CA2171579A1 - Piperidine derivatives, process for the preparation thereof and application thereof in therapeutics - Google Patents
Piperidine derivatives, process for the preparation thereof and application thereof in therapeuticsInfo
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- CA2171579A1 CA2171579A1 CA002171579A CA2171579A CA2171579A1 CA 2171579 A1 CA2171579 A1 CA 2171579A1 CA 002171579 A CA002171579 A CA 002171579A CA 2171579 A CA2171579 A CA 2171579A CA 2171579 A1 CA2171579 A1 CA 2171579A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
A compound of formula (I)
Description
~11 1 57q The present invention relates to piperidine derivatives, a process for their preparation and their application in therapeutics.
The present invention provides a compound of formula (I) R~ N~,~, H (I) X`J` R3 in which X represents an oxygen atom or a methylene group, Rl represents a chlorine or fluorine atom or a methyl, methoxy or amino group, and R2 and R3 independently represent a hydrogen atom or a methyl group, in the form of the free base or an addition salt with a pharmaceutically acceptable acid.
The preferred compounds according to the invention are those in which, X represents an oxygen atom and Rl is at position 8 on the phenyl ring.
The particularly preferred compounds of formula ~I) are (S)-8-fluoro-4-methyl-2-t4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazotl,5,4-de]tl,4]benzoxazine and (S)-8-fluoro-4-methyl-2-t4-(lH-imidazol-4-yl)piperidin-1-yl]-4~5-dihydroimidazo[l~5~4-de]tl,4]benzoxazine.
Some compounds of formula (I) contain an asymmetric ~ 71~79 asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers, pure or in the form of mixtures, including racemic mixtures, form part of the invention.
The mesomeric forms of the compounds of formula (I) also form part of the invention.
The compounds of formula (I) can be prepared by reaction of a compound of formula (II), in which X, Rl and R2 are as defined in formula (I) and Y represents a halogen atom, in particular a chlorine atom, with a compound of formula ~III), in which R3 is as defined in formula (I), according to Scheme 1.
Scheme 1 (~1) (111) (1) The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to the person skilled in the art.
Thus, the compound of formula (III) in which R3 is a hydrogen atom is described in Arch. Pharmaz., 306 (12), 934-942 (1973).
The compound of formula (III) in which R3 is a methyl group can be prepared according to the process described in EP-A-0,507,650.
The compounds of formula (II), in which Y is a chlorine atom and X, Rl and R2 are as defined in formula (I), can be prepared by the reduction of a compound of formula (IV) ~ % ~ (IV) which is then reacted with urea to give a compound of formula (V) Rl~ >=O (V) ,~,1~
Rz which is then treated with phosphoryl chloride.
The compounds of formula (IV) can be prepared by reaction of a compound of formula (VI) Rl ~ Nx ~ Rz (VI) with bis(1,1-dimethylethyl) dicarbonate, nitration of a compound of formula (VII) coo~- ~u R~ ~ Nx ~ Rz (VII) and hydrolysis of a compound of formula ~VIII) t~2 COO~ U
~N~ (VIII) ~ XJ
Some compounds of formula ~IV) can also be prepared from compounds of formula (IX) NO
~ x ~ (IX) in which X and R2 are as defined in formula (I).
In particular, compounds of formula (IVa) NOz H
Cl ~ x ~ (IVa) can be prepared by chlorination of the compounds of formula (IX).
The preparation of the compound of formula (IX), in which R2 is a methyl group and X an oxygen atom, is described in EP-A-0,646,583.
The compound of formula (IX) in which R2 is a hydrogen atom and X an oxygen atom can be prepared by 217157~
An analogous process.
Compounds of formula ~IVb) ~ ~ R2 (IVb) in which R2 is as defined in formula (I) can also be prepared by nitration of a compound of formula ~X) ~N~R2 (X) The compounds of formula (X) are typically prepared by cyclization of 2-bromo-5-fluorophenol with a compound of formula (XI) HO ~ COO~u (X~
The following Examples illustrate the preparation of compounds according to the present invention. Microanalyses and NMR spectra have confirmed the structures of the products obtained. The (y:x) ratios correspond to the (base:acid) ratio. The numbers between brackets refer to the table given later which 21 7 157~
illustrates the chemical structures and the physical properties of some compounds according to the invention.
Example 1 (Compound No. 1) ~S)-8-chloro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de]~1,4]benzoxazine 1.1. (S)-7-chloro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine 5.82 g (0.030 mol) of (S)-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 135 ml of acetic acid at 45C. 5.16 g (0.038 mol) of _-chlorosuccinimide are rapidly added and the reaction mixture is stirred for 4 hours at 50C. It is then poured into water and extracted 3 times with diethyl ether. The organic phases are combined, washed with water and then with an aqueous sodium hydroxide solution and dried. The solvent is evaporated to dryness.
6.7 g of product are obtained.
Melting point : 95C
1.2. (S)-8-chloro-4-methyl-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazin-2(lH)-one A suspension between 8.9 g (0.039 mol) of (S)-7-chloro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine in 250 ml of ethanol and a catalytic amount 2~ 7 1 579 of Raney nickel are introduced into a Parr apparatus.
Hydrogenation is carried out for 2 hours at room temperature under a pressure of 70 kPa (10 psi). The catalyst is then filtered off and washed with ethanol, the filtrate is recovered and the solvent is evaporated to dryness.
3.4 g ~0.056 mol) of urea are ~dded to the residue thus obtained and heating is carried out with an oil bath at 170-180C for 1 hour. The solid obtained is then taken up in a mixture of water and diethyl ether (50:50), and the precipitate formed is filtered off, washed with diethyl ether and then with water and dried under vacuum over phosphorous pentoxide. 6.3 g of product are obtained, which product is purified by chromatography on a silica gel column with a mixture of dichloromethane and methanol (97:3).
5.2 g of product are obtained.
1.3 (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine 100 ml of phosphoryl chloride are poured onto 5.2 g (0.023 mol) of (S)-8-chloro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(lH)-one.
The mixture is heated at reflux for 2 hours, the solvent is then evaporated to dryness and the residue is taken up in ice-cold water ~nd then in a concentrated aqueous ammonia solution. Extraction is then carried out with diethyl ether, the organic phases are combined and dried and the solvent is evaporated to dryness. 4.5 g of residue are obtained, which residue is purified by chromatography on a silica gel column with a mixture of hexane and ethyl acetate (97:3).
4.1 g of product ~re obtained in the form of an oil.
1.4. ~S)-8-chloro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-l-yl]-4~5-dihydroimidazo-t1,5,4-de][1,4]benzoxazine A mixture of 1.35 g (0.0082 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, 1 g (0.0041 mol) of (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazotl,5,4-de]tl~4]benzoxazine and 4.5 ml of isoamyl alcohol is heated at 120C for 12 hours with stirring. The solvent is then evaporated to dryness and the residue is purified by chromatography on a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5).
After recrystallization from acetone, 0.7 g of product is obtained in the base form.
Melting point : 208C
[~]DO = -23.8 (c = 0.01, methanol) Example 2 (Compound No. 2) (S)-8-chloro-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazotl,5,4-de]tl,4]tbenzoxazine There is obtained, from a mixture of (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazo-21 7 i 57~
g [l~5~4-de]tl~4]benzoxazine and 4-(lH-imidazol-4-yl)piperidine, treated under the conditions of Example 1.4, after recrystallization from acetone, 0.6 g of product in the base form.
S Melting point : 215C
[cr~D = -3-7 (c = O.01, methanol) Example 3 (Compound No. 5) 8-fluoro-2-t4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-5,6-dihydro-4H-imidazot4,5,1-ij]quinoline 3.1. 1,1-dimethylethyl 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate A mixture of 16.5 g ~0.1 mol) of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline and 32 g (0.146 mol) of bis(l,l-dimethylethyl) dicarbonate in 100 ml of 15 tetrahydrofuran is heated at 60C for 3 days. The solvent is then evaporated to dryness and the remaining dicarbonate is driven off using a vane pump. The residue is purified by chromatography on silica gel with a mixture of hexane and ethyl acetate (so:10).
20 24.5 g of product are obtained in the form of an oil.
