HK1113927B - Substituted triazole derivatives as oxytocin antagonists - Google Patents
Substituted triazole derivatives as oxytocin antagonists Download PDFInfo
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- HK1113927B HK1113927B HK08103169.1A HK08103169A HK1113927B HK 1113927 B HK1113927 B HK 1113927B HK 08103169 A HK08103169 A HK 08103169A HK 1113927 B HK1113927 B HK 1113927B
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Description
[ technical field ] A method for producing a semiconductor device
The present invention relates to a class of substituted triazoles having activity as oxytocin antagonists, their use, methods for their preparation and compositions containing these inhibitors. Such inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E).
[ summary of the invention ]
The present invention provides compounds of formula (I):
wherein:
m is in the range of 1 to 4 and n is 1 or 2, with the proviso that m + n is in the range of 2 to 5;
x is selected from O, NH, N (C)1-C6) Alkyl, NC (O) (C)1-C6) Alkyl, N (SO)2(C1-C6) Alkane (I) and its preparation methodBasic group), S and SO2；
R1Selected from:
(i) a phenyl ring or a naphthyl ring;
(ii) 5-to 6-membered aromatic heterocycles and N-oxides thereof containing 1 to 3 heteroatoms independently selected from N, O and S;
(iii) 9-to 10-membered bicyclic aromatic heterocycles and N-oxides thereof containing 1 to 4 heteroatoms independently selected from N, O and S; and
(iv) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2C (O) OH and C (O) NH2；
R2Selected from:
(i) h or hydroxy;
(ii)(C1-C6) Alkyl optionally substituted by O (C)1-C6) Alkyl or phenyl substitution;
(iii)O(C1-C6) Alkyl optionally substituted by O (C)1-C6) Alkyl substitution;
(iv)NH(C1-C6) Alkyl, the alkyl being optionally substituted by O (C)1-C6) Alkyl substitution;
(v)N((C1-C6) Alkyl radical)2One or two of these alkyl groups being optionally substituted by O (C)1-C6) Alkyl substitution;
(vi) a 5-to 8-membered N-linked saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms, each independently selected from N, O and S, wherein at least one heteroatom is N and the ring may optionally include one or two carbonyl groups; the ring being optionally substituted by one or more groups selected from CN, halogen, (C)1-C6) Alkyl, O (C)1-C6) Alkyl, NH (C)1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、C(O)(C1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2、C(O)OH、C(O)NH2And C (O) OCH2Substitution of the group of Ph; and
(vii) a 5-to 7-membered N-linked heteroaromatic ring containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein at least one heteroatom is N; the ring being optionally substituted by one or more groups selected from CN, halogen, (C)1-C6) Alkyl, O (C)1-C6) Alkyl, NH (C)1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2、C(O)OH、C(O)NH2And C (O) OCH2Substitution of the group of Ph;
R3selected from H, (C)1-C6) Alkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R4、R5、R6and R7Each independently selected from H, halogen, hydroxy, CN, (C)1-C6) Alkyl, NH (C)1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2And O (C)1-C6) An alkyl group; and is
R8Selected from H, (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, CH2OH、CH2NH2、CH2NH(C1-C6) Alkyl radical, CH2N((C1-C6) Alkyl radical)2、CN、C(O)NH2、C(O)NH(C1-C6) Alkyl and C (O) N ((C)1-C6) Alkyl radical)2；
A tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
Unless otherwise specified, alkyl and alkoxy groups may be straight or branched chain and contain 1 to 6 carbon atoms and typically 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl and hexyl. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, and n-butoxy.
Halogen represents fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
The heterocyclic ring may be saturated, partially saturated or aromatic. Examples of saturated heterocyclic radicals are tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolane (sulfolan), dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, azanylOxygen nitrogen base, oxygen nitrogen heteroRadical, sulfur nitrogen heteroPhenyl, thiazolinyl and diazepanyl (diazapanyl). Examples of aromatic heterocyclic groups are pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2, 3-triazolyl, 1, 2, 4-triazolyl, 1-oxa-2, 3-oxadiazolyl, 1-oxa-2, 4-oxadiazolyl, 1-oxa-2, 5-oxadiazolyl, 1-oxa-3, 4-oxadiazolyl, 1-thia-2, 3-oxadiazolyl, 1-thia-2, 4-oxadiazolyl, 1-thia-2, 5-oxadiazolyl, 1-thia-3, 4-oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. Examples of bicyclic aromatic heterocyclic groups are benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl and isoquinolinyl.
Ph represents a phenyl group.
Unless otherwise indicated, the term (substituted) means substituted with one or more defined groups. In the case where the groups may be selected from a variety of alternative groups, the selected groups may be the same or different.
In one embodiment, the present invention provides a compound of formula (I), wherein:
m is in the range of 1 to 4 and n is 1 or 2, with the proviso that m + n is in the range of 2 to 5;
x is selected from O, NH, N (C)1-C6) Alkyl and N (SO)2(C1-C6) Alkyl groups);
R1selected from:
(i) a phenyl ring;
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms; and
(iii) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) O (C)1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2C (O) OH and C (O) NH2；
R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iv)NH(C1-C3) Alkyl, the alkyl being optionally substituted by O (C)1-C3) Alkyl substitution;
(v)N((C1-C3) Alkyl radical)2One or two of these alkyl groups being optionally substituted by O (C)1-C3) Alkyl substitution;
(vi) a 5-to 6-membered N-linked saturated heterocyclic ring containing 1 to 2 nitrogen atoms; the ring may optionally include one or two carbonyl groups; the ring being optionally substituted by C (O) NH2Or C (O) OCH2Ph substitution; and
(vii) a 5-to 6-membered N-linked heteroaromatic ring containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein at least one heteroatom is N;
R3selected from H, (C)1-C6) Alkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R4、R5、R6and R7Each independently selected from H, halogen, hydroxy, CN, (C)1-C6) Alkyl, NH (C)1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2And O (C)1-C6) An alkyl group; and is
R8Selected from H, (C)1-C3) Alkyl, (C)1-C3) Alkoxy (C)1-C3) Alkyl radical, CH2OH、CH2NH2、CH2NH(C1-C3) Alkyl radical, CH2N((C1-C3) Alkyl radical)2、CN、C(O)NH2、C(O)NH(C1-C3) Alkyl and C (O) N ((C)1-C3) Alkyl radical)2；
A tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
In another embodiment, the present invention provides a compound of formula (I), wherein:
m is in the range of 1 to 3 and n is 1 or 2;
x is selected from O, NH, N (C)1-C3) Alkyl and N (SO)2(C1-C3) Alkyl groups);
R1selected from:
(i) a phenyl ring;
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms; and
(iii) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、O(C1-C6) Alkyl, C (O) O (C)1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2C (O) OH and C (O) NH2；
R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iv)NH(C1-C3) Alkyl, the alkyl being optionally substituted by O (C)1-C3) Alkyl substitution; and
(v)N((C1-C3) Alkyl radical)2One or two of these alkyl groups being optionally substituted by O (C)1-C3) Alkyl substitution;
R3selected from H, (C)1-C6) Alkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R4、R5、R6and R7Each independently selected from H, halogen, hydroxy and (C)1-C6) Alkyl and O (C)1-C6) An alkyl group; and is
R8Selected from H, methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl, CH2OH、CH2NH2、CH2NHCH3、CH2N(CH3)2、CN、C(O)NH2、C(O)NHCH3And C (O) N (CH)3)2；
A tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
In another embodiment, the present invention provides a compound of formula (I), wherein:
m is 1 or 2 and n is 1 or 2;
x is selected from O, NH, NCH3And N (SO)2CH3)；
R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, and 2-pyridonyl, each of which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2；
R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution; and
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
R3is H or (C)1-C3) An alkyl group;
R4、R5、R6and R7Each independently selected from H, chloro, fluoro, hydroxy, methyl and methoxy; and is
R8Is H or methyl;
a tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
In another embodiment, the present invention provides a compound of formula (I), wherein:
m and n are both 1, or m and n are both 2, or m is 1 and n is 2;
x is O or NCH3；
R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and 2-pyridonyl, each of which is optionally substitutedIs optionally substituted with one to three substituents independently selected from chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF3、N(CH3)2、C(O)N(CH3)2And C (O) NH2；
R2Selected from H, hydroxy, methyl, methoxy and ethoxy;
R3is H or CH3；
R4Is H or methyl;
R5is hydroxy or methoxy;
R6and R7Both are H; and is
R8Is H or methyl;
a tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
In another embodiment, the present invention provides a compound of formula (I), wherein:
m and n are both 1, or m and n are both 2, or m is 1 and n is 2;
x is O;
R1selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, and 2-pyridonyl, each of which is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF3、N(CH3)2、C(O)N(CH3)2And C (O) NH2；
R2Selected from H, methyl, methoxy and ethoxy;
R3、R4、R6、R7and R8Is H; and is
R5Is methoxy;
a tautomer thereof, or a pharmaceutically acceptable salt, solvate, or polymorph of the compound or tautomer.
In one embodiment, m is in the range of 1 to 3 and n is 1 or 2. In another embodiment, m is 1 or 2 and n is 1 or 2. In another embodiment, m and n are both 1, or m and n are both 2, or m is 1 and n is 2.
In one embodiment, X is selected from O, NH, N (C)1-C6) Alkyl and N (SO)2(C1-C6) Alkyl groups). In another embodiment, X is selected from O, NH, N (C)1-C3) Alkyl and N (SO)2(C1-C3) Alkyl groups). In another embodiment, X is selected from O, NH, NCH3And N (SO)2CH3). In another embodiment, X is O or NCH3. In another embodiment, X is O.
In one embodiment, R1Selected from:
(i) a phenyl ring or a naphthyl ring;
(ii) 5-to 6-membered aromatic heterocycles and N-oxides thereof containing 1 to 3 heteroatoms independently selected from N, O and S;
(iii) a 9-to 10-membered bicyclic aromatic heterocycle containing 1 to 4 nitrogen atoms; and
(iv) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) O (C)1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O)N((C1-C6) Alkyl radical)2C (O) OH and C (O) NH2。
In another embodiment, R1Selected from:
(i) a phenyl ring;
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms; and
(iii) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) O (C)1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2C (O) OH and C (O) NH2。
In another embodiment, R1Selected from:
(i) a phenyl ring;
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms; and
(iii) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) O (C)1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2C (O) OH and C (O) NH2。
In another embodiment, R1Selected from:
(i) a phenyl ring;
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms; and
(iii) a 2-pyridonyl group;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2。
In another embodiment, R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and 2-pyridonyl, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2。
In another embodiment, R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, and 2-pyridonyl, each of which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2。
In another embodiment, R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, and 2-pyridonyl, each of which is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF3、N(CH3)2、C(O)N(CH3)2And C (O) NH2。
In another embodiment, R1Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and 2-pyridonyl, each of which is optionally substituted with one to three substituents independently selected from the group consisting of chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF3、N(CH3)2、C(O)N(CH3)2And C (O) NH2。
In one embodiment, R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iv)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(v)NH(C1-C3) Alkyl, the alkyl being optionally substituted by O (C)1-C3) Alkyl substitution;
(vi)N((C1-C3) Alkyl radical)2Wherein one or two of these alkyl groups are optionally substituted by O (C)1-C3) Alkyl substitution;
(vii) a 5-to 6-membered N-linked saturated heterocyclic ring containing 1 to 2 nitrogen atoms; the ring may optionally include one or two carbonyl groups; the ring being optionally substituted by C (O) NH2Or C (O) OCH2Ph substitution; and
(viii) a 5-to 6-membered N-linked heteroaromatic ring containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein at least one heteroatom is N.
In another embodiment, R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iv)NH(C1-C3) Alkyl, the alkyl being optionally substituted by O (C)1-C3) Alkyl substitution; and
(v)N((C1-C3) Alkyl radical)2Wherein one or two of these alkyl groups are optionally substituted by O (C)1-C3) Alkyl substitution.
In another embodiment, R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution; and
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution.
In another embodiment, R2Selected from H, hydroxy, methyl, methoxy and ethoxy. In another embodiment, R2Selected from the group consisting of H, methyl, methoxy and ethoxy.
In one embodiment, R3Is H or (C)1-C3) An alkyl group. In another embodiment, R3Is H or CH3. In another embodiment, R3Is H.
In a kind of implementationIn the scheme, R4、R5、R6And R7Each independently selected from H, halogen, hydroxy and (C)1-C6) Alkyl and O (C)1-C6) An alkyl group. In another embodiment, R4、R5、R6And R7Each independently selected from H, halogen, hydroxy and (C)1-C3) Alkyl and O (C)1-C3) An alkyl group. In another embodiment, R4、R5、R6And R7Each independently selected from H, chloro, fluoro, hydroxy, methyl and methoxy. In another embodiment, R4Is H or methyl; r5Is hydroxy or methoxy; and R is6And R7Both are H. In another embodiment, R4、R6And R7Is H and R5Is methoxy.
In one embodiment, R8Selected from H, (C)1-C3) Alkyl, (C)1-C3) Alkoxy (C)1-C3) Alkyl radical, CH2OH、CH2NH2、CH2NH(C1-C3) Alkyl radical, CH2N((C1-C3) Alkyl radical)2、CN、C(O)NH2、C(O)NH(C1-C3) Alkyl and C (O) N ((C)1-C3) Alkyl radical)2. In another embodiment, R8Selected from H, methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl, CH2OH、CH2NH2、CH2NHCH3、CH2N(CH3)2、CN、C(O)NH2、C(O)NHCH3And C (O) N (CH)3)2. In another embodiment, R8Selected from the group consisting of H, methyl, ethyl, methoxymethyl, methoxyethyl, and CN. In another embodiment, R8Is H or methyl. In another embodiment, R8Is H.
It is to be understood that the present invention encompasses all combinations of particular embodiments of the invention as described hereinabove consistent with the definition of the compound of formula (I).
Representative compounds of formula (I) are:
5- [3- [4- (3-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
2-methoxy-5- {3- (methoxymethyl) -5- [4- (2-methylphenoxy) piperidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine;
5- [3- [4- (5-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (3-fluoro-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [4- (2-chlorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
3- {3- [3- (4-fluoro-2-methylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -6-methoxy-2-methylpyridine;
5- [3- [4- (4-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (4-fluoro-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
2-methoxy-5- { 3-methyl-5- [4- (2-methylphenoxy) piperidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine;
5- {3- [4- (2-chlorophenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [4- (3, 4-difluorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [3- (2-ethyl-4-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (3, 5-difluorophenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [3- (2, 3-dimethylphenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- [3- [4- (3, 5-difluorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [3- (4-fluoro-2-methylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- {3- [3- (2, 3-dimethylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
2-methoxy-5- (3- (methoxymethyl) -5- {3- [3- (trifluoromethyl) phenoxy ] azetidin-1-yl } -4H-1, 2, 4-triazol-4-yl) pyridine;
5- {3- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
2-methoxy-5- (3- (methoxymethyl) -5- {4- [ (3-methylpyridin-4-yl) oxy ] piperidin-1-yl } -4H-1, 2, 4-triazol-4-yl) pyridine;
3- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -2-methylbenzonitrile;
2-methoxy-5- {3- [4- (3-methoxy-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } pyridine; and
5- [3- [3- (3-chlorophenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
and tautomers thereof and pharmaceutically acceptable salts, solvates, and polymorphs of these compounds or tautomers.
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and base salts thereof.
Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, benzazole, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, pyroglutamate, dihydrogenphosphate, dihydrogensulfonate, salts of sodium, dihydrogensulfate, salts of sodium, potassium, Sucrose, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and hydroxynaphthoate.
Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine (benzathine), calcium, choline, diethylamine, diethanolamine, glycinate, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.
For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use' (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of the following three methods:
(i) by reacting a compound of formula (I) with the desired acid or base;
(ii) removing acid-or base-labile protecting groups from suitable precursors of compounds of formula (I) by using a desired acid or base; or
(iii) One salt of a compound of formula (I) is converted to another by reaction with an appropriate acid or base or with the aid of a suitable ion exchange column.
All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.
The compounds of the present invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.
Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of these complexes see J Pharm Sci, 64(8), 1269-.
All references hereinafter to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
The compounds of the present invention include compounds of formula (I) as defined above, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of formula (I) as defined below.
As mentioned above, so-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Thus, particular derivatives of the compounds of formula (I) which may themselves have little or no pharmacological activity when administered into or onto the body may be converted into compounds of formula (I) having the desired activity, for example by hydrolytic cleavage. These derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS symposium series (T.Higuchi and W.Stella) and "Bioreversible Carriers in drug design", Pergamon Press, 1987(E.B.Roche eds., American pharmaceutical Association).
Prodrugs according to the invention may be produced, for example, by replacing appropriate functional groups present in a compound of formula (I) with specific moieties known to those skilled in the art, e.g. as "pre-moieties" as described in H.Bundgaard "Design of Prodrugs" (Elsevier, 1985).
Some embodiments of prodrugs according to the invention include
(i) When the compounds of the formula I contain carboxylic acid functions, esters thereof, for example, where the hydrogen of the carboxylic acid function of the compounds of the formula (I) is replaced by (C)1-C8) An alkyl-substituted compound; and
(ii) when the compounds of formula (I) contain primary or secondary amino functions, amides thereof, for example where, as the case may be, one or two hydrogens of the amino function of the compound of formula (I) are replaced by (C)1-C10) Alkanoyl substituted compounds.
Other embodiments of the substituent groups as exemplified above and other prodrug type embodiments may be found in the above references. Furthermore, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
Also included within the scope of the present invention are metabolites of the compounds of formula (I), i.e. compounds that are formed in vivo after administration of a drug. Some examples of metabolites according to the invention include
(i) When the compound of formula (I) contains a methyl group, the hydroxymethyl derivative thereof (-CH)3→-CH2OH)；
(ii) When the compound of formula (I) contains an alkoxy group, its hydroxy derivative (-OR → -OH);
(iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (-NR)1R2→-NHR1or-NHR2)；
(iv) When the compound of formula (I) contains a secondary amino group, its primary amino derivative (-NHR)1→-NH2)；
(v) When the compound of formula (I) contains a phenyl moiety, its phenolic derivative (-Ph → -PhOH); and
(vi) when the compound of formula (I) contains an amide group, its carboxylic acid derivative (-CONH)2→COOH)。
The compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When the compounds of formula (I) contain an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Tautomerism (tautomerism or tautomerism) can occur when structural isomers can interconvert via a low energy barrier. This may take the form of proton tautomerism in compounds of formula (I) containing, for example, a keto group, or so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound may exhibit more than one isomerism.
Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one isomerism, and mixtures of one or more thereof. Also included are acid addition salts in which the counterion is optically active (e.g., d-lactate or 1-lysine salt) or racemic (e.g., d 1-tartrate or d 1-arginine salt).
The cis/trans isomers may be isolated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallisation.
Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative), for example using chiral High Pressure Liquid Chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, in the case of compounds of formula (I) containing an acidic or basic moiety, a base or acid, for example 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization and converted to the corresponding pure enantiomers by one or both of these diastereomers in a manner well known to those skilled in the art.
The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin, using a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50%, typically 2 to 20% by volume of isopropanol and 0 to 5% by volume of alkylamine, typically 0.1% diethylamine. The eluate is concentrated to provide an enriched mixture.
The invention includes all crystalline forms of the compound of formula (I), including racemates and racemic mixtures (agglomerates). Stereoisomeric agglomerates can be isolated by techniques of the academic society known to those skilled in the art-see, for example, "Stereochemistry of organic Compounds" (Wiley, New York, 1994) from E.L.Eliel and S.H.Wilen.
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually predominating in nature.
Is suitable for being included in the bookExamples of isotopes in compounds of the invention include hydrogen isotopes (e.g.2H and3H) carbon isotopes (e.g. of the formulae11C、13C and14C) chlorine isotopes (e.g. of the formulae36Cl), isotopes of fluorine (e.g. of fluorine18F) Iodine isotopes (e.g. iodine)123I and125I) nitrogen isotopes (e.g. of the formulae13N and15n), isotopes of oxygen (e.g. of15O、17O and18o), isotopes of phosphorus (e.g. of32P) and sulfur isotopes (e.g. of the formula35S)。
Certain isotopically-labelled compounds of formula (I), for example those with a radioisotope, are useful in drug and/or matrix tissue distribution studies. Radioactive isotope tritium (i.e. tritium) for its ease of incorporation and ease of detection3H) And carbon-14 (i.e.14C) Is particularly suitable for this purpose.
With heavier isotopes (e.g. deuterium, i.e.2H) Substitution may provide specific therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances.
Using positron-emitting isotopes (e.g. of the type11C、18F、15O and13n) substitution is applicable to Positron Emission Tomography (PET) studies for detecting occupancy of matrix receptors.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, in which a suitable isotopically-labelled reagent is used in place of the unlabelled reagent previously used.
Pharmaceutically acceptable solvates of the invention include solvates in which the crystallization solvent may be isotopically substituted, e.g. D2O、d6-acetone, d6-DMSO。
Also within the scope of the present invention are intermediate compounds as defined below, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined above for the compound of formula (I). The present invention includes all polymorphs of the above mentioned substances and their crystal habit.
When preparing the compounds of formula (I) according to the invention, the skilled person is not restricted to routinely select the form of the intermediate that provides the best combination of features for this purpose. These characteristics include melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product can be purified upon isolation.
The compounds of the invention for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuous solid state ranging from fully amorphous to fully crystalline. For example, it can be obtained as a solid block, powder or film by a method such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). They are usually administered in a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the present invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. These compositions and their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19 th edition (Mack publishing company, 1995).
The compounds of the present invention may be administered orally. Oral administration may include swallowing to allow the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be used whereby the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid preparations such as tablets, capsules containing microparticles, liquids or powders, dragees (including liquid filled), chewables, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films, pessaries (ovules), sprays, and liquid preparations.
Liquid preparations include suspensions, solutions, syrups and vinous preparations. These formulations can be used as fillers in soft or hard capsules and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by reconstitution of a solid, for example from a sachet.
The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, such as the Expert Opinion in Therapeutic Patents described in Liang and Chen,11(6) 981-.
For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with low paper alkyl groups, starch, pregelatinized starch, and sodium alginate. Disintegrants typically comprise from 1 to 25 wt% of the dosage form, more preferably from 5 to 20 wt% of the dosage form.
Binders are commonly used to impart adhesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous fluorene and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate.
The tablets may also optionally contain surfactants (e.g., sodium lauryl sulfate and polysorbate 80) and glidants (e.g., silicon dioxide and talc). When present, the surfactant may comprise 0.2% to 5% by weight of the tablet, and the glidant may comprise 0.2% to 1% by weight.
Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants typically comprise from 0.25 to 10% by weight of the tablet, preferably from 0.5 to 3% by weight. Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste masking agents.
Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant. The tablet blend may be compressed directly or by roller compression to form tablets. Alternatively, the tablet blend or partial blend may be wet, dry or melt granulated, melt frozen or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Formulation of tablets is discussed in "Pharmaceutical Dosage Forms" by h.lieberman and l.lachman: tablets ", volume 1 (MarcelDekker, New York, 1980).
Consumable oral films for human or veterinary use are typically soft, water-or water-swellable film dosage forms, which may be fast-dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation may perform more than one function.
The compounds of formula (I) may be water soluble or insoluble. The water soluble compound typically comprises from 1 wt% to 80 wt% of the solute, more typically from 20 wt% to 50 wt% of the solute. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (I) may be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99 wt%, more typically in the range of 30 to 80 wt%.
Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste masking agents.
Films such as the present invention are typically prepared by evaporative drying of a thin aqueous film coated on a peelable substrate support or paper. This can be done in a drying oven or tunnel, typically a combi-coat dryer, or by freeze drying or vacuum.
Solid formulations for oral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release.
Suitable modified release formulations for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details of other suitable delivery techniques (e.g., high energy dispersion and permeability and coated particles) can be found in Verma et al, "Pharmaceutical technology on-line", 25(2), 1-14 (2001). The use of chewing gum for achieving controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the bloodstream, into muscles or into the internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients (e.g. salts, carbohydrates) and buffers (preferably to a pH of 3 to 9), but for some applications may be more suitably formulated as sterile nonaqueous solutions or in dry form for use with a suitable carrier (e.g. sterile, pyrogen-free water). Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of the compounds of formula (I) used in the preparation of the non-enteric solution may be increased by using appropriate formulation techniques, for example the addition of solubility enhancers. Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release. The compounds of the present invention may thus be formulated as solid, semi-solid or thixotropic liquids for administration as an implantable drug depot providing modified release of the active compound. Examples of these formulations include drug-coated vascular stents and poly (d 1-lactic acid-co-glycolic acid) (PGLA) microspheres.
The compounds of the invention may also be administered topically to the skin or mucosa, i.e., on the skin or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers that may be added-see for example J Pharm Sci by Finnin and Morgan,88(10) 955- "958 (10 months 1999). Other means of topical administration include by electroporation, iontophoresis, sonophoresis and microneedle injection or needle-free (e.g. Powderject)TM、BiojectTMEtc.) for delivery. Formulations for topical administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release.
The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder from a dry powder inhaler (either alone as a mixture, e.g. a dry blend with lactose, or as particles of a mixing component, e.g. mixed with a phospholipid, such as phosphatidylcholine) or as an aerosol spray from a pressurised container, pump, nebuliser (preferably a nebuliser using electrohydrodynamics to produce a fine mist) or nebuliser, with or without the use of a suitable propellant (e.g. 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3,3, 3-heptafluoropropane). For intranasal use, the powder may comprise a bioadhesive agent, such as chitosan or cyclodextrin.
A pressurized container, pump, sprayer, atomizer or sprinkler comprising: solutions or suspensions of the compounds of the invention, e.g. comprising ethanol, aqueous ethanol or suitable alternative agents for dispersing, dissolving or prolonging the release of the activity; one or more propellants as a solvent; and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.
Prior to use in dry powder or suspension formulations, the drug product is micron-sized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base (for example, lactose or starch) and a potency-modifying agent (for example, 1-leucine, mannitol or magnesium stearate). Lactose can be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
Suitable solution formulations for use in nebulizers using electrohydrodynamics to generate fine mist may contain 1 μ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μ l to 100 μ l. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.
Suitable flavoring agents (e.g., menthol and levomenthol) or sweetening agents (e.g., saccharin or saccharin sodium) may be added to those formulations of the invention for inhalation/intranasal administration.
Formulations for inhalation/intranasal administration may be formulated for immediate release and/or modified release using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve delivering a metered amount. The unit according to the invention is generally arranged for administration of a metered dose or "puff" containing from 2 to 30mg of a compound of formula (I). The total daily dose will typically be in the range of 50 to 100mg, which may be administered in a single dose or more typically as divided doses throughout the day.
The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used if appropriate. Formulations for rectal/vaginal administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release.
The compounds of the invention may also be administered directly to the eye or ear, usually in the form of drops of a micron-sized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate or vesicular systems, such as, for example, micro-vesicles or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., gellan gum) may be added along with a preservative (e.g., benzalkonium chloride).
These formulations may also be delivered by iontophoresis. Formulations for ocular/otic administration may also be formulated for immediate release and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted or programmed release.
The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers to modify their solubility, dissolution rate, taste masking, bioavailability and/or stability for any of the above modes of administration. For example, drug-cyclodextrin complexes are generally found to be suitable for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which may be found in international patent applications WO 91/11172, WO94/02518 and WO 98/55148.
Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, may conveniently be combined in a kit (kit) suitable for co-administration of these compositions. The kit of the invention thus comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention, and means for separately retaining these compositions, such as a container, a divided bottle or a divided foil packet. The example of the kit is a conventional blister pack used for encapsulating tablets, capsules and the like. The kits of the invention are particularly suitable for administration of different dosage forms (e.g., oral and parenteral), for administration of separate compositions at different dosage intervals, or for the mutual titration of separate compositions. To aid compliance, kits typically include directions for administration and may be provided with so-called memory aids.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 50mg to 100mg, which of course depends on the mode of administration and efficacy. For example, oral administration may require a total daily dose of 50mg to 100 mg. The total daily dose may be administered in single or divided doses and may be outside the typical ranges given herein at the discretion of the physician. These doses are based on an average human subject having a weight of about 60kg to 70 kg. A physician will readily be able to determine dosages for subjects whose weights fall outside this range, such as infants and elderly.
For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
Preparation process
Compounds of formula (I) wherein m, n, X and R are as described in scheme 1 can be prepared1To R8As described herein.
Scheme 1
LG represents a suitable leaving group such as methanesulfonate or toluenesulfonate and is typically methanesulfonate. When LG is methanesulfonate, the compounds of the general formula (II) can be prepared as described in WO 97/25322, page 64. Thiourea formation can be achieved by preparing a compound of formula (III) from a compound of formula (II) by step (i) in which process step (i) compound (II) is reacted with a suitable aminopyridine under ambient conditions in the presence of a suitable thiocarbonyldransferase agent (e.g. 1 '1-thiocarbonyldi-2 (1H) -pyridinone (j. org. chem.1986, 51, 2613) or 1, 1' -thiocarbonyldiimidazole, typically 1 '1-thiocarbonyldi-2 (1H) -pyridinone) and a suitable base (e.g. triethylamine, pyridine or hunig's base)) in a suitable solvent (e.g. dichloromethane or tetrahydrofuran) for 18 to 24 hours. Typical conditions include
a) 1 equivalent of the appropriate aminopyridine is reacted with 1 equivalent of 1' 1-thiocarbonyldi-2 (1H) -pyridinone in dichloromethane at 0 to 25 ℃ for 1 hour, followed by
b) To dichloromethane were added 1 equivalent of compound (II) and 1 equivalent of triethylamine and stirred under ambient conditions for 18 hours.
Alternatively, step (i) may involve the formation of urea by coupling compound (II) with a suitable aminopyridine in the presence of a suitable carbonyl transfer agent (e.g. N, N '-carbonyldiimidazole), followed by subsequent sulfonation using a suitable sulfonating agent (e.g. Lawesson's reagent).
In another embodiment, the compounds of formula (III) may be prepared as described in scheme 2. The compound of formula (IV) may be prepared from the compound of formula (III) by a process step (ii) which comprises methylating thiourea (III) using a suitable methylating agent (e.g. methyl iodide or methyl p-toluenesulfonate) in the presence of a suitable base (e.g. potassium tert-butoxide) in a suitable solvent (e.g. tetrahydrofuran or diethyl ether) between 0 ℃ and the reflux temperature of the solvent for about 18 hours. Typical conditions comprise reacting 1 equivalent of compound (III), 1 to 1.2 equivalents of potassium tert-butoxide, 1 to 1.2 equivalents of methyl p-toluenesulfonate in tetrahydrofuran at ambient conditions for 1 to 18 hours.
