CA2261808A1 - 1-azoniabicyclo¬2.2.1|heptane derivatives and pharmaceutical compositions containing them - Google Patents
1-azoniabicyclo¬2.2.1|heptane derivatives and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- CA2261808A1 CA2261808A1 CA002261808A CA2261808A CA2261808A1 CA 2261808 A1 CA2261808 A1 CA 2261808A1 CA 002261808 A CA002261808 A CA 002261808A CA 2261808 A CA2261808 A CA 2261808A CA 2261808 A1 CA2261808 A1 CA 2261808A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- unsubstituted
- compound
- alkyl
- monosubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- 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
Abstract
A compound of formula (I), wherein A is a divalent radical selected from A1)-O-CO-; A2)-CH2-O-CO; A3)-O-CH2-CO-; A4)-O-CH2-CH2-; A5)-N(R1)-CO-; A6)-N(R1)-CO-CO; A7)-N(R1)-CH2-CH2-; A8)-O-CH2-; wherein R1 is hydrogen or (C1-C4)alkyl, and Am is (1). Said compound is useful as a neurokinin receptor antagonist.
Description
CA 02261808 1999-01-2~
1-Azoniabicyclo[2.2.1]heptane derivatives and pharmaceutical compositions containin~ them The present invention relates to novel substituted heterocyclic compounds, to a method of preparing them and to the pharmaceutical compositions containing 5 them as the active principle.
More particularly, the present invention relates to a novel class of substituted heterocyclic compounds for therapeutic use in pathological phenomenainvolving the tachykinin system, such as: pain (D. Regoli et al., Life Sciences,1987, 40, 109-117), allergy and inflammation (J.E. Morlay et al., Life Sciences,1987, 41, 527-544), circulatory insuff1ciency (J. Losay et al., 1977, Substance P, Von Euler, I.S. and Pemow ed., 287-293, Raven Press, New York), gastrointestinaldisorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders and neuropsychiatric disorders (C.A. Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93), these examples being neither limiting nor exclusive.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both thecentral nervous system and the peripheral nervous system. The tachykinin receptors have been recognized and are classifled into three types: NKl, NK2, NK3.
Substance P (SP) is the endogenous ligand of the NKl receptors, neurokinin A
(NKA) that of the NK2 receptors and neurokinin B (NKB) that of the NK3 receptors.
The NKl, NK2 and NK3 receptors have been identified in different species.
A review by C.A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the antagonists specif1c for the NKl receptor: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
For the NK2 receptor, a non-peptide selective antagonist, SR 48968, has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the human NK3 receptor is concerned, the selective non-peptide antagonist (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, or SR 142801, has been described (Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, CA 02261808 1999-01-2~
July 31 - August 3. C~n~di~n J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0. 9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, 1995, April 6 - 8; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur.
Congress Pharmacol., Milan, 1995, June 16- 19).
Patent application EP-A-336230 describes peptide derivatives which are substance P and neurokinin A antagonists useful for the treatment and preventionof asthma.
International patent applications WO 90/05525, WO 90/05729, WO
91/09844 and WO 91/18899 and European patent applications EP-A-0436334, EP-10 A-0429466 and EP-A-0430771 describe substance P antagonists.
European patent applications EP-A-0428434, EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538, EP-A-591040, EP-A-0625509 and EP-A-0630887 and international patent applications WO 94/10146, WO 94/29309, WO 94/26735, WO 95/05377, WO 95/12577, WO 95/16682, WO 95/28389, 15 WO 96/06094 and WO 96/05193 also relate to neurokinin receptor antagonists.
Novel substituted heterocyclic compounds have now been found which are neurokinin receptor antagonists.
Thus, according to one of its features, the present invention relates to compounds of the formula ~A
Am-(CH2)n,-C-CH,-N-T (I) Ar~
in which:
- A is a divalent radical selected from:
A ~ ) -O-CO-A2) -CH2-O-CO-A3)-O-CH2-CO-A4) -O-CH2-CH2-As) -N(Rl )-CO-A6) -N(RI )-CO-CO-A7) -N(RI )-CH2-CH2-A8)-O-CH2-in which R~ is a hydrogen or a (C~-C4)alkyl;
- m is or 3;
- Arl is a phenyl which is unsubstituted or monosubstituted or polysubstituted by CA 02261808 1999-01-2~
a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C,-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (Cl-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom;
a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
10 - T is a group selected from CH,-Z, -CH(C6H5)2 and -C(C6H5)3; T can also be the group -CO-B-Z if A is a divalent radical selected from -O-CH,-CH,-, -N(R~)- CH2-CH2- and -O-CH2-;
- B is a direct bond or a methylene;
- Z is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group; and - Am is a group of the formula Ar2-(CH2)"~N-~3 X(~) in which:
- Ar, is a pyridyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C~-C4)alkyl, a trifluoromethyl, a nitro and a methylenedioxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C,-C4)alkyl;
- n is zero or one; and _5 - X Q is an anion;
and the salts thereof, where appropriate, with mineral or organic acids.
The compounds of formula (I) according to the invention include the racemates as well as the optically pure isomers.
More particularly, the radical Z can be a phenyl group which can be 30 unsubstituted or may contain one or more substituents.
If Z is a phenyl group, it can be monosubstituted or disubstituted, especially in the 2,4-position but also, for example, in the 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted, especially in the 2,4,6-position but also, for example, in CA 02261808 1999-01-2j the 2~3,4-, 2,3,5-, 2,4,5- or 3,4,5-position; tetrasubstituted, for example in the 2,3,4,5-position; or pentasubstituted.
The radical Z can also be a bicyclic aromatic group such as 1- or 2-naphthyl; or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl,hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy ortrifluoromethyl group, in which the alkyl and alkoxy groups are Cl-C4.
The radical Z can also be a pyridyl, thi~di~701yl, indolyl, indazolyl, 10 imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzo-thiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phth~l~7inyl, quinazolinyl, acridinyl, isothiazolyl, iso-15 chromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl,hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group, in which the alkyl and alkoxy groups are C~-C~.
In particular, the invention relates to compounds of formula (I) in which:
- Z is Z' and is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (Cl-C~)alkyl; a benzylamino; a carboxyl; a (C~-C~0)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C~-C~0)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C,-C~0)alkylthio; a formyloxy; a (C~-C6)alkylcarbonyloxy; a formylamino; a (C~-C6)alkylcarbonylamino; a benzoylamino; a (C~-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C ~-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C~-C~)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C~-CA 02261808 1999-01-2~
C4)alkyl, a hydroxyl or a (C,-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin- 1 -yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C,-C4)alkyl, a hydroxyl or a (C~-C4)alkoxy; or - a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl, an imidazolyl or a furyl.
It is possible to form salts of the compounds of formula (I) other than the quaternary ammonium salts. These salts include those with mineral and organic 10 acids which permit a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic or camphosulfonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, 15 naphthalene-2-sulfonate, benzenesulfonate, gluconate, citrate, isethionate or p-toluenesulfonate .
The anions X Q are those normally used to salify quaternary ammonium ions and are preferably chloride, bromide, iodide, acetate, hydrogensulfate, methane-sulfonate, paratoluenesulfonate and benzenesulfonate ions.
O It is preferable to use the pharmaceutically acceptable anions, for example chloride, methanesulfonate or benzenesulfonate.
In the present description, the alkyl groups or alkoxy groups are linear or branched; halogen atom is understood as meaning a chlorine, bromine, fluorine oriodine atom.
In the substituents of the group Z = phenyl, (C,-C,O)alkyl is understood as meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl or a decyl or n-decyl;
(C3-C8)cycloalkyl optionally substituted by a methyl is understood as meaning for 30 example a cyclopropyl~ a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, a cycloheptyl or a cyclooctyl;(Cl-C~u)alkoxy is understood as meaning for example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, a hexyloxy, a heptyloxy, a nonyloxy or a decyloxy; (C3-C8)cycloalkoxy 35 optionally substituted by a methyl is understood as meaning for example a CA 02261808 1999-01-2~
cyclopropoxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcyclohexyloxy, a cyclo-heptyloxy or a cyclooctyloxy; (C~-C~0)alkylthio is understood as meaning for example a methylthio, an ethylthio, an n-propylthio, an isopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, a hexylthio, S a heptylthio, an octylthio, a nonylthio or a decylthio; (C~-C6)alkylcarbonyloxy is understood as meaning for example an acetoxy, a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or a heptanoyloxy; (C ~ -C6)alkylcarbonylamino is understood as meaning for example an acetylamino, a propionylamino, a butyryl-amino, an isobutyrylamino, a valerylamino, a caproylamino or a heptanoylamino;
10 (C~-C4)alkoxycarbonyl is understood as meaning for example a methoxycarbonyl,an ethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, an n-butoxy-carbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or a tert-butoxycarbonyl;
and (C3-C7)cycloalkoxycarbonyl is understood as meaning for example a cyclo-propoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, a 15 cyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.
Advantageously, the radical Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl7 a (C~-C~)alkyl, a hydroxyl or a (C,-C~)alkoxy; a naphthyl which is unsubstituted or monosubstituted or poly-20 substituted by a halogen, a trifluoromethyl, a (C~-C4)alkyl, a hydroxyl or a (C,-C~)alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl.
One group of preferred compounds according to the present invention consists of those of the formula ,Aa~
Am-CH2-CH,-C-CH2-N-CH2-Za (la) Arla in which:
- Aa is a divalent radical selected from: -O-CO-, -CH2-O-CO-, -O-CH2-CO,-N(R~)-CO- and -N(R~)-CO-CO-, in which R~ is a hydrogen or a (C,-C4)alkyl;
30 - Am is a group of the formula ~ C
Ar2 (CH,)n~--N--X~) CA 02261808 1999-01-2~
- nisOor 1;
- X(~) is a pharmaceutically acceptable anion;
- Ar2 is as defined above for a compound of formula (I);
- Arla is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C I -C4)alkyl and a trifluoromethyl, said substituents being identical or different; and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C~-C~O)alkyl, a (Cl-CIO)alkoxy and a hydroxyl, said substituents being identical or different.
Among these compounds, those of the formula , Aa Am-CH2-CH,-C-CH2-N-CH2-Z'a (I'a) Ar'la in which:
- Aa is as defined above for a compound of formula (Ia);
15 - Ama is a group of the formula ~ ,3 - xQ is a pharmaceutically acceptable anion;
- Ar'la is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z'a is a 3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a 274-bis-(trifluoromethyl)phenyl;
are particularly preferred.
Another group of preferred compounds according to the invention consists of those of the formula ,Ab ~
Am-CH2-CH,-C- CH2-N-CO-B-Za (Ib) Arla 25 in which:
- Ab is the divalent radical -O-CH2-CH2-, -N(RI)-CH2-CH2- or -O-CH2-, in which R~ is a hydrogen or a (C~-C4)alkyl;
- Am is a group of the formula CA 02261808 1999-01-2~
Ar, (CH~)n~ N--X¢
- nisOor l;
- B is a direct bond or a methylene;
- X~ is a pharmaceutically acceptable anion;
5 - Ar, is as defined above for a compound of formula (I); and - Arla and Za are as defined above for a compound of formula (Ia).
Among these compounds, those of the formula Al~
Ama-CH7-CH,-C-CH2-N-CO-B-Z"a (I~b) Ar'~a in which:
10 - B is a direct bond or a methylene;
- Ama is as defined above for a compound of formula (I'a);
- Ab is as defined above for a compound of formula (Ib);
- Ar'la is as defined above for a compound of formula (I'a); and - Z"a is a phenyl substituted in the 3-position by a halogen or a (C~-C~O)alkoxygroup if B is a methylene, or Z"a is a 3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a 2,4-bis(trifluoromethyl)phenyl if B is a direct bond;
are particularly preferred.
According to another of its features, the present invention relates to a method of preparing the compounds of formula (I) and the salts thereof, 20 characterized in that:
I ) a compound of the formula A
E-O-(CH2)m-C-CH~-NH (II) Arl and A are as defined above for a compound of formula (I) and E is hydrogen or an O-protecting group, is treated - either with a functional derivative of an acid of the formula HOCO-B-Z (III) in which B and Z are as defined above for (I), if it is intended to prepare a compound of formula (I) in which T is -CO-B-Z, - or with a halogenated derivative of the formula CA 02261808 1999-01-2~
Hal-CH,-Z (IV) in which Z is as defined above and Hal is a halogen, preferably bromine or chlorine, if it is intended to prepare a compound of formula (I) in which T is -CH2-Z, - or with a halogenated derivative of the formula Hal-CH(C6Hs)2 (V) if it is intended to prepare a compound of formula (I) in which T is a group -CH(C6Hs)2, - or with a halogenated derivative of the formula Hal-C-(C6Hs)3 (VI) if it is intended to prepare a compound of formula (I) in which T is a group -C(C6Hs)3~
to give a compound of the formula , A~
E-O-(CH~)",-C-CH,-N-T (VII) Arl 2) the O-protecting group is removed, if apl)lopliate, by reaction with an acid or a base to give the alcohol of the formula ~A ~
HO-(CH2)m-C-CH2-N-T (VIII) Arl 3) the alcohol (VIII) is treated with a compound of the formula -Cl (IX) 20 in which Y is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the forrnula , A
Y-SO2-O-(CH2)",-C-CH2- N-T (X) Ar, 4) the compound (X) is reacted with a cyclic tertiary amine of the formula Ar2-(CH2) ~ ' N (XI) 25 in which Ar2 and n are as defined for a compound of formula (I); and 5) the resulting product is isolated in the forrn of a sulfonate and, if CA 02261808 1999-01-2~
appropriate, a sulfonic acid salt, or optionally the anion and, if apl)ropliate, the resulting acid salt are exchanged with another anion and, if appropriate, another salt with a pharmaceutically acceptable mineral or organic acid.
If E is an O-protecting group, this is selected from the conventional O-protecting groups well known to those skilled in the art~ such as, for example, tetrahydropyran-2-yl, benzoyl or a (Cl-C4)alkylcarbonyl.
In step I ), the functional derivative of the acid (III) used is the acid itself or alternatively one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, the acid chloride or an activated ester such as the 10 paranitrophenyl ester.
If the acid of formula (III) itself is used, the reaction is carried out in the presence of a coupling agent used in peptide chemistry, such as 1,3- dicyclohexylcarbodiimide or benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in the presence of a base such as triethylamine15 or N,N-diisopropylethylamine, in an inert solvent such as dichloromethane or N,N-dimethylformamide, at a temperature between 0~C and room temperature.
If an acid chloride is used, the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine, at a temperature between -60~C and room temperature.
~0 If a halogenated derivative of formula (IV), (V) or (Vl) is used~ the reaction is carried out in an inert solvent such as tetrahydrofuran, N,N-dimethylfonnamide or dimethyl sulfoxide, in the presence of a base such as potassium te)t-butylate, sodium hydride or lithium diisopropylamide, at a temperature between 0~C and 80~C.
The resulting compound of formula (VII) is deprotected in step 2), if appropriate, by the methods known to those skilled in the art. For example, if E is a tetrahydropyran-2-yl group, the deprotection is effected by acid hydrolysis using hydrochloric acid in a solvent such as ether or methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol, or 30 using an Amberlyst~ resin in a solvent such as methanol. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. If E is a benzoyl group or a (Cl-C4)alkylcarbonyl group, the deprotection is effected by hydrolysis in an alkaline medium using for example an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in35 an inert solvent such as water, methanol, ethanol or dioxane or a mixture of these CA 02261808 1999-01-2~
solvents, at a temperature between 0~C and the reflux temperature of the solvent.
In step 3), the reaction of the alcohol of formula (VIII) with a sulfonyl chloride of formula (IX) is carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20~C and the reflux temperature of the solvent.
In step 4), if a compound of formula (X) is reacted with a compound of formula (XI), the reaction is carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene or propan-2-ol, in the 10 presence or absence of a base. If a base is used, it is selected from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound of formula (XI), in the presence of an alkali 15 metal iodide such as potassium iodide or sodium iodide. If -A- in the compound of formula (X) is the divalent radical -0-C0- or -CH2-0-C0-, the reaction is carried out at a temperature between room temperature and 80~C. If -A- in the compound of formula (X) is the divalent radical -0-CH2-C0-, -0-CH2-CH~-, -N(R~)-C0-C0-, -N(R~)-CH,-CH~-? -N(R~)-C0- or -0-CH2-, the reaction is carried out at a 0 temperature between room temperature and 1 00~C.
The resulting products of forrnula (I) are isolated in the form of a sulfonate (YS030 ) or alternatively the sulfonate anion of the resulting quaternary salt is optionally exchanged with another pharmaceutically acceptable anion.
The sulfonate anion YS03 Q origin~ting from the reaction between the ~5 compound of formula (XI) and the compound of formula (X) can be exchanged, insitu or after isolation of the compound of formula (I) n which X(3 is the ion YS03~), with another ion xQ by the conventional methods, for example by exchange in solution with saturated sodium chloride solution or with hydrochloric acid solution if X (~ is a chloride anion, or by exchange of the anion via elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68~ or Duolite A375~.
The compounds of formula (II) are prepared by a variety of procedures.
The cornpounds of fomlula (lI) in which -A- is the divalent radical ~H2~C0- and E is hyd~gen or an O~otecbng group are p~ed acw[ding to SCHEME 1 below, in which m and Ar~
are as defined for a compound of fonnula (~) and Pr is an O~tecbng g[~up as defir~l above for E.
.
Pr-O-(CH2)m-Br + Arl-CH2-CN
(XII) I (XIII) al Pr-O-(CH~)m-CH-CN (XIV) Ar~
bl CH,-OH
Pr-O-(CH2)m-f-CN (XV) Ar~
c .
CH~-OH
Pr-O-(CH, ),ll-C- CH~-NH2 (XVI) Ar dl /o\ ~/o f H2 C II: -A- = -CH2-O-CO-, Pr-o-(cH2)m-c\~cH ~NH ~ E = -Pr Ar, el ~\ C '~O II: -A- = -CH2-O-CO-, HO-(CH~)n,-C\cH ~NH ~ E = H
Ar, .
CA 02261808 1999-01-2~
In step _ of SCHEME 1, a compound of formula (XII) is reacted with a compound of formula (XIII) by the method described in patent applications EP-A-0428434 and EP-A-0474561.
The resulting compound (XIV) is reacted in step b 1 with aqueous 5 formaldehyde solution in the presence of a base such as 1,8-diazabicyclo[5.4.0]-- undec-7-ene, in a solvent such as 1,2-dimethoxyethane, at a temperature between room temperature and the reflux temperature of the solvent.
The nitrile derivative of formula (XV) is reduced in step cl to give the primary amine of formula (XVI). This reduction can be effected by means of hydrogen in the presence of a catalyst such as Raney~ nickel, platinum oxide or palladium-on-charcoal, in an inert solvent such as an alcohol, for example ethanol, by itself or mixed with aqueous ammonia, or by means of a reducing agent such aslithium aluminum hydride, diisobutylaluminum hydride or borane in THF, in a solvent such as toluene, hexane, petroleum ether, xylene or tetrahydrofuran. Thereaction is carried out at a temperature between 0~C and 70~C.
In step ~, the compound (XVI) is reacted with a reactive derivative of carbonic acid, such as phosgene, in solution in toluene, or 1, I '-carbonyldiimidazole, in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in a chlorinated solvent such as dichloromethane or 1,2- dichloroethane, or an ether such as tetrahydrofuran, at a temperature between -70~C and room temperature, to give a compound of the expected formula (II) in which E is an O-protecting group.
Using the methods described above, the O-protecting group is removed by hydrolysis (step e 1) to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -O-CH,-CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 2 below, in which m and Arl are as defined for a compound of formula (I). Prl and Pr~ are the O-protecting group Pr as defined above for E; more particularly, Prl is an O-protecting group hydrolyzable in an acid medium and Pr2 is an O-protecting group hydrolyzable in a basic medium.
H~ ~ O (XVII) C' Arl a2 .
HO-CH-CN (XVIII) Ar~
b2 .
Pr~-O-CH-CN (XIX) Ar, c~
O-Pr~
Pr2-O-(CH7)m-C-CN (XX) Ar~
d2 .
O-Prl Pr2~0~(CH2)m~C~CH2~NH2 (XXI) Ar, j2 1 e2 ~ OH O-Pr~ O
Pr2-o-(cH2)m-c-cH2-NH2Pr2-o-(cH2)m-f-cH2-NH-c-cH2 Ar~ Ar, (XXIV) (XXII) k2 f2 .
CA 02261808 1999-01-2~
OH O
Pr2-O-(CH2)m-~-CH2~NH~ C-CH2-Hal (XXIII) Arl g2 h2 o,CH~\C~~ o~CH2\C~~
Pr2-O-(CH2)m~c\cH ,NH HO-(CH2) -C\ NH
Arl Arl II:-A-=-O-CH2-CO- II:-A-=-O-CH2-CO-E=Pr2 ,E=H
li2 o/CH2\ C~~
Prl-o-(cH~)m-c\cH ~NH
Ar, II: -A- = -O-CH2-CO-E = Prl In step a2 of SCHEME 2, the synthesis of a cyanohydrin of formula (XVIII) from an aldehyde of formula (XVII) is effected by the methods well known to those skilled in the art, such as, for example, the one described in Organic Syntheses; Wiley, New York, 1932; Collect. vol. 1, p. 336, or by an adaptation of this method utilizing the action of sodium metabisulfite and potassium cyanide in aqueous solution.
In step b2, the hydroxyl group of the compound of fonnula (XVIII) is protected by the methods known to those skilled in the art.
The resulting compound of formula (XIX) is treated in step c2 with a strong base~ such as lithium diisopropylamide, potassium tert-butylate or sodium hydride, to give a carbanion, which is reacted with a compound of the formula CA 02261808 1999-01-2~
Hal-(CH2)m-O-Pr2, in which Hal is a halogen, preferably bromine or chlorine, to give the compound of formula (XX). The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran, diethyl ether or 1,2-dimethoxy-ethane), an amide (for example N,N-dimethylformamide) or an aromatic hydro-S carbon (for example toluene or xylene), at a temperature between -70~C and +60~C.
The nitrile derivative of formula (XX) is reduced in step d2 by the methods described above to give the primary amine of formula (XXI).
In step e2, the compound of fonnula (XXI) is reacted with a compoulld of 10 the formula Hal-CO-CH2-Hal, in which Hal is a halogen, preferably chlorine orbromine, in the presence of a base such as a tertiary amine (for example triethylamine, N-methylmorpholine or pyridine), to give a compound of formula (XXII). The reaction is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for 15 example tetrahydrofuran or dioxane) or an amide (for example N,N-dimethyl-formamide), at a temperature between -70~C and room temperature.
In step f2, the O-protecting group Pr~ is removed from the compound of formula (XXII) by acid hydrolysis using the methods described above.
Alternatively, the O-protecting group Pr~ is removed from the compound of 20 formula (XXI) by acid hydrolysis in step j2, after which the resulting compound (XXIV) is reacted in step k2 with a compound of the formula Hal-CO-CH2-Hal by the methods described above in step e2.
The resulting compound of formula (XXIII) is cyclized in the presence of a base to give the compound of the expected fonnula (II). If it is desired to obtain a 25 compound of formula (II) in which E is a protecting group Pr2, a base such as an alkali metal carbonate (for example potassium carbonate), an alkali metal hydride (for example sodium hydride) or potassium tert-butylate is used in an inert solvent such as an aromatic hydrocarbon (for example xylene or toluene), an amide (for example N,N-dimethylformamide) or an ether (for example tetrahydrofuran), at a 30 temperature between -30~C and the reflux temperature of the solvent (step 2). If it is desired to obtain a compound of fonnula (II) in which E is hydrogen, a base such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) in concentrated aqueous solution is used in a solvent such as an alkanol (for example propan-2-ol) or an amide (for example N,N-dimethylformamide) or a 35 mixture of these solvents, at a temperature between room temperature and the CA 02261808 1999-01-2~
reflux temperature of the solvent (step h2).
