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US 6,444,809 B1Granted
Therapeutic heterocycles
AssigneeZeneca Limited
InventorScott Carson Miller
Life of this patent
Estimating the term…
Abstract
Compounds of formula I wherein G, J, L, M, m and D have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.
Claims12
A process for preparing a compound according to formula I
- wherein:
- m is 2 or 3;
- D is a residue of formula Ia or formula Ib
- Q is phenyl which may have one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (C1-3)alkoxy, (C1-3)alkyl and methylenedioxy;
- or
- Q is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may have a halo substituent;
- or
- Q is biphenylyl;
- or
- Q is carbon-linked indolyl which may have a benzyl substituent at the 1-position;
- Qa is hydrogen, (C1-4)alkyl, or a radical of formula —(CH2)q—NR5R6 in which q is 2 or 3 and R5 and R6 are independently (C1-4)alkyl or NR5R6 is piperidino or 4-benzylpiperidino;
- R1 is hydrogen, methyl or (C2-6)n-alkyl which may have a terminal amino radical;
- R2 is —C(═O)R3, —C(═O)OR3 or —C(═J1)NHR3 in which J1 is oxygen or sulfur and R3 is hydrogen, (C1-6)alkyl, phenyl(C1-3)alkyl (which phenyl may have one or more substituents selected from halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl), pyridyl(C1-3)alkyl, naphthyl(C1-3)alkyl, pyridylthio(C1-3)alkyl, styryl, 1-methylimidazol-2-ylthio(C1-3)alkyl, aryl (which may have one or more substituents selected from halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl), heteroaryl (which may have one or more halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl substituents), or R3 may be α-hydroxybenzyl when R2 is —COR3;
- n is 0, 1, 2 or 3;
- J2 is oxygen or two hydrogens;
- p is 1 or 2, and when p is 2, n is 1 and J2 is two hydrogens;
- L6 is carbonyl or methylene;
- r is 0, 1, 2 , or 3;
- R4 is phenyl which may have one or more substituents selected from halo, trifluoromethyl, (C1-4)alkyl, hydroxy or (C1-4)alkoxy;
- naphthyl which may have one or more substituents selected from halo, trifluoromethyl, (C1-4)alkyl or hydroxy;
- pyridyl;
- thienyl;
- indolyl;
- quinolinyl;
- benzothienyl or imidazolyl;
- or when L6 is carbonyl, the group —(CH2)r—R4 may be aryl, heteroaryl or a benzyl group having an α-substituent selected from hydroxy, (C1-4)alkoxy and (C1-4)alkyl, and further wherein the aryl, heteroaryl or phenyl portion of the benzyl group may have one or more substituents selected independently from halo, trifluoromethyl, (C1-4)alkyl, hydroxy and (C1-4)alkyl, hydroxy and (C1-4)alkoxy;
- G denotes a single bond, a double bond or a divalent hydrocarbon radical;
- J denotes a radical joined to the ring by a single bond if G denotes a double bond or, otherwise, a radical joined by a double bond;
- M denotes a heteroatom or substituted heteroatom;
- and
- L denotes a hydrocarbon radical in which the 1-position is attached to M;
- wherein the values of G, J, M and L in combination are selected from
- (a) G is a single bond;
- J is oxo or thioxo;
- M is oxy, thio or NR12;
- and L is L1;
- (b) G is a single bond;
- J is NR8;
- M is NR7;
- and L is L1;
- (c) G is a double bond, J is OR7, SR7 or NR9R10;
- M is nitrogen;
- and L is L1;
- (d) G is methylene which may have one or two methyl substituents;
- J is oxo, thio or NR11;
- M is oxy, thio, sulfinyl, sulfonyl or NR7;
- and L is L2;
- (e) G is a single bond;
- J is oxo, thioxo or NR11;
- M is nitrogen;
- and L is L3;
- (f) G is methine, which may have a (1-3C)alkyl substituent;
- J is oxo, thioxo or NR11;
- M is nitrogen;
- and L is L4;
- and
- (g) G is cis-vinylene, which may have one or two methyl substituents;
- J is oxo, thioxo, or NR11;
- M is nitrogen;
- and L is L5;
- wherein
- R7 is hydrogen or (C1-3)alkyl;
- R8 is hydrogen, (C1-3)alkyl, cyano, (C1-3)alkylsulfonyl or nitro;
- R9 and R10 are independently hydrogen or (C1-3)alkyl or the radical NR9R10 is pyrrolidino, piperidino, morpholino, thiomorpholino or its S-oxide, or piperazino which may have a (C1-3)alkyl substituent at the 4-position;
- R11 is hydrogen or (C1-3)alkyl;
- R12 is hydrogen, (C1-3)alkyl, RaOC(═O)CH2— or RbRcNC(═O)CH2—, where
- Ra is hydrogen or (C1-3)alkyl, and
- Rb and Rc are independently hydrogen, (C1-3)alkyl, phenyl or benzyl;
- L1 is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L1 itself may have one or two methyl substituents;
