-2- biphenylyPaminolcarbonyl ⁇ oxy)methyll-8,8-dimethyI-8- azoniabicyclo [3.2.11 octane trifluoroacetate
  • Example 104 (3-g « ⁇ o)-8-azabicyclo[3.2.11oct-3-ylmethyl 2- biphenylylcarbamate
  • PS-PPh 3 -Pd (0.020 g, 0.0026 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromo-5-fluorophenyl)carbamate (0.063 g, 0.18 mmol) in DME (1 mL) in a 4 mL glass vial.
  • a solution of 3-chlorophenyl boronic acid (0.055 g, 0.35 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K2CO 3 (0.056 g, 0.41 mmol) in H 2 O (0.5 mL).
  • Example 108 8-methyl-8-azabicvclor3.2.1Ioct-3-yl (3'-chloro-4'-fluoro-2- biphenylyPcarbamate PS-PPh 3 -Pd (0.020 g, 0.0026 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromo-5-chlorophenyl)carbamate (0.035 g, 0.095 mmol) in DME (1 mL) in a microwave reactor tube.
  • Pd(PPh3)4 (0.089 g, 0.077 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromophenyl)carbamate (0.130 g, 0.383 mmol) in DME (1 mL) in a 4 mL glass vial with a magnetic stir bar.
  • a solution of 3- chlorophenylboronic acid (0.090 g, 0.58 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K CO3 (0.200 g, 1.44 mmol) in H 2 O
  • Pd(PPh 3 ) 4 (0.089 g, 0.077 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromophenyl)carbamate (0.060 g, 0.177 mmol) in DME (1 mL) in a 4 mL glass vial with a magnetic stir bar .
  • a solution of phenylboronic acid (0.043 g, 0.354 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K 2 CO 3 (0.056 g, 0.407 mmol) in H 2 O (0.5 mL).
  • the glass vial was capped and heated at 80° C for 16 h.
  • Example 136 3-( ⁇ [(3'-chloro-2-biphenylvPaminolearbonyl ⁇ oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.11octane bromide
  • the aqueous layer was extracted with DCM (1 x 4 mL), and the combined organic layers were diluted with 50 mL of DCM. This solution was loaded onto a 10 g aminopropyl SPE cartridge primed with 60 mL of DCM. The cartridge was then sequentially eluted with DCM (1 x 60 mL), Et 2 O (1 x 60 mL), EtOAc (5 x 60 mL), and MeOH (1 x 60 mL). The title compound was found in the EtOAc fractions, which were concentrated under reduced pressure to yield (3-endo)- 8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2-bromo-4-fluorophenyl)carbamate (0.343 g).
  • PS-PPh 3 -Pd (0.020 g, 0.0026 mmol) was added to a solution of (3-ewfo)-8-me hyl-
  • the glass vial was capped, and the reaction was agitated in an shaker at 80 °C for 48 h.
  • the resin was removed by gravity filtration, washed with DME (l l mL) and EtOH (l x l mL), and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in DCM (4 mL) and transferred onto a 6 mL hydrophobic frit. H 2 O (2 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 x 4 mL).
  • Example 138 3-( ⁇ f(3'-chloro-5-fluoro-2-biphenylvPaminolcarbonylloxy)-8,8- dimethyl-8-azoniabicvclo[3.2.11octane bromide
  • Example 140 (3-g/ ⁇ foH( ⁇ K3'-chloro-2- biphenylvPaminolcarbonylloxy)methyll-8,8-dimethyl-8- azoniabicyclo[3.2.11octane bromide
  • inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo functional assays:
  • Fluo-3- acetoxymethyl ester fluorescent indicator dye (Fluo-3 AM, Molecular Probes, Eugene, OR) and incubated 1 hr at 37° C. The dye-containing media was then aspirated, replaced with fresh media (without Fluo-3 AM), and cells were incubated for 10 minutes at 37° C.
  • mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes. Mice were then challenged with an aerosol of methacholine (10 mg/ml) for 2 minutes. Penh was recorded continuously for 7 min starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterward. Data for each mouse were analyzed and plotted by using GraphPad PRISM software. This experiment allows the determination of duration of activity of the administered compound.
  • the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
  • respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
  • the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • the present invention may be used to treat a mammal, including a human, in need of treatment.
  • active ingredient means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • Compounds of formula (I) will be administered via inhalation via the mouth or nose.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (e.g., lactose or starch), organic or inorganic salts (e.g., calcium chloride, calcium phosphate or sodium chloride), polyalcohols (e.g., mannitol), or mixtures thereof, alternatively with one or more additional materials, such additives included in the blend formulation to improve chemical and/or physical stability or performance of the formulation, as discussed below, or mixtures thereof.
  • a suitable powder base such as mono-, di- or poly-saccharides (e.g., lactose or starch), organic or inorganic salts (e.g., calcium chloride, calcium phosphate or sodium chloride), polyalcohols (e.g., mannitol), or mixtures thereof, alternatively with one or more additional materials, such additives included in the
  • Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient.
  • the compound of the invention may be presented without excipients, or may be formed into particles comprising the compound, optionally other therapeutically active materials, and excipient materials, such as by co-precipitation or coating.
  • the medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).
  • reservoir dry powder inhaler By reservoir dry powder inhaler (RDPI) it is meant as an inhaler having a reservoir form pack suitable for comprising multiple (un-metered doses) of medicament in dry powder form and including means for metering medicament dose from the reservoir to a delivery position.
  • the metering means may for example comprise a metering cup or perforated plate, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
  • multi-dose dry powder inhaler MDPI
  • the carrier has a blister pack form, but it could also, for example, comprise a capsule-based pack form or a carrier onto which medicament has been applied by any suitable process including printing, painting and vacuum occlusion.
  • the formulation can be pre-metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715).
  • An example of a unit-dose device is Rotahaler (see GB 2064336).
  • the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.
  • the strip is sufficiently flexible to be wound into a roll.
  • the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
  • the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
  • the multi-dose pack is a blister pack comprising multiple blisters for containment of medicament in dry powder form.
  • the blisters are typically arranged in regular fashion for ease of release of medicament therefrom.
  • the multi-dose blister pack comprises plural blisters arranged in generally circular fashion on a disk-form blister pack.
  • the multi- dose blister pack is elongate in form, for example comprising a strip or a tape.
  • the multi-dose blister pack is defined between two members peelably secured to one another.
  • the device is usually provided with an opening station comprising peeling means for peeling the members apart to access each medicament dose.
  • the device is adapted for use where the peelable members are elongate sheets which define a plurality of medicament containers spaced along the length thereof, the device being provided with indexing means for indexing each container in turn. More preferably, the device is adapted for use where one of the sheets is a base sheet having a plurality of pockets therein, and the other of the sheets is a lid sheet, each pocket and the adjacent part of the lid sheet defining a respective one of the containers, the device comprising driving means for pulling the lid sheet and base sheet apart at the opening station.
  • metered dose inhaler it is meant a medicament dispenser suitable for dispensing medicament in aerosol form, wherein the medicament is comprised in an aerosol container suitable for containing a propellant-based aerosol medicament formulation.
  • the aerosol container is typically provided with a metering valve, for example a slide valve, for release of the aerosol form medicament formulation to the patient.
  • the aerosol container is generally designed to deliver a predetermined dose of medicament upon each actuation by means of the valve, which can be opened either by depressing the valve while the container is held stationary or by depressing the container while the valve is held stationary.
  • Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g.
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
  • a canister eg an aluminium canister
  • a valve eg a metering valve
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum aerodynamic particle size for inhalation into the bronchial system for localized delivery to the lung is usually 1-1 O ⁇ m, preferably 2- 5 ⁇ m.
  • the optimum aerodynamic particle size for inhalation into the alveolar region for achieving systemic delivery to the lung is approximately .5-3 ⁇ m, preferably 1-3 ⁇ m.
  • Particles having an aerodynamic size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • Average aerodynamic particle size of a formulation may be measured by, for example cascade impaction.
  • Average geometric particle size may be measured, for example by laser diffraction, optical means.
  • the particles of the active ingredient as produced may be size reduced by conventional means eg by controlled crystallization, micronisation or nanomilling .
  • the desired fraction may be separated out by air classification.
  • particles of the desired size may be directly produced, for example by spray drying, controlling the spray drying parameters to generate particles of the desired size range.
  • the particles will be crystalline, although amorphous material may also be employed where desirable.
  • an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention, such that the "coarse" carrier is rion-respirable.
  • the excipient When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
  • Additive materials in a dry powder blend in addition to the carrier may be either respirable, i.e., aerodynamically less than 10 microns, or non-respirable, i.e., aerodynamically greater than 10 microns.
  • Suitable additive materials which may be employed include amino acids, such as leucine; water soluble or water insoluble, natural or synthetic surfactants, such as lecithin (e.g., soya lecithin) and solid state fatty acids (e.g., lauric, palmitic, and stearic acids) and derivatives thereof (such as salts and esters); phosphatidylcholines; sugar esters.
  • Additive materials may also include colorants, taste masking agents (e.g., saccharine), anti-static-agents, lubricants (see, for example, Published PCT Patent Appl. No.
  • WO 87/905213 the teachings of which are incorporated by reference herein
  • chemical stabilizers e.g., stearic acid or polymers, e.g. polyvinyl pyrolidone, polylactic acid
  • active material or active material containing particles see, for example, Patent Nos. US 3,634,582, GB 1,230,087, GB 1,381,872, the teachings of which are incorporated by reference herein).
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • Preferred unit dosage formulations are those containing an effective dose, as herein before recited, or an appropriate fraction thereof, of the active ingredient.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Muscarinic Acetylcholine Receptor Antagonists and methods of using them are provided.