3.2 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate A solution of 18.4 g (0.0697 mol) of l,l-dimethylethyl 6-fluoro-2-methyl-1,2,3,4-tetrahydroguinoline-1-carboxylate and 13.8 ml 217i~7~
of anhydrous N,N,N',N'-tetramethylethylenediamine in 350 ml of Anhydrous diethyl ether is cooled to -78C.
64.2 ml of a 1.3N solution of sec-butyl iodide in a mixture of cyclohexane and pentane are then added over 30 minutes. The reaction mixture is stirred for 1 hour at -78C and then 12.3 g (0.103 mol) of isobutyl nitrate are added. The reaction mixture is stirred for 1.5 hours at -70C and is then neutralized by being poured into ice-cold water. Extraction is carried out with diethyl ether, the organic phases are combined, washed with water and dried and the solvent is then evaporated to dryness. The residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of hexane and ethyl acetate ~90:10).
8.1 g of product are obtained.
3.3. 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroguinoline A mixture of 8.6 g (0.0261 mol) of 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate, 30 ml of concentrated hydrochloric acid, 20 ml of toluene and 30 ml of water is heated at the reflux temperature for one day. The mixture is then allowed to return to room temperature, separation is carried out by settling and extraction is carried out with toluene. The organic phases are combined, washed with water And dried and the solvent is then evaporated to dryness.
5.6 g of product are obtained.
Melting point: 56C
3.4. 8-fluoro-4-ethyl-5,6-dihydro-4H-imidazo-t4,5,1-i~]quinol-2(lH)-one A suspension of 5.5 g (0.026 mol) of 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline in 150 ml of ethanol and a catalytic amount of Raney nickel are introduced into a Parr apparatus and hydrogenation is then carried out for 1 hour at room temperature under a pressure of 0.21 MPa (30 p5i). The catalyst is then filtered off and washed with ethanol, the filtrate is recovered and the solvent i8 evaporated to dryness. The residue is added to 2.6 g (0.043 mol) of urea and heating is carried out with an oil bath at 175C for 1.5 hours. The solid obtained is taken up in a mixture of water and diethyl ether (50:50) and the precipitate formed is then filtered off, washed with diethyl ether and with water and dried under vacuum over phosphorus pentoxide.
4.2 g of product are obtained.
3.5. 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-i~]guinoline 100 ml of phosphoryl chloride are poured onto 4.2 g (0.02 mol) of 8-fluoro-4-methyl-5,6-dihydro-4H-imidazot4,5,1-i ]quinol-2(lH)-one and the mixture is 21 7 1 51~
then heated at reflux for 2 hours. The solvent is then evaporated to dryness and the residue is taken up in ice-cold water And then in a concentrated Aqueous ammonia solution. Extraction is carried out with diethyl ether, the organic phases are combined and dried and the solvent is then evaporated to dryness.
The residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of hexane and ethyl acetate (70:30).
2.4 g of product are obtained.
Melting point : 80C
3.6. 8-fluoro-2-~4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-5,6-dihydro-4H-imidazot4,5,1-ij]guinoline A mixture of 0.94 g ~0.00625 mol) of 4-(lH-imidazol-4-yl)piperidine, 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo-t4,5,1-i~]quinoline and 3.5 ml of isoamyl alcohol is heated at 120C for 18 hours with stirring. The solvent is then evaporated to dryness and the residue is purified by chromatography on a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5).
After recrystallization from acetone, 0.85 g of product is obtained in the base form.
Melting point : 175-177C
Example 4 (Compound No. 6) 8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-5,6-dihydro-4H-imidazo-[4,5,1-i ]quinoline There is obtained, from 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-i~quinoline and 1 g (0.00623 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, treated under the conditions of Example 3.6, after recrystallization from acetone, 0.7 g of product in the base form.
Melting point : 255C
Example 5 (Compound No. 8) (S)-4-methyl-2-[4-(5-methyl-1-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-8-amine 5.1. (S)-5,7-dinitro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine 7.7 g (0.04 mol) of (S)-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 176 ml of acetic acid at 60C. 2.8 ml (0.044 mol) of nitric acid are added dropwise, the reaction mixture is stirred for 45 minutes at 600C and then 176 ml of water are added. The reaction mixture is cooled to 0C and the precipitate formed is filtered off, washed with water and dried under vacuum.
The present invention provides a compound of formula (I) R~ N~,~, H (I) X`J` R3 in which X represents an oxygen atom or a methylene group, Rl represents a chlorine or fluorine atom or a methyl, methoxy or amino group, and R2 and R3 independently represent a hydrogen atom or a methyl group, in the form of the free base or an addition salt with a pharmaceutically acceptable acid.
The preferred compounds according to the invention are those in which, X represents an oxygen atom and Rl is at position 8 on the phenyl ring.
The particularly preferred compounds of formula ~I) are (S)-8-fluoro-4-methyl-2-t4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazotl,5,4-de]tl,4]benzoxazine and (S)-8-fluoro-4-methyl-2-t4-(lH-imidazol-4-yl)piperidin-1-yl]-4~5-dihydroimidazo[l~5~4-de]tl,4]benzoxazine.
Some compounds of formula (I) contain an asymmetric ~ 71~79 asymmetric carbon atom. They can therefore exist in the form of enantiomers. These enantiomers, pure or in the form of mixtures, including racemic mixtures, form part of the invention.
The mesomeric forms of the compounds of formula (I) also form part of the invention.
The compounds of formula (I) can be prepared by reaction of a compound of formula (II), in which X, Rl and R2 are as defined in formula (I) and Y represents a halogen atom, in particular a chlorine atom, with a compound of formula ~III), in which R3 is as defined in formula (I), according to Scheme 1.
Scheme 1 (~1) (111) (1) The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to the person skilled in the art.
Thus, the compound of formula (III) in which R3 is a hydrogen atom is described in Arch. Pharmaz., 306 (12), 934-942 (1973).
The compound of formula (III) in which R3 is a methyl group can be prepared according to the process described in EP-A-0,507,650.
The compounds of formula (II), in which Y is a chlorine atom and X, Rl and R2 are as defined in formula (I), can be prepared by the reduction of a compound of formula (IV) ~ % ~ (IV) which is then reacted with urea to give a compound of formula (V) Rl~ >=O (V) ,~,1~
Rz which is then treated with phosphoryl chloride.
The compounds of formula (IV) can be prepared by reaction of a compound of formula (VI) Rl ~ Nx ~ Rz (VI) with bis(1,1-dimethylethyl) dicarbonate, nitration of a compound of formula (VII) coo~- ~u R~ ~ Nx ~ Rz (VII) and hydrolysis of a compound of formula ~VIII) t~2 COO~ U
~N~ (VIII) ~ XJ
Some compounds of formula ~IV) can also be prepared from compounds of formula (IX) NO
~ x ~ (IX) in which X and R2 are as defined in formula (I).
In particular, compounds of formula (IVa) NOz H
Cl ~ x ~ (IVa) can be prepared by chlorination of the compounds of formula (IX).
The preparation of the compound of formula (IX), in which R2 is a methyl group and X an oxygen atom, is described in EP-A-0,646,583.
The compound of formula (IX) in which R2 is a hydrogen atom and X an oxygen atom can be prepared by 217157~
An analogous process.
Compounds of formula ~IVb) ~ ~ R2 (IVb) in which R2 is as defined in formula (I) can also be prepared by nitration of a compound of formula ~X) ~N~R2 (X) The compounds of formula (X) are typically prepared by cyclization of 2-bromo-5-fluorophenol with a compound of formula (XI) HO ~ COO~u (X~
The following Examples illustrate the preparation of compounds according to the present invention. Microanalyses and NMR spectra have confirmed the structures of the products obtained. The (y:x) ratios correspond to the (base:acid) ratio. The numbers between brackets refer to the table given later which 21 7 157~
illustrates the chemical structures and the physical properties of some compounds according to the invention.
Example 1 (Compound No. 1) ~S)-8-chloro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de]~1,4]benzoxazine 1.1. (S)-7-chloro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine 5.82 g (0.030 mol) of (S)-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 135 ml of acetic acid at 45C. 5.16 g (0.038 mol) of _-chlorosuccinimide are rapidly added and the reaction mixture is stirred for 4 hours at 50C. It is then poured into water and extracted 3 times with diethyl ether. The organic phases are combined, washed with water and then with an aqueous sodium hydroxide solution and dried. The solvent is evaporated to dryness.
6.7 g of product are obtained.
