Patent Application
20090182033
This invention relates to bicyclo[2.2.1]hept-2-ylamine derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of M3 muscarinic receptor mediated diseases, for example respiratory diseases.
Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.
There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1-M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319-379).
In the lungs, muscarinic receptors M1, M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit. Care Med., 158 (5 part 3) S 154-160). M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.
Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev Respir Dis; 129:856-870). In addition, inflammatory conditions can lead to a loss of inhibitory M2 receptor activity which results in increased levels of acetylcholine release following vagal nerve stimulation (Fryer et al, 1999, Life Sci., 64, (6-7) 449-455). The resultant increased activation of M3 receptors leads to enhanced airway obstruction. Thus the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where enhanced M3 receptor activity is implicated. Indeed, contemporary treatment strategies currently support regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al. 2001, Am Rev Respir Crit. Care Med; 163:1256-1276)
Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs. Thus M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of airway disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 muscarinic receptors, especially those compounds with a long duration of action, enabling a once-daily dosing regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to deliver anticholinergic drugs directly to the respiratory tract is advantageous as it allows lower doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that are retained on the receptor or in the lung would allow reduction of unwanted side effects that could be seen with systemic administration of the same drugs.
Tiotropium (Spiriva™) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.
Additionally ipratropium is a muscarinic antagonist marketed for the treatment of COPD.
Other muscarinic receptor modulators have been referred to. For example: U.S. Pat. No. 4,353,922 describes muscarinic modulators based upon a [2.2.1]azabicycloheptane ring system. EP418716 and US005610163 describe various [3.2.1]azabicyclooctane ring systems. WO06/017768 describes [3.3.1]azabicyclononane ring systems. [2.2.2]azabicyclooctane systems (quinuclidines) have been previously described, for example in US2005/0209272 and WO06/048225. [3.1.0]azabicyclohexane systems have been described in, for example in WO06/035282. [3.2.1]azabicyclooctane systems have been described in for example WO06/035303.
According to the invention, there is provided a compound of formula (I):
wherein
R1 is C1-C6-alkyl or a hydrogen atom; and R2 is a hydrogen atom or a group —R5, or a group, -Z-Y—R5, or a group -Z-NR9R10, or a group -Z-N(R9)C(O)R11; and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
R4 is selected from one of the groups of formula (a), (b), (c) or (d);
Z is a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group;
Y is a bond or oxygen atom;
R5 is an C1-C6-alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group;
R6 is C1-C6-alkyl or a hydrogen atom;
R7a and R7b are a C1-C6-alkyl group or halogen;
n and m are independently 0, 1, 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl and hydrogen;
R8c is —OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, or a hydrogen atom;
R9 and R10 are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)-group; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;
R11 is C1-C6-alkyl or a hydrogen atom;
Ar1 is aryl, heteroaryl or cycloalkyl;
Ar2 are independently aryl, heteroaryl or cycloalkyl; and
Q is an oxygen atom, —CH2—, —CH2CH2— or a bond;
or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof.
In one subset of the compounds of the invention:
R1 is C1-C6-alkyl or a hydrogen atom and R2 is C1-C6-alkyl, a hydrogen atom or a group -Z-Y—R5, or a group -Z-NR9R10;
R3 is a lone pair; or C1-C6-alkyl, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
R4 is selected from one of the groups of formula (a) or (b) or (c):
Z is a C1-C8-alkylene group;
Y is a bond or oxygen atom;
R5 is an aryl or aryl(C1-C8-alkyl)-group;
R6 is C1-C6-alkyl or a hydrogen atom;
R7a and R7b are independently a C1-C6-alkyl group or halogen;
n and m are independently 0, 1, 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, heteroaryl, C1-C6-alkyl, cycloalkyl and hydrogen;
R8c is —OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, or a hydrogen atom;
R9 and R10 are independently a hydrogen atom, C1-C6-alkyl, aryl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)-group; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom.
Compounds of the invention exist in either the syn- or anti-forms;
Compounds of the invention also exist with the group —NR1R2R3 in either the exo or endo orientation;
Currently it is preferred that the compounds of the invention be predominantly in the anti-endo configuration.