- L2 is ethylene or trimethylene which radical L2 itself may have one or two methyl substituents;
- L3 is prop-2-en-1-yliden-3-yl, which radical L3 itself may have one or two methyl substituents;
- L4 is cis-vinylene, which radical L4 itself may have one or two methyl substituents;
- and
- L5 is methine, which radical L5 itself may have a (C1-3)alkyl substituent;
- and compounds wherein the nitrogen identified by Δ is an N-oxide or a quadricovalent ammonium nitrogen where the fourth radical on the nitrogen is (C1-4)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion,
- or a pharmaceutically acceptable salt of said compound of formula I or said N-oxide, said process comprising
- a) reductively alkylating 4-oxopiperidine under mild acid conditions with an aldehyde of formula IV
- followed by reduction with sodium cyanoborohydride in an alcoholic solvent, or, alkylating said piperidine with an alkylating agent of formula V
- wherein Y is a leaving up selected from iodide, bromide, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, to form a piperidone of formula VII
- b) reductively alkylating said piperidone of formula VII with an amine of formula HML-NH2 to form an amine of formula III
- c) cyclizing said amine by reacting it with a diactivated carbonic acid derivative selected from 1,1′-carbonyldiimidazole, chloroformate esters selected from methyl, ethyl or phenyl esters, and carbonate diesters selected from phosgene, diphosgene and triphosgene;
- or with a diactivated thiocarbonyl derivative selected from 1,1′-thiocarbonyldi-2(1H)-pyridone, 1,1′-thiocarbonyldiimidazole, phenyl chlorodithioformate and thiophosgene;
- said cyclization being carried in an inert solvent, selected from chloroform, tetrahydrofuran or toluene, at a temperature from about ambient temperature to the reflux temperature of the reaction mixture to form a compound of said formula I.
80 more elements
The process according to claim 1, for preparing a compound according to formula I
- wherein:
- G is a single bond;
- J is oxo;
- M is NR12;
- L is L1, and R12, D and m are as defined in claim 3, and
- wherein said step b) comprises:
- cyclizing said amine by reacting it with a diactivated carbonic acid derivative selected from 1,1′-carbonyldiimidazole, chloroformate esters selected from methyl, ethyl or phenyl esters, and carbonate diesters selected from phosgene, diphosgene and triphosgene.
4 more elements
A process for preparing a compound according to formula I
- wherein:
- m is 2 or 3;
- D is a residue of Ia or formula Ib
- Q is phenyl which may have one or two substituents independently selected from halo, trifluoromethyl, hydroxy, (C1-3)alkoxy, (C1-3)alkyl and methylenedioxy;
- or
- Q is thienyl, imidazolyl, benzo[b]thiophenyl or naphthyl any of which may have a halo substituent;
- or
- Q is biphenylyl;
- or
- Q is carbon-linked indolyl which may have a benzyl substituent at the 1-position;
- Qa is hydrogen, (C1-4)alkyl, or a radical of formula —(CH2)q—NR5R6 in which q is 2 or 3 and R5 and R6 are independently (C1-4)alkyl or NR5R6 is piperidino or 4-benzylpiperidino;
- R1 is hydrogen, methyl or (C2-6)n-alkyl which may have a terminal amino radical;
- R2 is —C(═O)R3, —C(═O)OR3 or —C(═J1)NHR3 in which J1 is oxygen or sulfur and R3 is hydrogen, (C1-6)alkyl, phenyl(C1-3)alkyl (which phenyl may have one or more substituents selected from halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl), pyridyl(C1-3)alkyl, naphthyl(C1-3)alkyl, pyridylthio(C1-3)alkyl, styryl, 1-methylimidazol-2-ylthio(C1-3)alkyl, aryl (which may have one or more substituents selected from halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl), heteroaryl (which may have one or more halo, hydroxy, (C1-4)alkoxy or (C1-4)alkyl substituents), or R3 may be α-hydroxybenzyl when R2 is —COR3;
- n is 0, 1, 2 or 3;
- j2is oxygen or two hydrogens;
- p is 1 or 2, and when p is 2, n is 1 and J2 is two hydrogens;
- L6 is carbonyl or methylene;
- r is 0, 1, 2, or 3;
- R4 is phenyl which may have one or more substituents selected from halo, trifluoromethyl, (C1-4)alkyl, hydroxy or (C1-4)alkoxy;
- naphthyl which may have one or more substituents selected from halo, trifluoromethyl, (C1-4)alkyl or hydroxy;
- pyridyl;
- thienyl;
- indolyl;
- quinolinyl;
- benzothienyl or imidazolyl;