Description

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS FIELD OF THE INVENTION
This invention relates to the olefinic derivatives of novel biphenyl 8- azoniabicyclo [3.2.1] octane compounds, pharmaceutical compositions, and use thereof in treating muscarinic acetylcholine receptor mediated diseases of the respiratory tract. BACKGROUND OF THE INVENTION Acetylcholine released from cholinergic neurons in the peripheral and central nervous systems affects many different biological processes through interaction with two major classes of acetylcholine receptors - the nicotinic and the muscarinic acetylcholine receptors. Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein coupled receptors that have seven transmembrane domains. There are five subtypes of mAChRs, termed M1-M5, and each is the product of a distinct gene. Each of these five subtypes displays unique pharmacological properties. Muscarinic acetylcholine receptors are widely distributed in vertebrate organs where they mediate many of the vital functions. Muscarinic receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, M3 mAChRs mediate contractile responses. For review, please see Caulfield (1993 Pharmac. Ther. 58:319-79). In the lungs, mAChRs have been localized to smooth muscle in the trachea and bronchi, the submucosal glands, and the parasympathetic ganglia. Muscarinic receptor density is greatest in parasympathetic ganglia and then decreases in density from the submucosal glands to tracheal and then bronchial smooth muscle. Muscarinic receptors are nearly absent from the alveoli. For review of mAChR expression and function in the lungs, please see Fryer and Jacoby (1998 Am JRespir
Crit Care Med 158(5, pt 3) S 154-60). Three subtypes of mAChRs have been identified as important in the lungs,
Mi, M2 and M3 mAChRs. The M3 mAChRs, located on airway smooth muscle, mediate muscle contraction. Stimulation of M3 mAChRs activates the enzyme phospholipase C via binding of the stimulatory G protein Gq/11 (Gs), leading to liberation of phosphatidyl inositol-4,5-bisphosphate, resulting in phosphorylation of contractile proteins. M3 mAChRs are also found on pulmonary submucosal glands. Stimulation of this population of M3 mAChRs results in mucus secretion. M2 mAChRs make up approximately 50-80% of the cholinergic receptor population on airway smooth muscles. Although the precise function is still unknown, they inhibit catecholaminergic relaxation of airway smooth muscle via inhibition of cAMP generation. Neuronal M2 mAChRs are located on , postganglionic parasympathetic nerves. Under normal physiologic conditions, neuronal M mAChRs provide tight control of acetylcholine release from parasympathetic nerves. Inhibitory M2 mAChRs have also been demonstrated on sympathetic nerves in the lungs of some species. These receptors inhibit release of noradrenaline, thus decreasing sympathetic input to the lungs. Mi mAChRs are found in the pulmonary parasympathetic ganglia where they function to enhance neurotransmission. These receptors have also been localized to the peripheral lung parenchyma, however their function in the parenchyma is unknown. Muscarinic acetylcholine receptor dysfunction in the lungs has been noted in a variety of different pathophysiological states. In particular, in asthma and chronic obstructive pulmonary disease (COPD), inflammatory conditions lead to loss of inhibitory M2 muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle, causing increased acetylcholine release following vagal nerve stimulation (Fryer et al. 1999 Life Sci 64 (6-7) 449- 55). This mAChR dysfunction results in airway hyperreactivity and hyperresponsiveness mediated by increased stimulation of M3 mAChRs. Thus the identification of potent mAChR antagonists would be useful as therapeutics in these mAChR-mediated disease states. COPD is an imprecise term that encompasses a variety of progressive health problems including chronic bronchitis, chronic bronchiolitis and emphysema, and it is a major cause of mortality and morbidity in the world. Smoking is the major risk factor for the development of COPD; nearly 50 million people in the U.S. alone smoke cigarettes, and an estimated 3,000 people take up the habit daily. As a result, COPD is expected to rank among the top five as a world- wide health burden by the year 2020. Inhaled anti-cholinergic therapy is currently considered the "gold standard" as first line therapy for COPD (Pauwels et al. 2001 Am. J. Respir. Crit. Care Med. 163:1256-1276). Despite the large body of evidence supporting the use of anti-cholinergic therapy for the treatment of airway hyperreactive diseases, relatively few anti- cholinergic compounds are available for use in the clinic for pulmonary indications.
More specifically, in United States, Ipratropium Bromide (Atrovent©' and
Combivent®, in combination with albuterol) is currently the only inhaled anti- cholinergic marketed for the treatment of airway hyperreactive diseases. While this compound is a potent anti-muscarinic agent, it is short acting, and thus must be administered as many as four times daily in order to provide relief for the COPD patient. In Europe and Asia, the long-acting anti-cholinergic Tiotropium Bromide
(Spiriva©) was recently approved, however this product is currently not available in the United States. Thus, there remains a need for novel compounds that are capable of causing blockade at mAChRs which are long acting and can be administered once-daily for the treatment of airway hyperreactive diseases such as asthma and COPD. Since mAChRs are widely distributed throughout the body, the ability to apply anti-cholinergics locally and/or topically to the respiratory tract is particularly advantageous, as it would allow for lower doses of the drug to be utilized.
Furthermore, the ability to design topically active drugs that have long duration of action, and in particular, are retained either at the receptor or by the lung, would allow the avoidance of unwanted side effects that may be seen with systemic anti- cholinergic use. SUMMARY OF THE INVENTION This invention provides for a method of treating a muscarinic acetylcholine receptor (mAChR) mediated disease, wherein acetylcholine binds to an mAChR and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. This invention also relates to a method of inhibiting the binding of acetylcholine to its receptors in a mammal in need thereof which comprises administering to aforementioned mammal an effective amount of a compound of Formula (I). The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure:
Figure imgf000005_0001
(I) wherein:
n is 0 or 1 ;
Ha is an hydrogen atom in the exo postion,
Rl and R2 are, independently, selected from the group consisting of a bond, hydrogen and methyl;
R3 is selected from the group consisting of hydrogen and Cl-4 alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, C2-4 alkenyl, halo substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted C 1 -4 alkyl, and (CR9R9)qNC(O)Ra R6, R7 and R8 are, independently, selected from the group consisting of hydrogen, halogen, cyano, Cl-4 alkyl, C2-4 alkenyl, Cl-4 alkoxy, halo-substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted Cl-4 alkyl, and (CR9R9)qNC(O)Ra; or two of either R6, R7 or R8 moieties together may form a 5 to 6 membered saturated or unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
Ra is selected form the group consisting of hydrogen, Cl-4 alkyl, and halo substituted Cl-4 alkyl; R9 is hydrogen or C 1 -4 alkyl q is 0, or an integer having a value of 1 to 4;
X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
All of the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below. For use herein the term "the aryl, heteroaryl, and heterocyclic containing moieties" refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term "moieties" and "rings" may be interchangeably used throughout. As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Cι _ι oalkyl; Cι _ιo alkoxy, such as methoxy or ethoxy; S(O)m' Cι _ιo alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the
NRioRll group; NHC(O)R9; C(O)NRιoRli; C(O)OH; S(O)2NRιoRli;
NHS(O)2R9, Ci-io alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Cι_io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O)m'Cι -io alkyl; amino, mono & di-substituted alkyl amino, such as in the NRh)Rl 1 group; Ci-io alkyl, or halosubstituted C i _1 o alkyl, such as CF3.
The following terms, as used herein, refer to: • "halo" - all halogens, that is chloro, fluoro, bromo and iodo. • "Cι_ιo lkyl" or "alkyl" - both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, rø-propyl, zso-propyl, «-butyl, sec-butyl, iso-butyl, tert- butyl, π-pentyl and the like. • "cycloalkyl" is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. • "alkenyl" is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. • "aryl" - phenyl and naphthyl; • "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole. • "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfur may be optionally oxidized to the sulfone or the sulfoxide. • "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean Cl-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. • "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety. • "wherein two Rl moieties (or two Y moieties) may together form a 5 or 6 membered saturated or unsaturated ring" is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Illustrative compounds of the present invention include Examples 1 through 140, disclosed on pages 24 - 62 of the specification hereinafter.
Preferred compounds of Formula (I) include:
(3-e«<io)-3-[({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-eftdø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e«(io)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-3-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-e«<io)-8-azabicyclo[3.2.1]oct-3-ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3-e«co)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-2-biphenylyl)carbamate;
(3 -endo)-8 -azabicyclo [3.2.1 ] oct-3 -ylmethyl (3 '-chloro-5 -hy droxy-2- biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-erø<iø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-chloro-6-fluoro-2- biphenylyl)carbamate trifluoroacetate; (3-e« ø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-fluoro-2-biphenylyl)carbamate;
(3-enc ø)-3-[({[(3,-chloro-5-hydroxy-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3 -endo)-3 -[({ [(3 '-chloro-4-fluoro-2-biphenylyl)amino] carbonyl } oxy)methyl] -8 ,8 - dimethyl-8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-e«<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-methyl-2- biphenylyl)carbamate trifluoroacetate;
(S-e^^-δ-azabicyclotS^.lJoct-S-ylmethy^S'-chloro^-fluoro^- biphenylyl)carbamate trifluoroacetate; (3-en ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-3'-methyl-2- biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4,4'-difluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-era/ø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-chloro-4'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«dø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate; (3-e«<iø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-chloro-4'-fluoro-2- biphenylyl)carbamate;
(3-e«<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-2-biphenylyl)carbamate;
(3-e«dø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3',5-difluoro-2-biphenylyl)carbamate trifluoroacetate; (3-e«rfø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4',5-difluoro-3,-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-endø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (4'-fluoro-2-biphenylyl)carbamate;
(3-e«^ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (5-fluoro-3'-methyl-2- biphenylyl)carbamate trifluoroacetate; (3 -endo)-3 - [( { [(3 '-chloro-3 -methyl-2-biphenylyl)amino] carbonyl } oxy)methyl] -8, 8 - dimethyl-8-azoniabicyclo[3.2. ljoctane trifluoroacetate; (3-e«iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3 -en do)- 8-azabicyclo [3.2.1 ] oct-3 -ylmethyl (3 '-chloro-4'-fluoro-3 -methyl-2- biphenylyι)carbamate trifluoroacetate; (3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4-methyl-2-biphenylyl)carbamate;
(3-e« o)-3-[({[(3'-chloro-6-fluoro-2- biphenylyl)(methyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl-8- azoniabicy clo [3.2.1] octane trifluoroacetate;
(3-e«dø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-4'-fluoro-5-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-erødø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4-fluoro-2-biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-methyl-2-biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',6-difluoro-2- biphenylyl)carbamate; (3-en dø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (4'-fluoro-4-methyl-2- biphenylyι)carbamate trifluoroacetate;
(3-eπ ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-eπt ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (6-fluoro-2-biphenylyl)carbamate; (3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3',4-dichloro-4'-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e«fi?ø)-3-({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1 ] octane bromide;
(3-e«<iø)-3-({[(3'-chloro-3,4'-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3 -endo)-3 -( { [(3 '-chloro-5 -fluoro-2-biphenylyl)amino] carbonyl } oxy)- 8, 8 -dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3 -endo)-3 -( { [(3 '-chloro-4'-fluoro-2-biphenylyl)amino] carbonyl } oxy)-8 , 8 -dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-e«£/ø)-3-({[(3'-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide; (3-e«c?ø)-3-({[(3',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1 joctane bromide;
(3-e« ø)-3-({[(3'-chloro-4',6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1 ]octane bromide; (3-en ø)-3-({[(3,-chloro-3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate;
(3-e« ø)-3-({[(3'-chloro-5-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-e«^ø)-3-({[(3',5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. ljoctane bromide;
(3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-3,4'-difluoro-2- biphenylyl)carbamate; (3-eπfifø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-2-biphenylyl)carbamate;
(3-e«c?ø)-3-({[(3,-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide;
(3-ent ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',6-difluoro-2- biphenylyl)carbamate; (3 -endo)-3 -( { [(3 -fluoro-2-biphenylyl)amino] carbonyl } oxy)-8 , 8 -dimethyl-8 - azoniabicyclo[3.2.1]octane bromide;
(3-eflrfø)-8-methyl-8-azabicyclo[3.2.1]oct-3~yl (3',5-dichloro-4'-fluoro-2- biphenylyl)carbamate;
(3-e«<iø)-3-({[(3'-chloro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-e«^o)-3-{[(2-biphenylylamino)carbonyl]oxy}-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide;
(3-e«cø)-3-({[(3'-chloro-4,-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1 joctane bromide; (3-e/ϊ^ø)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. ljoctane bromide; (3-e« ø)-3-({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide;
(3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3-fluoro-2-biphenylyl)carbamate;
(3-e« ø)-3-({[(3',4-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-e«<iø)-3-({[(5-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide;
(3-e« ø)-8,8-dimethyl-3-({[(4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8- azoniabicyclo [3.2.1] octane bromide; (3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (5-fluoro-2-biphenylyl)carbamate;
(3-e«dø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-6-fiuoro-2- biphenylyl)carbamate;
(3-e« o)-3-({[(3'-chloro-3-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide; and (3-endo)-3-({ [(6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide
More preferred compounds Formula (I) useful in the present invention include:
(3-e«<iø)-3-[({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane trifluoroacetate;
(3-en dø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-5-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e«<iø)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-e«<iø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3 '-chloro-3 -methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e <iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-2-biphenylyl)carbamate; (3-eπ ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-hydroxy-2- biphenylyι)carbamate; (3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«β?ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-6-fluoro-2- biphenylyl)carbamate trifluoroacetate; (3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3,-fluoro-2-biphenylyl)carbamate;
(3 -endo)-3 -[({ [(3 '-chloro-5 -hydroxy-2-biphenylyl)amino] carbonyl} oxy)methyl] -8,8- dimethyl-8-azoniabicyclo[3.2. l]octane trifluoroacetate;
(3-e«<iø)-3-[({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2.1 ]octane trifluoroacetate; (3-e«<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«dø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e« o)-8-azabicyclo [3.2.1 ] oct-3 -ylmethyl (4'-fluoro-3 '-methyl-2- biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (2',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4,4'-difluoro-2- biphenylyl)carbamate trifluoroacetate; (3-en dø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-4'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate;
(3-e«dø)-8~azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4'-fluoro-2- biphenylyl)carbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-2-biphenylyl)carbamate;
(3-e7ϊ ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-e ø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (4',5-difluoro-3'-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-en o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-2-biphenylyl)carbamate; (3-en ctø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (5-fluoro-3 '-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e« ø)-3-({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide; (3-e« ø)-3-({[(3'-chloro-3,4'-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide;
(3-e«i ø)-3-({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3-e« ø)-3-({[(3'-chloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-en£tø)-3-({[(3'-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide;
(3-e« ø)-3-({[(3',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide; (3-endo)-3-({ [(3'-chloro-4',6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide;
(3 -endo)-3 -( { [(3 '-chloro-3 -fluoro-2-biphenylyl)amino] carbonyl } oxy)- 8 , 8 -dimethyl-
8-azoniabicyclo [3.2.1] octane bromide;
(3-e«βfø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate;
(3-eπ o)-3-({[(3'-chloro-5-methyl-2-biphenylyl)ammo]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3-en ø)-3-({[(3',5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide; (3-e^ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-3,4'-difluoro-2- biphenylyl)carbamate;
(S-ew^-S-methyl-δ-azabicycloP^.^oct-S-y^S'-cliloro^-biphenyly^carbamate;
(3-e« ø)-3-({[(3'-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-e«^ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',6-difluoro-2- biphenylyl)carbamate; (3-e« ø)-3-({[(3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-e«cfø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3',5-dichloro-4'-fluoro-2- biphenylyl)carbamate; (3-e« ø)-3-({[(3'-chloro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide;
(3-e«^ø)-3-{[(2-biphenylylamino)carbonyl]oxy}-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-ew< o)-3-({[(3'-chloro-4'-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-e«<iø)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-en ø)-3-({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3-fluoro-2-biphenylyl)carbamate;
(3-e« o)-3-({[(3',4-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-e« ø)-3-({[(5-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. ljoctane bromide; (3-e«<iø)-8,8-dimethyl-3-({[(4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8- azoniabicyclo[3.2.1]octane bromide;