Compounds of the invention can also exist as optical isomers since substituted bicyclic ring systems can lack a plane of symmetry. The absolute configuration of the molecule can be defined using Cahn-Ingold-Prelog rules to assign the R or S designation to each position. To avoid confusion the ring numbering used below is employed.
However, compounds of the invention include racemates, single enantiomers and mixtures of the enantiomers in any ratio, since all such forms have muscarinic M3 receptor modulating activity to varying extents.
A preferred class of compounds of the invention consists of quaternary ammonium salts of formula (I) wherein the nitrogen shown in formula (I) is quaternary nitrogen, carrying a positive charge.
Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; ‘wheezy-infant syndrome’), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis);
gastrointestinal-tract disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and
cardiovascular disorders such as vagally induced sinus bradycardia.
For treatment of respiratory conditions, administration by inhalation will often be preferred, and in such cases administration of compounds (I) which are quaternary ammonium salts will often be preferred. In many cases, the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose. For treatment of gastrointestinal-tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be preferred.
Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient.
Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated.
Unless otherwise qualified in the context in which they are used herein, the following terms have the following meanings:
R1 is C1-C6-alkyl or a hydrogen atom; and R2 is a hydrogen atom or a group —R5, or a group, -Z-Y—R5, or a group -Z-NR9R10; or a group -Z-N(R9)C(O)R11 and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is quaternary nitrogen and carries a positive charge;
Where a group -R5, or a group -Z-Y—R5, or a group -Z-NR9R10, or a group -Z-N(R9)C(O)R11 is present in R2:
Currently preferred are compounds of the invention wherein, in the group —NR1, R2R3, R1 is methyl or ethyl, R2 is a group -Z-Y—R5 as discussed above, especially wherein R5 is a cyclic lipophilic group such as phenyl, Y is a bond or —O—, and -Z- is a straight or branched alkylene radical linking the nitrogen and —YR5 by a chain of up to 12, for example up to 9, carbon atoms, and R3 is methyl, so that the nitrogen is quaternised and carries a positive charge.
R4 is selected from one of the groups of formula (a), (b), (c) or (d);
In the group (a), R6 may be C1-C6-alkyl such as methyl or ethyl or a hydrogen atom; Ar1 may be an aryl group such as phenyl, a heteroaryl group such as thienyl, especially 2-thienyl, or a cycloalkyl group such as cyclohexyl, cyclopentyl, cyclopropyl, or cyclobutyl; ring substituents R7a and R7b may be independently a C1-C6-alkyl group, such as methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl, or halogen such as fluoro, chloro or bromo; and m and n may be independently 0, 1, 2 or 3.
In the groups (b) and (d), R8a and R8b may be independently selected from any of those aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, C1-C6-alkyl, or cycloalkyl groups specifically mentioned in the discussion of R5 above. Additionally, R8b may also be a hydrogen atom. R8c may be —OH, a hydrogen atom, C1-C6-alkyl such as methyl or ethyl, or hydroxy-C1-C6-alkyl such as hydroxymethyl. Presently preferred is the case where R8c is —OH. Preferred combinations of R8a and R8b, especially when R8a is —OH, include those wherein (i) each of R8a and R8b is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, oxazolyl, thiazolyl, furyl and especially thienyl such a 2-thienyl; (ii) R8a and R8b are both optionally substituted phenyl; (iii) one of R8a and R8b is optionally substituted phenyl and the other is cycloalkyl such as cyclopropyl, cyclobutyl, cycloheptyl, cyclooctyl or especially cyclopentyl or cyclohexyl; and (iv) one of R8a and R8b is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, thienyl, oxazolyl, thiazolyl, or furyl; and the other is cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
In the group (c), R8c may be —OH, a hydrogen atom, C1-C6-alkyl such as methyl or ethyl, or hydroxy-C1-C6-alkyl such as hydroxymethyl. Presently preferred is the case where R8c is —OH. Each Ar2 is an aryl, heteroaryl or cycloalkyl ring and may be, for example, any of those aryl, heteroaryl, C1-C6-alkyl, or cycloalkyl rings specifically mentioned in the discussion of R5 above. Preferred Ar2 rings include phenyl. The bridge -Q between the two Ar2 rings is —O—, —CH2— or —CH2CH2—.