Melting point : 95C
1.2. (S)-8-chloro-4-methyl-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazin-2(lH)-one A suspension between 8.9 g (0.039 mol) of (S)-7-chloro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine in 250 ml of ethanol and a catalytic amount 2~ 7 1 579 of Raney nickel are introduced into a Parr apparatus.
Hydrogenation is carried out for 2 hours at room temperature under a pressure of 70 kPa (10 psi). The catalyst is then filtered off and washed with ethanol, the filtrate is recovered and the solvent is evaporated to dryness.
3.4 g ~0.056 mol) of urea are ~dded to the residue thus obtained and heating is carried out with an oil bath at 170-180C for 1 hour. The solid obtained is then taken up in a mixture of water and diethyl ether (50:50), and the precipitate formed is filtered off, washed with diethyl ether and then with water and dried under vacuum over phosphorous pentoxide. 6.3 g of product are obtained, which product is purified by chromatography on a silica gel column with a mixture of dichloromethane and methanol (97:3).
5.2 g of product are obtained.
1.3 (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine 100 ml of phosphoryl chloride are poured onto 5.2 g (0.023 mol) of (S)-8-chloro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(lH)-one.
The mixture is heated at reflux for 2 hours, the solvent is then evaporated to dryness and the residue is taken up in ice-cold water ~nd then in a concentrated aqueous ammonia solution. Extraction is then carried out with diethyl ether, the organic phases are combined and dried and the solvent is evaporated to dryness. 4.5 g of residue are obtained, which residue is purified by chromatography on a silica gel column with a mixture of hexane and ethyl acetate (97:3).
4.1 g of product ~re obtained in the form of an oil.
1.4. ~S)-8-chloro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-l-yl]-4~5-dihydroimidazo-t1,5,4-de][1,4]benzoxazine A mixture of 1.35 g (0.0082 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, 1 g (0.0041 mol) of (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazotl,5,4-de]tl~4]benzoxazine and 4.5 ml of isoamyl alcohol is heated at 120C for 12 hours with stirring. The solvent is then evaporated to dryness and the residue is purified by chromatography on a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5).
After recrystallization from acetone, 0.7 g of product is obtained in the base form.
Melting point : 208C
[~]DO = -23.8 (c = 0.01, methanol) Example 2 (Compound No. 2) (S)-8-chloro-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazotl,5,4-de]tl,4]tbenzoxazine There is obtained, from a mixture of (S)-2,8-dichloro-4-methyl-4,5-dihydroimidazo-21 7 i 57~
g [l~5~4-de]tl~4]benzoxazine and 4-(lH-imidazol-4-yl)piperidine, treated under the conditions of Example 1.4, after recrystallization from acetone, 0.6 g of product in the base form.
S Melting point : 215C
[cr~D = -3-7 (c = O.01, methanol) Example 3 (Compound No. 5) 8-fluoro-2-t4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-5,6-dihydro-4H-imidazot4,5,1-ij]quinoline 3.1. 1,1-dimethylethyl 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate A mixture of 16.5 g ~0.1 mol) of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline and 32 g (0.146 mol) of bis(l,l-dimethylethyl) dicarbonate in 100 ml of 15 tetrahydrofuran is heated at 60C for 3 days. The solvent is then evaporated to dryness and the remaining dicarbonate is driven off using a vane pump. The residue is purified by chromatography on silica gel with a mixture of hexane and ethyl acetate (so:10).
20 24.5 g of product are obtained in the form of an oil.
3.2 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate A solution of 18.4 g (0.0697 mol) of l,l-dimethylethyl 6-fluoro-2-methyl-1,2,3,4-tetrahydroguinoline-1-carboxylate and 13.8 ml 217i~7~
of anhydrous N,N,N',N'-tetramethylethylenediamine in 350 ml of Anhydrous diethyl ether is cooled to -78C.
64.2 ml of a 1.3N solution of sec-butyl iodide in a mixture of cyclohexane and pentane are then added over 30 minutes. The reaction mixture is stirred for 1 hour at -78C and then 12.3 g (0.103 mol) of isobutyl nitrate are added. The reaction mixture is stirred for 1.5 hours at -70C and is then neutralized by being poured into ice-cold water. Extraction is carried out with diethyl ether, the organic phases are combined, washed with water and dried and the solvent is then evaporated to dryness. The residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of hexane and ethyl acetate ~90:10).
8.1 g of product are obtained.
3.3. 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroguinoline A mixture of 8.6 g (0.0261 mol) of 1,1-dimethylethyl 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate, 30 ml of concentrated hydrochloric acid, 20 ml of toluene and 30 ml of water is heated at the reflux temperature for one day. The mixture is then allowed to return to room temperature, separation is carried out by settling and extraction is carried out with toluene. The organic phases are combined, washed with water And dried and the solvent is then evaporated to dryness.
5.6 g of product are obtained.
Melting point: 56C
3.4. 8-fluoro-4-ethyl-5,6-dihydro-4H-imidazo-t4,5,1-i~]quinol-2(lH)-one A suspension of 5.5 g (0.026 mol) of 6-fluoro-2-methyl-8-nitro-1,2,3,4-tetrahydroquinoline in 150 ml of ethanol and a catalytic amount of Raney nickel are introduced into a Parr apparatus and hydrogenation is then carried out for 1 hour at room temperature under a pressure of 0.21 MPa (30 p5i). The catalyst is then filtered off and washed with ethanol, the filtrate is recovered and the solvent i8 evaporated to dryness. The residue is added to 2.6 g (0.043 mol) of urea and heating is carried out with an oil bath at 175C for 1.5 hours. The solid obtained is taken up in a mixture of water and diethyl ether (50:50) and the precipitate formed is then filtered off, washed with diethyl ether and with water and dried under vacuum over phosphorus pentoxide.
4.2 g of product are obtained.
3.5. 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-i~]guinoline 100 ml of phosphoryl chloride are poured onto 4.2 g (0.02 mol) of 8-fluoro-4-methyl-5,6-dihydro-4H-imidazot4,5,1-i ]quinol-2(lH)-one and the mixture is 21 7 1 51~
then heated at reflux for 2 hours. The solvent is then evaporated to dryness and the residue is taken up in ice-cold water And then in a concentrated Aqueous ammonia solution. Extraction is carried out with diethyl ether, the organic phases are combined and dried and the solvent is then evaporated to dryness.
The residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of hexane and ethyl acetate (70:30).
2.4 g of product are obtained.
Melting point : 80C
3.6. 8-fluoro-2-~4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-5,6-dihydro-4H-imidazot4,5,1-ij]guinoline A mixture of 0.94 g ~0.00625 mol) of 4-(lH-imidazol-4-yl)piperidine, 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo-t4,5,1-i~]quinoline and 3.5 ml of isoamyl alcohol is heated at 120C for 18 hours with stirring. The solvent is then evaporated to dryness and the residue is purified by chromatography on a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (95:5:0.5).
After recrystallization from acetone, 0.85 g of product is obtained in the base form.
Melting point : 175-177C
Example 4 (Compound No. 6) 8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-5,6-dihydro-4H-imidazo-[4,5,1-i ]quinoline There is obtained, from 0.7 g (0.0031 mol) of 2-chloro-8-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-i~quinoline and 1 g (0.00623 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, treated under the conditions of Example 3.6, after recrystallization from acetone, 0.7 g of product in the base form.
Melting point : 255C
Example 5 (Compound No. 8) (S)-4-methyl-2-[4-(5-methyl-1-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-8-amine 5.1. (S)-5,7-dinitro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine 7.7 g (0.04 mol) of (S)-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 176 ml of acetic acid at 60C. 2.8 ml (0.044 mol) of nitric acid are added dropwise, the reaction mixture is stirred for 45 minutes at 600C and then 176 ml of water are added. The reaction mixture is cooled to 0C and the precipitate formed is filtered off, washed with water and dried under vacuum.
8.13 g of product are obtained.
Nelting point : 170C
5.2. ~S)-3-methyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazin-5-amine 7.63 g (0.032 mol) of (S)-5,7-dinitro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine are heated to 50C and a solution of 30.52 g (0.391 mol) of sodium sulphide and of 10.70 g of sodium hydrogencarbonate dissolved in 46 ml of water is added dropwise.