(3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (5-fluoro-2-biphenylyl)carbamate; and
(3-etj ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-6-fluoro-2- biphenylyl)carbamate.
Even more preferred compounds Formula (I) useful in the present invention include:
(3-e« o)-3-[({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-e«do)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-5-fluoro-2- biphenylyl)carbamate trifluoroacetate; (3-eR ø)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-3-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-era ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3-eratø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-2-biphenylyl)carbamate;
(3-enc?ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-hydroxy-2- biphenylyl)carbamate;
(3-e«dø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-en^ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-6-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3 -endό)-3 -( { [(3 '-chloro-2-biphenylyl)amino] carbonyl} oxy)-8 , 8-dimethyl- 8 - azoniabicyclo[3.2.1]octane bromide; (3-endo)-3-({ [(3'-chloro-3,4'-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo [3.2.1 ] octane bromide;
(3-ent ø)-3-({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3-e« ø)-3-({[(3'-chloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-e« ø)-3-({[(3'-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo [3.2.1 ] octane bromide;
(3-e«^ø)-3-({[(3',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide; (3-e»<iø)-3-({[(3'-chloro-4,,6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-e« ø)-3-({[(3'-chloro-3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo [3.2.1 ] octane bromide;
(3-e^ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate;
(3 -endo)-3 -( { [(3 '-chloro-5 -methy 1-2 -biphenylyl)amino] carbonyl } oxy)-8 , 8 -dimethyl-
8-azoniabicyclo[3.2.1]octane bromide; (3-e« ø)-3-({[(3,,5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide;
(3-e«< ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-3,4'-difluoro-2- biphenylyl)carbamate; (3-e«dø)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (3'-chloro-2-biphenylyl)carbamate;
(3-e« ø)-3-({[(3'-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo [3.2.1 ] octane bromide;
(3-eπ ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',6-difluoro-2- biphenylyl)carbamate; (3-e« ø)-3-({[(3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide;
(3-e« ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3',5-dichloro-4'-fluoro-2- biphenylyi)carbamate;
(3-e« ø)-3-({[(3'-chloro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3 -endo)-3 - { [(2-biphenylylamino)carbonyl] oxy } - 8 , 8-dimethyl- 8- azoniabicyclo[3.2.1]octane bromide;
(3-e/ ø)-3-({[(3'-chloro-4'-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide; and (3-e«β?ø)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide.
Particularly preferred compounds of the present invention include: (3-endo)-3-({[(3'-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide; and
3-endo)-3-[({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane trifluoroacetate.
METHODS OF PREPARATION The compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for these Schemes is applicable for producing compounds of Formula (I) having a variety of different Rx groups (X=l to 7) which are reacted, employing substituents which are suitable protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula (I), this is merely for illustration purpose only.
Figure imgf000018_0001
1 (I, R1=R2=H)
Reagents and conditions: a) Diphenylphosphoryl azide, triethylamine, CHC13; b) HX, solvent Scheme 1
As outlined in Scheme 1, the desired compounds of Formula (I) can be prepared via the Curtius reaction of a suitable biphenyl acid 1 with the suitably protected [3.2.1] bicyclic alcohol 2 using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent. Removal of the protecting group using standard conditions such as treatment with p-toluenesulfonic acid in acetonitrile gives the compound of Formula (I). The required [3.2.1] bicyclic alcohol 2 is not commercially available but can be prepared from compound 6 which has been previously described in the literature (T. Momone et al, J.C.S. Perkin. Trans. 1, 9, 1997. 1307-14). As shown in Scheme 2, compound 7 was prepared by the Wittig reaction of compound 6 using standard reagents such as methyltriphenyl phosphonium bromide and potassium tert- butoxide. Hydroboration of alkene 7 with disiamylborane followed by oxidation produced the alcohol 8. Subsequent removal of the benzylic moiety of 8 under hydrogenation conditions followed by protection of the ring nitrogen with a BOC group using standard conditions such as treatment with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide gave the desired alcohol 2.
Figure imgf000019_0001
Scheme 2
Alternatively, if the suitable bi-phenyl acid 1 is not commercially available, the desired compounds of Formula (I) can also be prepared as outlined in Scheme 3.
Figure imgf000019_0002
(I, R1=R2=H) Reagents and conditions: a) Diphenylphosphoryl azide, triethylamine, b) Pd(Ph)4, base, DMF/H2O c) HX, solvent Scheme 3
A suitable carboxylic acid 3 can be reacted with the suitably protected [3.2.1] bicyclic alcohol 2 via the Curtius reaction using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent. The intermediate 4 thus formed can be coupled to a suitable boronic acid 5 using standard methods well known in the art such as the Suzuki coupling with catalytic tetrakis(triphenylphosphino)palladium (0) in dimethylformamide and water in a presence of a base such as sodium carbonate or triethylamine. Removal of the protecting group on 4 using standard conditions such as treatment with p- toluenesulfonic acid in acetonitrile gives the compound of Formula (I).
As outlined in scheme 4, in the case where the compound of general formula (I) is a dimethyl quaternary salt (Rl and R2 = CH3), it may be prepared by reacting the corresponding secondary amine (I, R1=R2=H) with a suitable alkylating reagent such as methyl bromide or methyl iodide with a base such as potassium carbonate in an inert solvent such as dimethylformamide.
Conditions
Figure imgf000020_0001
Figure imgf000020_0002
(l, R1=R2=H) (I, R1 and R2 =CH3) Reagents and conditions: MeBBr or Mel, K2CO3, DMF. Scheme 4
In some cases, alkylation of the carbonate nitrogen may also occur. A representative example is shown in Scheme 5.
Figure imgf000021_0001
Scheme 5 The compounds of general formula (I) may also be prepared as depicted in Scheme 6. A suitable carboxylic acid 3 can be reacted with the commercially available bicyclic alcohol 9 via the Curtius reaction using standard reagents well known in the art such as the commercially available diphenylphosphoryl azide (DPP A) reagent. The intermediate 10 thus formed can be coupled to a suitable boronic acid 5 using standard methods well known in the art such as the Suzuki coupling with polymer supported (triphenylphosphino)palladium(O) in DME and water in a presence of a base such as potassium carbonate to give the compound of Formula (I) (R1=CH3, R2=nothing). Reacting this compound with a suitable methylating agent such as methyl iodide or methyl bromide leads to the corresponding dimethyl quaternary salt of Formula (I) (R1=R2=CFL).
Figure imgf000022_0001
(I, R1=R2=CH3) (Ij R1=CHs R2=nothing)
Reagents and conditions: a) Diphenylphosphoryl azide, triethylamine, b) PS-Ph3- Pd, base, DME/H2O c) MeBr or Mel, DCM/Acetonitrile Scheme 6
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following Examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. Most reagents and intermediates are commercially available or are prepared according to procedures in the literature. The preparation of intermediates not described in the literature is illustrated below. Flash column chromatography was carried out using Merck 9385 silica unless stated otherwise. LC/MS analyses were conducted under the following conditions: • Column: 3.3cm x 4.6mm ID, 3um ABZ+PLUS • Flow Rate: 3ml/min • Injection Volume: 5μl • Temp: Room temperature • Solvents: A: 0.1 % Formic Acid + 1 OmMolar Ammonium Acetate. B: 95% Acetonitrile + 0.05% Formic Acid • Gradient: Time A% B% 0.00 100 0 0.70 100 0 4.20 0 100 5.30 0 100 5.50 100 0
The Mass Directed Automated Preparative (MDAP) was conducted under the conditions described in System A or in System B:
System A: Formate salts
• The preparative column used was a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5m)
• UN detection wavelength : 200-320nM • Flow rate : 20ml/min
• Inj ection Volume : 0.5ml
• Solvent A : 0.1% formic acid
• Solvent B : 95% acetonitrile + 0.05% formic acid
System B TFA salts
• The preparative column used was a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5m)
• UV detection wavelength : 200-320nM
• Flow rate : 20ml/min • Injection Volume: 0.5ml
• Solvent A : water + 0.1% trifluoroacetic acid
• Solvent B : acetonitrile + 0.1% trifluoroacetic acid
The Gilson preparatory HPLC was conducted under the following conditions:
• Column: 75 x 33mm I. D. , S-5um, 12nm
• Flow rate: 30mL/min
• Injection Volume: 0.800 mL • Room temperature
• Solvent A: 0.1% trifluoroacetic acid in water
• Solvent B : 0.1% trifluoroacetic acid in acetonitrile
The following examples are intended to be illustrative of the present invention but not limiting in any way.
Preparation of 1,1-dimethylethyl -(3-ewrfo)-(hvdroxymethyl)-8- azabicyclo [3.2.11 octane-8-carboxylate
Step a: Preparation of 3-methylidene-8-(phenylmethyl)-8-azabicyclo[3.2.11octane A 500 ml flask with side arm, stirring bar, N2 inlet, and septum stopper was charged with a solution of potassium tert-butoxide in THF (82 ml, 1M ) and methyltriphenyl phosphonium bromide (29.2 g, 82 mmol). It was cooled to 0 °C under dry N2, and anhydrous THF (140 ml) was added via syringe at 0 °C. The ylid solution was stirred for 20 min. 8-(Phenylmethyl)-8-azabicyclo[3.2.1]octan-3-one (14.0 g, 65 mmol) in anhydrous THF ( ml) was added via syringe at 0 °C and the solution was stirred 1 h at room temperature then quenched with water (6 ml). The mixture was acidified to pH 1 and THF was removed in vacuo at 30 °C. The residue was diluted with water (450 ml) and Ph3PO was extracted with toluene (3 X 200 ml). The aqueous solution was basified with 6N NaOH (-35 ml), and extracted with ethyl acetate (3 X 200ml). The organic layers were combined, washed with saturated NaCl (3 X 100 ml), dried over Na^O^ and evaporated to yield a crude product which was purified by flash chromatography (400g of silica, ethyl acetate containing 0.1% TEA). 3-Methylidene-8-(phenylmethyl)-8-azabicyclo[3.2.1]octane was recovered as a yellow oil (11.3 g, 81.5 %). LC/MS ESI , 1.27 min, MH+ 214; NMR (CDC13, 400MHz; δ): 1.58 ppm (q, 2H), 1.80-2.05 ppm (m, 4H), 2.55 ppm (d, 2H), 3.28 ppm (s, 2H), 3.65 ppm (s, 2H), 4.80 ppm (s, 2H), 7.29 ppm (t, IH), 7.35 ppm (t, 2H), 7.46 ppm (d, 2H).
Step b: Preparation of (3-ere oV8-(phenylmethyl)-8-azabicyclor3.2.1"loct-3- yll methanol A solution of disiamylborane was prepared by addition of 1.0 M borane in THF (20 ml, 20 mmol) to a 2.0 M solution of 2-methyl-2-butene in THF (20 ml, 40 mmol) at
0 °C under N . The solution was stirred 1 h at 0 °C before addition of 3- methylidene-8-(phenylmethyl)-8-azabicyclo[3.2.1]octane (1.07 g, 5 mmol) in 10 ml anhydrous THF. After 0.5 h at 0 °C the reaction mixture was warmed up to room temperature and allowed to stir overnight. The borane was quenched by careful addition of water (2 ml). The stirred solution was then oxidized at 0 °C by adding dropwise an aqueous solution of 30 % H2O2 (3.87 ml, 45 mmol) over 30 minutes.
The reaction mixture was neutralized with 3N HC1 and the solvent was evaporated. The residue was taken up in ethyl acetate. Evaporation gave a viscous crude oil which was used directly for step c.
Step c: Removal of the benzyl group and protection with a BOC group A solution of (3-erc<iø)-8-(phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]methanol (1.16 g) (Schneider et al, Arch. Pharm., 1975, 308-365) in exhanol (20 ml) and 6N HC1 (1 ml) containing palladium hydroxide on carbon (Pearlman's catalyst, 2.27 g, 22% (w/w)) was hydrogenated (55 psi H2) at room temperature for 2 days. The catalyst was filtered off over Celite and the filtrate was evaporated under vacuum. The residue and di-tert-butyl dicarbonate (1.63 g, 7.5 mmol) were dissolved in 30 ml of dioxane: 1 N NaOH (2: 1) and stirred overnight at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate (3 X 25 ml)and water (25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue oil was purified by flash chromatography (150g of silica, hexane:ethyl acetate (1:1, containing 0.1% 2.0 M NH3 in methanol)). A colorless oil (0.65 g) was obtained. LC/MS ESI RT 1.65 min, MH+ 242. NMR (CDC13, 400MHz; δ) 4.15 ppm (broad, 2H), 3.64 ppm (d, 2H), 2.20 ppm (broad, 2H),1.97 ppm (broad, 2H), 1.85 ppm (m, IH), 1.60 ppm (m, 2H), 1.40-1.50 ppm (s+broad, 11H) .
Intermediate 1: 1,1-Dimethylethyl (3-ew<fo)-r({[(2-bromo-5- methylphenyl)amino]carbonyl}oxy)methyn-8-azabicyclo[3.2.πoctane-8- carboxylate A solution of 2-bromo-5-methylbenzoic acid (430mg) in chloroform (10ml) was treated with diphenylphosphoryl azide (450 μl) and triethylamine (450 μl). The resulting reaction mixture was heated at 60°C for 10 minutes then treated with a solution of 1,1-dimethylethyl -(3-e«<iø)-(hydroxymethyl)-8-azabicyclo[3.2.1]octane- 8-carboxylate (470mg) in chloroform (2ml). The reaction mixture was heated at reflux for 6 hours. The cooled solution was loaded onto a SPE cartridge (Si, lOg). Elution with chloroform, followed by evaporation of the solvent gives the title compound (920mg). LC/MS ESI R, 3.93 mins MET 453.
Intermediate 2: 1,1-dimethylethyl (3-endo)-\(j\(2- bromophenyI)amino1carbonyl}oxy)methyll-8-azabicycIo[3.2.1]octane-8- carboxylate
The title compound was prepared from 2-bromobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI R.. 3.79 mins MET
439.
Intermediate 3: 1,1-dimethylethyl (3-g«</o)-{[({[2-bromo-3,4- bis(methyIoxy)phenyllamino}carbonvhoxylmethyl}-8-azabicyclof3.2.11octane-
8-carboxylate
The title compound was prepared from 2-bromo-3,4-bis(methyloxy)benzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ
3.63 mins MH* 499 . Intermediate 4: 1,1-dimethylethyl (3-g/ rfo -[((f(2-bromo-5- ehlorophenyl")amino1carbonyl}oxy)methyll-8-azabicyclo[3.2.πoctane-8- carboxylate The title compound was prepared from 2-bromo-5-chlorobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 4.05 mins MIT 473.
Intermediate 5: 1,1-dimethylethyl (3-er«foV(IY 2-bromo-5- (methyloxy)phenynamino}carbonyI)oxy1methyl}-8-azabicyclo[3.2.11octane-8- carboxylate
The title compound was prepared from 2-bromo-5-(methyloxy)benzoic acid using the procedure described for the preparation of intermediate 1. NMR (d -DMSO 400MHz; δ) 7.84 (br, IH), 7.46-7.35 (m,lH), 7.18-7.11 (m,lH), 6.56-6.51 (m,lH), 4.33-4.10 (m's,4H), 3.81 (s,3H), 2.31-1.95 (m's,5H), 1.74-1.64 (m,2H), 1.5-1.41 (m's, HH)
Intermediate 6: 1,1-dimethylethyl (3-g//< Q)-{[({[5-(acetylamino")-2- bromophenyllamino|carbonyl)oxy1methyl|-8-azabicycIo[3.2.11octane-8- carboxylate
The title compound was prepared from 5-(acetylamino)-2-bromobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 3.49 mins MET 496 .
Intermediate 7: 1,1-dimethylethyl (3-e«rføV[( (2-bromo-4- methvIphenyl)aminolcarbonylloxy methvIl-8-azabicyclo[3.2.11octane-8- carboxylate
The title compound was prepared from 2-bromo-4-methylbenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 3.91 mins Mi? 453 . Intermediate 8: 1,1-dimethylethyl (3-gn</ø)-f({[(2-bromo-6- methylphenvI)amino1carbony oxy methyll-8-azabicyclo[3.2.πoctane-8- carboxylate
The title compound was prepared from 2-bromo-6-methylbenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI R..3.64 mins MET 453 .
Intermediate 9: 1,1-dimethylethyl (3-gw<foM({f(2-bromo-5- fluorophenyl)amino1carbonyl}oxy)methyIl-8-azabicyclo[3.2.11octane-8- carboxylate
The title compound was prepared from 2-bromo-5-fluorobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI R-.3.92 mins MET 457 .
Intermediate 10: 1,1-dimethylethyl (3-g«</g)-[({[(2-bromo-3- fluorophenyl)aminolearbonyl}oxy)methyll-8-azabicyclof3.2.11octane-8- carboxylate
The title compound was prepared from 2-bromo-3-fluorobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 3.83 mins MET 457 .
Intermediate 11: 1,1-dimethylethyl (3-gw</ø)-f({f(2-bromo-4- fluorophenyl)amino1carbonyl}oxy methyll-8-azabicvclo[3.2.πoctane-8- carboxylate The title compound was prepared from 2-bromo-4-fluorobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI R-.3.78 mins MIT 457 .
Intermediate 12: methyl 3'-chloro-5-[(phenylmethyl)oxyl-2- biphenylcarboxylate
Nitrogen was bubbled slowly through a stirred mixture of dioxane (3ml), cesium carbonate (600mg) l,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (8.5mg) and palladium acetate (5.5mg) for 5 minutes. A mixture of methyl 4- [(phenylmethyl)oxy]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (390mg) and 3- chloroboronic acid (231mg) were added and the vessel was sealed. The resulting mixture was heated in a microwave (Smith Creator, 150°C, 10 minutes). After cooling, the reaction mixture was diluted with dichloromethane (5ml), filtered through Hyflo and evaporated. The residue was purified by chromatography (20g Si, Flashmaster2) eluting with ethyl acetate/cyclohexane (2:98). The title compound was recovered as a white solid (280mg). LC/MS ESI Rτ 3.88 mins MET 353.
Intermediate 13: 3'-chloro-5-[(phenylmethyl)oxyl-2-biphenylearboxylic acid
A mixture of methyl 3'-chloro-5-[(phenylmethyl)oxy]-2-biphenylcarboxylate , methanol (5ml), tetrahydrofuran (5ml) and 2N sodium hydroxide (3ml) was heated at 60°C for 2 hours. The cooled solution was added to 2N hydochloric acid (50ml) and extracted with dichloromethane (3x50ml),. The organic fractions were combined, dried (MgSO4) and evaporated to give the title compound as a white powder (380mg). LC/MS ESI Rτ 3.74 mins Mff 339 .
Intermediate 14: 1,1-dimethylethyl (3-gw</o>({[({3'-chloro-5- f(phenyImethyI)oxy1-2-biphenylvπamino)carbonylloxy}methyl)-8- azabicyclof3.2.1]octane-8-carboxylate
The title compound was prepared from 3 '-chloro-5- [(phenylmethyι)oxy] -2- biphenylcarboxylic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 4.09 mins MH" 577 .
Intermediate 15: 1,1-dimethylethyl (3-g«</oVf({[(3'-chloro-5-hydroxy-2- biphenylyl)amino1carbonylloxy)methyn-8-azabicyclof3.2.11octane-8- carboxylate
A mixture of palladium acetate (6mg), triethylamine (11 μl) and triethylsilane (125 μl) in dichloromethane (2ml) was stirred for 5 minutes to give a black suspension. A solution of 1,1-dimethylethyl (3-e« ø)-({[({3'-chloro-5-[(phenylmethyl)oxy]-2- biphenylyl}amino)carbonyl]oxy}methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (280 mg) in dichloromethane was added dropwise and the resulting reaction mixture was stirred for 16 hours. Further palladium acetate (6mg), triethylamine (11 μl) and triethylsilane (125 μl) were added and further stirring continued for 24 hours. The mixture was treated with aqueous ammonium chloride (5ml) and extracted with dichloromethane (2x5ml). The combined organic fractions were evaporated and the residue was dissolved in tetrahydrofuran (2ml) then treated with a IM solution of tetrabutylammonium fluoride in THF (1ml). The resulting solution was stirred for 1 hour, the solvent was removed under vacuum to give a residue which was diluted with cyclohexane then loaded onto a SPE cartridge (Si 20g). Elution with a mixture cylcoheaxne/diethyl ether gives the title compound (180mg). NMR (d6-DMSO 400MHz; δ) 7.84-7.65 (br,lH), 7.51-7.21 (m's, 3H), 7.26-7.21 (m, IH, excess), 6.87-6.81 (m,lH), 6.76-6.71 (m,lH), 6.39-6.15 (br m,lH), 5.16 (br,lH), 4.29-4.01 (m's,4H), 2.20-1.26 (m's,18H, excess).
Intermediate 16: 1,1-dimethylethyl (3-g«</oVF({[(2-bromo-6- fluorophenyl)amino1carbonyl}oxy)methyl1-8-azabicycIo[3.2.11octane-8- carboxylate