The compound of formula (V) may be prepared from the compound of formula (IV) by a process step (iii) which comprises reacting the compound of formula (IV) with a suitable hydrazide R, optionally in the presence of a suitable acid catalyst (e.g. trifluoroacetic acid or p-toluenesulfonic acid) in a suitable solvent (e.g. tetrahydrofuran or n-butanol) at a temperature between room temperature and the reflux temperature of the solvent2R3CHCONHNH2And (4) reacting. Typical conditions comprise reacting 1 equivalent of compound (IV), an excess of hydrazide R2R3CHCONHNH2And trifluoroacetic acid (catalytic amount) in tetrahydrofuran while heating at reflux for 1 to 18 hours.
Alternatively, the compound of formula (V) may be prepared from the compound of formula (III) using process steps (ii) and (III) in a "one-pot" synthesis.
The compounds of the formula (VI) are commercially available or known from the literature.
The compounds of formula (I) can be prepared from compounds of formulae (V) and (VI) by process step (iv) in which compound (VI) is treated with a suitable strong base (e.g. sodium hydride or potassium tert-butoxide) and then reacted with compound (V) in a suitable solvent (e.g. N, N-dimethylformamide or dimethylsulfoxide) at a temperature between room temperature and the reflux temperature of the solvent for 18 to 40 hours. Typical conditions comprise reacting 2 equivalents of compound (VI), 2 equivalents of sodium hydride and 1 equivalent of compound (V) in N, N-dimethylformamide while heating at 100 ℃ for up to 40 hours.
Scheme 2
Compounds of formula (VII) can be prepared as described in j.org.chem. (1980), 45, 4219. The compounds of formula (II) can be prepared as described in WO 97/25322, page 64.
The compounds of formula (III) may be prepared from compounds of formula (II) and formula (VII) by process step (v) in which compounds (VII) and (II) are reacted together under ambient conditions in a suitable solvent, such as dichloromethane or tetrahydrofuran, optionally in the presence of a suitable base, such as triethylamine, pyridine or ranibidine base, for 2 to 24 hours. Typical conditions comprise reacting 1 equivalent of compound (VI) and 1 equivalent of compound (II) in dichloromethane at ambient conditions for 2 to 24 hours.
Alternatively, the compounds of formula (I) may also be prepared as described in scheme 3.
Scheme 3
Y represents O or N (C)1-C6) An alkyl group.
Z represents a suitable functional group, such as OH or halogen. When Y ═ O, Z is typically OH; when Y is N (C)1-C6) When alkyl, Z is usually halogen, especially chlorine or bromine.
PG represents a suitable protecting group. When Y ═ O, PG is typically an acyl group or a benzyl group. When Y is N (C)1-C6) In the case of alkyl, PG is usually Boc or CBz.
PG' represents a suitable amine protecting group, such as benzyl or Boc.
The compounds of formula (VIII) can be prepared by methods analogous to those used in m.g. banwell (j.org.chem.2003, 68, 613).
Compounds of general formula (IX) can be prepared from compounds of general formula (VIII) by process step (vi) which comprises deprotecting the amine groups using standard methodologies as described in "Protecting group Organic Synthesis" by t.w. greene and p.wutz. Typical conditions comprise reacting 1 equivalent of compound (VIII) in the presence of a suitable catalyst (e.g. 10% Pd/C) in a suitable solvent (e.g. ethanol/water (90: 10) or tetrahydrofuran) under hydrogen at 60psi at room temperature for 2 to 18 hours.
Compounds of formula (X) can be prepared from compounds of formula (IX) by process step (i) as described in scheme 1.
Alternatively, compounds of formula (X) can be prepared from compounds of formula (IX) and (VII) by process step (v) as described in scheme 2.
The compounds of formula (XI) can be prepared from compounds of formula (X) by process step (ii) as described in scheme 1.
Compounds of formula (XII) can be prepared from compounds of formula (XI) by process step (iii) as described in scheme 1.
Compounds of formula (XIII) can be prepared from compounds of general formula (XII) by process step (vii) which comprises deprotecting Y using standard methodologies as described in "protective groups in Organic Synthesis" by t.w. greene and p.wutz.
When PG ═ acyl, typical conditions comprise reaction of 1 equivalent of compound (XI) with 2.5 to 3 equivalents of potassium carbonate in dichloromethane at ambient conditions for 18 hours.
When PG ═ benzyl, typical conditions comprise reaction of 1 equivalent of compound (XI) in the presence of a suitable catalyst (e.g. 10% Pd/C) in a suitable solvent (e.g. ethanol/water (90: 10) or tetrahydrofuran) under hydrogen at 60psi at room temperature for 2 to 18 hours.
Can be prepared from compounds of the formula (XIII) and R by process step (viii)1Z (XIV) to prepare the compound of formula (I).
When Z ═ OH, the compound of formula (I) can be obtained by suitable reaction (typically Mitsunobu reaction) of compound (XIII) with (XIV) in the presence of a suitable phosphine (e.g. tri-N-butyl phosphine or triphenylphosphine) and a suitable azo compound (e.g. diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate) in a solvent (e.g. dichloromethane, tetrahydrofuran or N, N-dimethylformamide) at a temperature between 25 and 115 ℃ for 1 to 48 hours. Typical conditions comprise reacting 1 equivalent of compound (I), 2 equivalents of compound (XIV), 3 equivalents of triphenylphosphine and 2 equivalents of di-tert-butyl azodicarboxylate in dichloromethane at 25 ℃ for 4 hours.
When X is N (C)1-C6) When alkyl and Z ═ halogen (e.g. Cl), the compound of formula (I) can be obtained by suitable reaction (typically N-alkylation) of compound (XIII) with (XIV) in the presence of a suitable base (e.g. N, N-diisopropylethylamine or triethylamine) in a suitable solvent (e.g. N, N-dimethylformamide or dimethylsulfoxide) at elevated temperature for 1 to 18 hours. Typical conditions comprise reacting 1 equivalent of compound (XIII), 1 to 1.2 equivalents of compound (XIV) and 1 to 2 equivalents of N, N-diisopropylethylamine in dimethylsulfoxide at elevated temperature for 16 hours.
Alternatively, the compounds of formula (I) may be prepared as described in scheme 4.
Scheme 4
Y represents O or N (C)1-C6) An alkyl group.
PG "represents a suitable amine protecting group, typically benzyl.
When Y ═ O, compounds of general formula (XV) are commercially available.
When Y is N (C)1-C6) When alkyl, the compounds of formula (XV) may be prepared as described on page 22 of WO 03/089412.
The compounds of general formula (XVI) can be prepared from compounds of formulae (XV) and (VI) by process step (viii) as described in scheme 3.
Compounds of general formula (XVII) can be prepared from compounds of formula (XVI) by process step (vi) as described in scheme 3.
The compounds of general formula (XVIII) can be prepared from compounds of formula (XVII) by process step (i) as described in scheme 1.
Alternatively, compounds of formula (XVIII) can be prepared from compounds of formula (XVII) and (VII) by process step (v) as described in scheme 2.
The compounds of general formula (XIX) can be prepared from compounds of formula (XVIII) by process step (ii) as described in scheme 1.
The compounds of general formula (I) can be prepared from compounds of formula (XIX) by process step (iii) as described in scheme 1.
Alternatively, compounds of general formula (I) can be prepared from compounds of formula (XVIII) in a one pot synthesis by a combination of process steps (ii) and (iii) as described in scheme 1.
In another embodiment, compounds of formula (I) may be prepared as described in scheme 5, wherein X ═ O andm, n and R1To R8As described herein.
Scheme 5
PG' "is a suitable amine protecting group, typically benzhydryl.
Compounds of formula (XX) are commercially available.
A compound of formula (XXI) may be prepared from a compound of formula (XX) by process step (ix) which comprises a ketone (XX) and an "active" alkyl (organometallic alkyl, e.g. R)8MgI、R8MgCl or R8Li) to form the corresponding tertiary alcohol of formula (XXI). Typical conditions comprise 1 equivalent of compound (XX) and 2 to 2.5 equivalents of R8MgI is reacted in a suitable solvent (e.g., tetrahydrofuran or diethyl ether) at 0 to 25 ℃ for 1 to 8 hours.
Compounds of formula (XXII) can be prepared from compounds of formulae (XXI) and (VI) by process step (viii) as described in scheme 3.
Compounds of formula (XXIII) can be prepared from compounds of formula (XXII) by process step (vi) as described in scheme 3.
The compound of formula (XXIV) can be prepared from the compound of formula (XXIII) by process step (i) as described in scheme 1.
Compounds of formula (XXV) can be prepared from compounds of formula (XXIV) by process step (ii) as described in scheme 1.
The compounds of formula (I) can be prepared from compounds of formula (XXV) by process step (iii) as described in scheme 1.
Alternatively, scheme 6 provides a route to the compounds of formula (I).
Scheme 6
The compounds of formula (XXVI) can be prepared as described in WO 04/062665, page 46.
Compounds of formula (XXVII) may be prepared from compounds of formula (XXVI) by process step (x) which comprises treating compound (XXVI) with a suitable thiocarbonyltransferase thiourea, for example 1' 1-thiocarbonyldi-2 (1H) -pyridinone (j.org.chem.1986, 51, 2613), in a suitable solvent, for example dichloromethane or tetrahydrofuran, under ambient conditions for 1 to 18 hours. Typical conditions comprise 1.0 equivalent of compound (XXVI) and 1.0 equivalent of 1' 1i thiocarbonyldi-2 (1H) -pyridinone in dichloromethane at room temperature for 18 hours.
Compounds of formula (XXVIII) can be prepared from compounds of general formula (XXVII) by process step (i) as described in scheme 1.
Compounds of formula (XXIX) can be prepared from compounds of general formula (XXVIII) by process step (ii) as described in scheme 1.
Compounds of formula (XXX) can be prepared from compounds of general formula (XXIX) by process step (ii) as described in scheme 1.
Compounds of formula (I) can be prepared from compounds of general formulae (XXX) and (VI) by process step (iv) as described in scheme 1.
The preparation of all the novel starting materials disclosed in the above reactions and prior methods is well known and the reagents and reaction conditions appropriate for their efficacy or preparation and procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the examples and preparations herein.
The compounds of the present invention are useful because they have pharmacological activity in mammals, including humans. More particularly, it is useful for the treatment or prevention of conditions in which modulation of oxytocin levels may provide beneficial effects. Disease conditions that may be mentioned include sexual dysfunction (especially premature ejaculation), pre-term labor, complications of labor, appetite and eating conditions, benign prostatic hyperplasia, early birth, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder and neuropsychiatric disorders.
Sexual Dysfunction (SD) is a significant clinical problem that can affect both men and women. The cause of SD can be both organic and psychological. Organic aspects of SD are typically caused by underlying vascular disease (e.g., those associated with hypertension or diabetes), prescribed medication, and/or psychiatric disorders (e.g., depression). Physiological factors include fear, sexual anxiety, and interpersonal conflict. SD impairs sexual function, reduces self-esteem and destroys interpersonal relationships thereby inducing personal apprehension. In the clinic, SD pathologies have been classified into Female Sexual Dysfunction (FSD) pathologies and Male Sexual Dysfunction (MSD) pathologies (Melman et al, j. urology, 1999,161，5-11)。
FSD may be defined as a female being difficult or unable to satisfy sexual expression. FSD is a collective term for several different female pathologies (leiplus, s.r. (1998) Definition and classification of female sextual disorders. int.j.immunity res.,10S104-S106; berman, J.R., Berman, L, and Goldstein, I. (1999) Female sextual dysfunction, Inc., pathobiology, evaluation and treatment options, Urology,54,385-391). Women may have a lack of desire, difficulty arousing or orgasm, pain during intercourse, or a combination of these problems. Several diseases, medications, injuries or psychological problems can cause FSD. The treatment in progress is directed to treating specific subtypes of FSD, primarily for desire and arousal of the pathology.
The type of FSD is best determined by the stage of its reaction with normal female sex: desire, arousal, and orgasm contrast are defined (Leiblum, S.R. (1998). Definition and classification of functional sexual disorders, int.J. Impotence Res., 10, S104-S106). Desire or libido is the driver of sexual expression. Performance typically includes sexual thoughts when in phase with a partner of interest or when exposed to other sexual stimuli. Arousal is a vascular response to sexual stimulation, an important component of which is genital engorgement and includes increased vaginal lubrication, vaginal lengthening, and increased genital sensation/sensitivity. Orgasm is the release of sexual tension that reaches the apex during arousal.
Thus, FSD occurs when a woman is under-responsive or otherwise unsatisfactory in any of these phases (usually desire, arousal or orgasm). Categories of FSD include hypoactive sexual desire conditions, sexual arousal conditions, orgasmic disorders and dyspareunia conditions. While the compounds of the invention will improve the response of the genitals to sexual stimulation (as in female sexual arousal conditions), in this case they may also improve associated pain, sexual intercourse related concerns and discomfort and thus treat other female sexual conditions.
Thus, according to another aspect of the present invention, there is provided the use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of hypoactive sexual desire conditions, sexual arousal conditions, orgasmic disorders and sexual pain conditions, more preferably for the treatment or prevention of sexual arousal conditions, orgasmic disorders and sexual pain conditions and optimally for the treatment or prevention of sexual arousal conditions.
Hypoactive sexual desire condition exists if the woman has no or little desire for sex and no or little sexual thoughts or fantasy. Such FSD may be caused by low testosterone levels, which are attributed to natural menopause or surgical menopause. Other causes include disease, medication, fatigue, depression, and anxiety.
Female sexual arousal pathology (FASD) is characterized by an inadequate genital response to sexual stimulation. The genitals do not experience congestion manifested as normal sexual arousal. Vaginal walls are poorly lubricated and therefore painful for intercourse. Orgasm may be hindered. Arousal symptoms can be caused by estrogen deprivation during menopause or after parturition and during lactation, and by diseases with vascular components such as diabetes and atherosclerosis. Other causes arise from treatment with diuretics, antihistamines, antidepressants (e.g., SSRIs), or antihypertensive agents. Dyspareunia conditions (including dyspareunia and vaginismus) are characterized by pain caused by insertion and may be caused by drug therapy to reduce lubrication, endometriosis, pelvic inflammation, inflammatory bowel disease or urinary tract problems.
The prevalence of FSD is difficult to assess, because the term encompasses several issues, some of which are difficult to measure, and because the focus on treating FSD is a relatively recent matter. Sexual problems in many women are directly related to the female aging process or to chronic diseases such as diabetes and hypertension.
Because FSD is composed of several subtypes that exhibit symptoms during separate phases of the sexual response cycle, there is no monotherapy. Current treatment of FSD is primarily focused on psychological or interrelationship issues. Treatment of FSD is evolving into more clinical and basic scientific research devoted to the study of this medical problem. Female sexual disorders are not all psychologically in pathophysiology, particularly for those individuals who may have angiogenic dysfunction (e.g., FSAD) components that contribute to the overall female sexual disorder. No drug is currently licensed for the treatment of FSD. Empirical drug therapy includes estrogen administration (either locally or as hormone replacement therapy), androgens, or mood-altering drugs (such as buspirone or trazodone). Such treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.
Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines female sexual arousal pathology (FSAD) as:
"persistent or recurrent failure to achieve or maintain adequate lubrication-swelling response to sexual arousal until the sexual activity is completed. Disorders necessarily cause significant apprehension or human-to-human distress. ", a
Evoked responses consist of pelvic vascular congestion, vaginal lubrication, and swelling of the external genitalia. Disorders cause significant anxiety and/or man-to-man distress. FSAD is a highly prevalent sexual condition affecting premenopausal, perimenopausal, and post-menopausal (± HRT) women. It is associated with concomitant conditions such as depression, cardiovascular disease, diabetes and UG conditions.
The main consequences of FSAD are lack of congestion/swelling, lack of lubrication and lack of pleasant genital sensation. Secondary consequences of FSAD are decreased desire to sex, pain during intercourse and difficulty in achieving orgasm.
Male Sexual Dysfunction (MSD) is often associated with erectile dysfunction (also known as Male Erectile Dysfunction (MED)) and/or a condition of ejaculation, such as premature ejaculation, orgasm deficiency (inability to achieve orgasm) or a condition of desire, such as a hypoactive condition (lack of interest in sex).
PE is a relatively common sexual dysfunction in men. It has been defined in several different ways, but the most widely accepted is the diagnostic and statistical manual of mental conditions iv (mental Disorder iv), which states:
"PE is lifelong persistent or recurrent ejaculation with minimal sexual stimulation before, during or shortly after insertion and before the patient wishes. The clinician must consider factors that affect the duration of the excitement phase, such as age, freshness to the sexual partner or stimuli, and frequency of sexual activity. Disorders cause significant anxiety or man-to-man predicament. ", a
International taxonomy definition of disease 10 describes:
"inability to delay ejaculation sufficiently to enjoy making love, which is expressed as either: (1) ejaculation occurs before or shortly after the onset of sexual intercourse (if a time limit is required: before or within 15 seconds of the onset of sexual intercourse); (2) ejaculation occurs in the absence of sufficient erection to enable intercourse. The problem is not a result of long-term continence of sexual activity
Other definitions that have been used include taxonomies according to the following criteria:
● is associated with orgasm of partner
● duration between insertion and ejaculation
● insertion times and ability to autonomously control
Psychological factors may be involved in PE, where interrelationships, anxiety, depression, previous failure all play a role.
Ejaculation is dependent on the sympathetic and parasympathetic nervous systems. Efferent impulses reach the vas deferens via the sympathetic nervous system and the epididymis produces smooth muscle contraction, moving the sperm to the posterior urethra. Similar contractions of the seminal vesicle, prostate and bulbar urethra increase the volume and fluid content of semen. The discharge of seminal fluid is regulated by efferent impulses originating from a pool of log spinothalamic cells in the lumbosacral spinal cord (Coolen and Truitt, Science, 2002,2971566) that pass through the parasympathetic nervous system and cause rhythmic contractions of the bulbocavernosus, ischial cavernosal muscles and pelvic floor muscles. Cortical control of ejaculation is still at issue in humans. The medial anterior optic zone and paraventricular nucleus of the inferior colliculus appear to be involved in ejaculation in rats.
Ejaculation comprises two separate components-ejaculation and ejaculation. Seminiferous is the deposition of semen and spermatozoa from the remote epididymis, vas deferens, seminal vesicles and prostate into the prostatic urethra. This deposition is followed by forced expulsion of seminal fluid contents from the urethra. Ejaculation is different from orgasm, which is purely a brain event. Typically these two processes occur simultaneously.
Ejaculation is accompanied in mammals by a pulse of oxytocin in the peripheral serum. Plasma concentrations of oxytocin, but not vasopressin, in men are significantly elevated at or before ejaculation. Oxytocin does not induce ejaculation itself; this process is under neural control via alpha 1 adrenergic receptors/100% of the sympathetic nerves originating from the lumbar region of the spinal cord. Systemic pulsing of oxytocin may play a role in the peripheral ejaculation. It can be used to regulate the contraction of ducts and glandular lobules throughout the male genital tract, thus affecting, for example, the fluid volumes of the different ejaculatory components. Oxytocin release into the brain at the center can affect sexual behavior, subjective assessment of arousal (orgasm) and the latency of subsequent ejaculation.
Accordingly, in one aspect the present invention provides the use of a compound of formula (I) (without the provisos) for the manufacture of a medicament for the prevention or treatment of sexual dysfunction, preferably male sexual dysfunction, most preferably premature ejaculation.
It has been demonstrated in the scientific literature that the number of oxytocin receptors in the uterus increases during pregnancy, most significantly before the onset of labour (Gimpl and fahreholz, 2001, physiologealreviews,81(2),629-683.). Without being bound by any theory, it is known that inhibition of oxytocin may be involved in arresting preterm birth and in addressing births combination.
Accordingly, another aspect of the present invention provides the use of a compound of formula (I) (without the proviso) for the manufacture of a medicament for the prevention or treatment of premature birth and birthing combination.
Oxytocin plays a role in feeding; which reduces the desire to eat (Arletti et al, Peptides, 1989,10,89). It is possible to increase the desire to eat by suppressing oxytocin. Oxytocin inhibitors are therefore useful in the treatment of appetite and eating conditions.
Thus, a further aspect of the invention provides the use of a compound of formula (I) (without provisos) for the manufacture of a medicament for the prevention or treatment of appetite and eating conditions.
Oxytocin was implicated as one of the causes of Benign Prostatic Hyperplasia (BPH). Analysis of prostate tissue has shown that BPH patients have increased oxytocin content (Nicholson and Jenkin, adv.&Biol.，1995，395,529). Oxytocin antagonists may help in the treatment of this condition.
Accordingly, a further aspect of the present invention provides the use of a compound of formula (I) (without provisos) for the manufacture of a medicament for the prevention or treatment of benign prostatic hyperplasia.
Oxytocin plays a role in the cause of dysmenorrhea due to its activity as a uterine vasoconstrictor (Akerlund, ann. ny acad. sci., 1994,734,47). Oxytocin antagonists may have therapeutic effects on this condition。
Accordingly, a further aspect of the present invention provides the use of a compound of formula (I) (without provisos) for the manufacture of a medicament for the prevention or treatment of dysmenorrhea.
It is to be understood that all references herein to treatment include curative, palliative and prophylactic treatment.
The compounds of the present invention may be co-administered with one or more agents selected from the group consisting of:
1) one or more selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), such as dapoxetine (dapoxetine), paroxetine (parooxetine), 3- [ (dimethylamino) methyl ] -4- [4- (methylthio) phenoxy ] benzenesulfonamide (example 28, WO 0172687), 3- [ (dimethylamino) methyl ] -4- [ 3-methyl-4- (methylthio) phenoxy ] benzenesulfonamide (example 12, WO0218333), N-methyl-N- ({3- [ 3-methyl-4- (methylthio) phenoxy ] -4-pyridyl } methyl) amine (example 38, PCT application No. PCT/IB 02/01032);
2) one or more local anesthetics;
3) one or more alpha-adrenergic receptor antagonists (also known as alpha-adrenergic receptor blockers, alpha-receptor blockers, or alpha-blockers); suitable alpha1-adrenergic receptor antagonists include: phentolamine (phentolamine), prazosin (prazosin), phentolamine mesylate (phentolamine mesylate), trazodone, alfuzosin (alfuzosin), indoramine (indoramin), naftopidil (naftopidil), tasalosin (tamsulosin), phenoxybenzamine, rauwoolfa alkaloid, Recordatio 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin (doxazosin), example 19 of WO 9830560, terazosin (terazosin), and abanoquine (abanoquin); suitable alpha2-adrenergic receptor antagonists include: dianiline (dibenanine), tolazoline (tolazoline), tramazoline (trimazosin), efaroxan (efaroxan), yohimbine (yohimbine), idazoxan (idazoxan), clonidine (clonidine), and dianiline; suitable non-selective alpha-kidneyAdrenergic receptor antagonists include: dapiprazole (dapiprazole); other alpha-adrenergic receptor antagonists are described in PCT application WO99/30697, published on month 6 and 14 of 1998 and in U.S. patents: 4,188,390, respectively; 4,026,894, respectively; 3,511,836, respectively; 4,315,007, respectively; 3,527,761, respectively; 3,997,666, respectively; 2,503,059, respectively; 4,703,063, respectively; 3,381,009, respectively; 4,252,721 and 2,599,000, each of which is incorporated herein by reference;
4) one or more cholesterol lowering agents, such as statins (e.g. atorvastatin)/Lipitor-trademark) and fibrates;
5) 5-hydroxytryptamine receptor agonists, antagonists or modulators, more particularly agonists, antagonists or modulators of e.g. the 5HT1A, 5HT2A, 5HT2C, 5HT3, 5HT6 and/or 5HT7 receptors, including one or more of those described in WO-09902159, WO-00002550 and/or WO-00028993;
6) one or more NEP inhibitors, preferably wherein the NEP is EC 3.4.24.11 and more preferably wherein the NEP inhibitor is a selective inhibitor of EC 3.4.24.11, more preferably a selective NEP inhibitor is a selective inhibitor of EC 3.4.24.11, having an IC of less than 100nM50(e.g., opatritalat, lapachalat), suitable NEP inhibitor compounds are described in EP- ｃA-1097719; IC against NEP and ACE50The values can be used in the published patent application EP1097719-A1 No. [0368 ]]To [0376]Determined by the method described in paragraph;
7) one or more antagonists or modulators of the vasopressin receptor, such as, for example, lecovatan (SR 49059), conivaptan (conivaptan), atosiban (atosiban), VPA-985, CL-385004, vasopressin (Vasotocin);
8) apomorphine (apomorphine) -the teaching of the use of apomorphine as A medicament can be found in US-A-5945117;
9) dopamine agonists (specifically selective D2, selective D3, selective D4 and quasi-selective D2 agents), such as Pramipexole (Pramipexole) (compound No. PNU95666 in Pharmacia Upjohn), ropinirole (ropinariole), apomorphine, sunmaniole (surmaniole), quinlorane (quineloran), PNU-142774, bromocriptine (bromocriptine), cabergoline (carpergoline), Lisuride (Lisuride);
10) melanocortin (melanocortin) receptor agonists (e.g., melanotan ii (melanotan ii) and PT141) and selective MC 3 and MC4 agonists (e.g., THIQ);
11) monoamine transport inhibitors, such as Noradrenaline (Noradrenaline) reuptake inhibitors (NRI), especially selective NRI, e.g. reboxetine (reboxetine) in its racemic (R, R/S, S) or optically pure (S, S) enantiomeric form, especially (S, S) -reboxetine, other 5-hydroxytryptamine reuptake inhibitors (SRI) (e.g. paroxetine, dapoxetine) or Dopamine Reuptake Inhibitors (DRI);
12)5-HT1Aantagonists (e.g., lobazoltan); and
13) PDE inhibitors, such as PDE2 (e.g. erythro-9- (2-hydroxy-3-nonyl) -adenine) and example 100 of EP 0771799-incorporated herein by reference), and in particular PDE5 inhibitors, such as pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in EP- ｃA-0463756; pyrazolo [4, 3-d ] pyrimidin-7-ones as disclosed in EP-A-0526004; pyrazolo [4, 3-d ] pyrimidin-7-ones as disclosed in international patent application publication WO 93/06104; the isomeric pyrazolo [3, 4-d ] pyrimidin-4-ones disclosed in international patent application publication WO 93/07149; quinazolin-4-one disclosed in International patent application publication WO 93/12095; pyrido [3, 2-d ] pyrimidin-4-one as disclosed in international patent application publication WO 94/05661; purine-6-ones disclosed in International patent application publication WO 94/00453; pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in international patent application publication WO 98/49166; pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in international patent application publication WO 99/54333; pyrazolo [4, 3-d ] pyrimidin-4-one as disclosed in EP-A-0995751; pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in international patent application publication WO 00/24745; pyrazolo [4, 3-d ] pyrimidin-4-one as disclosed in EP-A-0995750; a compound disclosed in International application publication WO 95/19978; a compound disclosed in international application publication WO99/24433 and a compound disclosed in international application publication WO 93/07124; pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in international application publication WO 01/27112; pyrazolo [4, 3-d ] pyrimidin-7-one as disclosed in international application publication WO 01/27113; the compounds disclosed in EP-A-1092718 and the compounds disclosed in EP-A-1092719.
Preferred PDE5 inhibitors for use in the present invention:
5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil), also known as 1- [ [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-ethoxyphenyl ] sulfonyl ] -4-methylpiperazine (see EP-A-0463756);
5- (2-ethoxy-5-morpholinylacetylphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see EP-A-0526004);
3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl ] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 98/49166);
3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 99/54333);
(+) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl ] -2-methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, also known as 3-ethyl-5- {5- [ 4-ethylpiperazin-1-ylsulfonyl ] -2- ([ (1R) -2-methoxy-1-methylethyl ] oxy) pyridin-3-yl } -2-methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 99/54333);
5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, also known as 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-keto-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine (see WO01/27113, example 8);
5- [ 2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-methylpiperidin-4-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO01/27113, example 15);
5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2-phenyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO01/27113, example 66);
5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 01/27112, example 124);
5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (see WO 01/27112, example 132);
(6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (IC-351), i.e. the compounds of examples 78 and 95 of International application publication WO95/19978, and the compounds of examples 1, 3, 7 and 8;
2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one (vardenafil)), also known as 1- [ [3- (3, 4-dihydro-5-methyl-4-keto-7-propylimidazo [5, 1-f ] -as-triazin-2-yl) -4-ethoxyphenyl ] sulfonyl ] -4-ethylpiperazine, i.e. the compounds of examples 20, 19, 337 and 336 of international application publication WO 99/24433; and
the compound of example 11 of International application publication WO93/07124 (EISAI); and
compounds 3 and 14 from Rotella D P, j.med.chem., 2000, 43, 1257.
Other PDE5 inhibitors useful in the present invention include:
4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy ] -3(2H) pyridazinone; 1- [4- [ (1, 3-benzodioxol-5-ylmethyl) amino ] -6-chloro-2-quinazolinyl ] -4-piperidine-carboxylic acid, monosodium salt; (+) -cis-5, 6a, 7, 9, 9, 9 a-hexahydro-2- [4- (trifluoromethyl) -benzyl-5-methyl-cyclopent-4, 5] imidazo [2, 1-b ] purin-4 (3H) one; furazolicin (furazlocillin); cis-2-hexyl-5-methyl-3, 4, 5, 6a, 7, 8, 9, 9 a-octahydrocyclopenta [4, 5] -imidazo [2, 1-b ] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5 (5-morpholinylacetyl-2-n-propoxyphenyl) -3-n-propyl-1, 6-dihydro-7H-pyrazolo (4, 3-d) pyrimidin-7-one; 1- [4- [ (1, 3-benzodioxol-5-ylmethyl) amino ] -6-chloro-2-quinazolinyl ] -4-piperidinecarboxylic acid, monosodium salt; pharmaprojects No. 4516 (GlaxoWellcome); pharmaprojects No. 5051 (Bayer); pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); pharmaprojects No. 5069 (Schering Plough); GF-196960(Glaxo Wellcome); e-8010 and E-4010 (Eisai); bay-38-3045 and 38-9456(Bayer) and Sch-51866.
The contents of the published patent applications and journal articles, and in particular the therapeutically active compounds of the claims, and the compounds exemplified therein, are incorporated herein by reference in their entirety.
More preferred PDE5 inhibitors for use in the present invention are selected from the group consisting of:
5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil);
(6R, 12aR) -2, 3, 6, 7, 12, 12 a-hexahydro-2-methyl-6- (3, 4-methylenedioxyphenyl) pyrazino [2 ', 1': 6, 1] pyrido [3, 4-b ] indole-1, 4-dione (IC-351);
2- [ 2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl ] -5-methyl-7-propyl-3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one (vardenafil); and
5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one or 5- (5-acetyl-2-butoxy-3-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one and pharmaceutically acceptable salts thereof.