This reaction mixture is slowly brought to the reflux temperature and then, after stirring for 30 minutes, a quantity of water is poured in. The reaction mixture is allowed to cool and is extracted three times with ethyl ether. The organic phases are combined, washed with water and dried and the solvent is then evaporated to dryness.
5.98 g of product are obtained.
5.3. (S~-4-methyl-8-nitro-4,5-dihydroimidazo-t1,5,4-de]tl,4]benzoxazin-2(lH)-one 3.43 g (0.057 mol) of urea are added to 5.98 g (0.029 mol) of (S)-3-methyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazin-5-amine and the mixture is heated for 2 hours at 175C. It is taken up in boiling water and the precipitate is filtered off and washed with water.
The filtrate is extracted with dichloromethane and the organic extracts are washed with water, dried and evaporated under vacuum. The residue is purified by 2171~79 chromatography on a silica gel column, elution being carried out with a dichloromethane:methanol (98:2) mixture.
3.86 g of product are obtained.
5.4. ~S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazotl,5,4-de]tl,4]benzoxazine 3.86 g of (0.021 mol) of (S)-4-methyl-8-nitro-4,5-dihydroimidazot1,5,4-de][l,4]benzoxazin-2(lH)-one are heated at the reflux temperature for 3 hours in the presence of 76 ml of phosphoryl chloride.
The solvent is evaporated to dryness and the residue is taken up in ice. The reaction mixture is basified with agueous ammonia and the precipitate formed is filtered off, rinsed with water and pulled dry. It is dried in a vacuum oven. The residue is purified by chromatography on a silica gel column, elution being carried out with a dichloromethane:methanol ~99:1) mixture.
3.6 g of product are obtained.
5.5. (S)-4-methyl-8-nitro-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de]tl,4]benzoxazine A mixture of 1.87 g (0.00788 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, 1 g (0.00394 mol) of (S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazotl,5,4-de][1,4]benzoxazine and 5 ml of isoamyl alcohol is heated at 120C for 5 hours with 2 i 7 1 57~
stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (94:6:0.6).
After recrystallization from ethanol, 1.3 g of product are obtained in the base form.
Melting point : 125C
5.6. (S)-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazin-8-amine A suspension of 1.1 g (0.00287 mol) of (S)-4-methyl-8-nitro-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine in 50 ml of ethanol and a catalytic amount of platinum oxide are introduced into a Parr flask and hydrogenation is then carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and washed with ethanol and with ethyl acetate, the filtrate is recovered and the solvent is evaporated to dryness.
0.8 g of product is obtained, which product crystallizes in the base form.
Melting point : 245C
[~] 20 = -23.4 (c = 0.01, methanol).
Example 6 (Compound No. 7) (S)-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-8-amine There are obtained, from a mixture of (S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazo-[1,5,4-de]tl,4]benzoxazine and 4-(lH-imidazol-4-yl)piperidine, treated under the conditions of Example 5.5, after chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (94:6:0.6), 1.3 g of product, which product is treated under the conditions of Example 5.6.
0.7 g of product is obtained in the base form.
Nelting point : 235-238C
[~] 20 = _ 1. 4 (c = 0.01, methanol) Example 7 (Compound No. 14) (S)-8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[l~5~4-de][1,4]benzoxazine 7.1. 1,1-dimethylethyl (S)-[2-(2-bromo-5-fluorophenoxy)-1-methylethyl]carbamate 130 g (0.74 mol) of 1,1-dimethylethyl (S)-(2-hydroxy-1-methylethyl)carbamate and 191 g ~0.728 mol) of triphenylphosphine are placed in a 4-litre three-necked, round-bottomed flask containing 2.3 litres of toluene. The mixture is cooled with an ice 2171~7~
bath and 115 ml (0.726 mol) of diethyl azodicarboxylate are added dropwise. The reaction mixture is left stirring for 1 hour, 100 g (0.52 mol) of 2-bromo-5-fluorophenol are added dropwise, the reaction mixture is stirred for 2 hours at 0C, the temperature of the reaction mixture is allowed to return to room temperature and the reaction mixture is left stirring overnight. The precipitate obtained is then filtered off ~nd the filtrate is washed with lN sodium hydroxide solution and water, dried and evaporated. The residue obtained is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane and heptane (70:30).
170 g of product are obtained.
[~]20 = _ 45.6O (c = 0.01, dichloromethane) 7.2. ~S)-1-(2-bromo-5-fluorophenoxy)propan-2-amine 170 g (0.48 mol) of 1,1-dimethylethyl (S)-t2-(2-bromo-5-fluorophenoxy)-1-methylethyl]carbamate dissolved in 520 ml of water and 260 ml of 12N
hydrochloric acid are heated at reflux for 2 hours.
500 ml of ice-cold water are poured in and extraction is carried out once with 600 ml of toluene and once with 400 ml of ether. The aqueous phase is cooled in an ice-cold water bath and is basified with lON sodium hydroxide solution. Extraction is carried out three times with 500 ml of ether and the organic phases are combined, washed twice with water and once with a 2`171~79 saturated aqueous sodium chloride solution, dried and evaporated under reduced pressure.
118 g of product are obtained in the form of an oil.
[C~]D0 = ~ 2.8 (c = 0.01, dichloromethAne) 7.3. (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine 72 g (0.768 mol) of sodium tert-butoxide are placed in 1 litre of toluene in a 4-litre three-necked flask under an inert atmosphere. 5 g of tetrakis(triphenylphosphine)palladium and then a solution of 120 g (0.48 mol) of (S)-1-(2-bromo-5-fluorophenoxy)propan-2-amine in 250 ml of toluene are ~dded. The reaction mixture is heated to 110C and is left stirring for 2.5 hours. 3 g of catalyst are again added and, after stirring for 5.5 hours at 110C, the reaction mixture is allowed to cool and 1 litre of water is added. The reaction mixture is stirred, is allowed to separate by settling and the aqueous layer is extracted with toluene. The organic phases are combined, washed with water and dried and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a silica gel column, elution being carried out with dichloromethane.
21.5 g of product are obtained.
[tr]20 = - 4.8 (c = 0.01, methanol) 7.4. (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine A solution of 21.5 g (0.128 mol) of (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine in 60 ml of pyridine is cooled with an ice bath, 15.1 g (0.15 mol) of acetic anhydride are added and the mixture is allowed to return to room temperature And is stirred for 48 hours. It is poured onto ice-cold water and extracted twice with ether. The organic phases are combined, washed successively with water, with dilute hydrochloric acid, with water and with brine and are then dried and the solvent is evaporated under reduced pressure.
24.2 g of product are obtained.
t~] 20 = t 102.9 (c = o.01, dichloromethane) 7.5. ~S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine 24 g (0.114 mol) of (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 350 ml of acetic acid. 8.4 ml (0.134 mol) of nitric acid are added dropwise and the reaction mixture is left stirring for 4 hours at approximately 100C. The acetic acid is evaporated under reduced pressure, 100 ml of toluene and 500 ml of 3N sodium hydroxide solution are added and the reaction mixture is left stirring at the reflux temperature for 3 hours. The reaction mixture is separated by settling and the agueous layer is extracted with toluene. The organic phases are combined, washed with water, dried and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane and heptane (50:50). Two products are separated.
3.8 g of (S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are obtained Melting point : 116C
t~20 = - 65 (c = 0.016, dichloromethane) and 15 g of its regioisomer, (S)-7-fluoro-3-methyl-6-nitro-3,4-dihydro-2_-1,4-benzoxazine are obtained Melting point : 132C
[~] 20 = _79.7 (c = 0.01, dichloromethane) 7.6. (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine A solution of 3.45 g (0.0162 mol) of ~S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine in 90 ml of ethanol and a catalytic amountof platinum oxide are introduced into a Parr flask.
Hydrogenation is carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and washed with ethanol, the filtrate is recovered and the solvent is evaporated to dryness. 2.9 g of crystalline product are obtained.
Melting point : 72C
2 1 7 1~79 [~]D0 = _ 70.30 (c = 0.01, dichloromethane) 7.7. (8)-8-fluoro-4-methyl-4,5-dihydroimidazo-tl,5,4-de][1,4]benzoxazin-2(lH)-one 2.9 g (0.0162 mol) of (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine are heated at 175C with an oil bath for 1.5 hours in the presence of 1.8 g (0.03 mol) of urea. The residue is taken up in a water:ether (50:50) mixture and is triturated in order to obtain a precipitate which is filtered off, washed with water and with ether and then dried.