If appropliate, a compound of formula (II) in which E is an O-protecting group Prl is prepared in step i2 by the methods known to those skilled in the art.
- The compounds of formula (II) in which -A- is the divalent radical -O-CH2-5 CH,- and E is hydrogen or an O-protecting group are prepared according to SCHEME 3 below, in which m and Ar~ are as defined for a compound of formula (I) and Prl and Pr2 are as defined in SCHEME 2 abo~/e.
, CH,, C~~ (II): -A- = O-CH2-CO-E-O-(CH?),l,-C, ,NHE = H, Prl or Pr2 CH, Arl a3 O, CH2, CH (II): -A- = O-CH2-CH2-E-O-(CH~)m-C--CH / NH~ E = H~ Prl or Pr2 Ar~
In step a3 of SCHEME 3, a compound of formula (II) in which -A- is the divalent radical -O-CH2-CO- and E is hydrogen or an O-protecting group, obtainedaccording to SCHEME 2, is reduced. The reduction is effected by means of a 15 reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or borane in THF, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at a temperature between room temperature and the reflux temperature of the solvent.
The compounds of formula (II) in which -A- is the divalent radical -O-CO-20 and E is hydrogen or an O-protecting group are prepa ed according to SCHEME 4below, in which m and Arl are as defined for a compound of formula (I) and Pr and Pr, are as defined in SCHEME 2 above.
O-Prl Pr-O-(CH2)m-C-CH2-NH2 (XXI) Ar~
a4 OH
Pr-O-(CH,)m-C-CH2-NH (XXIV) Ar~
b4 .
o C II:-A-=-O-CO-Pr2-O-(CH2)~ll~c\cH ~N ' E = Pr2 Ar~
c4 o C ~ II:-A-=-O-CO---HO-(CH2) -C\ NH ~ E =H
Ar~
In step a4 of SCHEME 4 the O-protecting group Prl of the compound of 5 fonnula (XXI) obtained in step d2 of SCHEME 2 is removed by acid hydrolysis using the methods described above.
The resulting compound of formula (XXIV) is reacted in step b4 with a reactive derivative of carbonic acid such as l l -carbonyldiimidazole phosgene in toluene or p-nitrophenyl chloroformate in the presence of a base such as 10 triethylamine NN-diisopropylethylamine or N-methylmorpholine to give a compound of the expected formula (II) in which E is an O-protecting group. The reaction is carried out in an inert solvent such as a chlorinated solvent (for example 1,2-dichloroethane or dichloromethane), an ether such as tetrahydrofuran, an amide such as N,N-dimethylformamide or an aromatic solvent such as toluene, at a temperature between -60~C and room temperature.
Using the methods described above, the O-protecting group Pr2 is removed 5 by basic hydrolysis (step c4) to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -N(RI)-CO-CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 5 below, in which m, Arl and R~ are as defined for a compound of 10 formula (I) and Pr~ is as defined above.
H ~ ~ (XVII) Arl a5 .
Rl-NH-CH-CN (XXV) Arl b5 .
R~
Boc-N-CH-CN (XXVI) Ar, c5 Boc-N-Rl Prl-O-(CH,)",-C-CN (XXVII) Arl dS
Boc-N-R~
Prl-O-(CH2)m-C-cH2~NH2 (XXVIII) Ar, le NH-R~
HO-(CH2)m-f-CH2-NH2 (XX ) f5 o N/ C\ c~~
HO-(CH2)m-f \CH / NH
Ar~
(II): -A- = -N(RI )-CO-CO-E=H
gS
o R~ \ ~ C c~ ~
Prl-o-(cH2)m-c\cH ~N
Ar~
(II): -A- = -N(R~)-CO-CO-E = Prl In step aS of SCHEME S an a-amino nitrile compound of formula (XXV) is prepared from an aldehyde of formula (XVII) by the method described in Tetrahedron Letters 1984 25 (41) 4583-4586 using an amine of the formula CA 02261808 1999-01-2~
H~N-R~ .
The amino group of the compound of forrnula (XXV) is protected in step bS by an N-protecting group such as tert-butoxycarbonyl (Boc) or benzyloxy-carbonyl, for example, using the methods known to those skilled in the art. The 5 tert-butoxycarbonyl group is illustrated in SCHEME 5 above.
The resulting compound of formula (XXVI) is treated in step c5 with a strong base to form a carbanion, which is reacted with a compound of the formulaHal-(CH2)m-O-Prl to give a compound of formula (XXVII). The reaction is carried out by the method described in step c2 of SCHEME 2.
The nitrile derivative of formula (XXVII) is reduced in step dS by the methods described above to give the primary amine of formula (XXVIII).
In step e5, the O-protecting group and the N-protecting group are removed from the compound of formula (XXVIII) by acid hydrolysis with hydrochloric acid or trifluoroacetic acid, for example, in a solvent such as an alcohol (for example methanol), an ether (for example diethyl ether, dioxane or tetrahydrofuran) or achlorinated solvent (for example dichloromethane), at a temperature between 0~C
and the reflux temperature of the reaction mixture.
In step f5, the compound of the expected formula (II) is prepared by application or adaptation of the method described by R. Granger, H. Orzalesi andY. Robbe in Trav. Soc. Pharm. Montpellier, 1965, 25, Fasc. 4, 313-317, using thereaction of a compound of formula (XXIX) with diethyl oxalate in an alcoholic solvent such as ethanol, or an aromatic solvent such as toluene, or a mixture ofthese solvents, at a temperature between room temperature and the reflux temperature of the reaction mixture.
~5 If appropriate, a compound of formula (II) in which E is an O-protecting group Prl is prepared in step ~5 by the methods known to those skilled in the art.
The compounds of formula (II) in which -A- is the divalent radical -N(RI)-CH,-CH,- and E is hydrogen or an O-protecting group are prepared according to SCHEME 6 below, in which m, R~ and Arl are as defined for a compound of fonnula (I) and Pr~ is an O-protecting group as defined above for E.
CA 02261808 1999-01-2~
R,\ /C c~O
(II):-A-=-N(R~)-CO-CO-Pr~ o-(CH )n,-C~CH ' ~ E = Pr~
Arl a6 .
R~ \ /CH ~ CH
, (II):-A-=-N(Rl) Prl-o-(cH~)nl-c\cH, NH l E = Pr~
Arl b6 .
R~\N~' ?~CH? ~
(II): -A- = -N(R~ )-CH~-CH?-HO-(CH2),,,-C~cH ~ ~ E = H
Arl In step a6 of SCHEME 6, a compound of formula (II) in which -A- is the 5 divalent radical -N(R~)-CO-CO- and E is an O-protecting group, obtained in step ~5 of SCHEME 5, is reduced. The reduction is effected by means of a reducing agent such as lithium aluminum hydride, in an inert solvent such as an ether (for example tetrahydrofuran, 1,2-dimethoxyethane or diethyl ether) or an aromatic solvent such as toluene, at a temperature between room temperature and the reflux 10 temperature of the solvent.
If appropriate, the O-protecting group is r moved in step b6 by acid hydrolysis using the methods described above to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -N(R~)-15 CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 7 below, in which m, R~ and Ar~ are as defined for a compound of CA 02261808 1999-01-2~
formula (I) and Pr~ is as defined in SCHEME 2 above.
NH-R~
HO-(CH2)m-C-CH2-NH2 (XXIX) Arl I a7 NH-RI
Prl-O-(CH2)m-C-cH2~NH2 (XXX) Arl b7 .
R~ ~ ~~ ~
N C II: -A- = -N(R~ )-CO-Pr~-O-(CH~ ,-C~CH -NH ~ E=Pr Ar, c7 .
R~ "0 N C II:-A-=-N(R,)-CO-HO-(CH~)n~-c\cH "NH ' E = H
Ar, In step a7, the hydroxyl of the compound of formula (XXIX), obtained in step e5 of SCHEME 5, is protected by the methods known to those skilled in the art.
In step b7, the resulting compound of formula (XXX) is reacted with a 10 reactive derivative of carbonic acid, such as l,l'-carbonyldiimidazole, phosgene in toluene, or p-nitrophenyl chloroformate, in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, to give an expected compound of forimula (II) in which E is an O-protecting group. The CA 02261808 1999-01-2~
reaction is carried out in an inert solvent such as a chlorinated solvent (for example 1,2-dichloroethane or dichloromethane), an ether (for example tetrahydrofuran), an amide (for example N,N-dimethylformamide) or an aromatic solvent (for example toluene), at a temperature between -60~C and 60~C.
If applopliate, a compound of formula (II) in which E is hydrogen is prepared in step c7 by the methods known to those skilled in the art.
The compounds of formula (II) in which -A- is the divalent radical -O-CH2-and E is hydrogen or an O-protecting group are prepared according to SCHEME 8 below, in which m and Ar~ are as defined for a compound of formula (I) and Pr, is 10 as defined in SCHEME 2 above.
OH
Pr2-O-(CH2)n,-C-cH2~NH2 (XXIV) Ar~
a8 .
O CH, Il:-A-=-O-CH2-Pr,-O-(CH2)m-C\cH ,N ~ E = Pr2 Arl !b8 O CH2 II:-A-=-O-CH2-HO-(CH2) -C NH E = H ,1 In step a8 of SCHEME 8, a compound of formula (XXIV) is reacted with aqueous formaldehyde solution in an inert solvent such as tetrahydrofuran, at a temperature between room temperature and the reflux temperature of the solvent, to give a compound of the expected formula (II) in which E is an O-protecting group.
CA 02261808 1999-01-2~
Using the methods described above, the O-protecting group Pr2 is removed by basic hydrolysis (step b8) to give the compound of formula (n) in which E is hydrogen.
The compounds of formula (XI) are prepared by known methods such as 5 those described in the following publications:
- J. Chem. Soc., 1937, 1523-1526;
- J. Chem. Soc., 1938, 400.
The compounds of formula (XI) can also be prepared according to SCHEME 9 below, in which n and Ar2 are as defined for a compound of formula 10 (I) and Bz is the benzyl radical.
Ar2-(cH2)n /--\
~ NH
HOOC/ \J
~ (XXXI) ~
Ar~-(cH2)n / \ Ar~-(cH2)n /--\
HOOC>~/N-Bz HO-CH>~/NH
(XXXII) \ / (XXXIV) b9~ ~d9 Ar~-(cH2)n ~( N-Bz (XXXIII) Ar,-(CH,~N-Bz, CH3SO3 (XXXV) Ar2-(CH2)~N
(XI) In step a9 of SCHEME 9, the nitrogen atom of the piperidine of fonnula 5 (XXXI) is protected by a beuzyl group using the methods known to those skilled in the art.
The carboxyl group in the 4-position of the resulting piperidine of formula (XXXII) is reduced in step b9 to give the compound of formula (XXXIII) substituted in the 4-position by a hydroxymethyl group. The reduction is effected 10 by means of a reducing agent such as borane in THF or the borane/dimethyl sulfide CA 02261808 1999-01-2~
complex, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or dichloromethane, at a temperature between room temperature and the reflux temperature of the solvent.
The compound of formula (XXXIII) can also be obtained from the 5 compound of formula (XXXI) by reduction of the carboxyl group (step c9), followed by protection of the nitrogen of the resulting piperidine of formula (XXXIV) (step d9) by the methods mentioned above.
In step e9, the compound (XXXIII) is reacted with methanesulfonyl chloride, in the presence of a base such as triethylamine, to give the cyclized 10 compound of formula (XXXV) in quaternary ammonium form. The reaction is carried out in an inert solvent such as dichloromethane or toluene, at a temperature between -20~C and the reflux temperature of the solvent.
The compound (XXXV) is deprotected in step f9 by the methods known to those skilled in the art. This gives the expected compounds of forrnula (XI).
lS The piperidines of formula (XXXI) are known or are prepared by known methods such as those described in international patent application WO 94/26735.In particular, a compound of formula (XXXI) in which n = 1 can be prepared by the acid hydrolysis of a corresponding piperidine substituted in the 4-position by a cyano group, which itself is obtained by reacting a 4-cyanopiperidine 20 with a halide of the formula Ar~-CH,-Hal in the presence of a base such as sodium diisopropylamide.
The 4-cyanopiperidine is obtained by reacting isonipecotamide with phosphorus oxychloride.
The enantiomers of the compounds according to the invention, of the 25 formula ~A
Am-(cH2)nl-c*-cH~-N-T (I*) Ar in which:
- ' *" means that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and 30 A and T are as defined for the compounds of formula (I);
and the salts thereof, where appropriate, with mineral or organic acids, are novel compounds which form part of the invention.
Resolution of the racemic mixtures of the compounds of formula (I) makes it possible to isolate the enantiomers of formula (I*). It is preferable however to resolve the racemic mixtures from a compound of formula (II) or an intermediate which is useful for the preparation of a compound of formula (II).
Thus if it is desired to prepare the enantiomers (I*) of the compounds of S formula (I) in which -A- is the divalent radical -CH -O-CO- the racemic mixture of an intermediate of the formula HO-(CH2),l,-C-CH.-NH (XXXVI) Ar~ are as defined for a compound of formula (I) which is obtained by removal of the O-protecting group Pr from a compound offormula (XVI) by the methods described above is resolved.
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -O-CO- -O-CH2-CO- -O-CH2-CH2- or -O-CH - the racemic mixture of an intermediate of the formula OH
Pr2-o-(cH2)m-c-cH~-NH2 (XXIV) Ar, in which m and Ar~ are as defined for a compound of formula (I) and Pr2 is as 15 defined in SCHEME 2 above is resolved.
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -O-CH2-CH2- it is also possible to resolve the racemic mixture of a compound of the formula CH \CH I (II): -A- = -O-CH2-CH2-HO-(CH2) -C\ NH l E = H
Arl 20 in which m and R~ are as defined for a compound of formula (I).
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -N(R~)-CO- -N(R~)-CO-CO- or -N(R~)-CH,-CH,- the racemic mixture of an intermediate of the formula NH-R~
HO-(CH2)m-C-cH2-NH2 (XXIX) Ar~
CA 02261808 1999-01-2~
in which m, Ar~ and Rl are as defined for a compound of formula (I), is resolved.
If resolution of the racemates is effected on the intermediates of formula (XXXVI), (XXIV), (XXIX) or (II) [-A- = -O-CH2-CH2- and E = H], this can be done by known methods involving the formation of a salt with optically active 5 acids, for example with (+)- or (-)-tartaric acid. The diastereoisomers are then separated by conventional methods such as crystallization or chromatography, after which the optically pure enantiomers are obtained by hydrolysis.
The compounds of formula (I) above also include those in which one or more hydrogen, carbon or iodine atoms have been replaced with their radioactive isotope, for example tritium, carbon-14 or iodine-125. Such labeled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical tests as receptor ligands.
The affinity of the compounds for the tachykinin receptors was evaluated in vitro by several biochemical tests using radioligands:
1) The binding of [1-5I]BH-SP (substance P labeled with iodine-125 using Bolton-Hunter's reagent) to the NK, receptors of human Iymphoblasts.
2) The binding of [l25I]His-NKA to the NK2 receptors of the rat duodenum or bladder.
3) The binding of [~~5I]His[MePhe7]NKB to the NK3 receptors of the rat 0 cerebral cortex, the guinea-pig cerebral cortex and the gerbil cerebral cortex, and to the human NK3 cloned receptors expressed by CHO cells (Buell et al., FEBS
Letters, 1992, 299, 90-95).
The tests were performed according to X. Emonds-Alt et al. (Eur. J.
Pharmacol., 1993, 250, 403- 413).
The compounds according to the invention generally have an affinity for the above-mentioned tachykinin receptors, with an inhibition constant Ki preferably below 10-S M.
In particular, the compounds of the present invention are active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as drugs.
The compounds of the present invention are generally atlmini~tered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
Thus, according to another of its features, the present invention relates to pharmaceutical compositions in which a compound of formula (I) or a phannaceutically acceptable salt thereof is present as the active principle.
The compounds of formula (I) above and the pharmaceutically acceptable salts thereof can be used in daily doses of 0.01 to 100 mg per kilogram of body weight of the m~mm~l to be treated, preferably in daily doses of 0.1 to 50 mg/kg.
In humans, the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
In the pharmaceutical compositions of the present invention for oral, 10 sublingual, inhalational, subcutaneous, intramuscular, intravenous, transdermal, local or rectal a-lmini~tration, the active principles can be a-lmini~tered to animals and humans in unit forms of a(lmini~tration, mixed with conventional pharmaceutical carriers. The appropriate unit forms of a~mini~tration include oral forrns such as tablets, gelatin capsules, powders, granules and solutions or 15 suspensions to be taken orally, sublingual and buccal fonns of a~lmini~tratioll, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of a~lminictration and rectal forms of administration.
When a solid composition in the fonn of tablets is prepared, the main active principle is mixed with a phannaceutical vehicle such as silica, gelatin, starch, 20 lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose~ various polymers or other appropriate substances or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetennined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the 25 active principle with a diluent such as a glycol or a glycerol ester, and incorporating the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, a flavoring and an appropriate color.
The water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal a~mini~tration is effected using suppositories, which are prepared with binders melting at the rectal temperature, for example cocoa butter or 35 polyethylene glycols.
CA 02261808 1999-01-2~
Parenteral, intranasal or intraocular admini~tration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions whichcontain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
Administration by inhalation is effected using an aerosol which contains for example sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle in powder form, by itself or associated with an excipient.
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In each dosage unit, the active principle of formula (I) is present in the amounts appropriate to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and the intended type of a~mini~tration, l S for example tablets, gelatin capsules and the like, sachets, ampoules, syrups and the like, and drops, so that such a dosage unit contains from 0.5 to 1000 mg of active principle, preferably from 2.5 to 250 mg, to be a~lmini~tered one to four times a day.
The above-mentioned compositions can also contain other active products such as, for example, bronchodilators, antitussives, antihistamines, anti-inflamm~tories, antiemetics and chemotherapeutic agents.
According to another of its features, the present invention relates to the use of the products of formula (I) for the preparation of drugs intended for the treatment of physiological disorders associated with an excess of tachykinins, and all neurokinin-dependent pathological conditions of the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems, as well as pain and migraine.
Non-limiting examples are:
- acute and chronic pain associated for example with migraine, with pains experienced by cancer and angina patients, and with chronic inflamm~tory processes such as osteoarthritis and rheumatoid arthritis, - infl~mm:~tions such as neurogenic inflamm~tions, chronic inflamm~tory diseases, for example obstructive chronic respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity, for example to pollen and mites, rheumatoid arthritis, fibrositis, osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, CA 02261808 1999-01-2~
inflamm:~tion of the intestines (irritable colon), prostatitis, nervous bladder,incontinence, cystitis, urethritis and nephritis, ophthalmic diseases such as conjunctivitis and vitreoretinopathy, and skin diseases such as contact dermatitis, atopical dermatitis, urticaria, eczema, pruritus and burns, especially sunburn, - diseases of the immune system associated with suppression or stimulation of the functions of the immune cells, for example rheumatoid arthritis, psoriasis, .Crohn's disease, diabetes, lupus and rejection reactions following transplantation, - small-cell lung cancers and demyelination diseases such as multiple sclerosis or amyotrophic lateral sclerosis, - diseases of the central nervous system of the neuropsychiatric or neurologicaltype, such as anxiety, vigilance disorders, mood disorders, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drug dependence, alcoholism, Down's syndrome and Huntington's chorea, as well as neurodegenerative diseases and stress-related somatic disorders, - diseases of the gastrointestinal system, such as nausea, vomiting of any origin, irritable colon, gastric and duodenal ulcers, esophageal ulcers, diarrhea and hypersecretions, - diseases of the cardiovascular system, such as hypertension, the vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms, circulatory diseases due to vasodilation, Reynauld's diseases, fibrosis and collagen diseases, and - heart rate and rhythm disorders, in particular those caused by pain or stress.The present invention also includes a method of treating said complaints at the doses indicated above.
2 5 The following abbreviations are used in the Preparations and in the Examples:
Me. Ome: methyl, methoxy Et, Oet: ethyl, ethoxy EtOH: ethanol 30 MeOH: methanol Ether: diethyl ether Iso ether: diisopropyl ether DMF: dimethylformamide DMSO: dimethyl sulfoxide 35 DCM: dichloromethane CA 02261808 1999-01-2~
THF: tetrahydrofuran AcOEt: ethyl acetate Na2CO3 sodium carbonate NaHCO3 sodium hydrogencarbonate NaCI: sodium chloride Na2SO4 sodium sulfate MgSO4 magnesium sulfate NaOH: sodium hydroxide HCI: hydrochloric acid 10 TFA: trifluoroacetic acid Hydrochloric ether: saturated solution of hydrochloric acid in ether KCN: potassium cyanide Na2S,Os sodium metabisulfite DBU: 178-diazabicyclo[5.4.0]undec-7-ene 15 NH~CI: ammonium chloride M.p.: melting point RT: room temperature Silica H: silica gel 60H, marketed by Merck (DARMSTADT) NMR: nuclear magnetic resonance 20 ~: chemical shift s: singlet bs: broad singlet d: doublet t: triplet 25 qd: quadruplet mt: multiplet u: unresolved signals PREPARATIONS
Preparation 1.1 5-(3 ,4-Dichlorophenyl)-5 -[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one A) 2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile A suspension of 17.75 g of sodium hydride (80% dispersion in oil) in 750 35 ml of THF is cooled in an ice bath, a solution of 100 g of 3,4-dichlorophenyl-CA 02261808 1999-01-2~
acetonitrile in 250 ml of THF is added dropwise and the reaction mixture is stirred for two hours at RT. It is cooled to -20~C, a solution of 112.36 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 120 ml of THF is added dropwise and the reaction mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is washed twice with a buffer solution of pH 4, with a buffer solution of pH 7 and twice with saturated NaCI solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 113.5 g 10 of the expected product, which is used as such.
B) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)-butanenitrile A mixture of 12.56 g of the compound obtained in the previous step, 9.6 g of 37% aqueous formaldehyde solution and 0.3 g of DBU in 25 ml of 1,2-15 dimethoxyethane is refluxed for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with water, twice with a buffer solution of pH 4, twice with water and twice with saturated NaCI solution and dried over Na2SO~ and the solvent is evaporatedoff under vacuum to give 17 g of the expected product, which is used as such.
20 C) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)-butylamine A mixture of 17 g of the compound obtained in the previous step and 6 g of Raney~ nickel in 300 ml of EtOH and 40 ml of 20% aqueous ammonia solution is hydrogenated for 5 hours at 40~C and at atmospheric pressure. The catalyst is 25 filtered off and the filtrate is concentrated under vacuum. The residue is taken up with DCM, the organic phase is washed with water and with saturated NaCI
solution and dried over MgSO~ and the solvent is evaporated off under vacuum to give 16.5 g of the expected product in the form of an oil, which is used as such.
D) 5-(3,4-Dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3- oxazin-2-oDe 24.6 g of a 20% solution of phosgene in toluene, diluted in l50 ml of DCM, are cooled to -70~C, a solution of 16.5 g of the compound obtained in the previous step and 5.7 g of triethylamine in 100 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is 35 concentrated under vacuum, the residue is taken up with a water/AcOEt mixture and the product which crystallizes at the interphase is filtered off to give a first crop of the expected product. After dec~nt~tion of the filtrate, the organic phase is washed with water, with a buffer solution of pH 4 and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The 5 residue is taken up with AcOEt and the crystalline product formed is filtered off to give the second crop of the product. A total of 4.5 g of the expected product isobtained.