- or when L6 is carbonyl, the group —(CH2)r—R4 may be aryl, heteroaryl or a benzyl group having an α-substituent selected from hydroxy, (C1-4)alkoxy and (C1-4)alkyl, and further wherein the aryl, heteroaryl or phenyl portion of the benzyl group may have one or more substituents selected independently from halo, trifluoromethyl, (C1-4)alkyl, hydroxy and (C1-4)alkyl, hydroxy and (C1-4)alkoxy;
- G denotes a single bond, a double bond or a divalent hydrocarbon radical;
- J denotes a radical joined to the ring by a single bond if G denotes a double bond or, otherwise, a radical joined by a double bond;
- M denotes a heteroatom or substituted heteroatom;
- and
- L denotes a hydrocarbon radical in which the 1-position is attached to M;
- wherein the values of G, J, M and L in combination are selected from
- (a) G is a single bond;
- J is oxo or thioxo;
- M is oxy, thio or NR12;
- and L is L1;
- (b) G is a single bond;
- J is NR8;
- M is NR7;
- and L is L1;
- (c) G is a double bond, J is OR7, SR7 or NR9R10;
- M is nitrogen;
- and L is L1;
- (d) G is methylene which may have one or two methyl substituents;
- J is oxo, thio or NR11;
- M is oxy, thio, sulfinyl, sulfonyl or NR7;
- and L is L2;
- (e) G is a single bond;
- J is oxo, thioxo or NR11;
- M is nitrogen;
- and L is L3;
- (f) G is methine, which may have a (1-3C)alkyl substituent;
- J is oxo, thioxo or NR11;
- M is nitrogen;
- and L is L4;
- and
- (g) G is cis-vinylene, which may have one or two methyl substituents;
- J is oxo, thioxo, or NR11;
- M is nitrogen;
- and L is L5;
- wherein
- R7 is hydrogen or (C1-3)alkyl;
- R8 is hydrogen, (C1-3)alkyl, cyano, (C1-3)alkylsulfonyl or nitro;
- R9 and R10 are independently hydrogen or (C1-3)alkyl or the radical NR9R10 is pyrrolidino, piperidino, morpholino, thiomorpholino or its S-oxide, or piperazino which may have a (C1-3)alkyl substituent at the 4-position;
- R11 is hydrogen or (C1-3)alkyl;
- R12 is hydrogen, (C1-3)alkyl, RaOC(═O)CH2— or RbRcNC(═O)CH2—, where
- Ra is hydrogen or (C1-3)alkyl, and
- Rb and Rc are independently hydrogen, (C1-3)alkyl, phenyl or benzyl;
- L1 is ethylene, cis-vinylene, trimethylene or tetramethylene which radical L1 itself may have one or two methyl substituents;
- L2 is ethylene or trimethylene which radical L2 itself may have one or two methyl substituents;
- L3 is prop-2-en-1-yliden-3-yl, which radical L3 itself may have one or two methyl substituents;
- L4 is cis-vinylene, which radical L4 itself may have one or two methyl substituents;
- and
- L5 is methine, which radical L5 itself may have a (C1-3)alkyl substituent;
- and compounds wherein the nitrogen identified by Δ is an N-oxide or a quadricovalent ammonium nitrogen where the fourth radical on the nitrogen is (C1-4)alkyl or benzyl and the associated counterion is a pharmaceutically acceptable anion,
- or a pharmaceutically acceptable salt of said compound of formula I or said N-oxide, said process comprising:
- a) reacting a protected 4-oxopiperidine of the following formula
- wherein Pr is a protecting group such as benzyloxycarbonyl, with an amine of formula HM-L-NH2 to form an amine of the formula III
- b) cyclizing said amine by reacting it with a diactivated carbonic acid derivative selected from 1,1′-carbonyldiimidazole, chloroformate esters selected from methyl, ethyl or phenyl esters, and carbonate diesters selected from phosgene, diphosgene and triphosgene;
- or with a diactivated thiocarbonyl derivative selected from 1,1′-thiocarbonyldi-2(1H)pyridone, 1,1′-thiocarbonyldiimidazole, phenyl chlorodithioformate and thiophosgene;
- said cyclization being carried in an inert solvent, selected from chloroform, tetrahydrofuran or toluene, at a temperature from about ambient temperature to the reflux temperature of the reaction mixture to form a compound having the following formula
- and deprotecting said compound to form a piperidine of formula II,
- c) reductively alkylating said piperidine of formula II under mild acid conditions with an aldehyde of formula IV
- followed by reduction with sodium cyanoborohydride in an alcoholic solvent, or, alkylating said piperidine of formula II with an alkylating agent of formula V
- wherein Y is a leaving group selected from iodide, bromide, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate to form said compound of formula I.
82 more elements
Dependencies are inferred from the claim text.