3.1 g of product are obtained.
Melting point : 175C
t~ 20 = + 33.9o (c = o.o1, dimethylformamide) 7.8. (S)-2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de]t1,4]benzoxazine 3.1 g (0.0148 mol) of tS)-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(lH)-one are heated at the reflux temperature for 3 hours in 70 ml of phosphoryl chloride. The solvent is evaporated to dryness, the residue is taken up in ice-cold water and the pH of the mixture is adjusted to 8 with aqueous ammonia. Extraction is carried out twice with ether, the organic phases are combined, washed with water and dried and the solvent is evaporated to dryness.
Purification is carried out by chromatography on a silica gel column, elution being carried out with a 2l7 l 57~
mixture of ethyl acetate and heptane (50:50).
1.85 g of product are obtained.
Melting point : 102C
[~]DO = _ 15.85 (c = 0.01, dichloromethane) 7.9. ~S)-8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine A mixture of 1.47 g (0.00617 mol) of 4-(5-methyl-la-imidazol-4-yl)piperidine, 0.7 g (0.00308 mol) of (S)-2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine and 4 ml of isoamyl alcohol is heated at 120C for 24 hours with stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and agueous ammonia (95/5/0.5)-After recrystallization from ethanol, 0.6 g of product is obtained in the base form.
Melting point: 224C
[~]20 = _ 11.0 (c = 0.991, methanol) Example 8 (Compound No. 13) (S)-8-fluoro-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (Z)-but-2-enedioate (1:2) There is obtained, from a mixture of (S)-21 71~79 2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine and 4-~lH-imidazol-4-yl)piperidine, treated under the conditions of Example 7.9., the product in the base form which is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5).
By adding to the base two equivalents of maleic acid in methanol, 0.26 g of maleate is obtained.
Melting point : 142C
[h]20 = + 8.13 (c = 0.504, methanol) Rey to the table :
in the "Salt" column : the ratio between brackets represents the ratio (salt:base); the absence of any mention means that the product is in the base form; "HCl" corresponds to a hydrochloride and "mal."
corresponds to a maleate 2171~79 ~ o ~
.C N ~ N
t~
P~ U a~ 0 N 1 O .~
_ N N N NU~ N Ul N
~I N
,1~1 ~r ~ I 1 5 ~ I I I I
Z~
f ~ ~ U~ I I U~ I U
~ZJ
Z~z~ I X ~ U~
)~x U U U U
,~ ~
# O O O O ~ ~ O O
2 i 7 1~7~
., --, ..
~, o ,, ., ,c I I I I 1 r~ N ~ N N ~ ~ N
o~J Ir~ ~ ~ N
~, _~1 0 ~ ~ N r~
~I
U ~ U C~
P: I I I I I I I I
X O O O O O O O O -I
O 0, o ,1 ~, 1 n ,, 0 o o o U ~, 21 71~9 The compounds of the invention formed the subject of pharmacological tests which demonstrAted their advantage as therapeutically active substances.
They were in particular tested for their inhibitory effects on the binding of t3H]-(8)-zacopride to type 5-HT3 serotoninergic receptors of the rat cortex, according to the method described by N.M. Barnes et al., in J. Pharm. Pharmacol., ~0, 548-551 ~1988).
Male Sprague-Dawley rats (OFA, Iffa credo) weighing 200 to 250 g are humanely killed and their brains are removed. The cortex is dissected and is homogenized using a Polytron- mill (7.20 s position) in 20 volumes of 25 mM Tris buffer ~pH = 7.4, 22C). The homogenate is centrifuged for 10 min at 45000 x g (in a 8Orvall centrifuge equipped with an 8S34 rotor) and the pellet is then resuspended in 10 volumes of Tris buffer and incubated at 37C for 10 min with stirring. The suspension is then diluted to 20 volumes using Tris buffer and centrifuging is carried out under the same conditions as above. The pellet obtained is resuspended in 5 volumes of Tris buffer and then divided into 5 ml aliquot fractions which are frozen at -80C. On the day of the experiment, the preparation is defrosted to 4C
and then diluted 1.2 times using Tris-NaCl incubation buffer (25 mM Tris, 150 mM NaCl, pH = 7.4, 22C).
The membrane suspension (100 ~1, 1 mg of proteins) is incubated at 25C for 25 min in the presence of 0.5 nM
of [3H]-(S)-zacopride (specific activity :
75-85 Ci/mmol, Amersham, Little Chalfont, United Kingdom) in a final volume of 500 ~l Tris-NaCl buffer, in the absence or in the presence of the test compound.
Incubation is halted by filtration using ~hatman GF/B
filters pretreated with polyethyleneimine (0.1%). Each reaction tube is prediluted with 4 ml of Tris-NaCl buffer and then rinsed 3 times with 4.5 ml of Tris-NaCl buffer.
The filters are cut up beforehand before drying in an oven (120C, 5 min). The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 10 ~M
of MDL 72222.
For each concentration of study compound, the percentage of inhibition of the specific binding of [3H]-(S)-zacopride and then the concentration of the compound which inhibits 50% of the specific binding of [3H]-(S)-zacopride (IC50) are determined.
The IC50 values of the compounds of the invention lie between 0.5 nM and 1 ~M.
The compounds of the invention were also studied for their affinity with respect to 5-HT4 receptors in the striatum of guinea pigs according to the method described by Grossman et al. in Br. J.
Pharmacol., 109, 618-624 (1993).
Guinea pigs ~Hartley, Charles River) weighing 300 to 400 g are humanely killed and their brains are removed.
217157~
The striata are excised and are frozen at -80C. On the day of the experiment, the tissue is defrosted to +4C
in 33 volumes of 50 mM Hepes-NaOH buffer (pH 7.4 at 20C) ~nd is homogenized using a Polytron~ mill. The homogenate is centrifuged for 10 min at 48,000 x g, the pellet is recovered, i8 resuspended and is recentrifuged under the same conditions. The final pellet is suspended in Hepes-NaOH buffer l30 mg of fresh tissue/ml). This membrane suspension is used as iS.
100 ~l of the membrane suspension are incubated at 0C
for 120 minutes, in the presence of 0.1 nM of [~]GR113808 (specific activity 80-85 Ci/mmol), in a final volume of 1 ml of Hepes-NaOH buffer (50 mM, pH =
7.4), in the absence or in the presence of the compound under test. Incubation is halted by filtration through Whatman GF/BR filters pretreated with 0.1%
polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0C and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 30 ~M serotonin.
The specific binding represents 90% of the total radioactivity recovered on the filter.
For each concentration of study compound, the percentage of inhibition of the specific binding of [3H]GR118808 and then the concentration of the tested compound which inhibits 50% of the specific binding (IC~) are determined.
The IC~ values of the compounds of the invention lie between 0.02 and 2 ~M.
The results of the biological tests show that the compounds of the invention are antagonists of 5-HT3 And/or 5-HT4 serotoninergic receptors.
They may hence be used for the treatment and prevention of disorders in which 5-HT3 and 5-HT4 receptors are involved, such as nausea and vomiting, for example following antitumour treatment or the administration of an anaesthetic; disorders of the central nervous system such as schizophrenia, mania, anxiety and depression;
disorders of cognition such as senile dementia or Alzheimer's presenile dementia; dyskinesia, pain, migraine and headache; disorders associated with alcohol or drug dependence or withdrawal; disorders of gastrointestinal function such as dyspepsia, peptic ulcer, heartburn, flatulence; disorders of the cardiovascular system and respiratory disorders.
They may also be used for the treatment and prevention of disorders such as diarrhoea, irritable colon, oesophageal reflux, intestinal motor disorders, disorders of intestinal secretion, cystic fibrosis of the pancreas, carcinoid syndrome and incontinence.
The present invention also provides a pharmaceutical composition which comprises a compound of formula (I) and an excipient, which may be in any form suitable for oral or parenteral administration, 2l71579 such as a tablet, dragée, capsule, including a hard gelatin capsule, or a suspension or solution to be swallowed or injected, and in doses that enable 0.005 to 5 mg/kg to be administered 1 to 4 times a day.
The present invention al~o provides a compound of formula (I) for use in a method of treatment of the human or animal body.