Of the R4 options (a), (b), (c) and (d), it is presently preferred that R4 be a group (a) or (b) or (c).
A preferred subclass of compounds with which the invention is concerned consists of those of formula (IA)
wherein ring A is an optionally substituted phenyl ring, or a monocyclic heterocyclic ring of 5 or 6 ring atoms, or a phenyl-fused-heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R8a is phenyl, thienyl, cyclopentyl or cyclohexyl; R8b is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 10; Y is a bond or —O—, and X− is a pharmaceutically acceptable anion. In compounds (IA), it is currently preferred that ring A is optionally substituted phenyl, wherein optional substituents are selected from alkoxy, halo especially fluoro or chloro, C1-C3-alkyl, amino C1-C3-acyl, amino C1-C3-alkyl, and aminosulfonyl.
Another preferred subclass of compounds with which the invention is concerned consists of those of formula (IB)
wherein ring B is an optionally substituted phenyl ring or a monocyclic heterocyclic ring of 5 or 6 ring atoms or an aryl-fused heterocycloalkyl ring; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 10; Y is a bond or —O—; and R6, Ar1, R7a and R7b are as defined for group (a) above; and X− is a pharmaceutically acceptable anion. In compounds (IB), it is currently preferred that ring B is (i) optionally substituted phenyl, wherein optional substituents are selected from alkoxy, halo especially fluoro or chloro, C1-C3-alkyl, amino C1-C3-acyl, amino C1-C3-alkyl, and aminosulfonyl;
Another preferred subclass of compounds with which the invention is concerned consists of those of formula (IC)
wherein ring C is an optionally substituted phenyl ring or a monocyclic heterocyclic ring of 5 or 6 ring atoms or an aryl-fused heterocycloalkyl ring; Q is an oxygen atom, —CH2—, —CH2CH2— or a bond; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 provided that s+t is not greater than 10 and Y is a bond or —O—; and X− is a pharmaceutically acceptable anion. In compounds (IC), it is currently preferred that ring C is optionally substituted phenyl, wherein optional substituents are selected from alkoxy, halo especially fluoro or chloro, C1-C3-alkyl, amino C1-C3-acyl, amino C1-C3-alkyl, and aminosulfonyl;
In subclasses (IA), (IB) and (IC), s+t may be, for example 1, 2, 3, 4, 5, 6, or 7 and may arise from suitable combinations of t and s such as where t is 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7. In compounds (IA), (IB) and (IC), a currently preferred combination of t, Y and s is where t is 0, s is 3, and Y is —O—. A further currently preferred combination is where Y is a bond and s+t is 2, 3 or 4.
In subclasses (IA), (IB) and (IC) as in the compounds of the invention generally, compounds predominantly in the anti-endo configuration are preferred.
Examples of compounds of the invention include those of the Examples herein.