The title compound was prepared from 2-bromo-6-fluorobenzoic acid using the procedure described for the preparation of intermediate 1. LC/MS ESI Rτ 3.45 mins MET 457 .
Example 1: (3-g«<fo")-8-Azabicyclof3.2.1]oct-3-ylmethyl [3'-(trifluoromethyl)-2- biphenylyll carbamate
A solution of 3'-(trifluoromethyl)-2-biphenylcarboxylic acid (0.05 mmol) in chloroform (0.5ml) was successively treated with a solution of diphenylphosphoryl azide (1 lμl) in chloroform (0.2ml) then a solution of triethylamine (1 lμl) in chloroform (0.2ml). The resulting solution was maintained at 50°C for 10 minutes then treated with a solution of 1,1-dimethylethyl
Figure imgf000030_0001
azabicyclo[3.2.1]octane-8-carboxylate (12mg) in chloroform (0.2ml). After heating at reflux for 16 hours, the cooled solution was purified by loading onto a SPE cartridge (NH , 500mg) then eluting with chloroform. After removing the solvent under vacuum, the residue was dissolved in acetonitrile (0.5ml), treated with a solution of j!?-toluenesulfonic acid (lOmg) in acetonitrile (0.5ml) and the resulting mixture was heated at reflux for 3 hours. The cooled solution was purified by loading onto a SPE cartridge (SCX, 500mg) then washing with methanol and eluting with 2M ammonia in methanol to give the title compound. LC/MS ESI Rp 2.33 mins MH+ 405.
Example 2: (3-g/κføV8-AzabicycIof3.2.11oct-3-ylmethyl[4-fluoro-4'- (trifluoromethyl)-2-biphenylyllcarbamate
The title compound was prepared from 4-fluoro-4'-(trifluoromethyl)-2- biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI Rτ 2.43 mins MH 423.
Example 3: (3-g«rfQV8-azabicyclof3.2.11oct-3-vImethyl-3',4'-bis(methyloxy)-2- biphenylyl] carbamate.
The title compound was prepared from 4'-methyl-3 '-(methyloxy)-2- biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI RT 2.12 mins MH" 397.
Example 4: (3-en o)-8-Azabicyclo[3.2.11oct-3-ylmethyl (4'-butyl-2- biphenylyDcarbamate The title compound was prepared from 4'-butyl-2-biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI RT 2.58 mins MH+ 393.
Example 5: (3-g«rfoV8-Azabicyclof3.2.11oct-3-ylmethyl[5-chloro-4'- (trifluoromethyI)-2-biphenylyricarbamate The title compound was prepared from 5-chloro-4'-(trifluoromethyl)-2- biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI RT 2.52 mins MH+ 439. Example 6: (3-gw<fo)-8-Azabicvclo[3.2.11oct-3-ylmethyl[6-chloro-4'- (trifluoromethyf)-2-biphenylvHcarbamate
The title compound was prepared from 6-chloro-4 '-(trifluoromethyl)-2- biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI R, 2.48 mins MET 439.
Example 7: (3-gf*<fo)-8-Azabicvclo [3.2.11 oct-3-ylmethyl (2'-methyl-2- biphenylvDcarbamate
The title compound was prepared from 2'-methyl-2-biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI R-. 2.26 mins MET 351.
Example 8: (3-gw<foV8-Azabievclo[3.2.11oct-3-ylmethyl (4'-hydroxy-2- biphenylvDcarbamate The title compound was prepared from 4'-hydroxy-2-biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI RT 2.04 mins MH+ 353.
Example 9: (3-gn<foV8-azabicyclo[3.2.πoet-3-ylmethyl [4'-(trifluoromethylV2- biphenylyll carbamate
The title compound was prepared from 4'-(trifluoromethyl)-2-biphenylcarboxylic acid according to the procedure outlined in example 1. LC/MS ESI Rτ 2.35 mins MH" 405.
Example 10: (3-g«<foV8-azabicyclo [3.2.11 oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylvDcarbamate trifluoroacetate
A solution of (3 -endό)- [( { [(2-bromo-5methylphenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate (45 mg) and (3-chlorophenyl)boronic acid (23.4 mg) in dimethylformamide (0.75ml) was treated with sodium carbonate (30mg), tetrakis(triphenylphosphino)palladium (0) (58 mg) and water (0.25ml). The mixture was placed in a sealed reaction tube and heated in a microwave (CEM Explorer, 150°C, 10 minutes, pressure 250psi, power 100W). After cooling to room temperature, the solvent was removed under vacuum. The residue was dissolved in chloroform (1ml) then washed sequentially with 2N hydrochloric acid (0.5ml) and water (0.5ml). The organic phase was separated and the solvent was removed under vacuum. The residue was dissolved in acetonitrile (1 ml) and treated wit p- toluenesulfonic acid (20mg) . The resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the solution was purified by loading onto a SPE cartridge (SCX, 500mg) then washing with methanol and eluting with 2M ammonia in methanol. The solvent was removed under vacuum and the residue was purified by MDAP to afford the title compound. LC/MS ESI Rτ 2.57 mins MIL" 385.
Example 11: (3-gn^ø)-3-({f({3'-chIoro-5-[(phenylmethyl oxyl-2- biphenylyl)amino')carbonynoxy}methyl)-8-azoniabicyclo[3.2.11octane 4- methylbenzenesulfonate
A solution of 1,1-dimethylethyl (3-e«c?ø)-({[({3'-chloro-5-[(phenylmethyl)oxy]-2- biphenylyl}amino)carbonyl]oxy}methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 lmg) and j9-toluenesulfonic acid (12mg) in chloroform (0.5ml) was heated in a microwave (Smith Creator, 100°C, 7 minutes). After cooling to room temperature, the solvent was removed under vacuum. The resulting residue was purified by flash tube after elution with DCM/MeOH/NH3 (75:25 :2) to give the title compound (7 mg) as its p-toluene sulfonate salt. NMR (d6-DMSO 400MHz; δ) 7.80-7.65 (m, 2H), 7.49-7.13 (m's,13H, excess), 7.05-6.94 (m, IH), 6.91-6.85 (m,lH), 5.07 (s,2H), 4.15-3.90 (m's,4H), 2.36 (s,3H), 2.31-2.08 (m's,5H), 1.96-1.80 (m, 2H), 1.68-1.53 (m,2H).
Example 12: (3-g«<foV8-azabicyclof3.2.πoct-3-ylmethyl (3'-chloro-5-hydroxy-2- biphenylyDcarbamate
A solution of 1,1-dimethylethyl (3-endo)-[({[(3'-chloro-5-hydroxy-2- biphenylyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (1 lmg) and p-toluenesulfonic acid (12mg) in chloroform (0.5ml) was heated in a microwave (Smith Creator, 100°C,7 minutes). After cooling to room temperature, the solvent was removed under vacuum. The resulting residue was purified by MDAP to give the title compound (2.5mg). LC/MS ESI Rτ 2.25 mins MIL" 387.
Example 13: r3-g/?</øV8-azabicvcIo[3.2.11oct-3-yImethyl (2',4'-dichloro-2- biphenylvDcarbamate
A solution of 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (44 mg) and (2,4-dichlorophenyl)boronic acid (28 mg) in dimethylformamide (0.75ml) was treated with sodium carbonate (30mg), tetrakis(triphenylphosphino)palladium (0) (35 mg) and water (0.25ml). The mixture was placed in a sealed reaction tube and heated in a microwave (CEM Explorer, 150°C, 10 minutes, pressure 250psi, power 100W). After cooling to room temperature, the solvent was removed under vacuum. The residue was dissolved in chloroform (1ml) then washed sequentially with 2N hydrochloric acid (0.5ml) and water (0.5ml). The organic phase was separated and the solvent was removed under vacuum. The residue was dissolved in acetonitrile (1 ml) and treated with p- toluenesulfonic acid (20mg) . The resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the solution was purified by loading onto a SPE cartridge (SCX, 500mg) then washing with methanol and eluting with 2M ammonia in methanol. The solvent was removed under vacuum and the residue was purified by MDAP to afford the title compound (20mg). LC/MS ESI Rτ 2.6 mins MH+ 379.
Example 14: (3-gM<foV8-azabicvclof3.2.πoct-3-ylmethyl (2',4',6'-trimethyl-2- biphenylvDcarbamate
According to the procedure outlined in example 13, (2,4,6-trimethylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino] carbonyl } oxy)methyl] -8 -azabicyclo [3.2.1 ] octane- 8 -carboxylate were reacted to generate the title compound. LC/MS ESI p 1.9 mins MET1" 380. Example 15: (3-g«rfo)-8-azabicyclo [3.2.11 oct-3-ylmethyl (2',3'-dimethyl-2- biphenylvDcarbamate
According to the procedure outlined in example 10, (2,3-dimethylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R-. 2.47 mins MET 365.
Example 16: (3-gH<foV8-azabicvclo[3.2.11oct-3-vImethyl (2',5'-dimethyl-2- biphenylvDcarbamate According to the procedure outlined in example 10, 2,5-dimethylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.49 mins MH+ 365.
Example 17: (3-g«</ø)-8-azabicyclo[3.2.11oct-3-ylmethyl (4t-fluoro-3'-methyl-2- biphenylyDcarbamate
According to the procedure outlined in example 10, (4-fluoro-3- methylphenyl)boronic and 1,1-dimethylethyl (3-endό)-[({[(2- bromophenyl)amino] carbonyl } oxy)methyl] -8-azabicyclo [3.2.1] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.4 mins MIL1" 369.
Example 18: (3-g/3<fo)-8-azabicycIo [3.2.1] oct-3-ylmethyl (4'-fluoro-2'-methyl-2- biphenylyhcarbamate
According to the procedure outlined in example 10, (4-fluoro-2- methylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino] carbonyl } oxy)methyl] -8-azabicyclo [3.2.1] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.41 mins MH+ 369.
Example 19: (3-endo)-8-azabicyclo[3.2.11oct-3-ylmethyl (4'-ethyl-2- biphenylvDcarbamate
According to the procedure outlined in example 10, (4-ethylphenyl)boronic acid and 1,1-dimethylethyl (3-en ø)-[({[(2-bromophenyl)amino]carbonyl}oxy)methyl]-8- azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.48 mins MH+ 365.
Example 20: (3-g«</oV8-azabicyclo[3.2.πoct-3-ylmethyl [2-(2- naphthalenvDphenyll carbamate
According to the procedure outlined in example 10, 2-naphthalenylboronic acid and 1 , 1 -dimethylethyl (3 -endo)-[({ [(2-bromophenyl)amino] carbonyl} oxy)methyl] -8- azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.50 mins MH+ 387.
Example 21: (3-g»rfø)-8-azabicyclof3.2.11oct-3-ylmethyl (4'-fluoro-2- biphenylvDcarbamate
According to the procedure outlined in example 10, (4-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -en do)- [( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.28 mins MH+ 355.
Example 22: (3-g/ι<fo)-8-azabieyclo [3.2.11 oct-3-ylmethyl (3'- [(trifluoromethv oxyl -2-biphenylyl) carbamate According to the procedure outlined in example 10, {3-
[(trifluoromethyl)oxy]phenyl}boronic acid and 1,1-dimethylethyl (3-eπ ø)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.52 mins MH"1" 421.
Example 23: (3-endo)-8-azabicyclo[3.2.11oct-3-ylmethyl 13'- f(methyloxy)methyl1-2-biphenylyI1carbamate
According to the procedure outlined in example 10, {3-
[(methyloxy)methyl]phenyl}boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.27 mins MET1" 381. Example 24: (3-gw<foV8-azabicvclo [3.2.11 oct-3-ylmethvI (2'-fluoro-2- biphenylyDcarbamate
According to the procedure outlined in example 10, (2-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -en do)- [({ [(2-bromophenyl)amino] carbonyl} oxy)methyl]- 8-azabicyclo[3.2.1 ]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.24 mins MET" 355.
Example 25: (3-g/iffoV8-azabicvclor3.2.11oct-3-ylmethyl [2'-(trifluoromethvD-2- biphenylyll carbamate According to the procedure outlined in example 10, (2-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.45 mins MH+ 405.
Example 26: (3-g«*fo -8-azabieyclo[3.2.11oct-3-ylmethyl [4'-(l.l-dimethylethvP- 2-biphenylvH carbamate
According to the procedure outlined in example 10, [4-(l,l- dimethylethyl)phenyl]boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.65 mins MH * 393.
Example 27: (3-g«<fo)-8-azabievclo[3.2.11oct-3-ylmethyl l,l':4M"-terphenyI-2- ylcarbamate
According to the procedure outlined in example 10, 4-biphenylylboronic acid and 1,1 -dimethylethyl (3 -endo)- [( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] -8 - azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.64 mins MH+ 413.
Example 28: (3-gw<foV8-azabicvclo[3.2.11oct-3-ylmethyl (2',3'-difluoro-2- biphenylvDcarbamate
According to the procedure outlined in example 10, (2,3-difluorophenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.29 mins MET1" 373.
Example 29: (3-g/»foV8-azabicvclo[3.2.11oct-3-ylmethyl (4'-methyl-2- biphenylyPcarbamate
According to the procedure outlined in example 10, (4-methylphenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.38 mins MH+ 351.
Example 30: (3-g«rfo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-methyl-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e«^o)-[({[(2-bromophenyl)ammo]carbonyl}oxy)methyl]- 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.37 mins MH+ 351.
Example 31: (3-g«<fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-fluoro-2- biphenylyPcarbamate According to the procedure outlined in example 10, (3-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)-[( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.28 mins MH+ 355.
Example 32: (3-gjι</oV8-azabicyclof3.2.11oct-3-ylmethyl (2'-fluoro-4'-methyl-2- biphenylyPcarbamate
According to the procedure outlined in example 10, (2-fluoro-4- methylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.38 mins MH"1" 369. Example 33: (3-g«<foV8-azabicvclo [3.2.11 oct-3-ylmethyl (3'-cyano-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (3-cyanophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo [3.2. l]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.21 mins Mtf" 362.
Example 34: (3-g«</o)-8-azabicyclo[3.2.11oct-3-ylmethyl [4'-(methyloxy)-2- biphenylyll carbamate According to the procedure outlined in example 10, [4-(methyloxy)phenyl]boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino] carbonyl } oxy)methyl] -8 -azabicyclo [3.2.1] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.29 mins MH+ 367.
Example 35: (3-gfl<fo)-8-azabicvelo[3.2.πoct-3-ylmethyI [3'-(methyloxy)-2- biphenylyll carbamate
According to the procedure outlined in example 10, [3-(methyloxy)phenyl]boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.29 mins MH4" 367.
Example 36: (3-g«</o)-8-azabicyclo[3.2.11oct-3-ylmethyl (2'-chloro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (2-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-erø ø)-[({[(2-bromophenyl)amino]carbonyl}oxy)methyl]- 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.33 mins MH+ 371.
Example 37: (3-g/ </ø)-8-azabicyclof3.2.11oct-3-yImethyl [2'-(methyloxy)-2- biphenylyll carbamate
According to the procedure outlined in example 10, [2-(methyloxy)phenyl]boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2- bromophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.27 mins MH+ 367.
Example 38: (3-g«rfo)-8-azabicvclo[3.2.11oct-3-ylmethyl (4'-chloro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (4-chlorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromophenyl)amino] carbonyl} oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.39 mins MH1" 371.
Example 39: (3-gfl<fo)-8-azabicvclo[3.2.11oct-3-ylmethyl (3'-chloro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)-[({ [(2-bromophenyl)ammo]carbonyl}oxy)methyl]- 8-azabicyclo [3.2. l]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.39 mins MH+ 371.
Example 40: (3-g«</ø -8-azabicyclo[3.2.11oct-3-ylmethyI (3'-chloro-4'-fluoro-2- biphenylvPcarbamate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e«< ø)-[({[(2-bromophenyl)amino]carbonyl}oxy)methyl]- 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.42 mins MH÷ 389.
Example 41: (3-gn</o -8-azabicyclo[3.2.11oet-3-ylmethyl (3'-chloro-4'-fluoro-4- methyl-2-biphenylvPcarbamate
According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-5- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.78 mins MH+ 403. Example 42: (3-gw<fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (4-methyl-2- biphenylyPcarbamate
According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3 -endo)- [( { [(2-bromo-5 -methylphenyl)amino] carbonyl} oxy)methyl] - 8-azabicyclo [3.2.1 ]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.6 mins MH+ 351.
Example 43: (3-gn< o)-8-azabicyclof3.2.11oct-3-ylmethyl [3'-chIoro-4'-fluoro-5,6- bis(methyloxy)-2-biphenylyl1carbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-eπ<io)-{[({[2-bromo-3,4- bis(methyloxy)phenyl]amino}carbonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI R 2.56 mins MH+ 449.
Example 44: (3-gnt?øV8-azabicyclo[3.2.11oct-3-ylmethyl (4-chloro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl-(3 -endo)- [({ [(2-bromo-5 -chlorophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.71 mins MH+ 371.
Example 45: (3-gwrf )-8-azabicycIo[3.2.11oct-3-ylmethyl [3'-chloro-4'-fluoro-4- (methyloxyV2-biphenylyl]carbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-erødo)-{[({[2-bromo-5- (methyloxy)phenyl]amino}carbonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.71 mins Mt 419. Example 46: (3-g«<foV8-azabievclo[3.2.11oct-3-ylmethyI [4-(methyloxy -2- biphenylyll carbamate
According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3 -endo)- {[({ [2-bromo-5-(methyloxy)phenyl] amino } carbonyl) oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.54 mins MH 367.
Example 47: (3-g«<foV8-azabicvclo [3.2.11 oct-3-ylmethyl (3'-chloro-5-methyl-2- biphenylyPcarbamate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [({ [(2-bromo-4-methylphenyl)amino]carbonyloxy) methyl]-8~azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.72 ins MH " 385.
Example 48: (3-g/f<fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-4'-fluoro-5- methyl-2-biphenylyPcarbamate
According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-eπ ø)-[({[(2-bromo-4- methylphenyl)ammo]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.78 mins MH+ 403.
Example 49: (3-g«rfoV8-azabicvclo [3.2.11 oct-3-ylmethyl (5-methyl-2- biphenylvPcarbamate According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3 -endo)- [( { [(2-bromo-4-methylphenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC MS ESI Rτ 2.59 mins MH+ 351. Example 50: (3-g«<foV8-azabicyclo [3.2.11 oct-3-ylmethyl (3'-chloro-3-methyl-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-6- methylphenyl)amino]carbonyl} oxy)methyl]-8-azabicyclo [3.2.1 ]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.6 mins MH+ 385.
Example 51: (3-g/ </øV8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-4-fhιoro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromo-5 -fluorophenyl)amino] carbonyl } oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.74 mins MH+ 389.
Example 52: (3-gw</ø)-8-azabicyclo[3.2.11oct-3-ylmethyI (4-fluoro-2- biphenylyPcarbamate
According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3 -endo)- [({ [(2-bromo-5 -fluorophenyl)amino] carbonyl} oxy)methyl] - 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.6 mins MH* 355.
Example 53: (3-gfi<fo)-8-azabicvclo[3.2.11oct-3-ylmethyI (3,-chIoro-4',6-difluoro- 2-biphenylvPcarbamate According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-3- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R 2.72 mins MH+ 407. Example 54: (3-gM<fo)-8-azabicvclo[3.2.11oct-3-ylmethyl (6-fluoro-2- biphenylvPcarbamate
According to the procedure outlined in example 10, phenylboronic acid and 1,1- dimethylethyl (3-endo)-[({ [(2-bromo-3-fluorophenyl)amino]carbonyl} oxy)methyl]- 8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.53 mins MlY 355.
Example 55: (3-g«rfo)-8-azabicvclo[3.2.11oct-3-ylmethyl (3,-chloro-4',5-difluoro- 2-biphenylvPcarbamate
According to the procedure outlined in example 10, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-4- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.71 mins MH+ 407.
Example 56: (3-g«<fo)-8-azabicvclo[3.2.11oct-3-ylmethyl [3'-chloro-4- (methyloxy -2-biphenylyll carbamate trifluoroacetate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3 -endo)- {[({[2-bromo-A- methyloxyphenyl]amino}carbonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC MS ESI RT 2.67 mins MH+ 401.
Example 57: (3-gw<foV8-azabicyclo [3.2.11 oct-3-ylmethyl [4-(acetylamino)-3'~ chloro-2-biphenylyll carbamate trifluoroacetate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-{[({[5-(acetylamino)-2-bromophenyl]amino} carbonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.45 mins MH+ 428. Example 58: (3-g/ι</ø)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-6-fluoro-2- biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-3-fluorophenyl)amino]carbonyl} oxy)methyl]-8-azabicyclo[3.2. l]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.66 mins Mt 389.
Example 59: (3-g»</o)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-chloro-5-fluoro-2- biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 10, (3-chlorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-4-fluorophenyl)amino]carbonyl} oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.50 mins MH+ 389.
Example 60: (3-g/f< o -8-azabicyclo[3.2.11oct-3-ylmethyl (3'-fluoro-4-methyl-2- biphenylyPcarbamate trifluoroacetate
A solution of 1,1-dimethylethyl (3-e7?dø)-[({[(2-bromo-5-methylphenyι) ammo]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (45 mg) and (3-fluorophenyι)boronic acid (21 mg) in dimethylformamide (0.75ml) was treated with triethylamine (42μl), tetrakis(triphenylphosphino)palladium (0) (58 mg) and water (0.25ml). The mixture was placed in a sealed reaction tube and heated in a microwave (CEM Explorer, 150°C, 10 minutes, pressure 250psi, power 100W). After cooling to room temperature, the solvent was removed under vacuum. The residue was dissolved in chloroform (1ml) then washed sequentially with 2N hydrochloric acid (0.5ml) and water (0.5ml). The organic phase was separated and the solvent was removed under vacuum. The residue was dissolved in acetonitrile
(lml) and treated with^-toluenesulfonic acid (20mg) . The resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the solution was » purified by loading onto a SPE cartridge (SCX, 500mg) then washing with methanol and eluting with 2M ammonia in methanol. The solvent was removed under vacuum and the residue was purified by MDAP to afford the title compound (4.9 mg).
LC/MS ESI Rτ 2.63 mins MH+ 369. Example 61: (3-endo - 8-azabicvclo[3.2.11oct-3-ylmethyl (4-chloro-3'-fluoro-2- biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-5-chlorophenyl)amino] carbonyl}oxy)mefhyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.72 mins MH+ 389.
Example 62: (3-gλirfoV8-azabicyclo[3.2.πoct-3-ylmethyl (3'-fluoro-5-methyl-2- biphenylvDcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-4- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.62 mins MH+ 369.
Example 63: (3-gn<fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3'-fluoro-3-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e fo)-[({[(2-bromo-6- methylphenyl)amino] carbonyl } oxy)methyl] -8-azabicyclo [3.2.1] octane-8 - carboxylate were reacted to generate the title compound. LC/MS ESI R 2.50 mins MH+ 369.
Example 64: (3-g«<foy8-azabicvclo[3.2.11oct-3-ylmethyl (3',4-difluoro-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-5- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.63 mins MH4" 373. Example 65: (3-gw<fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (3',5-difluoro-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromo-4-fluorophenyl)amino] carbonyl } oxy)methyl]-8-azabicyclo[3.2. l]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.55 mins MH+ 373.
Example 66: (3-g«<foV8-azabicvelor3.2.11oct-3-ylmethyl (4'-fluoro-3',4- dimethyl-2-biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluoro-3 -methy Iphenyl) boronic acid and 1,1-dimethylethyl (3-en ø)-[({[(2-bromo-5-methylphenyι) amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1 ] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.73 mins MH+ 383.
Example 67: (3-g«<fo)-8-azabicyclo[3.2.11oet-3-ylmethyl (4-chIoro-4'-fluoro-3'- methvI-2-biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluoro-3-methylphenyl) boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-5-chlorophenyl)amino] carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.8 mins MH+ 403.
Example 68: (3-g«<foV8-azabicvclo[3.2.11oct-3-ylmethyl (4'-fluoro-3',5- dimethyl-2-biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluoro-3- methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-4- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.72 mins MH+ 383. Example 69: (3-g/ι<foV8-azabicvclor3.2.11oct-3-ylmethyl (4'-fluoro-3,3'- dimethyl-2-biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluoro-3- methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-6- methylphenyl)ammo]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI R 2.59 mins MH+ 383.
Example 70: (3-g«<foV8-azabicvclo[3.2.11oct-3-ylmethyl (4,4'-difluoro-3'- methyl-2-biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluoro-3- methylphenyl)boronic acid and 1,1-dimethylethyl (3-e/π/ø)-[({[(2-bromo-5- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R 2.72 mins MlY 387.
Example 71: (3-g«rfo)-8-azabicyclo[3.2.11oct-3-ylmethyl (4',5-difluoro-3'- methyl-2-biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluoro-3- methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-4- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.65 mins MH+ 387.
Example 72: (3-g«<fo)-8-azabicyclo[3.2.1]oct-3-yImethyl (3',4-dichloro-4f-fluoro- 2-biphenyIvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (3-chloro-4-fluorophenyl) boronic acid and 1,1-dimethylethyl (3-e«cfø)-[({[(2-bromo-5-chlorophenyl) amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.81 mins MH+ 423. Example 73: (3-gιι<foV8-azabicvclof3.2.11oct-3-ylmethyl (3'-chloro-4'-fluoro-3- methvI-2-biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-chloro-4- fluorophenyl)boronic acid and 1,1-dimethylethyl (3-eτπtø)-[({[(2-bromo-6- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.63 mins MH* 403.
Example 74: (3-g«<føV8-azabicyclof3.2.11oct-3-ylmethyl (3'-chloro-4,4'-difluoro- 2-biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-chloro-4-fluorophenyl) boronic acid and 1,1-dimethylethyl (3-e«rfø)-[({[(2-bromo-5-fluorophenyl)amino] carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.72 mins MH+ 407.
Example 75: (3-gw</øV8-azabicvclo[3.2.11oct-3-vlmethyl (2'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate
According to the procedure outlined in example 60, (2-fluoroρhenyl)boronic acid and 1,1-dimethylethyl (3-e«dø)-[({[(2-bromo-5-methylphenyl)amino] carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.59 mins MlY 369.
Example 76: (3-gw</o)-8-azabicyclof3.2.11oct-3-yImethyI (4-chloro-2'-fluoro-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (2-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-ewfo)-[({[(2-bromo-5- chlorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.66 mins MET1" 389. Example 77: (3-g»<foV8-azabicvclo [3.2.11 oct-3-ylmethyl (2'-fluoro-5-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (2-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-erødø)-[({[(2-bromo-4- methy Ipheny l)amino] carbonyl } oxy)methy 1] - 8 -azabicyclo [3.2.1] octane- 8 - carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.57 mins MH+ 369.
Example 78: (3-g/t<foV8-azabicvelo[3.2.11oct-3-ylmethyl (2'-fluoro-3-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (2-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2-bromo-6- methylphenyl)amino] carbonyl} oxy)methyl] - 8-azabicyclo [3.-2.1] octane-8 - carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.46 mins MH 369.
Example 79: (3-g«<foV8-azabicvclo[3.2.11oct-3-ylmethyl (2',5-difluoro-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (2-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-eτκfo)-[({[(2-bromo-4- fluorophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo [3.2.1] octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.62 mins MH+ 369.
Example 80: (3-g«</o -8-azabicyclo[3.2.11oct-3-ylmethyl (4'-fluoro-4-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromo-5 - methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.62 mins MH+ 369. Example 81: (3-g«<fø)-8-azabicvclof3.2.11oct-3-ylmethyl (4-chloro-4'-fluoro-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e fo)~[({[(2-bromo-5- chlorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.70 mins MH+ 389.
Example 82: (3-gwrfoV8-azabicyclo [3.2.11 oct-3-ylmethyl (4'-fluoro-5-methyl-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-e«t ø)-[({[(2-bromo-4- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.62 mins
MH+ 369.
Example 83: (3-g/»fo)-8-azabicyclo[3.2.11oct-3-ylmethyl (4'-fluoro-3-methyl-2- biphenylvPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-en ø)-[({[(2-bromo-6- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2. l]octane-8- carboxylate were reacted to generate the title compound. LC MS ESI R 2.48 mins
MH+ 369.
Example 84: (3-g«<fo)-8-azabicyclo [3.2.11 oct-3-ylmethyl (4,4'-difluoro-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-fluorophenyl)boronic acid and 1,1-dimethylethyl (3-eπ o)-[({[(2-bromo-5- fluorophenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo [3.2.1 ] octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI R 2.62 mins MH+ 373. Example 85: (3-gfttfoV8-azabicvclo[3.2.11oct-3-ylmethyl (3',4-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1 , 1 -dimethylethyl (3 -endo)- [( { [(2-bromo-5 - methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.7 mins MH+ 365.
Example 86: (3-g«<foV8-azabicvelo[3.2.11oct-3-ylmethyI (4-chIoro-3'-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e«dø)-[({[(2-bromo-5- chlorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI Rτ 2.78 mins MH " 385.
Example 87: (3-g«</oV8-azabicvclo[3.2.11oct-3-ylmethyl (3',5-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e/«/ø)-[({[(2-bromo-4- methy lphenyl)amino] carbonyl } oxy)methyl] - 8-azabicyclo [3.2.1] octane-8 - carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.68 mins
MH+ 365.
Example 88: (3-g«<fo)-8-azabicyclo[3.2.11oct-3-ylmethyI (3,3'-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-6- methylphenyl)amino] carbonyl } oxy)methyl] -8-azabicyclo [3.2.1] octane-8 - carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.55 mins MH+ 365. Example 89: (3-gw</oV8-azabicyclo[3.2.11oct-3-ylmethyl (4-fluoro-3'-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-endo)-[({[(2-bro o-5- ιluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.70 mins MET1" 369.
Example 90: (3-g»rfoV8-azabicvelof3.2.11oct-3-ylmethyl (5-fluoro-3'-methyl-2- biphenylvPcarbamate trifluoroacetate According to the procedure outlined in example 60, (3-methylphenyl)boronic acid and 1,1-dimethylethyl (3-emfo)-[({[(2-bromo-4- fluorophenyl)amino] carbonyl } oxy)methyl] -8-azabicyclo [3.2.1 ]octane-8 -carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.62 mins MH+ 369.
Example 91: (3-gw<foV8-azabicvclor3.2.11oct-3-ylmethyl (4,4'-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e«<iø)-[({[(2-bromo-5- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.71 mins MH+ 365.
Example 92: (3-g«tfoV8-azabicyclo[3.2.11oct-3-ylmethyl (4-chloro-4t-methyI-2- biphenylyPcarbamate trifluoroacetate According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-ewdø)-[({[(2-bromo-5- chlorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.79 mins MH4" 385. Example 93: (3-gf*<foy8-azabicvclo[3.2.11oct-3-ylmethyl (4',5-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« o)-[({[(2-bromo-4- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2. l]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.70 mins MH+ 365.
Example 94: (3-gwrfo -8-azabicyclo[3.2.11oct-3-ylmethyl (3,4'-dimethyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e« ø)-[({[(2-bromo-6- methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8- carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.55 mins ME^ 365.
Example 95: (3-gw<foV8-azabicyclof3.2.11oct-3-ylmethyl (4-fluoro-4'-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-methylphenyl)boronic acid and 1,1-dimethylethyl (3-e7? ø)-[({[(2-bromo-5- fluorophenyl)amino]carbonyl} oxy)methyl]-8-azabicyclo[3.2.1 ]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI R 2.70 mins MET1" 369.
Example 96: (3-gw<foV8-azabicyclo[3.2.πoct-3-ylmethyl (5-fluoro-4'-methyl-2- biphenylyPcarbamate trifluoroacetate
According to the procedure outlined in example 60, (4-methylρhenyl)boronic acid and 1,1-dimethylethyl (3-erafo)-[({[(2-bromo-4- fluorophenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate were reacted to generate the title compound. LC/MS ESI RT 2.64 mins MH+ 369. Example 97: (3-g/*<foH({[(3'-chloro-4-fluoro-2- biphenylyPamino]carbonyl)oxy methvn-8,8-dimethyl-8- azoniabicyclo [3.2.11 octane trifluoroacetate
A solution of (3-ew ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-fluoro-2- biphenylyPcarbamate (47mg) in DMF (1ml) was treated with potassium carbonate (17mg) and methyl iodide (30ul). After 16h the solvent was evaporated and the residue purified by MDAP to give the title compound. LC/MS ESI RT 2.55 mins MH 417.
Example 98: (3-gn<foH(f [(3'-chloro-5-hvdroxy-2- biphenylvPaminolcarbonvDoxy)methvn-8,8-dimethyl-8- azoniabicyclo[3.2.11octane trifluoroacetate
The title compound was prepared from (3-eπJø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 -chloro-5-hydroxy-2-biphenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI Rτ 2.22 mins MEL 415.
Example 99: (3-gw<foH(f r(3'-chloro-3-methyl-2- biphenylyPaminol carb ony 1} oxy)methy 1] -8,8-dimethy 1-8- azoniabicyclo[3.2.11octane trifluoroacetate The title compound was prepared from (3-eπ<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 -chloro-3 -methyl-2-biρhenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI Rτ 2.45 mins MEf 413.
Example 100: β-gwffoH fβ'-ehloro-ό-fluoro^- biphenylyP(methyPaminolcarbonyl}oxy)methyn-8,8-dimethyl-8- azoniabicyclo [3.2.11 octane trifluoroacetate
The title compound was prepared from (3-endø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-6-fluoro-2-biphenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI Rτ 2.51 mins MDEL 431. Example 101: (3-gwrfo -[({[(3'-chloro-5-fluoro-2- biphenylyPaminolcarbonvUoxy)methyll-8,8-dimethyl-8- azoniabicyclo[3.2.πoctane trifluoroacetate
The title compound was prepared from (3-erc<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-fluoro-2-biphenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI Rτ 2.47 mins MIL 417.
Example 102: (3-g ι^o)-[({[(3'-chloro-3-fluoro-2- biphenylyPfmethyPaminolcarbonyPoxy^methyll-S^-dimethyl-S- azoniabicyclo[3.2.11octane trifluoroacetate
The title compound was prepared (3-ercdø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 - chloro-3 -fluoro-2-biphenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI Rτ 2.54 mins MET 431.
Example 103: (3-gwrfoV[((f(3'-chloro-2- biphenylyPaminolcarbonyl}oxy)methyll-8,8-dimethyI-8- azoniabicyclo [3.2.11 octane trifluoroacetate
The title compound was prepared from (3~ercdø)-bicyclo[3.2.1]oot-3-ylmethyl (3'- chloro-2-biphenylyl)carbamate according to the procedure outlined in example 97. LC/MS ESI R,. 2.45 mins MET 400.
Example 104: (3-g«< o)-8-azabicyclo[3.2.11oct-3-ylmethyl 2- biphenylylcarbamate
A mixture of 1,1-dimethylethyl -(3-eπ ø)-(hydroxymethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate (162 mg) and 2-isocyanato-biphenyl (130.7 mg) in DMF (2 ml) was stirred at room temperature for 1 hour. The reaction mixture was purified directly by Gilson preparatory HPLC to give (3-endo)-3-(bi ea l-2- ylcarbamoyloxymethyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (190 mg, 65%), which was dissolved in 12 ml of methylene chloride and 3 ml of TFA. The above mixture was heated at 65°C for 2 hours, concentrated and redissoved in ethyl acetate (30 ml). The organic phase was washed with 1 N sodium hydroxide (10 ml). The aqueous phase was extracted with ethyl acetate (3 X 10 ml). The combined organics were washed with brine (10 ml) and dried over Na2SO4 to give the title compound (98 mg, 75%). LC/MS ESI Rτ 1.62min M*337
Intermediate 17: 8-methyl-8-azabicyclo[3.2.11oct-3-yl (2- bromophenvDcarbamate
A solution of 2-bromobenzoic acid (1.00 g, 5.00 mmol) in THF (10 mL) was added to a Radleys® Carousel Reaction tube fitted with magnetic stirring bar. Diphenylphoshine azide (1.18 mL, 5.50 mmol) was then added, followed by ethylamine (1.40 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (1.19 g, 7.50 mmol) was then added. Stirring continued for 16 h at 75 °C, and the precipitated phosphonic acid was removed by vacuum filtration. The filtrate was then concentrated under reduced pressure. The residue was dissolved in DCM (6 ml), and the solution was transferred to a 10 mL hydrophobic frit that contained H2O (3 mL). The aqueous layer was extracted with DCM (1 x 4 mL), and the combined organic layers were diluted with 50 mL of DCM. This solution was loaded onto a 10 g normal phase aminopropyl SPE cartridge primed with 60 mL of DCM. The cartridge was then sequentially eluted with DCM (1 x 60 mL), Et2O (1 x
60 mL), EtOAc (5 x 60 mL), and MeOH (1 x 60 mL). The title compound was found in the EtOAc fractions, which were concentrated under reduced pressure to yield the title compound 0.309 g (18%). LC/MS ESI Rτ 1.44 min, MH* 339.
The following intermediates in Table 1 were prepared according to the procedure outlined for intermediate 17.
Table 1
Figure imgf000058_0001
Figure imgf000058_0002
Example 105: 8-methyl-8-azabicyclo[3.2.11oct-3-yl (3'-chloro-4-fluoro-2- biphenylyPcarbamate
PS-PPh3-Pd (0.020 g, 0.0026 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromo-5-fluorophenyl)carbamate (0.063 g, 0.18 mmol) in DME (1 mL) in a 4 mL glass vial. A solution of 3-chlorophenyl boronic acid (0.055 g, 0.35 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K2CO3 (0.056 g, 0.41 mmol) in H2O (0.5 mL). The glass vial was capped, and the reaction was agitated in an Innova® Shaker at 80 °C for 48 h. The resin was removed by gravity filtration, washed with DME (l x l mL) and EtOH (1 x 1 mL), and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (4 mL) and transferred onto a 6 mL hydrophobic frit. H2O (2 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 x 4 mL). The combined organic layers were concentrated under reduced pressure and purified by Gilson® preparatory HPLC to yield the title compound (0.030 g, 43%). LC/MS ESI Rτ 1.73 min, MH" 389.
The following examples in Table 2 were prepared according to the procedure outlined in Example 105. Table 2
Figure imgf000059_0001
Figure imgf000059_0002
Example 108: 8-methyl-8-azabicvclor3.2.1Ioct-3-yl (3'-chloro-4'-fluoro-2- biphenylyPcarbamate PS-PPh3-Pd (0.020 g, 0.0026 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromo-5-chlorophenyl)carbamate (0.035 g, 0.095 mmol) in DME (1 mL) in a microwave reactor tube. A solution of 3-chlorophenyl boronic acid (0.030 g, 0.19 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K2CO3 (0.030 g, 0.22 mmol) in H2O (0.5 mL). The reaction vial was capped and heated at 165° C for 10 min. The resin was removed by gravity filtration, washed with DME (l x l mL) and EtOH (l l mL), and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (4 mL) and transferred onto a 6 mL hydrophobic frit. H2O (2.0 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 x 4 mL). The combined organic layers were concentrated under reduced pressure and purified by Gilson® preparatory HPLC to yield the title compound (0.021 g, 54%). LC/MS ESI Rτ 1.76 min, MF? 405
The following examples in Table 3 were prepared according to the procedure outlined in Example 108. Table 3
Figure imgf000060_0001
Figure imgf000060_0002
Example 111: Preparation of 8-methyl-8-azabicyclo[3.2.11oct-3-yl (3'-chloro-2- biphenylyPcarbamate
Pd(PPh3)4 (0.089 g, 0.077 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromophenyl)carbamate (0.130 g, 0.383 mmol) in DME (1 mL) in a 4 mL glass vial with a magnetic stir bar. A solution of 3- chlorophenylboronic acid (0.090 g, 0.58 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K CO3 (0.200 g, 1.44 mmol) in H2O
(0.5 mL). The glass vial was capped and heated at 80° C for 16 h. The reaction mixture was concentrated under reduced pressure, taken up in DCM (4 mL), and transferred onto a 6 mL hydrophobic frit. H O (2 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 4 mL). The combined organic layers were concentrated under reduced pressure and purified by Gilson® preparatory HPLC to yield the title compound (0.042 g, 30%). LC/MS ESI Rτ 1.74 min, MH 371.
The following examples in Table 4 were prepared according to the procedure outlined in Example 111. Table 4
Figure imgf000061_0001
Figure imgf000061_0002