Preparation 1.2 5-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-10 2H- 1,3-oxazin-2-one A) 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile A solution of 50.8 g of 3,4-dichlorophenylacetonitrile in 250 ml of THF is added dropwise at a temperature below 20~C to a suspension of 12 g of sodium hydride (55% dispersion in oil) in 175 ml of THF and the reaction mixture is stirred for 2 hours at RT. It is cooled to -20~C, a solution of 62.5 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 60 ml of THF is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is poured into a solution of 31 g of ammonium chloride in 1.4 liters of water and extracted with ether, the combined organic phases are washed with saturated NaClsolution and dried over MgSO~ and the solvents are evaporated off under vacuum.
The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (95/5; vlv) as the eluent to give 64 g of the expected product, which isused as such.
B) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)-pentanenitrile A mixture of 15 g of the compound obtained in the previous step. 11.2 g of 37% aqueous formaldehyde solution and 0.35 g of DBU in 30 ml of 1,2-dimethoxyethane is refluxed for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, twice with a buffer solution of pH 4, twice with water and twice with saturated NaCI solution and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (80/20; v/v) as the eluent to give 15.5 g of the expected product, which is used as such.
C) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)-CA 02261808 1999-01-2~
pentylamine A mixture of 15.5 g of the compound obtained in the previous step and 5 g of Raney~ nickel in 200 ml of EtOH and 40 ml of 20% aqueous ammonia solution is hydrogenated for S hours at 30~C and at atmospheric pressure. The catalyst is5 filtered off and the filtrate is concentrated under vacuum. The residue is taken up with DCM, the organic phase is washed with water and with saturated NaCI
solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 14.9 g of the expected product in the form of an oil, which is used as such.
D) 5-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one 21.4 g of a 20% solution of phosgene in toluene~ diluted in 120 ml of DCM, are cooled to -70~C, a solution of 14.9 g of the compound obtained in the previous step and 4.98 g of triethylamine in 80 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is taken up with water and extracted withether, the organic phase is washed with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.5 g of the expected product, which is used as such.
Preparation 1.3 6-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one A) 2-(3,4-Dichlorophenyl)-2-hydroxyacetonitrile A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na2S2O5 in 300 ml of water is stirred overnight at RT. The reaction mixture is cooled to 0~C, a'5 solution of 52 g of KCN in 100 ml of water is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and thesolvent is evaporated off under vacuum to give 76 g of the expected product, which is used as such.
B) 2-(3,4-Dichlorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile A solution of 76 g of the compound obtained in the previous step and 0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM is cooled to 0~C, a solution of 39 g of 3,4-dihydro-2H-pyran in 50 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is washed with saturated NaHCO3 solution and with water, the organic phase is dried CA 02261808 1999-01-2~
over Na2SO~, and the solvent is evaporated off under vacuum to give 33 g of the expected product after cryst~lli7~tion at 0~C from pentane. M.p. = 61~C.
C) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)-butanenitrile 56 ml of a 2 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 32 g of the compound obtained in the previous step in 50 ml of THF is added dropwise and the mixture is stirred for I hour at -60~C. A solutionof 25.4 g of2-bromoethyl benzoate in 50 ml of THF is then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to 10 RT. It is concentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water and with a buffer solution of pH 4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/5; v/v) as the eluent to give 34 g of the expected product, which is used as such.
15 D) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine A mixture of 34 g of the compound obtained in the previous step and 10 g of Raney~ nickel in 400 ml of EtOH and 40 ml of concentrated aqueous ammonia solution is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and extracted with ether, the organic phase is washed with saturated NaCI
solution and dried over Na,SO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using a gradient of a DCM/MeOH
mixture (from 100/1; v/v to 100/3; v/v) as the eluent to give 16 g of the expected product, which is used as such.
E) N-(2-Bromoacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-butylamine A solution of 16 g of the compound obtained in the previous step and 4.8 g of triethylamine in 100 ml of DCM is cooled to -60~C, a solution of 5.68 g of bromoacetyl chloride in 20 ml of DCM is added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with a buffer solution of pH
4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The product obtained is dissolved in the minimum amount of MeOH and acidified to pH I by the addition of a saturated solution of gaseous HCI in ether, and the solvents are evaporated off under vacuum. The residue is taken up with water and CA 02261808 1999-01-2~
extracted with AcOEt, the organic phase is washed with saturated NaHCO3 solution and with water and dried over Na2SO~ and the solvent is evaporated off under vacuum to give 16 g of the expected product, which is used as such.
F) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one A mixture of 16 g of the compound obtained in the previous step, 50 ml of propan-2-ol, 15 ml of 10 N NaOH solution and 10 ml of DMF is stirred for 4 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on 10 silica H using a gradient of a DCM/MeOH mixture (from 100/3; v/v to 100/5; v/v) as the eluent to give 6.1 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.05 ppm: mt: 2H
3.0 to 4.4 ppm: u: 6H
4.5 ppm: t: lH
1-Azoniabicyclo[2.2.1]heptane derivatives and pharmaceutical compositions containin~ them The present invention relates to novel substituted heterocyclic compounds, to a method of preparing them and to the pharmaceutical compositions containing 5 them as the active principle.
More particularly, the present invention relates to a novel class of substituted heterocyclic compounds for therapeutic use in pathological phenomenainvolving the tachykinin system, such as: pain (D. Regoli et al., Life Sciences,1987, 40, 109-117), allergy and inflammation (J.E. Morlay et al., Life Sciences,1987, 41, 527-544), circulatory insuff1ciency (J. Losay et al., 1977, Substance P, Von Euler, I.S. and Pemow ed., 287-293, Raven Press, New York), gastrointestinaldisorders (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25, 39-50), neurological disorders and neuropsychiatric disorders (C.A. Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93), these examples being neither limiting nor exclusive.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both thecentral nervous system and the peripheral nervous system. The tachykinin receptors have been recognized and are classifled into three types: NKl, NK2, NK3.
Substance P (SP) is the endogenous ligand of the NKl receptors, neurokinin A
(NKA) that of the NK2 receptors and neurokinin B (NKB) that of the NK3 receptors.
The NKl, NK2 and NK3 receptors have been identified in different species.
A review by C.A. Maggi et al. looks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharmacol., 1993, 13, 23-93).
The following non-peptide compounds may be mentioned among the antagonists specif1c for the NKl receptor: CP-96345 (J. Med. Chem., 1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).
For the NK2 receptor, a non-peptide selective antagonist, SR 48968, has been described in detail (Life Sci., 1992, 50, PL101-PL106).
As far as the human NK3 receptor is concerned, the selective non-peptide antagonist (+)-N-[1-[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, or SR 142801, has been described (Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, CA 02261808 1999-01-2~
July 31 - August 3. C~n~di~n J. Physiol. Pharmacol., 1994, 72 (suppl. 2), 25, Abst. III. 0. 9.; Life Sci., 1994, 56 (1), 27-32; British Pharmacol. Society, Canterbury, 1995, April 6 - 8; Eur. J. Pharmacol., 1995, 278 (1), 17-25; 1st Eur.
Congress Pharmacol., Milan, 1995, June 16- 19).
Patent application EP-A-336230 describes peptide derivatives which are substance P and neurokinin A antagonists useful for the treatment and preventionof asthma.
International patent applications WO 90/05525, WO 90/05729, WO
91/09844 and WO 91/18899 and European patent applications EP-A-0436334, EP-10 A-0429466 and EP-A-0430771 describe substance P antagonists.
European patent applications EP-A-0428434, EP-A-0474561, EP-A-512901, EP-A-515240, EP-A-559538, EP-A-591040, EP-A-0625509 and EP-A-0630887 and international patent applications WO 94/10146, WO 94/29309, WO 94/26735, WO 95/05377, WO 95/12577, WO 95/16682, WO 95/28389, 15 WO 96/06094 and WO 96/05193 also relate to neurokinin receptor antagonists.
Novel substituted heterocyclic compounds have now been found which are neurokinin receptor antagonists.
Thus, according to one of its features, the present invention relates to compounds of the formula ~A
Am-(CH2)n,-C-CH,-N-T (I) Ar~
in which:
- A is a divalent radical selected from:
A ~ ) -O-CO-A2) -CH2-O-CO-A3)-O-CH2-CO-A4) -O-CH2-CH2-As) -N(Rl )-CO-A6) -N(RI )-CO-CO-A7) -N(RI )-CH2-CH2-A8)-O-CH2-in which R~ is a hydrogen or a (C~-C4)alkyl;
- m is or 3;
- Arl is a phenyl which is unsubstituted or monosubstituted or polysubstituted by CA 02261808 1999-01-2~
a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C,-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (Cl-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom;
a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
10 - T is a group selected from CH,-Z, -CH(C6H5)2 and -C(C6H5)3; T can also be the group -CO-B-Z if A is a divalent radical selected from -O-CH,-CH,-, -N(R~)- CH2-CH2- and -O-CH2-;
- B is a direct bond or a methylene;
- Z is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group; and - Am is a group of the formula Ar2-(CH2)"~N-~3 X(~) in which:
- Ar, is a pyridyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C~-C4)alkyl, a trifluoromethyl, a nitro and a methylenedioxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C,-C4)alkyl;
- n is zero or one; and _5 - X Q is an anion;
and the salts thereof, where appropriate, with mineral or organic acids.
The compounds of formula (I) according to the invention include the racemates as well as the optically pure isomers.
More particularly, the radical Z can be a phenyl group which can be 30 unsubstituted or may contain one or more substituents.
If Z is a phenyl group, it can be monosubstituted or disubstituted, especially in the 2,4-position but also, for example, in the 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted, especially in the 2,4,6-position but also, for example, in CA 02261808 1999-01-2j the 2~3,4-, 2,3,5-, 2,4,5- or 3,4,5-position; tetrasubstituted, for example in the 2,3,4,5-position; or pentasubstituted.
The radical Z can also be a bicyclic aromatic group such as 1- or 2-naphthyl; or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl,hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy ortrifluoromethyl group, in which the alkyl and alkoxy groups are Cl-C4.
The radical Z can also be a pyridyl, thi~di~701yl, indolyl, indazolyl, 10 imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzo-thiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phth~l~7inyl, quinazolinyl, acridinyl, isothiazolyl, iso-15 chromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl,hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group, in which the alkyl and alkoxy groups are C~-C~.
In particular, the invention relates to compounds of formula (I) in which:
- Z is Z' and is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (Cl-C~)alkyl; a benzylamino; a carboxyl; a (C~-C~0)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C~-C~0)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C,-C~0)alkylthio; a formyloxy; a (C~-C6)alkylcarbonyloxy; a formylamino; a (C~-C6)alkylcarbonylamino; a benzoylamino; a (C~-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C ~-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C~-C~)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C~-CA 02261808 1999-01-2~
C4)alkyl, a hydroxyl or a (C,-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin- 1 -yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C,-C4)alkyl, a hydroxyl or a (C~-C4)alkoxy; or - a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl, an imidazolyl or a furyl.
It is possible to form salts of the compounds of formula (I) other than the quaternary ammonium salts. These salts include those with mineral and organic 10 acids which permit a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic or camphosulfonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, 15 naphthalene-2-sulfonate, benzenesulfonate, gluconate, citrate, isethionate or p-toluenesulfonate .
The anions X Q are those normally used to salify quaternary ammonium ions and are preferably chloride, bromide, iodide, acetate, hydrogensulfate, methane-sulfonate, paratoluenesulfonate and benzenesulfonate ions.
O It is preferable to use the pharmaceutically acceptable anions, for example chloride, methanesulfonate or benzenesulfonate.
In the present description, the alkyl groups or alkoxy groups are linear or branched; halogen atom is understood as meaning a chlorine, bromine, fluorine oriodine atom.
In the substituents of the group Z = phenyl, (C,-C,O)alkyl is understood as meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl or a decyl or n-decyl;
(C3-C8)cycloalkyl optionally substituted by a methyl is understood as meaning for 30 example a cyclopropyl~ a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, a cycloheptyl or a cyclooctyl;(Cl-C~u)alkoxy is understood as meaning for example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, a hexyloxy, a heptyloxy, a nonyloxy or a decyloxy; (C3-C8)cycloalkoxy 35 optionally substituted by a methyl is understood as meaning for example a CA 02261808 1999-01-2~
cyclopropoxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcyclohexyloxy, a cyclo-heptyloxy or a cyclooctyloxy; (C~-C~0)alkylthio is understood as meaning for example a methylthio, an ethylthio, an n-propylthio, an isopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, a hexylthio, S a heptylthio, an octylthio, a nonylthio or a decylthio; (C~-C6)alkylcarbonyloxy is understood as meaning for example an acetoxy, a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or a heptanoyloxy; (C ~ -C6)alkylcarbonylamino is understood as meaning for example an acetylamino, a propionylamino, a butyryl-amino, an isobutyrylamino, a valerylamino, a caproylamino or a heptanoylamino;
10 (C~-C4)alkoxycarbonyl is understood as meaning for example a methoxycarbonyl,an ethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, an n-butoxy-carbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or a tert-butoxycarbonyl;
and (C3-C7)cycloalkoxycarbonyl is understood as meaning for example a cyclo-propoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, a 15 cyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.
Advantageously, the radical Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl7 a (C~-C~)alkyl, a hydroxyl or a (C,-C~)alkoxy; a naphthyl which is unsubstituted or monosubstituted or poly-20 substituted by a halogen, a trifluoromethyl, a (C~-C4)alkyl, a hydroxyl or a (C,-C~)alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl.
One group of preferred compounds according to the present invention consists of those of the formula ,Aa~
Am-CH2-CH,-C-CH2-N-CH2-Za (la) Arla in which:
- Aa is a divalent radical selected from: -O-CO-, -CH2-O-CO-, -O-CH2-CO,-N(R~)-CO- and -N(R~)-CO-CO-, in which R~ is a hydrogen or a (C,-C4)alkyl;
30 - Am is a group of the formula ~ C
Ar2 (CH,)n~--N--X~) CA 02261808 1999-01-2~
- nisOor 1;
- X(~) is a pharmaceutically acceptable anion;
- Ar2 is as defined above for a compound of formula (I);
- Arla is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C~-C4)alkoxy, a (C I -C4)alkyl and a trifluoromethyl, said substituents being identical or different; and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C~-C~O)alkyl, a (Cl-CIO)alkoxy and a hydroxyl, said substituents being identical or different.
Among these compounds, those of the formula , Aa Am-CH2-CH,-C-CH2-N-CH2-Z'a (I'a) Ar'la in which:
- Aa is as defined above for a compound of formula (Ia);
15 - Ama is a group of the formula ~ ,3 - xQ is a pharmaceutically acceptable anion;
- Ar'la is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and - Z'a is a 3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a 274-bis-(trifluoromethyl)phenyl;
are particularly preferred.
Another group of preferred compounds according to the invention consists of those of the formula ,Ab ~
Am-CH2-CH,-C- CH2-N-CO-B-Za (Ib) Arla 25 in which:
- Ab is the divalent radical -O-CH2-CH2-, -N(RI)-CH2-CH2- or -O-CH2-, in which R~ is a hydrogen or a (C~-C4)alkyl;
- Am is a group of the formula CA 02261808 1999-01-2~
Ar, (CH~)n~ N--X¢
- nisOor l;
- B is a direct bond or a methylene;
- X~ is a pharmaceutically acceptable anion;
5 - Ar, is as defined above for a compound of formula (I); and - Arla and Za are as defined above for a compound of formula (Ia).
Among these compounds, those of the formula Al~
Ama-CH7-CH,-C-CH2-N-CO-B-Z"a (I~b) Ar'~a in which:
10 - B is a direct bond or a methylene;
- Ama is as defined above for a compound of formula (I'a);
- Ab is as defined above for a compound of formula (Ib);
- Ar'la is as defined above for a compound of formula (I'a); and - Z"a is a phenyl substituted in the 3-position by a halogen or a (C~-C~O)alkoxygroup if B is a methylene, or Z"a is a 3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a 2,4-bis(trifluoromethyl)phenyl if B is a direct bond;
are particularly preferred.
According to another of its features, the present invention relates to a method of preparing the compounds of formula (I) and the salts thereof, 20 characterized in that:
I ) a compound of the formula A
E-O-(CH2)m-C-CH~-NH (II) Arl and A are as defined above for a compound of formula (I) and E is hydrogen or an O-protecting group, is treated - either with a functional derivative of an acid of the formula HOCO-B-Z (III) in which B and Z are as defined above for (I), if it is intended to prepare a compound of formula (I) in which T is -CO-B-Z, - or with a halogenated derivative of the formula CA 02261808 1999-01-2~
Hal-CH,-Z (IV) in which Z is as defined above and Hal is a halogen, preferably bromine or chlorine, if it is intended to prepare a compound of formula (I) in which T is -CH2-Z, - or with a halogenated derivative of the formula Hal-CH(C6Hs)2 (V) if it is intended to prepare a compound of formula (I) in which T is a group -CH(C6Hs)2, - or with a halogenated derivative of the formula Hal-C-(C6Hs)3 (VI) if it is intended to prepare a compound of formula (I) in which T is a group -C(C6Hs)3~
to give a compound of the formula , A~
E-O-(CH~)",-C-CH,-N-T (VII) Arl 2) the O-protecting group is removed, if apl)lopliate, by reaction with an acid or a base to give the alcohol of the formula ~A ~
HO-(CH2)m-C-CH2-N-T (VIII) Arl 3) the alcohol (VIII) is treated with a compound of the formula -Cl (IX) 20 in which Y is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the forrnula , A
Y-SO2-O-(CH2)",-C-CH2- N-T (X) Ar, 4) the compound (X) is reacted with a cyclic tertiary amine of the formula Ar2-(CH2) ~ ' N (XI) 25 in which Ar2 and n are as defined for a compound of formula (I); and 5) the resulting product is isolated in the forrn of a sulfonate and, if CA 02261808 1999-01-2~
appropriate, a sulfonic acid salt, or optionally the anion and, if apl)ropliate, the resulting acid salt are exchanged with another anion and, if appropriate, another salt with a pharmaceutically acceptable mineral or organic acid.
If E is an O-protecting group, this is selected from the conventional O-protecting groups well known to those skilled in the art~ such as, for example, tetrahydropyran-2-yl, benzoyl or a (Cl-C4)alkylcarbonyl.
In step I ), the functional derivative of the acid (III) used is the acid itself or alternatively one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, the acid chloride or an activated ester such as the 10 paranitrophenyl ester.
If the acid of formula (III) itself is used, the reaction is carried out in the presence of a coupling agent used in peptide chemistry, such as 1,3- dicyclohexylcarbodiimide or benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in the presence of a base such as triethylamine15 or N,N-diisopropylethylamine, in an inert solvent such as dichloromethane or N,N-dimethylformamide, at a temperature between 0~C and room temperature.
If an acid chloride is used, the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine, at a temperature between -60~C and room temperature.
~0 If a halogenated derivative of formula (IV), (V) or (Vl) is used~ the reaction is carried out in an inert solvent such as tetrahydrofuran, N,N-dimethylfonnamide or dimethyl sulfoxide, in the presence of a base such as potassium te)t-butylate, sodium hydride or lithium diisopropylamide, at a temperature between 0~C and 80~C.
The resulting compound of formula (VII) is deprotected in step 2), if appropriate, by the methods known to those skilled in the art. For example, if E is a tetrahydropyran-2-yl group, the deprotection is effected by acid hydrolysis using hydrochloric acid in a solvent such as ether or methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol, or 30 using an Amberlyst~ resin in a solvent such as methanol. The reaction is carried out at a temperature between room temperature and the reflux temperature of the solvent. If E is a benzoyl group or a (Cl-C4)alkylcarbonyl group, the deprotection is effected by hydrolysis in an alkaline medium using for example an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in35 an inert solvent such as water, methanol, ethanol or dioxane or a mixture of these CA 02261808 1999-01-2~
solvents, at a temperature between 0~C and the reflux temperature of the solvent.
In step 3), the reaction of the alcohol of formula (VIII) with a sulfonyl chloride of formula (IX) is carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20~C and the reflux temperature of the solvent.
In step 4), if a compound of formula (X) is reacted with a compound of formula (XI), the reaction is carried out in an inert solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene or propan-2-ol, in the 10 presence or absence of a base. If a base is used, it is selected from organic bases such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, or from alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound of formula (XI), in the presence of an alkali 15 metal iodide such as potassium iodide or sodium iodide. If -A- in the compound of formula (X) is the divalent radical -0-C0- or -CH2-0-C0-, the reaction is carried out at a temperature between room temperature and 80~C. If -A- in the compound of formula (X) is the divalent radical -0-CH2-C0-, -0-CH2-CH~-, -N(R~)-C0-C0-, -N(R~)-CH,-CH~-? -N(R~)-C0- or -0-CH2-, the reaction is carried out at a 0 temperature between room temperature and 1 00~C.
The resulting products of forrnula (I) are isolated in the form of a sulfonate (YS030 ) or alternatively the sulfonate anion of the resulting quaternary salt is optionally exchanged with another pharmaceutically acceptable anion.
The sulfonate anion YS03 Q origin~ting from the reaction between the ~5 compound of formula (XI) and the compound of formula (X) can be exchanged, insitu or after isolation of the compound of formula (I) n which X(3 is the ion YS03~), with another ion xQ by the conventional methods, for example by exchange in solution with saturated sodium chloride solution or with hydrochloric acid solution if X (~ is a chloride anion, or by exchange of the anion via elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68~ or Duolite A375~.
The compounds of formula (II) are prepared by a variety of procedures.
The cornpounds of fomlula (lI) in which -A- is the divalent radical ~H2~C0- and E is hyd~gen or an O~otecbng group are p~ed acw[ding to SCHEME 1 below, in which m and Ar~
are as defined for a compound of fonnula (~) and Pr is an O~tecbng g[~up as defir~l above for E.
.
Pr-O-(CH2)m-Br + Arl-CH2-CN
(XII) I (XIII) al Pr-O-(CH~)m-CH-CN (XIV) Ar~
bl CH,-OH
Pr-O-(CH2)m-f-CN (XV) Ar~
c .
CH~-OH
Pr-O-(CH, ),ll-C- CH~-NH2 (XVI) Ar dl /o\ ~/o f H2 C II: -A- = -CH2-O-CO-, Pr-o-(cH2)m-c\~cH ~NH ~ E = -Pr Ar, el ~\ C '~O II: -A- = -CH2-O-CO-, HO-(CH~)n,-C\cH ~NH ~ E = H
Ar, .
CA 02261808 1999-01-2~
In step _ of SCHEME 1, a compound of formula (XII) is reacted with a compound of formula (XIII) by the method described in patent applications EP-A-0428434 and EP-A-0474561.
The resulting compound (XIV) is reacted in step b 1 with aqueous 5 formaldehyde solution in the presence of a base such as 1,8-diazabicyclo[5.4.0]-- undec-7-ene, in a solvent such as 1,2-dimethoxyethane, at a temperature between room temperature and the reflux temperature of the solvent.
The nitrile derivative of formula (XV) is reduced in step cl to give the primary amine of formula (XVI). This reduction can be effected by means of hydrogen in the presence of a catalyst such as Raney~ nickel, platinum oxide or palladium-on-charcoal, in an inert solvent such as an alcohol, for example ethanol, by itself or mixed with aqueous ammonia, or by means of a reducing agent such aslithium aluminum hydride, diisobutylaluminum hydride or borane in THF, in a solvent such as toluene, hexane, petroleum ether, xylene or tetrahydrofuran. Thereaction is carried out at a temperature between 0~C and 70~C.
In step ~, the compound (XVI) is reacted with a reactive derivative of carbonic acid, such as phosgene, in solution in toluene, or 1, I '-carbonyldiimidazole, in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in a chlorinated solvent such as dichloromethane or 1,2- dichloroethane, or an ether such as tetrahydrofuran, at a temperature between -70~C and room temperature, to give a compound of the expected formula (II) in which E is an O-protecting group.
