WO2005044266A1 - Alkynes i - Google Patents
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- WO2005044266A1 WO2005044266A1 PCT/US2004/034517 US2004034517W WO2005044266A1 WO 2005044266 A1 WO2005044266 A1 WO 2005044266A1 US 2004034517 W US2004034517 W US 2004034517W WO 2005044266 A1 WO2005044266 A1 WO 2005044266A1
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
- C07C15/40—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals
- C07C15/42—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic
- C07C15/48—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts substituted by unsaturated carbon radicals monocyclic the hydrocarbon substituent containing a carbon-to-carbon triple bond
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- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
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- C07C25/24—Halogenated aromatic hydrocarbons with unsaturated side chains
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
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- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Definitions
- the present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising said novel compounds.
- mGluR metabotropic glutamate receptors
- CNS central nervous system
- Eight metabotropic glutamate receptor subtypes have been identified and are subdivided into three groups based on sequence similarity.
- Group I consists of mGluRl and mGluR5. These receptors activate phospholipase C and increase neuronal excitability.
- Group II consisting of mGluR2 and mGluR3 as well as group III, consisting of mGluR4, mGluR ⁇ , mGluR7 and mGluR ⁇ are capable of inhibiting adenylyl cyclase activity and reduce synaptic transmission.
- the lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".
- Gastro-esophageal reflux disease is the most prevalent upper gastrointestinal tract disease. Current pharmacotherapy aims at reducing gastric acid secretion, or at neutralizing acid in the esophagus. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990)
- Gastroenterol. Clin. N. Amer. 19, pp. 517-535 has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
- TLESRs transient lower esophageal sphincter relaxations
- the problem underlying the present invention was to find new compounds useful in the treatment of GERD.
- WO 01/16121 Al discloses a compound A-L-B, where A is a 5-, 6- or 7-membered heterocycle
- L is an alkenylene, alkynylene or azo
- B is a hydrocarbyl; cyclohydrocarbyl; heterocycle (optionally containing one or more double bonds); or aryl.
- WO 99/02497 A2 discloses compounds of the formula
- X may be an alkenylene or an alkynylene bonded via vicinal unsaturated carbon atoms, or an azo group; and R 5 may be an aromatic or heteroaromatic group.
- WO03/022846 Al discloses inter alia the compound 4-(4-pyridin-2-yl-but-3-ynyl)- benzonitrile.
- the compound is an intermediate in a process for producing compounds useful for treating cancer.
- Outline of the invention
- the present invention is directed to novel compounds according to the general formula I:
- R 1 is selected from hydrogen, - alkyl, C -C 6 cycloalkyl, aryl and heteroaryl, wherein the aryl or heteroaryl may be substituted by C 1 -C 4 alkyl;
- R 2 is selected from hydrogen and - alkyl
- R 3 is selected from hydrogen, -C 4 alkyl, F, CF 3 , CHF 2 and CH 2 F;
- R 4 is selected from hydrogen, F, CF 3 , CHF 2 , CH 2 F and CH 3 ;
- R 5 is selected from hydrogen and F
- R 6 is selected from hydrogen and F
- Q is selected from C 1 -C 4 alkyl, optionally substituted by Ci-C 4 alkyl or C 1 -C 4 alkoxy;
- Y 1 is selected from hydrogen; halogen; nitrile; C 1 -C 4 alkoxy; C 1 -C 4 alkyl wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom; benzyloxy; nitro in the meta or para position; and C1-C 4 alkyl ester;
- Y 2 is selected from hydrogen; halogen; nitrile; -C 4 alkoxy; C 1 -C 4 alkyl wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom; and
- C 1 -C 4 alkyl ester Y 3 is selected from hydrogen; halogen; nitrile; C1-C4 alkoxy; C 1 -C 4 alkyl wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom; and C 1 -C 4 alkyl ester; or
- Y and Y may form an aromatic or non-aromatic ring, optionally substituted by halogen, nitrile, C C 4 alkoxy, C 1 -C 4 alkyl wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluorine atom, benzyloxy or -C 4 alkyl ester; as well as pharmaceutically acceptable salts, hydrates, isoforms and or optical isomers thereof, with the exception of 4-(4-pyridin-2-yl-but-3-ynyl)-benzonitrile.