The present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously. Preferred combinations would have two or three different pharmaceutical compositions. Suitable therapeutic agents for a combination therapy with compounds of the invention include:
One or more other bronchodilators such as PDE3 inhibitors;
Methyl xanthines such as theophylline;
Other muscarinic receptor antagonists;
A corticosteroid, for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181, WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920;
A non-steroidal glucocorticoid receptor agonist;
A β2-adrenoreceptor agonist, for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901, GSK-159802, GSK-64244, GSK-678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651, US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/016601, WO04/22547, WO04/32921, WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762, WO04/39766, WO04/45618, WO04/46083, WO04/71388, WO04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167, US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121, WO05/040103, WO05/044787, WO04/071388, WO05/058299, WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841, WO05/092860, WO05/092887, WO05/092861, WO05/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091, US20050171147, WO05/092870, WO05/077361, DE10258695, WO05/111002, WO05/111005, WO05/110990, US2005/0272769 WO05/110359, WO05/121065, US2006/0019991, WO06/016245, WO06/014704, WO06/031556, WO06/032627, US2006/0106075, US2006/0106213, WO06/051373, WO06/056471;
A leukotriene modulator, for example montelukast, zafirlukast or pranlukast;
protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333;
Human neutrophil elastase inhibitors, such as sivelestat and those described in WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701, WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930;
Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cilomilast, ONO-6126 or IC-485;
Phosphodiesterase-7 inhibitors;
An antitussive agent, such as codeine or dextramorphan;
Kinase inhibitors, particularly P38 MAPKinase inhibitors;
P2X7 anatgonists;
iNOS inhibitors;
A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;
A dopamine receptor antagonist;
TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;
A2a agonists such as those described in EP1052264 and EP1241176;
A2b antagonists such as those described in WO2002/42298;
Modulators of chemokine receptor function, for example antagonists of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-265610, SB-225002, MCP-1(9-76), RS-504393, MLN-1202, INCB-3284;
Compounds which modulate the action of prostanoid receptors, for example a PGD2 (DP1 or CRTH2), or a thromboxane A2 antagonist eg ramatroban;
Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; Interleukin 1 receptor antagonists, such as Kineret;
Interleukin 10 agonists, such as Ilodecakin;
HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;
Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, gefitinib;
Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, anti-histamines.
The weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.
The magnitude of prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. In general, the daily dose range for inhalation will lie within the range of from about 0.1 μg to about 10 mg per kg body weight of a human, preferably 0.1 μg to about 0.5 mg per kg, and more preferably 0.1 μg to 50 μg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. Compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01-99% by weight of active compound. Preferably, a unit dose comprises the active compound in an amount of 1 μg to 10 mg. For oral administration suitable doses are 10 μg per kg to 100 mg per kg, preferably 40 μg per kg to 4 mg per kg.
Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.
The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.
For delivery by inhalation, the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation.
By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl2F2) and HFA-152 (C2H4F2) and isobutane.
In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.
Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μm.
In the case of an aerosol-based formulation, an example is:
The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Additionally, compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.
The compounds of the invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein.
It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in “Protective groups in organic chemistry” John Wiley and Sons, 1999, may be used.
Compounds of the invention may be prepared according to the routes illustrated in Scheme 1.
Compounds of general formula (I) wherein Ra, Rb and Rc and R4 are as defined for R1, R2, R3 and R4 in compounds of formula (I) can be prepared from compounds of general formula (II):
by reaction with a compound of general formula (III):
Rc-X (III)
wherein X is a leaving group such as halogen, tosylate, mesylate. The reaction can be performed in a range of solvents, such as acetonitrile, chloroform, DMF or DMSO, at a temperature from 0° C. to the reflux temperature of the solvent, preferably from ambient temperature to the reflux temperature of the solvent.
Compounds of general formula (I) exist in two enantiomeric forms which can be prepared in homochiral form by starting with homochiral (XII). Alternatively, chiral separation of racemic material by chiral hplc may be undertaken.
Compounds of general formula (II) wherein R4 is the group of formula (a), as defined above and R6 is H may be prepared from compounds of general formula (IV):
wherein Ra and Rb are as defined above, by reaction with a compound of general formula (V):
wherein R7a, R7b, n and m are as defined for general formula (I). The reaction may take place in a range of non-nucleophilic organic solvents such as DMF or toluene at a range of temperatures, preferably between 0° C. and the reflux temperature of the solvent.
Compounds of general formula (V) are well known in the art and are readily available or can be prepared by known methods.
Compounds of general formula (II) in which R4 is the group of formula (b) as defined above, may be prepared from compounds of general formula (IV) by reaction with a compound of general formula (VI):
wherein R8a, R8b, and R8c are as defined for general formula (I) and LG is a leaving group, for example, an O-alkyl, halogen or 1-imidazolyl group. The reaction is conducted in the presence of a strong base such as NaH in a solvent such as toluene, THF or dichloromethane at a range of temperatures, preferably between 0° C. and the reflux temperature of the solvent.