Using the methods described above, the O-protecting group is removed by hydrolysis (step e 1) to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -O-CH,-CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 2 below, in which m and Arl are as defined for a compound of formula (I). Prl and Pr~ are the O-protecting group Pr as defined above for E; more particularly, Prl is an O-protecting group hydrolyzable in an acid medium and Pr2 is an O-protecting group hydrolyzable in a basic medium.
H~ ~ O (XVII) C' Arl a2 .
HO-CH-CN (XVIII) Ar~
b2 .
Pr~-O-CH-CN (XIX) Ar, c~
O-Pr~
Pr2-O-(CH7)m-C-CN (XX) Ar~
d2 .
O-Prl Pr2~0~(CH2)m~C~CH2~NH2 (XXI) Ar, j2 1 e2 ~ OH O-Pr~ O
Pr2-o-(cH2)m-c-cH2-NH2Pr2-o-(cH2)m-f-cH2-NH-c-cH2 Ar~ Ar, (XXIV) (XXII) k2 f2 .
CA 02261808 1999-01-2~
OH O
Pr2-O-(CH2)m-~-CH2~NH~ C-CH2-Hal (XXIII) Arl g2 h2 o,CH~\C~~ o~CH2\C~~
Pr2-O-(CH2)m~c\cH ,NH HO-(CH2) -C\ NH
Arl Arl II:-A-=-O-CH2-CO- II:-A-=-O-CH2-CO-E=Pr2 ,E=H
li2 o/CH2\ C~~
Prl-o-(cH~)m-c\cH ~NH
Ar, II: -A- = -O-CH2-CO-E = Prl In step a2 of SCHEME 2, the synthesis of a cyanohydrin of formula (XVIII) from an aldehyde of formula (XVII) is effected by the methods well known to those skilled in the art, such as, for example, the one described in Organic Syntheses; Wiley, New York, 1932; Collect. vol. 1, p. 336, or by an adaptation of this method utilizing the action of sodium metabisulfite and potassium cyanide in aqueous solution.
In step b2, the hydroxyl group of the compound of fonnula (XVIII) is protected by the methods known to those skilled in the art.
The resulting compound of formula (XIX) is treated in step c2 with a strong base~ such as lithium diisopropylamide, potassium tert-butylate or sodium hydride, to give a carbanion, which is reacted with a compound of the formula CA 02261808 1999-01-2~
Hal-(CH2)m-O-Pr2, in which Hal is a halogen, preferably bromine or chlorine, to give the compound of formula (XX). The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran, diethyl ether or 1,2-dimethoxy-ethane), an amide (for example N,N-dimethylformamide) or an aromatic hydro-S carbon (for example toluene or xylene), at a temperature between -70~C and +60~C.
The nitrile derivative of formula (XX) is reduced in step d2 by the methods described above to give the primary amine of formula (XXI).
In step e2, the compound of fonnula (XXI) is reacted with a compoulld of 10 the formula Hal-CO-CH2-Hal, in which Hal is a halogen, preferably chlorine orbromine, in the presence of a base such as a tertiary amine (for example triethylamine, N-methylmorpholine or pyridine), to give a compound of formula (XXII). The reaction is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), an ether (for 15 example tetrahydrofuran or dioxane) or an amide (for example N,N-dimethyl-formamide), at a temperature between -70~C and room temperature.
In step f2, the O-protecting group Pr~ is removed from the compound of formula (XXII) by acid hydrolysis using the methods described above.
Alternatively, the O-protecting group Pr~ is removed from the compound of 20 formula (XXI) by acid hydrolysis in step j2, after which the resulting compound (XXIV) is reacted in step k2 with a compound of the formula Hal-CO-CH2-Hal by the methods described above in step e2.
The resulting compound of formula (XXIII) is cyclized in the presence of a base to give the compound of the expected fonnula (II). If it is desired to obtain a 25 compound of formula (II) in which E is a protecting group Pr2, a base such as an alkali metal carbonate (for example potassium carbonate), an alkali metal hydride (for example sodium hydride) or potassium tert-butylate is used in an inert solvent such as an aromatic hydrocarbon (for example xylene or toluene), an amide (for example N,N-dimethylformamide) or an ether (for example tetrahydrofuran), at a 30 temperature between -30~C and the reflux temperature of the solvent (step 2). If it is desired to obtain a compound of fonnula (II) in which E is hydrogen, a base such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide) in concentrated aqueous solution is used in a solvent such as an alkanol (for example propan-2-ol) or an amide (for example N,N-dimethylformamide) or a 35 mixture of these solvents, at a temperature between room temperature and the CA 02261808 1999-01-2~
reflux temperature of the solvent (step h2).
If appropliate, a compound of formula (II) in which E is an O-protecting group Prl is prepared in step i2 by the methods known to those skilled in the art.
- The compounds of formula (II) in which -A- is the divalent radical -O-CH2-5 CH,- and E is hydrogen or an O-protecting group are prepared according to SCHEME 3 below, in which m and Ar~ are as defined for a compound of formula (I) and Prl and Pr2 are as defined in SCHEME 2 abo~/e.
, CH,, C~~ (II): -A- = O-CH2-CO-E-O-(CH?),l,-C, ,NHE = H, Prl or Pr2 CH, Arl a3 O, CH2, CH (II): -A- = O-CH2-CH2-E-O-(CH~)m-C--CH / NH~ E = H~ Prl or Pr2 Ar~
In step a3 of SCHEME 3, a compound of formula (II) in which -A- is the divalent radical -O-CH2-CO- and E is hydrogen or an O-protecting group, obtainedaccording to SCHEME 2, is reduced. The reduction is effected by means of a 15 reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride or borane in THF, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or toluene, at a temperature between room temperature and the reflux temperature of the solvent.
The compounds of formula (II) in which -A- is the divalent radical -O-CO-20 and E is hydrogen or an O-protecting group are prepa ed according to SCHEME 4below, in which m and Arl are as defined for a compound of formula (I) and Pr and Pr, are as defined in SCHEME 2 above.
O-Prl Pr-O-(CH2)m-C-CH2-NH2 (XXI) Ar~
a4 OH
Pr-O-(CH,)m-C-CH2-NH (XXIV) Ar~
b4 .
o C II:-A-=-O-CO-Pr2-O-(CH2)~ll~c\cH ~N ' E = Pr2 Ar~
c4 o C ~ II:-A-=-O-CO---HO-(CH2) -C\ NH ~ E =H
Ar~
In step a4 of SCHEME 4 the O-protecting group Prl of the compound of 5 fonnula (XXI) obtained in step d2 of SCHEME 2 is removed by acid hydrolysis using the methods described above.
The resulting compound of formula (XXIV) is reacted in step b4 with a reactive derivative of carbonic acid such as l l -carbonyldiimidazole phosgene in toluene or p-nitrophenyl chloroformate in the presence of a base such as 10 triethylamine NN-diisopropylethylamine or N-methylmorpholine to give a compound of the expected formula (II) in which E is an O-protecting group. The reaction is carried out in an inert solvent such as a chlorinated solvent (for example 1,2-dichloroethane or dichloromethane), an ether such as tetrahydrofuran, an amide such as N,N-dimethylformamide or an aromatic solvent such as toluene, at a temperature between -60~C and room temperature.
Using the methods described above, the O-protecting group Pr2 is removed 5 by basic hydrolysis (step c4) to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -N(RI)-CO-CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 5 below, in which m, Arl and R~ are as defined for a compound of 10 formula (I) and Pr~ is as defined above.
H ~ ~ (XVII) Arl a5 .
Rl-NH-CH-CN (XXV) Arl b5 .
R~
Boc-N-CH-CN (XXVI) Ar, c5 Boc-N-Rl Prl-O-(CH,)",-C-CN (XXVII) Arl dS
Boc-N-R~
Prl-O-(CH2)m-C-cH2~NH2 (XXVIII) Ar, le NH-R~
HO-(CH2)m-f-CH2-NH2 (XX ) f5 o N/ C\ c~~
HO-(CH2)m-f \CH / NH
Ar~
(II): -A- = -N(RI )-CO-CO-E=H
gS
o R~ \ ~ C c~ ~
Prl-o-(cH2)m-c\cH ~N
Ar~
(II): -A- = -N(R~)-CO-CO-E = Prl In step aS of SCHEME S an a-amino nitrile compound of formula (XXV) is prepared from an aldehyde of formula (XVII) by the method described in Tetrahedron Letters 1984 25 (41) 4583-4586 using an amine of the formula CA 02261808 1999-01-2~
H~N-R~ .
The amino group of the compound of forrnula (XXV) is protected in step bS by an N-protecting group such as tert-butoxycarbonyl (Boc) or benzyloxy-carbonyl, for example, using the methods known to those skilled in the art. The 5 tert-butoxycarbonyl group is illustrated in SCHEME 5 above.
The resulting compound of formula (XXVI) is treated in step c5 with a strong base to form a carbanion, which is reacted with a compound of the formulaHal-(CH2)m-O-Prl to give a compound of formula (XXVII). The reaction is carried out by the method described in step c2 of SCHEME 2.
The nitrile derivative of formula (XXVII) is reduced in step dS by the methods described above to give the primary amine of formula (XXVIII).
In step e5, the O-protecting group and the N-protecting group are removed from the compound of formula (XXVIII) by acid hydrolysis with hydrochloric acid or trifluoroacetic acid, for example, in a solvent such as an alcohol (for example methanol), an ether (for example diethyl ether, dioxane or tetrahydrofuran) or achlorinated solvent (for example dichloromethane), at a temperature between 0~C
and the reflux temperature of the reaction mixture.
In step f5, the compound of the expected formula (II) is prepared by application or adaptation of the method described by R. Granger, H. Orzalesi andY. Robbe in Trav. Soc. Pharm. Montpellier, 1965, 25, Fasc. 4, 313-317, using thereaction of a compound of formula (XXIX) with diethyl oxalate in an alcoholic solvent such as ethanol, or an aromatic solvent such as toluene, or a mixture ofthese solvents, at a temperature between room temperature and the reflux temperature of the reaction mixture.
~5 If appropriate, a compound of formula (II) in which E is an O-protecting group Prl is prepared in step ~5 by the methods known to those skilled in the art.
The compounds of formula (II) in which -A- is the divalent radical -N(RI)-CH,-CH,- and E is hydrogen or an O-protecting group are prepared according to SCHEME 6 below, in which m, R~ and Arl are as defined for a compound of fonnula (I) and Pr~ is an O-protecting group as defined above for E.
CA 02261808 1999-01-2~
R,\ /C c~O
(II):-A-=-N(R~)-CO-CO-Pr~ o-(CH )n,-C~CH ' ~ E = Pr~
Arl a6 .
R~ \ /CH ~ CH
, (II):-A-=-N(Rl) Prl-o-(cH~)nl-c\cH, NH l E = Pr~
Arl b6 .
R~\N~' ?~CH? ~
(II): -A- = -N(R~ )-CH~-CH?-HO-(CH2),,,-C~cH ~ ~ E = H
Arl In step a6 of SCHEME 6, a compound of formula (II) in which -A- is the 5 divalent radical -N(R~)-CO-CO- and E is an O-protecting group, obtained in step ~5 of SCHEME 5, is reduced. The reduction is effected by means of a reducing agent such as lithium aluminum hydride, in an inert solvent such as an ether (for example tetrahydrofuran, 1,2-dimethoxyethane or diethyl ether) or an aromatic solvent such as toluene, at a temperature between room temperature and the reflux 10 temperature of the solvent.
If appropriate, the O-protecting group is r moved in step b6 by acid hydrolysis using the methods described above to give the compound of formula (II) in which E is hydrogen.
The compounds of formula (II) in which -A- is the divalent radical -N(R~)-15 CO- and E is hydrogen or an O-protecting group are prepared according to SCHEME 7 below, in which m, R~ and Ar~ are as defined for a compound of CA 02261808 1999-01-2~
formula (I) and Pr~ is as defined in SCHEME 2 above.
NH-R~
HO-(CH2)m-C-CH2-NH2 (XXIX) Arl I a7 NH-RI
Prl-O-(CH2)m-C-cH2~NH2 (XXX) Arl b7 .
R~ ~ ~~ ~
N C II: -A- = -N(R~ )-CO-Pr~-O-(CH~ ,-C~CH -NH ~ E=Pr Ar, c7 .
R~ "0 N C II:-A-=-N(R,)-CO-HO-(CH~)n~-c\cH "NH ' E = H
Ar, In step a7, the hydroxyl of the compound of formula (XXIX), obtained in step e5 of SCHEME 5, is protected by the methods known to those skilled in the art.
In step b7, the resulting compound of formula (XXX) is reacted with a 10 reactive derivative of carbonic acid, such as l,l'-carbonyldiimidazole, phosgene in toluene, or p-nitrophenyl chloroformate, in the presence of a base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, to give an expected compound of forimula (II) in which E is an O-protecting group. The CA 02261808 1999-01-2~
reaction is carried out in an inert solvent such as a chlorinated solvent (for example 1,2-dichloroethane or dichloromethane), an ether (for example tetrahydrofuran), an amide (for example N,N-dimethylformamide) or an aromatic solvent (for example toluene), at a temperature between -60~C and 60~C.
If applopliate, a compound of formula (II) in which E is hydrogen is prepared in step c7 by the methods known to those skilled in the art.
The compounds of formula (II) in which -A- is the divalent radical -O-CH2-and E is hydrogen or an O-protecting group are prepared according to SCHEME 8 below, in which m and Ar~ are as defined for a compound of formula (I) and Pr, is 10 as defined in SCHEME 2 above.
OH
Pr2-O-(CH2)n,-C-cH2~NH2 (XXIV) Ar~
a8 .
O CH, Il:-A-=-O-CH2-Pr,-O-(CH2)m-C\cH ,N ~ E = Pr2 Arl !b8 O CH2 II:-A-=-O-CH2-HO-(CH2) -C NH E = H ,1 In step a8 of SCHEME 8, a compound of formula (XXIV) is reacted with aqueous formaldehyde solution in an inert solvent such as tetrahydrofuran, at a temperature between room temperature and the reflux temperature of the solvent, to give a compound of the expected formula (II) in which E is an O-protecting group.
CA 02261808 1999-01-2~
Using the methods described above, the O-protecting group Pr2 is removed by basic hydrolysis (step b8) to give the compound of formula (n) in which E is hydrogen.
The compounds of formula (XI) are prepared by known methods such as 5 those described in the following publications:
- J. Chem. Soc., 1937, 1523-1526;
- J. Chem. Soc., 1938, 400.
The compounds of formula (XI) can also be prepared according to SCHEME 9 below, in which n and Ar2 are as defined for a compound of formula 10 (I) and Bz is the benzyl radical.
Ar2-(cH2)n /--\
~ NH
HOOC/ \J
~ (XXXI) ~
Ar~-(cH2)n / \ Ar~-(cH2)n /--\
HOOC>~/N-Bz HO-CH>~/NH
(XXXII) \ / (XXXIV) b9~ ~d9 Ar~-(cH2)n ~( N-Bz (XXXIII) Ar,-(CH,~N-Bz, CH3SO3 (XXXV) Ar2-(CH2)~N
(XI) In step a9 of SCHEME 9, the nitrogen atom of the piperidine of fonnula 5 (XXXI) is protected by a beuzyl group using the methods known to those skilled in the art.
The carboxyl group in the 4-position of the resulting piperidine of formula (XXXII) is reduced in step b9 to give the compound of formula (XXXIII) substituted in the 4-position by a hydroxymethyl group. The reduction is effected 10 by means of a reducing agent such as borane in THF or the borane/dimethyl sulfide CA 02261808 1999-01-2~
complex, in an inert solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or dichloromethane, at a temperature between room temperature and the reflux temperature of the solvent.
The compound of formula (XXXIII) can also be obtained from the 5 compound of formula (XXXI) by reduction of the carboxyl group (step c9), followed by protection of the nitrogen of the resulting piperidine of formula (XXXIV) (step d9) by the methods mentioned above.
In step e9, the compound (XXXIII) is reacted with methanesulfonyl chloride, in the presence of a base such as triethylamine, to give the cyclized 10 compound of formula (XXXV) in quaternary ammonium form. The reaction is carried out in an inert solvent such as dichloromethane or toluene, at a temperature between -20~C and the reflux temperature of the solvent.
The compound (XXXV) is deprotected in step f9 by the methods known to those skilled in the art. This gives the expected compounds of forrnula (XI).
lS The piperidines of formula (XXXI) are known or are prepared by known methods such as those described in international patent application WO 94/26735.In particular, a compound of formula (XXXI) in which n = 1 can be prepared by the acid hydrolysis of a corresponding piperidine substituted in the 4-position by a cyano group, which itself is obtained by reacting a 4-cyanopiperidine 20 with a halide of the formula Ar~-CH,-Hal in the presence of a base such as sodium diisopropylamide.
The 4-cyanopiperidine is obtained by reacting isonipecotamide with phosphorus oxychloride.
The enantiomers of the compounds according to the invention, of the 25 formula ~A
Am-(cH2)nl-c*-cH~-N-T (I*) Ar in which:
- ' *" means that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and 30 A and T are as defined for the compounds of formula (I);
and the salts thereof, where appropriate, with mineral or organic acids, are novel compounds which form part of the invention.
Resolution of the racemic mixtures of the compounds of formula (I) makes it possible to isolate the enantiomers of formula (I*). It is preferable however to resolve the racemic mixtures from a compound of formula (II) or an intermediate which is useful for the preparation of a compound of formula (II).
Thus if it is desired to prepare the enantiomers (I*) of the compounds of S formula (I) in which -A- is the divalent radical -CH -O-CO- the racemic mixture of an intermediate of the formula HO-(CH2),l,-C-CH.-NH (XXXVI) Ar~ are as defined for a compound of formula (I) which is obtained by removal of the O-protecting group Pr from a compound offormula (XVI) by the methods described above is resolved.
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -O-CO- -O-CH2-CO- -O-CH2-CH2- or -O-CH - the racemic mixture of an intermediate of the formula OH
Pr2-o-(cH2)m-c-cH~-NH2 (XXIV) Ar, in which m and Ar~ are as defined for a compound of formula (I) and Pr2 is as 15 defined in SCHEME 2 above is resolved.
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -O-CH2-CH2- it is also possible to resolve the racemic mixture of a compound of the formula CH \CH I (II): -A- = -O-CH2-CH2-HO-(CH2) -C\ NH l E = H
Arl 20 in which m and R~ are as defined for a compound of formula (I).
If it is desired to prepare the enantiomers (I*) of the compounds of formula (I) in which -A- is the divalent radical -N(R~)-CO- -N(R~)-CO-CO- or -N(R~)-CH,-CH,- the racemic mixture of an intermediate of the formula NH-R~
HO-(CH2)m-C-cH2-NH2 (XXIX) Ar~
CA 02261808 1999-01-2~
in which m, Ar~ and Rl are as defined for a compound of formula (I), is resolved.
If resolution of the racemates is effected on the intermediates of formula (XXXVI), (XXIV), (XXIX) or (II) [-A- = -O-CH2-CH2- and E = H], this can be done by known methods involving the formation of a salt with optically active 5 acids, for example with (+)- or (-)-tartaric acid. The diastereoisomers are then separated by conventional methods such as crystallization or chromatography, after which the optically pure enantiomers are obtained by hydrolysis.
The compounds of formula (I) above also include those in which one or more hydrogen, carbon or iodine atoms have been replaced with their radioactive isotope, for example tritium, carbon-14 or iodine-125. Such labeled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical tests as receptor ligands.
The affinity of the compounds for the tachykinin receptors was evaluated in vitro by several biochemical tests using radioligands:
1) The binding of [1-5I]BH-SP (substance P labeled with iodine-125 using Bolton-Hunter's reagent) to the NK, receptors of human Iymphoblasts.
2) The binding of [l25I]His-NKA to the NK2 receptors of the rat duodenum or bladder.
3) The binding of [~~5I]His[MePhe7]NKB to the NK3 receptors of the rat 0 cerebral cortex, the guinea-pig cerebral cortex and the gerbil cerebral cortex, and to the human NK3 cloned receptors expressed by CHO cells (Buell et al., FEBS
Letters, 1992, 299, 90-95).
The tests were performed according to X. Emonds-Alt et al. (Eur. J.
Pharmacol., 1993, 250, 403- 413).
The compounds according to the invention generally have an affinity for the above-mentioned tachykinin receptors, with an inhibition constant Ki preferably below 10-S M.
In particular, the compounds of the present invention are active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as drugs.
The compounds of the present invention are generally atlmini~tered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.
Thus, according to another of its features, the present invention relates to pharmaceutical compositions in which a compound of formula (I) or a phannaceutically acceptable salt thereof is present as the active principle.
The compounds of formula (I) above and the pharmaceutically acceptable salts thereof can be used in daily doses of 0.01 to 100 mg per kilogram of body weight of the m~mm~l to be treated, preferably in daily doses of 0.1 to 50 mg/kg.
In humans, the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
In the pharmaceutical compositions of the present invention for oral, 10 sublingual, inhalational, subcutaneous, intramuscular, intravenous, transdermal, local or rectal a-lmini~tration, the active principles can be a-lmini~tered to animals and humans in unit forms of a(lmini~tration, mixed with conventional pharmaceutical carriers. The appropriate unit forms of a~mini~tration include oral forrns such as tablets, gelatin capsules, powders, granules and solutions or 15 suspensions to be taken orally, sublingual and buccal fonns of a~lmini~tratioll, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of a~lminictration and rectal forms of administration.
When a solid composition in the fonn of tablets is prepared, the main active principle is mixed with a phannaceutical vehicle such as silica, gelatin, starch, 20 lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose~ various polymers or other appropriate substances or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetennined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the 25 active principle with a diluent such as a glycol or a glycerol ester, and incorporating the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, a flavoring and an appropriate color.
The water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal a~mini~tration is effected using suppositories, which are prepared with binders melting at the rectal temperature, for example cocoa butter or 35 polyethylene glycols.
CA 02261808 1999-01-2~
Parenteral, intranasal or intraocular admini~tration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions whichcontain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
Administration by inhalation is effected using an aerosol which contains for example sorbitan trioleate or oleic acid, as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle in powder form, by itself or associated with an excipient.
The active principle can also be formulated as microcapsules, with one or more carriers or additives if appropriate.
In each dosage unit, the active principle of formula (I) is present in the amounts appropriate to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and the intended type of a~mini~tration, l S for example tablets, gelatin capsules and the like, sachets, ampoules, syrups and the like, and drops, so that such a dosage unit contains from 0.5 to 1000 mg of active principle, preferably from 2.5 to 250 mg, to be a~lmini~tered one to four times a day.
The above-mentioned compositions can also contain other active products such as, for example, bronchodilators, antitussives, antihistamines, anti-inflamm~tories, antiemetics and chemotherapeutic agents.
According to another of its features, the present invention relates to the use of the products of formula (I) for the preparation of drugs intended for the treatment of physiological disorders associated with an excess of tachykinins, and all neurokinin-dependent pathological conditions of the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous systems, as well as pain and migraine.