- Halogen is chloro, fluoro, bromo or iodo.
- C 1 -C 4 alkyl is a straight or branched alkyl group, each independently containing 1, 2, 3 or 4 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl or isopropyl.
- the alkyl groups may contain one or more heteroatoms selected from O, N and S. Examples of such groups are methyl-ethylether, methyl -ethylamine and methyl- thiomethyl.
- Cycloalkyl is a cyclic alkyl, each independently containing 3, 4, 5 or 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- C C 4 alkoxy is an alkoxy group containing 1, 2, 3 or 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy or isopropoxy.
- aryl means aromatic rings with 6-14 carbon atoms including both single rings and polycyclic compounds, such as phenyl, benzyl or naphtyl.
- heteroaryl as used herein means aromatic rings with 5-14 carbon atoms, including both single rings and polycyclic compounds, such as imidazopyridine, in which one or several of the ring atoms is either oxygen, nitrogen or sulphur, such as furanyl or thiophenyl.
- salts of the compound of formula I are also within the scope of the present invention.
- Such salts are for example salts formed with mineral acids such as hydrochloric acid; alkali metal salts such as sodium or potassium salts; or alkaline earth metal salts such as calcium or magnesium salts.
- novel compounds according to the present invention are useful in therapy.
- said compounds are useful for the inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastro- esophageal reflux disorder (GERD).
- TLESRs transient lower esophageal sphincter relaxations
- GERD gastro- esophageal reflux disorder
- the compounds according to the present invention are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
- a further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD).
- FD functional dyspepsia
- Yet another aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant IBS.
- IBS irritable bowel syndrome
- a further aspect of the invention is the use of a compound according to formula I, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
- Still a further aspect of the invention is a method for the treatment of any one of the conditions mentioned above, whereby a pharmaceutically effective amount of a compound according to formula I above, is administered to a subject suffering from said condition(s).
- the compounds of formula I are useful for the treatment and/or prevention of acute and chronic neurological and psychiatric disorders, anxiety and chronic and acute pain disorders.
- said compounds are useful for the prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, migraine and gout.
- isomers is herein defined as compounds of formula I, which differ by the position of their functional groups and/or orientation.
- orientation is meant stereoisomers, diastereoisomers, regioisomers and enantiomers.
- isoforms as used herein is defined as compounds of formula I which differ by their crystal lattice, such as crystalline compounds and amorphous compounds.
- TLESR transient lower esophageal sphincter relaxations
- the wording "reflux” is herein defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.
- the wording "GERD”, gastro-esophageal reflux disease, is herein defined in accordance with van Heerwarden, M.A., SmoutA.J.P.M., 2000; Diagnosis of reflux disease. Bailliere 's Clin. Gastroenterol. 14, pp. 759-774.
- the compounds of formula I above may be synthesized by a Sonogashira coupling (Tetrahedron Letters 1975, 50, 4467, S. Thorand, N. Krause J. Org. Chem., 1998, 63, 8551-8553, M. Erdelyi, A. Gogoll, J. Org. Chem., 2001, 66, 4165-4169) of the aryl bromide A and the alkyne B in the presence of a base such as triethyl arnine at room temperature to 60 °C (Scheme 1):
- the terminal alkyne B is not commercially available it is made via the intermediate G, which can be obtained by one of two routes (Scheme 2).
- One route is by coupling of an aryl iodide C with allyl alcohol D in DMF at room temperature to 60 °C.
- the other route is by first reducing the carboxylic acid E to the alcohol F using lithium aluminium hydride in THF, starting at 0 °C and ending at reflux temperature and then oxidising the alcohol F to the aldehyde G using Dess-Martin periodinane in DCM at room temperature with a catalytic amount of trifluoroacetic acid.
- Route 1 is by coupling of an aryl iodide C with allyl alcohol D in DMF at room temperature to 60 °C.