The present invention further provides the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment or prevention of a disorder in which 5-HT3 and/or 5-HT4 receptors are involved.
There is also disclosed a method of treatment of a subject suffering from a disorder in which 5-HT3 and/or 5-HT4 receptors are involved which comprises administering to that subject an effective amount of a compound of formula (I).
The present invention also provides a composition for treating or preventing a disorder in which 5-HT3 and/or 5-HT4 receptors are involved comprising a compound of formula (I) and a pharmaceutically acceptable adjuvant.
Nelting point : 170C
5.2. ~S)-3-methyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazin-5-amine 7.63 g (0.032 mol) of (S)-5,7-dinitro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine are heated to 50C and a solution of 30.52 g (0.391 mol) of sodium sulphide and of 10.70 g of sodium hydrogencarbonate dissolved in 46 ml of water is added dropwise.
This reaction mixture is slowly brought to the reflux temperature and then, after stirring for 30 minutes, a quantity of water is poured in. The reaction mixture is allowed to cool and is extracted three times with ethyl ether. The organic phases are combined, washed with water and dried and the solvent is then evaporated to dryness.
5.98 g of product are obtained.
5.3. (S~-4-methyl-8-nitro-4,5-dihydroimidazo-t1,5,4-de]tl,4]benzoxazin-2(lH)-one 3.43 g (0.057 mol) of urea are added to 5.98 g (0.029 mol) of (S)-3-methyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazin-5-amine and the mixture is heated for 2 hours at 175C. It is taken up in boiling water and the precipitate is filtered off and washed with water.
The filtrate is extracted with dichloromethane and the organic extracts are washed with water, dried and evaporated under vacuum. The residue is purified by 2171~79 chromatography on a silica gel column, elution being carried out with a dichloromethane:methanol (98:2) mixture.
3.86 g of product are obtained.
5.4. ~S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazotl,5,4-de]tl,4]benzoxazine 3.86 g of (0.021 mol) of (S)-4-methyl-8-nitro-4,5-dihydroimidazot1,5,4-de][l,4]benzoxazin-2(lH)-one are heated at the reflux temperature for 3 hours in the presence of 76 ml of phosphoryl chloride.
The solvent is evaporated to dryness and the residue is taken up in ice. The reaction mixture is basified with agueous ammonia and the precipitate formed is filtered off, rinsed with water and pulled dry. It is dried in a vacuum oven. The residue is purified by chromatography on a silica gel column, elution being carried out with a dichloromethane:methanol ~99:1) mixture.
3.6 g of product are obtained.
5.5. (S)-4-methyl-8-nitro-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de]tl,4]benzoxazine A mixture of 1.87 g (0.00788 mol) of 4-(5-methyl-lH-imidazol-4-yl)piperidine, 1 g (0.00394 mol) of (S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazotl,5,4-de][1,4]benzoxazine and 5 ml of isoamyl alcohol is heated at 120C for 5 hours with 2 i 7 1 57~
stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (94:6:0.6).
After recrystallization from ethanol, 1.3 g of product are obtained in the base form.
Melting point : 125C
5.6. (S)-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazin-8-amine A suspension of 1.1 g (0.00287 mol) of (S)-4-methyl-8-nitro-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine in 50 ml of ethanol and a catalytic amount of platinum oxide are introduced into a Parr flask and hydrogenation is then carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and washed with ethanol and with ethyl acetate, the filtrate is recovered and the solvent is evaporated to dryness.
0.8 g of product is obtained, which product crystallizes in the base form.
Melting point : 245C
[~] 20 = -23.4 (c = 0.01, methanol).
Example 6 (Compound No. 7) (S)-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-8-amine There are obtained, from a mixture of (S)-2-chloro-4-methyl-8-nitro-4,5-dihydroimidazo-[1,5,4-de]tl,4]benzoxazine and 4-(lH-imidazol-4-yl)piperidine, treated under the conditions of Example 5.5, after chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (94:6:0.6), 1.3 g of product, which product is treated under the conditions of Example 5.6.
0.7 g of product is obtained in the base form.
Nelting point : 235-238C
[~] 20 = _ 1. 4 (c = 0.01, methanol) Example 7 (Compound No. 14) (S)-8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[l~5~4-de][1,4]benzoxazine 7.1. 1,1-dimethylethyl (S)-[2-(2-bromo-5-fluorophenoxy)-1-methylethyl]carbamate 130 g (0.74 mol) of 1,1-dimethylethyl (S)-(2-hydroxy-1-methylethyl)carbamate and 191 g ~0.728 mol) of triphenylphosphine are placed in a 4-litre three-necked, round-bottomed flask containing 2.3 litres of toluene. The mixture is cooled with an ice 2171~7~
bath and 115 ml (0.726 mol) of diethyl azodicarboxylate are added dropwise. The reaction mixture is left stirring for 1 hour, 100 g (0.52 mol) of 2-bromo-5-fluorophenol are added dropwise, the reaction mixture is stirred for 2 hours at 0C, the temperature of the reaction mixture is allowed to return to room temperature and the reaction mixture is left stirring overnight. The precipitate obtained is then filtered off ~nd the filtrate is washed with lN sodium hydroxide solution and water, dried and evaporated. The residue obtained is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane and heptane (70:30).
170 g of product are obtained.
[~]20 = _ 45.6O (c = 0.01, dichloromethane) 7.2. ~S)-1-(2-bromo-5-fluorophenoxy)propan-2-amine 170 g (0.48 mol) of 1,1-dimethylethyl (S)-t2-(2-bromo-5-fluorophenoxy)-1-methylethyl]carbamate dissolved in 520 ml of water and 260 ml of 12N
hydrochloric acid are heated at reflux for 2 hours.
500 ml of ice-cold water are poured in and extraction is carried out once with 600 ml of toluene and once with 400 ml of ether. The aqueous phase is cooled in an ice-cold water bath and is basified with lON sodium hydroxide solution. Extraction is carried out three times with 500 ml of ether and the organic phases are combined, washed twice with water and once with a 2`171~79 saturated aqueous sodium chloride solution, dried and evaporated under reduced pressure.
118 g of product are obtained in the form of an oil.
[C~]D0 = ~ 2.8 (c = 0.01, dichloromethAne) 7.3. (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine 72 g (0.768 mol) of sodium tert-butoxide are placed in 1 litre of toluene in a 4-litre three-necked flask under an inert atmosphere. 5 g of tetrakis(triphenylphosphine)palladium and then a solution of 120 g (0.48 mol) of (S)-1-(2-bromo-5-fluorophenoxy)propan-2-amine in 250 ml of toluene are ~dded. The reaction mixture is heated to 110C and is left stirring for 2.5 hours. 3 g of catalyst are again added and, after stirring for 5.5 hours at 110C, the reaction mixture is allowed to cool and 1 litre of water is added. The reaction mixture is stirred, is allowed to separate by settling and the aqueous layer is extracted with toluene. The organic phases are combined, washed with water and dried and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a silica gel column, elution being carried out with dichloromethane.
21.5 g of product are obtained.
[tr]20 = - 4.8 (c = 0.01, methanol) 7.4. (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine A solution of 21.5 g (0.128 mol) of (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine in 60 ml of pyridine is cooled with an ice bath, 15.1 g (0.15 mol) of acetic anhydride are added and the mixture is allowed to return to room temperature And is stirred for 48 hours. It is poured onto ice-cold water and extracted twice with ether. The organic phases are combined, washed successively with water, with dilute hydrochloric acid, with water and with brine and are then dried and the solvent is evaporated under reduced pressure.
24.2 g of product are obtained.
t~] 20 = t 102.9 (c = o.01, dichloromethane) 7.5. ~S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine 24 g (0.114 mol) of (S)-4-acetyl-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine are dissolved in 350 ml of acetic acid. 8.4 ml (0.134 mol) of nitric acid are added dropwise and the reaction mixture is left stirring for 4 hours at approximately 100C. The acetic acid is evaporated under reduced pressure, 100 ml of toluene and 500 ml of 3N sodium hydroxide solution are added and the reaction mixture is left stirring at the reflux temperature for 3 hours. The reaction mixture is separated by settling and the agueous layer is extracted with toluene. The organic phases are combined, washed with water, dried and evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane and heptane (50:50). Two products are separated.
3.8 g of (S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine are obtained Melting point : 116C
t~20 = - 65 (c = 0.016, dichloromethane) and 15 g of its regioisomer, (S)-7-fluoro-3-methyl-6-nitro-3,4-dihydro-2_-1,4-benzoxazine are obtained Melting point : 132C
[~] 20 = _79.7 (c = 0.01, dichloromethane) 7.6. (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine A solution of 3.45 g (0.0162 mol) of ~S)-7-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-1,4-benzoxazine in 90 ml of ethanol and a catalytic amountof platinum oxide are introduced into a Parr flask.
Hydrogenation is carried out for 1 hour at room temperature under a pressure of 0.28 MPa (40 psi). The catalyst is filtered off and washed with ethanol, the filtrate is recovered and the solvent is evaporated to dryness. 2.9 g of crystalline product are obtained.
Melting point : 72C
2 1 7 1~79 [~]D0 = _ 70.30 (c = 0.01, dichloromethane) 7.7. (8)-8-fluoro-4-methyl-4,5-dihydroimidazo-tl,5,4-de][1,4]benzoxazin-2(lH)-one 2.9 g (0.0162 mol) of (S)-7-fluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine are heated at 175C with an oil bath for 1.5 hours in the presence of 1.8 g (0.03 mol) of urea. The residue is taken up in a water:ether (50:50) mixture and is triturated in order to obtain a precipitate which is filtered off, washed with water and with ether and then dried.
3.1 g of product are obtained.
Melting point : 175C
t~ 20 = + 33.9o (c = o.o1, dimethylformamide) 7.8. (S)-2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de]t1,4]benzoxazine 3.1 g (0.0148 mol) of tS)-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(lH)-one are heated at the reflux temperature for 3 hours in 70 ml of phosphoryl chloride. The solvent is evaporated to dryness, the residue is taken up in ice-cold water and the pH of the mixture is adjusted to 8 with aqueous ammonia. Extraction is carried out twice with ether, the organic phases are combined, washed with water and dried and the solvent is evaporated to dryness.
Purification is carried out by chromatography on a silica gel column, elution being carried out with a 2l7 l 57~
mixture of ethyl acetate and heptane (50:50).
1.85 g of product are obtained.
Melting point : 102C
[~]DO = _ 15.85 (c = 0.01, dichloromethane) 7.9. ~S)-8-fluoro-4-methyl-2-[4-(5-methyl-lH-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine A mixture of 1.47 g (0.00617 mol) of 4-(5-methyl-la-imidazol-4-yl)piperidine, 0.7 g (0.00308 mol) of (S)-2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine and 4 ml of isoamyl alcohol is heated at 120C for 24 hours with stirring. The solvent is evaporated to dryness and the residue is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and agueous ammonia (95/5/0.5)-After recrystallization from ethanol, 0.6 g of product is obtained in the base form.
Melting point: 224C
[~]20 = _ 11.0 (c = 0.991, methanol) Example 8 (Compound No. 13) (S)-8-fluoro-2-[4-(lH-imidazol-4-yl)piperidin-1-yl]-4-methyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (Z)-but-2-enedioate (1:2) There is obtained, from a mixture of (S)-21 71~79 2-chloro-8-fluoro-4-methyl-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine and 4-~lH-imidazol-4-yl)piperidine, treated under the conditions of Example 7.9., the product in the base form which is purified by chromatography on a silica gel column, elution being carried out with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5).
By adding to the base two equivalents of maleic acid in methanol, 0.26 g of maleate is obtained.
Melting point : 142C
[h]20 = + 8.13 (c = 0.504, methanol) Rey to the table :
in the "Salt" column : the ratio between brackets represents the ratio (salt:base); the absence of any mention means that the product is in the base form; "HCl" corresponds to a hydrochloride and "mal."
corresponds to a maleate 2171~79 ~ o ~
.C N ~ N
t~
P~ U a~ 0 N 1 O .~
_ N N N NU~ N Ul N
~I N
,1~1 ~r ~ I 1 5 ~ I I I I
Z~
f ~ ~ U~ I I U~ I U
~ZJ
Z~z~ I X ~ U~
)~x U U U U
,~ ~
# O O O O ~ ~ O O
2 i 7 1~7~
., --, ..
~, o ,, ., ,c I I I I 1 r~ N ~ N N ~ ~ N
o~J Ir~ ~ ~ N
~, _~1 0 ~ ~ N r~
~I
U ~ U C~
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X O O O O O O O O -I
O 0, o ,1 ~, 1 n ,, 0 o o o U ~, 21 71~9 The compounds of the invention formed the subject of pharmacological tests which demonstrAted their advantage as therapeutically active substances.
They were in particular tested for their inhibitory effects on the binding of t3H]-(8)-zacopride to type 5-HT3 serotoninergic receptors of the rat cortex, according to the method described by N.M. Barnes et al., in J. Pharm. Pharmacol., ~0, 548-551 ~1988).
Male Sprague-Dawley rats (OFA, Iffa credo) weighing 200 to 250 g are humanely killed and their brains are removed. The cortex is dissected and is homogenized using a Polytron- mill (7.20 s position) in 20 volumes of 25 mM Tris buffer ~pH = 7.4, 22C). The homogenate is centrifuged for 10 min at 45000 x g (in a 8Orvall centrifuge equipped with an 8S34 rotor) and the pellet is then resuspended in 10 volumes of Tris buffer and incubated at 37C for 10 min with stirring. The suspension is then diluted to 20 volumes using Tris buffer and centrifuging is carried out under the same conditions as above. The pellet obtained is resuspended in 5 volumes of Tris buffer and then divided into 5 ml aliquot fractions which are frozen at -80C. On the day of the experiment, the preparation is defrosted to 4C
and then diluted 1.2 times using Tris-NaCl incubation buffer (25 mM Tris, 150 mM NaCl, pH = 7.4, 22C).
The membrane suspension (100 ~1, 1 mg of proteins) is incubated at 25C for 25 min in the presence of 0.5 nM
of [3H]-(S)-zacopride (specific activity :
75-85 Ci/mmol, Amersham, Little Chalfont, United Kingdom) in a final volume of 500 ~l Tris-NaCl buffer, in the absence or in the presence of the test compound.
Incubation is halted by filtration using ~hatman GF/B
filters pretreated with polyethyleneimine (0.1%). Each reaction tube is prediluted with 4 ml of Tris-NaCl buffer and then rinsed 3 times with 4.5 ml of Tris-NaCl buffer.
The filters are cut up beforehand before drying in an oven (120C, 5 min). The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 10 ~M
of MDL 72222.
For each concentration of study compound, the percentage of inhibition of the specific binding of [3H]-(S)-zacopride and then the concentration of the compound which inhibits 50% of the specific binding of [3H]-(S)-zacopride (IC50) are determined.
The IC50 values of the compounds of the invention lie between 0.5 nM and 1 ~M.
The compounds of the invention were also studied for their affinity with respect to 5-HT4 receptors in the striatum of guinea pigs according to the method described by Grossman et al. in Br. J.
Pharmacol., 109, 618-624 (1993).
Guinea pigs ~Hartley, Charles River) weighing 300 to 400 g are humanely killed and their brains are removed.
217157~
The striata are excised and are frozen at -80C. On the day of the experiment, the tissue is defrosted to +4C
in 33 volumes of 50 mM Hepes-NaOH buffer (pH 7.4 at 20C) ~nd is homogenized using a Polytron~ mill. The homogenate is centrifuged for 10 min at 48,000 x g, the pellet is recovered, i8 resuspended and is recentrifuged under the same conditions. The final pellet is suspended in Hepes-NaOH buffer l30 mg of fresh tissue/ml). This membrane suspension is used as iS.
100 ~l of the membrane suspension are incubated at 0C
for 120 minutes, in the presence of 0.1 nM of [~]GR113808 (specific activity 80-85 Ci/mmol), in a final volume of 1 ml of Hepes-NaOH buffer (50 mM, pH =
7.4), in the absence or in the presence of the compound under test. Incubation is halted by filtration through Whatman GF/BR filters pretreated with 0.1%
polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0C and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 30 ~M serotonin.
The specific binding represents 90% of the total radioactivity recovered on the filter.
For each concentration of study compound, the percentage of inhibition of the specific binding of [3H]GR118808 and then the concentration of the tested compound which inhibits 50% of the specific binding (IC~) are determined.