Non-limiting examples are:
- acute and chronic pain associated for example with migraine, with pains experienced by cancer and angina patients, and with chronic inflamm~tory processes such as osteoarthritis and rheumatoid arthritis, - infl~mm:~tions such as neurogenic inflamm~tions, chronic inflamm~tory diseases, for example obstructive chronic respiratory diseases, asthma, allergies, rhinitis, coughs, bronchitis, hypersensitivity, for example to pollen and mites, rheumatoid arthritis, fibrositis, osteoarthritis, psoriasis, ulcerative colitis, Crohn's disease, CA 02261808 1999-01-2~
inflamm:~tion of the intestines (irritable colon), prostatitis, nervous bladder,incontinence, cystitis, urethritis and nephritis, ophthalmic diseases such as conjunctivitis and vitreoretinopathy, and skin diseases such as contact dermatitis, atopical dermatitis, urticaria, eczema, pruritus and burns, especially sunburn, - diseases of the immune system associated with suppression or stimulation of the functions of the immune cells, for example rheumatoid arthritis, psoriasis, .Crohn's disease, diabetes, lupus and rejection reactions following transplantation, - small-cell lung cancers and demyelination diseases such as multiple sclerosis or amyotrophic lateral sclerosis, - diseases of the central nervous system of the neuropsychiatric or neurologicaltype, such as anxiety, vigilance disorders, mood disorders, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, drug dependence, alcoholism, Down's syndrome and Huntington's chorea, as well as neurodegenerative diseases and stress-related somatic disorders, - diseases of the gastrointestinal system, such as nausea, vomiting of any origin, irritable colon, gastric and duodenal ulcers, esophageal ulcers, diarrhea and hypersecretions, - diseases of the cardiovascular system, such as hypertension, the vascular aspects of migraine, edema, thrombosis, angina pectoris, vascular spasms, circulatory diseases due to vasodilation, Reynauld's diseases, fibrosis and collagen diseases, and - heart rate and rhythm disorders, in particular those caused by pain or stress.The present invention also includes a method of treating said complaints at the doses indicated above.
2 5 The following abbreviations are used in the Preparations and in the Examples:
Me. Ome: methyl, methoxy Et, Oet: ethyl, ethoxy EtOH: ethanol 30 MeOH: methanol Ether: diethyl ether Iso ether: diisopropyl ether DMF: dimethylformamide DMSO: dimethyl sulfoxide 35 DCM: dichloromethane CA 02261808 1999-01-2~
THF: tetrahydrofuran AcOEt: ethyl acetate Na2CO3 sodium carbonate NaHCO3 sodium hydrogencarbonate NaCI: sodium chloride Na2SO4 sodium sulfate MgSO4 magnesium sulfate NaOH: sodium hydroxide HCI: hydrochloric acid 10 TFA: trifluoroacetic acid Hydrochloric ether: saturated solution of hydrochloric acid in ether KCN: potassium cyanide Na2S,Os sodium metabisulfite DBU: 178-diazabicyclo[5.4.0]undec-7-ene 15 NH~CI: ammonium chloride M.p.: melting point RT: room temperature Silica H: silica gel 60H, marketed by Merck (DARMSTADT) NMR: nuclear magnetic resonance 20 ~: chemical shift s: singlet bs: broad singlet d: doublet t: triplet 25 qd: quadruplet mt: multiplet u: unresolved signals PREPARATIONS
Preparation 1.1 5-(3 ,4-Dichlorophenyl)-5 -[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one A) 2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile A suspension of 17.75 g of sodium hydride (80% dispersion in oil) in 750 35 ml of THF is cooled in an ice bath, a solution of 100 g of 3,4-dichlorophenyl-CA 02261808 1999-01-2~
acetonitrile in 250 ml of THF is added dropwise and the reaction mixture is stirred for two hours at RT. It is cooled to -20~C, a solution of 112.36 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 120 ml of THF is added dropwise and the reaction mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is washed twice with a buffer solution of pH 4, with a buffer solution of pH 7 and twice with saturated NaCI solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 113.5 g 10 of the expected product, which is used as such.
B) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)-butanenitrile A mixture of 12.56 g of the compound obtained in the previous step, 9.6 g of 37% aqueous formaldehyde solution and 0.3 g of DBU in 25 ml of 1,2-15 dimethoxyethane is refluxed for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with water, twice with a buffer solution of pH 4, twice with water and twice with saturated NaCI solution and dried over Na2SO~ and the solvent is evaporatedoff under vacuum to give 17 g of the expected product, which is used as such.
20 C) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)-butylamine A mixture of 17 g of the compound obtained in the previous step and 6 g of Raney~ nickel in 300 ml of EtOH and 40 ml of 20% aqueous ammonia solution is hydrogenated for 5 hours at 40~C and at atmospheric pressure. The catalyst is 25 filtered off and the filtrate is concentrated under vacuum. The residue is taken up with DCM, the organic phase is washed with water and with saturated NaCI
solution and dried over MgSO~ and the solvent is evaporated off under vacuum to give 16.5 g of the expected product in the form of an oil, which is used as such.
D) 5-(3,4-Dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3- oxazin-2-oDe 24.6 g of a 20% solution of phosgene in toluene, diluted in l50 ml of DCM, are cooled to -70~C, a solution of 16.5 g of the compound obtained in the previous step and 5.7 g of triethylamine in 100 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is 35 concentrated under vacuum, the residue is taken up with a water/AcOEt mixture and the product which crystallizes at the interphase is filtered off to give a first crop of the expected product. After dec~nt~tion of the filtrate, the organic phase is washed with water, with a buffer solution of pH 4 and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The 5 residue is taken up with AcOEt and the crystalline product formed is filtered off to give the second crop of the product. A total of 4.5 g of the expected product isobtained.
Preparation 1.2 5-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-10 2H- 1,3-oxazin-2-one A) 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile A solution of 50.8 g of 3,4-dichlorophenylacetonitrile in 250 ml of THF is added dropwise at a temperature below 20~C to a suspension of 12 g of sodium hydride (55% dispersion in oil) in 175 ml of THF and the reaction mixture is stirred for 2 hours at RT. It is cooled to -20~C, a solution of 62.5 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 60 ml of THF is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is poured into a solution of 31 g of ammonium chloride in 1.4 liters of water and extracted with ether, the combined organic phases are washed with saturated NaClsolution and dried over MgSO~ and the solvents are evaporated off under vacuum.
The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (95/5; vlv) as the eluent to give 64 g of the expected product, which isused as such.
B) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)-pentanenitrile A mixture of 15 g of the compound obtained in the previous step. 11.2 g of 37% aqueous formaldehyde solution and 0.35 g of DBU in 30 ml of 1,2-dimethoxyethane is refluxed for 1 hour. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, twice with a buffer solution of pH 4, twice with water and twice with saturated NaCI solution and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (80/20; v/v) as the eluent to give 15.5 g of the expected product, which is used as such.
C) 2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)-CA 02261808 1999-01-2~
pentylamine A mixture of 15.5 g of the compound obtained in the previous step and 5 g of Raney~ nickel in 200 ml of EtOH and 40 ml of 20% aqueous ammonia solution is hydrogenated for S hours at 30~C and at atmospheric pressure. The catalyst is5 filtered off and the filtrate is concentrated under vacuum. The residue is taken up with DCM, the organic phase is washed with water and with saturated NaCI
solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 14.9 g of the expected product in the form of an oil, which is used as such.
D) 5-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one 21.4 g of a 20% solution of phosgene in toluene~ diluted in 120 ml of DCM, are cooled to -70~C, a solution of 14.9 g of the compound obtained in the previous step and 4.98 g of triethylamine in 80 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is taken up with water and extracted withether, the organic phase is washed with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.5 g of the expected product, which is used as such.
Preparation 1.3 6-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one A) 2-(3,4-Dichlorophenyl)-2-hydroxyacetonitrile A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na2S2O5 in 300 ml of water is stirred overnight at RT. The reaction mixture is cooled to 0~C, a'5 solution of 52 g of KCN in 100 ml of water is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and thesolvent is evaporated off under vacuum to give 76 g of the expected product, which is used as such.
B) 2-(3,4-Dichlorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile A solution of 76 g of the compound obtained in the previous step and 0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM is cooled to 0~C, a solution of 39 g of 3,4-dihydro-2H-pyran in 50 ml of DCM is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is washed with saturated NaHCO3 solution and with water, the organic phase is dried CA 02261808 1999-01-2~
over Na2SO~, and the solvent is evaporated off under vacuum to give 33 g of the expected product after cryst~lli7~tion at 0~C from pentane. M.p. = 61~C.
C) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)-butanenitrile 56 ml of a 2 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 32 g of the compound obtained in the previous step in 50 ml of THF is added dropwise and the mixture is stirred for I hour at -60~C. A solutionof 25.4 g of2-bromoethyl benzoate in 50 ml of THF is then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to 10 RT. It is concentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water and with a buffer solution of pH 4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/5; v/v) as the eluent to give 34 g of the expected product, which is used as such.
15 D) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine A mixture of 34 g of the compound obtained in the previous step and 10 g of Raney~ nickel in 400 ml of EtOH and 40 ml of concentrated aqueous ammonia solution is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and extracted with ether, the organic phase is washed with saturated NaCI
solution and dried over Na,SO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using a gradient of a DCM/MeOH
mixture (from 100/1; v/v to 100/3; v/v) as the eluent to give 16 g of the expected product, which is used as such.
E) N-(2-Bromoacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-butylamine A solution of 16 g of the compound obtained in the previous step and 4.8 g of triethylamine in 100 ml of DCM is cooled to -60~C, a solution of 5.68 g of bromoacetyl chloride in 20 ml of DCM is added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with a buffer solution of pH
4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The product obtained is dissolved in the minimum amount of MeOH and acidified to pH I by the addition of a saturated solution of gaseous HCI in ether, and the solvents are evaporated off under vacuum. The residue is taken up with water and CA 02261808 1999-01-2~
extracted with AcOEt, the organic phase is washed with saturated NaHCO3 solution and with water and dried over Na2SO~ and the solvent is evaporated off under vacuum to give 16 g of the expected product, which is used as such.
F) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one A mixture of 16 g of the compound obtained in the previous step, 50 ml of propan-2-ol, 15 ml of 10 N NaOH solution and 10 ml of DMF is stirred for 4 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on 10 silica H using a gradient of a DCM/MeOH mixture (from 100/3; v/v to 100/5; v/v) as the eluent to give 6.1 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.05 ppm: mt: 2H
3.0 to 4.4 ppm: u: 6H
4.5 ppm: t: lH
7.3to8.3ppm:u:4H
G) 6-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one A solution of 1.7 g of the compound obtained in the previous step and 0.003 g of p-toluenesulfonic acid monohydrate in 50 ml of DCM is cooled to 0~C, 20 0.588 g of 3,4-dihydro-2H-pyran in 10 ml of DCM is added dropwise and the reaction mixture is stirred for I hour at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed witll saturated NaHCO3 solution and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH
25 mixture (100/2; v/v) as the eluent to give 1.8 g of the expected product, which is used as such.
Preparation 1.4 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one A mixture of 4.8 g of the compound obtained in step E of Preparation 1.3 30 and 1.4 g of K2CO3 in 100 ml of xylene is heated at 130~C overnight. After cooling to RT, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed with a buft'er solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a 35 DCM/MeOH mixture (100/1; v/v) as the eluent to give 1.4 g of the expected , . . .
CA 02261808 1999-01-2~
product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.45 ppm: mt: 2H
3.75 ppm: AB system: 2H
3.9 to 4.5 ppm: u: 4H
7.4 to 7.9 ppm: u: 8H
G) 6-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one A solution of 1.7 g of the compound obtained in the previous step and 0.003 g of p-toluenesulfonic acid monohydrate in 50 ml of DCM is cooled to 0~C, 20 0.588 g of 3,4-dihydro-2H-pyran in 10 ml of DCM is added dropwise and the reaction mixture is stirred for I hour at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed witll saturated NaHCO3 solution and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH
25 mixture (100/2; v/v) as the eluent to give 1.8 g of the expected product, which is used as such.
Preparation 1.4 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one A mixture of 4.8 g of the compound obtained in step E of Preparation 1.3 30 and 1.4 g of K2CO3 in 100 ml of xylene is heated at 130~C overnight. After cooling to RT, the reaction mixture is filtered and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed with a buft'er solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a 35 DCM/MeOH mixture (100/1; v/v) as the eluent to give 1.4 g of the expected , . . .
CA 02261808 1999-01-2~
product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.45 ppm: mt: 2H
3.75 ppm: AB system: 2H
3.9 to 4.5 ppm: u: 4H
7.4 to 7.9 ppm: u: 8H
8.25 ppm: bs: lH
This compound can also be obtained by following the three steps of the method described below.
A') 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride This compound is described in step A of Preparation 1.7.
B') N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-butylamine A solution of 20 g of the compound obtained in the previous step and 10.3 g of triethylamine in 100 ml of DCM is cooled to 0~C, 5.8 g of chloroacetyl chloride are added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 22 g of the expected product, which is used as such.
C') 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one A solution of 22 g of the compound obtained in the previous step in 600 ml of THF is cooled to -10~C, 11.42 g of potassium tert-butylate are added and the reaction mixture is stirred until dissolution is complete. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.8 g of the expected product after crystallization from ether.
Preparation 1.5 2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)morpholine A suspension of 1.6 g of lithium aluminum hydride in 25 ml of THF is heated to 60~C, a solution of 4 g of the compound obtained in step F of Preparation 1.3 in 20 ml of THF is added dropwise and the mixture is stirred for 30 minutes under reflux. After cooling, 1.5 ml of water, 1.5 ml of 4 N NaOH and then 4.5 mlof water are added. The mineral salts are filtered off on Célite~, the filtrate is CA 02261808 1999-01-2~
decanted and the organic phase is evaporated under vacuum. The residue is taken up with ether and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 3.6 g of the expected product.
Preparation 1.6 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine A) S-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)-pentanenitrile 47 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 19.3 g of the compound obtained in step B of 10 Preparation 1.3 in 100 ml of THF is added dropwise and the mixture is stirred for 30 minutes at -60~C. 17 g of 3-bromopropyl benzoate are then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with saturated NaCI solution and dried 15 over Na,SO4 and the solvent is evaporated off under vacuum to give 21 g of the expected product after crystallization from hexane.
B) S-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine A mixture of 20 g of the compound obtained in the previous step and 7 g of 20 Raney~ nickel in 300 ml of MeOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum.
The residue is taken up with water and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 20 g of the expected product, which is used as such.
25 C) N-(2-Chloroacetyl)-S-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine A solution of 9 g of the compound obtained in the previous step and 2.4 g of triethylamine in 100 ml of DCM is cooled to 0~C, a solution of 2.23 g of chloroacetyl chloride in 20 ml of DCM is added dropwise and the reaction mixture30 is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and thesolvent is evaporated off under vacuum to give 9.5 g of the expected product, which is used as such.
D) N-(2-Chloroacetyl)-S-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-pentylamine ~ 41 A saturated solution of gaseous HCI in ether is added to a solution of 9 g of the compound obtained in the previous step in 50 ml of DCM and 50 ml of MeOH
until the pH is 1, and the mixture is stirred for 30 minutes at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with 5 water and with saturated NaHCO3 solution and dried over Na2SO4 and the solventis evaporated off under vacuum. The residue is chromatographed on silica H usinga DCM/MeOH mixture (100/3; v/v) as the eluent to give 4.7 g of the expected' product, which is used as such.
E) 6-(3,4-Dichlorophenyl)-6-(3-hydroxypropyl)morpholin-3-one A mixture of 2.95 g of the compound obtained in the previous step, 40 ml of propan-2-ol and 3 ml of 10 N NaOH solution is stirred for 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (100/2; v/v to 100/5; v/v) as the eluent to give 0.5 g of the expected product. M.p. = 130- 132~C.
F) 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine A suspension of 0.82 g of lithium aluminum hydride in 10 ml of THF is heated to 60~C, a solution of 2 g of the compound obtained in the previous step in 20 ml of THF is added dropwise and the mixture is stirred for 30 minutes under reflux. After cooling, I ml of water, 1 ml of 4 N NaOH and then 3 ml of water are added. The mineral salts are filtered off on Célite~, the filtrate is decanted and the organic phase is evaporated under vacuum. The residue is taken up with ether anddried over Na2SO4 and the solvent is evaporated off under vacuum to give 2 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 0.8 to 2.2 ppm: u: 4H
2.5 to 3.7 ppm: u: 8H
4.3 ppm: t: lH
7.2 to 7.7 ppm: u: 3H
CA 02261808 1999-01-2~
Preparation 1.7 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one A) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride A saturated solution of gaseous HCI in ether is added at RT to a solution of 12 g of the compound obtained in step D of Preparation 1.3 in 50 ml of MeOH
until the pH is 1, and the reaction mixture is stirred for I hour at RT. It is concentrated under vacuum, the residue is taken up with DCM and the precipitate formed is filtered off and washed with ether to give 3.4 g of the expected product after recrystallization from propan-2-ol. M.p. = 200-204~C.
10 B) 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one 1.4 g of 1,1 '-carbonyldiimidazole are added at RT to a solution of 3 g of the compound obtained in the previous step and 0.85 g of triethylamine in 30 ml of 1,2-dichloroethane and the reaction mixture is stirred for 30 minutes at RT and then heated at 50~C for 2 hours. It is concentrated under vacuum, the residue is15 taken up with water and extracted with DCM, the organic phase is washed with a buffer solution of pH 2 and with water and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 3 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 6 ppm: mt: 2H
0 3.75 ppm: AB system: 2H
4.35 ppm: mt: 2H
7.4 to 7.8 ppm: u: 8H
7.9 ppm: s: IH
Preparation 1.8 '5 6-(3,4-Dichlorophenyl)- I -methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]- piperazine-2,3 -dione A) 2-(3,4-Dichlorophenyl)-2-(methylamino)acetonitrile hydrochloride A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyano-trimethylsilane is cooled in an ice bath, 10 mg of zinc iodide are added and themixture is stirred for 30 minutes at RT. 20 ml of a 33% solution of methylamine in EtOH are then added and the mixture is heated at 40~C for 2 hours. The solvent is concentrated under vacuum, the residue is extracted with ether and the organic phase is dried over MgSO4 and filtered. A saturated solution of gaseous HCI in ether is added to the filtrate until the pH is 1, and acetone is then added until the product precipitates. The precipitate formed is filtered off, washed with ether and .
CA 02261808 1999-01-2~
dried to give 12.8 g ofthe expected product. M.p. = 172~C.
B) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)acetonitrile Concentrated NaOH solution is added to an aqueous suspension of 12.8 g of the compound obtained in the previous step until the pH is 13, the mixture is5 extracted with ether, the organic phase is dried over MgSO4 and the solvent isevaporated off under vacuum. The residue is taken up with 20 ml of 1,4-dioxane, 12.5 g of di-tert-butyl dicarbonate are added and the reaction mixture is heated at 60CC for 2 hours. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with a buffer solution of pH 2, with saturated 10 NaCI solution and with 10% Na,CO3 solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicausing heptane and then a heptane/AcOEt mixture (96/4; v/v) as the eluent to give12.7 g of the expected product, which is used as such.
C) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydro-pyran-2-yloxy)butanenitrile A solution of 11.1 g of the compound obtained in the previous step in 60 ml of DMF is added dropwise to a suspension of 1.5 g of sodium hydride (60%
dispersion in oil) in 50 ml of DMF, the temperature being maintained at 25~C, and the mixture is stirred for I hour at RT. A solution of 8.1 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 20 ml of DMF is then added and the reaction mixture is heated at 60~C for 4 hours. At'ter cooling to RT, it is poured into amixture of ice and a buffer of pH 2 and extracted with ether, the organic phase is washed twice with water and dried over MgSO~ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using heptane and then a heptane/AcOEt mixture (75/25; vlv) as the eluent to give 13.2 g of the expected product, which is used as such.
D) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydro-pyran-2-yloxy)butylamine A mixture of 13.2 g of the compound obtained in the previous step and 4 g of Raney~ nickel in 150 ml of EtOH and 50 ml of 20% aqueous ammonia solution is hydrogenated at 30~C and at atmospheric pressure. After 5 hours, the catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.6 g of the expected product, which is used as such.
CA 02261808 1999-01-2~
E) 2-(3,4-Dichlorophenyl)-4-hydroxy-2-(methylamino)butylamine hydrochloride A mixture of 4.6 g of the compound obtained in the previous step and 10 ml of concentrated HCI solution in 40 ml of MeOH is heated at 70~C for 1 hour. The solvent is then concentrated under vacuum, the residue is taken up with acetone and the precipitate formed is filtered off, washed with ether and dried to give 2.79 g of the expected product. M.p. = 240~C (dec.).
F) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)- 1 -methylpiperazine-2,3-dione Concentrated NaOH solution is added to an aqueous suspension of 5.3 g of the compow~d obtained in the previous step until the pH is 13, the mixture is 10 extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained (4 g) is taken up with 50 ml of EtOH, 2.57 g of diethyl oxalate are added and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum and the residue is taken up with 60 ml of toluene and refluxed for 70 hours. It is concentrated under vacuum to give 2.8 g 15 of the expected product after crystallization from DCM. M.p. = 260~C.
G) 6-(3,4-Dichlorophenyl)-l-methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]-piperazine-2,3 -dione 0.1 g of p-toluenesulfonic acid monohydrate and then 1.26 ml of 3,4-dihydro-2H-pyran are added to a suspension of 2.8 g of the compound obtained in 20 the previous step in 50 ml of DCM and the reaction mixture is stirred overnight at RT. It is washed with 10% Na,CO3 solution and with water, the organic phase is dried over MgSO~ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using AcOEt and then an AcOEt/MeOH mixture (93/7;
v/v) as the eluent to give 3.1 g of the expected product, which is used as such. Preparation 1.9 2-(3,4-Dichlorophenyl)- I -methyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]-piperazine A solution of 2 g of the compound obtained in Preparation 1.8 in 20 ml of THF is added dropwise to a suspension of 1.2 g of lithium aluminum hydride in 2030 ml of THF and the mixture is refluxed for 1 hour. After cooling, 5 ml of water are added, the mineral salts are filtered off, the filtrate is concentrated under vacuum, the residue is taken up with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.9 g of the expected product in the form of an oil.
CA 02261808 1999-01-2~
Preparation 1.10 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one A) 2-(3,4-Difluorophenyl)-2-hydroxyacetonitrile A solution of 80.2 g of Na2S2Os in 250 ml of water is heated to 50~C, 50 g 5 of 3,4-difluorobenzaldehyde are added and the reaction mixture is stirred for 1 hour at 50~C and left to stand overnight at RT. It is cooled to 0~C, a solution of 77.7 g of KCN in 100 ml of water is added dropwise, the mixture is stirred while the temperature is allowed to rise to RT, and stirring is then continued for 1 hour at RT. The reaction mixture is extracted with ether, the organic phase is washed with 10 water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 48 g of the expected product, which is used as such.
B) 2-(3,4-Difluorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile A solution of 48 g of the compound obtained in the previous step and 0.2 g of p-toluenesulfonic acid monohydrate in 500 ml of DCM is cooled to 0~C, a solution of 28.6 g of 3,4-dihydro-2H-pyran in 50 ml of DCM is added dropwise, the mixture is stirred while the temperature is allowed to rise to RT, and stirring is then continued overnight at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 10%
Na2CO3 solution and with water and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/15; v/v) as the eluent to give 43 g of the expected product, which is used as such.
C) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile 133 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 43 g of the compound obtained in the previous step in 250 ml of THF is added dropwise and the mixture is stirred for 30 minutes at -60~C. A
solution of 45.8 g of 2-bromoethyl benzoate in 100 ml of THF is then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extractedwith ether, the organic phase is washed with water and with a buffer solution of pH
4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/5; v/v) as the eluent to give 47 g of the expected product, which is used as such.
D) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine A mixture of 47 g of the compound obtained in the previous step and 10 g of Raney~ nickel in 400 ml of EtOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum.
The residue is taken up with water and extracted with ether, the organic phase is 5 washed with water and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 45 g of the expected product, which is used as such.
E) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine hydrochloride A saturated solution of gaseous HCI in ether is added at RT to a solution of 45 g of the compound obtained in the previous step in 250 ml of MeOH until the 10 pH is 1, and the reaction mixture is stirred for 30 minutes at RT. It is concentrated under vacuum, the residue is taken up with ether and the precipitate formed is filtered off and washed with ether to give 15 g of the expected product after recrystallization from propan-2-ol. M.p. = 202-204~C.
F) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine A solution of 12.2 g of the compound obtained in the previous step and 7.88 g of triethylamine in 100 ml of DCM is cooled to 0~C, a solution of 3.85 g of chloroacetyl chloride in 100 ml of DCM is added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with an ether/AcOEt mixture (50/50; v/v), the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 13.5 g of the expected product, which is used as such.
G) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one A mixture of 13.5 g of the compound obtained in the previous step and 20.7 g of' K,C03 in 100 ml of toluene is refluxed overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with ether and the mixture isfiltered. The filtrate is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/1; v/v) as the eluent to give 4.9 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.35 ppm: mt: 2H
3.65 ppm: AB system: 2H
3.8 to 4.35 ppm: u: 4H
CA 02261808 1999-01-2~
7.1 to 7.8 ppm: u: 8H
8.2 ppm: bs: lH
Preparation 1.11 - 2-(3,4-Difluorophenyl)-2-(2-hydroxyethyl)morpholine A suspension of 1.8 g of lithium aluminum hydride in 20 ml of THF is added dropwise at RT to a solution of 2.8 g of the compound obtained in Preparation 1.10 in 20 ml of THF and the mixture is then refluxed for 5 hours.
After cooling, 2 ml of water, 2 ml of 4 N NaOH and then 6 ml of water are added.The mineral salts are filtered off and the filtrate is concentrated under vacuum.
10 The residue is dissolved in DCM, acidified to pH I by the addition of a saturated solution of gaseous HCI in ether, and extracted with water, the aqueous phase iswashed with ether, rendered alkaline to pH 8 by the addition of concentrated NaOH
solution, and extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 0.77 g of 15 the expected product.
Preparation 1.12 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one I g of 1 ?1 '-carbonyldiimidazole is added at RT to a solution of 2.1 g of the compound obtained in step E of Preparation 1.10 and 0.63 g of triethylamine in 50 20 ml of 1,2-dichloroethane and the reaction mixture is then stirred for I hour at RT
and heated for 2 hours at 50~C. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO~ and the solvent is evaporated off under vacuum to give 1.5 g of the expected product.
Preparation 1.13 5-(3,4-Dichlorophenyl)- 1 -methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]-imidazolidin-2-one A) 2-(3,4-Dichlorophenyl)-2-(methylamino)-4-(tetrahydropyran-2-yloxy)-butylamine A mixture of 3.4 g of the compound obtained in step E of Preparation 1.8, 0.05 g of p-toluenesulfonic acid monohydrate and 2.1 ml of 3,4-dihydro-2H-pyran in 30 ml of DMF is heated at 60~C for 45 minutes. The reaction mixture is pouredonto ice, rendered alkaline by the addition of concentrated NaOH and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the 35 solvent is evaporated off under vacuum to give 4.3 g of the expected product, CA 02261808 1999-01-2~
which is used as such.
B) 5-(3,4-Dichlorophenyl)- I-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]-imidazolidin-2-one 1.6 g of l,1'-carbonyldiimidazole are added to a solution of 3.2 g of the 5 compound obtained in the previous step in 100 ml of 1,2-dichloroethane and thereaction mixture is stirred for 30 minutes at RT. It is then heated at 60~C for 2 hours and concentrated under vacuum. The residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2, with saturated NaCl solution and with 10% Na,CO3 solution and dried over MgSO4 and the solvent is 10 evaporated off under vacuum. The residue is chromatographed on silica H usingDCM and then a DCM/MeOH mixture (98/2; vlv) as the eluent to give 2.4 g of the expected product in the form of an oil.
Preparation 1.14 6-[3 -(Benzoyloxy)propyl] -6-(3,4-dichlorophenyl)morpholin-3-one l 5 A mixture of 7.5 g of the compound obtained in step D of Preparation 1.6, 9.3 g of K,CO3 and 3.75 g of sodium iodide in 100 ml of methyl ethyl ketone is refluxed overnight. After cooling, the reaction mixture is concentrated under vacuum, the residue is taken up with ether, the mineral salts are filtered off, the filtrate is washed with a buffer solution of pH 2 and with water, the organic phase 20 is dried over MgSO, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a gradient of a DCM/MeOH
mixture (from 99/1; v/v to 9812; vlv) as the eluent to ~ive 1.3 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 1.1 to2.3ppm:u:4H
3.65 ppm: AB system: 2H
3.8 to 4.4 ppm: u: 4H
7.2 to 8.05 ppm: u: 8H
8.2ppm:s:1H
Preparation 1.15 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-) isomer A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylallline, (+) isomer A solution of 41 g of L-(+)-tartaric acid in 1200 ml of MeOH is heated to the reflux temperature, a solution of 81.4 g of the compound obtained in step E of Preparation 1.10, in the form of the free base, in 200 ml of MeOH is then added all at once and the mixture is left to crystallize for 48 hours while the temperature is allowed to return to RT. The crystals formed are filtered off and washed with ether to give 42.5 g of the tartaric acid salt.
[a]D20 = +36.2~ (c = l; DMF) The resulting salt is recrystallized from 1450 ml of 70~ EtOH to give 35 g of the tartaric acid salt after the crystals formed have been filtered off and washed with ether.
[a]D20 = +38.9o (c = 1; DMF) The resulting salt is taken up with 2000 ml of AcOEt, 40 ml of 10%
This compound can also be obtained by following the three steps of the method described below.
A') 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride This compound is described in step A of Preparation 1.7.
B') N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-butylamine A solution of 20 g of the compound obtained in the previous step and 10.3 g of triethylamine in 100 ml of DCM is cooled to 0~C, 5.8 g of chloroacetyl chloride are added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 22 g of the expected product, which is used as such.
C') 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one A solution of 22 g of the compound obtained in the previous step in 600 ml of THF is cooled to -10~C, 11.42 g of potassium tert-butylate are added and the reaction mixture is stirred until dissolution is complete. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.8 g of the expected product after crystallization from ether.
Preparation 1.5 2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)morpholine A suspension of 1.6 g of lithium aluminum hydride in 25 ml of THF is heated to 60~C, a solution of 4 g of the compound obtained in step F of Preparation 1.3 in 20 ml of THF is added dropwise and the mixture is stirred for 30 minutes under reflux. After cooling, 1.5 ml of water, 1.5 ml of 4 N NaOH and then 4.5 mlof water are added. The mineral salts are filtered off on Célite~, the filtrate is CA 02261808 1999-01-2~
decanted and the organic phase is evaporated under vacuum. The residue is taken up with ether and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 3.6 g of the expected product.
Preparation 1.6 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine A) S-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)-pentanenitrile 47 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 19.3 g of the compound obtained in step B of 10 Preparation 1.3 in 100 ml of THF is added dropwise and the mixture is stirred for 30 minutes at -60~C. 17 g of 3-bromopropyl benzoate are then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and with saturated NaCI solution and dried 15 over Na,SO4 and the solvent is evaporated off under vacuum to give 21 g of the expected product after crystallization from hexane.
B) S-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine A mixture of 20 g of the compound obtained in the previous step and 7 g of 20 Raney~ nickel in 300 ml of MeOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum.
The residue is taken up with water and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 20 g of the expected product, which is used as such.
25 C) N-(2-Chloroacetyl)-S-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine A solution of 9 g of the compound obtained in the previous step and 2.4 g of triethylamine in 100 ml of DCM is cooled to 0~C, a solution of 2.23 g of chloroacetyl chloride in 20 ml of DCM is added dropwise and the reaction mixture30 is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and thesolvent is evaporated off under vacuum to give 9.5 g of the expected product, which is used as such.
D) N-(2-Chloroacetyl)-S-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxy-pentylamine ~ 41 A saturated solution of gaseous HCI in ether is added to a solution of 9 g of the compound obtained in the previous step in 50 ml of DCM and 50 ml of MeOH
until the pH is 1, and the mixture is stirred for 30 minutes at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with 5 water and with saturated NaHCO3 solution and dried over Na2SO4 and the solventis evaporated off under vacuum. The residue is chromatographed on silica H usinga DCM/MeOH mixture (100/3; v/v) as the eluent to give 4.7 g of the expected' product, which is used as such.
E) 6-(3,4-Dichlorophenyl)-6-(3-hydroxypropyl)morpholin-3-one A mixture of 2.95 g of the compound obtained in the previous step, 40 ml of propan-2-ol and 3 ml of 10 N NaOH solution is stirred for 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (100/2; v/v to 100/5; v/v) as the eluent to give 0.5 g of the expected product. M.p. = 130- 132~C.
F) 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine A suspension of 0.82 g of lithium aluminum hydride in 10 ml of THF is heated to 60~C, a solution of 2 g of the compound obtained in the previous step in 20 ml of THF is added dropwise and the mixture is stirred for 30 minutes under reflux. After cooling, I ml of water, 1 ml of 4 N NaOH and then 3 ml of water are added. The mineral salts are filtered off on Célite~, the filtrate is decanted and the organic phase is evaporated under vacuum. The residue is taken up with ether anddried over Na2SO4 and the solvent is evaporated off under vacuum to give 2 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 0.8 to 2.2 ppm: u: 4H
2.5 to 3.7 ppm: u: 8H
4.3 ppm: t: lH
7.2 to 7.7 ppm: u: 3H
CA 02261808 1999-01-2~
Preparation 1.7 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one A) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine hydrochloride A saturated solution of gaseous HCI in ether is added at RT to a solution of 12 g of the compound obtained in step D of Preparation 1.3 in 50 ml of MeOH
until the pH is 1, and the reaction mixture is stirred for I hour at RT. It is concentrated under vacuum, the residue is taken up with DCM and the precipitate formed is filtered off and washed with ether to give 3.4 g of the expected product after recrystallization from propan-2-ol. M.p. = 200-204~C.
10 B) 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one 1.4 g of 1,1 '-carbonyldiimidazole are added at RT to a solution of 3 g of the compound obtained in the previous step and 0.85 g of triethylamine in 30 ml of 1,2-dichloroethane and the reaction mixture is stirred for 30 minutes at RT and then heated at 50~C for 2 hours. It is concentrated under vacuum, the residue is15 taken up with water and extracted with DCM, the organic phase is washed with a buffer solution of pH 2 and with water and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 3 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 6 ppm: mt: 2H
0 3.75 ppm: AB system: 2H
4.35 ppm: mt: 2H
7.4 to 7.8 ppm: u: 8H
7.9 ppm: s: IH
Preparation 1.8 '5 6-(3,4-Dichlorophenyl)- I -methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]- piperazine-2,3 -dione A) 2-(3,4-Dichlorophenyl)-2-(methylamino)acetonitrile hydrochloride A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml of cyano-trimethylsilane is cooled in an ice bath, 10 mg of zinc iodide are added and themixture is stirred for 30 minutes at RT. 20 ml of a 33% solution of methylamine in EtOH are then added and the mixture is heated at 40~C for 2 hours. The solvent is concentrated under vacuum, the residue is extracted with ether and the organic phase is dried over MgSO4 and filtered. A saturated solution of gaseous HCI in ether is added to the filtrate until the pH is 1, and acetone is then added until the product precipitates. The precipitate formed is filtered off, washed with ether and .
CA 02261808 1999-01-2~
dried to give 12.8 g ofthe expected product. M.p. = 172~C.
B) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)acetonitrile Concentrated NaOH solution is added to an aqueous suspension of 12.8 g of the compound obtained in the previous step until the pH is 13, the mixture is5 extracted with ether, the organic phase is dried over MgSO4 and the solvent isevaporated off under vacuum. The residue is taken up with 20 ml of 1,4-dioxane, 12.5 g of di-tert-butyl dicarbonate are added and the reaction mixture is heated at 60CC for 2 hours. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with a buffer solution of pH 2, with saturated 10 NaCI solution and with 10% Na,CO3 solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicausing heptane and then a heptane/AcOEt mixture (96/4; v/v) as the eluent to give12.7 g of the expected product, which is used as such.
C) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydro-pyran-2-yloxy)butanenitrile A solution of 11.1 g of the compound obtained in the previous step in 60 ml of DMF is added dropwise to a suspension of 1.5 g of sodium hydride (60%
dispersion in oil) in 50 ml of DMF, the temperature being maintained at 25~C, and the mixture is stirred for I hour at RT. A solution of 8.1 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 20 ml of DMF is then added and the reaction mixture is heated at 60~C for 4 hours. At'ter cooling to RT, it is poured into amixture of ice and a buffer of pH 2 and extracted with ether, the organic phase is washed twice with water and dried over MgSO~ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using heptane and then a heptane/AcOEt mixture (75/25; vlv) as the eluent to give 13.2 g of the expected product, which is used as such.
D) 2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydro-pyran-2-yloxy)butylamine A mixture of 13.2 g of the compound obtained in the previous step and 4 g of Raney~ nickel in 150 ml of EtOH and 50 ml of 20% aqueous ammonia solution is hydrogenated at 30~C and at atmospheric pressure. After 5 hours, the catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 12.6 g of the expected product, which is used as such.
CA 02261808 1999-01-2~
E) 2-(3,4-Dichlorophenyl)-4-hydroxy-2-(methylamino)butylamine hydrochloride A mixture of 4.6 g of the compound obtained in the previous step and 10 ml of concentrated HCI solution in 40 ml of MeOH is heated at 70~C for 1 hour. The solvent is then concentrated under vacuum, the residue is taken up with acetone and the precipitate formed is filtered off, washed with ether and dried to give 2.79 g of the expected product. M.p. = 240~C (dec.).
F) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)- 1 -methylpiperazine-2,3-dione Concentrated NaOH solution is added to an aqueous suspension of 5.3 g of the compow~d obtained in the previous step until the pH is 13, the mixture is 10 extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained (4 g) is taken up with 50 ml of EtOH, 2.57 g of diethyl oxalate are added and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum and the residue is taken up with 60 ml of toluene and refluxed for 70 hours. It is concentrated under vacuum to give 2.8 g 15 of the expected product after crystallization from DCM. M.p. = 260~C.
G) 6-(3,4-Dichlorophenyl)-l-methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]-piperazine-2,3 -dione 0.1 g of p-toluenesulfonic acid monohydrate and then 1.26 ml of 3,4-dihydro-2H-pyran are added to a suspension of 2.8 g of the compound obtained in 20 the previous step in 50 ml of DCM and the reaction mixture is stirred overnight at RT. It is washed with 10% Na,CO3 solution and with water, the organic phase is dried over MgSO~ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using AcOEt and then an AcOEt/MeOH mixture (93/7;
v/v) as the eluent to give 3.1 g of the expected product, which is used as such. Preparation 1.9 2-(3,4-Dichlorophenyl)- I -methyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]-piperazine A solution of 2 g of the compound obtained in Preparation 1.8 in 20 ml of THF is added dropwise to a suspension of 1.2 g of lithium aluminum hydride in 2030 ml of THF and the mixture is refluxed for 1 hour. After cooling, 5 ml of water are added, the mineral salts are filtered off, the filtrate is concentrated under vacuum, the residue is taken up with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.9 g of the expected product in the form of an oil.
CA 02261808 1999-01-2~
Preparation 1.10 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one A) 2-(3,4-Difluorophenyl)-2-hydroxyacetonitrile A solution of 80.2 g of Na2S2Os in 250 ml of water is heated to 50~C, 50 g 5 of 3,4-difluorobenzaldehyde are added and the reaction mixture is stirred for 1 hour at 50~C and left to stand overnight at RT. It is cooled to 0~C, a solution of 77.7 g of KCN in 100 ml of water is added dropwise, the mixture is stirred while the temperature is allowed to rise to RT, and stirring is then continued for 1 hour at RT. The reaction mixture is extracted with ether, the organic phase is washed with 10 water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 48 g of the expected product, which is used as such.
B) 2-(3,4-Difluorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile A solution of 48 g of the compound obtained in the previous step and 0.2 g of p-toluenesulfonic acid monohydrate in 500 ml of DCM is cooled to 0~C, a solution of 28.6 g of 3,4-dihydro-2H-pyran in 50 ml of DCM is added dropwise, the mixture is stirred while the temperature is allowed to rise to RT, and stirring is then continued overnight at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 10%
Na2CO3 solution and with water and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/15; v/v) as the eluent to give 43 g of the expected product, which is used as such.
C) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile 133 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooled to -60~C, a solution of 43 g of the compound obtained in the previous step in 250 ml of THF is added dropwise and the mixture is stirred for 30 minutes at -60~C. A
solution of 45.8 g of 2-bromoethyl benzoate in 100 ml of THF is then added dropwise at -60~C and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is concentrated under vacuum, the residue is extractedwith ether, the organic phase is washed with water and with a buffer solution of pH
4 and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a toluene/AcOEt mixture (100/5; v/v) as the eluent to give 47 g of the expected product, which is used as such.
D) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine A mixture of 47 g of the compound obtained in the previous step and 10 g of Raney~ nickel in 400 ml of EtOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum.
The residue is taken up with water and extracted with ether, the organic phase is 5 washed with water and dried over Na,SO4 and the solvent is evaporated off under vacuum to give 45 g of the expected product, which is used as such.
E) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine hydrochloride A saturated solution of gaseous HCI in ether is added at RT to a solution of 45 g of the compound obtained in the previous step in 250 ml of MeOH until the 10 pH is 1, and the reaction mixture is stirred for 30 minutes at RT. It is concentrated under vacuum, the residue is taken up with ether and the precipitate formed is filtered off and washed with ether to give 15 g of the expected product after recrystallization from propan-2-ol. M.p. = 202-204~C.
F) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine A solution of 12.2 g of the compound obtained in the previous step and 7.88 g of triethylamine in 100 ml of DCM is cooled to 0~C, a solution of 3.85 g of chloroacetyl chloride in 100 ml of DCM is added dropwise and the reaction mixture is stirred for 30 minutes. It is concentrated under vacuum, the residue is extracted with an ether/AcOEt mixture (50/50; v/v), the organic phase is washed with water, with a buffer solution of pH 4 and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 13.5 g of the expected product, which is used as such.
G) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one A mixture of 13.5 g of the compound obtained in the previous step and 20.7 g of' K,C03 in 100 ml of toluene is refluxed overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with ether and the mixture isfiltered. The filtrate is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/1; v/v) as the eluent to give 4.9 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.35 ppm: mt: 2H
3.65 ppm: AB system: 2H
3.8 to 4.35 ppm: u: 4H
CA 02261808 1999-01-2~
7.1 to 7.8 ppm: u: 8H
8.2 ppm: bs: lH
Preparation 1.11 - 2-(3,4-Difluorophenyl)-2-(2-hydroxyethyl)morpholine A suspension of 1.8 g of lithium aluminum hydride in 20 ml of THF is added dropwise at RT to a solution of 2.8 g of the compound obtained in Preparation 1.10 in 20 ml of THF and the mixture is then refluxed for 5 hours.
After cooling, 2 ml of water, 2 ml of 4 N NaOH and then 6 ml of water are added.The mineral salts are filtered off and the filtrate is concentrated under vacuum.
10 The residue is dissolved in DCM, acidified to pH I by the addition of a saturated solution of gaseous HCI in ether, and extracted with water, the aqueous phase iswashed with ether, rendered alkaline to pH 8 by the addition of concentrated NaOH
solution, and extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 0.77 g of 15 the expected product.
Preparation 1.12 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one I g of 1 ?1 '-carbonyldiimidazole is added at RT to a solution of 2.1 g of the compound obtained in step E of Preparation 1.10 and 0.63 g of triethylamine in 50 20 ml of 1,2-dichloroethane and the reaction mixture is then stirred for I hour at RT
and heated for 2 hours at 50~C. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with a buffer solution of pH 2 and with water and dried over MgSO~ and the solvent is evaporated off under vacuum to give 1.5 g of the expected product.
Preparation 1.13 5-(3,4-Dichlorophenyl)- 1 -methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]-imidazolidin-2-one A) 2-(3,4-Dichlorophenyl)-2-(methylamino)-4-(tetrahydropyran-2-yloxy)-butylamine A mixture of 3.4 g of the compound obtained in step E of Preparation 1.8, 0.05 g of p-toluenesulfonic acid monohydrate and 2.1 ml of 3,4-dihydro-2H-pyran in 30 ml of DMF is heated at 60~C for 45 minutes. The reaction mixture is pouredonto ice, rendered alkaline by the addition of concentrated NaOH and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the 35 solvent is evaporated off under vacuum to give 4.3 g of the expected product, CA 02261808 1999-01-2~
which is used as such.
B) 5-(3,4-Dichlorophenyl)- I-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]-imidazolidin-2-one 1.6 g of l,1'-carbonyldiimidazole are added to a solution of 3.2 g of the 5 compound obtained in the previous step in 100 ml of 1,2-dichloroethane and thereaction mixture is stirred for 30 minutes at RT. It is then heated at 60~C for 2 hours and concentrated under vacuum. The residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2, with saturated NaCl solution and with 10% Na,CO3 solution and dried over MgSO4 and the solvent is 10 evaporated off under vacuum. The residue is chromatographed on silica H usingDCM and then a DCM/MeOH mixture (98/2; vlv) as the eluent to give 2.4 g of the expected product in the form of an oil.
Preparation 1.14 6-[3 -(Benzoyloxy)propyl] -6-(3,4-dichlorophenyl)morpholin-3-one l 5 A mixture of 7.5 g of the compound obtained in step D of Preparation 1.6, 9.3 g of K,CO3 and 3.75 g of sodium iodide in 100 ml of methyl ethyl ketone is refluxed overnight. After cooling, the reaction mixture is concentrated under vacuum, the residue is taken up with ether, the mineral salts are filtered off, the filtrate is washed with a buffer solution of pH 2 and with water, the organic phase 20 is dried over MgSO, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a gradient of a DCM/MeOH
mixture (from 99/1; v/v to 9812; vlv) as the eluent to ~ive 1.3 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 1.1 to2.3ppm:u:4H
3.65 ppm: AB system: 2H
3.8 to 4.4 ppm: u: 4H
7.2 to 8.05 ppm: u: 8H
8.2ppm:s:1H
Preparation 1.15 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-) isomer A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylallline, (+) isomer A solution of 41 g of L-(+)-tartaric acid in 1200 ml of MeOH is heated to the reflux temperature, a solution of 81.4 g of the compound obtained in step E of Preparation 1.10, in the form of the free base, in 200 ml of MeOH is then added all at once and the mixture is left to crystallize for 48 hours while the temperature is allowed to return to RT. The crystals formed are filtered off and washed with ether to give 42.5 g of the tartaric acid salt.
[a]D20 = +36.2~ (c = l; DMF) The resulting salt is recrystallized from 1450 ml of 70~ EtOH to give 35 g of the tartaric acid salt after the crystals formed have been filtered off and washed with ether.
[a]D20 = +38.9o (c = 1; DMF) The resulting salt is taken up with 2000 ml of AcOEt, 40 ml of 10%
10 Na2CO3 solution are added and then, after stirring and decantation, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 23.5 g of the expected product after cryst~lli7~tion from an iso ether/pentane mixture. M.p. = 100.5-100.6~C.
[a]D20 = +42.5o (c = 1; MeOH) 15 B) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine, (+) isomer A solution of 23.5 g of the compound obtained in the previous step and 8.1 g of triethylamine in 300 ml of DCM is cooled to 0~C, a solution of 8.3 g of chloroacetyl chloride in 50 ml of DCM is added dropwise and the reaction mixtureis stirred for 30 minutes at 0~C. It is concentrated under vacuum, the residue is extracted with an AcOEt/ether mixture (50/50; v/v), the organic phase is washed with a buffer solution of pH 2 and dried over MgSO4 and the solvent is evaporated off under vacuum to give 24.8 g of the expected product after crystallization from an iso ether/pentane mixture.