Compounds of general formula (VI) wherein R8a, R8b, and R8c are as defined for general formula (I) and Y is an O-alkyl, halogen or 1-imidazolyl group can be prepared from compounds of general formula (VII) by known methods.
Compounds of general formula (VII) are well known in the art and are readily available or can be prepared by known methods such as those described in WO01/04118.
Compounds of general formula (II) in which R4 is the group of formula (c) as defined above, may be prepared from compounds of general formula (IV) by reaction with a compound of general formula (VIa):
wherein Ar2, R8c Q and LG are as defined above, using conditions similar to those employed for the preparation of compounds of formula (II) by reaction of compounds of formula (IV) with compounds of formula (VI) above.
Compounds of formula (VIa) may be prepared from compounds of formula (VIIa) by methods analogous to those used for the preparation of compounds of formula (VI) from compounds of formula (VII) above.
Compounds of general formula (VII) are well known in the art and are readily available or can be prepared by known methods.
Compounds of general formula (IV) can be prepared from compounds of general formula (VIII):
by reaction with hydrogen in the presence of a catalyst, preferably palladium hydroxide on carbon, in a polar solvent such as MeOH or EtOAc, optionally in the presence of a protic acid such as sulphuric or acetic acid.
Compounds of general formula (VIII) can be prepared from compounds of general formula (IX):
by reaction with an amine of general formula (X):
RaRbNH (X)
in the presence of a reducing agent such as sodium triacetoxyborohydride in a polar solvent such as THF or DCE, optionally in the presence of acetic acid.
Compounds of general formula (IX) can be prepared from compounds of general formula (XI):
by reaction with a tin reagent, preferably Bu3SnH and a radical initiator, preferably AIBN. The reaction can be performed in a range of solvents, preferably toluene, at a range of temperatures, preferably between room temperature and the reflux temperature of the solvent.
Compounds of general formula (XI) can be prepared from compounds of general formula (XII):
by reaction with benzyl alcohol. The reaction is performed in the presence of a strong base such as NaH in a range of solvents, preferably THF or DMF at a range of temperatures, preferably between −78° C. and ambient temperature.
Compounds of formula (XII) are known in the art and can be prepared from homochiral starting bicycle[3.2.0]heptenone by bromination (Synthesis (1977), 155-166). The resolution of the bicycloheptenone is described in EP0074856.
The following non-limiting Examples illustrate the invention.
All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.
Where products were purified by column chromatography, ‘flash silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3×6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778). All solvents and commercial reagents were used as received.
All compounds containing a basic centre(s), which were purified by HPLC, were obtained as the TFA salt unless otherwise stated.
Waters Micromass ZQ with a C18-reverse-phase column (30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:
LC-MS Method 2
Waters Micromass ZQ with a C18-reverse-phase column (Higgins Clipeus 5 micron C18 100×3.0 mm or equivalent), elution with A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid. Gradient:
Abbreviations used in the experimental section:DCM=dichloromethane; EtOH=ethanol; DIPEA=di-isopropylethylamine; EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP=dimethylaminopyridine; RT=room temperature; HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; TFA=trifluoroacetic acid; Rt=retention time.
To a suspension of NaH (60% dispersion in oil; 433 mg, 10.8 mmol) in dry THF (7 mL) under N2 was added dropwise benzyl alcohol (1.07 mL, 10.4 mmol). The mixture was stirred for 30 mins then cooled to −30° C. and treated dropwise with a solution of (±)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one (1.32 g, 4.9 mmol) in dry THF (6 mL) and the reaction mixture was allowed to warm up to 0° C. over 2 h. The tan coloured heterogeneous mixture was diluted with ethyl acetate and then washed with 10% aqueous citric acid solution, water and brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography eluting with 15% ether/pentane to give the title compound as a colourless syrup (609 mg). 1H NMR (CDCl3, 400 MHz): δ 1.79 (1H, ddd, J=14.3 Hz, 4.2 Hz, 1.5 Hz), 2.15 (1H, m), 2.65 (1H, m), 2.80 (1H, m), 2.82 (1H, d, J=19.1 Hz), 2.86 (1H, m), 4.03 (1H, q, J=1.8 Hz), 4.50 (1H, d, J=11.7 Hz), 4.53 (1H, d, J=11.7 Hz), 4.71 (1H, m), 7.27-7.40 (5H, m).
To a mixture of (±)-7-benzyloxy-5-bromo-bicyclo[2.2.1]heptan-2-one (609 mg, 2.06 mmol) and AIBN (34 mg, 0.21 mmol) in 30 mL dry degassed toluene was added dropwise tributyltin hydride (0.72 mL, 2.68 mmol) and the solution was heated to 80° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, adsorbed onto diatomaceous earth and chromatographed eluting with 1-15% ether/pentane to give the title compound as a colourless gum (446 mg). 1H NMR (CDCl3, 400 MHz): δ 1.49 (2H, m), 1.99 (1H, d, J=18.5 Hz), 2.10 (3H, m), 2.62 (1H, m), 2.67 (1H, m), 3.91 (1H, s), 4.51 (1H, d, J=11.7 Hz), 4.53 (1H, d, J=11.7 Hz), 7.27-7.39 (5H, m).
To a solution of (±)-7-benzyloxy-bicyclo[2.2.1]heptan-2-one (262 mg, 1.21 mmol) and dimethylamine (2M solution in THF, 1.21 mL, 2.42 mmol) in 2 mL dry DCE was added acetic acid (69 μL, 1.21 mmol) followed by sodium triacetoxyborohydride (385 mg, 1.82 mmol) and a small amount of 3 Å molecular sieves. The mixture was stirred at ambient temperature for 6 h. The reaction was quenched with 10 mL saturated aqueous sodium bicarbonate solution and stirred for 10 mins. The reaction mixture was extracted twice with EtOAc and the combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound as a pale yellow oil (259 mg), which was used without further purification. LC-MS (Method 1): Rt 1.73 min, m/z 246.21 [MH+].
A solution of (±)-(7-benzyloxy-bicyclo[2.2.1]hept-2-yl)-dimethylamine (236 mg, 0.96 mmol) in dry MeOH (8 mL) was added to 20 wt % palladium hydroxide on carbon (50 mg). The reaction vessel was evacuated and purged with nitrogen three times and then a 25% solution of sulfuric acid in MeOH (320 μL, 1.5 mmol) was added. The reaction was stirred under an atmosphere of hydrogen (hydrogen balloon) for 20 h. The reaction was quenched with 200 mg solid sodium carbonate and 3 mL water and evaporated. The residue was partitioned between DCM and brine and the layers separated. The aqueous phase was extracted four more times with DCM and the combined organic phase was dried over sodium sulfate and evaporated to give a 3:1 mixture of the title compound and recovered starting material as a colourless oil that was used without further purification (105 mg).
A solution of a 3:1 mixture of (±)-2-dimethylamino-bicyclo[2.2.1]heptan-7-ol and (±)-(7-benzyloxy-bicyclo[2.2.1]hept-2-yl)-dimethyl-amine (96 mg) in dry toluene (2 mL) was treated with 2-biphenyl isocyanate (145 mg, 0.74 mmol) and the mixture was heated at 80° C. for 2.5 h. The volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 2-6% MeOH/DCM to give the title compound as a colourless syrup (125 mg). LC-MS (Method 1): Rt 7.05 min, m/z 351.16 [MH+]. LC-MS (Method 1): Rt 2.01 and 2.09 min, m/z 351.27 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 0.99 (1H, dd, J=12.7 Hz, 4.9 Hz), 1.34 (1H, m), 1.51 (1H, m), 1.73 (1H, m), 1.83 (2H, m), 2.13 (6H, s), 2.20 (2H, m), 2.39 (1H, m), 4.72 (1H, s), 6.57 (1H, s, br), 7.13 (1H, td, J=7.5, 1.2 Hz), 7.22 (1H, dd, J=7.5, 1.7 Hz), 7.36 (3H, m), 7.40 (1H, m), 7.48 (2H, m), 8.06 (1H, s, br).
The title compound was prepared from (1S,2R,3R)-2,3-dibromo-bicyclo[3.2.0]heptan-6-one and methyl-(3-phenylpropyl)-amine using analogous methods to those in Example 1. 1H NMR (CDCl3, 400 MHz): δ 0.91-0.95 (1H, m), 1.32-1.38 (1H, m), 1.54-1.62 (2H, m), 1.68-1.89 (6H, m), 1.98 (1H, m), 2.08 (3H, m), 2.26-2.29 (3H, m), 2.59-2.63 (2H, m), 3.97 (1H, m), 7.15-7.19 (3H, m), 7.25-7.29 (2H, m).
A solution of anti (1S,2S) 2-[methyl-(3-phenyl-propyl)-amino]bicyclo[2.2.1]heptan-7-ol (165 mg, 0.63 mmol) in dry toluene (10 mL) was stirred at ambient temperature under a nitrogen atmosphere with sodium hydride (76 mg of a 60% dispersion in mineral oil). When gas evolution had subsided, hydroxy-di-thiophen-2-yl-acetic acid ethyl ester (205 mg, 0.76 mmol) was added portion wise over 5 minutes before the reaction was immediately placed in a preheated oil bath at 80° C. After 1 h the reaction was allowed to cool before being quenched with sat. ammonium chloride solution. The reaction was extracted into ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo. Purification by chromatography using 0-3% methanol-CH2Cl2 as eluent gave the title compound as a gum (127 mg). LC-MS (Method 2): Rt 7.90 min, m/z 482 [MH]+. 1H NMR (CDCl3, 400 MHz): δ 0.88-1.01 (1H, m), 1.21-1.34 (2H, m), 1.46-1.59 (1H, m), 1.68-1.87 (4H, m), 2.01-2.09 (3H, s), 2.18-2.27 (3H, m), 2.30-2.37 (2H, m), 2.54-2.60 (2H, m), 4.75-4.97 (1H, m), 4.83 (1H, m), 6.93-6.97 (2H, m), 7.12-7.18 (5H, m), 7.22-7.28 (4H, m).
A solution of anti (1S,2S) hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1]hept-7-yl ester (33 mg, 0.069 mmol) in a 30% w/w solution of methyl bromide in acetonitrile (1 mL) was heated in a sealed tube for 2 days at 50° C. The solvent was removed and purification by chromatography using 0-10% methanol-CH2Cl2 as eluent gave the title compound as a foam (33 mg). LC-MS (Method 2): Rt 7.45 min, m/z 496 [M]+; 1H NMR (CDCl3, 400 MHz) δ 1.33-1.41 (1H, m), 1.45-1.56 (1H, m), 1.57-1.67 (2H, m), 1.69-1.79 (1H, m), 2.04-2.21 (3H, m), 2.43 (1H, m), 2.64-2.79 (3H, m), 3.23 (3H, s), 3.25 (3H, s), 3.43-3.55 (1H, m), 3.56-3.68 (1H, m), 4.31 (1H, m), 4.89-4.92 (1H, m), 5.02-5.05 (1H, m), 6.93-6.99 (2H, m), 7.10-7.30 (9H, m).
The following examples were prepared in a similar manner to that described for examples 1-3.
The inhibitory effects of compounds of the present invention at the M3 muscarinic receptor were determined by the following binding assays:
Radioligand binding studies utilising [3H]-N-methyl scopolamine ([3H]-NMS) and commercially available cell membranes expressing the human muscarinic receptors (M2 and M3) were used to assess the affinity of muscarinic antagonists for M2 and M3 receptors. Membranes in TRIS buffer were incubated in 96-well plates with [3H]-NMS and M3 antagonist at various concentrations for 3 hours. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Can berra Packard Topcount scintillation counter
The half-life of antagonists at each muscarinic receptor was measured using the alternative radioligand [3H]-QNB and an adaptation of the above affinity assay. Antagonists were incubated for 3 hours at a concentration 10-fold higher than their Ki, as determined with the [3H]-QNB ligand, with membranes expressing the human muscarinic receptors. At the end of this time, [3H]-QNB was added to a concentration 25-fold higher than its Kd for the receptor being studied and the incubation continued for various time periods from 15 minutes up to 180 minutes. Membranes and bound radioligand were then harvested by filtration and allowed to dry overnight. Scintillation fluid was then added and the bound radioligand counted using a Can berra Packard Topcount scintillation counter.