A particularly preferred PDE5 inhibitor is 5- [ 2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one (sildenafil), also known as 1- [ [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-ethoxyphenyl ] sulfonyl ] -4-methylpiperazine, and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.
Preferred agents for co-administration with the compounds of the invention are PDE5 inhibitors, selective 5-hydroxytryptamine reuptake inhibitors (SSRI), vasopressin V, as described above1AAntagonists, alpha-adrenergic receptor antagonists, NEP inhibitors, dopamine agonists and melanocortin receptor agonists. Particularly preferred agents for co-administration are PDE5 inhibitors, SSRIs and V as described herein1AAn antagonist.
The compounds of formula (I) may be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
The present invention provides compositions comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.
Suitable assays for determining oxytocin antagonist activity of a compound are described in detail below.
Oxytocin receptor beta-lactamase assay:
substance(s)
Cell culture media/reagents
A: cell culture medium
Nutrient Mix
F12 Ham′s
Fetal Bovine Serum (FBS)
Geneticin (Geneticin)
Qixin (Zeocin)
Trypsin/EDTA
PBS (phosphate buffered saline)
HEPES
B: reagent
Oxytocin
OT receptor-specific antagonists
Molecular-scale dimethyl sulfoxide (DMSO)
Trypan blue solution 0.4%
CCF4-AM (solution A)
Poloney (Pluronic) F127 (solution B)
24% PEG, 18% TR40 (solution C)
Probenecid (dissolved in 200mM NaOH, solution D)
The method comprises the following steps:
cell culture: the cells used were CHO-OTR/NFAT-beta-lactamase. The NFAT- β -lactamase expression construct was transfected into a CHO-OTR cell line and a population of pure lines was isolated via fluorescence activated cell sorting (FASC). Appropriate clones were selected for the assay.
Growth medium
90％F12 Nutrient Mix，15mM HEPES
10％FBS
400 ug/ml Geneticin
200 mu g/mL of zixin
2mM L-Glutamine
Assay medium
99.5% F12 nutrient cocktail, 15mM HEPES
0.5％FBS
Recovery of cells-a vial of frozen cells was quickly thawed in a 37 ℃ water bath and the cell suspension was transferred to a T225 flask with 50mL of fresh growth medium and then at 37 ℃, 5% CO2The cells were then incubated in an incubator until the cells adhered to the flask. The following day the medium was replaced with 50mL of fresh growth medium.
Culturing the cells-CHO-OTR-NFAT- β -lactamase cells were grown in growth medium. Cells were harvested when they reached 80-90% confluence, the medium was removed and washed with pre-warmed PBS. PBS was then removed and trypsin/EDTA (3mL for T225 cm) was added2Flask), then 37 ℃/5% CO2Incubate for 5 minutes in an incubator. When cells were isolated, pre-warmed growth medium (7mL for T225 cm) was added2Flask) and the cells were resuspended and gently mixed by pipetting to achieve a single cell suspension. The cells were split into T225 flasks at a ratio of 1: 10 (3 days of growth) and 1: 30 (5 days of growth) in 35mL growth medium.
The method for detecting the beta-lactamase comprises the following steps:
the first day: cell plate preparation
Cells grown at 80-90% confluency were harvested and counted. Preparation of 2X 10 in growth Medium5Cell suspension/mL and Black clear at 384 wellsMu.l of cell suspension was added to the bottom plate. The blank containing the diluent from each reagent was used for background subtraction.
The plates were incubated at 37 ℃ with 5% CO2Incubate overnight.
The next day: cell stimulation
● mu.l of antagonist/compound (diluted in assay medium containing 1.25% DMSO ═ antagonist diluent) was added to the appropriate wells and incubated at 37 ℃ with 5% CO2Incubate for 15 minutes.
● mu.l oxytocin constituting the assay medium was added to all wells and incubated at 37 ℃ with 5% CO2The cells were incubated for 4 hours.
● an additional separate 384-well cell plate was used to generate an oxytocin dose response curve. (10. mu.l of antagonist diluent was added to each well followed by 10. mu.l oxytocin addition followed by treatment of cells according to antagonist/compound cell plate).
1mL of 6 XLoading buffer was prepared with the enhanced loading schedule (this required scaling up depending on the number of plates to be screened).
● mu.l of solution A (1 mM CCF4-AM in anhydrous DMSO) was added to 60. mu.l of solution B (100 mg/mL poloxamine-F127 + 0.1% acetic acid in DMSO) and vortexed.
● the resulting solution was added to 925 μ l of solution C (24% w/w PEG400 in water, 18% TR40 v/v).
● mu.l of solution D (200mM probenecid in 200mM NaOH) was added.
● mu.l of 6 Xloading buffer were added to all wells and incubated for 1.5-2 hours at room temperature in the dark.
● Using LJL Analyst reading plates, excitation 405nm, emission 450nm and 530nm, optimal, lag time 0.40. mu.s integration, 4 flashes, bottom reading.
Using the assays described above, the compounds of the invention all exhibit oxytocin antagonist activity expressed as Ki values of less than 1 μ M. Preferred embodiments have Ki values of less than 200nM and particularly preferred embodiments have Ki values of less than 50 nM. The compound of example 48 has a Ki value of 1.8 nM. The compound of example 43 has a Ki value of 4.2 nM. The compound of example 25 has a Ki value of 9 nM. The compound of example 28 has a Ki value of 13.8 nM.
The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:
filter, available from J.Rettenmaier, Germany&Sohne
APCI + atmospheric pressure chemical ionization (Positive Scan)
CDCl3Deuterated chloroform
d doublet peak
doublet of dd doublet
DMSO methyl sulfoxide
ES + electrospray ionization positive scan
eq equivalent weight
1H NMR proton nuclear magnetic resonance spectroscopy
HRMS high resolution mass spectrometry
LCMS liquid chromatography-mass spectrometry
LRMS low resolution mass spectrometry
MS (Low resolution) Mass Spectrometry
m multiplet
PXRD powder X-ray diffraction
Peak value of m/z mass spectrum
q quartet peak
s single peak
t triplet peak
Chemical shift of delta
Preparation 1: azetidin-3-yl methanesulfonate hydrochloride
A mixture of 1- (benzhydryl) azetidin-3-yl methanesulfonate (page 64 of WO 97/25322) (20g, 63mmol) and chloroethyl chloroformate (10mL, 95mmol) in dichloromethane (100mL) was heated at reflux for 2.5 h. The reaction mixture was then concentrated in vacuo and the residue redissolved in methanol (100mL) and heated under reflux for an additional 2.5 hours. The mixture was then cooled to room temperature and concentrated in vacuo to afford the title compound as a white solid in quantitative yield of 9.6 g.1H NMR(400MHz，DMSO-d6)δ：3.28(s，3H)，4.06(m，2H)，4.31(m，2H)，5.34(m，1H)
Preparation 2: 1- { [ (6-methoxypyridin-3-yl) amino ] thiocarbonyl } azetidin-3-yl methanesulfonate
A solution of 5-amino-2-methoxypyridine (6.4g, 51.5mmol) in dichloromethane (20mL) was added to an ice-cooled solution of 1' 1-thiocarbonyldis-2 (1H) -pyridone (12.05g, 51.5mmol) in dichloromethane (100mL) and the mixture was mixedThe mixture was stirred for 1 hour. The product of preparation 1 (9.6g, 51.5mmol) and triethylamine (7.24mL, 51.5mmol) were then added and the mixture was stirred for 18 h. The reaction mixture was then filtered and the filtrate was washed with 10% citric acid, sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 95: 5) to provide the title compound as a pink solid in 29% yield 4.7 g.1H NMR(400MHz，DMSO-d6)δ：2.48(s，3H)，3.82(s，3H)，4.17(m，2H)，4.48(m，2H)，5.35(m，1H)，6.78(d，1H)，7.73(dd，1H)，8.08(d，1H)；LRMS APCI m/z318[M+H]+
Preparation 3: n- (6-methoxypyridin-3-yl) -3- [ (methylsulfonyl) oxy ] azetidine-1-thiocarbonylimide methyl ester
Potassium tert-butoxide (1.8g, 16.3mmol) was added to a solution of the product of preparation 2 (4.3g, 13.6mmol) in tetrahydrofuran (100mL) and the mixture was stirred at room temperature for 30 min. Methyl p-toluenesulfonate (3.63g, 16.3mmol) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with water and brine and extracted with ether (2 × 50 mL). The combined organic solutions were then dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to provide the title compound as a red oil in 82% yield 3.76 g.1H NMR(400MHz，CDCl3)δ：2.20(s，3H)，3.05(s，3H)，3.90(s，3H)，4.18(m，2H)，4.35(m，2H)，5.23(m，1H)，6.65(d，1H)，7.20(dd，1H)，7.75(d，1H)；LRMS APCI m/z332[M+H]+
Preparation 4: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl methanesulfonate
A mixture of preparation 3 (1.5g, 4.5mmol), acethydrazide (671mg, 9mmol) and trifluoroacetic acid (3 drops, catalyst) in tetrahydrofuran (50mL) was heated at reflux for 4 hours. The cooled mixture was then diluted with a mixture of water and brine (30: 70) and extracted with ethyl acetate (3X 50 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 97.5: 2.5) to provide the title compound as a light brown oil in 50% yield of 720 mg.1H NMR(400MHz，CDCl3)δ：2.24(s，3H)，3.04(s，3H)，4.02(s，3H)，4.14(m，2H)，4.37(m，2H)，5.30(m，1H)，6.91(d，1H)，7.72(dd，1H)，7.18(d，1H)；LRMS APCI m/z 340[M+H]+
Preparation 5: 2-methoxy acethydrazide
Hydrazine monohydrate (9.85mL, 202mmol) was added to a solution of methyl methoxyacetate (10mL, 101mmol) in methanol (50mL) and the mixture was heated at 70 ℃ for 18 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was azeotroped with toluene (× 2) to yield a white solid. The solid was triturated with ether and the resulting solid was dried under vacuum at 50 ℃ for 30 minutes to provide the title compound as a white solid in 95% yield 9.98 g.1H NMR(400MHz，DMSO-d6)δ：3.26(s，3H)，3.79(s，2H)，4.22(bs，2H)，8.97(bs，1H)
Preparation 6: 1- [5- (methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl methanesulfonate
A mixture of preparation 3 (1g, 3mmol), preparation 5 (629mg, 6mmol) and trifluoroacetic acid (3 drops) in tetrahydrofuran (20mL) was heated at reflux for 8 hours. The cooled mixture was then diluted with a mixture of water and brine (30: 70) and extracted with ethyl acetate (3X 30 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 95: 5) to provide the title compound as a light brown oil in 72% yield of 800 mg.1H NMR(400MHz，CDCl3)δ：3.03(s，3H)，3.27(s，3H)，3.98(s，3H)，4.06(m，2H)，4.20(m，2H)，4.32(s，2H)，5.23(m，1H)，6.84(d，1H)，7.60(dd，1H)，8.17(d，1H)；LRMS APCI m/z 370[M+H]+
Preparation 7: 1- [ 5-isopropyl-4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl methanesulfonate
The title compound was prepared in 30% yield from the product of preparation 3 and 2-methylpropanoic acid hydrazide (Bioorganic & Medicinal Chemistry, 2003, 11, 1381) using the same method as described for preparation 6.
1H NMR(400MHz，CDCl3)δ：1.22(d，6H)，2.67(m，1H)，3.02(s，3H)，3.97(m，2H)，3.99(s，3H)，4.06(m，2H)，5.18(m，1H)，6.87(d，1H)，7.45(dd，1H)，8.08(d，1H)；LRMS APCI m/z 368[M+H]+
Preparation 8: 1- (benzhydryl) -3-methylazetidin-3-ol
Methyl magnesium iodide (3M in diethyl ether, 1.4mL, 4.2mmol) was added dropwise to an ice-cooled solution of 1- (benzhydryl) -3-azetidinone (1g, 4.20mmol) in diethyl ether (25mL) and the mixture was stirred at 0 ℃ for 1 hour. The crude reaction mixture was then directly purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to provide the title compound as a pale yellow oil in 68% yield of 730 mg.
1H NMR(CDCl3，400MHz)δ：1.54(s，3H)，3.02(m，2H)，3.22(m，2H)，4.39(s，1H)，7.20(m，4H)，7.26(m，4H)，7.41(m，2H)；LRMS ESI+m/z 254[M+H]+
Preparation 9: 1- (benzhydryl) -3- (3-fluorophenoxy) -3-methylazetidine
A mixture of 3-fluorophenol (0.2mL, 2.2mmol) and triphenylphosphine (648mg, 2.5mmol) in toluene (8mL) was warmed to 95 ℃. A mixture of preparation 8 (500mg, 2mmol) and diisopropyl azodicarboxylate (0.5mL, 2.47mmol) in toluene (4mL) was then added and the reaction mixture was stirred at 95 ℃ for 18 h. The cooled reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (95: 5) to afford the title compound as a yellow oil in 93% yield.1H NMR(CDCl3，400MHz)δ：1.77(s，3H)，3.25(m，2H)，3.50(m，2H)，4.45(s，1H)，6.40(d，1H)，6.46(d，1H)，6.63(t，1H)，6.98(m，1H)，7.19(m，4H)，7.32(m，4H)，7.48(m，2H)；LRMS APCI+m/z 348[M+H]+
Preparation 10: 3- (3-fluorophenoxy) -3-methylazetidine hydrochloride
1-Chloroethyl chloroformate (0.3mL, 2.76mmol) was added to an ice-cooled solution of the product of preparation 9 (1.34g, 4.43mmol) in dichloromethane (10mL) and the mixture was heated at reflux for 3 hours. The reaction mixture was then concentrated in vacuo and the residue redissolved in methanol. The solution was then heated at reflux for 3 hours. The reaction mixture was then cooled, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (95: 5) to provide the title compound as a crystalline solid in 60% yield 200 mg.