~5 [a]D~~ = +26.1~ (c = l; MeOH) C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-) isomer A solution of 23.6 g of the compound obtained in the previous step in 750 ml of THF is cooled to 0~C, 13.7 g of potassium te7t-butylate are added and the reaction mixture is stirred for 15 minutes. It is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH
mixture (from 100/1; v/v to 100/1.5; v/v) as the eluent to give 14.5 g of the expected product after crystallization from pentane.
[a]D20= -7.1~ (c = l; MeOH) Preparation 1.16 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+) isomer A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (-) isomer The filtration and wash liquors obtained from the crystallization and then recrystallization of the tartaric acid salt prepared in step A of Preparation 1.15 are concentrated under vacuum. The residue is treated with 10% Na2CO3 solution and extracted with AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 49 g of the amino alcohol in the form of a mixture of isomers. The amino alcohol is dissolved in 120 ml of MeOH and this solution is added all at once to a refluxing solution of 24.1 g of D-(-)-tartaric acid in 730 ml of MeOH. The mixture is left to crystallize for 48 hours while the temperature is allowed to return to RT. The crystals formed are filtered off andwashed with ether to give 40.7 g of the tartaric acid salt.
The resulting salt is recrystallized from 1445 ml of 70~ EtOH to give 35 g of the tartaric acid salt after the crystals fonned have been filtered off and washed with ether. The resulting salt is taken up with 2000 ml of AcOEt, 10% Na.CO3 solution is added and then, after stirring and decantation, the organic phase iswashed with water and dried over MgSO~ and the solvent is evaporated off under vacuum to give 27 g of the expected product. M.p. = 102~C.
[a]D20 = -40.5~ (c = l; MeOH) B) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine, (-) isomer A solution of 27 g of the compound obtained in the previous step and 13 ml of triethylamine in 500 ml of DCM is cooled to -30~C, 5.8 g of chloroacetyl chloride are added dropwise and the reaction mixture is stirred for 15 minutes. It is then washed with water, with 1 N HCI solution and with 10% Na2CO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuumto give 28.6 g of the expected product after crystallization from an iso ether/pentane mixture. M.p. = 63~C.
[a]D~~=-31.5~ (c = I; MeOH) C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+) isomer A solution of 28.5 g of the compound obtained in the previous step in 250 ml of THF is cooled to -30~C, 18.5 g of potassium tert-butylate are added all atonce and the reaction mixture is stirred for 45 minutes. It is poured into 1000 ml of CA 02261808 1999-01-2~
a buffer solution of pH 2 and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 20.5 g of the expected product after crystallization from an ether/iso ether mixture. M.p. =
9~~C.
[a]D20 = +8.2o (c = 1; MeOH) Preparation 1.17 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (-) isomer A solution of 12 g of the compound obtained in Preparation 1.15 ((-) isomer) in 75 ml of THF is added dropwise at RT to 100 ml of a 1 M solution of borane in THF and the reaction mixture is stirred for 30 minutes at RT. It is then refluxed for 3 hours, 40 ml of a I M solution of borane in THF are added and reflux is continued for 30 minutes. 80 ml of boiling MeOH are added and reflux is continued for 30 minutes. The reaction mixture is cooled in an ice bath, 30 ml of a saturated solution of gaseous HCI in ether are added and the reaction mixture isstirred overnight at RT. It is concentrated under vacuum, the residue is taken up with 10% Na CO3 solution and extracted with ether, the organic phase is washed with water and with saturated NaCI solution and dried over MgSO4 and the solventis evaporated off under vacuum to give 11.2 g of the expected product in the form of an oil.
0 Preparation 1.18 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (+) isomer A mixture of 19.9 g of the compound obtained in Preparation 1.16 ((+) isomer) and 300 ml of a I M solution of borane in THF is heated at 60~C for 2 hours. 60 ml of boiling MeOH are added and reflux is continued for 30 minutes.
25 The reaction mixture is cooled to 10~C, 50 ml of a solution of gaseous HCI in ether are added and the reaction mixture is left to stand overnight at RT. It is concentrated under vacuum, the residue is taken up with 300 ml of 10% Na,CO3 solution,300 ml of ether are added and the mixture is stirred for 30 minutes. After decantation, the organic phase is dried over MgSO4 and the solvent is evaporated30 off under vacuum to give 20 g of the expected product in the form of an oil.
Preparation 1.19 2-[2-(Benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)morpholine A solution of 6 g of the compound obtained in Preparation 1.4 in 30 ml of THF is added dropwise at RT to 76 ml of a 1 M solution of borane in THF and the 35 mixture is then refluxed for 4 hours. 30 ml of MeOH are added dropwise and ... . .
CA 02261808 1999-01-2~
reflux is continued for 30 minlltç~. The reaction mixture is cooled to 0~C,30 ml of a saturated solution of gaseous HCI in ether are added and the reaction mixture is stirred overnight at RT. It is concentrated under vacuum, the residue is taken up with 10% Na2CO3 solution and extracted with ether, the organic phase is washed with 10% Na2CO3 solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 5 g of the expected product.
Preparation 1.20 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (-) isomer A mixture of 4 g of the compound obtained in step A of Preparation 1.16 ((-) isomer) and 2.2 g of l,l'-carbonyldiimidazole in 40 ml of DCM is stirred for 30 minutes at RT and then refluxed for I hour. After cooling to RT, the reactionmixture is washed twice with I N HCI solution, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 4.18 g of the expected product after crystallization from iso ether. M.p. = 147~C.
[a]D20 = -62.2~ (c = l; DMF) Preparation 1.21 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine 48 g of the compound obtained in Preparation I .10 are added in portions at RT to 700 ml of a 1 M solution of borane in THF and the mixture is then heated at 60~C for 2 hours. 150 ml of MeOH are added dropwise and heating is continued for 30 minutes. The reaction mixture is cooled to 10~C, 120 ml of hydrochloric ether are added and the reaction mixture is left to stand overnight at RT. It isconcentrated under vacuum, the residue is taken up with 600 ml of saturated Na,CO3 solution and 500 ml of ether and the mixture is stirred for 1 hour at RT.After decantation, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with 400ml of propan-2-ol, 15 g of fumaric acid are added, the mixture is stirred for 30minutes and the precipitate formed is filtered off. It is taken up with 400 ml of 10~/o Na2CO3 solution and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 22 g of the expected product in the form of an oil.
Preparation 1.22 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidine 4 g of 37% aqueous formaldehyde solution are added to a solution of 9 g of the compound obtained in step A of Preparation 1.7 (in the form of the free base) in .
CA 02261808 1999-01-2~
100 ml of THF and the mixture is then refluxed for 30 minutes and stirred overnight at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 9 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.4 ppm: mt: 2H
3.2 ppm: mt: 2H
3.8 to 5.0 ppm: u: 4H
7.0 to 8.0 ppm: u: 8H
Preparation 1.23 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (+) isomer This compound is prepared by the procedure described in Preparation 1.20 from the compound obtained in step A of Preparation 1.15 ((+) isomer).
[a]D20 = +61~ (c = 1; DMF) Preparation 2.1 4-Phenyl- I -azabicyclo[2.2.1]heptane methanesulfonate A) 1-Benzyl-4-carboxy-4-phenylpiperidine 106 ml of 30% NaOH solution are added to a suspension of 100 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 600 ml of water, the resulting solution is then cooled to 5~C, a solution of 47.6 g of benzyl bromide in 100 ml of acetone is added dropwise and the mixture is stirred for 1 hour while the temperature is allowed to rise to RT. The acetone is evaporated off under vacuumand the pH of the remaining aqueous phase is brought to 9.5 by the addition of concentrated HCI solution, and then adjusted to 8.5 by the addition of 2 N HCI
solution. The precipitate formed is filtered off and washed with water and then with acetone to give 70 g of the expected product. M.p. = 286~C.
B ) I -Benzyl-4-(hydroxymethyl)-4-phenylpiperidine A suspension of 70 g of the compound obtained in the previous step in 150 ml of THF is cooled to 5~C, 237 ml of a 1 M solution of borane in THF are added rapidly and the mixture is then refluxed for I hour. A further 474 ml of a 1 M
solution of borane in THF are then added and reflux is continued for 3 hours.
While the mixture is hot, 100 ml of MeOH are added over 30 minutes and then 150 ml of concentrated HCI solution are added over 30 minutes. After cooling to RT, the reaction mixture is diluted with water, rendered alkaline by the addition of 30%
CA 02261808 1999-01-2~
NaOH solution and extracted with an ether/THF mixture, the organic phase is washed with water and dried over Na,SO~ and the solvents are evaporated off under vacuum to give 16 g of the expected product after two cryst~lli7~tions from cyclohexane. M.p. = 127~C .
This compound can also be obtained by following the two steps of the method described below.
A') 4-(Hydroxymethyl)-4-phenylpiperidine hydrochloride A mixture of 10.25 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate and 150 ml of a 1 M solution of borane in THF is refluxed for 1 hour. While the 10 mixture is hot, 30 ml of MeOH are added over 20 minutes; after cooling to RT, a saturated solution of gaseous HCI in ether is added until the pH is 1, and the mixture is stirred overnight at RT. The solvents are concelltrated under vacuum and the residue is taken up with hot acetone and left to crystallize. The crystals fomled are filtered off and washed with acetone and then with ether to give 11.1 g 15 of the expected product. M.p. = 263~C.
B') l-Benzyl-4-(hydroxymethyl)-4-phenylpiperidine A solution of 20.5 g of the compound obtained in the previous step in 100 ml of water and 200 ml of acetone is heated to 40~C, 27 ml of 30% NaOH solution are added, a solution of 17 g of benzyl bromide in 50 ml of acetone is then added 20 dropwise and the mixture is stirred for 1 hour. The acetone is evaporated off, the residue is diluted with water and the precipitate formed is filtered off, washed with water and dried. The precipitate is taken up with 800 ml of hot cyclohexane, an insoluble material is filtered off and the filtrate is left to crystallize at RT to give 19.3 g of the expected product.
25 C) 4-Phenyl- 1 -benzyl- 1 -azoniabicyclo[2.2. l ]heptane methanesulfonate A mixture of 14.05 g of the compound obtained in step B and 5.55 g of triethylamine in 200 ml of DCM is cooled to 5~C, a solution of 6.01 g of methane-sulfonyl chloride in 15 ml of DCM is added dropwise and the mixture is stirred for 15 minutes at RT. It is concentrated under vacuum at 30~C, the residue is extracted 30 with 500 ml of AcOEt, the organic phase is washed with water and dried over Na,SO~ and the solvent is evaporated off under vacuum to give 19.1 g of an oil, which is dissolved in 180 ml of n-butanol and refluxed for 2 hours. It is concentrated under vacuum, the residue is taken up with 150 ml of hot acetone and the mixture is stirred at RT. The crystalline product obtained is filtered off and washed with ether to give 16.85 g of the expected product. M.p. = 193~C.
CA 02261808 1999-01-2~
D) 4-Phenyl- 1 -azabicyclo[2.2.1]heptane methanesulfonate A mixture of 15 g of the compound obtained in the previous step and 1.5 g of 10% palladium-on-charcoal in 150 ml of 95~ EtOH is hydrogenated for 4 hours at 40~C and at atmospheric pressure. The catalyst is filtered off on Célite~ and5 washed with EtOH and the filtrate is concentrated under vacuum. The residue istaken up with hot AcOEt and left to crystallize to give 10.1 g of the expected product after filtration. M.p. = 130~C.
5-(3,4-Difluorophenyl)-5-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]-10 ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one chloride monohydrate, (+) isomer A) 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)-3-[3,5-bis(trifluoromethyl)-benzyl]oxazolidin-2-one, (+) isomer 1.2 g of potassium tert-butylate are added at RT to a solution of 3.5 g of the compound obtained in Preparation 1.23 ((+) isomer) in a mixture of 50 ml of THF
and 10 ml of DMF and the mixture is stirred for 30 minutes at RT. 2.7 g of 3,5-bis(trifluoromethyl)benzyl chloride are then added and the reaction mixture is heated at 60~C for 6 hours. It is poured into 200 ml of buffer of pH 2 and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicaH using DCM as the eluent to give 3.6 g of the expected product.
B) 5-(3,4-Difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]- oxazolidin-2-one, (+) isomer A mixture of 3.6 g of the compound obtained in the previous step and 0.32 g of lithium hydroxide monohydrate in 50 ml of MeOH and 5 ml of water is stirredfor 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using DCM and then a DCM/MeOH
mixture (98/2; vlv) as the eluent to give 2.6 g of the expected product.
C) 5-(3,4-Difluorophenyl)-5-[2-methanesulfonyloxyethyl]-3-[3,5-bis-(trifluoromethyl)benzyl]oxazolidin-2-one, (+) isomer A solution of 2.6 g of the compound obtained in the previous step in 50 ml of DCM is cooled to 0~C, 1.14 ml of triethylamine and then 0.62 ml of methane-sulfonyl chloride are added and the reaction mixture is stirred for 10 minutes. It is CA 02261808 1999-01-2~
concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice witll water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 3 g of the expected product, which is used as such.
D) 5-(3,4-Difluorophenyl)-5-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one chloride monohydrate, (+) isomer A mixture of 2.4 g of the compound obtained in the previous step, 1.6 g of 4-phenyl-1-azabicyclo[2.2.1]heptane methanesulfonate and 1.7 g of K,C03 in 2 ml of DMF is heated at 80~C for 5 hours. After cooling to RT, the reaction mixture is 10 poured into water and extracted with DCM, the organic phase is washed with 10%
HCI solution and with saturated NaCI solution and dried over Na~SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicaH using a DCM/MeOH mixture (100/5; v/v) as the eluent to give 1.46 g of the expected product.
[a]D~~ = +25.8~ (c = l; MeOH) Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0 to 2.4 ppm: u: 4H
2.5 ppm: t: 2H
3.1 to 4.0 ppm: u: 10H
4.6 ppm: AB system: 2H
7.0to8.1 ppm:u: llH
6-(3,4-Dichlorophenyl)-6-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]-ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one chloride A) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)-benzyl]morpholin-3 -one A mixture of 2.1 g of the compound obtained in Preparation 1.4 and 0.616 g of potassium tert-butylate in 50 ml of THF is stirred for 30 minutes at RT, 1.44 g of 3,5-bis(trifluoromethyl)benzyl chloride are added and the reaction mixture isrefluxed for 1 hour. It is concentrated under vacuum, the residue is taken up with a buffer solution of pH 4 and extracted with ether, the organic phase is washed with water and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/0.5; v/v) as the eluent to give 1.8 g of the expected product.
CA 02261808 1999-01-2~
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.4 ppm: mt: 2H
4.05 ppm: AB system: 2H
4.15to4.6ppm:u:4H
4.75 ppm: AB system: 2H
7.3to8.2ppm:u: llH
B) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzyl]- morpholin-3-one A mixture of 1.8 g of the compound obtained in the previous step and 4 ml of concentrated NaOH solution in 30 ml of MeOH is stirred for 30 minutes at 0~C
and stirring is then continued for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1.1 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0ppm:t:2H
2.9to3.45ppm:mt:2H
3.9 ppm: AB system: 2H
4.2 ppm: AB system: 2H
4.45ppm:t: lH
4.7 ppm: AB system: 2H
7.1to8.2ppm:u:6H
C) 6-(3,4-Dichlorophenyl)-6-[2-(methanesulfonyloxy)ethyl]-4-[3,5-bis(trifluoro-methyl)benzyl]morpholin-3-one 0.25 g of methanesulfonyl chloride is added at RT to a solution of 1.1 g of the compound obtained in the previous step and 0.22 g of triethylamine in 30 ml of DCM and the reaction mixture is stirred for 1 hour. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and dried over Na2SOil and the solvent is evaporated off under vacuum to give 1.2 g of the expected product, which is used as such.
D) 6-(3,4-Dichlorophenyl)-6-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one chloride A mixture of 1.5 g of the compound obtained in the previous step, 0.67 g of 4-phenyl-1-azabicyclo[2.2.1]heptane methanesulfonate and 1 g of K2CO3 in 2 ml of DMF is heated at 80-100~C for 3 hours. After cooling to RT, the reaction CA 02261808 1999-01-2~
mixture is poured into water and extracted with DCM, the organic phase is washedwith 10% HCI solution, with saturated NaCI solution and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 100/5; v/v to 5 100/7.5; v/v) as the eluent. The product obtained is dissolved in hot DCM and poured into pentane and the precipitate formed is filtered off to give 0.4 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0to2.7ppm:u:6H
3.0to4.05ppm:u: 10H
4.2to5.0ppm:u:4H
7.2to8.2ppm:u: llH
[a]D20 = +42.5o (c = 1; MeOH) 15 B) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine, (+) isomer A solution of 23.5 g of the compound obtained in the previous step and 8.1 g of triethylamine in 300 ml of DCM is cooled to 0~C, a solution of 8.3 g of chloroacetyl chloride in 50 ml of DCM is added dropwise and the reaction mixtureis stirred for 30 minutes at 0~C. It is concentrated under vacuum, the residue is extracted with an AcOEt/ether mixture (50/50; v/v), the organic phase is washed with a buffer solution of pH 2 and dried over MgSO4 and the solvent is evaporated off under vacuum to give 24.8 g of the expected product after crystallization from an iso ether/pentane mixture.
~5 [a]D~~ = +26.1~ (c = l; MeOH) C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-) isomer A solution of 23.6 g of the compound obtained in the previous step in 750 ml of THF is cooled to 0~C, 13.7 g of potassium te7t-butylate are added and the reaction mixture is stirred for 15 minutes. It is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2 and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH
mixture (from 100/1; v/v to 100/1.5; v/v) as the eluent to give 14.5 g of the expected product after crystallization from pentane.
[a]D20= -7.1~ (c = l; MeOH) Preparation 1.16 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+) isomer A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (-) isomer The filtration and wash liquors obtained from the crystallization and then recrystallization of the tartaric acid salt prepared in step A of Preparation 1.15 are concentrated under vacuum. The residue is treated with 10% Na2CO3 solution and extracted with AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 49 g of the amino alcohol in the form of a mixture of isomers. The amino alcohol is dissolved in 120 ml of MeOH and this solution is added all at once to a refluxing solution of 24.1 g of D-(-)-tartaric acid in 730 ml of MeOH. The mixture is left to crystallize for 48 hours while the temperature is allowed to return to RT. The crystals formed are filtered off andwashed with ether to give 40.7 g of the tartaric acid salt.
The resulting salt is recrystallized from 1445 ml of 70~ EtOH to give 35 g of the tartaric acid salt after the crystals fonned have been filtered off and washed with ether. The resulting salt is taken up with 2000 ml of AcOEt, 10% Na.CO3 solution is added and then, after stirring and decantation, the organic phase iswashed with water and dried over MgSO~ and the solvent is evaporated off under vacuum to give 27 g of the expected product. M.p. = 102~C.
[a]D20 = -40.5~ (c = l; MeOH) B) N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxy-butylamine, (-) isomer A solution of 27 g of the compound obtained in the previous step and 13 ml of triethylamine in 500 ml of DCM is cooled to -30~C, 5.8 g of chloroacetyl chloride are added dropwise and the reaction mixture is stirred for 15 minutes. It is then washed with water, with 1 N HCI solution and with 10% Na2CO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuumto give 28.6 g of the expected product after crystallization from an iso ether/pentane mixture. M.p. = 63~C.
[a]D~~=-31.5~ (c = I; MeOH) C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+) isomer A solution of 28.5 g of the compound obtained in the previous step in 250 ml of THF is cooled to -30~C, 18.5 g of potassium tert-butylate are added all atonce and the reaction mixture is stirred for 45 minutes. It is poured into 1000 ml of CA 02261808 1999-01-2~
a buffer solution of pH 2 and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 20.5 g of the expected product after crystallization from an ether/iso ether mixture. M.p. =
9~~C.
[a]D20 = +8.2o (c = 1; MeOH) Preparation 1.17 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (-) isomer A solution of 12 g of the compound obtained in Preparation 1.15 ((-) isomer) in 75 ml of THF is added dropwise at RT to 100 ml of a 1 M solution of borane in THF and the reaction mixture is stirred for 30 minutes at RT. It is then refluxed for 3 hours, 40 ml of a I M solution of borane in THF are added and reflux is continued for 30 minutes. 80 ml of boiling MeOH are added and reflux is continued for 30 minutes. The reaction mixture is cooled in an ice bath, 30 ml of a saturated solution of gaseous HCI in ether are added and the reaction mixture isstirred overnight at RT. It is concentrated under vacuum, the residue is taken up with 10% Na CO3 solution and extracted with ether, the organic phase is washed with water and with saturated NaCI solution and dried over MgSO4 and the solventis evaporated off under vacuum to give 11.2 g of the expected product in the form of an oil.
0 Preparation 1.18 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (+) isomer A mixture of 19.9 g of the compound obtained in Preparation 1.16 ((+) isomer) and 300 ml of a I M solution of borane in THF is heated at 60~C for 2 hours. 60 ml of boiling MeOH are added and reflux is continued for 30 minutes.
25 The reaction mixture is cooled to 10~C, 50 ml of a solution of gaseous HCI in ether are added and the reaction mixture is left to stand overnight at RT. It is concentrated under vacuum, the residue is taken up with 300 ml of 10% Na,CO3 solution,300 ml of ether are added and the mixture is stirred for 30 minutes. After decantation, the organic phase is dried over MgSO4 and the solvent is evaporated30 off under vacuum to give 20 g of the expected product in the form of an oil.
Preparation 1.19 2-[2-(Benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)morpholine A solution of 6 g of the compound obtained in Preparation 1.4 in 30 ml of THF is added dropwise at RT to 76 ml of a 1 M solution of borane in THF and the 35 mixture is then refluxed for 4 hours. 30 ml of MeOH are added dropwise and ... . .
CA 02261808 1999-01-2~
reflux is continued for 30 minlltç~. The reaction mixture is cooled to 0~C,30 ml of a saturated solution of gaseous HCI in ether are added and the reaction mixture is stirred overnight at RT. It is concentrated under vacuum, the residue is taken up with 10% Na2CO3 solution and extracted with ether, the organic phase is washed with 10% Na2CO3 solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 5 g of the expected product.
Preparation 1.20 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (-) isomer A mixture of 4 g of the compound obtained in step A of Preparation 1.16 ((-) isomer) and 2.2 g of l,l'-carbonyldiimidazole in 40 ml of DCM is stirred for 30 minutes at RT and then refluxed for I hour. After cooling to RT, the reactionmixture is washed twice with I N HCI solution, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 4.18 g of the expected product after crystallization from iso ether. M.p. = 147~C.
[a]D20 = -62.2~ (c = l; DMF) Preparation 1.21 2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine 48 g of the compound obtained in Preparation I .10 are added in portions at RT to 700 ml of a 1 M solution of borane in THF and the mixture is then heated at 60~C for 2 hours. 150 ml of MeOH are added dropwise and heating is continued for 30 minutes. The reaction mixture is cooled to 10~C, 120 ml of hydrochloric ether are added and the reaction mixture is left to stand overnight at RT. It isconcentrated under vacuum, the residue is taken up with 600 ml of saturated Na,CO3 solution and 500 ml of ether and the mixture is stirred for 1 hour at RT.After decantation, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with 400ml of propan-2-ol, 15 g of fumaric acid are added, the mixture is stirred for 30minutes and the precipitate formed is filtered off. It is taken up with 400 ml of 10~/o Na2CO3 solution and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 22 g of the expected product in the form of an oil.
Preparation 1.22 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidine 4 g of 37% aqueous formaldehyde solution are added to a solution of 9 g of the compound obtained in step A of Preparation 1.7 (in the form of the free base) in .