The IC~ values of the compounds of the invention lie between 0.02 and 2 ~M.
The results of the biological tests show that the compounds of the invention are antagonists of 5-HT3 And/or 5-HT4 serotoninergic receptors.
They may hence be used for the treatment and prevention of disorders in which 5-HT3 and 5-HT4 receptors are involved, such as nausea and vomiting, for example following antitumour treatment or the administration of an anaesthetic; disorders of the central nervous system such as schizophrenia, mania, anxiety and depression;
disorders of cognition such as senile dementia or Alzheimer's presenile dementia; dyskinesia, pain, migraine and headache; disorders associated with alcohol or drug dependence or withdrawal; disorders of gastrointestinal function such as dyspepsia, peptic ulcer, heartburn, flatulence; disorders of the cardiovascular system and respiratory disorders.
They may also be used for the treatment and prevention of disorders such as diarrhoea, irritable colon, oesophageal reflux, intestinal motor disorders, disorders of intestinal secretion, cystic fibrosis of the pancreas, carcinoid syndrome and incontinence.
The present invention also provides a pharmaceutical composition which comprises a compound of formula (I) and an excipient, which may be in any form suitable for oral or parenteral administration, 2l71579 such as a tablet, dragée, capsule, including a hard gelatin capsule, or a suspension or solution to be swallowed or injected, and in doses that enable 0.005 to 5 mg/kg to be administered 1 to 4 times a day.
The present invention al~o provides a compound of formula (I) for use in a method of treatment of the human or animal body.
The present invention further provides the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment or prevention of a disorder in which 5-HT3 and/or 5-HT4 receptors are involved.
There is also disclosed a method of treatment of a subject suffering from a disorder in which 5-HT3 and/or 5-HT4 receptors are involved which comprises administering to that subject an effective amount of a compound of formula (I).
The present invention also provides a composition for treating or preventing a disorder in which 5-HT3 and/or 5-HT4 receptors are involved comprising a compound of formula (I) and a pharmaceutically acceptable adjuvant.
Claims (10)
1. A compound of formula (I) (I) in which X represents an oxygen atom or a methylene group, R1 represents a chlorine or fluorine atom or a methyl, methoxy or amino group, and R2 and R3 independently represent a hydrogen atom or a methyl group, in the form of the free base or an addition salt with a pharmaceutically acceptable acid.
2. A compound according to claim 1 which is in the form of a pure enantiomer.
3. A compound according to claim 1 or 2, in which X represents an oxygen atom and R1 is at position 8 on the phenyl ring.
4. (S)-8-Fluoro-4-methyl-2-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine in the form of the free base or an addition salt with a pharmaceutically acceptable acid.
5. (S)-8-Fluoro-4-methyl-2-[4-(1H-imidazol-4-yl)piperidin-1-yl]-4,5-dihydroimidazo-[1,5,4-de][1,4]benzoxazine in the form of the free base or an addition salt with a pharmaceutically acceptable acid.
6. A process for the preparation of a compound of formula (I) according to claim 1, in which process a compound of formula (II) (II) in which X, R1 and R2 are as defined in claim 1 and Y
represents a halogen atom, is reacted with a compound of formula (III) (III) in which R3 is as defined in claim 1 to give a compound of formula (I) and optionally converting the compound obtained into a salt thereof with a pharmaceutically acceptable acid.
represents a halogen atom, is reacted with a compound of formula (III) (III) in which R3 is as defined in claim 1 to give a compound of formula (I) and optionally converting the compound obtained into a salt thereof with a pharmaceutically acceptable acid.
7. A compound of formula (I) according to claim 1 whenever prepared by the process of claim 6.
8. A pharmaceutical composition which comprises a compound of formula (I) according to claim 1, 4 or 5 and an excipient.
9. A compound of formula (I) as defined in claim 1, 4 or 5 for use in a method of treatment of the human or animal body.
10. A composition for treating or preventing a disorder in which 5-HT3 and/or 5-HT4 receptors are involved comprising a compound of formula (I) as defined in any one of claims 1, 4 and 5 and a pharmaceutically acceptable adjuvant.
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| Application Number | Priority Date | Filing Date | Title |
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| FR9502863A FR2731708B1 (en) | 1995-03-13 | 1995-03-13 | PIPERIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
| FR9502863 | 1995-03-13 |
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| CA002171579A Abandoned CA2171579A1 (en) | 1995-03-13 | 1996-03-12 | Piperidine derivatives, process for the preparation thereof and application thereof in therapeutics |
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| Country | Link |
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| EP (1) | EP0732334A1 (en) |
| JP (1) | JPH08269058A (en) |
| KR (1) | KR960034205A (en) |
| CN (1) | CN1140174A (en) |
| AU (1) | AU4800896A (en) |
| CA (1) | CA2171579A1 (en) |
| CZ (1) | CZ75496A3 (en) |
| FR (1) | FR2731708B1 (en) |
| HU (1) | HUP9600624A2 (en) |
| IL (1) | IL117455A0 (en) |
| NO (1) | NO961000L (en) |
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| ATE284886T1 (en) * | 2000-08-08 | 2005-01-15 | Sanofi Aventis | BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE |
| FR2816941B1 (en) * | 2000-11-23 | 2003-01-31 | Sanofi Synthelabo | BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| JP2021530442A (en) * | 2018-06-28 | 2021-11-11 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co., Ltd. | Condensed tricyclic heterocyclic compounds and their therapeutic use |
Family Cites Families (3)
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| FR2674855B1 (en) * | 1991-04-03 | 1994-01-14 | Synthelabo | PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
| FR2696176B1 (en) * | 1992-09-28 | 1994-11-10 | Synthelabo | Piperidine derivatives, their preparation and their therapeutic application. |
| FR2710915B1 (en) * | 1993-10-04 | 1995-11-24 | Synthelabo | Piperidine derivatives, their preparation and their therapeutic use. |
-
1995
- 1995-03-13 FR FR9502863A patent/FR2731708B1/en not_active Expired - Fee Related
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1996
- 1996-03-04 EP EP96400452A patent/EP0732334A1/en not_active Withdrawn
- 1996-03-12 CN CN96107315A patent/CN1140174A/en active Pending
- 1996-03-12 CZ CZ96754A patent/CZ75496A3/en unknown
- 1996-03-12 NZ NZ286164A patent/NZ286164A/en unknown
- 1996-03-12 NO NO961000A patent/NO961000L/en unknown
- 1996-03-12 KR KR1019960006462A patent/KR960034205A/en not_active Application Discontinuation
- 1996-03-12 IL IL11745596A patent/IL117455A0/en unknown
- 1996-03-12 HU HU9600624A patent/HUP9600624A2/en unknown
- 1996-03-12 JP JP8054560A patent/JPH08269058A/en active Pending
- 1996-03-12 PL PL96313204A patent/PL313204A1/en unknown
- 1996-03-12 AU AU48008/96A patent/AU4800896A/en not_active Abandoned
- 1996-03-12 CA CA002171579A patent/CA2171579A1/en not_active Abandoned
- 1996-03-12 ZA ZA961994A patent/ZA961994B/en unknown
- 1996-03-12 SK SK341-96A patent/SK34196A3/en unknown
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| US6979683B2 (en) | 2000-11-23 | 2005-12-27 | Sanofi-Synthelabo | Benzimidazole derivatives, preparation and therapeutic use thereof |
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Also Published As
| Publication number | Publication date |
|---|---|
| FR2731708B1 (en) | 1997-04-30 |
| CZ75496A3 (en) | 1996-10-16 |
| AU4800896A (en) | 1996-09-26 |
| CN1140174A (en) | 1997-01-15 |
| EP0732334A1 (en) | 1996-09-18 |
| PL313204A1 (en) | 1996-09-16 |
| HUP9600624A2 (en) | 1997-01-28 |
| KR960034205A (en) | 1996-10-22 |
| NO961000D0 (en) | 1996-03-12 |
| HU9600624D0 (en) | 1996-05-28 |
| SK34196A3 (en) | 1996-10-02 |
| IL117455A0 (en) | 1996-07-23 |
| JPH08269058A (en) | 1996-10-15 |
| ZA961994B (en) | 1996-09-03 |
| FR2731708A1 (en) | 1996-09-20 |
| NO961000L (en) | 1996-09-16 |
| NZ286164A (en) | 1996-11-26 |
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| FZDE | Discontinued |