1H NMR(DMSO-d6，400MHz)δ：3.35(s，3H)，4.18(m，4H)，6.65(m，2H)，6.84(t，1H)，7.35(m，1H)；LRMS ESI+m/z 182[M+H]+
Preparation 11: 3- (3-fluorophenoxy) -N- (6-methoxypyridin-3-yl) -3-methylazetidine-1-thiocarboxamide
5-isothiocyanato-2-methoxypyridine [ (172.9mg, 1.04mmol), J.org.chem. (1980), 45, 4219]To a solution of preparation 10 (200mg, 1.04mmol) in dichloromethane (3mL) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to afford the crude title compound in quantitative yield. This material was used for other reactions without purification.1H NMR(DMSO-d6，400MHz)δ：1.77(s，3H)，4.04(s，3H)，4.33(m，2H)，4.50(m，2H)，6.50(m，2H)，6.74(m，2H)，7.23(m，1H)，7.44(dd，1H)，8.10(m，1H)；LRMS ESI+m/z 348[M+H]+
Preparation 12: 3- (3-fluorophenoxy) -N- (6-methoxypyridin-3-yl) -3-methylazetidine-1-thiocarbonylimide methyl ester
The title compound was prepared from the product of preparation 11 in 46% yield as a pale yellow oil using the same procedure as described for preparation 3.1H NMR(CDCl3，400MHz)δ：1.78(s，3H)，2.36(s，3H)，3.97(s，3H)，4.30(m，2H)，4.58(m，2H)，6.43(m，2H)，6.75(m，2H)，7.17(d，1H)，7.24(m，1H)，7.78(d，1H)；LRMS ESI+m/z 362[M+H]+
Preparation 13: 3-isothiocyanato-6-methoxy-2-methylpyridine
6-methoxy-2-methyl-3-pyridylamine [ (500mg, 3.6mmol), page 46 of WO 04/062665]A solution in dichloromethane (10mL) was added to an ice-cooled solution of 1' 1-thiocarbonyldis-2 (1H) -pyridone (840mg, 3.6mmol) in dichloromethane (10mL) and the mixture was stirred for 18H. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound as a yellow solid in 79% yield.1HNMR(CDCl3，400MHz)δ：2.52(s，3H)，3.92(s，3H)，6.56(d，1H)，7.38(d，1H)；LRMS ESI+m/z 181[M+H]+
Preparation 14: 1- { [ (6-methoxy-2-methylpyridin-3-yl) amino ] carbosulfanyl } azetidin-3-yl methanesulfonate
A mixture of preparation 1 (535mg, 2.84mmol), preparation 13 (515mg, 2.84mmol) and triethylamine (0.4mL, 2.84mmol) in dichloromethane was stirred at room temperature for 18 h. The reaction mixture was then filtered and the residue was partitioned between ethyl acetate and brine. The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a light yellow solid in 71% yield of 670 mg.
1H NMR(CDCl3，400MHz)δ：2.44(s，3H)，3.08(s，3H)，3.95(s，3H)，4.20(m，2H)，4.40(m，2H)，5.20(m，1H)，6.62(d，1H)，7.49(d，1H)；LRMS ESI+m/z 332[M+H]+
Preparation 15: n- (6-methoxy-2-methylpyridin-3-yl) -3- [ (methylsulfonyl) oxy ] azetidine-1-thiocarbonylimide methyl ester
The title compound was prepared as a brown oil in 98% yield from the product of preparation 14 using the same method as described for preparation 3.
1H NMR(CDCl3，400MHz)δ：2.34(s，3H)，2.46(s，3H)，3.06(s，3H)，3.90(s，3H)，4.16(m，2H)，4.30(m，2H)，5.20(m，1H)，6.53(d，1H)，7.10(d，1H)；LRMS ESI+m/z 346[M+H]+
Preparation 16: 1- [4- (6-methoxy-2-methylpyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl methanesulfonate
The title compound was prepared in 35% yield from the product of preparation 15 and acethydrazide using the same method as described for preparation 4.1H NMR(CDCl3，400MHz)δ：2.12(s，3H)，2.22(s，3H)，3.06(s，3H)，3.95(s，3H)，4.03(m，2H)，4.10(m，2H)，5.20(m，1H)，6.70(d，1H)，7.37(d，1H)；LRMS ESI+m/z 346[M+H]+
Preparation 17: piperidin-4-yl acetate
10% Pd/C (500mg) was added to 1-benzylpiperidin-4-yl acetate [ (11g, 47mmol), J.org.chem.68(2), 613-; 2003]A solution in a mixture of ethanol and water (90: 10, 110mL) and the mixture was stirred at 60 ℃ under 60psi of hydrogen for 18 hours. Then the reaction mixture is passed throughFiltration, washing with ethanol, and concentration of the filtrate in vacuo afforded the title product in 92% yield 7.2 g.
1H NMR(CDCl3，400MHz)δ：1.60(m，2H)，1.81-2.18(m，5H)，2.78(m，2H)，2.95-3.18(m，2H)，4.82(m，1H)；LRMS APCI+m/z 145[M+H]+
Preparation 18: 1- { [ (6-methoxypyridin-3-yl) amino ] carbonothioyl | piperidin-4-yl acetate
The title compound was prepared in 19% yield from 5-amino-2-methoxypyridine, 1' 1-thiocarbonyldi-2 (1H) -pyridone and the product of preparation 17 using the same method as described for preparation 2.1H NMR(CDCl3，400MHz)δ：1.78-1.85(m，2H)，1.98-2.08(m，2H)，2.18(s，3H)，3.79-3.87(m，2H)，3.95(s，3H)，4.02-4.12(m，2H)，5.01-5.09(m，1H)，6.89(d，1H)，6.99(s，1H)，7.58(d，1H)，7.97(s，1H)；LRMS APCI m/z 310[M+H]+
Preparation 19: 4-hydroxy-N- (6-methoxypyridin-3-yl) piperidine-1-thiocarboxamide
The title compound was prepared in 67% yield from piperidin-4-ol, 5-amino-2-methoxypyridine and 1' 1-thiocarbonyldis-2 (1H) -pyridone using the same method as described for preparation 2.1HNMR(400MHz，CDCl3)δ：1.59-1.79(m，2H)，1.90-2.04(m，2H)，3.64-3.76(m，2H)，3.93(s，3H)，4.00-4.10(m，1H)，4.14-4.22(m，1H)，6.78(d，1H)，7.04-7.20(s，1H)，7.62(6，1H)，7.98(s，1H)LRMS APCI m/z 268[M+H]+
Preparation 20: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl acetate
Potassium tert-butoxide (0.91g, 8.10mmol) was added to a solution of preparation 18 (2.28g, 7.36mmol) in tetrahydrofuran (20mL) and the mixture was stirred at room temperature for 30 min. Methyl p-toluenesulfonate (1.81g, 8.10mmol) was added and the mixture was stirred for 18 hours. The reaction mixture was then concentrated in vacuo and the residue redissolved in dichloromethane. The solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to afford an oil. The oil was dissolved in tetrahydrofuran (5mL), trifluoroacetic acid (0.28mL, 3.68mmol) and acetohydrazide (1.09g, 14.7mmol) was added and the mixture was heated at reflux for 18 h. The cooled mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as an oil in 49% yield 1.2 g.
1H NMR(CDCl3，400MHz)δ：1.57-1.70(m，2H)，1.79-1.90(m，2H)，2.01(s，3H)，2.22(s，3H)，2.94-3.01(m，2H)，3.22-3.31(m，2H)，3.99(s，3H)，4.80-4.92(m，1H)，6.89(d，1H)，7.52(d，1H)，8.12(s，1H)
Preparation 21: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-ol
A mixture of preparation 20 (1.2g, 3.62mmol) and 1M potassium carbonate solution (10mL, 10mmol) in methanol (20mL) was stirred at room temperature for 24 h. The reaction mixture was then concentrated in vacuo and the aqueous residue was extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 90: 10) afforded the title compound as a solid in 45% yield 472.5 mg.
1H NMR(CDCl3，400MHz)δ：1.41-1.55(m，2H)，1.71(s，1H)，1.80-1.90(m，2H)，2.22(s，3H)，2.85-2.94(m，2H)，3.22-3.31(m，2H)，3.77-3.82(m，1H)，3.99(s，3H)，6.89(d，1H)，7.52(d，1H)，8.12(s，1H)；LRMS APCI m/z 332[M+H]+
Preparation 22: 3- [ (1-Benzylpiperidin-4-yl) oxy ] -2-methylpyridine
1-benzyl-4-hydroxypiperidine (1.5g, 7.8mmol) and 3-hydroxy-2-methylpyridine (1.75g, 16mmol) are added to a mixture of polymer-supported triphenylphosphine (1g, 3mmol) and di-tert-butyl azodicarboxylate (3.61g, 16mmol) in dichloromethane (10mL) and the mixture is stirred at room temperature for 3 hours. Trifluoroacetic acid (16mL) was then added and the mixture was stirred for an additional 1 hour then concentrated in vacuo. The residue was suspended in dichloromethane and basified with 2M sodium hydroxide solution (5 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (90: 10: 1) to give the title compound as a liquid in 51% yield 1.12 g.
1H NMR(CDCl3，400MHz)δ：1.79-1.88(m，2H)，1.90-2.01(m，2H)，2.25-2.41(m，2H)，2.44(s，3H)，2.64-2.78(m，2H)，3.53(s，2H)，4.28-4.39(m，1H)，7.00-7.09(m，2H)，7.19-7.38(m，5H)，8.14(m，1H)；LRMS APCI m/z 283[M+H]+
Preparation 23: 2-methyl-3- (piperidin-4-yloxy) pyridines
10% Pd/C (approximately 100mg) was added to a solution of preparation 22 (1.12g, 3.96mmol) in a mixture of ethanol and water (90: 10, 11mL) and the mixture was stirred at 60 ℃ under 60psi of hydrogen for 18 h. Then the reaction mixture is passed throughFiltration was carried out and the filtrate was concentrated in vacuo. The residue was redissolved in ethanol/water (90: 10, 11mL) and 10% Pd/C (approximately 100mg) was added. The reaction mixture was then stirred at 60 ℃ under 60psi of hydrogen. After 18 hours, the mixture is filteredFiltration, washing with ethanol, and concentration of the filtrate in vacuo. The residue was triturated with ether to provide the title compound as a solid in 74% yield 565 mg.1H NMR(CDCl3，400MHz)δ：2.10-2.20(m，2H)，2.30-2.41(m，2H)，2.49(s，3H)，3.29-3.40(m，4H)，4.61-4.70(m，1H)，7.02-7.13(m，2H)，8.12(m，1H)；LRMS APCI+m/z 193[M+H]+
Preparation 24: n- (6-methoxypyridin-3-yl) -4- [ (2-methylpyridin-3-yl) oxy ] piperidine-1-thiocarboxamide
5-isothiocyanato-2-methoxypyridine [ (172.9mg, 1.04mmol), J.org.chem. (1980), 45, 4219]To a solution of preparation 23 (200mg, 1.04mmol) in dichloromethane (3mL) was added and the mixture was stirred at room temperature for 72 hours. The resulting precipitate was filtered off and washed with water, dichloromethane and diethyl ether to provide a portion of the title compound. The filtrate was then diluted with water and acidified with 10% citric acid. Separating the aqueous layer, adding hydrogen carbonateThe sodium solution was basified and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a further white solid. The two solids were combined to give 48% overall yield (180 mg).1H NMR(DMSO-d6，400MHz)δ：1.69-1.81(m，2H)，1.95-2.09(m，2H)，2.48(s，3H)，3.83(s，3H)，3.87-3.98(m，2H)，4.05-4.19(m，2H)，4.83-4.90(m，1H)，7.44-7.51(m，1H)，7.56-7.62(m，1H)，7.79-7.85(m，1H)，7.93(s，1H)，8.19(d，1H)，9.32(s，1H)；LRMSAPCI m/z 359[M+H]+
Preparation 25: 2- [ (1-Benzylpiperidin-4-yl) oxy ] -3-methylpyridine
Potassium tert-butoxide (1.08g, 8.62mmol) was added to a solution of 1-benzyl-4-hydroxypiperidine (1.5g, 7.84mmol) in dimethyl sulfoxide (5mL) and the mixture was stirred at room temperature for 1 hour. 2-fluoro-3-methylpyridine (957mg, 8.62mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium bicarbonate solution and brine. The organic solution was then dried over magnesium sulfate and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 70: 30) to provide the title compound as a solid in 85% yield 1.9 g.
1H NMR(CDCl3，400MHz)δ：1.79-1.94(m，2H)，1.98-2.09(m，2H)，2.17(s，3H)，2.37-2.47(m，2H)，2.68-2.77(m，2H)，3.61-3.51(bs，2H)，5.12-5.20(m，1H)，6.74(m，1H)，7.24-7.37(m，6H)，7.95(m，1H)；LRMS APCI m/z 283[M+H]+
Preparation 26: 4- [ (1-benzylpiperidin-4-yl) oxy ] pyridine
The title compound was prepared as an oil in 52% yield from 1-benzyl-4-hydroxypiperidine and 4-chloropyridine (979mg, 8.62mmol) using the same method as described for preparation 25.
1H NMR(CDCl3，400MHz)δ：1.81-1.96(m，2H)，1.98-2.18(m，2H)，2.30-2.48(m，2H)，2.70-2.83(m，2H)，3.52-3.70(m，2H)，4.40-4.50(m，1H)，6.72-6.80(m，2H)，7.22-7.39(m，5H)，8.40(m，2H)；LRMS APCI m/z 269[M+H]+
Preparation 27: 4- [ (2, 3-dimethylpyridin-4-yl) oxy ] piperidine-1-carboxylic acid tert-butyl ester
Potassium tert-butoxide (4.70g, 42mmol) was added to a solution of 1-Boc-4-hydroxypiperidine (4.05g, 20.1mmol) in dimethyl sulfoxide (20mL) and the mixture was stirred at room temperature for 1 hour. 4-chloro-2, 3-lutidine (3.58g, 20.1mmol) was then added and the reaction mixture was stirred at 50 ℃ for 18 h. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium bicarbonate solution and brine. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (100: 0 to 94: 6: 0.6) to provide the title compound as an oil in 39% yield of 2.4 g.
1H NMR(CDCl3，400MHz)δ：1.44(s，9H)，1.75-1.85(m，2H)，1.87-1.95(m，2H)，2.15(s，3H)，2.50(s，3H)，3.42-3.53(m，2H)，3.56-3.65(m，2H)，4.57-4.62(m，1H)，6.64(d，1H)，8.21(d，1H)；LRMS APCI m/z 307[M+H]+
Preparation 28: 4- [ (3-methylpyridin-4-yl) oxy ] piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-3-methylpyridine hydrochloride using a method analogous to preparation 27. The reaction mixture was stirred for 72 hours to provide the title compound in 87% yield.1H NMR(CDCl3，400MHz)δ：1.44(s，9H)，1.75-1.85(m，2H)，1.87-1.97(m，2H)，2.18(s，3H)，3.42-3.53(m，2H)，3.56-3.65(m，2H)，4.57-4.65(m，1H)，6.72(d，1H)，8.29(s，1H)，8.35(d，1H)；LRMS APCI m/z 293[M+H]+
Preparation 29: 3-methyl-2- (piperidin-4-yloxy) pyridines
The title compound was prepared as a gum in 62% yield from the product of preparation 25 using the same method as described for preparation 17.
1H NMR(CDCl3，400MHz)δ：1.79-1.94(m，2H)，1.96-2.20(m，5H)，2.89-3.00(m，2H)，3.18-3.26(m，2H)，5.24-5.35(m，1H)，6.74(m，1H)，7.38(m，1H)，7.95(m，1H)；LRMS APCI m/z 193[M+H]+
Preparation 30: 4- (piperidin-4-yloxy) pyridines
The title compound was prepared as a solid in 82% yield from the product of preparation 26 using the same method as described for preparation 23.
1H NMR(CDCl3，400MHz)δ：1.94-2.02(m，2H)，2.20-2.29(m，2H)，3.06-3.18(m，2H)，3.22-3.32(m，2H)，4.60-4.67(m，1H)，6.80(d，2H)，8.43(d，2H)；LRMS APCI+m/z 179[M+H]+
Preparation of 31: 2, 3-dimethyl-4- (piperidin-4-yloxy) pyridine dihydrochloride
A solution of preparation 27 (1.3g, 4.24mmol) in hydrochloric acid (4M in dioxane, 5mL) was stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene to afford the title compound as a white solid in 91% yield 800 mg.
1H NMR(DMSO-d6，400MHz)δ：1.91-2.02(m，2H)，2.15-2.24(m，5H)，2.48(s，3H)，3.09-3.17(m，2H)，3.18-3.24(m，2H)，5.09-5.15(m，1H)，7.59(d，1H)，8.58(d，1H)，9.19-9.38(m，2H)；LRMS APCI+m/z 207[M+H]+
Preparation 32: 3-methyl-4- (piperidin-4-yloxy) pyridine dihydrochloride
The title compound was prepared as a white solid in 82% yield from the product of preparation 28 using the same method as described for 31.
1H NMR(DMSO-d6，400MHz)δ：1.92-2.05(m，2H)，2.16-2.24(m，5H)，3.11-3.19(m，4H)，5.15-5.17(m，1H)，7.73(d，1H)，8.64(s，1H)，8.72(m，1H)，9.39-9.57(m，2H)；LRMS APCI+m/z 193[M+H]+
Preparation 33: n- (6-methoxypyridin-3-yl) -4- [ (3-methylpyridin-2-yl) oxy ] piperidine-1-thiocarboxamide
The title compound was prepared from the product of preparation 29 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) using a method analogous to preparation 24. Tlc analysis showed that the reaction would be complete after 18 hours (compare 72 hours in preparation 24) providing the desired product as a solid in 58% yield.
1H NMR(CDCl3，400MHz)δ：1.93-2.00(m，2H)，2.05-2.18(m，2H)，2.20(s，3H)，3.95(s，3H)，4.02-4.09(m，4H)，5.40-5.45(m，1H)，6.72-6.81(m，2H)，7.01(bs，1H)，7.40(m，1H)，7.59(m，1H)，7.95-7.99(m，2H)；LRMS APCI m/z 359[M+H]+
Preparation 34: n- (6-methoxypyridin-3-yl) -4- (pyridin-4-yloxy) piperidine-1-thiocarboxamide
5-Isocyanato-2-methoxypyridine [ (829mg, 4.99mmol), J.org.chem. (1980), 45, 4219] was added to a solution of preparation 30 (890mg, 4.99mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 20 h. The resulting precipitate was filtered off and washed with diethyl ether to provide the title compound as a white solid in 43% yield of 738 mg.
1H NMR(CDCl3，400MHz)δ：1.95-2.05(m，2H)，2.06-2.15(m，2H)，3.93-4.01(m，5H)，4.03-4.12(m，2H)，4.72-4.79(m，1H)，6.75-6.85(m，3H)，7.12(m，1H)，7.58(m，1H)，7.98(m，1H)，8.40-8.44(m，2H)；LRMS APCI m/z 345[M+H]+
Preparation 35: n- (6-methoxypyridin-3-yl) -4- (2-methylphenoxy) piperidine-1-thiocarboxamide
5-isothiocyanato-2-methoxypyridine [ (829mg, 4.99mmol), J.org.chem. (1980), 45, 4219]To 4- (2-methylphenoxy) -piperidine hydrochloride [ (990mg, 4.3mmol), j.med.chem. (1978), 21, 309]And a solution of N, N-diisopropylethylamine (0.79mL, 4.7mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 3 hours. The organic solution was then diluted with dichloromethane and washed with sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to afford the title compound as a solid in 85% yield 1.3 g. LRMS APCI M/z 358[ M + H ]]+
Preparation 36: 4- [ (2, 3-dimethylpyridin-4-yl) oxy ] -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarboxamide
5-Isocyanato-2-methoxypyridine [ (476mg, 2.86mmol), J.org.chem. (1980), 45, 4219] was added to a solution of the product of preparation 31 (800mg, 2.86mmol) and N, N-diisopropylethylamine (1.45mL, 8.58mmol) in dichloromethane (10mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between dichloromethane and water and the organic layer was separated and washed with sodium bicarbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to provide the title compound as a solid in 80% yield 857 mg.
1H NMR(CDCl3，400MHz)δ：1.92-2.13(m，4H)，1.97(s，3H)，2.50(s，3H)，3.88-3.97(m，5H)，4.10-4.19(m，2H)，4.69-4.75(m，1H)，6.61(d，1H)，6.77(m，1H)，7.10(s，1H)，7.58(dd，1H)，7.98(m，1H)，8.22(m，1H)；LRMS APCI m/z 373[M+H]+
Preparation 37: n- (6-methoxypyridin-3-yl) -4- [ (3-methylpyridin-4-yl) oxy ] piperidine-1-thiocarboxamide
The title compound was prepared as a white solid in 63% yield from the product of preparation 32 using the same method as described for 36.
1H NMR(CDCl3，400MHz)δ：1.94-2.01(m，2H)，2.02-2.13(m，2H)，2.19(s，3H)，3.85-3.97(m，5H)，4.08-4.15(m，2H)，4.72-4.79(m，1H)，6.71-6.6.74(m，2H)，7.16(m，1H)，7.56(dd，1H)，7.95(m，1H)，8.25(m，1H)，8.34(m，1H)；LRMS APCI m/z 359[M+H]+
Preparation 38: n- (6-methoxypyridin-3-yl) -4- [ (3-methylpyridin-2-yl) oxy ] piperidine-1-thiocarbonylimide methyl ester
Potassium tert-butoxide (160mg, 1.43mmol) was added to a solution of preparation 33 (465mg, 1.30mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 1 hour. Methyl p-toluenesulfonate (271mg, 1.43mmol) was then added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was separated and washed with sodium bicarbonate solution and brine. The organic solution was then dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil in 93% yield 450 mg.
1H NMR(CDCl3，400MHz)δ：1.81-1.95(m，2H)，2.05-2.15(m，5H)，2.20(s，3H)，3.59-3.65(m，2H)，3.72-3.79(m，2H)，3.95(s，3H)，5.38-5.43(m，1H)，6.69-6.81(m，1H)，6.77-7.01(m，1H)，7.20(dd，1H)，7.40(m，1H)，7.76(m，1H)，7.79(m，1H)；LRMS APCI m/z373[M+H]+
Preparation 39: n- (6-methoxypyridin-3-yl) -4- (2-methylphenoxy) piperidine-1-thiocarbonylimide methyl ester
The title compound was prepared in quantitative yield as an oil from the product of preparation 35 and methyl tosylate using the same method as described for 38. LRMS ESI M/z 394[ M + H ]]+
Preparation 40: 4-hydroxy-N- (6-methoxypyridin-3-yl) piperidine-1-thiocarbonylimide methyl ester
The title compound was prepared from the product of preparation 19 using the same method as preparation 38. The crude compound was purified by column chromatography on silica gel eluting with methylene chloride: methanol (95: 5) to provide the title compound as a colorless oil in 57% yield.
1H NMR(CDCl3，400MHz)δ：1.50(d，1H)，1.55-1.65(m，2H)，1.92-2.00(m，2H)，2.10(s，3H)，3.21-3.29(m，2H)，3.89-3.99(m，4H)，4.00-4.09(m，2H)，6.65(d，1H)，7.18(d，1H)，7.71(s，1H)；LRMS APCI m/z 282
Preparation 41: 4- [ (2, 3-dimethylpyridin-4-yl) oxy ] -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarbonylimide methyl ester
The title compound was prepared from the product of preparation 36 in quantitative yield as a colorless oil using the same method as preparation 38.
1H NMR(CDCl3，400MHz)δ：1.82-1.95(m，2H)，2.01-2.10(m，2H)，2.12(s，3H)，2.18(s，3H)，2.50(s，3H)，3.65-3.82(m，4H)，3.82(s，3H)，4.63-4.69(m，1H)，6.62(d，1H)，6.69(d，1H)，7.18(dd，1H)，7.76(m，1H)，8.22(m，1H)；LRMS APCI m/z 387[M+H]+
Preparation 42: 1- [5- (methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] piperidin-4-ol
The title compound was prepared in 55% yield from the product of preparation 40 using the same method as described for preparation 4.
1H NMR(CDCl3，400MHz)δ：1.41(d，1H)，1.47-1.55(m，2H)，1.77-1.85(m，2H)，2.84-2.95(m，2H)，3.28-3.35(m，5H)，3.73-4.01(m，1H)，3.98(s，3H)，4.30(s，2H)，6.82(d，1H)，7.62(m，1H)，8.22(m，1H)；LRMS APCI m/z 320[M+H]+
Preparation 43: 1-benzyl-4- (2-chlorophenoxy) piperidine
Triphenylphosphine (1.91g, 7.31mmol) was added to an ice-cooled solution of diisopropyl azodicarboxylate (1.48g, 7.31mmol) in dichloromethane (15mL) and the mixture was stirred for 10 min. A solution of 2-chlorophenol (806mg, 6.27mmol) and 1-benzyl-4-hydroxypiperidine (1g, 5.22mmol) in dichloromethane (5mL) was then added dropwise to the ice-cooled reaction mixture and stirring continued for an additional 72 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in ether and extracted with saturated citric acid solution (5 × 10 mL). The combined aqueous solutions were then basified with sodium hydroxide and extracted with dichloromethane (2 × 20 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil in 89% yield 1.4 g.
1H NMR(CDCl3，400MHz)δ：1.85-1.95(m，2H)，1.97-2.08(m，2H)，2.32-2.47(m，2H)，3.58(s，2H)，4.46-4.34(m，1H)，6.87-6.95(m，2H)，7.16-7.22(m，1H)，7.20(dd，1H)，7.26-7.37(m，6H)
Preparation 44: 1-benzyl-4- (3, 5-difluorophenoxy) piperidine
From 1-benzyl-4-hydroxypiperidine and 3 using the same method as described for preparation 435-Difluorophenol the title compound was prepared. The crude compound was purified by column chromatography on silica gel eluting with methylene chloride: methanol (95: 5) to provide the desired product in 63% yield. LRMS APCI M/z 304[ M + H ]]+
Preparation 45: 4- (2-chlorophenoxy) piperidine hydrochloride
1-Chloroethyl chloroformate (0.95g, 6.65mmol) was added to an ice-cooled solution of the product of preparation 43 (1.34g, 4.43mmol) and "proton sponge" 1, 8-bis (dimethylamino) naphthalene (951mg, 4.43mmol) in dichloromethane (15mL) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then washed with 10% citric acid solution (2X 5mL) and brine (5mL), dried over magnesium sulfate and concentrated in vacuo. The residue was then dissolved in methanol and heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue triturated with ether to provide the title compound as a white solid in 69% yield 890 mg.1H NMR(DMSO-d6，400MHz)δ：1.80-1.95(m，2H)，2.05-2.20(m，2H)，3.05-3.30(m，4H)，4.70-4.85(m，1H)，6.90-7.00(m，1H)，7.15-7.30(m，2H)，7.35-7.45(m，1H)，8.70-9.20(brm，2H)；LRMS APCI m/z 212/248[M+H]+
Preparation 46: 4- (3, 5-Difluorophenoxy) piperidine hydrochloride
The title compound was prepared from the product of preparation 44 in quantitative yield as a white solid using the same method as described for preparation 45.1H NMR(DMSO-d6，400MHz)δ：1.77-1.88(m，2H)，2.02-2.18(m，2H)，2.95-3.10(m，2H)，3.13-3.23(m，2H)，4.62-4.71(m，1H)，6.73-6.82(m，3H)，9.00-9.19(brm，2H)；LRMSAPCI m/z 214[M+H]+
Preparation 47: 4- (2-chlorophenoxy) -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarboxamide
The product of preparation 45 and 5-isothiocyanato-2-methoxypyridine [ (829mg, 4.99mmol), J.org.chem. (1980), 45, 4219 were prepared by the same procedure as described in 35]The title compound was prepared. The crude compound was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (100: 0 to 99: 1: 0.5) to provide the title compound as a white solid in 74% yield.1H NMR(CDCl3，400MHz)δ：1.95-2.10(m，4H)，3.90-4.10(m，5H)，4.20-4.30(m，2H)，4.65-4.75(m，1H)，6.80(d，1H)，6.90-7.05(m，3H)，7.15-7.30(m，1H)，7.37(d，1H)，7.75-7.90(m，1H)，8.05(s，1H)
Preparation 48: 4- (3, 5-Difluorophenoxy) -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarboxamide
The same procedure as described in 35 was used to self-prepare 46 product and 5-isothiocyanato-2-methoxypyridine [ (829mg, 4.99mmol), J.org.chem. (1980), 45, 4219]The title compound was prepared as a solid in 85% yield. LRMS APCI M/z 380[ M + H ]]+
Preparation 49: 4- [ methyl (pyridin-2-yl) amino ] piperidine-1-carboxylic acid tert-butyl ester
A mixture of tert-butyl 4- (methylamino) piperidine-1-carboxylate (page 22 of WO 03/089412) (2g, 9.33mmol), 2-bromopyridine (1.35mL, 13.99mmol) and N, N-diisopropylethylamine (2.5mL, 13.99mmol) was heated at 130 ℃ for 3 hours. Potassium carbonate (2g, 14mmol) was added and the reaction mixture was heated at 130 ℃ for a further 8 hours. 2-bromopyridine (1mL, 10.36mmol) was then added to the mixture and heating continued at 130 ℃ for 36 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (30mL) and water (15 mL). The organic layer was separated and extracted with a saturated citric acid solution (2 × 15mL), and the combined aqueous solution was basified with sodium bicarbonate and extracted with dichloromethane (2 × 30 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (0: 100 to 50: 50) to afford the title compound in 646mg 24% yield.1H NMR(CDCl3，400MHz)δ：1.45(s，9H)，1.55-1.70(m，4H)，2.78-2.90(m，5H)，4.10-4.30(m，2H)，4.65-4.80(m，1H)，6.45-6.55(m，2H)，7.40-7.45(m，1H)，8.10-8.15(m，1H)；LRMS APCI m/z 292[M+H]+
Preparation 50: N-methyl-N-piperidin-4-ylpyridin-2-amine dihydrochloride
Hydrogen chloride gas was passed through an ice-cooled solution of preparation 49 (640mg, 2.19mmol) in dichloromethane (10mL) until saturation was reached. The reaction mixture was then stirred at room temperature for 18 hours, after which the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane (× 3), dissolved in methanol and heated at reflux for 5 min. The reaction mixture was then concentrated in vacuo and the residue triturated with ether and dried under vacuum at 60 ℃ to afford the title compound as a solid in 95% yield 550 mg.
1H NMR(CDCl3，400MHz)δ：1.70-1.90(m，2H)，2.00-2.20(m，2H)，2.70-3.20(m，5H)，3.25-3.80(m，2H)，4.50-4.70(m，1H)，6.80-7.00(m，1H)，7.20-7.50(m，1H)，7.90-8.20(m，1H)，8.90-9.40(m，2H)；LRMS APCI m/z192[M+H]+
Preparation 51: n- (6-methoxypyridin-3-yl) -4- [ methyl (pyridin-2-yl) amino ] piperidin-1-thiocarboxamide
The title compound was prepared in quantitative yield from 5-amino-2-methoxypyridine, 1' 1-thiocarbonyldi-2 (1H) -pyridone and the product of preparation 50 using the same method as described for preparation 2.