The rate at which [3H]-QNB is detected binding to the muscarinic receptors is related to the rate at which the antagonist dissociates from the receptor, ie. to the half life of the antagonists on the receptors.
All Example compounds that were tested in this assay showed binding affinity Ki values of <10 nM, except for Example 6 which exhibited a Ki value of <100 nM.
IN an alternative M3 receptor binding assay, CHO cells expressing the human M3 receptor were seeded and incubated overnight in 96 well collagen coated plates (black-wall, clear bottom) at a density of 50000/75 μL of medium in 3% serum. The following day, a calcium-sensitive dye (Molecular Devices, Cat # R8041) was prepared in HBSS buffer with the addition of 5 mM probenecid (pH 7.4). An equal volume of the dye solution (75 μL) was added to the cells and incubated for 45 minutes followed by addition of 50 μL of muscarinic antagonists or vehicle. After a further 15 minutes the plate was read on a FLEXstation™ (excitation 488 nm, emission 525 nm) for 15 seconds to determine baseline fluorescence. The muscarinic agonist Carbachol was then added at an EC80 concentration and the fluorescence measured for a further 60 seconds. The signal was calculated by subtracting the peak response from the mean of the baseline fluorescence in control wells in the absence of antagonist. The percentage of the maximum response in the presence of antagonist was then calculated in order to generate IC50 curves.
The inhibitory effects of compounds of the present invention at the M3 muscarinic Receptor may be evaluated in the following ex-viva and in vivo assays:
By way of illustration, the compound of Example 3 exhibited an IC50 value of <10 nM in this assay.
Male Guinea pigs (Dunkin Hartley), weighing 500-600 g housed in groups of 5 were individually identified. Animals were allowed to acclimatize to their local surroundings for at least 5 days. Throughout this time and study time animals were allowed access to water and food ad libitum.
Guinea pigs were anaesthetized with the inhaled anaesthetic Halothane (5%). Test compound or vehicle (0.25-0.50 mL/kg) was administered intranasally. Animals were placed on a heated pad and allowed to recover before being returned to their home cages.
Up to 24 hrs post dosing guinea pigs were terminally anaesthetized with Urethane (250 μg/mL, 2 mL/kg). At the point of surgical anaesthesia, the jugular vein was cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10 U/mL) for i.v. administration of methacholine. The trachea was exposed and cannulated with a rigid portex cannula and the oesophagus cannulated transorally with a flexible portex infant feeding tube.
The spontaneously breathing animal was then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure transducer. The tracheal cannula was attached to a pneumotach and the oesophageal cannula attached to a pressure transducer.
The oesophageal cannula was positioned to give a baseline resistance of between 0.1 and 0.2 cmH20/mL/s. A 2 minute baseline reading was recorded before i.v. administration of methacholine (up to 30 μg/kg, 0.5 mL/kg). A 2 minute recording of the induced constriction was taken from the point of i.v. administration.
The software calculated a peak resistance and a resistance area under the curve (AUC) during each 2 minute recording period which was used to analyse the bronchoprotective effects of test compounds.
As an illustrative example, the compound of Example 3 was shown to be bronchoprotective 1 hr after dosing, shown in the accompanying drawings.
The accompanying drawing is a bar chart showing the effect of Example 3 (3 μg/kg, i.n.) on methacholine-induced bronchoconstriction in the Guinea pig.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0525675.5 | Dec 2005 | GB | national |
| 0619309.8 | Sep 2006 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2006/004675 | 12/14/2006 | WO | 00 | 12/3/2008 |