CA 02261808 1999-01-2~
100 ml of THF and the mixture is then refluxed for 30 minutes and stirred overnight at RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 9 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.4 ppm: mt: 2H
3.2 ppm: mt: 2H
3.8 to 5.0 ppm: u: 4H
7.0 to 8.0 ppm: u: 8H
Preparation 1.23 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (+) isomer This compound is prepared by the procedure described in Preparation 1.20 from the compound obtained in step A of Preparation 1.15 ((+) isomer).
[a]D20 = +61~ (c = 1; DMF) Preparation 2.1 4-Phenyl- I -azabicyclo[2.2.1]heptane methanesulfonate A) 1-Benzyl-4-carboxy-4-phenylpiperidine 106 ml of 30% NaOH solution are added to a suspension of 100 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 600 ml of water, the resulting solution is then cooled to 5~C, a solution of 47.6 g of benzyl bromide in 100 ml of acetone is added dropwise and the mixture is stirred for 1 hour while the temperature is allowed to rise to RT. The acetone is evaporated off under vacuumand the pH of the remaining aqueous phase is brought to 9.5 by the addition of concentrated HCI solution, and then adjusted to 8.5 by the addition of 2 N HCI
solution. The precipitate formed is filtered off and washed with water and then with acetone to give 70 g of the expected product. M.p. = 286~C.
B ) I -Benzyl-4-(hydroxymethyl)-4-phenylpiperidine A suspension of 70 g of the compound obtained in the previous step in 150 ml of THF is cooled to 5~C, 237 ml of a 1 M solution of borane in THF are added rapidly and the mixture is then refluxed for I hour. A further 474 ml of a 1 M
solution of borane in THF are then added and reflux is continued for 3 hours.
While the mixture is hot, 100 ml of MeOH are added over 30 minutes and then 150 ml of concentrated HCI solution are added over 30 minutes. After cooling to RT, the reaction mixture is diluted with water, rendered alkaline by the addition of 30%
CA 02261808 1999-01-2~
NaOH solution and extracted with an ether/THF mixture, the organic phase is washed with water and dried over Na,SO~ and the solvents are evaporated off under vacuum to give 16 g of the expected product after two cryst~lli7~tions from cyclohexane. M.p. = 127~C .
This compound can also be obtained by following the two steps of the method described below.
A') 4-(Hydroxymethyl)-4-phenylpiperidine hydrochloride A mixture of 10.25 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate and 150 ml of a 1 M solution of borane in THF is refluxed for 1 hour. While the 10 mixture is hot, 30 ml of MeOH are added over 20 minutes; after cooling to RT, a saturated solution of gaseous HCI in ether is added until the pH is 1, and the mixture is stirred overnight at RT. The solvents are concelltrated under vacuum and the residue is taken up with hot acetone and left to crystallize. The crystals fomled are filtered off and washed with acetone and then with ether to give 11.1 g 15 of the expected product. M.p. = 263~C.
B') l-Benzyl-4-(hydroxymethyl)-4-phenylpiperidine A solution of 20.5 g of the compound obtained in the previous step in 100 ml of water and 200 ml of acetone is heated to 40~C, 27 ml of 30% NaOH solution are added, a solution of 17 g of benzyl bromide in 50 ml of acetone is then added 20 dropwise and the mixture is stirred for 1 hour. The acetone is evaporated off, the residue is diluted with water and the precipitate formed is filtered off, washed with water and dried. The precipitate is taken up with 800 ml of hot cyclohexane, an insoluble material is filtered off and the filtrate is left to crystallize at RT to give 19.3 g of the expected product.
25 C) 4-Phenyl- 1 -benzyl- 1 -azoniabicyclo[2.2. l ]heptane methanesulfonate A mixture of 14.05 g of the compound obtained in step B and 5.55 g of triethylamine in 200 ml of DCM is cooled to 5~C, a solution of 6.01 g of methane-sulfonyl chloride in 15 ml of DCM is added dropwise and the mixture is stirred for 15 minutes at RT. It is concentrated under vacuum at 30~C, the residue is extracted 30 with 500 ml of AcOEt, the organic phase is washed with water and dried over Na,SO~ and the solvent is evaporated off under vacuum to give 19.1 g of an oil, which is dissolved in 180 ml of n-butanol and refluxed for 2 hours. It is concentrated under vacuum, the residue is taken up with 150 ml of hot acetone and the mixture is stirred at RT. The crystalline product obtained is filtered off and washed with ether to give 16.85 g of the expected product. M.p. = 193~C.
CA 02261808 1999-01-2~
D) 4-Phenyl- 1 -azabicyclo[2.2.1]heptane methanesulfonate A mixture of 15 g of the compound obtained in the previous step and 1.5 g of 10% palladium-on-charcoal in 150 ml of 95~ EtOH is hydrogenated for 4 hours at 40~C and at atmospheric pressure. The catalyst is filtered off on Célite~ and5 washed with EtOH and the filtrate is concentrated under vacuum. The residue istaken up with hot AcOEt and left to crystallize to give 10.1 g of the expected product after filtration. M.p. = 130~C.
5-(3,4-Difluorophenyl)-5-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]-10 ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one chloride monohydrate, (+) isomer A) 5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)-3-[3,5-bis(trifluoromethyl)-benzyl]oxazolidin-2-one, (+) isomer 1.2 g of potassium tert-butylate are added at RT to a solution of 3.5 g of the compound obtained in Preparation 1.23 ((+) isomer) in a mixture of 50 ml of THF
and 10 ml of DMF and the mixture is stirred for 30 minutes at RT. 2.7 g of 3,5-bis(trifluoromethyl)benzyl chloride are then added and the reaction mixture is heated at 60~C for 6 hours. It is poured into 200 ml of buffer of pH 2 and extracted with ether, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicaH using DCM as the eluent to give 3.6 g of the expected product.
B) 5-(3,4-Difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]- oxazolidin-2-one, (+) isomer A mixture of 3.6 g of the compound obtained in the previous step and 0.32 g of lithium hydroxide monohydrate in 50 ml of MeOH and 5 ml of water is stirredfor 2 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using DCM and then a DCM/MeOH
mixture (98/2; vlv) as the eluent to give 2.6 g of the expected product.
C) 5-(3,4-Difluorophenyl)-5-[2-methanesulfonyloxyethyl]-3-[3,5-bis-(trifluoromethyl)benzyl]oxazolidin-2-one, (+) isomer A solution of 2.6 g of the compound obtained in the previous step in 50 ml of DCM is cooled to 0~C, 1.14 ml of triethylamine and then 0.62 ml of methane-sulfonyl chloride are added and the reaction mixture is stirred for 10 minutes. It is CA 02261808 1999-01-2~
concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice witll water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 3 g of the expected product, which is used as such.
D) 5-(3,4-Difluorophenyl)-5-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one chloride monohydrate, (+) isomer A mixture of 2.4 g of the compound obtained in the previous step, 1.6 g of 4-phenyl-1-azabicyclo[2.2.1]heptane methanesulfonate and 1.7 g of K,C03 in 2 ml of DMF is heated at 80~C for 5 hours. After cooling to RT, the reaction mixture is 10 poured into water and extracted with DCM, the organic phase is washed with 10%
HCI solution and with saturated NaCI solution and dried over Na~SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicaH using a DCM/MeOH mixture (100/5; v/v) as the eluent to give 1.46 g of the expected product.
[a]D~~ = +25.8~ (c = l; MeOH) Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0 to 2.4 ppm: u: 4H
2.5 ppm: t: 2H
3.1 to 4.0 ppm: u: 10H
4.6 ppm: AB system: 2H
7.0to8.1 ppm:u: llH
6-(3,4-Dichlorophenyl)-6-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]-ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one chloride A) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)-benzyl]morpholin-3 -one A mixture of 2.1 g of the compound obtained in Preparation 1.4 and 0.616 g of potassium tert-butylate in 50 ml of THF is stirred for 30 minutes at RT, 1.44 g of 3,5-bis(trifluoromethyl)benzyl chloride are added and the reaction mixture isrefluxed for 1 hour. It is concentrated under vacuum, the residue is taken up with a buffer solution of pH 4 and extracted with ether, the organic phase is washed with water and dried over Na,SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/0.5; v/v) as the eluent to give 1.8 g of the expected product.
CA 02261808 1999-01-2~
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.4 ppm: mt: 2H
4.05 ppm: AB system: 2H
4.15to4.6ppm:u:4H
4.75 ppm: AB system: 2H
7.3to8.2ppm:u: llH
B) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzyl]- morpholin-3-one A mixture of 1.8 g of the compound obtained in the previous step and 4 ml of concentrated NaOH solution in 30 ml of MeOH is stirred for 30 minutes at 0~C
and stirring is then continued for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 1.1 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0ppm:t:2H
2.9to3.45ppm:mt:2H
3.9 ppm: AB system: 2H
4.2 ppm: AB system: 2H
4.45ppm:t: lH
4.7 ppm: AB system: 2H
7.1to8.2ppm:u:6H
C) 6-(3,4-Dichlorophenyl)-6-[2-(methanesulfonyloxy)ethyl]-4-[3,5-bis(trifluoro-methyl)benzyl]morpholin-3-one 0.25 g of methanesulfonyl chloride is added at RT to a solution of 1.1 g of the compound obtained in the previous step and 0.22 g of triethylamine in 30 ml of DCM and the reaction mixture is stirred for 1 hour. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and dried over Na2SOil and the solvent is evaporated off under vacuum to give 1.2 g of the expected product, which is used as such.
D) 6-(3,4-Dichlorophenyl)-6-[2-[4-phenyl- 1 -azoniabicyclo[2.2.1]hept- 1 -yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one chloride A mixture of 1.5 g of the compound obtained in the previous step, 0.67 g of 4-phenyl-1-azabicyclo[2.2.1]heptane methanesulfonate and 1 g of K2CO3 in 2 ml of DMF is heated at 80-100~C for 3 hours. After cooling to RT, the reaction CA 02261808 1999-01-2~
mixture is poured into water and extracted with DCM, the organic phase is washedwith 10% HCI solution, with saturated NaCI solution and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 100/5; v/v to 5 100/7.5; v/v) as the eluent. The product obtained is dissolved in hot DCM and poured into pentane and the precipitate formed is filtered off to give 0.4 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 ~: 2.0to2.7ppm:u:6H
3.0to4.05ppm:u: 10H
4.2to5.0ppm:u:4H
7.2to8.2ppm:u: llH
Claims (10)
1. Compound of the formula in which:
- A is a divalent radical selected from:
- A1)-O-CO-- A2)-CH2-O-CO-- A3)O-CH2-CO-- A4)-O-CH2-CH2-- A5)-N(R1)-CO-- A6)-N(R1)-CO-CO-- A7)-N(R1)-CH2-CH2-- A8)-O-CH2-in which R1 is a hydrogen or a (C1-C4)alkyl;
- m is 2 or 3;
- Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C1-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom;
a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
- T is a group selected from CH2-Z, -CH(C6H5)2 and -C(C6H5)3; T can also be the group -CO-B-Z if A is a divalent radical selected from -O-CH2-CH2-, -N(R1)- CH2-CH2- and -O-CH2-;
- B is a direct bond or a methylene;
- z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubtituted or disubstituted by a (Cl-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a 1- or 2-naphthyl; or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy or trifluoromethyl group, in which the alkyl and alkoxy groups are C1-C4;
- a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, bezofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group, in which the alkyl and alkoxy groups are C1-C4; and -Am is a group of the formula in which:
- Ar2 is a pyridyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl, a nitro and a methylenedioxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl;
- n is zero or one; and - X~ is a pharamceutically acceptable anion;
and the salts thereof, where appropriate, with mineral or organic acids.
- A is a divalent radical selected from:
- A1)-O-CO-- A2)-CH2-O-CO-- A3)O-CH2-CO-- A4)-O-CH2-CH2-- A5)-N(R1)-CO-- A6)-N(R1)-CO-CO-- A7)-N(R1)-CH2-CH2-- A8)-O-CH2-in which R1 is a hydrogen or a (C1-C4)alkyl;
- m is 2 or 3;
- Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C1-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom;
a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
- T is a group selected from CH2-Z, -CH(C6H5)2 and -C(C6H5)3; T can also be the group -CO-B-Z if A is a divalent radical selected from -O-CH2-CH2-, -N(R1)- CH2-CH2- and -O-CH2-;
- B is a direct bond or a methylene;
- z is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubtituted or disubstituted by a (Cl-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a 1- or 2-naphthyl; or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy or trifluoromethyl group, in which the alkyl and alkoxy groups are C1-C4;
- a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, bezofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as the alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group, in which the alkyl and alkoxy groups are C1-C4; and -Am is a group of the formula in which:
- Ar2 is a pyridyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl, a nitro and a methylenedioxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl;
- n is zero or one; and - X~ is a pharamceutically acceptable anion;
and the salts thereof, where appropriate, with mineral or organic acids.
2. Optically pure compound according to claim 1, of the formula in which:
- "*" means that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and - Am, m, Ar1, A and T are as defined for the compounds of formula (I) in claim 1;
and the salts thereof with mineral or organic acids.
- "*" means that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and - Am, m, Ar1, A and T are as defined for the compounds of formula (I) in claim 1;
and the salts thereof with mineral or organic acids.
3. A compound according to either one of claims 1 or 2, of formula (I) or (I*) in which:
- Z is Z' and is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubtituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; or - a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl, an imidazolyl or a furyl; and - Am, m, Ar1, and T are as defined for a compound of formula (I) in claim 1;
and the salts thereof with mineral or organic acids.
- Z is Z' and is:
- a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubtituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoylamino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy, said substituents being identical or different; and a (pyrrolidin-1-yl)carbonylamino, said substituents being identical or different;
- a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; or - a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl, an imidazolyl or a furyl; and - Am, m, Ar1, and T are as defined for a compound of formula (I) in claim 1;
and the salts thereof with mineral or organic acids.
4. Compound according to one of claims 1 or 2, of the formula in which:
- Aa is a divalent radical selected from: -O-CO-, -CH2-O-CO-, -O-CH2-CO-, -N(R1)-CO- and -N(R1)-CO-CO-, in which R1 is a hydrogen or a (C1-C4)alkyl;
- Am is a group of the formula - n is 0 or 1;
- X~ is a pharmaceutically acceptable anion;
- Ar2 is as defined for a compound of formula (I) in claim 1;
- Ar1a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl and a trifluoromethyl, said substituents being identical or different; and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom, a trifluoromethyl, a (C1-C10)alkyl, a (C1-C10)alkoxy and a hydroxyl, said substituents being identical or different.
- Aa is a divalent radical selected from: -O-CO-, -CH2-O-CO-, -O-CH2-CO-, -N(R1)-CO- and -N(R1)-CO-CO-, in which R1 is a hydrogen or a (C1-C4)alkyl;
- Am is a group of the formula - n is 0 or 1;
- X~ is a pharmaceutically acceptable anion;
- Ar2 is as defined for a compound of formula (I) in claim 1;
- Ar1a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl and a trifluoromethyl, said substituents being identical or different; and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom, a trifluoromethyl, a (C1-C10)alkyl, a (C1-C10)alkoxy and a hydroxyl, said substituents being identical or different.
5. Compound according to one of claims 1 or 2, of the formula in which:
- Ab is the divalent radical -O-CH2-CH2-, -N(R1)-CH2-CH2- or -O-CH2-, in which R1 is a hydrogen or a (C1-C4)alkyl;
- Am is a group of the formula - n is 0 or 1;
- B is a direct bond or a methylene;
- X- is a pharmaceutically acceptable anion;
- Ar2 is as defined for a compound of formula (I) in claim 1;
- Ar1a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl and a trifluoromethyl, said substituents being identical or different, and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom, a trifluoromethyl, a (C1-C10)alkyl, a (C1-C10)alkoxy and a hydroxyl, said substituents being identical or different.
- Ab is the divalent radical -O-CH2-CH2-, -N(R1)-CH2-CH2- or -O-CH2-, in which R1 is a hydrogen or a (C1-C4)alkyl;
- Am is a group of the formula - n is 0 or 1;
- B is a direct bond or a methylene;
- X- is a pharmaceutically acceptable anion;
- Ar2 is as defined for a compound of formula (I) in claim 1;
- Ar1a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl and a trifluoromethyl, said substituents being identical or different, and - Za is a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom, a trifluoromethyl, a (C1-C10)alkyl, a (C1-C10)alkoxy and a hydroxyl, said substituents being identical or different.
6. Method of preparing the compounds of formula (I) according to claim 1 and the salts thereof, characterized in that 1) a compound of the formula in which m, Ar1 and A are as defined for a compound of formula (I) in claim 1 and E is hydrogen or an O-protecting group, is treated - either with a functional derivative of an acid of the formula HOCO-B-Z (III) in which B and Z are as defined above for (I) in claim 1, if it is intended to prepare a compound of formula (I) in which T is -CO-B-Z, - or with a halogenated derivative of the formula Hal-CH2-Z (IV) in which Z is as defined in claim 1 and Hal is a halogen, if it is intended to prepare a compound of formula (I) in which T is -CH2-Z, - or with a halogenated derivative of the formula Hal-CH(C6H5)2 (V) if it is intended to prepare a compound of formula (I) in which T is a group -CH(C6H5)2, - or with a halogenated derivative of the formula Hal-C-(C6H5)3 (VI) if it is intended to prepare a compound of formula (I) in which T is a group -C(C6H5)3, to give a compound of the formula in which E, m, Ar1, A and T are as defined above;
2) the O-protecting group is removed, if appropriate, by reaction with an acid or a base to give the alcohol of the formula in which m, Ar1, A and T are as defined above;
3) the alcohol (VIII) is treated with a compound of the formula Y-SO2-Cl (IX) in which Y is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the formula in which Y, m, Ar1, A and Y are as defined above;
4) the compound (X) is reacted with a cyclic tertiary amine of the formula in which Ar2 and n are as defined for (I) in claim 1; and 5) the resulting product is isolated in the form of a sulfonate and, if appropriate, a sulfonic acid salt, or optionally the anion and, if appropriate, the resulting acid salt are exchanged with another anion and, if appropriate, another salt with a pharmaceutically acceptable mineral or organic acid.
2) the O-protecting group is removed, if appropriate, by reaction with an acid or a base to give the alcohol of the formula in which m, Ar1, A and T are as defined above;
3) the alcohol (VIII) is treated with a compound of the formula Y-SO2-Cl (IX) in which Y is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the formula in which Y, m, Ar1, A and Y are as defined above;
4) the compound (X) is reacted with a cyclic tertiary amine of the formula in which Ar2 and n are as defined for (I) in claim 1; and 5) the resulting product is isolated in the form of a sulfonate and, if appropriate, a sulfonic acid salt, or optionally the anion and, if appropriate, the resulting acid salt are exchanged with another anion and, if appropriate, another salt with a pharmaceutically acceptable mineral or organic acid.
7. Pharmaceutical composition which contains as the active principle a compound according to any one of claims 1 to 5, or a pharmaceutically acceptablesalt thereof.
8. Pharmaceutical composition according to claim 7 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutical excipient.
9. Pharmaceutical composition according to claim 8 which contains 0.5 to 1000 mg of active principle.
10. Pharmaceutical composition according to claim 9 which contains 2.5 to 250 mg of active principle.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9609439A FR2751654B1 (en) | 1996-07-26 | 1996-07-26 | SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR9609439 | 1996-07-26 | ||
| PCT/FR1997/001393 WO1998004561A1 (en) | 1996-07-26 | 1997-07-25 | 1-azoniabicyclo[2.2.1]heptane derivatives and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2261808A1 true CA2261808A1 (en) | 1998-02-05 |
Family
ID=9494521
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002261808A Abandoned CA2261808A1 (en) | 1996-07-26 | 1997-07-25 | 1-azoniabicyclo¬2.2.1|heptane derivatives and pharmaceutical compositions containing them |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0915882A1 (en) |
| JP (1) | JP2000515878A (en) |
| AU (1) | AU3854597A (en) |
| BR (1) | BR9710517A (en) |
| CA (1) | CA2261808A1 (en) |
| FR (1) | FR2751654B1 (en) |
| NO (1) | NO312244B1 (en) |
| WO (1) | WO1998004561A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2873373B1 (en) * | 2004-07-23 | 2006-09-08 | Sanofi Synthelabo | DERIVATIVES OF 4-ARYLMORPHOLIN-3-ONE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| MX2009007916A (en) | 2007-01-24 | 2009-07-31 | Glaxo Group Ltd | Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2696178B1 (en) * | 1992-09-30 | 1994-12-30 | Sanofi Elf | Quaternary basic amides, process for their preparation and pharmaceutical compositions containing them. |
| FR2729954B1 (en) * | 1995-01-30 | 1997-08-01 | Sanofi Sa | SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1996
- 1996-07-26 FR FR9609439A patent/FR2751654B1/en not_active Expired - Fee Related
-
1997
- 1997-07-25 BR BR9710517A patent/BR9710517A/en not_active IP Right Cessation
- 1997-07-25 CA CA002261808A patent/CA2261808A1/en not_active Abandoned
- 1997-07-25 AU AU38545/97A patent/AU3854597A/en not_active Abandoned
- 1997-07-25 JP JP10508555A patent/JP2000515878A/en active Pending
- 1997-07-25 WO PCT/FR1997/001393 patent/WO1998004561A1/en not_active Application Discontinuation
- 1997-07-25 EP EP97935628A patent/EP0915882A1/en not_active Withdrawn
-
1999
- 1999-01-22 NO NO19990278A patent/NO312244B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU3854597A (en) | 1998-02-20 |
| NO990278L (en) | 1999-01-22 |
| NO312244B1 (en) | 2002-04-15 |
| NO990278D0 (en) | 1999-01-22 |
| BR9710517A (en) | 1999-08-17 |
| JP2000515878A (en) | 2000-11-28 |
| EP0915882A1 (en) | 1999-05-19 |
| FR2751654B1 (en) | 1998-10-23 |
| FR2751654A1 (en) | 1998-01-30 |
| WO1998004561A1 (en) | 1998-02-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2157807C2 (en) | Substituted heterocyclic compounds, method of their synthesis and pharmaceutical composition | |
| US5780466A (en) | Substituted heterocyclic compounds method of preparing them and pharmaceutical compositions in which they are present | |
| KR100238343B1 (en) | Novel n-(3, 4-dichlorophenyl-propyl)-piperidine derivatives as selective human nk3-receptor antagonists | |
| RU2083574C1 (en) | Polycyclic amine-containing compounds or their salts, their optically pure isomers, method of synthesis of polycyclic amine-containing compounds, cyclic amine-containing compounds or their salts, their optically pure isomers and pharmaceutical composition showing antagonistic activity with respect to neurokinin receptors | |
| FR2738245A1 (en) | NOVEL PIPERIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| HUT73226A (en) | With arylaliphatic and alkyl-groups n-substituted novel amides, method for their preparation and pharmaceutical compositions containing same | |
| MXPA03010133A (en) | Novel piperidinecarboxamide derivatives, method for preparing same and pharmaceutical compositions containing same. | |
| BG64623B1 (en) | Novel morpholine derivatives, method for the production thereof and pharmaceutical preparations containing said derivatives | |
| CA2261808A1 (en) | 1-azoniabicyclo¬2.2.1|heptane derivatives and pharmaceutical compositions containing them | |
| KR100477164B1 (en) | Substituted heterocyclic compounds, preparation method thereof and pharmaceutical compositions containing same | |
| AU731788B2 (en) | Substituted heterocyclic compounds, preparation method therefor and pharmaceutical compositions containing same | |
| FR2729952A1 (en) | New substd heterocycle(s) useful as neurokinin receptor antagonists | |
| MXPA99000736A (en) | 1-azoniabicyclo[2.2.1]heptane derivatives and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |