U.S. patent number RE46,417 [Application Number 15/019,009] was granted by the patent office on 2017-05-30 for quinuclidine derivatives and their use as muscarinic m3 receptor ligands.
This patent grant is currently assigned to Almirall, S.A.. The grantee listed for this patent is Almirall, S.A.. Invention is credited to Maria Antonia Buil Albero, Dolors Fernandez Forner, Maria Prat Quinones.
United States Patent |
RE46,417 |
Fernandez Forner , et
al. |
May 30, 2017 |
**Please see images for:
( Certificate of Correction ) ** |
Quinuclidine derivatives and their use as muscarinic M3 receptor
ligands
Abstract
A compound according to formula (I) ##STR00001## wherein:
.COPYRGT. is a phenyl ring, a C.sub.4 to C.sub.9 heteroaromatic
compound containing one or more heteroatoms, or a naphthalenyl,
5,6,7,8-tetrahydronaphthalenyl or biphenyl group; which shows high
affinity for muscarinic M.sub.3 receptors (Hm3).
Inventors: |
Fernandez Forner; Dolors
(Barcelona, ES), Prat Quinones; Maria (Barcelona,
ES), Buil Albero; Maria Antonia (Barcelona,
ES) |
Applicant: |
Name |
City |
State |
Country |
Type |
Almirall, S.A. |
Sant Feliu de Llobregat |
N/A |
ES |
|
|
Assignee: |
Almirall, S.A. (Barcelona,
ES)
|
Family
ID: |
8309225 |
Appl.
No.: |
15/019,009 |
Filed: |
February 9, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
PCT/EP00/06469 |
Jul 7, 2000 |
|
|
|
Reissue of: |
10047464 |
Jan 14, 2002 |
6750226 |
Jun 15, 2004 |
|
|
Foreign Application Priority Data
|
|
|
|
|
Jul 14, 1999 [ES] |
|
|
9901580 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/56 (20130101); A61K 9/0073 (20130101); A61K
31/4745 (20130101); A61K 31/439 (20130101); A61K
47/26 (20130101); A61K 9/0075 (20130101); A61K
31/56 (20130101); A61P 13/10 (20180101); A61P
11/14 (20180101); A61K 45/06 (20130101); A61P
43/00 (20180101); A61P 11/00 (20180101); A61P
13/02 (20180101); A61P 1/04 (20180101); A61K
9/0075 (20130101); A61K 31/4745 (20130101); A61K
9/0073 (20130101); A61P 1/12 (20180101); A61P
1/00 (20180101); A61P 11/06 (20180101); A61P
11/08 (20180101); A61K 47/26 (20130101); A61P
11/02 (20180101); C07D 453/02 (20130101); A61P
13/06 (20180101); C07D 453/02 (20130101); A61K
31/439 (20130101); A61P 27/16 (20180101); A61P
13/00 (20180101); A61K 45/06 (20130101); A61P
1/06 (20180101); A61K 31/4745 (20130101); A61K
31/4745 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); A61K 31/56 (20130101); A61K
31/56 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101); Y10S 514/826 (20130101); Y10S
514/826 (20130101) |
Current International
Class: |
A61K
31/439 (20060101); A61K 31/56 (20060101); C07D
453/02 (20060101); C07D 453/04 (20060101); A61K
9/00 (20060101); A61K 31/435 (20060101); A61P
1/00 (20060101); A61P 1/04 (20060101); A61P
13/02 (20060101); A61P 13/06 (20060101); A61K
45/06 (20060101); A61K 47/26 (20060101); A61K
31/4745 (20060101); A61K 31/46 (20060101); A61K
31/345 (20060101); A61P 1/06 (20060101); C07D
453/00 (20060101); A61P 13/00 (20060101); A61P
11/14 (20060101); A61P 11/08 (20060101); A61P
11/06 (20060101); A61P 11/02 (20060101); A61P
11/00 (20060101); A61P 1/12 (20060101); A61P
43/00 (20060101); A61P 27/16 (20060101); A61P
13/10 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2062854 |
|
Sep 1992 |
|
CA |
|
0003445 |
|
Aug 1979 |
|
EP |
|
0069715 |
|
Jan 1983 |
|
EP |
|
0166294 |
|
Jan 1986 |
|
EP |
|
2165159 |
|
Apr 1986 |
|
EP |
|
0205247 |
|
Dec 1986 |
|
EP |
|
0302699 |
|
Feb 1989 |
|
EP |
|
0 418 716 |
|
Mar 1991 |
|
EP |
|
0 424 021 |
|
Apr 1991 |
|
EP |
|
0424790 |
|
May 1991 |
|
EP |
|
2242134 |
|
Sep 1991 |
|
EP |
|
0505321 |
|
Sep 1992 |
|
EP |
|
0424790 |
|
Aug 1993 |
|
EP |
|
0424021 |
|
Mar 1994 |
|
EP |
|
0418716 |
|
Apr 1994 |
|
EP |
|
0 747 355 |
|
Dec 1996 |
|
EP |
|
0 801 067 |
|
Oct 1997 |
|
EP |
|
0603229 |
|
Jun 1998 |
|
EP |
|
2012964 |
|
Mar 1970 |
|
FR |
|
1219606 |
|
Jan 1971 |
|
GB |
|
2041763 |
|
Sep 1980 |
|
GB |
|
178679 |
|
Jun 1982 |
|
HU |
|
WO 87/07502 |
|
Dec 1987 |
|
WO |
|
WO 91/02558 |
|
Mar 1991 |
|
WO |
|
WO 91/04252 |
|
Apr 1991 |
|
WO |
|
WO 91/14468 |
|
Oct 1991 |
|
WO |
|
WO 92/00771 |
|
Jan 1992 |
|
WO |
|
WO 92/04928 |
|
Feb 1992 |
|
WO |
|
WO 92/03175 |
|
Mar 1992 |
|
WO |
|
WO 92/04068 |
|
Mar 1992 |
|
WO |
|
WO 92/04345 |
|
Mar 1992 |
|
WO |
|
WO 92/04346 |
|
Mar 1992 |
|
WO |
|
WO 92/09322 |
|
Jun 1992 |
|
WO |
|
WO 94/14492 |
|
Jul 1994 |
|
WO |
|
WO 95/24889 |
|
Sep 1995 |
|
WO |
|
WO 96/04346 |
|
Feb 1996 |
|
WO |
|
WO 96/19968 |
|
Jul 1996 |
|
WO |
|
WO 96/32150 |
|
Oct 1996 |
|
WO |
|
WO 97/00703 |
|
Jan 1997 |
|
WO |
|
WO 97/01337 |
|
Jan 1997 |
|
WO |
|
WO 97/12687 |
|
Apr 1997 |
|
WO |
|
WO 97/28801 |
|
Aug 1997 |
|
WO |
|
WO 97/34871 |
|
Sep 1997 |
|
WO |
|
WO 98/15280 |
|
Apr 1998 |
|
WO |
|
WO 99/51205 |
|
Oct 1999 |
|
WO |
|
WO 01/50080 |
|
Jul 2001 |
|
WO |
|
WO 01/50080 |
|
Jul 2001 |
|
WO |
|
WO 2013/175013 |
|
Nov 2013 |
|
WO |
|
Other References
Alabaster, V., "Discovery and Development of Selective M3
Antagonists for Clinical Use," Life Sciences, 1997, 60 (13-14),
1053-1060. cited by applicant .
Atrovent.RTM. (ipratropium bromide) Inhalation Solution Prescribing
Information, Boehringer Ingelheim International GmbH 830885-R,
Revised Oct. 1998. cited by applicant .
Auerbach, D. et al., "Routine Nebuilzed Ipratropium and Albuterol
Together are Better Than Either Alone in COPD*," The Combivent
Inhalation Solution Study Group, Chest, 1997 112,1514-1521. cited
by applicant .
Ayres, JG et al. Thorax 52(Supp 1): S1-S21 (1997). cited by
applicant .
Banner, K. et al., "The Effect of Selective Phosphodiesterase 3 and
4 Isoenzyme Inhibitors and Established Anti-Asthma Drugs on
Inflammatory Cell Activation," British Journal of Pharmacology,
1996, 119, 1255-1261. cited by applicant .
Barnes, P. et al., "The Effect of Platelet Activating Factor on
Pulmonary-Adrenoceptors," British Journal of Pharmacology, 1987,
90, 709-715. cited by applicant .
Barnes, P. et al., Eds., Asthma, vol. 2, Lippincott-Raven,
Philadelphia, 1997, ISBN 0-397-51682-7, Chapter 142: Compliance by
H. Mawhinney et al., pp. 2099-2113. cited by applicant .
Beasley, R. et al., "Withdrawal of Fenoterol and the End of the New
Zealand Asthma Mortality Epidemic," International Archives of
Allergy and Immunology, 1995, 107, 325-327. cited by applicant
.
Berenbaum, M., "Synergy, Additivism and Antagonism in
Immunosuppression, A Critical Review," Clinical and Experimental
Immunology, 1977, 28, 1-18. cited by applicant .
Berenbaum, M., "What is Synergy?," Pharmacological Reviews, 1989,
41, 93-141 and Errata, p. 422. cited by applicant .
Berkow, R. et al., Eds., The Merck Manual of Diagnosis and Therapy,
Sixteenth Edition, 1992, Foreword and Chapter 34, "Airways
Obstruction Asthma," pp. 646-657. cited by applicant .
Bone, R. et al., "In Chronic Obstructive Pulmonary Disease, A
Combination oflpratropium and Albuterol is More Effective that
Either Agent Alone: An 85-Day Multicenter Trial," Combivent
Inhalation Aerosol Study Group, Chest, 1994, 105, 1411-1419. cited
by applicant .
British Thoracic Society, "BTS Guidelines for the Management of
Chronic Obstructive Pulmonary Disease," The COPD Guidelines Group
of the Standards of Care Committee of the BTS, Thorax, 1997, 52,
Supplement 5, SI-S28. cited by applicant .
Brodde, 0-E., "1- and 2-Adrenoceptors in the Human Heart:
Properties, Function, and Alterations in Chronic Heart Failure,"
Pharmacological Reviews, 1991, 43 (2), 203-242. cited by applicant
.
Bryant, D., "Nebulized Ipratropium Bromide in the Treatment of
Acute Asthma," Chest Journal, 88(1), 24-29. cited by applicant
.
Calverley, P.M.A., Ed., Chronic Obstructive Pulmonary Disease,
Chapman and Hall, London, 1995, ISBN 0 412 46450, Chapter 16:
Bronchodilators: Basic Pharmacology by P.J. Barnes, pp. 391 and
398-401. cited by applicant .
Christensen et al., "1,4-Cyclohexanecarboxylates: Potent and
Selective Inhibitors of Phosphodiesterase 4 for the Treatment of
Asthma," J. Med. Chem. 41:821-835 (1998). cited by applicant .
Clarkson, E. et al., "Binding and Active Transport of Large
Analogues of Acetylcholine by Cholinergic Synaptic Vesicles In
Vitro," Journal of Neurochemistry, 1992, 59, 695-700. cited by
applicant .
Costain, D. et al., "Guidelines for Management of Asthma in Adults:
I-Chronic Persistent Asthma," Br. Med. J. 301: 651-653 (1990).
cited by applicant .
Dent, et al., "Effectis of a Selective PDE4 Inhibitor, D-22888, on
Human Airways and Eosinophils in vitro and Late Phase Allergic
Pulmonary Eosinophilia in Guinea Pigs," Pulmonary Pharma &
Thera. 11:13-21 (1998). cited by applicant .
Disse, B. et al., "BA 679 BR, A Novel Long-Acting Anticholinergic
Bronchodilator," Life Sciences, 1993, 52, 537-544. cited by
applicant .
Dompeling, E. et al., "Slowing the Deterioration of Asthma and
Chronic Obstructive Pulmonary Disease Observed During
Bronchodilator Therapy by Adding Inhaled Corticosteroids," Annals
of Internal Medicine, 1993, 118, 770-778. cited by applicant .
Easton, P. et al., "A Comparison of the Bronchodilating Effects of
a Beta-2 Andrenergic Agent (Albuterol) and an Anticholinergic Agent
(Ipratropium Bromide), Given by Aerosol Alone or in a Sequence,"New
England Journal of Medicine, 1986,315 (12), 735-730. cited by
applicant .
Eglen, R. et al, "Muscarinic Receptor Subtypes and Smooth Muscle
Function," Pharmacological Reviews, 1996, 48 (4), 531-565. cited by
applicant .
Eglen, RM et al., "Muscarinic Receptor Subtypes: Pharmacology and
Therapeutic Potential," DN & P, 10(8): 462-469 (Oct. 1997).
cited by applicant .
Emea, "Note for Guidance on Dose Response Information to Support
Drug Registration," ICH Topic E 4. 1994. CPMP/ICH/378/95. cited by
applicant .
Foye, et al., Principles of Medicinal Chemistry, 4th Edition, pp.
338-340 (1995). cited by applicant .
Frith, P. et al., "Oxitropium Bromide, Dose-Response and
Time-Response Study of a New Anticholinergic Bronchodilator Drug,"
Chest, 1986, 89 (2), 249-253. cited by applicant .
Gao, SH et al., Stereochemistry of the heterocyclic alcohols
containing piperidine unit, Gaodeng Xuexiao Huaxue Xuebao, vol. 20:
p. 232-236 (1999). cited by applicant .
Global Initiative for Asthma, Global Strategy for Asthma Management
and Prevention, NIH Publication No. 02-3659, Issued Jan. 1995,
revised 2002. cited by applicant .
Godoviko et al., "Synthesis and Muscarinolytic Activity of
Quinuclidinyl Benzylate Iodoalkylates," Pharmceutical Chemistry
Journal, vol. 19, No. 9, 602-604 (1985). cited by applicant .
Gross, N. et al., "Dose Response to Ipratropium as a Nebulized
Solution in Patients with Chronic Obstructive Pulmonary Disease, A
Three-Center Study," American Review of Respiratory Disease, 1989,
139, 1188-1191. cited by applicant .
Gross, N. et al., "Inhalation by Nebulization of
Albuterol-Ipratropium Combination (Dey Combination) is Superior to
Either Agent Alone in the Treatment of Chronic Obstructive
Pulmonary Disease," Respiration, 1998, 65, 354-362. cited by
applicant .
Gross, N. et al., "Role of the Parasympathetic System in Airway
Obstruction Due to Emphysema," New England Journal of Medicine,
1984, 16 311 (7), 421-425. cited by applicant .
Hancox, RJ et al., "Randomised trial of an inhaled B2 agonist,
inhaled corticosteroids and their combination in the treatment of
asthma," Thorax, 54: 482-487 (1999). cited by applicant .
Hardman, J. et al., Eds., Goodman and Gilman's: The Pharmacological
Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York, 1996,
Chapter 28: Drugs Used in the Treatment of Asthma by W. Serafin,
pp. 659-682. cited by applicant .
Instructions for Medicine, The Merck Manual, M., "MIR", vol. 2, p.
693. cited by applicant .
English Translation of Instructions for Medicine, The Merck Manual,
M., "MIR", 1997, vol. 2, p. 693. cited by applicant .
Johnson, M., "Salmeterol," Medicinal Research Reviews, 1995, 15
(3), 225-257. cited by applicant .
Lopez-Vidiero, M. et al., "Effect of Atropine on Sputum
Production," Thorax, 1975, 30, 543-547. cited by applicant .
Lund, H. et al., "Quaternization Reactions," Acta Chemica
Scandinavica, 1973, 27, 383-390. cited by applicant .
Lygo, B. et al., "Asymmetric Approaches to
2-Hydroxymethylquinuclidine Derivatives," Tetrahedron, 1999, 55,
2795-2810. cited by applicant .
Maesen, F.P.V. et al., "Ba 679 Br, A New Long-Acting Antimuscarinic
Bronchodilator: A Pilot Dose-Escalation Study in COPD," European
Respiratory Journal, 1993, 6, 1031-1036. cited by applicant .
Martin, L. "Drugs for Asthma/COPD--A Medical Primer for
Physicians," http://www/lakesidepress.com/pulmonary/Asthma-Rx.html
(updated Feb. 1999). cited by applicant .
Merck Manual of Diagnosis and Therapy, Robert Berkow ed., 16th
Edition, p. 646-657 (1992). cited by applicant .
Mery, P-F. et al., "Muscarinic Regulation of the L-Type Calcium
Current in Isolated Cardiac Myocytes," Life Sciences, 1997, 60,
(13-14), 1113-1120. cited by applicant .
Nishikawa, M. et al., "Effect of Short and Long-Acting
2-Adrenoceptor Agonists on Pulmonary 2-Adrenoceptor Expression in
Human Lung," European Journal of Pharmacology, 1996,318, 123-129.
cited by applicant .
Nishimura, et al., "Additive effect of oxitropium bromide in
combination with inhaled corticosteroids in the treatment of
elderly patients with chronic asthma," Allergology International
48: 85-88 (1999). cited by applicant .
Noronha-Blob, L et al., Stereoselective antimuscarininc effects of
3-quinuclidinyl atrolactate and 3-quinuclidinyl
xanthene-9-carboxylate, European Journal of Pharmacology 211:97-103
(1992). cited by applicant .
Parfitt, K., Ed., Martindale: The Complete Drug Reference,
Thirty-Second Edition, 1999, 745-747. cited by applicant .
Rang, H et al., Eds., Pharmacology, Third Edition, 1995, Chapter
17, "The Respiratory System," pp. 351-366. cited by applicant .
Rang, HP et al., "Pharmacology," Churchill Livingston Inc., pp.
358-361 (1995). cited by applicant .
Rees, PJ "Bronchodilators in the therapy of chronic obstructive
pulmonary disease," Eur. Respir. Mon. 7:135-149 (1998). cited by
applicant .
Rennard, SI, (1998) "Anticholinergics and beta2-agonists: Efficacy,
Safety and Combination Therapy in Chronic Obstructive Pulmonary
Disease," Chapter 9, Barnes and Bulst (Ed.) The Role of
Anticholinergics in Chronic Obstructive Pulmonary Disease and
Chronic Asthma, pp. 137-144, Gardiner-Caldwell Communications
Limited. cited by applicant .
Rzeszotarski, W. et al., "Affinity and Selectivity of the Opitcal
Isomers of 3-Quinuclidinyl Benzilate and Related Muscarinic
Antagonists," Journal of Medicinal Chemistry, 1988, 31, 1463-1466.
cited by applicant .
Schmidt, R. "Dose-Finding Studies in Clinical Drug Development,"
Eur J Clin Pharmacol, 1988. 34:15-19. cited by applicant .
Serafin, W. "Drugs Used in the Treatment of Asthma," Goodman
Gilman's The Pharmacological Basis of Therapeutics, Chapter 28 ,
Joel G. Hardman et al eds, 9th Edition, pp. 659-682 (1996). cited
by applicant .
Sharma, V. et al. "Does Mammalian Heart Contain Only the
M2-Muscarinic Receptor Subtype?," Life Sciences, 1997, 60 (13-14),
1023-1029. cited by applicant .
Spitzer, W. et al., "The Use of P-Agonists and the Risk of Death
and Near Death from Asthma," New England Journal of Medicine, 1992,
326, 501-506. cited by applicant .
Suissa, S. et al., "Patterns of Increasing P-Agonist Use and the
Risk of Fatal or Near-Fatal Asthma," European Respiratory Journal,
1994, 7, 1602-1609. cited by applicant .
Tavakkoli et al., "Drug Treatment of Asthma in the 1990s,
Achievements and New Strategies," Drugs, 57(1): 1-8 (1999). cited
by applicant .
Teixera et al., "Phosphodiesterase (PDE) 4 inhibitors:
anti-inflammatory drugs of the future," TiPS, 18:164 (May 1997).
cited by applicant .
The Merck Manual of Diagnosis and Therapy, Seventeenth Edition,
1999, Foreword and Chapter 68, "Chronic Obstructive Airway
Disorders," pp. 555-583. cited by applicant .
Theolair.TM. Prescribing Information, 3M Phamaceuticals, 601000,
May 1998, 12 pages. cited by applicant .
Torphy, T. "Phosphodiesterase Isozymes, Molecular Targets for Novel
Antiasthma Agents," Am. J. Respit. Crit. Care Med., 157:351-370
(1998). cited by applicant .
Traunecker, W. et al., "Pharmacological Effects of a Combination of
Fenoterol Hydrobromide and Ipratropium Bromide," Respiration, 1986,
50 (4), 244-251. cited by applicant .
Walsh, D. et al., "Synthesis and Antiallergy Activity of
4-(Diarylhydroxymethyl)-1[3-(aryloxy)propyl]piperidines and
Structurally Related Compounds," Journal of Medicinal Chemistry,
1989,32, 105-118. cited by applicant .
Zaagsma, J. et al. "Muscarinic Control of Airway Function," Life
Sciences, 1997, 60 (13-14), 1061-1068. cited by applicant .
Etzler, F M. et al., "Particle size analysis; a comparative study
of various methods", Part. Part. Syst. Charact., vol. 12, Oct.
1995; pp. 217-224. cited by applicant .
Le Souef, P, "The meaning of lung dose", Allergy, vol. 54, Mar.
1999, pp. 93-96. cited by applicant .
6001 Chemical Abstracts, Columbus, Ohio, US. vol. 104(19).
XP-002128290, p. 659. (1 page total). cited by applicant .
Burtner, R. and Cusic, J. W. (1943). "Antispasmodics, II. Basic
Esters of Some Polynuclear Carboxylic Acids," J. Am. Chem. Soc.
65:1582-1585. cited by applicant .
Cohen, V. I. et al. (1992). "Synthesis and Receptor Affinities of
New 3-Quinuclidinyl
.alpha.-Heteroaryl-.alpha.-aryl-.alpha.-Hydroxyacetates," J. Pharm
Sciences 81:326-329. cited by applicant .
Davis, M. A. et al. (1963). "New Psychotropic Agents. VI. Basic
Esters of 5-Hydroxydibenzo[a,d] cycloheptadiene-5-carboxylic Acid,"
J. Med. Chem 6:513-516. cited by applicant .
Davis. M. A. et al (1964). "Anticonvulsants. I.
Dibenzo[a,d]cycloheptadiene-5-carboxamide and Related Compounds,"
J. Med. Chem. 7:88-94. cited by applicant .
Grob, C. A. and Brenneisen, P. (1958). "Die Synthese von 4-Brom-und
4-Hydroxy-Chinuclidin," Helv. Chim. Acta 41:1184-1191. cited by
applicant .
Heacock, R.A. et al. (1958). "Materials and Methods," The Annals of
Applied Biology, Marsh R. W. and Thomas, I, eds, Cambridge at the
University Press, vol. 46, pp. 356-365. cited by applicant .
Konzett, H. and Rossler, R. (1940). "Versuchsanordnung zu
Untersuchungnen an der Bronchialmuskulatur," Arch. Exp. Path.
Pharmacol. 195:71-74. cited by applicant .
Kumazawa, T. et al. (1994). "Inhibitors of Acyl-CoA:Cholesterol
Acyltransferase. 1. Synthesis and Hypocholesterolemic Activity of
Dibenz[b,e]oxepin-11carboxanilides," J. Med. Chem. 37(6): 804-810.
cited by applicant .
Larsson, L. et al. (1974). "The Hydrogen Bond Condition in Some
Anticholinergic Esters of Glycolic Acids. I" Acta Pharm. Suec.
11(3):304-308. cited by applicant .
May, E. L and Mossettig, E. (1948). "Studies in the Anthracene
Series. V. A Novel Rearrangement in the Reaction of Halomethyl
Ketones with Secondary Amines," J. Am. Chem. Soc. 70: 1077-1079.
cited by applicant .
Meyers, A. I. et al. (1980). "Resolution of .alpha.-Substituted
Mandelic Acids via Chiral Oxazolines Using Pressurized
Chromatography," J. Org. Chem. 45(14): 2912-2914. cited by
applicant .
Nyberg, K. et al. (1970). "Investigations of Dithienylglycolic
Esters," Acta Chem. Scand. 24:1590-1596. cited by applicant .
Rigaudy, J. et al. (1959). "Cetones Derivees du Dibenzo[a,d]
cycloheptadiene. La Dibenzo-2-,3-6,7 Cycloheptadienedione-4,5,"
Bull. Soc. Chim. France. 638-643. cited by applicant .
Ringdahl, R. et al. (1979). "Facile Preparation of the Enantiomers
of 3-Acetoxyquinuclidinol," Acta Pharm Suec. 16:281-283. cited by
applicant .
Sestanj, K. (1971). "A Facile Formation of Dibenzo[a,b]
cycloheptenylium Ion by Decarbonylation. Color Reactions of the
Cyhemptaminde Metabolites," Can. J. Chem. 49:664-665. cited by
applicant .
Ueda, I. (1975). "The Rearrangement of 10-Bromo-10,
11-Dihydrodibenzo[b,f]thiepin-11-one and Related Compounds in an
Alkaline Solution," Bulletin of the Chemical Society of Japan
48(8):2306-2309. cited by applicant .
Waelbroek, M. et al. (1990). "Binding of Selective Antagonists to
Four Muscarinic Receptors (M1 to M4) in Rat Forebrain," Mol.
Pharmacol. 38:267-273. cited by applicant.
|
Primary Examiner: Diamond; Alan
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner LLP
Claims
What is claimed is:
1. A compound according to formula (I) ##STR00015## wherein:
.COPYRGT. is a phenyl ring, a C.sub.4 to C.sub.9 heteroaromatic
group containing one or more heteroatoms or a naphthalenyl,
5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R.sup.1, R.sup.2
and R.sup.3 each independently represent a hydrogen atom or halogen
atom, or a hydroxy group, or a phenyl, --OR.sup.4, --SR.sup.4,
--NR.sup.4R.sup.5, --NHCOR.sup.4, --CONR.sup.4R.sup.5, --CN,
--NO.sub.2, --COOR.sup.4 or --CF.sub.3 group, or a straight or
branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group
which may optionally be substituted.[., for example,.]. with a
hydroxy .[.or alkoxy.]. group, wherein R.sup.4 and R.sup.5 each
independently represent a hydrogen atom, straight or branched
.[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group or
together form an alicyclic ring; or R.sup.1 and R.sup.2 together
form an aromatic, alicyclic or heterocyclic ring, n is an integer
from 0 to 4; A represents a --CH.sub.2--, --CH.dbd.CR.sup.6--,
--CR.sup.6.dbd.CH--, --CR.sup.6R.sup.7--, --CO--, --O--, --S--,
--S(O)--, SO.sub.2 or --NR.sup.6-- group, wherein R.sup.6 and
R.sup.7 each independently represent a hydrogen atom, straight or
branched .[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group
or R.sup.6 and R.sup.7 together form an alicyclic ring; m is an
integer from 0 to 8; provided that when m=0, A is not --CH.sub.2--;
p is an integer from 1 to 2 and the substitution in the
azoniabicyclic ring may be in the 2, 3 or 4 position including all
possible configurations of the asymmetric carbons; B represents a
group of formula i): ##STR00016## wherein R.sup.10 represents a
hydrogen atom, a hydroxy or methyl group; and R.sup.8 and R.sup.9
each independently represent ##STR00017## wherein R.sup.11
represents a hydrogen or halogen atom or a straight or branched
.[.lower.]. .Iadd.C.sub.1 to C.sub.4 .Iaddend.alkyl group; and
.[.X.]. .Iadd.X.sup.- .Iaddend.represents a pharmaceutically
acceptable anion of a mono or polyvalent acid.
.[.2. A compound according to claim 1, wherein any alkyl group
present as R.sup.1 to R.sup.7 or R.sup.11 contains from 1 to 4
carbon atoms..].
3. A compound according to claim 1 wherein p=2.
4. A compound according to claim 1 wherein .COPYRGT. represents a
phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,
5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl or
benzothiazolyl group.
5. A compound according to claim 4, wherein .COPYRGT. represents a
phenyl, pyrrolyl or thienyl group.
6. A compound according to claim 1 wherein R.sup.1, R.sup.2 and
R.sup.3 each independently represent a hydrogen or halogen atom or
a hydroxy, methyl, tert-butyl, --CH.sub.2OH, 3-hydroxypropyl,
--OMe, --NMe.sub.2, --NHCOMe, --CONH.sub.2, --CN, .[.--NO2.].
.Iadd.--NO.sub.2.Iaddend., --COOMe or --CF.sub.3 group.
7. A compound according to claim 6 wherein R.sup.1, R.sup.2 and
R.sup.3 each independently represent a hydrogen or halogen atom or
a hydroxy group.
8. A compound according to claim 7, wherein the halogen atom is
fluorine.
9. A compound according to claim 1 wherein A represents a
--CH.sub.2--, --CH.dbd.CH--, --CO--, --NH--, --NMe--, --O-- or
--S-- group; n is 0 or 1; and m is an integer from 1 to 6.
10. A compound according to claim 9, wherein A represents a
--CH.sub.2--, 13 CH.dbd.CH-- or --O-- group and m is 1, 2 or 3.
11. A compound according to claim 1 wherein the azoniabicyclo group
is substituted on the nitrogen atom with a 3-phenoxypropyl,
2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl,
4-phenylbutyl, 3-(2-hydroxyphenoxy)propyl,
3-(4-fluorophenoxy)propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,
2-thien-2-ylethyl or 3-thien-2-ylpropyl group.
12. A compound according to claim 1 wherein B represents a group of
formula (i) and R.sup.8 and R.sup.9 each independently represent a
phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3-furyl group and
R.sup.11 represents a hydrogen atom.
13. A compound according to claim 1 wherein .[.X.]. .Iadd.X.sup.-
.Iaddend.represents a bromide, chloride or trifluoroacetate
anion.
14. A compound according to claim 1 wherein the azoniabicyclo group
is substituted in the 3-position.
15. A compound according to claim 14, wherein the substituent in
the 3 position has (R) configuration.
16. A compound according to claim 15, wherein R.sup.8 is different
from R.sup.9 in group i), and the asymmetric carbon to which
R.sup.8 and R.sup.9 are bonded has the (R) configuration.
17. A compound according to claim 15, wherein R.sup.8 is different
from R.sup.9 in group i), and the asymmetric carbon to which
R.sup.8 and R.sup.9 are bonded has the (S) configuration.
18. A compound according to claim 1 which is a single
stereoisomer.
19. A compound according to claim 1 which is
3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1azoniabicyclo[2.2.2]octane;
bromide.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo-
[2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2-
]octane; bromide.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azon-
ia-bicyclo [2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniab-
icyclo [2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azonia-
bicyclo [2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoni-
abicyclo [2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]-
octane; bromide.Iadd., .Iaddend.
.[.3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[-
2.2.2]octane; bromide.].
.Iadd.3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicycl-
o[2.2.2]octane; bromide, .Iaddend.
.[.3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabi-
cyclo[2.2.2]octane; bromide.].
.Iadd.3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azonia-
bicyclo[2.2.2]octane; bromide, .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bic-
yclo[2.2.2]octane; bromide.Iadd., .Iaddend.
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1--
azoniabicyclo [2.2.2]octane; chloride.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-
-azoniabicyclo [2.2.2]octane; Trifluoroacetate.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-
-bicyclo[2.2.2]octane; trifluoroacetate.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabi-
cyclo[2.2.2]octane; bromide.Iadd., .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniab-
icyclo[2.2.2]octane; bromide.Iadd., .Iaddend.
1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabic-
yclo[2.2.2]octane; trifluoroacetate.Iadd., or .Iaddend.
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; bromide.
20. A compound according to claim 1 characterised in that it has an
IC.sub.50 value for muscarinic M.sub.3 receptors (Hm3) of less than
35 nM.
.[.21. A process for the preparation of a compound of formula (I)
##STR00018## which comprises reacting an alkylating agent of
formula (II) ##STR00019## with a compound of formula (III)
##STR00020## wherein, in each of formulae I, II and III, R.sup.1,
R.sup.2 R.sup.3, .COPYRGT., A, X, B, n, m and p are as defined in
any one of claims 1 to 12 or 13 to 19..].
.[.22. A process according to claim 21 characterised in that the
resulting reaction mixture is purified by solid phase
extraction..].
23. A pharmaceutical composition comprising a compound according to
claim 1 in admixture with a pharmaceutically acceptable carrier or
diluent.
24. A method for treating respiratory, urinary and/or
gastrointestinal disease which method comprises administering to a
human or animal patient in need of such treatment an effective
amount of a compound according to .[.any one of claims.].
.Iadd.claim .Iaddend.1 .[.to 12, 13 to 20.]. or of a pharmaceutical
composition according to claim 23.
25. A method for treating COPD, chronic bronchitis, asthma and/or
.[.ehinitis.]. .Iadd.rhinitis .Iaddend.which method comprises
administering to a human or animal patient in need of such
treatment an effective amount of a compound according to .[.any one
of claims.]. .Iadd.claim .Iaddend.1 .[.to 12, 13 to 20.]. or of a
pharmaceutical composition according to claim 23.
.Iadd.26. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; X.sup.- or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.-
2]octane; X.sup.-, wherein X.sup.- represents a pharmaceutically
acceptable anion of a mono or polyvalent acid. .Iaddend.
.Iadd.27. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; X.sup.- or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.-
2]octane; X.sup.-, wherein X.sup.- represents chloride, bromide,
iodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate,
maleate, fumarate, citrate, oxalate, succinate, tartrate, malate,
mandelate, methanesulfonate, or p-toluenesulfonate. .Iaddend.
.Iadd.28. A compound according to claim 27, wherein X.sup.-
represents chloride, bromide, iodide, sulfate, nitrate, acetate,
trifluoroacetate, maleate, oxalate, or succinate. .Iaddend.
.Iadd.29. A compound according to claim 27, wherein X.sup.-
represents chloride, bromide, or trifluoroacetate. .Iaddend.
.Iadd.30. A compound chosen from
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; bromide or
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.-
2]octane; bromide. .Iaddend.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority from Spain application No. 9901580
filed Jul. 14, 1999 and PCT application No. PCT/EP00/06469 filed
Jul. 7, 2000, the contents of each are incorporated herein by
reference.
This invention relates to new therapeutically useful quinuclidine
derivatives, to some processes for their preparation and to
pharmaceutical compositions containing them.
The novel structures according to the invention are antimuscarinic
agents with a potent and long lasting effect. In particular, these
compounds show high affinity for muscarinic M.sub.3
receptors(Hm3).
In accordance with their nature as M.sub.3 antagonists, the new
compounds are suitable for treating the following diseases:
respiratory disorders such as chronic obstructive pulmonary disease
(COPD), chronic bronchitis, bronchial hyperreactivity, asthma and
rhinitis; urological disorders such as urinary incontinence,
pollakinuria in neuripenia pollakinuria, neurogenic or unstable
bladder, cystospasm and chronic cystitis; and gastrointestinal
disorders such as irritable bowel syndrome, spastic colitis,
diverticulitis and peptic ulceration.
The compounds claimed are also useful for the treatment of the
respiratory diseases detailed above in association with
.beta..sub.2 agonists, steroids, antiallergic drugs or
phosphodiesterase IV inhibitors.
Compounds of the present invention may also be expected to have
anti-tussive properties.
Depending on their nature the new compounds may be suitable for
treating vagally induced sinus bradycardia.
Compounds with related structures have been described as
anti-spasmodics and anti-cholinergic agents in several patents.
For example, in patent FR 2012964 are described quinuclidinol
derivatives of the formula:
##STR00002## in which R is H, OH or an alkyl group having 1 to 4
carbon atoms; R.sub.1 is a phenyl or thienyl group; and R.sub.2 is
a cyclohexyl, cyclopentyl or thienyl group, or, when R is H,
R.sub.1 and R.sub.2 together with the carbon atom to which they are
attached, form a tricyclic group of the formula:
##STR00003## in which X is --O--, --S-- or --CH.sub.2--, or an acid
addition or quaternary ammonium salt thereof.
EP-418716 describes thienyl carboxylate esters of formula
##STR00004## wherein A is a group
##STR00005## m and n=1 or 2 Q is a --CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.dbd.CH--, group
##STR00006## Q' is a .dbd.NR or NRR.dbd. group; R.sub.1 is a
thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, optionally
substituted; R.sub.2 is H, OH, C.sub.1-C.sub.4 alkoxy or
C.sub.1-C.sub.4 alkyl and R.sub.a is H, F, Cl, CH.sub.3-- or
--NR.
U.S. Pat. No. 5,654,314 describes compounds of formula:
##STR00007## wherein R is an optionally halo- or
hydroxy-substituted C.sub.1-4 alkyl group; R is a C.sub.1-4 alkyl
group; or R and R.dbd. together form a C.sub.4-6 alkylene group;
X.sup.- is an anion; and R.sub.1 is H, OH, --CH.sub.2OH, C.sub.1-4
alkyl or C.sub.1-4 alkoxy.
The present invention provides new quinuclidine derivatives with
potent antagonist activity at muscarinic M.sub.3 receptors which
have the chemical structure described in formula (I):
##STR00008## wherein: .COPYRGT. is a phenyl ring, a C.sub.4 to
C.sub.9 heteroaromatic group containing one or more heteroatoms
(preferably selected from nitrogen, oxygen and sulphur atoms), or a
naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group;
R.sup.1, R.sup.2 and R.sup.3 each independently represent a
hydrogen or halogen atom, or a hydroxy group, or a phenyl,
--OR.sup.4, --SR.sup.4, --NR.sup.4R.sup.5, --NHCOR.sup.4,
--CONR.sup.4R.sup.5, --CN, --NO.sub.2, --COOR.sup.4 or --CF.sub.3
group, or a straight or branched lower alkyl group which may
optionally be substituted, for example, with a hydroxy or alkoxy
group, wherein R.sup.4 and R.sup.5 each independently represent a
hydrogen atom, straight or branched lower alkyl group, or together
form an alicyclic ring; or R.sup.1 and R.sup.2 together form an
aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to
4; A represents a --CH.sub.2--, --CH.dbd.CR.sup.6--,
--CR.sup.6.dbd.CH--, --CR.sup.6R.sup.7--, --CO--, --O--, --S--,
--S--(O)--, SO.sub.2 or --NR.sup.6-- group, wherein R.sup.6 and
R.sup.7 each independently represent a hydrogen atom, straight or
branched lower alkyl group, or R.sup.6 and R.sup.7 together form an
alicyclic ring; m is an integer from 0 to 8; provided that when
m=0, A is not --CH.sub.2--; p is an integer from 1 to 2 and the
substitution in the azoniabicyclic ring may be in the 2, 3 or 4
position including all possible configurations of the asymmetric
carbons; B represents a group of formula i) or ii):
##STR00009## wherein R.sup.10 represents a hydrogen atom, a hydroxy
or methyl group; and R.sup.8 and R.sup.9 each independently
represents
##STR00010## wherein R.sup.11 represents a hydrogen or halogen
atom, or a straight or branched lower alkyl group and Q represents
a single bond, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --O--,
--O--CH.sub.2--, --S--, --S--CH.sub.2-- or --CH.dbd.CH--, and when
i) or ii) contain a chiral centre they may represent either
configuration; X represents a pharmaceutically acceptable anion of
a mono or polyvalent acid.
In the quaternary ammonium compounds of the present invention
represented by formula (I) an equivalent of an anion (X.sup.-)is
associated with the positive charge of the N atom. X.sup.- may be
an anion of various mineral acids such as, for example, chloride,
bromide, iodide, sulfate, nitrate, phosphate, and organic acids
such as, for example, acetate, maleate, fumarate, citrate, oxalate,
succinate, tartrate, malate, mandelate, methanesulfonate and
p-toluenesulfonate. X.sup.- is preferably an anion selected from
chloride, bromide, iodide, sulphate, nitrate, acetate, maleate,
oxalate or succinate. More preferably X.sup.- is chloride, bromide
or trifluoroacetate.
The compounds of the present invention represented by the formula
(I) described above, which may have one or more assymetric carbons,
include all the possible stereoisomers. The single isomers and
mixtures of the isomers fall within the scope of the present
invention.
If any of R.sup.1 to R.sup.7 or R.sup.11 represents an alkyl group,
it is preferred that said alkyl group contains 1 to 8, preferably 1
to 6 and more preferably 1 to 4 carbon atoms. In particular it is
preferred that any alkyl group is represented by a methyl, ethyl,
propyl, including i-propyl, butyl including a n-butyl, sec-butyl
and tert-butyl.
The alicyclic and heterocyclic rings mentioned in relation to
formula (I) preferably comprise from 3 to 10, preferably from 5 to
7 members. The aromatic rings mentioned in relation to formula (I)
above preferably contain from 6 to 14, preferably 6 or 10
members.
Preferred compounds of formula (I) are those wherein .COPYRGT.
represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl,
naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl,
imidazolyl or benzothiazolyl group, in particular a phenyl,
pyrrolyl, or thienyl group; R.sup.1, R.sup.2 and R.sup.3 each
independently represent a hydrogen or halogen atom, or a hydroxyl,
methyl, tert-butyl, --CH.sub.2OH, 3-hydroxypropyl, --OMe,
--NMe.sub.2, --NHCOMe, --CONH.sub.2, --CN, --NO.sub.2, --COOMe or
--CF.sub.3 group, in particular a hydrogen atom, a hydroxy group or
a halogen atom, wherein the halogen atom is preferably fluorine;
n=0 or 1; m is an integer from 1 to 6, particularly 1, 2 or 3; A
represents a --CH.sub.2--, --CH.dbd.CH--, --CO--, --NH--, --NMe--,
--O-- or --S-- group, in particular a --CH.sub.2--, --CH.dbd.CH--
or --O-- group.
It is also preferred that p=2 and the substituent group --OC(O)B
attached to the azoniabicyclo[2.2.2]octane is at the 3 position,
preferably having the (R) configuration.
Further preferred compounds of formula I are those wherein B is a
group of formula i) or ii) as defined above wherein, if B is a
group of formula (i), R.sup.8 and R.sup.9 each independently
represent a phenyl, 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group,
wherein R.sup.11 is hydrogen atom; and, if B is a group of formula
(Ii), Q represents a single bond, --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --O-- or --S-- group, in particular a
single bond, --CH.sub.2--, --CH.sub.2--CH.sub.2-- or --O-- group,
most preferably a single bond or --O-- group; and in any case
R.sup.10 is a hydrogen atom or a hydroxy or methyl group; and when
i) or ii) contain a chiral centre they may represent either the (R)
or the (S) configuration.
Most preferably the --OC(O)B group in formula (I) is
diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy,
2,2-diphenylpropionyloxy, -hydroxy-2-phenyl-2-thien-2-yl-acetoxy,
2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,
2-hydroxy-2,2-di-thien-2-ylacetoxy,
2-hydroxy-2,2-di-thien-3-ylacetoxy,
9-hydroxy-9[H]-fluorene-9-carbonyloxy,
9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,
9-hydroxy-9[H]-xanthene-9-carbonyloxy,
9-methyl-9[H]-xanthene-9-carbonyloxy,
2,2-bis(4-fluorophenyl)-2-hydroxyacetoxy,
2-hydroxy-2,2-di-p-tolylacetoxy, 2,2-difuran-2-yl-2-hydroxy
acetoxy, 2,2-dithien-2-ylpropionyloxy,
9,10-dihydroanthracene-9-carbonyloxy, 9
[H]-thioxanthene-9-carbonyloxy, or
5[H]-dibenzo[a,d]cycloheptene-5-carbonyloxy. Especially preferred
compounds are those wherein the --OC(O)B group in formula (I) is
diphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy,
2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,
2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,
2-hydroxy-2,2-di-thien-2-ylacetoxy,
2-hydroxy-2,2-di-thien-3-ylacetoxy,
9-hydroxy-9[H]-fluorene-9-carbonyloxy,
9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,
9-hydroxy-9[H]-xanthene-9-carbonyloxy or
9-methyl-9[H]-xanthene-9-carbonyloxy.
The most preferred compounds of formula (I) are those wherein the
azoniabicyclo group is substituted on the nitrogen atom with a
3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,
4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl,
3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,
2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl,
3(methylphenylamino)propyl, 3-phenylsulfanylpropyl,
3-o-tolyloxypropyl, 3-(2,4,6-trimethylphenoxy)propyl,
3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,
3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl,
3-(naphthalen-2-yloxy) propyl, 3-(naphthalen-1-yloxy) propyl,
3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,
3-(3-trifluoromethyl phenoxy)propyl, 3-(3-cyanophenoxy)propyl,
3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl,
3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy) propyl,
3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl,
3-(4-nitrophenoxy)propyl, 3-(3-nitrophenoxy)propyl,
3-(4-acetylaminophenoxy) propyl,
3-(3-methoxycarbonylphenoxy)propyl, 3-[4-(3-hydroxypropyl)
phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,
3-(3-hydroxymethylphenoxy)propyl, 3-(4-hydroxymethylphenoxy)propyl,
3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,
3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl,
3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl,
3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,
6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxyethyl group.
Especially preferred compounds are those wherein the azoniabicyclo
group is substituted on the nitrogen atom with a 3-phenoxypropyl,
2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl,
3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl,
3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,
2-thien-2-ylethyl or 3-thien-2-ylpropyl group.
The following compounds are intended to illustrate but not to limit
the scope of the present invention.
3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;
bromide
3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoni-
abicyclo[2.2.2]octane; bromide
3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2-
]octane; bromide
3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azon-
ia-bicyclo[2.2.2]octane; bromide
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniab-
icyclo[2.2.2]octane; bromide
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azonia-
bicyclo[2.2.2]octane; bromide
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoni-
abicyclo[2.2.2]octane; bromide
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2-
]octane; bromide
3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2-
.2]octane; bromide
3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyc-
lo[2.2.2]octane; bromide
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bic-
yclo[2.2.2]octane; bromide
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1--
azoniabicyclo[2.2.2]octane; chloride
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; trifluoroacetate
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-
-bicyclo[2.2.2]octane; trifluoroacetate
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabi-
cyclo[2.2.2]octane; bromide
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniab-
icyclo[2.2.2]octane; bromide
1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabic-
yclo[2.2.2]octane; trifluoroacetate
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; bromide
1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabi-
cyclo[2.2.2]octane; bromide
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azonia-
bicyclo[2.2.2]octane; bromide
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[-
2.2.2]octane; bromide
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoni-
abicyclo[2.2.2]octane; bromide
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabic-
yclo[2.2.2]octane; bromide
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniab-
icyclo[2.2.2]octane; bromide
1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.-
2]octane; bromide
1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2-
.2]octane; bromide
1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.-
2.2]octane; bromide
1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octa-
ne; bromide
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azonia-
bicyclo[2.2.2]octane; bromide
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[-
2.2.2]octane; bromide
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoni-
abicyclo[2.2.2]octane; bromide
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azonia-
-bicyclo[2.2.2]octane; bromide
The present invention also provides processes for preparing
compounds of formula (I).
The quaternary ammonium derivatives of general Formula I, may be
prepared by reaction of an alkylating agent of general Formula II
with compounds of general Formula III. In Formulas I, II and III,
R.sup.1, R.sup.2, R.sup.3, .COPYRGT., A, X, B, n, m and p are as
defined above.
##STR00011##
This alkylation reaction may be carried out by two different
experimental procedures, a) and b) which are described below. In
particular method b) provides a new experimental process, using
solid phase extraction methodologies, that allows the parallel
preparation of several compounds. Methods a) and b) are described
in the experimental section. Compounds of general Formula II which
are not commercially available have been prepared by synthesis
according to standard methods. For example, compounds wherein n=0
and A=--O--, --S-- or --NR.sup.6.sub.1 wherein R.sup.6 is as
defined above, were obtained by reaction of the corresponding
aromatic derivative or its potassium salt with an alkylating agent
of general formula Y--(CH.sub.2)m-X, wherein X may be a halogen and
Y may be a halogen or a sulphonate ester. In other examples,
compounds of general Formula II, where n>=1 were synthesised
from the corresponding alcohol derivative of general Formula IV by
known methods.
##STR00012##
Compounds of general Formula III may be prepared by three different
methods c, d and e illustrated in the following scheme and detailed
in the experimental section.
##STR00013##
Some compounds of general formula III where B is a group of formula
i), R.sup.8 and R.sup.9 are as described above and R.sup.10 is a
hydroxy group, may also be prepared from the glyoxalate esters of
general formula VII by reaction with the corresponding
organometallic derivative.
##STR00014##
Compounds of general formula VII may be prepared from the
corresponding glyoxylic acids following the standard methods c, d
and e described above and detailed in the experimental section. The
glyoxalate derivatives of formula VII where R.sup.8 is a 2-thienyl
or 2-furyl group have not been described before.
The following compounds are examples of compounds of general
formula III and VII which have not been described before:
9-Methyl-9[H]-fluorene-9-carboxylic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1c);
9-Methyl-9[H]-xanthene-9-carboxylic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1d);
2-Hydroxydithien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester
(intermediate I-4a). Oxothien-2-yl-acetic acid
1-azabicyclo[2.2.2]oct-4-yl ester (intermediate I-4b).
Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester
(intermediate I-4 g). Oxofuran-2-yl-acetic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e).
2-Hydroxy-2,2-difuran-2-yl-acetic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4d).
Compounds of Formula V could be:
4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO150080
4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et.
al. Helv. Chim. Acta (1958), 41, 1184-1190
3(R)-hydroxy-1-azabicyclo[2.2.2]octane or
3(S)-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R.
Acta Pharm Suec. (1979), 16, 281-283 and commercially available
from CU Chemie Uetikon GmbH.
The following examples are intended to illustrate, but not to
limit, the experimental procedures that have been described
above.
The structures of the prepared compounds were confirmed by
.sup.1H-NMR and MS. The NMR were recorded using a Varian 300 MHz
instrument and chemical shifts are expressed as parts per million
(.delta.) from the internal reference tetramethyl silane. Their
purity was determined by HPLC, using reverse phase chromatrography
on a Waters instrument, with values greater than 95% being
obtained. Molecular ions were obtained by electrospray ionization
mass spectometry on a Hewlett Packard instrument.
Method-a
EXAMPLE 20
Preparation of 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenyl
acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane,
Bromide
200 mg of (Furan-2-yl)-hydroxy-phenylacetic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester (0.6 mmol) were suspended in 4
ml of CH3CN and 6 ml of CHCl3. To this suspension were added 0.48
ml (3 mmol) of 3-phenoxypropyl bromide. After stirring for 72 h at
room temperature in inert atmosphere, solvents were evaporated.
Ether was added and the mixture stirred. The solid obtained was
filtered and washed several times with ether. The yield was 0.27 g
(83%) of title compound as a mixture of diastereomers.
.sup.1H-NMR (DMSO-d6): .delta. 1.50-2.20 (m, 6H), 2.25 (m, 1H),
3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20
(m, 1H), 6.25-6.35 (double dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H),
7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-Br].sup.+: 462; mp
166.degree. C.
Method-b
EXAMPLE 51
Preparation of 3(R)-(2-Hydroxy-2,2-di-thien-2-yl
acetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;
Trifluoroacetate
60 mg (0.17 mmols) of hydroxy-dithien-2-yl-acetic acid
1-aza-bicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 1 ml of
dmso. To this solution 188 mg (0.85 mmol) of
3-(naphthalen-1-yloxy)-propyl chloride were added. After stirring
overnight at room temperature, the mixture was purified by solid
phase extraction with a cation exchange Mega Bond Elut cartridge,
previously conditioned at pH=7.5 with 0.1 M NaH2PO4 buffer. The
reaction mixture was applied to the cartridge and washed first with
2 ml of DMSO and then three times with 5 ml of CH3CN, rinsing away
all starting materials. The ammonium derivative was eluted with 5
ml of 0.03 M TFA solution in CH3CN:CHCl3 (2:1). This solution was
neutralized with 300 mg of poly(4-vinylpyridine), filtered and
evaporated to dryness.
The yield was 17 mg (15%) of title compound. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.1 (m, 4H), 2.2-2.4 (m, 3H), 3.2-3.6 (m, 7H), 4.0 (m,
1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m 3H), 7.2 (m, 2H), 7.4-7.6
(m, 7H), 7.85 (d, 1H), 8.2 (d, 1H); MS [M-CF.sub.3COO].sup.+:
534.
Method-c
Methyl ester derivatives of general Formula VI were prepared by
standard methods of esterification from the corresponding
carboxylic acid or following the procedures described in examples
I-1e, I-1f and I-1g or according to procedures described in
literature: FR 2012964; Larsson. L et al. Acta Pharm. Suec. (1974),
11(3), 304-308; Nyberg, K. et. al. Acta Chem. Scand. (1970), 24,
1590-1596; and Cohen, V. I. et. al. J. Pharm. Sciences (1992), 81,
326-329.
EXAMPLE I-1a
Preparation of (Furan-2-yl)hydroxyphenylacetic acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid
methyl ester were dissolved in 85 ml of toluene. To this solution
were added 2.08 g (0.016 mols) of
3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224 g (5.6 mmols) of
HNa (60% dispersion in mineral oil). The mixture was refluxed with
continuous removal of distillate and when necessary replacement
with fresh toluene for 1.5 hours. The cooled mixture was extracted
with 2N HCl acid, the aqueous layer washed with ethyl acetate,
basified with K2CO3 and extracted with CHCl3. The organic layer was
dried over Na2SO4 and evaporated. The oil obtained (3.47 g)
crystallised after cooling at room temperature. This solid was
suspended in hexane and filtered. The yield was 2.5 g (54%) of a
mixture of diasteroisomers, mp: 140-142.degree. C.; GC/MS
[M].sup.+: 327; .sup.1H-NMR (CDCl3): .delta. 1.20-1.70 (m, 4H),
1.90-2.10 (m, 1H), 2.45-2.80 (m, 5H), 3.10-3.30 (m, 1H), 4.8 (bs,
OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m,
4H), 7.60-7.70 (m, 2H).
After four crystallizations of 0.5 g of this mixture from boiling
acetonitrile, 0.110 g of a pure diastereomer(I) were obtained. From
the mother liquors of crystallization was obtained the other
diastereomer (2). (*:configuration not assigned). Diastereomer 1
was hydrolysed to yield (+)-2-hydroxy-2-phenyl-2-furan-2-ylacetic
acid as a pure enantiomer, [.alpha.].sup.25.sub.D=+5.6 (c=2, EtOH).
Diastereomer 2 was hydrolysed to yield
(-)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pure
enantiomer, [.gamma.].sup.25.sub.D=-5.7 (c=2, EtOH).
Diastereomer 1: 2(*)--(Furan-2-yl)hydroxyphenylacetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
.sup.1H-NMR (CDCl3): .delta. 1.20-1.70 (m, 4H), 1.90 (m, 1H),
2.45-2.50 (m, 1H), 2.50-2.80 (m, 4H), 3.10-3.20 (m, 1H), 4.8 (bs,
OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m,
4H), 7.60-7.70 (m, 2H).
Diastereomer 2: 2(*)--(Furan-2-yl)hydroxyphenylacetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
.sup.1H-NMR (CDCl3): .delta. 1.20-1.70 (m, 4H), 2.10 (m, 1H),
2.50-2.80 (m, 5H), 3.20-3.30 (m, 1H), 4.8 (bs, OH), 4.90-5.0 (m,
1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H), 7.60-7.70 (m,
2H).
EXAMPLE I-1b
Preparation of Furan-2-ylhydroxythien-2-ylacetic acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Prepared as in example I-1a. The yield was 3.06 g (64.3%) of a
mixture of diastereoisomers, mp: 1721C; GC/MS [M].sup.+: 333;
.sup.1H-NMR (DMSO-d6): .delta. 1.21-1.27 (m, 1H), 1.41-1.60 (m,
3H), 1.87 (m, 1H), 2.36-2.69 (m, 5H), 3.02-3.14 (m, 1H), 4.75-4.82
(m, 1H), 6.24-6.25 (m, 1H), 6.42-6.45 (m, 1H), 7.01-7.06 (m, 1H),
7.11-7.14 (m, 2H), 7.51-7.54 (m, 1H), 7.66-7.69 (m, 1H).
EXAMPLE I-1c
Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Prepared as in example I-1a. The yield was 3.34 g of an oil (80%).
This product was solidified by formation of the oxalate salt (1:1),
mp: 1861C. MS [M free base+1].sup.+: 334.
Oxalate salt, .sup.1H-NMR (DMSO-d6): .delta. 1.43-1.55 (m, 2H),
1.68-1.78 (m, 2H), 1.75 (s, 3H), 2.02 (m, 1H), 2.70-2.90 (m, 1H),
2.92-3.15 (m, 4H), 3.50-3.57 (m, 1H), 4.88 (m, 1H), 7.35-7.47 (m,
4H), 7.62-7.70 (m, 2H), 7.89-7.91 (m, 2H).
EXAMPLE I-1d
Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Prepared as in example I-1a. The yield was 1.91 g of an oil (53%).
This product was solidified by formation of the oxalate salt (1:1),
mp: 1521C. MS [M free base+1].sup.+: 350.
Oxalate salt, .sup.1H-NMR (DMSO-d6): .delta. 1.20-1.30 (m, 1H),
1.40-1.52 (m, 1H), 1.64-1.81 (m, 2H), 1.90 (s, 3H), 2.0 (m, 1H),
2.53-2.66 (m, 1H), 2.71-2.76 (m, 1H), 2.97-3.10 (m, 3H), 3.44-3.52
(m, 1H), 4.90-4.92 (m, 1H), 7.12-7.18 (m, 4H), 7.32-7.38 (m, 2H),
7.43-7.48 (m, 2H), 8.0-9.8 (bs, 1H, H+).
EXAMPLE I-1e
Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic Acid Methyl
Ester
Lithium diisopropylamide (26.7 ml of a 2M solution in
heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a
stirred solution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237
mol) in THF (70 ml) at between 0 and 51C in N.sub.2 atmosphere. The
mixture was warmed to room temperature and refluxed 1.5 hours. The
reaction mixture was cooled to room temperature and a solution of
CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture
was stirred overnight at room temperature and evaporated. To the
residue in MeOH (70 ml) was added concentrated sulfuric acid (3.9
ml) in MeOH (25 ml), the mixture was refluxed for 2 hours and
evaporated. The residue was partitioned between chloroform and
saturated K2CO3 solution. The aqueous layer was extracted again
with chloroform and the organic layers were combined, washed with
water, dried over sodium sulphate and evaporated to dryness to
obtain 5.73 g of a brown oil. This product was purified by column
chromatography (silica gel, hexane/ethyl acetate 95:5) to yield
4.43 g (78.5%) of a pure product, structure confirmed by
.sup.1H-NMR.
.sup.1H-NMR (CDCl3): .delta. 1.80 (s, 3H), 3.60 (s, 3H), 7.50-7.65
(m, 4H), 7.75 (m, 2H), 8.0 (m, 2H).
EXAMPLE I-1f
Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic Acid Methyl
Ester
Prepared as in example I-1e. The yield was 2.65 g (47.2%).
.sup.1H-NMR (CDCl3): .delta. 1.90 (s, 3H), 3.6 (s, 3H), 7.05-7.35
(m, 8H).
EXAMPLE I-1g
Preparation of 9-Hydroxy-9[H]-xanthene-9-carboxylic Acid Methyl
Ester
Lithium diisopropylamide (20.3 ml of a 2M solution in
heptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a
stirred solution of 7 g (0.029 mol) of 9[H]-xantene-9-carboxylic
acid methyl ester (prepared by a standard method) in THF (70 ml) at
between 0 and 51C in N.sub.2 atmosphere. The mixture was stirred 1
h at this temperature and then was added by N2 pressure to a dry
solution of oxygen in ether at 01C. After 30 min, an equal volum of
NaHSO3, 40% aqueous solution, was added, and the reaction mixture
was warmed to room temperature and stirred for 30 min. The two
layers were separated and the aqueous phase was extracted twice
with ethyl acetate. The organic phases were combined, treated with
NaHSO3 (40% aqueous solution), washed with water, dried over sodium
sulphate and evaporated to dryness to obtain 8.89 g of a brown
solid.
This procedure was repeated with 5 g of starting material yielding
6.049 of the same brown solid. The products were combined and
purified by column chromatography (silica gel, hexane/ethyl acetate
90:10) to yield 7.60 g (global Rt: 59.4%) of a pure product,
structure confirmed by .sup.1H-NMR.
.sup.1H-NMR (DMSO-d6): .delta. 3.5 (s, 3H), 7.0 (s, 1H, OH), 7.2
(m, 4H), 7.4 (m, 2H), 7.55 (m, 2H).
Method-d
EXAMPLE I-2a
Preparation of
10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic Acid
1-azabicyclo[2.2.2]oct-3-(R)-yl Ester
2.15 g of 10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic
acid (9.0 mmol) were dissolved in 40 ml of CHCl3 (ethanol free).
The solution was cooled at 0.degree. C. and 0.86 ml of oxalyl
chloride (9.9 mmols) and a drop of DMF were added. The mixture was
stirred and allowed warm to room temperature. After an hour at this
temperature the solvents were evaporated and the residue was
dissolved in CHCl3 and evaporated again. This procedure was
repeated two times. The obtained oil was dissolved in 20 ml of
toluene and added to a solution of 1.26 g (9.9 mmol) of
3-(R)-hydroxy-1-azabicyclo[2.2.2]octane in 40 ml of hot toluene.
The reaction mixture was refluxed for 2 hours. After cooling the
mixture was extracted with 2N HCl acid. The aqueous layer was
basified with K2CO3 and extracted with CHCl3. The organic layer was
dried over Na2SO4 and evaporated to dryness. The residue was
purified by column chromatography (silica gel, CHCl3:MeOH:NH40H,
95:5:0.5). The yield was 1.5 g (48%); mp: 112-113.degree. C.; CG/MS
[M].sup.+: 347; .sup.1H-NMR (CDCl3): .delta. 1.10-1.35 (m, 2H),
1.40-1.52 (m, 1H), 1.52-1.68 (m, 1H), 1.90 (m, 1H), 2.40-2.60 (m,
2H), 2.60-2.77 (m, 3H), 2.83-2.96 (m, 2H), 3.07-3.19 (m, 1H),
3.25-3.40 (m, 2H), 4.80 (m, 2H), 7.10-7.30 (m, 8H).
10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid was
prepared as described in Kumazawa T. et al., J. Med. Chem., (1994),
37, 804-810.
EXAMPLE I-2b
Preparation of 5[H]-Dibenzo[a,d]cycloheptene-5-carboxylic Acid
1-azabicyclo[2.2.2]oct-3-(R)-yl Ester
Prepared as in example I-2a. The yield was 3.12 g (71%); mp 1291C;
MS [M+1].sup.+: 346; .sup.1H-NMR (DMSO-d6): .delta. 0.90-1.10 (m,
2H), 1.30-1.50 (m, 2H), 1.58 (m, 1H), 2.21-2.26 (m, 2H), 2.47-2.50
(m, 3H), 2.86-2.94 (m, 1H), 4.48-4.51 (m, 1H), 5.33 (s, 1H), 7.0
(m, 2H), 7.29-7.43 (m, 6H), 7.49-7.51 (m, 2H).
5[H]-Dibenzo[a,d]cycloheptene-5-carboxylic acid was prepared as
described in M. A. Davis et al; J. Med. Chem., (1964), Vol 7,
88-94.
EXAMPLE I-2c
Preparation of 9,10-Dihydroanthracene-9-carboxylic Acid
1-azabicyclo[2.2.2]oct-3-(R)-yl Ester
Prepared as in example I-2a. The yield was 0.77 g (62.6%); mp
1391C; MS [M+1].sup.+: 334; .sup.1H-NMR (DMSO-d6): .delta. 1.1-1.2
(m, 1H), 1.25-1.40 (m, 2H), 1.40-1.55 (m, 1H), 1.73 (m, 1H), 2.20
(m, 1H), 2.35-2.65 (m, 4H), 2.90-2.98 (m, 1H), 3.93-4.14 (dd, 2H,
J=1.8 Hz, J=4.3 Hz), 4.56 (m, 1H), 5.14 (s, 1H), 7.25-7.35 (m, 4H),
7.35-7.50 (m, 4H).
9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described
in E. L. May and E. Mossettig; J. Am. Chem. Soc., (1948), Vol 70,
1077-9.
Method-e
EXAMPLE I-3
Preparation of 2,2-Diphenylpropionic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
1.1 g (4.8 mmol) of 2,2-diphenylpropionic acid were dissolved in 20
ml of THF. To this solution were added 0.87 g (5.3 mmol) of
1,1=-carbonyldiimidazole and the mixture was refluxed for an hour.
The reaction was monitored by TLC following the formation of the
imidazolide. When the reaction was completed part of the solvent
was evaporated and 0.67 g (5.3 mmol) of
3-(R)-hydroxy-1-azabicyclo[2.2.2]octane were added. The reaction
mixture was refluxed for 16 h, cooled, diluted with ether and
washed with water. The organic layer was extracted with HCl 2N, the
acid solution basified with K2CO3 and extracted with CHCl3. The
organic solution was dried over Na2SO4 and evaporated to dryness to
yield 1.21 g (75.2%) of an oil that was identified as the title
ester.
0.64 g (1.9 mmol) of 2,2-Diphenylpropionic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 6 ml of
ketone and 0.085 g(0.95 mmol) of oxalic acid were added. After slow
addition of ether a white solid was formed. The yield was 0.33 g
(45.6%) of oxalate of 2,2-Diphenylpropionic acid
1-azabicyclo[2.2.2]oct-3(R)-yl ester; mp: 1461C; MS [M free
base+1].sup.+: 336.
Oxalate salt, .sup.1H-NMR (CDCl3): .delta. 1.40-1.64 (m, 2H), 1.90
(s, 3H), 1.80-2.0 (m, 2H), 2.31 (m, 1H), 2.73-2.85 (m, 1H),
3.0-3.10 (m, 1H), 3.10-3.32 (m, 3H), 3.53-3.70 (m, 1H), 5.13 (m,
1H), 7.14-7.40 (m, 10H), 9.25 (broad band, 2H, H+).
Method-f
EXAMPLE I-4a
Preparation of 2-Hydroxy-2,2-dithien-2-ylacetic Acid
1-azabicyclo[2.2.2]oct-4-yl Ester
A solution of 2-thienylmagnesium bromide was prepared from 220 mg
(9 mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in
15 ml of THF. This solution was added to 1.95 g (7 mmols) of
oxothien-2-yl -acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester
(intermediate I-4b) dissolved in 20 ml of THF. The mixture was
stirred at room temperature for 1 hour, refluxed for 1 hour,
cooled, treated with a saturated solution of ammonium chloride and
extracted with ether. After removal of the solvent the solid
obtained was recrystallised from acetonitrile to yield 1.45 g, of a
white solid (56%). .sup.1H-NMR (DMSO-d6): .delta. 1.80-2.0 (m, 6H),
2.80-3.0 (m, 6H), 7.0 (m, 2H), 7.13 (m, 2H), 7.18 (s, 1H), 7.51 (m,
2H); MS [M+1]: 350; mp 174.degree. C.
EXAMPLE I-4b
Preparation of Oxothien-2-yl-acetic Acid
1-azabicyclo[2.2.2]oct-4-yl Ester
Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution of
oxothien-2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide
(one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture
was stirred and allowed to warm at room temperature. After one hour
the solvent was evaporated. The residue was dissolved in chloroform
and evaporated again. This procedure was repeated two times. The
product obtained was disolved in CHCl3 (30 ml) and added to a
suspension of 1.1 g (0.009 mols) of
4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml of triethylamine (0,013
mols), 0.6 g (0.9 mmols) of N-(methylpolystyrene)-4-(methylamino)
pyridine at 70.degree. C. The mixture was refluxed for 1 hour,
cooled, filtered and washed with water. The title product was
extracted with a solution of diluted HCl, washed with CHCl3,
basified with K2CO3 and extracted again with CHCl3. After removal
of the solvent 1.47 g (45%) of a solid was obtained. .sup.1H-NMR
(dmso): .delta. 2.0 (m, 6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m,
1H), 8.3 (m, 1H).
EXAMPLE I-4c
Preparation of (Furan-2-yl)hydroxyphenylacetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in
THF), was added to a solution of 1.3 g (0.0052 mol) of
oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester
(intermediate I-4e-) dissolved in 15 ml of THF, at -701C in N2
atmosphere. The mixture was stirred at this temperature for 10
minuts, and then warmed to room temperature. After 1 hour, the
reaction mixture was treated with a saturated solution of ammonium
chloride and extracted three times with ethyl acetate The organic
phases were combined, washed with water and dried over Na2SO4.
After removal of the solvent, the solid obtained was treated with
ether and filtered to yield 0.67 g (40%) of a product whose
structure was confirmed by .sup.1H-NMR. This compound was also
prepared as is described in Example I-1a (Method c). The
diastereomers were separated by crystallization from acetonitrile
and distinguished by .sup.1H-NMR.
EXAMPLE I-4d
Preparation of 2-Hydroxy-2,2-difur-2-yl-acetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
The title compound was synthesised as in example I-4c from
intermediate I-4e--and 2-furanyl lithium which was prepared with
furane and butyl lithium following a standard method. The yield was
380 mg (8%). .sup.1H-NMR (CDCl3): .delta. 1.2-1.4 (m, 1H), 1.4-1.8
(m, 3H), 2.0 (m, 1H), 2.6-2.85 (m, 5H), 3.2 (m, 1H), 5.0 (m, 1H),
6.4 (m, 3H), 7.3 (m, 1H), 7.5 (m, 2H). MS [M+1].sup.+: 318.
EXAMPLE I-4e
Preparation of Oxofuran-2-yl-acetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of
oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide
(one drop) in 150 ml of chloroform (etanol free) at 01C. The
mixture was stirred and allowed to warm at room temperature. After
five hours the solvent was evaporated. The residue was dissolved in
chloroform and evaporated again. This procedure was repeated two
times. The product obtained was disolved in CHCl3 (150 ml) and a
solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150
ml) was added to this at 01C. The mixture was stirred and allowed
to warm at room temperature. After 15 h at r.t., the mixture was
washed with 10% aqueous potassium carbonate, then with water, dried
over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title
compound as a dark oil. Estructure confirmed by NMR.
.sup.1H-NMR (CDCl3): .delta. 1.40-1.60 (m, 1H), 1.60-1.80 (m, 2H),
1.80-2.05 (m, 1H), 2.20 (m, 1H), 2.70-3.10 (m, 5H), 3.30-3.45 (m,
1H), 5.10 (m, 1H), 6.7 (m, 1H), 7.7 (m, 1H), 7.8 (m, 1H).
EXAMPLE I-4f
Preparation of 2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
The title compound was prepared as described in example I-4c from
intermediate I-4 g. The yield was 3 g (33%) as a mixture of
diastereomers. After five crystallizations of 1.5 g of this mixture
from boiling isopropanol, 0.200 g of a pure diastereomer(1) were
obtained. The mother liquors from first crystallization were
enriched with the other diastereomer (2). Diastereomer 1 was
hidrolysed to yield (+)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid
as a pure enantiomer, [.alpha.].sup.25.sub.D=+25.4 (c=2, EtOH).
This value was assigned to the R configuration provided that in
literature (A. I. Meyers et. al. J. Org. Chem.(1980), 45(14), 2913)
the 2(S) enantiomer has been described whith [.alpha.].sup.25D=-20
(c=2, EtOH).
Diastereomer 1: 2(R)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester.
.sup.1H-NMR (DMSO-d6): .delta. 1.1-1.25 (m, 1H), 1.3-1.6 (m, 3H),
1.83 (m, 1H), 2.4-2.7 (m, 5H), 3.1 (m, 1H), 4.8 (m, 1H), 7.0 (m,
2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m,
1H).
Diastereomer 2: 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic Acid
1-aza Bicyclo[2.2.2]oct-3(R)-yl Ester.
.sup.1H-NMR (DMSO-d6): .delta. 1.1-1.25 (m, 1H), 1.4-1.6 (m, 3H),
1.9 (m, 1H), 2.3-2.7 (m, 5H), 3.05 (m, 1H), 4.8 (m, 1H), 7.0 (m,
2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5 (m,
1H).
EXAMPLE I-4g
Preparation of Oxothien-2-yl-acetic Acid
1-azabicyclo[2.2.2]oct-3(R)-yl Ester
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of
oxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide
(one drop) in 30 ml of chloroform (etanol free) at 01C. The mixture
was stirred and allowed to warm at room temperature. After one hour
the solvent was evaporated. The residue was dissolved in chloroform
and evaporated again. This procedure was repeated two times. The
product obtained was disolved in CHCl3 (30 ml) and a solution of
3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added
to this at 01C. The mixture was stirred and allowed to warm at room
temperature. After 1.5 h at r.t., the mixture was washed with 10%
aqueous potassium carbonate, then with water, dried over Na2SO4 and
evaporated to give 3.14 g (92.6%) of the title compound as a yellow
oil. .sup.1H-NMR (CDCl3): .delta. 1.40-1.50 (m, 1H), 1.50-1.70 (m,
1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05
(m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m,
1H), 8.10 (m, 1H).
Other carboxylic acids of Formula B--C(O)OH, whose preparation (or
the syntheses of their derivatives methyl ester, chloride or
imidazolide) have not been described in methods c, d, e or in the
Examples I-1e, 1-1f and I-1g, and that are not commercially
available, could be prepared as is described in the following
references: FR 2012964 M. A. Davis et al; J. Med. Chem. (1963), 6,
513-516. T. Kumazawa et al; J. Med. Chem, (1994), 37(6), 804-810.
M. A. Davis et al; J. Med. Chem., (1964), Vol (7), 88-94. Sestanj,
K; Can. J. Chem., (1971), 49, 664-665. Burtner, R.; J. Am. Chem.
Soc., (1943), 65, 1582-1585 Heacock R. A. et al.; Ann. Appl. Biol.,
(1958), 46(3), 352-365. Rigaudy J. et. al.; Bull. Soc. Chim.
France, (1959), 638-43. Ueda I. et al.; Bull. Chem. Soc. Jpn;
(1975), 48 (8), 2306-2309. E. L. May et. al.; J. Am. Chem. Soc.,
(1948), 70, 1077-9.
Also included within the scope of the present invention are
pharmaceutical composition which comprise, as the active
ingredient, at least one quinuclidine derivative of general formula
(I) in association with a pharmaceutically acceptable carrier or
diluent. Preferably the composition is made up in a form suitable
for oral administration.
The pharmaceutically acceptable carrier or diluents which are mixed
with the active compound or compounds, to form the composition of
this invention are well-known per se and the actual excipients used
depend inter alia on the intended method of administration of the
composition.
Compositions of this invention are preferably adapted for oral
administration. In this case, the composition for oral
administration may take the form of tablets, film-coated tablets,
liquid inhalant, powder inhalant and inhalation aerosol; all
containing one or more compounds of the invention; such
preparations may be made by methods well-known in the art.
The diluents which may be used in the preparations of the
compositions include those liquid and solid diluents which are
compatible with the active ingredient, together with colouring or
flavouring agents, if desired. Tablets or film-coated tablets may
conveniently contain between 500 and 1 mg, preferably from 5 to 300
mg of active ingredient. The inhalant compositions may contain
between 1.PHI.g and 1,000 .PHI.g, preferably from 10 to 800 .PHI.g
of active ingredient. In human therapy, the dose of the compound of
general formula (I) depend on the desired effect and duration of
treatment; adult doses are generally between 3 mg and 300 mg per
day as tablets and 10 .PHI.g and 800 .PHI.g per day as inhalant
composition.
Pharmacological Action
The following examples demonstrate the excellent pharmacological
activities of the compounds of the present invention. The results
on human muscarinic receptors binding and in the test on
bronchospasm in guinea pig, were obtained as described below.
Human Muscarinic Receptor Studies.
The binding of [.sup.3H]-NMS to human muscarinic receptors was
performed according to Waelbroek et al (1990) (1). Assays were
carried out at 25.degree. C. Membrane preparations from stably
transfected chinese hamster ovary-K1 cells (CHO) expressing the
genes for the human muscarinic receptors Hm3 were used.
For determination of IC.sub.50, membrane preparations were
suspended in DPBS to a final concentration of 89 .mu.g/ml for the
Hm3 subtype. The membrane suspension was incubated with the
tritiated compound for 60 min. After incubation the membrane
fraction was separated by filtration and the bound radioactivity
determined. Non specific binding was determined by addition of
10.sup.-4 M atropine. At least six concentrations were assayed in
duplicate to generate individual displacement curves.
TABLE-US-00001 COMPOUNDS BINDING TO RECEPTOR No M.sub.3 (IC.sub.50
nM) ATROPINE 3.2 IPRATROPIUM 3.0 1 31 2 15 7 22 8 4.8 17 14 18 6.6
20 6.8 35 13 36 2.7 39 3.8 44 4.4 53 5.6 71 8.2 74 16 77 3.1 78 5
84 9.9 89 5.4 99 31 100 14 101 7.6 109 31 114 14 116 23 126 13 127
16 128 8.8 129 6.3 136 11 137 6.9 138 19 146 13
(1) M. Waelbroek, M. Tastenoy, J. Camus, J Christophe. Binding of
selective antagonists to four muscarinic receptors (M1 to M4) in
rat forebrain. Mol. Pharmacol. (1990) 38: 267-273.
Our results show that the compounds of the present invention have
affinities for the M.sub.3 receptors which are very similar to the
reference compounds.
The compounds of the invention preferably have high affinities for
muscarinic M.sub.3 receptors (HM3), preferably human muscarinic
receptors. Affinity levels can typically be measured by in vitro
assays, for example, as described above.
Preferred compounds of the invention have an IC.sub.50 (nM) value
for M.sub.3 receptors of less than 35, preferably less than 25,20
or 15, more preferably less than 10, 8 or 5.
Test on Bronchospasm in Guinea Pig
The studies were performed according to Konzett and Rossler (2).
Aqueous solutions of the agents to be tested were nebulized and
inhaled by anaesthetized ventilated male guinea pigs
(Dunkin-Hartley). The bronchial response to intravenous
acetylcholine challenge was determined before and after drug
administration and the percent change in pulmonary resistance at
several time-points. 2. Konzett H., Roossler F. Versuchsanordnung
zu Untersuchungen ander bronchialmuskulatur. Arch. Exp. Path.
Pharmacol. 195: 71-74 (1940)
The compounds of the present invention inhibited the bronchospasm
response to acetylcholine with high potency and a long duration of
action.
From the above described results one of ordinary skill in the art
can readily understand that the compounds of the present invention
have excellent antimuscarinic activity (M.sub.3) and thus are
useful for the treatment of diseases in which the muscarinic
M.sub.3 receptor is implicated, including respiratory diseases such
as chronic obstructive pulmonary disease, chronic bronchitis,
asthma and rhinitis, urinary diseases such as urinary incontinence
and pollakinuria in neuripenia pollakinuria, neurogenic bladder,
nocturnal enuresis, unstable bladder, cystospasm and chronic
cystitis and gastrointestinal diseases such as irritable bowel
syndrome, spastic colitis and diverticulitis.
The present invention further provides a compound of formula (I) or
a pharmaceutically acceptable composition comprising a compound of
formula(I) for use in a method of treatment of the human or animal
body by therapy, in particular for the treatment of respiratory,
urinary or gastrointestinal disease.
The present invention further provides the use of a compound of
formula (I) or a pharmaceutically acceptable composition comprising
a compound of formula (I) for the manufacture of a medicament for
the treatment of respiratory, urinary or gastrointestinal
disease.
Further, the compounds of formula (I) and pharmaceutical
compositions comprising a compound of formula (I) can be used in a
method of treating respiratory, urinary or gastrointestinal
disease, which method comprises administering to a human or animal
patient in need of such treatment an effective amount of a compound
of formula (I) or a pharmaceutical composition comprising a
compound of formula (I).
The present invention will be further illustrated by the following
examples. The examples are given by way of illustration only and
are not to be construed as limiting.
EXAMPLE 1
3(R)-Diphenylacetoxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;
Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 500 mg, 81%. .sup.1H-NMR (CDCl3):
.delta. 1.72-2.18 (m, 6H), 2.35 (m, 1H), 3.0 (m, 1H), 3.23 (m, 1H),
3.59-3.88 (m, 5H), 4.0 (m, 2H), 4.30 (m, 1H), 5.1 (s, 1H), 5.25 (m,
1H), 6.8-6.9 (m, 2H), 6.9-7.0 (m, 1H), 7.2-7.4 (m, 12H); MS
[M-Br].sup.+: 456; mp 129.degree. C.