Example 117: 3-{[(2-biphenylylamino)carbonyIl oxy}-8,8-dimethyl-8- azoniabicyclo [3.2.11 octane bromide First step
Pd(PPh3)4 (0.089 g, 0.077 mmol) was added to a solution of 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (2-bromophenyl)carbamate (0.060 g, 0.177 mmol) in DME (1 mL) in a 4 mL glass vial with a magnetic stir bar . A solution of phenylboronic acid (0.043 g, 0.354 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K2CO3 (0.056 g, 0.407 mmol) in H2O (0.5 mL). The glass vial was capped and heated at 80° C for 16 h. The reaction mixture was concentrated under reduced pressure, taken up in DCM (4 mL), and transferred onto a 6 mL hydrophobic frit. H2O (2 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 4 mL). The combined organic layers were concentrated under reduced pressure and purified by Gilson preparatory HPLC to yield 8-methyl-8- azabicyclo [3.2.1 ] oct-3 -yl 2-biphenylylcarbamate (0.050 g, 83%). LC/MS ESI Rτ 1.54 min, MH" 337. Second step
A 2 M solution of MeBr in tert-butyl methyl ether (0.700 mL, 1.49 mmol) was added to a solution of 8-methyl-8-azabicyclo[3.2.1]oct-3-yl 2-biphenylylcarbamate (0.050 g, 0.15 mmol) in a mixture (1:1) of DCM/CH3CN (2 mL) in a glass vial with a magnetic stirring bar under argon. The reaction was stirred at room temperature for 16 h. The solvent was evaporated, and the product was dried under high vacuum to yield the title compound (0.050 g, 94%). LC/MS ESI Rτ 1.72 min, MET" 351
The following examples in Table 5 were prepared according to the procedure outlined in Example 117 reacting the appropriate boronic acid and bromo-phenyl intermediates. Table 6
Figure imgf000062_0001
Figure imgf000063_0001
Example 135: 3-(f[(3\5-dichloro-2-biphenyIyPaminolcarbonyr}oxy)-8,8- dimethyl-8-azoniabicyclof3.2.11octane bromide
Following the procedure outlined in Example 117, 8-methyl-8-azabicyclo[3.2.1]oct- 3-yl (2-bromo-4-chlorophenyl)carbamate was reacted sequentially with 3- chlorophenyl boronic acid and MeBr to give the title compound (6.7 mg). NMR (CD3OD, 400 MHz; δ): 1.92 ppm (d, 2H), 2.30-2.39 ppm (m, 4H), 2.80 ppm (d,
2H), 3.13 ppm (s, 3H), 3.18 ppm (s, 3H), 3.85-3.88 ppm (m, 2H), 7.35-7.49 ppm (comp, 8H). Example 136: 3-({[(3'-chloro-2-biphenylvPaminolearbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.11octane bromide
Following the procedure outlined in the 2nd step of Example 117, 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (3'-chloro-2-biphenylyl)carbamate was reacted with MeBr to give the title compound (43.7 mg). NMR (DMSO, 400 MHz; δ): 1.69 ppm (d, 2H), 2.08-2.25 ppm (m, 4H), 2.45 ppm (d, 2H), 3.01 ppm (s, 3H)S 3.08 ppm (s, 3H), 3.81 ppm (m, 2H), 4.75 ppm (t, IH), 7.35-7.49 ppm (comp, 8H), 9.06 ppm (s, IH).
Example 137: 3-({[(3'-chloro-4',5-difluoro-2-biphenylvPamino1carbonyl)oxyV 8,8-dimethyl-8-azoniabicvclo[3.2.11octane bromide
Preparation of (3-e»io)-8-methyl-8-azabicvclo[3.2.1]oct-3-yl (2-bromo-4- fluorophenvDcarbamate
A solution of 2-bromo-4-fluorobenzoic acid (1.09 g, 5.00 mmol) in THF (10 mL) was added to a carousel reaction tube fitted with magnetic stirring bar.
Diphenylphoshine azide (1.18 mL, 5.50 mmol) was then added, followed by ethylamine (1.40 mL, 10.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (1.19 g, 7.50 mmol) was then added. Stirring continued for 16 h at 75 °C, and the precipitated phosphonic acid was removed by vacuum filtration. The filtrate was then concentrated under reduced pressure. The residue was dissolved in DCM (6 ml), and the solution was transferred to a 10 mL hydrophobic frit that contained H2O (3 mL). The aqueous layer was extracted with DCM (1 x 4 mL), and the combined organic layers were diluted with 50 mL of DCM. This solution was loaded onto a 10 g aminopropyl SPE cartridge primed with 60 mL of DCM. The cartridge was then sequentially eluted with DCM (1 x 60 mL), Et2O (1 x 60 mL), EtOAc (5 x 60 mL), and MeOH (1 x 60 mL). The title compound was found in the EtOAc fractions, which were concentrated under reduced pressure to yield (3-endo)- 8-methyl-8-azabicyclo[3.2.1]oct-3-yl (2-bromo-4-fluorophenyl)carbamate (0.343 g). LC/MS ESI Rτ 1.39 min, MH+ 358. Preparation of 3-({ [(3'-chloro-4'.5-difluoro-2-biphenylyl)amino1carbonyl>oxy -8.8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide
PS-PPh3-Pd (0.020 g, 0.0026 mmol) was added to a solution of (3-ewfo)-8-me hyl-
8-azabicyclo[3.2.1]oct-3-yl (2-bromo-4-fluorophenyl)carbamate (0.068 g, 0.19 mmol) in DME (1 mL) in a 4 mL glass vial. A solution of 3-chloro4-fluorophenyl boronic acid (0.066 g, 0.38 mmol) in EtOH (1 mL) was added to the reaction mixture, followed by a solution of K2CO3 (0.056 g, 0.41 mmol) in H2O (0.5 mL).
The glass vial was capped, and the reaction was agitated in an shaker at 80 °C for 48 h. The resin was removed by gravity filtration, washed with DME (l l mL) and EtOH (l x l mL), and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (4 mL) and transferred onto a 6 mL hydrophobic frit. H2O (2 mL) was added to the solution and mixed to remove base. The layers were separated, and the aqueous layer was washed with DCM (1 x 4 mL). The combined organic layers were concentrated under reduced pressure and purified by Gilson® preparatory HPLC to yield an oil which was treated with a solution of 2 M solution of MeBr in tert-butyl methyl ether (0.700 mL, 1.49 mmol) in a mixture (1:1) of DCM/CH3CN (2 mL) in a glass vial with a magnetic stirring bar under argon. The resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated, and the product was dried under high vacuum to yield the title compound (0.437 mg). NMR (DMSO, 400 MHz; δ): 1.69 ppm (d, 2H), 2.10-2.40 ppm (m, 4H), 2.45 ppm (d, 2H), 3.02 ppm (s, 3H), 3.08 ppm (s, 3H), 3.81 ppm (m, 2H), 4.75 ppm (t, IH), 7.27-7.52 ppm (comp, 6H), 9.06 ppm (s, IH).
Example 138: 3-({f(3'-chloro-5-fluoro-2-biphenylvPaminolcarbonylloxy)-8,8- dimethyl-8-azoniabicvclo[3.2.11octane bromide
Following the procedure outlined in Example 117, 8-methyl-8-azabicyclo[3.2.1]oct- 3-yl (2-bromo-4-fluorophenyl)carbamate was reacted sequentially with 3- chlorophenyl boronic acid and MeBr to give the title compound (31.2 mg). NMR (DMSO, 400 MHz; δ): 1.75 ppm (d, 2H), 2.08-2.45 ppm (m, 4H), 2.46 ppm (d, 2H), 3.01 ppm (s, 3H), 3.09 ppm (s, 3H), 3.81 ppm (m, 2H), 4.79 ppm (t, IH), 7.19 ppm (t, IH), 7.19-7.49 ppm (comp, 6H), 9.16 ppm (s, IH). Example 139: 3-f{[(5-fluoro-2-biphenylvPaminolcarbonyl|oxyV8,,8-dimethyl-8- azoniabicyclo[3.2.11octane bromide
Following the procedure outlined in the 2nd step of Example 117, 8-methyl-8- azabicyclo[3.2.1]oct-3-yl (5-fluoro-2-biphenylyl)carbamate was reacted with MeBr to give the title compound (43.7 mg). NMR (DMSO, 400 MHz; δ): 1.68 ppm (d, 2H), 2.10-2.45 ppm (m, 4H), 2.46 ppm (d, 2H), 3.00 ppm (s, 3H), 3.07 ppm (s, 3H), 3.78 ppm (m, 2H), 4.70 ppm (t, IH), 7.23 ppm (t, IH), 7.39-7.43 ppm (comp, 8H), 8.95 ppm (s, IH).
Example 140: (3-g/κfoH({K3'-chloro-2- biphenylvPaminolcarbonylloxy)methyll-8,8-dimethyl-8- azoniabicyclo[3.2.11octane bromide
Preparation of LI -dimethylethyl 3-(endo)-\({\(3'-chloro-2- biphenylvDaminolcarbonvDoxy^methyn-δ-azabicvclorS^.^octane-δ-carboxylate A solution of the commercially available 3'chlorbiphenylcarboxylic acid (500 mg, 2.15 mmol) in THF (20 ml) was treated with diphenylphosphoryl azide (508 μl), triethylamine (620 μl) and 1,1-dimethylethyl -(3-erødø)-(hydroxymethyl)-8- azabicyclo[3.2.1]octane-8-carboxylate (622 mg). The reaction mixture was heated at reflux for 12 hours, cooled to room temperature, diluted with ethyl acetate and washed sequentially with 0.5N aqueous HC1, sat NaHCO3 and water. The organic layer was dried over MgSO4, filtered and evaporated to give a crude oil which was purified by flash chromatography. Elution with a ethyl acetate/hexane 1:3 mixture afforded 1,1-dimethylethyl 3-(g«rfø)-[({[(3'-chloro-2- biphenylyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate as an oil (904 mg). LC/MS ESI R, 2. 97 mins.
Preparation of (3-e^(io -8-azabicvclo[3.2.1]oct-3-ylmethyl C3'-chloro-2- biphenylyPcarbamate hydrochloride A mixture of 1,1-dimethylethyl 3-(e« ø)-[({[(3'-chloro-2- biphenylyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (904 mg) and 1HC1 in ether (10 ml) in methanol (5 ml) was allowed to stir at room temperature for 12 hours. The solvents were evaporated under vacuum. The resulting residue was redisolved in water (50 ml) then washed with ether (2 X 100 ml), basified to pH 13 with 2.5 N aq. NaOH (10 ml) then extracted with ethyl acetate (3 X 100 ml). The combined organic extracts were dried over MgSO4 and evaporated under vacuum to give (3-e«ttø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 - chloro-2~biphenylyI)carbamate hydrochloride as a white solid (550 mg). LC/MS ESI Rτ 1.83 mins MH+ 371.
Preparation of [(3-eπάfo -8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl (3'-chloro-2- biphenylyPcarbamate
A solution of NaBH (20.4 mg) was added to a mixture of (3-endo)-8- azabicyclo[3.2. l]oct-3 -ylmethyl (3'-chloro-2 -biphenylyPcarbamate hydrochloride (100 mg, 0.27 mmol) and formaldehyde (102.6 μl, 37% in water, 10.8 mmol) in methanol (5 ml). The resulting solution was allowed to stir at room temperature for 48 hours. More formaldehyde (100 μl) and NaBH4 (20 mg) were added to the reaction mixture. After 12 hours of stirring at room temperature, the solvents were evaporated under vacuum to give a residue which was partitioned between DCM (6 ml) and water (6 ml). The organic layer was separated and loaded onto a 2g NH2 SPE cartridge and sequentially eluted with DCM (3 x 5ml), ethyl acetate (2 X 5 ml) and methanol (2 X 5 ml). The last DCM fraction and the two ethyl acetate fractions were combined and evaporated to give (3-e« ø)-bicyclo[3.2.1]oct-3-ylmethyl (3'- chloro-2-biphenylyl)carbamate as a white solid (70 mg). LC/MS ESI RT 1.92 mins M+ 385.
Preparation of (3-endo)-[({ \(3 '-chloro-2-biphenylvPamino] carbonyl }oxy methyl]- 8,8-dimethyl-8-azoniabicyclo[3.2. l]octane bromide
A solution of [(3-e«£tO)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]methyl (3'-chloro-2- biphenylyl)carbamate (48 mg) in DMF (2 ml) and acetonitrile (2 ml) was treated with methyl brornide (50 μl of a 2M solution in t-butyl ethyl ether). After stirring at room temperature for 12h the solvents were evaporated under vacuum to give the title compound (57 mg). LC/MS ESI Rτ 1.81 mins M+ 399. The compounds of the present invention exhibit IC50 values of 1.5μM or less. Abbreviations
BOC tert-butyloxycarbonyl
DCM Dichloromethane
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethylsulfoxide
ESI Electrospray ionization
HPLC High pressure liquid chromatography
LC/MS Liquid chromatography/Mass spectrometry
MDAP Mass directed automated preparative
Rt Retention time
SPE Solid phase extraction
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
BIOLOGICAL EXAMPLES
The inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo functional assays:
Analysis of Inhibition of Receptor Activation by Calcium Mobilization: Stimulation of mAChRs expressed on CHO cells were analyzed by monitoring receptor-activated calcium mobilization as previously described (H. M.Sarau et al, 1999. Mol. Pharmacol. 56, 657-663). CHO cells stably expressing M3 mAChRs were plated in 96 well black wall/clear bottom plates. After 18 to 24 hours, media was aspirated and replaced with 100 μl of load media (EMEM with Earl's salts, 0.1 % RIA-grade BSA (Sigma, St. Louis MO), and 4 μM Fluo-3- acetoxymethyl ester fluorescent indicator dye (Fluo-3 AM, Molecular Probes, Eugene, OR) and incubated 1 hr at 37° C. The dye-containing media was then aspirated, replaced with fresh media (without Fluo-3 AM), and cells were incubated for 10 minutes at 37° C. Cells were then washed 3 times and incubated for 10 minutes at 37° C in 100 μl of assay buffer (0.1% gelatin (Sigma), 120 mM NaCl, 4.6 mM KC1, 1 mM KH2 PO4, 25 mMNaH CO3, 1.0 mM CaCl2, 1.1 mM MgCl2, 11 mM glucose, 20mM HEPES (pH 7.4)). 50 μl of compound (lxl 0"11 - lxlO"5 M . final in the assay) was added and the plates were incubated for 10 min. at 37° C. Plates were then placed into a fluorescent light intensity plate reader (FLIPR, Molecular Probes) where the dye loaded cells were exposed to excitation light (488 nm) from a 6 watt argon laser. Cells were activated by adding 50 μl of acetylcholine (0.1-10 nM final), prepared in buffer containing 0.1% BSA, at a rate of 50 μl/sec. Calcium mobilization, monitored as change in cytosolic calcium concentration, was measured as change in 566 nm emission intensity. The change in emission intensity is directly related to cytosolic calcium levels. The emitted fluorescence from all 96 wells is measured simultaneously using a cooled CCD camera. Data points are collected every second. This data was then plotting and analyzed using GraphPad PRISM software.
Methacholine-induced bronchoconstriction - potency and duration of action Airway responsiveness to methacholine was determined in awake, unrestrained Balb C mice (n = 6 each group). Barometric plethysmography was used to measure enhanced pause (Penh), a unitless measure that has been shown to correlate with the changes in airway resistance that occur during bronchial challenge with methacholine(2). Mice were pre-treated with 50 μl of compound (0.003-10 μg/mouse) in 50 μl of vehicle (10% DMSO) intranasally (i.n.) and were then placed in the plethysmography chamber a given amount of time following drug administration (15 min - 96 h). For potency determination, a dose response to a given drug was performed, and all measurements were taken 15 min following i.n. drug administration. For duration of action determination, measurements were taken anywhere from 15 min to 96 hours following i.n. drug administration. Once in the chamber, the mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes. Mice were then challenged with an aerosol of methacholine (10 mg/ml) for 2 minutes. Penh was recorded continuously for 7 min starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterward. Data for each mouse were analyzed and plotted by using GraphPad PRISM software. This experiment allows the determination of duration of activity of the administered compound.
The present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
FORMULATION-ADMINISTRATION Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients. The present invention may be used to treat a mammal, including a human, in need of treatment.
Hereinafter, the term "active ingredient" means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. Compounds of formula (I) will be administered via inhalation via the mouth or nose. Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (e.g., lactose or starch), organic or inorganic salts (e.g., calcium chloride, calcium phosphate or sodium chloride), polyalcohols (e.g., mannitol), or mixtures thereof, alternatively with one or more additional materials, such additives included in the blend formulation to improve chemical and/or physical stability or performance of the formulation, as discussed below, or mixtures thereof. Use of lactose is preferred. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, the compound of the invention may be presented without excipients, or may be formed into particles comprising the compound, optionally other therapeutically active materials, and excipient materials, such as by co-precipitation or coating. Suitably, the medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI). By reservoir dry powder inhaler (RDPI) it is meant as an inhaler having a reservoir form pack suitable for comprising multiple (un-metered doses) of medicament in dry powder form and including means for metering medicament dose from the reservoir to a delivery position. The metering means may for example comprise a metering cup or perforated plate, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation. By multi-dose dry powder inhaler (MDPI) is meant an inhaler suitable for dispensing medicament in dry powder form, wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple, define doses (or parts thereof) of medicament. In a preferred aspect, the carrier has a blister pack form, but it could also, for example, comprise a capsule-based pack form or a carrier onto which medicament has been applied by any suitable process including printing, painting and vacuum occlusion. The formulation can be pre-metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715). An example of a unit-dose device is Rotahaler (see GB 2064336). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose. Preferably, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet. In one aspect, the multi-dose pack is a blister pack comprising multiple blisters for containment of medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of medicament therefrom. In one aspect, the multi-dose blister pack comprises plural blisters arranged in generally circular fashion on a disk-form blister pack. In another aspect, the multi- dose blister pack is elongate in form, for example comprising a strip or a tape. Preferably, the multi-dose blister pack is defined between two members peelably secured to one another. US Patents Nos. 5,860,419, 5,873,360 and
5,590,645 describe medicament packs of this general type. In this aspect, the device is usually provided with an opening station comprising peeling means for peeling the members apart to access each medicament dose. Suitably, the device is adapted for use where the peelable members are elongate sheets which define a plurality of medicament containers spaced along the length thereof, the device being provided with indexing means for indexing each container in turn. More preferably, the device is adapted for use where one of the sheets is a base sheet having a plurality of pockets therein, and the other of the sheets is a lid sheet, each pocket and the adjacent part of the lid sheet defining a respective one of the containers, the device comprising driving means for pulling the lid sheet and base sheet apart at the opening station. By metered dose inhaler (MDI) it is meant a medicament dispenser suitable for dispensing medicament in aerosol form, wherein the medicament is comprised in an aerosol container suitable for containing a propellant-based aerosol medicament formulation. The aerosol container is typically provided with a metering valve, for example a slide valve, for release of the aerosol form medicament formulation to the patient. The aerosol container is generally designed to deliver a predetermined dose of medicament upon each actuation by means of the valve, which can be opened either by depressing the valve while the container is held stationary or by depressing the container while the valve is held stationary. Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size. The optimum aerodynamic particle size for inhalation into the bronchial system for localized delivery to the lung is usually 1-1 Oμm, preferably 2- 5μm. The optimum aerodynamic particle size for inhalation into the alveolar region for achieving systemic delivery to the lung is approximately .5-3 μm, preferably 1-3 μm. Particles having an aerodynamic size above 20μm are generally too large when inhaled to reach the small airways. Average aerodynamic particle size of a formulation may be measured by, for example cascade impaction. Average geometric particle size may be measured, for example by laser diffraction, optical means. To achieve a desired particle size, the particles of the active ingredient as produced may be size reduced by conventional means eg by controlled crystallization, micronisation or nanomilling .The desired fraction may be separated out by air classification. Alternatively, particles of the desired size may be directly produced, for example by spray drying, controlling the spray drying parameters to generate particles of the desired size range. Preferably, the particles will be crystalline, although amorphous material may also be employed where desirable. When an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention, such that the "coarse" carrier is rion-respirable. When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90μm and not less than 15% will have a MMD of less than 15μm. Additive materials in a dry powder blend in addition to the carrier may be either respirable, i.e., aerodynamically less than 10 microns, or non-respirable, i.e., aerodynamically greater than 10 microns. Suitable additive materials which may be employed include amino acids, such as leucine; water soluble or water insoluble, natural or synthetic surfactants, such as lecithin (e.g., soya lecithin) and solid state fatty acids (e.g., lauric, palmitic, and stearic acids) and derivatives thereof (such as salts and esters); phosphatidylcholines; sugar esters. Additive materials may also include colorants, taste masking agents (e.g., saccharine), anti-static-agents, lubricants (see, for example, Published PCT Patent Appl. No. WO 87/905213, the teachings of which are incorporated by reference herein), chemical stabilizers, buffers, preservatives, absorption enhancers, and other materials known to those of ordinary skill. Sustained release coating materials (e.g., stearic acid or polymers, e.g. polyvinyl pyrolidone, polylactic acid) may also be employed on active material or active material containing particles (see, for example, Patent Nos. US 3,634,582, GB 1,230,087, GB 1,381,872, the teachings of which are incorporated by reference herein). Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants. Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product. Preferred unit dosage formulations are those containing an effective dose, as herein before recited, or an appropriate fraction thereof, of the active ingredient. Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is