- the other route is by first reducing the carboxylic acid E to the alcohol F using lithium aluminium hydride in THF, starting at 0 °C and ending at reflux temperature and then oxidising the alcohol F to the alde
- the alkyne B is made as outlined in scheme 3: First the aldehyde G is converted to the dibromoalkene H by reaction with tetrabromomethane and triphenylphosphine in DCM at room temperature. Elimination with lithium bis(trimethylsilyl)amide in THF at -78 °C and subsequent halogen-lithium exchange with n-butyl lithium in THF/hexanes at -78 °C to room temperature gives, after quenching with water, the terminal alkyne B. The material B is then used for Sonogashira coupling as outlined in scheme 1.
- DCM is dried over 3 A molecular sieves. THF was distilled from Na/benzophenone just prior to use. All reactions are run under a nitrogen atmosphere. All glassware is dried in at 150 °C for at least two hours prior to its use. Phase separators from International Sorbent Technology (1ST) are used. Purification by chromatography is done either on silica gel 60 (0.040-0.063 mm), or by reverse phase chromatography with a C8 column. All NTVIR spectra are measured in ⁇ -chloroform.
- 2-bromo-6-methylpyridine is commercially available from Aldrich, (PPh 3 ) 2 PdCl 2 from Avacado, Pd (OAc) 2 from Aldrich, Cul from Fluka and 4-phenyl-but-l-yn from TCI. If not stated otherwise, the chemicals used are commercially available and are used as such without further purification.
- the compounds of formula I are in accordance with the present invention suitably formulated into pharmaceutical formulations for oral administration. Also rectal, parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations.
- the compounds of formula I are formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant.
- the carrier may be in the form of a solid, semi-solid or liquid diluent.
- the compound of formula I to be formulated is mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
- Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
- Hard gelatine capsules may contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, com starch, amylopectin, cellulose derivatives or gelatine.
- Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance(s) mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compound and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent.
- Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
- Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared, as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
- the compounds of formula I may be administered once or twice daily, depending on the severity of the patient's condition.
- a typical daily dose of the compounds of formula I is from 0.1 - 10 mg per kg body weight of the subject to be treated, but this will depend on various factors such as the route of administration, the age and weight of the patient as well as of severity of the patient' s condition. Examples
- Tetrabutylammonium chloride (6.95 g, 0.25 mol, 1.0 eq.) and sodium hydrogen carbonate (5.25 g, 0.625 mmol, 2.5 eq.) were dissolved reasonably in DMF (15 mL) under nitrogen. The mixture was cooled to 0 °C before 3-chloro-iodobenzene (5.96g, 3.10 mL, 0.25 mol), then allyl alcohol (2.18g, 2.56 mL, 0.375 mol, 1.50 eq.) and finally Pd(OAc) 2 (0.168g, 7.5 mmol, 0.03 eq.), the latter in small portions, was added.
- 3-(3-chlorophenyl)propanoic acid (0.923 g, 5.0 mmol) was dissolved in THF (12 mL) and cooled to 0 °C under nitrogen. Lithium aluminium hydride (0.380 g, 10.0 mmol, 2.0 eq.) was added portionwise. The mixture was allowed to reach room temperature, stirred 0.5h at that temperature and then refluxed for 0.5h.
- Tetrabromomethane (4.89 g, 14.76 mmol, 2.0 eq.) was dissolved in DCM (45 mL) and then cooled to 0 °C. Triphenylphosphine (3.87 g, 14.76 mmol, 2.0 eq.) was added. The orange solution was stirred 3 min. before the addition of Zn (0.97 g, 14.76 mmol, 2.0 eq.) in small portions. After stirring for 10 min. further, 3-(3-chlorophenyl)propanal (1.24 g, 7.38 mmol) in DCM (5 mL) was added. After another 10 min. the reaction mixture was allowed to reach room temperature and was stirred at that temperature for 14h.
- Example 12 Preparation of l-but-3-yn-l-yl-3-methylbenzene (compound 12): prepared according to method E above, with l-methyl-3-(4,4-dibromobut-3-en-l-yl)benzene as starting material.
- 6-bromo-2-methylpyridine (0.516 g, 3.0 mmol) was mixed with ethynyl(trimethyl)silane (0.324 g, 3.3 mmol, 1.10 eq.) and (PPh 3 ) 2 PdCl 2 (0.063 g, 0.09 mmol, 0.03 eq.) and triethylamine (1.21g, 1.67 mL, 12.0 mmol, 4.0 eq. was added at 0 °C. The mixture was stirred for l/2h at 0 °C before Cul (0.017 g, 0.09 mmol, 0.03 eq.) was added and the mixture was heated to room temperature over 15 min. After stirring 15 min.
- 2-methyl-6-[(trimethylsilyl)ethynyl]pyridine (0.038 g, 0.2 mmol, 2.0 eq.) was mixed with (3-bromopropyl)benzene (0.020 g, 0.1 mmol) and tetrabutylammonium triphenyldifluorosilicate (0.081 g, 0.3 mmol, 1.5 eq.) and heated at 60 °C for 24h in a sealed vial. LC/MS after that time showed the molecular weight of the product. Heating at 60 °C was continued for 24h further, but without any change in LC/MS.
- the compound was prepared according to method F above using (l-Methyl-but-3-ynyl)- benzene and 2-bromo-6-methy ⁇ pyridine as starting materials.
- the properties of the compounds of the invention can be analyzed using standard assays for pharmacological activity.
- glutamate receptor assays are well known in the art as described in for example Aramori et al., Neuron 8:757 (1992), Tanabe et al, Neuron 8:169 (1992), Miller et al, J. Neuroscience 15: 6103 (1995), Balazs, et al, J. Neurochemistry 69:151 (1997).
- the methodology described in these publications is incorporated herein by reference.
- the compounds of the invention can be studied by means of an assay (FLIPR) that measures the mobilization of intracellular calcium, [Ca 2+ ]i in cells expressing mGluR5 or another assay (IP3) that measures inositol phosphate turnover.
- FLIPR assay
- IP3 another assay
- Cells expressing human mGluR5d as described in WO97/05252 are seeded at a density of 100,000 cells per well on collagen coated clear bottom 96-well plates with black sides and experiments are done 24 h following seeding. All assays are done in a buffer containing 127 mM NaCl, 5 mM KC1, 2 mM MgCl 2 , 0.7 mM NaH 2 PO 4 , 2 mM CaCl 2 , 0.422 mg/ml NaHCO 3 , 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml BS A Fraction IV (pH 7.4).
- a 40 ⁇ l addition from the antagonist plate was followed by a 50 ⁇ L addition from the agonist plate.
- a 90 second interval separates the antagonist and agonist additions.
- the fluorescence signal is sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals immediately after each of the two additions. Responses are measured as the difference between the peak height of the response to agonist, less the background fluorescence within the sample period.
- IC 50 determinations are made using a linear least squares fitting program.
- GHEK stably expressing the human mGluR5d are seeded onto 24 well poly-L-lysine coated plates at 40 x 10 4 cells /well in media containing 1 ⁇ Ci/well [3H] myo-inositol. Cells were incubated overnight (16 h), then washed three times and incubated for 1 h at 37°C in HEPES buffered saline (146 mM NaCl, 4.2 mM KC1, 0.5 mM MgCl 2 , 0.1% glucose, 20 mM HEPES, pH 7.4) supplemented with 1 unit/ml glutamate pyruvate transaminase and 2 mM pyruvate.
- HEPES buffered saline 146 mM NaCl, 4.2 mM KC1, 0.5 mM MgCl 2 , 0.1% glucose, 20 mM HEPES, pH 7.4
- HEPES buffered saline containing 10 mM LiCl.
- Compounds are incubated in duplicate at 37°C for 15 min, then either glutamate (80 ⁇ M) or DHPG (30 ⁇ M) is added and incubated for an additional 30 min.
- the reaction is terminated by the addition of 0.5 ml perchloric acid (5%) on ice, with incubation at 4°C for at least 30 min.
- Samples are collected in 15 ml polypropylene tubes and inositol phosphates are separated using ion-exchange resin (Dowex AG1-X8 formate form, 200-400 mesh, BIORAD) columns.
- Inositol phosphate separation was done by first eluting glycero phosphatidyl inositol with 8 ml 30 mM ammonium formate. Next, total inositol phosphates is eluted with 8 ml 700 mM ammonium formate / 100 mM formic acid and collected in scintillation vials.
- the compounds are active in the assay above with IC 50 values less than 10 000 nM.
- the IC 50 value is less than 1 ⁇ M. In a further aspect of the invention, the IC 50 value is less than 100 nM.
- a multilumen sleeve/sidehole assembly (Dentsleeve, Sydney, South Australia) is introduced through the esophagostomy to measure gastric, lower esophageal sphincter (LES) and esophageal pressures.
- the assembly is perfused with water using a low-compliance manometric perfusion pump (Dentsleeve, Sydney, South Australia).
- An air-perfused tube is passed in the oral direction to measure swallows, and an antimony electrode monitored pH, 3 cm above the LES. All signals are amplified and acquired on a personal computer at 10 Hz.
- placebo (0.9% NaCl) or test compound is administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein.
- a nutrient meal (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach through the central lumen of the assembly at 100 ml/min to a final volume of 30 ml/kg.
- the infusion of the nutrient meal is followed by air infusion at a rate of 500 ml/min until an intragastric pressure of 10+1 mmHg is obtained.
- the pressure is then maintained at this level throughout the experiment using the infusion pump for further air infusion or for venting air from the stomach.
- the experimental time from start of nutrient infusion to end of air insufflation is 45 min. The procedure has been validated as a reliable means of triggering TLESRs.
- TLESRs is defined as a decrease in lower esophageal sphincter pressure (with reference to intragastric pressure) at a rate of >1 mmHg/s.
- the relaxation should not be preceded by a pharyngeal signal ⁇ 2s before its onset in which case the relaxation is classified as swallow- induced.
- the pressure difference between the LES and the stomach should be less than 2 mmHg, and the duration of the complete relaxation longer than 1 s.
- N number of dogs tested.
Abstract
Description
Claims
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CA002549967A CA2549967A1 (en) | 2003-10-31 | 2004-10-20 | Alkynes i |
JP2006538084A JP2007510645A (en) | 2003-10-31 | 2004-10-20 | Alkynes I |
EP04795653A EP1677789A1 (en) | 2003-10-31 | 2004-10-20 | Alkynes i |
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US56071503P | 2003-10-31 | 2003-10-31 | |
US60/560,715 | 2003-10-31 |
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PCT/US2004/034517 WO2005044266A1 (en) | 2003-10-31 | 2004-10-20 | Alkynes i |
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EP (1) | EP1677789A1 (en) |
JP (1) | JP2007510645A (en) |
CN (1) | CN1870999A (en) |
CA (1) | CA2549967A1 (en) |
WO (1) | WO2005044266A1 (en) |
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WO2005123703A2 (en) | 2004-06-17 | 2005-12-29 | Addex Pharmaceuticals Sa | Alkynyl derivatives as modulators of metabotropic glutamate receptors |
JP2009522220A (en) * | 2005-12-28 | 2009-06-11 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Substituted bis (hetero) aromatic N-ethylpropioramide and its use in the manufacture of a medicament |
JP2010508335A (en) * | 2006-11-04 | 2010-03-18 | ジボダン ネーデルランド サービシーズ ビー.ヴイ. | New fragrance compounds |
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- 2004-10-20 JP JP2006538084A patent/JP2007510645A/en active Pending
- 2004-10-20 EP EP04795653A patent/EP1677789A1/en not_active Withdrawn
- 2004-10-20 CA CA002549967A patent/CA2549967A1/en not_active Abandoned
- 2004-10-20 CN CNA2004800308708A patent/CN1870999A/en active Pending
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Also Published As
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CA2549967A1 (en) | 2005-05-19 |
CN1870999A (en) | 2006-11-29 |
JP2007510645A (en) | 2007-04-26 |
EP1677789A1 (en) | 2006-07-12 |
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