EXAMPLE 2
3(R)-(2-Hydroxy-2,2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[-
2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 280 mg,42%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.7 (m, 2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (m, 1H),
3.2-3.5 (m, 6H), 3.9-4.1 (m, 3H), 5.25 (m, 1H), 6.8 (bs, OH), 6.95
(m, 3H), 7.2-7.5 (m, 12H); MS [M-Br].sup.+: 472; mp 199.degree.
C.
EXAMPLE 3
3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azo-
niabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 400 mg,85%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H),
2.05-2.2 (m, 2H), 2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.3-3.5 (m,6H),
3.95 (m, 1H), 4.05 (m, 2H), 5.25 (m, 1H), 6.9-7.0 (m, 4H), 7.1-7.5
(m, 10H); MS [M-Br].sup.+: 508; mp 253.degree. C.
EXAMPLE 4
3(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyc-
lo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 300 mg,67%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.65 (m, 1H), 1.7-1.85 (m, 1H), 1.85-2.1 (m, 2H), 2.3
(m, 1H), 2.9-3.1 (m, 2H), 3.15-3.25 (m, 1H), 3.3-3.6 (m, 6H),
3.95-4.05 (m, 1H), 5.25 (m, 1H), 6.95 (s, OH), 7.1-7.5 (m, 13H); MS
[M-Br].sup.+: 478; mp 182.degree. C.
EXAMPLE 5
3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicycl-
o[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 500 mg, 54%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55-1.8 (m, 2H), 1.85-2.0 (m, 2H), 2.05-1.15 (m, 2H), 2.3
(s, 7H), 3.05-3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.95 (m, 1H), 4.05
(t, 2H), 5.2 (m, 1H), 6.8 (s, OH), 6.95 (m, 3H), 7.1-7.2 (m, 4H),
7.2-7.35 (m, 6H); MS [M-Br].sup.+: 500; mp 183.degree. C.
EXAMPLE 6
3(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]-
octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 650 mg, 74%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55-1.8 (m, 2H), 1.85-2.05 (m, 2H), 2.25 (s, 7H), 2.9-3.05
(m, 2H), 3.1-3.25 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m,
1H), 6.8 (s, OH), 7.1-7.2 (m, 4H), 7.2-7.35 (m, 9H); MS
[M-Br].sup.+: 470; mp 144.degree. C.
EXAMPLE 7
3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2-
]octane; Bromide
The title compound was synthesised according to methods e and a.
The yield of final step was 250 mg, 61%. .sup.1H-NMR (CDCl3):
.delta. 1.47-1.60 (m, 1H), 1.8-2.0 (m, 1H), 2.0 (s, 3H), 2.0-2.15
(m, 4H), 2.39 (s, 1H), 2.6 (m, 1H), 2.92 (d, 1H), 3.6 (m, 1H),
3.7-3.9 (m, 4H), 4.0 (m, 2H), 4.3 (m, 1H), 5.25 (m, 1H), 6.85 (m,
2H), 7.0 (m, 1H), 7.3 (m, 12H); MS [M-Br].sup.+: 470; mp
186.degree. C.
EXAMPLE 8
3(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoni-
abicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers
according to methods c and a. The yield of final step was 520 mg,
62%..sup.1H-NMR (DMSO-d6): .delta. 1.5-1.95 (m, 4H), 2.1 (m, 2H),
2.3 (m, 1H), 3.1 (m, 1H), 3.3-3.5 (m, 6H), 3.9 (m, 1H), 4.05 (t,
2H), 5.2 (m, 1H), 7.0 (m, 4H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m,
3H); MS [M-Br].sup.+: 478; mp 220.degree. C.
EXAMPLE 9
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)--
1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
10 mg, 23%. .sup.1H-NMR (DMSO-d6): .delta. 1.5-1.6 (m, 1H),
1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.05-2.1 (m, 2H), 2.3 (m, 1H),
3.05-3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.85-3.95 (m, 1H), 4.0 (t,
2H), 5.2 (m, 1H), 6.95 (m, 3H), 7.03 (m, 1H), 7.15 (dd, 1H), 7.2
(s, OH), 7.3-7.5 (m, 5H), 7.45-7.55 (m, 3H); MS [M-CF3COO].sup.+:
478.
EXAMPLE 10
3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxy
propyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 2. The yield of final step was
3 mg, 11%. .sup.1H-NMR (DMSO-d6): .delta. 1.6-1.75 (m, 2H), 1.8-2.0
(m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m,
6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m,
2H), 7.1 (dd, 1H), 7.18 (s, OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H),
7.51 (dd, 1H); MS [M-CF3COO].sup.+: 478.
EXAMPLE 11
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
9 mg, 22%. .sup.1H-NMR (DMSO-d6): .delta. 1.45-1.55 (m, 1H),
1.65-1.75 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H),
3.1-3.25 (m, 1H), 3.25-3.55 (m, 6H), 3.9-4.0 (m, 1H), 5.25 (m, 1H),
7.05 (m, 1H), 7.15 (m, 1H), 7.2 (m, 1H), 7.25-7.4 (m, 8H), 7.45 (m,
2H, 7.55 (m, 1H); MS [M-CF3COO].sup.+: 448.
EXAMPLE 12
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
11 mg, 26%. .sup.1H-NMR (DMSO-d6): .delta. 1.45-1.55 (m, 1H),
1.6-1.75 (m, 1H), 1.8-2.0 (m, 4H), 2.25 (m, 1H), 2.55 (t, 2H),
3.0-3.1 (m, 1H), 3.15-3.55 (m, 6H), 3.8-3.9 (m, 1H), 5.2 (m, 1H),
7.0 (m, 1H), 7.1 (m, 1H), 7.15-7.4 (m, 9H), 7.45 (m, 2H), 7.5 (m,
1H); MS [M-CF3COO].sup.+: 462.
EXAMPLE 13
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-thien-2-ylethyl-
)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
10 mg, 24%. .sup.1H-NMR (DMSO-d6): .delta. 1.45-1.55 (m, 1H),
1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H),
3.9-4.0 (m, 1H), 5.25 (m, 1H), 7.0 (m, 3H), 7.15 (dd, 1H), 7.2 (s,
OH), 7.3-7.4 (m, 3H), 7.45-7.55 (m, 4H); MS [M-CF3COO].sup.+:
454.
EXAMPLE 14
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropy-
l)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
8 mg, 19%. .sup.1H-NMR (DMSO-d6): .delta. 1.45-1.6 (m, 1H),
1.65-1.75 (m, 1H), 1.8-2.05 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H),
3.0-3.15 (m, 1H), 3.2-3.5 (m, 6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H),
6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.13 (dd, 1H), 7.2 (s, OH),
7.3-7.4 (m, 4H), 7.45-7.5 (m, 2H), 7.52 (dd, 1H); MS
[M-CF3COO].sup.+: 468.
EXAMPLE 15
3(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropy-
l)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 2. The yield of final step was
7 mg, 26%. .sup.1H-NMR (DMSO-d6): .delta. 1.6-1.75 (m, 2H), 1.8-2.0
(m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m,
6H), 3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m,
2H), 7.1 (dd, 1H), 7.18 (s, OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H),
7.51 (dd, 1H); MS [M-CF3COO].sup.+: 468.
EXAMPLE 16
3(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-phenoxy
ethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods f and b
from intermediate I-4f, diastereomer 1. The yield of final step was
11 mg, 26%. .sup.1H-NMR (DMSO-d6): .delta. 1.5-1.6 (m, 1H),
1.65-1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.25 (m, 1H), 3.15-3.6 (m, 5H),
3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m, 2H), 5.25 (m, 1H), 6.95-7.03 (m,
4H), 7.12 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 5H), 7.4-7.5 (m, 3H);
MS [M-CF3COO].sup.+: 464.
EXAMPLE 17
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers
according to methods c and a. The yield of final step was 240 mg,
77%. .sup.1H-NMR (DMSO-d6): .delta. 1.55-2.0 (m, 4H), 2.27 (m, 1H),
3.05-3.55 (m, 5H), 3.88-3.98 (m, 1H), 4.0-4.10 (m, 2H), 5.21 (m,
1H), 6.23-6.31 (doble dd, 1H), 6.36-6.48 (m, 2H), 6.83-6.90 (dd,
1H), 6.95 (d, OH), 7.26-7.66 (m, 11H); MS [M-Br].sup.+: 444; mp
99.degree. C.
EXAMPLE 18
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azonia-
bicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers
according to methods c and a. The yield of final step was 210 mg,
66%. .sup.1H-NMR (DMSO-d6): .delta. 1.50-2.05 (m, 4H), 2.27 (m,
1H), 3.20 (m, 1H), 3.37-3.65 (m, 4H), 3.65-3.75 (m, 2H), 4.04 (m,
1H), 4.40 (m, 2H), 5.21 (m, 1H), 6.23-6.32 (doble dd, 1H), 6.44 (m,
1H), 6.94-7.04 (m, 4H), 7.33-7.50 (m, 7H), 7.64 (m, 1H); MS
[M-Br].sup.+: 448; mp 163.degree. C.
EXAMPLE 19
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-phenoxy
ethyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-la, diastereomer 1. The yield of final step was
11 mg, 23%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-1.80 (m, 2H),
1.80-2.10 (m, 2H), 2.27 (m, 1H), 3.15-3.65 (m, 5H), 3.68 (m, 2H),
4.0 (m, 1H), 4.40 (t, 2H), 5.20 (m, 1H), 6.23 (d, 1H), 6.42 (m,
1H), 6.92-7.04 (m, 4H), 7.30-7.38 (m, 5H), 7.44-7.50 (m, 2H), 7.64
(m, 1H); MS [M-CF3COO].sup.+: 448.
EXAMPLE 20
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3phenoxypropyl)-1-azonia-
bicyclo[2.2.2]octane; Bromide
The title compound has been described in method-a-.
EXAMPLE 21
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxy
propyl)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a
from intermediate I-1a, diastereomer 1. The yield of final step was
1.15 g 99%. .sup.1H-NMR (DMSO-d6): .delta. 1.60-2.20 (m, 6H), 2.25
(m, 1H), 3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m,
2H), 5.20 (m, 1H), 6.25 (dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H),
7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-Br].sup.+: 462; mp
156.degree. C.
EXAMPLE 22
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxy
propyl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-la, diastereomer 2. The yield of final step was
10 mg, 20%. .sup.1H-NMR (DMSO-d6): .delta. 1.50-2.20 (m, 6H), 2.25
(m, 1H), 3.10 (m, 1H), 3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m,
2H), 5.20 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H),
7.30-7.50 (m, 7H), 7.70 (m, 1H); MS [M-CF3COO].sup.+: 462.
EXAMPLE 23
3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-phenethyl-1-azoniabicyclo-
[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers
according to methods c and b. The yield of final step was 12 mg,
13%. .sup.1H-NMR (DMSO-d6): .delta. 1.5 (m, 1H), 1.7 (m, 1H),
1.9-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H),
3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.3 (d, 1H), 6.45
(m, 1H), 6.95 (d, 1H), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m, 1H);
MS [M-CF.sub.3COO].sup.+: 432.
EXAMPLE 24
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoni-
abicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-1a, diastereomer 1. The yield of final step was
16 mg, 40%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-1.80 (m, 2H),
1.90-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H),
3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.26 (dd, 1H), 6.46
(m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m,
1H); MS [M-CF3COO].sup.+: 432.
EXAMPLE 25
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoni-
abicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-la, diastereomer 2. The yield of final step was
14 mg, 35% .sup.1H-NMR (DMSO-d6): .delta. 1.50-1.80 (m, 2H),
1.90-2.05 (m, 2H), 2.3 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H),
3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.32 (dd, 1H), 6.46
(m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m, 8H), 7.5 (m, 2H), 7.7 (m,
1H) MS [M-CF3COO].sup.+: 432.
EXAMPLE 26
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenylpropyl)--
1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-la, diastereomer 1. The yield of final step was
10 mg, 21%. .sup.1H-NMR (DMSO-d6): .delta. 1.60-1.75 (m, 2H),
1.80-2.0 (m, 4H), 2.25 (m, 1H), 2.50-2.60 (m, 2H), 3.0 (m, 1H),
3.10-3.50 (m, 6H), 3.83 (m, 1H), 5.17 (m, 1H), 6.25 (d, 1H), 6.45
(m, 1H), 6.95 (s, 1H), 7.20-7.40 (m, 8H), 7.46-7.48 (m, 2H), 7.66
(m, 1H); MS [M-CF3COO].sup.+: 446.
EXAMPLE 27
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-thien-2-ylethy-
l)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b
from intermediate I-la, diastereomer 1. The yield of final step was
9 mg, 19%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-1.80 (m, 2H),
1.85-2.05 (m, 2H), 2.30 (m, 1H), 3.10-3.40 (m, 3H), 3.40-3.60 (m,
6H), 3.95 (m, 1H), 5.24 (m, 1H), 6.27 (d, 1H), 6.47 (m, 1H), 6.96
(s, 1H), 7.0-7.04 (m 2H), 7.36-7.48 (m, 4H), 7.49-7.54 (m, 2H),
7.70 (m, 1H).; MS [M-CF3COO].sup.+: 438.
EXAMPLE 28
3(R)-[2(*)--(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-thien-2-ylprop-
yl)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesized according to methods c and b
from intermediate I-1a, diastereomer 1. The yield of final step was
9 mg, 19%. .sup.1H-NMR (DMSO-d6): .delta. 1.60-1.75 (m, 2H),
1.80-2.05 (m, 4H), 2.26 (m, 1H), 2.81 (t, 2H), 3.02 (m, 1H),
3.10-3.45 (m, 6H), 3.85 (m, 1H), 5.18 (m, 1H), 6.25 (d, 1H), 6.45
(m, 1H), 6.90-7.0 (m, 3H), 7.32-7.42 (m, 4H), 7.45-7.51 (m, 2H),
7.66 (m, 1H); MS [M-CF3COO].sup.+: 452.
EXAMPLE 29
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-phenethyl-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers
according to methods c and b. The yield of final step was 18 mg,
20%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-2.05 (m, 4H), 2.3 (m, 1H),
3.0 (m, 2H), 3.15-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 6.35
(dd, 1H), 6.45 (m, 1H), 7.05 (m, 1H), 7.2 (dd, 1H), 7.25-7.5 (m,
6H), 7.55 (m, 1H), 7.65 (m, 1H); MS [M-CF.sub.3COO].sup.+: 438.
EXAMPLE 30
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1
-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;
Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers
according to methods c and b. The yield of final step was 22 mg,
23%. .sup.1H-NMR (DMSO-d6): .delta. 2.65-2.05 (m, 4H), 2.3 (m, 1H),
3.15-3.65 (m, 7H), 4.05 (m, 1H), 4.4 (m, 2H), 5.15 (m, 1H), 6.35
(dd, 1H), 6.45 (m, 1H), 6.95-7.05 (m, 4H), 7.15 (d, 1H), 7.3-7.4
(m, 3H), 7.5 (dd, 1H), 7.65 (d, 1H); MS [M-CF.sub.3COO].sup.+:
454.
EXAMPLE 31
3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-
-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised as a mixture of diastereomers
according to methods c and b. The yield of final step was 15.4 mg,
15%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-2.1 (m, 6H), 7.05-7.55 (m,
9H), 3.95 (m, 1H), 5.1 (m, 1H), 6.35 (dd, 1H), 6.5 (m, 1H), 7.05
(m, 1H), 7.15 (m, 1H), 7.3 (d, 1H), 7.55 (m, 3H), 7.7 (dd, 2H), 8.0
(d, 2H); MS [M-CF.sub.3COO].sup.+: 480.
EXAMPLE 32
1-(3-phenoxypropyl)-3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-yl-acetoxy)-1--
azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised as a mixture of diastereomers
according to methods c and a. The yield of final step was 100 mg,
41%. .sup.1H-NMR (DMSO-d6): .delta. 1.65-2.05 (m, 4H), 2.1-2.0 (m,
2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.6 (6H), 3.9-4.1 (m, 3H), 5.1
(m, 1H), 6.35 (d, 1H), 6.45 (s, 1H), 6.95 (m, 3H), 7.05 (m, 1H),
7.2 (d, 1H), 7.3 (m, 3H), 7.55 (d, 1H), 7.7 (s, 1H); MS
[M-Br].sup.+: 520; mp 173.degree. C.
EXAMPLE 33
1-(3-phenoxypropyl)-3(R)-(2,2-difuran-2-yl-2-hydroxy
acetoxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods f and a.
The yield of final step was 200 mg, 60%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6-2.20 (m, 6H), 2.3 (m, 1H), 2.95-3.65 (m, 7H), 3.80-4.10
(m, 3H), 5.2 (m, 1H), 6.3-6.6 (m, 4H), 6.8-7.0 (m, 3H), 7.1 (s,
OH), 7.3 (m, 2H), 7.7 (m, 2H); MS [M-Br].sup.+: 452.
EXAMPLE 34
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]o-
ctane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 240 mg, 60%. .sup.1H-NMR (DMSO-d6):
.delta. 1.85-2.10 (m, 4H), 2.30 (s, 1H), 3.40 (m, 1H), 3.44-3.80
(m, 6H), 4.10 (m, 1H), 4.45 (m, 2H), 5.20 (m, 1H), 5.90 (s, 1H),
6.95-7.05 (m, 5H), 7.05-7.15 (m, 2H), 7.30-7.40 (m, 2H), 7.45 (m,
2H); MS [M-Br].sup.+: 454; mp 98.degree. C.
EXAMPLE 35
3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]-
octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 280 mg, 83%. .sup.1H-NMR (DMSO-d6):
.delta. 1.80-2.06 (m, 4H), 2.06-2.20 (m, 2H), 2.20-2.30 (m, 1H),
3.20-3.65 (m, 7H), 3.90-4.10 (m, 3H), 5.20 (m, 1H), 5.90 (s, 1H),
6.95-7.05 (m, 5H), 7.05-7.20 (m, 2H), 7.30-7.35 (m, 2H), 7.50 (m,
2H); MS [M-Br].sup.+: 468; mp 148.degree. C.
EXAMPLE 36
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.-
2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 180 mg, 59%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (4H, m), 2.35 (m, 1H), 3.0 (m, 2H), 3.2-3.6 (m,
7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.35 (m,
5H), 7.55 (m, 3H); MS [M-Br].sup.+: 454; mp 216.degree. C.
EXAMPLE 37
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyc-
lo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 450 mg, 58%. .sup.1H-NMR (CDCl3):
.delta. 1.8-2.1 (m, 6H), 2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H),
4.2 (m, 1H), 5.25 (m, 1H), 6.1 (bs, OH), 6.9 (m, 2H), 7.1-7.3 (m,
9H); MS [M-Br].sup.+: 468; mp 64.degree. C.
EXAMPLE 38
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicycl-
o[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 260 mg, 34%. .sup.1H-NMR (CDCl3):
.delta. 1.8-2.05 (m, 4H), 2.4 (m, 1H), 3.55-3.95 (m, 5H), 4.15-4.5
(m, 3H), 5.25 (m, 1H), 5.9 (s, OH), 6.15 (m, 1H), 6.85 (t, 1H),
6.9-7.05 (m, 3H), 7.15 (m, 1H), 7.2-7.45 (m, 7H); MS [M-Br].sup.+:
466; mp 124.degree. C.
EXAMPLE 39
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicycl-
o[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 320 mg, 40%. .sup.1H-NMR (CDCl3):
.delta. 1.6-2.0 (m, 8H), 2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H),
4.2 (m, 1H), 5.25 (m, 1H), 6.05 (bs, OH), 6.95 (m, 2H), 7.1-7.3 (m,
9H); MS [M-Br].sup.+: 482; mp 64.degree. C.
EXAMPLE 40
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.0 (m, 6H), 2.15 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m,
7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (d, 2H), 7.15 (d, 2H), 7.55
(m, 5H), 7.65 (t, 1H), 8.0 (d, 2H); MS[M-CF.sub.3COO].sup.+:
496.
EXAMPLE 41
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylaminopropyl)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 14%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.0 (m, 5H), 2.3 (m, 1H), 3.0-3.5 (m, 9H), 3.9 (m, 1H),
5.25 (m, 1H), 5.65 (t, 1H), 6.55 (m, 3H), 7.0 (d, 2H), 7.1 (t, 2H),
7.15 (m, 2H), 7.5 (m, 3H); MS[M-CF.sub.3COO].sup.+: 483.
EXAMPLE 42
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(methylphenylamino)propyl]--
1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 20 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 6H), 2.9 (s, 3H), 3.1 (m, 1H), 3.2-3.45 (m,
8H), 3.95 (m, 1H), 5.2 (m, 1H), 6.65 (t, 1H), 6.75 (d, 2H), 7.0 (m,
2H), 7, 2 (m, 4H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+: 497.
EXAMPLE 43
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylsulfanylpropyl)-1-azo-
niabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 800 mg, 83%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6-1.9 (m, 6H), 2.3 (m, 1H), 2.95 (t, 2H), 3.05 (m, 1H),
3.2-3.5 (m, 6H), 3.9 (m, 1H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m,
2H), 7.2 (m, 1H), 7.35 (m, 4H), 7.5 (m, 2H); MS [M-Br].sup.+:
500.
EXAMPLE 44
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 490 mg, 90%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 2.3 (m, 1H), 3.2
(m, 1H), 3.45 (m, 6H), 4.0 (m, 3H), 5.15 (m, 1H), 6.9 (m, 3H), 7.0
(m, 2H), 7.2 (m, 2H), 7.3 (t, 2H), 7.5 (m, 3H); MS [M-Br].sup.+:
484; mp 227.degree. C.
EXAMPLE 45
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-otolyloxypropyl)-1-azoniabi-
cyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b The
yield of final step was 19 mg, 18%. .sup.1H-NMR (DMSO-d6): .delta.
1.7-2.0 (m, 4H), 2.1-2.2 (m, 5H), 2.3 (m, 1H), 3.15-3.5 (m, 7H),
3.9-4.05 (m, 3H), 5.05 (m, 1H), 6.85 (t, 1H), 6.9 (d, 1H), 7.0 (m,
2H), 7.15 (m, 4H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+: 498.
EXAMPLE 46
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2,4,6-trimethylphenoxy)pro-
pyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 22 mg, 20%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7 (m, 2H), 1.95 (m, 2H), 2.1 (m, 2H), 2.2 (s, 9H), 2.35
(m, 1H), 3.2-3.5 (m, 7H), 3.7 (t, 2H), 3.95 (m, 1H), 5.25 (m, 1H),
6.8 (s, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 526.
EXAMPLE 47
1-[3-(2-tert-Butyl-6-methylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2--
ylacetoxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 16%. .sup.1H-NMR (DMSO-d6):
.delta. 1.3 (s, 9H), 2.7 (m, 2H), 2.9 (m, 2H), 2.1 (m, 2H), 2.2 (s,
3H), 2.3 (m, 1H), 3.2-3.5 (m, 7H), 3.8 (t, 2H), 5 3.95 (m, 1H), 5.2
(m, 1H), 6.9-7.15 (m, 7H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+:
554.
EXAMPLE 48
1-[3-(Biphenyl-4-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-
-azoniabicyclo[2.2.2]-octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 22 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7 (m, 2H), 1.9 (m, 2H), 2.15 (m, 2H), 2.3 (m, 1H),
3.2-3.5 (m, 7H), 3.95 (m, 1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m,
4H), 7.2 (m, 2H), 7.3 (t, 1H), 7.45 (t, 2H), 7.5 (m, 3H), 7.6 (m,
4H); MS [M-CF.sub.3COO].sup.+: 560.
EXAMPLE 49
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(5,6,7,8-tetrahydronaphthal-
en-2-yloxy)-propyl]-1-azoniabicyclo[2.2.2]octane;
Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 23 mg, 21%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7 (m, 6H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 2.65 (m, 4H),
3.15-3.5 (m, 7H), 3.95 (m, 2H), 5.25 (m, 1H), 6.65 (m, 2H), 6.95
(d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 538.
EXAMPLE 50
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3(naphthalen-2-ylox- y)
propyl]-1-azoniabicyclo[2.2.2]octane; .sup.30 Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 17 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.0 (m, 4H), 2.1 (m, 1H), 2.35 (m, 1H), 3.15-3.35 (m,
7H), 3.95 (m, 1H), 4.17 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15
(m, 3H), 7.35 (m, 2H), 7.5 (m, 4H), 7.85 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 534.
EXAMPLE 51
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-
-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound has been described in method-b-.
EXAMPLE 52
1-[3-(2-Chlorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1--
azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 20 mg, 18%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 2H), 7.0 (m, 3H), 7.2 (m,
3H), 7.35 (t, 1H), 7.45 (d, 1H), 7.55 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 519.
EXAMPLE 53
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1--
azoniabicyclo[2.2.2]octane; Chloride
The title compound was synthesised according to methods c and a.
The yield of final step was 180 mg, 59%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.25 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m,
6H), 3.95 (m, 2H), 4.0 (t, 2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.15 (m,
4H), 7.55 (m, 3H); MS [M-Cl].sup.+: 502; mp 160.degree. C.
EXAMPLE 54
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy-
)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 13%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 4H), 2.15 (m, 2H), 2.35 (m, 1H), 3.2 (m, 1H),
3.25-3.35 (m, 6H), 3.95 (m, 1H), 4.1 (t, 2H), 5.15 (m, 1H),! 7.05
(m, 3H), 7.2 (d, 2H), 7.25-7.35 (m, 2H), 7.55 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 520.
EXAMPLE 55
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-trifluoromethyl
phenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.1 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m,
2H), 7.25-7.35 (m, 3H), 7.5-7.6 (m, 4H); MS [M-CF.sub.3COO].sup.+:
552.
EXAMPLE 56
1-[3-(3-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-a-
zoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.1 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7, 18
(m, 2H), 7.3 (d, 1H), 7.45 (m, 2H), 7.55 (m, 4H); MS
[M-CF.sub.3COO].sup.+: 509.
EXAMPLE 57
1-[3-(4-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-a-
zoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 180 mg, 53%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.1 (d,
2H), 7.15 (m, 2H), 7.5 (m, 2H), 7.8 (d, 2H); MS [M-Br].sup.+: 509;
mp 158.degree. C.
EXAMPLE 58
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 18%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.15 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m,
6H), 3.75 (s, 3H), 3.95 (m, 1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.55
(m, 3H), 7.0 (m, 2H), 7.2 (m, 3H), 7.55 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 514.
EXAMPLE 59
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-methoxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 13%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.7 (s, 3H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.9 (s, 4H), 7.0
(m, 2H), 7.15 (m, 2H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+:
514.
EXAMPLE 60
1-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylac-
etoxy)-1-azoniabicyclo [2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 7H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m,
6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 5.95 (s, 2H), 6.4 (d, 1H), 6.65
(s, 1H), 6.85 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 528.
EXAMPLE 61
1-[3-(2-Carbamoylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-
-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 16%..sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H),
3.25-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t, 2H), 5.25 (m, 1H),
7.0-7.2 (m, 6H), 7.4-7.6 (m, 6H), 7.7 (d, 1H); MS
[M-CF.sub.3COO].sup.+: 527.
EXAMPLE 62
1-[3-(3-Dimethylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacet-
oxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.3 (m, 1H), 2.85 (s, 6H), 3.1-3.5 (m,
7H), 3.85-4.0 (m, 3H), 5.25 (m, 1H), 6.2 (m, 1H), 6.25 (d, 1H),
6.35 (d, 1H), 7.0 (m, 2H), 7.1 (t, 1H), 7.2 (m, 2H), 7.5 (m, 3H);
MS [M-CF.sub.3COO].sup.+: 527.
EXAMPLE 63
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-nitrophenoxy)propyl]-1-a-
zoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 22 mg, 20%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H),
3.3 3.5 (m, 6H), 3.95 (m, 1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m,
2H), 7.15 (m, 4H), 7.5 (m, 3H), 8.15 (d, 2H); MS
[M-CF.sub.3COO].sup.+: 529.
EXAMPLE 64
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-nitrophenoxy)propyl]-1-a-
zoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 16%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.95 (m,
1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.45 (dd,
1H), 7.55 (m, 3H), 7.6 (t, 1H), 7.75 (s, 1H), 7.85 (d, 1H); MS
[M-CF.sub.3COO].sup.+: 529.
EXAMPLE 65
1-[3-(4-Acetylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetox-
y)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.0 (s, 3H), 2.3 (m, 1H), 3.2 (m, 1H),
3.3-3.55 (m, 6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0
(m, 2H), 7.2 (m, 2H), 7.5 (m, 5H), 9.8 (s, 1H); MS
[M-CF.sub.3COO].sup.+: 541.
EXAMPLE 66
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxycarbonylphenoxy)p-
ropyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 16%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m,
6H), 3.85 (s, 3H), 3.95 (m, 1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m,
2H), 7.15 (m, 2H), 7.25 (dd, 1H), 7.45-7.6 (m, 6H); MS
[M-CF.sub.3COO].sup.+: 542.
EXAMPLE 67
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-{3-[4-(3-hydroxypropyl)phenoxy-
]propyl}-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 13%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6-2.15 (m, 8H), 2.3 (m, 1H), 2.55 (t, 2H), 3.2 (m, 1H),
3.25-3.55 (m, 9H), 3.85-4.0 (m, 3H), 4.45 (t, OH), 5.25 (m, 1H),
7.85 (d, 2H), 7.0 (m, 2H), 7.1 (d, 2H), 7.15 (m, 2H), 7.5 (m, 2H);
MS [M-CF.sub.3COO].sup.+: 542.
EXAMPLE 68
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxymethylphenoxy)pro-
pyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.2 (m, 6H), 2.35 (m, 1H), 3.1-3.5 (m, 7H), 3.9-4.05
(m, 3H), 4.5 (m, 2H), 5.0 (t, OH), 5.15 (m, 1H), 6.9-7.05 (m, 4H),
7.2 (m, 2H), 7.4 (d, 1H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+:
514.
EXAMPLE 69
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxymethylphenoxy)pro-
pyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.2 (m, 6H), 2.35 (m, 1H), 3.15-3.5 (m, 7H), 3.9 (m,
1H), 4.05 (t, 2H), 4.45 (d, 2H), 5, 25 (m, 2H), 6.8 (d, 1H), 6.9
(m, 2H), 7.2 (m, 2H), 7.25 (t, 1H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 514.
EXAMPLE 70
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxymethylphenoxy)pro-
pyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 17 mg, 16%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.2 (m, 6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.9-4.05
(m, 3H), 4.4 (d, 2H), 5.1 (t, OH), 5.25 (t, 1H), 6.9 (d, 2H), 7.0
(m, 2H), 7.2 (m, 2H), 7.25 (d, 2H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 514.
EXAMPLE 71
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 24 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m,
6H), 3.95 (m, 1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.7-6.85 (m, 3H),
6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m, 3H), 8.85 (s, OH);
MS [M-CF.sub.3COO].sup.+: 500.
EXAMPLE 72
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.1 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.25-3.5 (m,
6H), 3.95 (m, 3H), 5.25 (m, 1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.0 (m,
2H), 7.2 (m, 2H), 7.5 (t, 3H), 9.0 (s, OH); MS
[M-CF.sub.3COO].sup.+: 500.
EXAMPLE 73
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-
-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.15 (m, 6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m,
6H), 3.9-4.0 (m, 3H), 5.25 (m, 1H), 6.9-6.0 (m, 3H), 7.0-7.1 (m,
3H), 7.2 (m, 2H), 7.5 (m, 3H), 9.45 (s, OH); MS
[M-CF.sub.3COO].sup.+: 500.
EXAMPLE 74
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 21 mg, 22%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-1.8 (m, 2H), 1.8-2.0 (m, 2H), 2.0-2.15 (m, 2H), 2.3
(m, 1H), 3.05-3.2 (m, 3H), 3.2-3.5 (m, 4H), 3.8-3.95 (m, 3H), 5.2
(m, 1H), 6.05 (t, 2H), 6.75 (t, 2H), 7.0 (t, 2H), 7.15 (d, 2H),
7.55 (m, 3H);MS [M-CF.sub.3COO].sup.+: 457.
EXAMPLE 75
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-thien-2-ylbutyl)-1-az-
oniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-1.85 (m, 2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (t,
2H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 7.0 (t, 2H),
7.4 (d, 2H), 7.25 (t, 1H), 7.55 (m, 3H), 7.95 (d, 1H), 8.05 (d,
1H); MS [M-CF.sub.3COO].sup.+: 502.
EXAMPLE 76
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(1-methyl[1H]-imidazol-2-yl-
sulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 26 mg, 25%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7 (m, 2H), 1.85-2.05 (m, 4H), 2.3 (m, 1H), 3.25-3.5 (m,
7H), 3.6 (s, 3H), 3.9 (m, 1H), 4.2 (t, 2H), 5.2 (m, 1H), 7.0 (m,
3H), 7.15 (m, 2H), 7.3 (m, 1H), 7.5 (m, 3H); MS
[M-CF.sub.3COO].sup.+: 504.
EXAMPLE 77
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabi-
cyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 430 mg, 54%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6-1.8 (m, 2H), 2.3 (m, 1H), 3.15-3.3 (m, 4H), 3.35-3.55
(m, 5H), 3.95 (m, 1H), 5.25 (m, 1H), 7,0 (m, 4H), 7,15 (m, 2H),
7.4-7.5 (m, 4H); MS [M-Br].sup.+: 460; mp 206.degree. C.
EXAMPLE 78
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 600 mg, 77%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6-1.8 (m, 2H), 1.85-2.1 (m, 4H), 2.3 (m, 1H), 2.8 (t,
2H), 3.1-3.5 (m, 7H), 3.9 (m, 1H), 5.2 (m, 1H), 6.9-7.05 (m, 4H),
7.15 (m, 2H), 7.4 (d, 1H), 7.5 (m, 3H); MS [M-Br].sup.+: 474;
.sub.mp 138.degree. C.
EXAMPLE 79
1-[3-(Benzothiazol-2-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetox-
y)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesized according to methods c and b.
The yield of final step was 23 mg, 21%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.1 (m, 6H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m,
6H), 3.85 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 7.0 (t, 2H), 7.15 (m,
2H), 7.25 (m, 1H), 7.45 (m, 5H), 7.7 (d, 1H); MS
[M-CF.sub.3COO].sup.+: 541.
EXAMPLE 80
1-(3-Benzyloxypropyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabi-
cyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65 (m, 2H), 1.9 (m, 4H), 2.3 (m, 1H), 3.1-3.4 (m, 7H),
3.5 (t, 2H), 3.9 (m, 1H), 3.9 (s, 2H), 5.2 (m, 1H), 7.0 (m, 2H),
7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+:
498.
EXAMPLE 81
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[6-(4-phenylbutoxy)hexyl]-1-az-
oniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 560 mg, 60%. .sup.1H-NMR (CDCl3):
.delta. 1.2-1.75 (m, 16H), 1.8-2.1 (m, 4H), 2.4 (m, 1H), 2.6 (t,
2H), 3.3-3.75 (m, 11H), 4.2 (m, 1H), 5.3 (m, 1H), 6.0 (bs, OH),
6.95 (m, 2H), 7.15-7.3 (m, 9H); MS [M-Br].sup.+: 582.
EXAMPLE 82
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyc-
lo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 240 mg, 30%. .sup.1H-NMR
(DMSO-d6/CDCl3): .delta. 1.8-1.95 (m, 6H), 2.1 (m, 2H), 2.45 (m,
1H), 3.18 (m, 1H), 3.5-3.8 (m, 6H), 4.0 (t, 2H), 4.15 (m, 1H) 5.15
(m, 1H), 6.7 (s, OH), 6.9 (m, 5H), 7.15 (d, 1H), 7.25 (m, 5H); MS
[M-Br].sup.+: 498; mp 161.degree. C.
EXAMPLE 83
3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyc-
lo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 380 mg, 50%. .sup.1H-NMR (DMSO-d6):
.delta. 1-85 (m, 2H), 2.05 (m, 2H), 2.4 (m, 1H), 3.6-4.1 (m, 7H),
4.35 (m, 3H), 5.25 (m, 1H), 6.0 (bs, OH), 6.9 (m, 4H), 7.0 (t, 1H),
7.1 (dd, 2H), 7.2 (dd, 2H), 7.3 (t, 2H); MS [M-Br].sup.+: 470; mp
48.degree. C.
EXAMPLE 84
1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 17 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 4H), 2.3 (m, 1H), 3.2-3.55 (m, 7H), 3.85 (m,
2H), 4.5 (s, 2H), 5.25 (m, 1H), 7.0 (t, 2H), 7.15 (t, 2H), 7.3-7.4
(m, 4H), 7.5 (m, 3H); MS [M-CF.sub.3COO].sup.+: 484.
EXAMPLE 85
3(S)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 600 mg, 54%. .sup.1H-NMR
(DMSO-d6/CDCl3): .delta. 1.85-2.3 (m, 6H), 2.5 (m, 1H), 3.3 (m,
1H), 3.4 (d, 1H), 3.5-3.7 (m, 5H), 4.05 (t, 2H), 4.2 (m, 1H), 5.25
(m, 1H), 6.85 (d, 2H), 7.0 (m, 3H), 7.15 (m, 2H), 7.2 (d, 1H), 7.3
(m, 4H); MS [M-Br].sup.+: 484; mp 230.degree. C.
EXAMPLE 86
4-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo-
[2.2.2]octane; Bromide
The title compound was synthesised according to methods f and a.
The yield of final step was 290 mg, 60%. .sup.1H-NMR (DMSO-d6):
.delta. 2.15 (m, 2H), 2.35 (m, 6H), 3.35 (m, 2H), 3.65 (m, 6H),
4.05 (t, 2H), 6.9-7.05 (m, 5H), 7.1 (m, 2H), 7.3 (m, 3H), 7.55 (m,
2H); MS [M-Br].sup.+: 484; mp 1681C.
EXAMPLE 87
4-(2-Hydroxy-2,2-dithien-2-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]-
octane; Bromide
The title compound was synthesised according to methods f and a.
The yield of final step was 260 mg, 57%. .sup.1H-NMR (DMSO-d6):
.delta. 2.35 (m, 6H), 3.0 (m, 2H), 3.4 (m, 2H), 3.75 (m, 6H), 7.0
(m, 2H), 7.3-7.5 (m, 6H), 7.55 (m, 2H); MS [M-Br].sup.+: 454; mp
1951C.
EXAMPLE 88
1-(3-phenoxypropyl)-3(R)-(2,2-dithien-2-ylpropionyloxy)-1-azoniabicyclo[2-
.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 390 mg, 92%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.20 (m, 6H), 2.10 (s, 3H), 2.30 (bs, 1H), 3.10 (m,
1H), 3.30-3.60 (m, 6H), 3.95-4.10 (m, 3H), 5.20 (m, 1H), 6.90-7.05
(m, 5H), 7.05-7.10 (m, 2H), 7.25-7.35 (m, 2H), 7.50 (m, 2H); MS
[M-Br].sup.+: 482; mp 170.degree. C.
EXAMPLE 89
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicy-
clo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 300 mg, 76%. .sup.1H-NMR (DMSO-d6):
.delta. 1.6 (m, 1H), 1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m,
2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.6 (m, 6H), 3.9 (m, 1H), 4.05
(t, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H), 7.15 (m, 2H), 7.3
(t, 2H), 7.4-7.5 (m, 4H); MS [M-Br].sup.+: 484; mp 2191C.
EXAMPLE 90
3(R)-(2-Hydroxy-2,2-dithienyl-3-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoni-
abicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 300 mg, 77%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.6 (m, 1H), 1.6-1.75 (m, 1H), 1.8-2.1 (m, 4H), 2.25
(m, 1H), 2.8 (t, 2H), 3.05-3.5 (m, 7H), 3.8-3.95 (m, 1H), 5,15 (m,
1H), 6.75 (s, OH), 6.9-7.0 (m, 2H), 7.1 (m, 2H), 7.35-7.55 (m, 5H);
MS [M-Br].sup.+: 474; mp 1921C.
EXAMPLE 91
3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2-
.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 63 mg, 48%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.7 (m, 1H), 1.7-1.85 (m, 1H), 1.9-2.1 (m, 2H), 2.3 (m,
1H), 2.9-3.1 (m, 2H), 3.15-3.6 (m, 7H), 3.9-4.0 (m, 1H), 5.2 (m,
1H), 6.8 (s, OH), 7.1 (m, 2H), 7.25-7,35 (m, 5H), 7.4 (m, 2H), 7.5
(m, 2H); MS [M-CF3COO].sup.+: 454.
EXAMPLE 92
3(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-(3-phenylpropyl)-1-azoniabicy-
clo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 75 mg, 55%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-2.0 (m, 6H), 2.25 (m, 1H), 2.5-2.6 (m, 2H), 3.05-3.6
(m, 8H), 3.8-3.9 (m,1H), 5.15 (m,1H), 6.75 (s, OH), 7.1 (d, 2H),
7.2-7,35 (m, 5H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO].sup.+:
468.
EXAMPLE 93
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicycl-
o[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 68 mg, 48%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.8 (m, 6H), 1.8-2.0 (m, 2H), 2.25 (m, 1H), 2.6 (m,
2H), 3.05 (m,1H), 3.15-3.45 (m, 6H), 3.85 (m, 1H), 5.15 (m, 1H),
6.75 (s, OH), 7.1 (d, 2H), 7.2 (m, 2H), 7,3 (m, 3H), 7.4 (m, 2H),
7.5 (m, 2H); MS [M-CF3COO].sup.+: 482.
EXAMPLE 94
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabi-
cyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 65 mg, 49%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-1.65 (m, 1H), 1.65-1.78 (m, 1H), 1.85-2.05 (m, 2H), 2.3
(m, 1H), 3.1-3.6 (m, 9H), 3.95 (m, 1H), 5,2 (m, 1H), 6.75 (s, OH),
7.0 (m, 2H), 7.15 (m, 2H), 7.45 (m, 3H), 7,5 (m, 2H); MS
[M-CF3COO].sup.+: 460.
EXAMPLE 95
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyc-
lo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 63 mg, 43%. .sup.1H-NMR (DMSO-d6):
.delta. 1.5-2.0 (m, 8H), 2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H),
3.85 (m, 1H), 4.0 (m, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H),
7.1 (d, 2H), 7.2 (m, 2H), 7,3 (t, 2H), 7.45 (m, 2H), 7.5 (m, 2H);
MS [M-CF3COO].sup.+: 498.
EXAMPLE 96
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyc-
lo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 72 mg, 52%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.05 (m, 2H), 2.3
(m, 1H), 3.2-3.6 (m, 5H), 3.7 (m, 2H), 4.05 (m, 1H), 4.4 (m, 2H),
5.2 (m, 1H), 6.75 (s, OH), 6.95-7.05 (m, 3H), 7.1 (d, 2H), 7.3-7.5
(m, 6H); MS [M-CF3COO].sup.+: 470.
EXAMPLE 97
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-3-ylacetoxy)-1--
azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 79 mg, 54%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55-1.65 (m, 1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H),
2.05-2.2 (m, 2H), 2.3 (m, 1H), 3.1-3.2 (m, 1H), 3.25-3.55 (m, 6H),
3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 6.75 (s, OH), 6.95 (m,
2H), 7.15 (m, 4H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO].sup.+:
502.
EXAMPLE 98
3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicycl-
o[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 24 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.8-2.05 (m, 4H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.5 (m,
4H), 3.9 (m, 1H), 4.05 (m 2H), 5.25 (m, 1H), 6.35 (m,1H), 6.75 (s,
OH), 6.85 (t, 1H), 7.1 (m, 2H), 7.3-7.5 (m, 5H), 7.55 (m, 4H); MS
[M-CF3COO].sup.+: 502.
EXAMPLE 99
1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabi-
cyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 400 mg, 93%. .sup.1H-NMR (DMSO-d6):
.delta. 1.35-1.50 (m, 1H), 1.60-1.75 (m, 1H), 10 1.75-1.95 (m, 2H),
2.10 (m, 1H), 2.85 (m, 1H), 3.10 (d, 1H), 3.20-3.50 (m, 3H), 3.85
(m,1H), 4.0 (dd, 2H), 5.05 (m,1H), 6.40 (dd, 1H), 6.80-6.90 (d,
1H), 6.85 (s, OH), 7.20-7.50 (m, 7H), 7.60 (m, 4H), 7.80 (m, 2H);
MS [M-Br].sup.+: 452; mp 146.degree. C.
EXAMPLE 100
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azoni-
abicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 690 mg, 83%. .sup.1H-NMR (DMSO-d6):
.delta. 1.47 (m, 1H), 1.68 (m, 1H), 1.87 (m, 2H), 2.1 (m, 3H), 2.89
(m, 1H), 3.15 (d, 1H), 3.4 (m, 5H), 3.9 (m, 1H), 4.0 (m, 2H), 5.04
(m,1H), 6.85 (s, OH), 6.97 (m, 3H), 7.35 (m, 4H), 7.45 (m, 2H),
7.65 (m, 2H), 7.85 (m, 2H); MS [M-Br].sup.+: 470; mp 108.degree.
C.
EXAMPLE 101
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[-
2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 170 mg, 74%. .sup.1H-NMR (DMSO-d6):
.delta. 1.45 (m, 1H), 1.65 (m, 1H), 1.85 (m, 2H), 2.1 (m, 1H), 2.9
(m, 3H), 3.15 (m, 1H), 3.3-3.5 (m, 5H), 3.85 (m,1H), 5.05 (m,1H),
6.85 (s, OH), 7.2-7.4 (m, 7H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d,
1H), 7.85 (d, 2H); MS
[M-Br].sup.+: 440; mp 118.degree. C.
EXAMPLE 102
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 460 mg, 96%. .sup.1H-NMR (DMSO-d6):
.delta. 1.42 (m, 1H), 1.66 (m, 1H), 1.80-1.88 (m, 2H), 2.08 (m,
1H), 2.93 (m, 1H), 3.25-3.60 (m, 4H), 3.65 (m, 2H), 3.95 (m, 1H),
4.35 (m 2H), 5.02 (m,1H), 6.85 (s, 1H, OH), 6.97 (d, 2H), 7.04 (t,
1H), 7.20-7.45 (m, 6H), 7.55-7.60 (t, 2H), 7.80 (d, 2H); MS
[M-Br].sup.+: 456; mp 140.degree. C.
EXAMPLE 103
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-az-
oniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 15 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.45 (m, 1H), 1.65 (m, 1H), 1.7-2.0 (m, 4H), 2.1 (m, 1H),
2.75 (m, 1H), 3.0-3.2 (m 4H), 3.25-3.4 (m, 4H), 3.85 (m,1H), 5.05
(m, 1H), 6.85 (s, OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55-7.7 (m,
5H), 7.85 (d, 2H), 8.0 (d, 2H); MS [M-CF.sub.3COO].sup.+: 482.
EXAMPLE 104
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy-
)-1-azoniabicyclo[2.2.2]octane; Chloride
The title compound was synthesised according to methods c and a.
The yield of final step was 440 mg, 94%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 2H), 1.7-1.95 (m, 2H), 2.0-2.1 (m,
3H), 2.8 (m, 1H), 3.1 (d, 1H), 3.2-3.4 (m, 5H), 3.8 (m, 1H), 4.0
(t, 2H), 5.0 (m, 1H), 6.85 (s, OH), 6.95 (m, 2H), 7.15 (t, 2H),
7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d,
2H); MS [M-Br].sup.+: 488; mp 142.degree. C.
EXAMPLE 105
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbony-
loxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 13%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.6-1.9 (m, 3H), 2.1 (m, 3H), 2.8 (m, 1H), 3.1
(d, 1H), 3.2-3.4 (m, 5H), 3.85 (m, 1H), 4.05 (t, 2H), 5.0 (m, 1H),
6.85 (s, OH), 7.05 (t, 1H), 7.15-7.4 (m, 4H), 7.45 (t, 2H), 7.55
(d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-CF.sub.3COO].sup.+:
506.
EXAMPLE 106
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-az-
oniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.6 (m, 1H), 1.8 (m, 4H), 2.05 (m, 1H), 2.7
(m, 1H), 3, 0 (m, 3H), 3.2-3.4 (m, 6H), 3.8 (m, 1H), 5.0 (m, 1H),
5.6 (t, NH), 6.55 (m, 3H), 6.85 (s, OH), 7.1 (t, 2H), 7.35 (dd,
2H), 7.45 (dd, 2H), 7.55 (dd, 2H), 7.8 (d, 2H); MS
[M-CF.sub.3COO].sup.+: 469.
EXAMPLE 107
3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-[3-(4-hydroxyphenoxy)propy-
l]-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 15 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.95-2.05 (m,
2H), 2.1 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H) 3.25-3.4 (m, 5H),
3.8-3.9 (m, 3H), 5.0 (m, 1H), 6.7 (d, 2H), 6.75 (d, 2H), 6.85 (s,
OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85
(d, 2H), 9.0 (s, OH); MS [M-CF.sub.3COO].sup.+: 486.
EXAMPLE 108
1-(2-Benzyloxyethyl)-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoni-
abicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 470 mg, 96%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.7-1.9 (m, 2H), 2.1 (m, 1H),
2.9 (m, 1H), 3.15-3.5 (m, 6H), 3.75 (m, 2H), 3.85 (m, 1H), 4.5 (s,
2H), 5.0 (m, 1H), 6.85 (s, OH), 7.3-7.5 (m, 9H), 7.55 (m, 2H), 7.8
(d, 2H); MS [M-Br].sup.+: 470; mp 86.degree. C.
EXAMPLE 109
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thienyl-2-ylpropyl)-1-azo-
niabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 180 mg, 70%. .sup.1H-NMR (DMSO-d6):
.delta. 1.37 (m, 1H), 1.62 (m, 1H), 1.75-1.95 (m, 4H), 2.06 (m,
1H), 2.72 (m, 1H), 2.80 (m, 2H), 3.02-3.06 (m, 1H), 3.15-3.20 (m,
2H), 3.25-3.40 (m, 3H), 3.80 (m, 1H), 5.0 (m, 1H), 6.85 (s, 1H,
OH), 6.95-7.0 (m, 2H), 7.25-7.50 (m, 5H), 7.55-7.65 (m, 2H), 7.85
(d, 2H); MS [M-Br].sup.+: 460; mp 140.degree. C.
EXAMPLE 110
3(R)--
(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniab-
icyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 80 mg, 40%. .sup.1H-NMR (DMSO-d6):
.delta. 1.35 (m, 1H), 1.6 (m, 1H), 1.7-1.90 (m, 2H), 2.05 (m, 1H),
2.5 (m, 2H), 2.7 (m, 1H), 3.0 (m, 1H), 3.15 (m, 2H), 3.2-3.4 (m,
3H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85 (s, OH), 7.20-7.50 (m, 9H),
7.55 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO].sup.+: 454.
EXAMPLE 111
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicy-
clo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 74 mg, 35%. .sup.1H-NMR (DMSO-d6):
.delta. 1.35 (m, 1H), 1.45-1.65 (m, 5H), 1.7-1.90 (m, 2H), 2.05 (m,
1H), 2.55-2.75 (m, 3H), 3.0 (m, 1H), 3.15-3.45 (m, 5H), 3.75 (m,
1H), 5.0 (m, 1H), 6.85 (s, OH), 7.20 (m, 3H), 7.25-7.35 (m, 4H),
7.45-7.5 (m, 2H), 7.55-7.6 (dd, 2H), 7.85 (d, 2H); MS
[M-CF3COO].sup.+: 468.
EXAMPLE 112
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy-1-(2-thienyl-2-ylethyl)-1-azoni-
abicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 79 mg, 39%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 2.1 (m, 1H),
2.9 (m, 1H), 3.1-3.25 (m, 4H), 3.15-3.45 (m, 5H), 3.85 (m, 1H),
5.05 (m, 1H), 6.85 (s, OH), 7.0 (m, 2H), 7.35 (t, 2H), 7.45-7.5 (m,
3H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS[M-CF3COO].sup.+:
446.
EXAMPLE 113
3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 72 mg, 33%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.55-1.9 (m, 7H), 2.05 (m, 1H), 2.7 (m, 1H),
3.0 (m, 1H), 3.15-3.5 (m, 7H), 3.8 (m, 1H), 4.0 (m, 2H), 5.05 (m,
1H), 6.85 (s, OH), 6.95 (m, 3H), 7.25-7.35 (m, 4H), 7.4-7.45 (m,
2H), 7.6 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO].sup.+: 484.
EXAMPLE 114
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabic-
yclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 200 mg, 76%. .sup.1H-NMR (DMSO-d6):
.delta. 1.54 (m, 1H), 1.70-1.86 (m, 3H), 1.76 (s, 3H), 2.13 (m,
1H), 3.06 (m, 1H), 3.20-3.50 (m, 4H), 3.86 (m, 1H), 4.05 (dd, 2H),
5.02 (m, 1H), 6.43 (dd, 1H), 6.86 (d, 1H), 7.26-7.46 (m, 7H),
7.58-7.65 (m, 3H), 7.70-7.72 (m, 1H), 7.87-7.90 (m, 2H); MS
[M-Br].sup.+: 450; mp 234.degree. C.
EXAMPLE 115
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabi-
cyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 210 mg, 66%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.60-2.0 (m, 3H), 1.76 (s, 3H), 2.12 (m, 1H),
3.10-3.25 (m, 1H), 3.40-3.80 (m, 6H), 4.0 (m, 1H), 4.41 (m, 2H),
4.98 (m, 1H), 6.98-7.05 (m, 3H), 7.27-7.46 (m, 6H), 7.63-7.71 (m,
2H), 7.87-7.90 (m, 2H); MS [M-Br].sup.+: 454; mp 202.degree. C.
EXAMPLE 116
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 210 mg, 61%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.60-2.0 (m, 3H), 1.78 (s, 3H), 2.0-2.20 (m,
3H), 3.0-3.10 (m, 1H), 3.25-3.53 (m, 6H), 3.86 (m, 1H), 4.03 (m,
2H), 4.98 (m, 1H), 6.95-7.0 (m, 3H), 7.30-7.48 (m, 6H), 7.65-7.92
m, 4H); MS [M-Br].sup.+: 468; mp 204.degree. C.
EXAMPLE 117
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2-
.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 18 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.15 (m,
1H), 2.9-3.1 (m, 4H), 3.25-3.55 (m, 5H), 3.85 (m, 1H), 5.05 (m,
1H), 7.25-7.55 (m, 9H), 7.65 (d, 1H), 7.75 (d, 1H), 7.95 (d, 2H);
MS [M-CF.sub.3COO].sup.+: 438.
EXAMPLE 118
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azo-
niabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-2.05 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H)
3.0 (m, 1H), 3.1-3.5 (m, 8H), 3.85 (m, 1H), 7.35-7.5 (m, 4H), 7.55
(t, 2H), 7.65 (t, 2H), 7.7 (d, 1H), 7.9 (d, 2H), 8.0 (d, 2H); MS
[M-CF.sub.3COO].sup.+: 480.
EXAMPLE 119
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-
-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 23 mg, 23%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.15
(m, 3H), 3.0 (m, 1H), 3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t, 2H),
5.0 (m, 1H), 6.95 (m, 2H), 7.15 (t, 2H), 7.35-7.5 (m, 4H), 7.65 (d,
1H), 7.75 (d, 1H), 7.9 (d, 2H); MS [M-CF.sub.3COO].sup.+: 486.
EXAMPLE 120
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9H-fluorene-9-carbonylox-
y)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 20 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.2 (m,
3H), 3.0 (m, 1H), 3.25-3.55 (m, 6H), 3.85 (m, 1H), 4.1 (t, 2H), 5.0
(m, 1H), 7.05 (t, 1H), 7.2-7.5 (m, 6H), 7.65 (d, 1H), 7.75/d, 1H),
7.9 (d, 2H); MS [M-CF.sub.3COO].sup.+: 504.
EXAMPLE 121
3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azo-
niabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H),
2.95 (m, 1H), 3.05 (m, 2H), 3.15-3.45 (m, 6H), 3.8 (m, 1H), 5.0 (m,
1H), 5.65 (t, NH), 6.6 (m, 3H), 7.1 (t, 2H), 7.35-7.55 (m, 4H),
7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H); MS [M-CF.sub.3COO].sup.+:
467.
EXAMPLE 122
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy-
)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 22 mg, 22%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.9 (m, 3H), 1.75 (s, 3H), 2.0-2.15 (m,
3H), 3.0 (m, 1H), 3.25-3.5 (m, 6H), 3.8-3.95 (m, 3H), 5.0 (m, 1H),
6.7 (d, 1H), 6.75 (d, 1H), 7.35-7.45 (m, 4H), 7.65 (d, 1H), 7.75
(d, 1H), 7.9 (d, 2H), 9.0 (s, OH); MS [M-CF.sub.3COO].sup.+:
484.
EXAMPLE 123
1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 17 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 4H), 1.75 (s, 3H), 2.15 (m,
1H), 3.1 (m, 1H), 3.3-3.55 (m, 6H), 3.8-3.95 (m, 3H), 4.5 (s, 2H),
5.0 (m, 1H), 7.3-7.5 (m, 9H), 7.6-7.7 (m, 2H), 7.9 (d, 2H); MS
[M-CF.sub.3COO].sup.+: 468.
EXAMPLE 124
3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2-
.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 420 mg, 89%. .sup.1H-NMR (DMSO-d6):
.delta. 1.55 (m, 1H), 1.65-1.95 (m, 3H), 2.15 (m, 1H), 2.95 (m,
2H), 3.15 (m, 1H), 3.25-3.60 (m, 6H), 3.85 (m, 1H), 3.95-4.15 (dd,
2H, J1=1.8 Hz, J2=4.2 Hz), 5.02 (m, 1H), 5.25 (s, 1H), 7.25-7.43
(m, 11H), 7.48-7.55 (m, 2H); MS [M-Br].sup.+: 438; mp 216.degree.
C.
EXAMPLE 125
3(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 450 mg, 82%. .sup.1H-NMR (DMSO-d6):
.delta. 1.56 (m, 1H), 1.65-1.95 (m, 3H), 2.05-2.15 (m, 3H), 3.10
(m, 1H), 3.20-3.50 (m, 6H), 3.80 (m, 1H), 3.94-4.14 (m, 4H), 5.0
(m, 1H), 5.22 (s, 1H), 6.94-7.0 (m, 3H), 7.25-7.35 (m, 6H), 7.40
(m, 2H), 7.54-7.47 (m, 2H); MS [M-Br].sup.+: 468; mp 157.degree.
C.
EXAMPLE 126
1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-azoniabicyclo[2.2.2]-
octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 83 mg, 21%. .sup.1H-NMR (DMSO-d6):
.delta. 1.50-2.0 (m, 8H), 2.15 (m, 1H), 2.65 (m, 2H), 3.05-3.65 (m,
7H), 3.80 (m, 1H), 5.0 (m, 1H), 5.30 (s, 1H), 7.10-7.45 (m, 11H),
7.45-7.60 (m, 2H); MS [M-Br].sup.+: 468; mp 95.degree. C.
EXAMPLE 127
1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2-
.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 300 mg, 73%. .sup.1H-NMR (DMSO-d6):
.delta. 1.70-2.0 (m, 4H), 2.2 (m, 1H), 3.20-3.80 (m, 7H), 4.0 (m,
1H), 4.40 (m, 2H), 5.05 (m, 1H), 5.30 (s, 1H), 7.0-7.10 (m, 7H),
7.30-7.45 (m, 4H), 7.45-7.55 (m, 2H); MS [M-Br].sup.+: 456; mp
200.degree. C.
EXAMPLE 128
1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.-
2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 350 mg, 83%. .sup.1H-NMR (DMSO-d6):
.delta. 1.70-2.0 (m, 4H), 2.0-2.25 (m, 3H), 3.15-3.65 (m, 7H),
3.85-3.95 (m, 1H), 3.95-4.10 (m, 2H), 5.0 (m, 1H), 5.30 (s, 1H),
6.90-7.0 (m, 3H), 7.10-7.25 (m, 4H), 7.25-7.40 (m, 4H), 7.40-7.60
(m, 2H); MS [M-Br].sup.+: 470; mp 184.degree. C.
EXAMPLE 129
1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo
[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 100 mg, 44%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 4H), 2.1 (m, 1H), 2.9-3.05 (m, 2H), 3.15-3.6
(m, 7H), 3.85 (m, 1H), 5.05 (m, 1H), 5.3 (s, 1H)), 7.15-7.55 (m,
13H); MS [M-Br].sup.+: 440.