1. A compound of formula (I) as indicated below
Figure imgf000076_0001
Φ wherein:
n is 0 or 1 ;
Ha is a hydrogen atom in the exo postion,
Rl and R2 are, independently, selected from the group consisting of a bond, hydrogen and methyl;
R3 is selected from the group consisting of hydrogen and Cl-4 alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, C2-4 alkenyl, halo substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted C 1 -4 alkyl, and (CR9R9)qNC(O)Ra
R6, R7 and R8 are, independently, selected from the group consisting of hydrogen, halogen, cyano, Cl-4 alkyl, C2-4 alkenyl, Cl-4 alkoxy, halo-substituted Cl-4 alkyl, (CR9R9)qORa, hydroxy substituted Cl-4 alkyl, and (CR9R9)qNC(O)Ra; or two of either R6, R7 or R8 moieties together may form a 5 to 6 membered saturated or unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted; Ra is selected form the group consisting of hydrogen, Cl-4 alkyl, and halo substituted Cl-4 alkyl; R9 is hydrogen or Cl-4 alkyl q is 0, or an integer having a value of 1 to 4;
X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
A compound according to claim 1 selected from Examples 1 to 140.
3. A compound according to claim 1 selected from the group consisting of:
(3-eM£tO)-3-[({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-en<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-enc?ø)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2. ljoctane trifluoroacetate; (3-en<iø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-3-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«fifø)-8-azabicyclo[3.2.1]oct-3-ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3-ew< ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-2-biphenylyl)carbamate;
(3-ew ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-hydroxy-2- biphenylyPcarbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylyPcarbamate trifluoroacetate;
(3 -e« o)-8-azabicyclo [3.2.1 ]oct-3 -ylmethyl (3 '-chloro-6-fluoro-2- biphenylyl)carbamate trifluoroacetate; (3 -e« ø)-8-azabicyclo [3.2.1 ]oct-3 -ylmethyl (3 '-fluoro-2-biphenylyl)carbamate;
(3 -endo)-3 -[({ [(3 '-chloro-5 -hydroxy-2-biphenylyl)amino] carbonyl } oxy)methyι] -8 , 8- dimethyl-8-azoniabicyclo[3.2.1] octane trifluoroacetate; (3-e«Jø)-3-[({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-5-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-e/2<fo)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-4-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-3'-methyl-2- biphenylyPcarbamate;
(3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-eπt/ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4,4'-difluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-eπc ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-e«<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',5-difluoro-2- biphenylypcarbamate;
(3-erafo)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-chloro-4'-fluoro-2- biphenylyl)carbamate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-2-biphenylyl)carbamate; (3-eπt o)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3 -eπ ø)-8-azabicyclo [3.2.1 ] oct-3 -ylmethyl (4', 5 -difluoro-3 '-methy 1-2- biphenylyl)carbamate trifluoroacetate;
(3-efl6fo)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-2 -biphenylyPcarbamate; (3-e« ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (5-fluoro-3'-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«ttø)-3-[({[(3'-chloro-3-metlιyl-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo [3.2.1 ]octane trifluoroacetate;
(3-e« ø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-fluoro-4-methyl-2- biphenylyPcarbamate trifluoroacetate;
(3-eτπfo)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3'-chloro-4'-fluoro-3-methyl-2- biphenylyl)carbamate trifluoroacetate; (3 -eH )-8-azabicyclo [3.2.1] oct-3 -ylmethyl (4-methyl-2-biphenylyl)carbamate
(3-e« o)-3-[({[(3'-chloro-6-fluoro-2- biphenylyl)(methyl)amino] carbonyl} oxy)methyl]-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane trifluoroacetate; (3-ew/o)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-4'-fluoro-5-methyl-2- biphenylyPcarbamate trifluoroacetate;
(3-e«< ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4-fluoro-2-biphenylyl)carbamate;
(3-e«£ ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-methyl-2-biphenylyl)carbamate;
(3-e«< ø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',6-difluoro-2- biphenylyPcarbamate;
(3-e«<io)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-ew/o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-4-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-ew ø)-8-azabicyclo[3.2. l]oct-3-ylmethyl (6-fluoro-2 -biphenylyl)carbamate;
(3-e«ttO)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3',4-dichloro-4'-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3 -endo)-3 -( { [(3 '-chloro-2-biphenylyl)amino] carbonyl} oxy)- 8 , 8 -dimethyl- 8- azoniabicyclo[3.2. l]octane bromide; (3-e«<iø)-3-({[(3'-chloro-3,4'-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. ljoctane bromide;
(3-en< ø)-3-({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1] octane bromide;
(3-e«rfø)-3-({[(3'-chloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-endo)-3-({ [(3 '-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl} oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-endo)-3-({ [(3 ',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl} oxy)-8,8- dimethyl-8-azoniabicyclo [3.2.1 Joctane bromide; (3-e«rfø)-3-({[(3'-chloro-4',6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide; (3-en o)-3-({[(3'-chloro-3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3-e« o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate; (3-e«< <?)-3-({[(3'-chloro-5-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3-en<io)-3-({[(3',5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide;
(3-e^o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-3,4'-difluoro-2- biphenylyPcarbamate;
(3-e« o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-2-biphenylyl)carbamate;
(3-e«fi?o)-3-({[(3'-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide;
(3 -en dø)-8-methyl-8-azabicyclo [3.2.1 ]oct-3 -yl (3 '-chloro-4',6-difluoro-2- biphenylyl)carbamate;
(3-e«ctO)-3-({[(3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide;
(3-e ø)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3',5-dichloro-4'-fluoro-2- biphenylyl)carbamate; (3 -endo)-3 -( { [(3 '-chloro-4-methyl-2-biphenylyl)amino] carbonyl } oxy)-8 , 8-dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3-e« ø)-3-{[(2-biphenylylamino)carbonyl]oxy}-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-e«^ø)-3-({[(3'-chloro-4'-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-e«^ø)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1 ]octane bromide;
(3-e«ύfo)-3-({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2.1]octane bromide; (3-e/ϊ£ o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3-fluoro-2-biphenylyl)carbamate;
(3-e«( o)-3-({[(3,,4-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide; (3-e« o)-3-({[(5-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimefhyl-8- azoniabicyclo[3.2. ljoctane bromide;
(3-eπ<io)-8,8-dimethyl-3-({[(4-methyl-2-biphenylyl)ammo]carbonyl}oxy)-8- azoniabicyclo[3.2. l]octane bromide; (3-e« ø)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (5-fluoro-2-biphenylyl)carbamate; (3-en o)-8-methyl-8-azabicyclo[3.2.1] oct-3 -yl (3 '-chloro-6-fluoro-2- biphenylyl)carbamate;
(3-e« o)-3-({[(3'-chloro-3-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide; and (3-endo)-3-({ [(6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide.
4. A compound according to claim 3 selected from the group consisting of:
(3 -endo)-3 - [( { [(3 '-chloro-2-biphenylyl)amino] carbonyl } oxy)methyl] -8 , 8-dimethyl- 8-azoniabicyclo[3.2. ljoctane trifluoroacetate;
(3-eR<io)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 '-chloro-5 -fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e«ή?o)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane trifluoroacetate; (3-e«<iø)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3 '-chloro-3 -methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e77<io)-8-azabicyclo[3.2.1] oct-3 -ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3 -e« o)-8-azabicy clo [3.2.1] oct-3 -ylmethyl (3 '-chloro-2 -biphenylyPcarbamate;
(3~e«do)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-5-hydroxy-2- biphenylyPcarbamate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3 -endo)-8-azabicyclo [3.2.1 ]oct-3 -ylmethyl (3 '-chloro-6-fluoro-2- biphenylyl)carbamate trifluoroacetate; (3-ewdo)-8-azabicyclo[3.2. l]oct-3 -ylmethyl (3,-fluoro-2-biphenylyl)carbamate;
(3-e«rf )-3-[({[(3'-chloro-5-hydroxy-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane trifluoroacetate; (3 -endo)-3 - [( { [(3 '-chloro-4-fluoro-2-biphenylyl)amino] carbonyl } oxy)methyl] -8 ,8- dimethyl-8-azoniabicyclo[3.2.1]octane trifluoroacetate;
(3-en o)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (3'-chloro-5-methyl-2- biphenylyl)carbamate trifluoroacetate; (3-e«<io)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-3'-methyl-2- biphenylypcarbamate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-e«rfO)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4,4'-difluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-en^o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4'-fluoro-4-methyl-2- biphenylypcarbamate trifluoroacetate; (3-e«<io)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate; ι
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4'-fluoro-2- biphenylyl)carbamate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (2'-fluoro-2-biphenylyl)carbamate; (3-e« o)-8-azabicyclo[3.2. l]oct-3-ylmethyl (3',5-difluoro-2-biphenylyl)carbamate trifluoroacetate;
(3-e«£ o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4',5-difluoro-3'-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (4'-fluoro-2-biphenylyl)carbamate; (3-e«dø)-8-azabicyclo[3.2.1] oct-3 -ylmethyl (5-fluoro-3'-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e«( o)-3-({[(3'-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. ljoctane bromide;
(3-e«βto)-3-({[(3'-chloro-3,4'-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-e«£ o)-3-({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8 -azoniabicyclo [3.2.1] octane bromide; (3-e« o)-3-({[(3,-chloro-4,-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3 -endo)-3 -( { [(3 '-chloro-4',5-difluoro-2-biphenylyl)amino]carbonyl} oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1] octane bromide; (3-e« o)-3-({[(3',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide;
(3-e«t o)-3-({[(3'-chloro-4',6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. ljoctane bromide;
(3-e«<io)-3-({[(3'-chloro-3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2.1]octane bromide;
(3-e«βfo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylyl)carbamate;
(3-e« o)-3-({[(3'-chloro-5-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-en do)-3-({ [(3',5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-en o)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (3 '-chloro-3 ,4'-difluoro-2- biphenylyl)carbamate;
(3-e«ύ?o)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (3'-chloro-2-biphenylyl)carbamate; (3-e«i o)-3-({[(3'-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. ljoctane bromide;
(3-en o)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (3'-chloro-4',6-difluoiO-2- biphenylyl)carbamate;
(3-g« o)-3-({[(3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1 ]octane bromide;
(3-en<io)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3',5-dichloro-4'-fluoro-2- biphenylyl)carbamate;
(3-endo)-3-({ [(3 '-chloro-4-methyl-2-biphenylyl)amino] carbonyl} oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-e« o)-3-{[(2-biphenylylamino)carbonyl]oxy}-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide; (3-eπ o)-3-({[(3'-chloro-4'-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo [3.2.1 ]octane bromide;
(3-e« o)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. l]octane bromide; (3-e« o)-3-({[(3'-chloro-4-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8 -azoniabicyclo [3.2.1] octane bromide;
(3-e^ o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3-fluoro-2 -biphenylyPcarbamate;
(3-e«ώfe»)-3-({[(3',4-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1 ]octane bromide; (3-endo)-3-({ [(5-chloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1 ]octane bromide;
(3-e«ύfo)-8,8-dimethyl-3-({[(4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8- azoniabicyclo[3.2.1]octane bromide;
(3-en o)-8-methyl-8-azabicyclo[3.2. l]oct-3-yl (5-fluoro-2-biphenylyl)carbamate; and
(3-e o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-6-fluoro-2- biphenylyl)carbamate.
5. A compound according to claim 4 selected from the group consisting of (3 -endo)-3 - [( { [(3 '-chloro-2-biphenylyl)amino] carbonyl } oxy)methyl] - 8 , 8-dimethyl-
8 -azoniabicyclo [3.2.1] octane trifluoroacetate;
(3 -e«dø)-8-azabicyclo[3.2.1 ]oct-3 -ylmethyl (3 '-chloro-5-fluoro-2- biphenylyl)carbamate trifluoroacetate;
(3-e«£ o)-3-[({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)methyl]-8,8- dimethyl-8-azoniabicyclo [3.2.1 ] octane trifluoroacetate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-3-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e« σ)-8-azabicyclo[3.2. l]oct-3-ylmethyl 2-biphenylylcarbamate trifluoroacetate;
(3-e«£to)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-2-biphenylyl)carbamate; (3 -ercdo)-S-azabicyclo [3.2.1 ]oct-3 -ylmethyl (3 '-chloro-5-hydroxy-2- biphenylyl)carbamate; (3-en o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-4-methyl-2- biphenylyl)carbamate trifluoroacetate;
(3-e« o)-8-azabicyclo[3.2.1]oct-3-ylmethyl (3'-chloro-6-fluoro-2- biphenylypcarbamate trifluoroacetate; (3-e/2(i )-3-({[(3'-cWoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo [3.2.1] octane bromide;
(3 -endo)-3-( { [(3 '-chloro-3 ,4'-difluoro-2-biphenylyl)amino] carbonyl} oxy)-8 ,8- dimethyl-8-azoniabicyclo[3.2.1 ]octane bromide;
(3-e« <?)-3-({[(3'-chloro-5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2. l]octane bromide;
(3-e«<i(?)-3-({[(3'-chloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3 -endo)-3 -( { [(3 '-chloro-4', 5 -difluoro-2-bipheny lypamino] carbonyl } oxy)-8 ,8- dimethyl-8-azoniabicyclo [3.2.1 ]octane bromide; (3-e«fifo)-3-({[(3',5-dichloro-4'-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2.1]octane bromide;
(3-e«(iσ)-3-({[(3'-chloro-4',6-difluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyl-8-azoniabicyclo[3.2. l]octane bromide;
(3-e« o)-3-({[(3'-chloro-3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl- 8-azoniabicyclo[3.2. l]octane bromide;
(3-e« o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',5-difluoro-2- biphenylypcarbamate;
(3-e«<io)-3-({[(3'-chloro-5-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8 -azoniabicyclo [3.2. ljoctane bromide; (3-e«^o)-3-({[(3',5-dichloro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1 ]octane bromide;
(3-e« o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-3,4'-difluoro-2- biphenylyl)carbamate;
(3-e« o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-2-biphenylyl)carbamate; (3-e«i )-3-({[(3'-chloro-6-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-
8-azoniabicyclo[3.2. l]octane bromide; (3-e^o)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3'-chloro-4',6-difluoro-2- biphenylyl)carbamate;
(3-e« o)-3-({[(3-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2. ljoctane bromide; (3-e« <9)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl (3',5-dichloro-4'-fluoro-2- biphenylyl)carbamate;
(3 -endo)-3 -( { [(3 '-chloro-4-methyl-2-biphenylyl)amino] carbonyl } oxy)-8 ,8 -dimethyl-
8-azoniabicyclo[3.2. l]octane bromide;
(3-endo)-3-{ [(2-biphenylylamino)carbonyl]oxy} -8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide;
(3-entfo)-3-({[(3'-chloro-4'-fluoro-4-methyl-2-biphenylyl)amino]carbonyl}oxy)-8,8- dimethyI-8-azoniabicyclo[3.2. ljoctane bromide; and
(3-e«rfσ)-3-({[(5-fluoro-2-biphenylyl)amino]carbonyl}oxy)-8,8-dimethyl-8- azoniabicyclo[3.2.1]octane bromide.
6. A pharmaceutical composition for the treatment of muscarinic acetylcholine receptor mediated diseases comprising a compound according to claim 1 and a pharmaceutically acceptable carrier thereof.
7. A method of inhibiting the binding of acetylcholine to its receptors in a mammal in need thereof comprising administering a safe and effective amount of a compound according to claim 1.
8. A method of treating a muscarinic acetylcholine receptor mediated disease, wherein acetylcholine binds to said receptor, comprising administering a safe and effective amount of a compound according to claim 1.
9. A method according to claim 8 wherein the disease is selected from the group consisting of chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.
10. A method according to claim 8 wherein administration is via inhalation via the mouth or nose.
11. A method according to claim 8 wherein administration is via a medicament dispenser selected from a reservoir dry powder inhaler, a multi-dose dry powder inhaler or a metered dose inhaler.
12. A method according to claim 11 wherein the compound has a duration of action of 24 hours or more.
PCT/US2005/001333 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonists WO2005067537A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US10/585,830 US20080249127A1 (en) 2004-01-13 2005-01-13 Muscarinic Acetylcholine Receptor Antagonists
BRPI0506777-4A BRPI0506777A (en) 2004-01-13 2005-01-13 muscarinic acetylcholine receptor antagonists
EP05711495A EP1711183A4 (en) 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonists
JP2006549649A JP2007518740A (en) 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonist
CA002552880A CA2552880A1 (en) 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonists
AU2005204935A AU2005204935A1 (en) 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonists
IL176775A IL176775A0 (en) 2004-01-13 2006-07-10 Muscarinic acetylcholine receptor antagonists
NO20063636A NO20063636L (en) 2004-01-13 2006-08-11 Muscarinic acetylcholine receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US53609204P 2004-01-13 2004-01-13
US60/536,092 2004-01-13