EXAMPLE 130
1-(4-Oxo-4-phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicycl-
o[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.05 (m, 6H), 2.1 (m, 1H), 3.1-3.55 (m, 9H), 3.8 (m,
1H), 5.05 (m, 1H), 5.25 (s, 1H), 7.1-7.3 (m, 4H), 7.35 (t, 2H),
7.45-7.6 (m, 4H), 7.7 (d, 1H), 8.0 (d, 1H); MS
[M-CF.sub.3COO].sup.+: 482.
EXAMPLE 131
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azonia-
bicyclo[2.2.2]octane, Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 18 mg, 18%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.1 (m, 6H), 2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.8 (m,
1H), 4.0 (t, 2H), 5.0 (m, 1H), 5.3 (s, 1H), 6.95 (m, 2H), 7.1-7.3
(m, 6H), 7.4 (t, 2H), 7.5 (dd, 2H); MS [M-CF.sub.3COO].sup.+:
488.
EXAMPLE 132
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-az-
oniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 14 mg, 14%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-1.95 (m, 4H), 2.05-2.2 (m, 3H), 3.1-3.55 (m, 7H), 3.8
(m, 1H), 4.05 (t, 2H), 5.0 (m, 1H), 5.3 (s, 1H), 7.05 (t, 1H),
7.1-7.55 (m, 10H); MS [M-CF.sub.3COO].sup.+: 506.
EXAMPLE 133
1-(3-Phenylaminopropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicycl-
o[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 17 mg, 17%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-2.0 (m, 6H), 2.15 (m, 1H), 3.0-3.5 (m, 9H), 1.75 (m,
1H), 5.0 (m, 1H), 5.3 (s, 1H), 6.65 (t, NH), 6.55 (m, 3H), 0.05-7.3
(m, 6H), 7.35-7.55 (m, 4H); MS [M-CF.sub.3COO].sup.+: 469.
EXAMPLE 134
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoni-
abicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 21 mg, 20%. .sup.1H-NMR (DMSO-d6):
.delta. 1.7-2.1 (m, 6H), 2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.7-3.95
(m, 3H), 5.0 (m, 1H), 5.3 (s, 1H), 6.7 (d, 2H), 6.75 (d, 2H),
7.1-7.3 (m, 4H), 7.35-7.55 (m, 4H), 9.0 (s, OH); MS
[M-CF.sub.3COO].sup.+: 486.
EXAMPLE 135
1-(2-Benzyloxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2-
.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods d and b.
The yield of final step was 16 mg, 16%. .sup.1H-NMR (DMSO-d6):
.delta. 1.65-1.95 (m, 4H), 2.1 (m, 1H), 3.1-3.9 (m, 10H), 4.5 (s,
2H), 5.0 (m, 1H), 5.3 (s, 1H), 7.15 (m, 4H), 7.3-7.5 (m, 7H), 7.55
(t, 2H); MS [M-CF.sub.3COO].sup.+: 470.
EXAMPLE 136
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azonia-
bicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 340 mg, 71%. .sup.1H-NMR (DMSO-d6):
.delta. 1.30 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.10
(m, 3H), 2.70 (m, 1H), 2.90 (m, 1H), 3.2-3.5 (m, 5H), 3.80 (m, 1H),
4.0 (t, 2H), 5.05 (m, 1H), 6.90-7.0 (m, 3H), 7.20-7.35 (m, 7H),
7.40-7.46 (m, 2H), 7.65-7.70 (m, 2H); MS [M-Br].sup.+: 486; mp
219.degree. C.
EXAMPLE 137
3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[-
2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 290 mg, 64%. .sup.1H-NMR (DMSO-d6):
.delta. 1.32 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.1 (m, 1H),
2.75-2.90 (m, 3H), 3.05 (m, 1H), 3.30-3.50 (m, 5H), 3.82 (m, 1H),
5.05 (m, 1H), 7.20-7.40 (m, 10H), 7.40-7.50 (m, 2H), 7.65-7.70 (m,
2H); MS [M-Br].sup.+: 456; mp 221.degree. C.
EXAMPLE 138
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoni-
abicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 310 mg, 97%. .sup.1H-NMR (DMSO-d6):
.delta. 1.30 (m, 1H), 1.62 (m, 1H), 1.70-1.90 (m, 4H), 2.05 (m,
1H), 2.60 (m, 1H), 2.75-2.85 (m, 4H), 3.15 (m, 2H), 3.25-3.40 (m,
2H), 3.75 (m, 1H), 5.0 (m, 1H), 6.93 (m, 1H), 7.0 (m, 1H),
7.14-7.26 (m, 5H), 7.36-7.45 (m, 3H), 7.63-7.67 (m, 2H); MS
[M-Br].sup.+: 476; mp 111.degree. C.
EXAMPLE 139
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 85 mg, 41%. .sup.1H-NMR (DMSO-d6):
.delta. 1.30 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.05 (m,
1H), 2.5-2.6 (m, 2H), 2.80 (m, 1H), 3.05-3.75 (m, 7H), 5.05 (m,
1H), 7.1-7.45 (m, 12H), 7.65-7.70 (m, 2H); MS [M-CF3COO].sup.+:
470.
EXAMPLE 140
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicy-
clo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 84 mg, 38%. .sup.1H-NMR (DMSO-d6):
.delta. 1.30 (m, 1H), 1.4-1.85 (m, 7H), 2.05 (m, 1H), 2.5-2.6 (m,
2H), 2.80 (m, 1H), 3.05-3.4 (m, 6H), 3.7 (m, 1H), 5.05 (m, 1H),
7.15-7.35 (m, 10H), 7.4 (m, 1H), 7.65 (m, 2H); MS [M-CF3COO].sup.+:
484.
EXAMPLE 141
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-thien-2-ylethyl)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 81 mg, 39%. .sup.1H-NMR (DMSO-d6):
.delta. 1.30 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.05 (m, 1H),
2.75 (m, 1H), 3.0 (m, 1H), 3.1-3.2 (m, 2H), 3.3-3.6 (m, 5H), 3.8
(m, 1H), 5.05 (m, 1H), 6.95-7.0 (m, 2H), 7.15-7.3 (m, 5H), 7.45 (m,
3H), 7.65 (m, 2H); MS [M-CF3COO].sup.+: 462.
EXAMPLE 142
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 83 mg, 37%. .sup.1H-NMR (DMSO-d6):
.delta. 1.3 (m, 1H), 1.5-1.9 (m, 7H), 2.05 (m, 1H), 2.6 (m, 1H),
2,8 (m, 1H), 3.1-3.45 (m, 7H), 3.75 (m, 1H), 4.0 (m, 2H), 5.05
(m,1H), 6.95-7.0 (m, 3H), 7.15-7.45 (m, 9H), 7.65 (m, 2H); MS
[M-CF3COO].sup.+: 500.
EXAMPLE 143
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabic-
yclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 102 mg, 48%. .sup.1H-NMR (DMSO-d6):
.delta. 1.3 (m, 1H), 1.55-1.95 (m, 3H), 2.05 (m, 1H), 2,8 (m, 1H),
3.1 (m, 1H), 3.35-3.65 (m, 5H), 3.9 (m, 1H), 4.35 (m, 2H), 5.05 (m,
1H), 6.95 (d, 2H), 7.0-7.1 (m, 2H), 7.2 (m, 4H), 7.3-7.45 (m, 4H),
7.6 (t, 2H); MS [M-CF3COO].sup.+: 472.
EXEMPLE 144
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9H-xanthene-9-carbonyloxy)--
1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 99 mg, 44%. .sup.1H-NMR (DMSO-d6):
.delta. 1.3 (m, 1H), 1.6 (m, 1H), 1.7-2.0 (m, 4H), 2.05 (m, 1H),
2.7 (m, 1H), 2.9 (m, 1H), 3.2-3.5 (m, 5H), 3.75-3.85 (m,1H), 3.95
(m, 2H), 5.0 (m,1H), 6.95 (m, 2H), 7.1-7.3 (m, 7H), 7.45 (t, 2H),
7.65 (t, 2H); MS [M-CF3COO].sup.+: 504.
EXEMPLE 145
3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicy-
clo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 25 mg, 12%. .sup.1H-NMR (DMSO-d6):
.delta. 1.25-1.30 (m, 1H), 1.55-1.95 (m, 3H), 2.10 (m, 1H),
2.65-2.75 (m, 1H), 2.9 (m, 1H), 3.25-3.50 (m, 2H), 3.75-3.8 (m,1H),
3.95 (m, 2H), 4.2 (d, 1H), 5.0 (m, 1H), 6.35 (m, 1H), 6.80 (d, 1H),
7.05-7.50 (m, 8H), 7.60 (m, 4H); MS [M-CF3COO].sup.+: 468.
EXAMPLE 146
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniab-
icyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods c and a.
The yield of final step was 110 mg. .sup.1H-NMR (DMSO-d6): .delta.
1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H),
2.05-2.15 (m, 3H), 1.8 (m, 1H), 3.15 (m, 2H), 3.25-3.5 (m, 5H),
3.85 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H), 6.95-7.0 (m, 3H), 7.15-7.2
(m, 4H), 7.3-7.4 (m, 4H), 7.45 (d, 1H), 7.55 (d, 1H); MS
[M-Br].sup.+: 484; mp 195.degree. C.
EXAMPLE 147
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2-
.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 20%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H),
2.15 (m, 1H), 2.8-2.95 (m, 3H), 3.15 (d, 1H), 3.3-3.5 (m, 5H), 4.9
(m, 1H), 5.1 (m, 1H), 7.15 (m, 4H), 7.25-7.4 (m, 7H), 7.45 (d, 1H),
7.55 (d, 1H); MS [M-CF.sub.3COO].sup.+: 454.
EXAMPLE 148
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabi-
cyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 24 mg, 24%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H),
2.15 (m, 1H), 2.95 (m, 1H), 3.25 (m, 1H), 3.4-3.65 (m, 5H), 3.85
(m, 1H), 4.35 (t, 2H), 5.05 (m, 1H), 6.95 (d, 2H), 7.05 (t, 2H),
7.15 (m, 3H), 7.25-7.45 (m, 6H); MS [M-CF.sub.3COO].sup.+: 470.
EXAMPLE 149
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azo-
niabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 19%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 7H), 2.15 (m, 1H),
2.8 (m, 1H), 3.05-3.25 (m, 4H), 3.3-3.5 (m, 4H), 3.85 (m, 1H), 5.05
(m, 1H), 7.15 (m, 4H), 7.35 (t, 2H), 7.45-7.6 (m, 4H), 7.7 (t, 1H),
8.0 (d, 2H); MS [M-CF.sub.3COO].sup.+: 496.
EXAMPLE 150
1-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-
-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 25 mg, 24%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H),
1-95-2.1 (m, 2H), 2.15 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5
(m, 5H), 3.8 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H), 6.95 (m, 2H), 7.15
(m, 6H), 7.35 (t, 2H), 7.5 (dd, 2H); MS [M-CF.sub.3COO].sup.+:
502.
EXAMPLE 151
1-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyl-
oxy)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H),
2.0-2.15 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 7.05 (t, 1H), 7.1-7.4
(m, 8H), 7.5 (dd, 2H); MS [M-CF.sub.3COO].sup.+: 520.
EXAMPLE 152
3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azo-
niabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 16 mg, 15%. .sup.1H-NMR (DMSO-d6):
.delta. 1.35 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 4H), 1.9 (s, 3H),
2.1 (m, 1H), 2.7 (m, 1H), 2.95-3.05 (m, 3H), 3.1-3.4 (m, 6H), 3.75
(m, 1H), 5.0 (m, 1H), 5.6 (m, 1H), 6.55 (m, 3H), 7.05-7.15 (m, 6H),
7.3 (m, 2H), 7.45 (t, 2H); MS [M-CF.sub.3COO].sup.+: 483.
EXAMPLE 153
1-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy-
)-1-azoniabicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 19 mg, 18%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 2.75-2.05 (m, 4H), 1.9 (s, 3H),
2.15 (m, 1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8-3.95
(m, 3H), 5.05 (m, 1H), 6.65-6.8 (m, 4H), 7.2 (m, 4H), 7.35 (t, 2H),
7.5 (m, 2H), 9.0 (s, OH); MS [M-CF.sub.3COO].sup.+: 500.
EXAMPLE 154
1-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azonia-
bicyclo[2.2.2]octane; Trifluoroacetate
The title compound was synthesised according to methods c and b.
The yield of final step was 14 mg, 14%. .sup.1H-NMR (DMSO-d6):
.delta. 1.4 (m, 1H), 1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H),
2.1 (m, 1H), 2.9 (m, 1H), 3.2-3.5 (m, 6H), 3.75-3.95 (m, 3H), 4.5
(s, 2H), 5.05 (m, 1H), 7.15 (m, 4H), 7.3-7.5 (m, 9H); MS
[M-CF.sub.3COO].sup.+: 484.
EXAMPLE 155
1-(3-Phenoxypropyl)-3(R)-(9[H]-thioxanthene-9-carbonyloxy)-1-azonia-bicyc-
lo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 323 mg, 50%. .sup.1H-NMR (DMSO-d6):
.delta. 1.35 (m, 1H), 1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.0-2.2 (m,
3H), 2.75-2.90 (m, 1H), 3,12 (m, 1H), 3.25-3.50 (m, 5H), 3.80 (m,
1H), 4.0 (t, 2H), 5.0 (m, 1H), 5.6 (s, 1H), 6.94-7.0 (m, 3H),
7.22-7.41 (m, 6H), 7.45-7.64 (m, 4H); MS [M-Br].sup.+: 486; mp
157.degree. C.
EXAMPLE 156
1-(3-phenylallyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbo-
nyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 250 mg, 94%. .sup.1H-NMR (CDCl3):
.delta. 1.50-1.60 (m, 1H), 1.60-1.80 (m, 1H), 1.90 (m, 2H), 2.30
(m, 1H), 2.65-2.80 (m, 2H), 2.90-3.20 (m, 3H), 3.50 (d, 1H),
3.60-3.90 (m, 3H), 4.20 (m, 1H), 4.35-4.60 (doble dd, 2H), 5.10 (m,
1H), 5.15 (s, 1H), 6.05 (dd, 1H), 6.90-7.0 (m, 2H), 7.0-7.5 (m,
11H); MS [M-Br].sup.+: 464; mp 132.degree. C.
EXAMPLE 157
1-(3-phenoxypropyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-car-
bonyloxy)-1-azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 290 mg, 94%. .sup.1H-NMR (CDCl3):
.delta. 1.45-1.60 (m, 1H), 1.65-1.80 (m, 1H), 1.80-2.0 (m, 2H),
2.0-2.20 (m, 3H), 2.80-3.0 (m, 3H), 3.15-3.30 (m, 2H), 3.30-3.45
(d, 1H), 3.45-3.80 (m, 5H), 3.85-4.0 (m, 2H), 4.20 (m, 1H), 5.10
(m, 1H), 5.20 (s, 1H), 6.80-6.90 (d, 2H), 6.90-7.0 (t, 1H),
7.10-7.30 (m, 8H), 7.40 (m, 2H); MS [M-Br].sup.+: 482; mp
182.degree. C.
EXAMPLE 158
3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-(3-phenoxypropyl)-1--
azoniabicyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 180 mg, 56%. .sup.1H-NMR (DMSO-d6):
.delta. 1.2 (m, 1H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.95 (m, 1H),
2.1 (m, 2H), 2.8 (m, 1H), 2.95 (d, 1H), 3.25-3.45 (m, 5H), 3.8 (m,
1H), 4.05 (t, 2H), 4.9 (m, 1H), 5.45 (s, 1H), 6.9-7.1 (m, 5H),
7.3-7.5 (m, 9H), 7.55 (d, 2H); MS [M-Br].sup.+: 480; mp 1111C.
EXAMPLE 159
3(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-phenethyl-1-azoniabi-
cyclo[2.2.2]octane; Bromide
The title compound was synthesised according to methods d and a.
The yield of final step was 210 mg, 68%. .sup.1H-NMR (DMSO-d6):
.delta. 1.2 (m, 1H), 1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.85-3.1 (m,
4H), 3.3-3.5 (m, 5H), 3.85 (m, 1H), 4.95 (m, 1H), 5.45 (s, 1H),
7.05 (m, 2H), 7.25-7.5 (m, 11H), 7.55 (m, 2H); MS [M-Br].sup.+:
450; mp 2481C.
The Examples 160 to 164 illustrate pharmaceutical compositions
according to the present invention and procedure for their
preparation.
EXAMPLE 160
TABLE-US-00002 Preparation of a pharmaceutical composition: tablets
Formulation: Compound of the present invention 5.0 mg Lactose 113.6
mg Microcrystalline cellulose 28.4 mg Light silicic anhydride 1.5
mg Magnesium stearate 1.5 mg
Using a mixer machine, 15 g of the compound of the present
invention was mixed with 340.8 g of lactose and 85.2 g of
microcrystalline cellulose. The mixture was subjected to
compression moulding using a roller compactor to give a flake-like
compressed material. The flake-like compressed material was
pulverized using a hammer mill, and the pulverized material was
screened through a 20 mesh screen. A 4.5 g portion of light silicic
anhydride and 4.5 g of magnesium stearate were added to the
screened material and mixed. The mixer product was subjected to a
tablets making machine equipped with a die/punch system of 7.5 mm
in diameter, thereby obtaining 3,000 tablets each having 150 mg in
weight.
EXAMPLE 161
TABLE-US-00003 Preparation of a pharmaceutical composition: tablets
coated Formulation: Compound of the present invention 5.0 mg
Lactose 95.2 mg Corn starch 40.8 mg Polyvinylpyrrolidone K25 7.5 mg
Magnesium stearate 1.5 mg Hydroxypropylcellulose 2.3 mg
Polyethylene glycol 6000 0.4 mg Titanium dioxide 1.1 mg Purified
talc 0.7 mg
Using a fluidized bed granulating machine, 15 g of the compound of
the present invention was mixed with 285.6 g of lactose and 122.4 g
of corn starch. Separately, 22.5 g of polyinylpyrrolidone was
dissolved in 127.5 g of water to prepare a binding solution. Using
a fluidized bed granulating machine, the binding solution was
sprayed on the above mixture to give granulates. A 4.5 g portion of
magnesium stearate was added to the obtained granulates and mixed.
The obtained mixture was subjected to a tablet making machine
equipped with a die/punch biconcave system of 6.5 mm in diameter,
thereby obtaining 3,000 tablets, each having 150 mg in weight.
Separately, a coating solution was prepared by suspending 6.9 g of
hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol
6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6
g of water. Using a High Coated, the 3,000 tablets prepared above
were coated with the coating solution to give film-coated tablets,
each having 154.5 mg in weight.
EXAMPLE 162
TABLE-US-00004 Preparation of a pharmaceutical composition: liquid
inhalant Formulation: Compound of the present invention 400 .PHI.g
Physiological saline 1 ml
A 40 mg portion of the compound of the present invention was
dissolved in 90 ml of physiological saline, and the solution was
adjusted to a total volume of 100 ml with the same saline solution,
dispensed in 1 ml portions into 1 ml capacity ampoule and then
sterilized at 1151 for 30 minutes to give liquid inhalant.
EXAMPLE 163
TABLE-US-00005 Preparation of a pharmaceutical composition: powder
inhalant Formulation: Compound of the present invention 200 .PHI.g
Lactose 4,000 .PHI.g
A 20 g portion of the compound of the present invention was
uniformly mixed with 400 g of lactose, and a 200 mg portion of the
mixture was packed in a powder inhaler for exclusive use to produce
a powder inhalant.
EXAMPLE 164
TABLE-US-00006 Preparation of a pharmaceutical composition:
inhalation aerosol. Formulation: Compound of the present invention
200 .PHI.g Dehydrated (Absolute) ethyl alcohol USP 8,400 .PHI.g
1,1,1,2-Tetrafluoroethane (HFC-134A) 46,810 .PHI.g
The active ingredient concentrate is prepared by dissolving 0.0480
g of the compound of the present invention in 2.0160 g of ethyl
alcohol. The concentrate is added to an appropriate filling
apparatus. The active ingredient concentrate is dispensed into
aerosol container, the headspace of the container is purged with
Nitrogen or HFC-134A vapor (purging ingredients should not contain
more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of
HFC-134A propellant is then pressure filled into the sealed
container.
* * * * *
References