Publications (2)

Publication Number Publication Date
WO2005067537A2 true WO2005067537A2 (en) 2005-07-28
WO2005067537A3 WO2005067537A3 (en) 2006-05-18

Family

ID=34794385

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/001333 WO2005067537A2 (en) 2004-01-13 2005-01-13 Muscarinic acetylcholine receptor antagonists

Country Status (16)

Country Link
US (1) US20080249127A1 (en)
EP (1) EP1711183A4 (en)
JP (1) JP2007518740A (en)
KR (1) KR20060129017A (en)
CN (1) CN1929844A (en)
AR (1) AR049464A1 (en)
AU (1) AU2005204935A1 (en)
BR (1) BRPI0506777A (en)
CA (1) CA2552880A1 (en)
IL (1) IL176775A0 (en)
MA (1) MA28363A1 (en)
NO (1) NO20063636L (en)
PE (1) PE20050898A1 (en)
RU (1) RU2006129289A (en)
TW (1) TW200534855A (en)
WO (1) WO2005067537A2 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006005057A3 (en) * 2004-06-30 2006-09-28 Glaxo Group Ltd Muscarinic acetylcholine receptor antagonists
WO2007007282A2 (en) * 2005-07-11 2007-01-18 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
US7683173B2 (en) 2005-03-10 2010-03-23 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
WO2010094643A1 (en) 2009-02-17 2010-08-26 Glaxo Group Limited Quinoline derivatives and their uses for rhinitis and urticaria
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
EP3029026A4 (en) * 2013-07-30 2017-01-11 Dong-A ST Co., Ltd. Novel biphenyl derivative and method for preparing same
WO2019110521A1 (en) 2017-12-04 2019-06-13 Friedrich-Alexander-Universität Erlangen-Nürnberg Fluorophenyl substituted muscarinic receptor ligands with selectivity for m3 over m2
US11548931B2 (en) 2017-11-16 2023-01-10 Xl-Protein Gmbh PASylated VEGFR/PDGFR fusion proteins and their use in therapy

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007528420A (en) * 2004-03-11 2007-10-11 グラクソ　グループ　リミテッド Novel M3 muscarinic acetylcholine receptor antagonist
UY28871A1 (en) 2004-04-27 2005-11-30 Glaxo Group Ltd ANTAGONISTS OF THE MUSCARINIC ACETILCOLINE RECEIVER
US7598267B2 (en) * 2004-05-13 2009-10-06 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
EP1957075A4 (en) * 2004-11-15 2009-11-18 Glaxo Group Ltd Novel m3 muscarinic acetylcholine receptor antagonists
JP5379224B2 (en) 2009-04-30 2013-12-25 帝人ファーマ株式会社 Quaternary ammonium salt compounds
WO2014023325A1 (en) * 2012-08-06 2014-02-13 Fondazione Istituto Italiano Di Tecnologia Multitarget faah and cox inhibitors and therapeutical uses thereof
KR102239776B1 (en) * 2016-08-26 2021-04-13 동아에스티 주식회사 Novel salt of (r)-(1-methylpyrrolidin -3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystalline forms thereof
SG11201901431PA (en) 2016-08-26 2019-03-28 Dong A St Co Ltd Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and a crystal form thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1140998B (en) * 1980-06-18 1986-10-10 Valeas Ind Chimica E Farmaceut ENDO-8-METHYL-8-SIN-ALCHIL-8-AZONIABICYCLE OPEN SALTS PAR. SQUARE 3.2.1. CLOSED PAR. QUADRATA-OTTAN-3-ALCHILCARBOSSILATI, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE INGREDIENT
WO1995021820A1 (en) * 1994-02-10 1995-08-17 Yamanouchi Pharmaceutical Co., Ltd. Novel carbamate derivative and medicinal composition containing the same
CA2415468A1 (en) * 2000-07-11 2003-01-10 Yoshio Ogino Ester derivatives
US7365167B2 (en) * 2001-11-26 2008-04-29 Cell Matrix, Inc. Humanized collagen antibodies and related methods
CN1653068A (en) * 2002-05-07 2005-08-10 神经研究公司 Novel diazabicyclic biaryl derivatives
DE10255040A1 (en) * 2002-11-26 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New carbamic acid esters with anticholinergic activity
US7041674B2 (en) * 2002-11-26 2006-05-09 Boehringer Ingelhiem Pharma Gmbh & Co. Kg Carbamic acid esters with anticholinergic activity
EP1613307A4 (en) * 2003-04-07 2008-03-12 Glaxo Group Ltd M sb 3 /sb muscarinic acetylcholine receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP1711183A4 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006005057A3 (en) * 2004-06-30 2006-09-28 Glaxo Group Ltd Muscarinic acetylcholine receptor antagonists
EP1765339A2 (en) * 2004-06-30 2007-03-28 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
EP1765339A4 (en) * 2004-06-30 2009-09-02 Glaxo Group Ltd Muscarinic acetylcholine receptor antagonists
US7683173B2 (en) 2005-03-10 2010-03-23 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
WO2007007282A2 (en) * 2005-07-11 2007-01-18 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
WO2007007282A3 (en) * 2005-07-11 2007-05-10 Ranbaxy Lab Ltd Azabicyclo derivatives as muscarinic receptor antagonists
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
WO2010094643A1 (en) 2009-02-17 2010-08-26 Glaxo Group Limited Quinoline derivatives and their uses for rhinitis and urticaria
EP3029026A4 (en) * 2013-07-30 2017-01-11 Dong-A ST Co., Ltd. Novel biphenyl derivative and method for preparing same
US9828339B2 (en) 2013-07-30 2017-11-28 Dong-A St Co., Ltd Biphenyl derivatives and methods for preparing same
RU2644234C2 (en) * 2013-07-30 2018-02-09 Донг-А Ст Ко., Лтд New biphenyl derivative and method for its production
US11548931B2 (en) 2017-11-16 2023-01-10 Xl-Protein Gmbh PASylated VEGFR/PDGFR fusion proteins and their use in therapy
WO2019110521A1 (en) 2017-12-04 2019-06-13 Friedrich-Alexander-Universität Erlangen-Nürnberg Fluorophenyl substituted muscarinic receptor ligands with selectivity for m3 over m2

Also Published As

Publication number Publication date
IL176775A0 (en) 2006-10-31
AU2005204935A1 (en) 2005-07-28
KR20060129017A (en) 2006-12-14
EP1711183A2 (en) 2006-10-18
MA28363A1 (en) 2006-12-01
RU2006129289A (en) 2008-02-20
NO20063636L (en) 2006-10-04
AR049464A1 (en) 2006-08-09
CA2552880A1 (en) 2005-07-28
US20080249127A1 (en) 2008-10-09
JP2007518740A (en) 2007-07-12
BRPI0506777A (en) 2007-05-22
EP1711183A4 (en) 2009-04-01
TW200534855A (en) 2005-11-01
WO2005067537A3 (en) 2006-05-18
CN1929844A (en) 2007-03-14
PE20050898A1 (en) 2005-11-06

Similar Documents

Publication Publication Date Title
EP1711183A2 (en) Muscarinic acetylcholine receptor antagonists
EP1682142B1 (en) M3 muscarinic acetylcholine receptor antagonists
US20080287487A1 (en) Muscarinic Acetylcholine Receptor Antagonists
EP1740177B1 (en) Muscarinic acetylcholine receptor antagonists
US7579345B2 (en) Muscarinic acetylcholine receptor antagonists
US7767691B2 (en) Muscarinic acetylcholine receptor antagonists containing an azoniabiocyclo[2.2.1] heptane ring system
US7598267B2 (en) Muscarinic acetylcholine receptor antagonists
US20070238751A1 (en) Muscarinic Acetylcholine Receptor Antagonists
US20070293531A1 (en) Muscarinic Acetycholine Receptor Antagonists
EP1781103A2 (en) Muscarinic acetylcholine receptor antagonists
MXPA06007958A (en) Muscarinic acetylcholine receptor antagonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 176775

Country of ref document: IL

Ref document number: 2005204935

Country of ref document: AU

Ref document number: 2552880

Country of ref document: CA

Ref document number: 3964/DELNP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 12006501333

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 10585830

Country of ref document: US

Ref document number: 200605751

Country of ref document: ZA

Ref document number: PA/a/2006/007958

Country of ref document: MX

Ref document number: 06067685

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 2006549649

Country of ref document: JP

Ref document number: 548498

Country of ref document: NZ

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Ref document number: DE

WWE Wipo information: entry into national phase

Ref document number: 2005711495

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2005204935

Country of ref document: AU

Date of ref document: 20050113

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005204935

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020067016188

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2006129289

Country of ref document: RU

Ref document number: 1200601343

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 200580008126.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 2005711495

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020067016188

Country of ref document: KR

ENP Entry into the national phase

Ref document number: PI0506777

Country of ref document: BR