1H NMR(CDCl3，400MHz)δ：1.78-2.10(m，4H)，2.84(s，3H)，3.19-3.31(m，2H)，3.94(s，3H)，4.77-4.85(m，2H)，4.96-5.15(m，1H)，6.50(d，1H)，6.58(m，1H)，6.74(d，1H)，7.04(m，1H)，7.45(m，1H)，7.59(m，1H)，7.99(m，1H)，8.15(m，1H)；LRMS APCI m/z358[M+H]+
Preparation 52: 4- (methylamino) piperidine-1-carboxylic acid tert-butyl ester
10% Pd/C (2g) was added to a solution of tert-butyl 4-ketopiperidine-1-carboxylate (20g, 100mmol) in methylamine (33% in ethanol, 10mL) and the mixture was stirred at room temperature under 60psi of hydrogen for 18 h. Then the reaction mixture is passed throughFiltered and the filtrate concentrated in vacuo. The residue was azeotroped with dichloromethane (× 3) and dried under vacuum for 72 hours to afford the title compound as a solid in 98% yield 21.1 g. LRMS APCI M/z 215[ M + H ]]+
Preparation 53: 4- [ [ (benzyloxy) carbonyl ] (methyl) amino ] piperidine-1-carboxylic acid tert-butyl ester
N- (benzyloxycarbonyloxy) succinimide (5.5g, 22.16mmol) was added portionwise to a solution of preparation 52's product (5g, 23.33mmol) in dichloromethane (50mL) and the mixture was stirred at room temperature for 18 h. The reaction mixture was then washed with water (2X 20mL), saturated citric acid solution (20mL) and brine (20 mL). The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue triturated with pentane to afford the title compound as a solid in 81% yield 6.63 g.
1H NMR(CDCl3，400MHz)δ：1.40-1.80(m，13H)，2.60-3.00(m，5H)，3.95-4.40(m，3H)，5.15(s，2H)，7.20-7.50(m，5H)
Preparation 54: methyl (piperidin-4-yl) carbamic acid benzyl ester
Trifluoroacetic acid (30mL) was added to an ice-cooled solution of the product of preparation 53 (6.6g, 19mmol) in dichloromethane (30mL) and the reaction was stirred for 1 hour while the temperature was raised to 25 ℃. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (30mL) and 1M sodium hydroxide solution (20 mL).The organic layer was separated, washed with saturated 1M sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was then azeotroped with toluene (. times.2) to afford the title compound as an oil in quantitative yield of 4.64 g.1H NMR(CDCl3，400MHz)δ：1.55-1.75(m，4H)，2.15-2.55(brm，1H)，2.60-2.90(m，5H)，3.10-3.25(m，2H)，3.80-4.40(m，1H)，5.15(s，2H)，7.20-7.45(m，5H)；LRMS APCI m/z 249[M+H]+
Preparation 55: (1- { [ (6-Methoxypyridin-3-yl) amino ] carbothioyl } piperidin-4-yl) methylcarbamic acid benzyl ester
The title compound was prepared in 77% yield from 5-amino-2-methoxypyridine, 1' 1-thiocarbonyldis-2 (1H) -pyridone and the product of preparation 54 using the same method as described for preparation 2.
1H NMR(CDCl3，400MHz)δ：1.70-1.90(m，4H)，2.75-2.90(brs，3H)，3.00-3.20(m，2H)，3.95(s，3H)，4.05-4.50(m，1H)，4.70-4.90(m，2H)5.15(s，2H)，6.70-6.80(d，1H)，7.05-7.15(brs，1H)，7.30-7.45(m，5H)，7.50-7.60(d，1H)，7.95(s，1H)；LRMS APCI m/z415[M+H]+
Preparation 56: {1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } methyl carbamic acid benzyl ester
The title compound was prepared from the product of preparation 55, methyl tosylate and acethydrazide using the same procedure as described for preparation 20. The crude compound was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 93: 7) to provide the title compound in 67% yield.
1H NMR(CDCl3，400MHz)δ：1.50-1.80(m，4H)，2.20(s，3H)，2.70-3.00(m，5H)，3.30-3.45(m，2H)，4.00(s，3H)，4.05-4.20(m，1H)，5.10(s，2H)，6.85-6.95(m，1H)，7.20-7.40(m，5H)，7.45-7.55(m，1H)，8.10(s，1H)；LRMS APCI m/z 437[M+H]+
Preparation 57: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] -N-methylpiperidin-4-amine
10% Pd/C (200mg) was added to a solution of preparation 56 (2.13g, 4.88mmol) in a mixture of ethanol (25mL) and hydrochloric acid (2.5mL) and the reaction mixture was stirred at room temperature under 60psi of hydrogen for 80 hours. Then the reaction mixture is passed throughFiltered and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (50mL) and saturated sodium carbonate solution (20mL), and the aqueous layer was separated and extracted with dichloromethane (3X 10 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a foam in 87% yield 1.28 g. LRMS APCI M/z 303[ M + H ]]+
Preparation 58: n- (6-methoxypyridin-3-yl) -4- (pyridin-4-yloxy) piperidine-1-thiocarbonylimide methyl ester
The title compound was prepared as an oil in 99% yield from the product of preparation 34 and methyl tosylate using the same method as described for 38. LRMS APCI M/z 359[ M + H]+
Preparation 59: 2- (piperidin-4-yloxy) benzonitrile
1-Boc-4-hydroxypiperidine (20g, 99.35mmol) and 2-cyanophenol (11.82g, 99.35mmol) were added to a mixture of triphenylphosphine (26.06g, 99.35mmol) and di-tert-butyl azodicarboxylate (19.56mL, 99.35mmol) in tetrahydrofuran (800mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in hydrochloric acid (4M in dioxane, 300 mL). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was separated and washed with ethyl acetate (2 × 100 mL). The aqueous solution was then basified with 2M sodium hydroxide solution and then extracted with ether (3X 100 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid in quantitative yield. LRMS ESI M/z 203[ M + H ]]+
Preparation 60: 4- (2-cyanophenoxy) -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarboxamide
The title compound was prepared as a white solid in 75% yield from the product of preparation 59 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) using the same method as described for preparation 35.
LRMS APCI m/z 369[M+H]+
Preparation 61: 4- (2-Cyanophenoxy) -N- (6-methoxypyridin-3-yl) piperidine-1-thiocarbonylimide methyl ester
The title compound was prepared from the product of preparation 60 and methyl tosylate using the same method as described for 38. The crude product was triturated to provide the title compound as a white solid in 73% yield. LRMS APCI M/z 383[ M + H [ ]]+
Preparation 62: 1- (benzhydryl) -3-phenoxyazetidine
Phenol (6.68g, 75mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 2.82g, 75mmol) in toluene (50mL) and the mixture was heated at 60 ℃ for 2 h. The temperature was then increased to 80 ℃ and a solution of 1- (benzhydryl) -3-azetidinesulfonic acid (15g, 47mol) in toluene (150mL) was added dropwise. The reaction mixture was stirred at 80 ℃ for 2 hours, cooled and then washed with water and dilute sodium hydroxide solution. The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue recrystallized from water/isopropanol to provide the title compound as a solid in 84% yield 12.4 g. LRMS APCI M/z 316[ M + H ]]+
Preparation 63: 3-phenoxy azetidines
Mixing 10% Pd (OH)2/C (500mg) was added to a solution of preparation 62 (10g, 37mmol) in ethanol (160mL) and the mixture was stirred at 80 ℃ under 45psi of hydrogen for 18 h. Then the reaction mixture is passed throughFiltration, washing with ethanol, and concentration of the filtrate in vacuo. The residue was triturated with pentane to give the title compound in 69% yield 3.81 g.
LRMS APCI m/z 150[M+H]+
Preparation of 64: n- (6-methoxypyridin-3-yl) -3-phenoxyazetidine-1-thiocarboxamide
The title compound was prepared in 77% yield from the product of preparation 63 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) using the same method as described for preparation 35.
LRMS ESI m/z 316[M+H]+
Preparation 65: n- (6-methoxypyridin-3-yl) -3-phenoxyazetidine-1-thiocarbonylimide methyl ester
The title compound was prepared in 44% yield from the product of preparation 64 and methyl p-toluenesulfonate using the same method as described for preparation 3. LRMS ESI M/z 330[ M + H ]]+
Preparation 66: 2- [ (dimethylamino) methyl ] -3, 5-difluorophenol
Potassium carbonate (7.82g, 56.73mmol) was added to a solution of 3, 5-difluorophenol (4.92g, 37.82mmol) in acetonitrile (50 mL). N, N-dimethylmethyleneiminium iodide (7.34g, 39.71mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off, washed with ethyl acetate and the filtrate was partitioned between ethyl acetate (30mL) and water (15 mL). The organic layer was separated and extracted with saturated citric acid solution (2 × 15 mL). The combined aqueous solutions were basified to pH 7 with solid sodium bicarbonate and extracted with dichloromethane (2 × 30 mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil in 54% yield of 3.8 g. LRMS APCI M/z 188[ M + H ]]+
Preparation 67: acetic acid 2- (acetoxy) -4, 6-difluorobenzyl ester
Acetic anhydride (5.18g, 50.75mmol) was added to a solution of preparation 66 (3.80g, 20.30mmol) in toluene (25mL) and the mixture was heated at reflux for 1 hour. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (20mL), washed with water (× 2) and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 98: 2) to give the title compound in 61% yield of 3 g.1H NMR(400MHz，CDCl3)δ：2.05(s，3H)，2.35(s，3H)，5.08(s，2H)，6.70-6.80(m，2H)；LRMS APCI m/z 262[M+NH4]+
Preparation 68: 3, 5-difluoro-2-methylphenol
Sodium borohydride (2.28g, 60.40mmol) was added to a solution of the product of preparation 67 (2.85g, 12.08mmol) in 1, 2-dimethoxyethane (25mL) and the mixture was heated at 45 ℃ for 18 h. The reaction mixture was then cooled with an ice/acetone bath and quenched with a saturated ammonium chloride solution. The mixture was extracted with ether (2 × 20mL) and the combined organic solutions were washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo to afford the title compound in 75% yield 1.3 g.
1H NMR(400MHz，CDCl3)δ：2.10(s，3H)，5.10-5.20(brs，1H)，6.35-6.45(m，2H).
Preparation 69: 2-hydroxyacetylhydrazide
Hydrazine monohydrate (1.08g, 22.2mmol) was added to a solution of methyl glycolate (0.84mL, 11.1mmol) in methanol (10mL) and the mixture was heated at reflux for 2 hours and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a white solid in quantitative yield.1H NMR(400MHz，CDCl3)δ：4.04(s，2H)
Preparation 70: 4-hydroxy-3-methylbenzonitrile
A mixture of 4-hydroxy-3-methylbenzaldehyde (530mg, 3.91mmol) and hydroxylammonium chloride (406mg, 5.81mmol) in acetic acid (5mL) was heated at reflux for 90 minutes. The cooled reaction mixture was then diluted with ether (30mL) and washed with water (30 mL). The combined organic solutions were washed with brine, dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 97.5: 2.5) to provide the title compound as a light yellow oil in 66% yield of 345 mg.
1H NMR(400MHz，CDCl3)δ：2.25(s，3H)，6.84(d，1H)，7.37(d，1H)，7.40(s，1H)
Preparation 71: 3-chloro-4-hydroxybenzonitrile
The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxylammonium chloride using the same method as described for preparation 70. The title compound was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (100: 0 to 90: 10) to afford the title compound as a white solid in 76% yield.
1H NMR(400MHZ，CDCl3)δ：7.10(d，1H)，7.52(d，1H)，7.66(s，1H)
Preparation of 72: 2-chloro-3-hydroxybenzonitrile
A mixture of 2-chloro-3-hydroxybenzaldehyde [ (2g, 12.8mmol) page 34 of WO 2005007633 ] and hydroxylammonium chloride (1.33g, 19.6mmol) in acetic acid (20mL) was heated at reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford a white solid. The solid was then dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid in quantitative yield.
1H NMR(400MHz，CD3OD)δ：7.18(d，1H)，7.26(m，2H)
Preparation 73: 3-fluoro-2- (trifluoromethyl) phenol
A solution of 3-fluoro-2- (trifluoromethyl) bromobenzene (1g, 4.1mmol) in tetrahydrofuran (25mL) was added dropwise to n-butyllithium (2.5M in hexane, 3.2mL, 8mmol) at-78 deg.C, and the mixture was stirred at this temperature for 30 minutes. Trimethyl borate (1.84mL, 16.4mmol) was added and the reaction mixture was stirred at-78 ℃ for an additional 30 minutes and at room temperature for 18 hours. Then 2M sodium hydroxide solution (4mL) and 35% hydrogen peroxide solution (2mL) were added and the mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with ether (100 mL). The aqueous layer was separated and the organic solution was washed with 2M sodium hydroxide solution. The combined basic washes were acidified with 2M hydrochloric acid, extracted with ether (2 × 50mL) and the organic solution was concentrated in vacuo to afford the title compound as a yellow oil in 40% yield 300 mg.
1H NMR(400MHz，CD3OD)δ：6.64(m，1H)，6.75(d，1H)，7.36(q，1H)
Preparation 74: 3-hydroxy-2-methylbenzonitrile
Reacting 3-methoxy-2-methylBenzonitrile [ (1g, 6.79mmol) on page 6 of US 5965766]And a solution of tetra-n-butylammonium iodide (4.12g, 17mmol) in dichloromethane (15mL) was cooled to-78 deg.C and purged with nitrogen. Boron trichloride (1M in dichloromethane, 17mL, 17mmol) was added dropwise and the mixture was stirred at-78 ℃ for 15 min and at room temperature for 3 h. The reaction mixture was quenched with water, stirred for 30 minutes and concentrated in vacuo. The aqueous residue was extracted with ether and the organic solution was washed with water (× 5), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown solid in 91% yield 826 mg.1H NMR(400MHz，CDCl3)δ：2.20(s，3H)，7.10(m，1H)，7.20(d，1H)，10.10(s，1H)；LRMS APCI m/z132[M-H]-
Preparation 75: 3-hydroxy-2-methylbenzamide
Oxalyl chloride (4.19mL, 48mmol) was added to an ice-cooled solution of 3-hydroxy-2-methylbenzoic acid (3.62g, 24mmol) in dichloromethane (30 mL). N, N-dimethylformamide (2mL) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was concentrated three times in vacuo from toluene. The residue was then suspended in tetrahydrofuran (10mL), added to an ice-cooled 0.88 ammonia solution (10mL) and stirred for 2.5 hours while the temperature was raised to ambient temperature. The reaction mixture was then extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo, and the residue was concentrated in vacuo from acetone and triturated with ether to afford the title compound as a solid in 45% yield. LRMS APCI M/z 152[ M + H ]]+
Preparation of 76: 3-hydroxy-N, N, 2-trimethylbenzamide
The title compound was prepared as a solid in 42% yield from 3-hydroxy-2-methylbenzoic acid and dimethylamine using the same method as described for preparation 75.
1H NMR(400MHz，CDCl3)δ：1.95(s，3H)，2.70(s，3H)，2.95(s，3H)，6.55(d，1H)，6.80(d，1H)，7.00(m，1H)，9.50(s，1H)；LRMS APCI m/z 180[M+H]+
Preparation 77: 2- (methoxymethyl) phenol
A solution of 2-hydroxybenzyl alcohol (5g, 40mmol) in methanol (25mL) was heated in a sealed vessel at 150 ℃ for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by fractional distillation (90 ℃/10mmHg) to afford the title compound as a colorless liquid in 58% yield of 3.22 g. LRMS APCI M/z 137[ M-H ]]-
Preparation 78: 3- (2-chloro-4-fluorophenoxy) -1- (benzhydryl) azetidine
A mixture of methanesulfonic acid 1- (benzhydryl) -3-azetidinyl ester (363.8g, 1.15mol), potassium carbonate (330g, 2.38mol) and 2-chloro-4-fluorophenol (140g, 0.96mol) in acetonitrile (2.5L) was heated at reflux for 4.5 hours. The cooled reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (1L) and water (500 mL). The organic layer was separated, dried over sodium sulfate, concentrated in vacuo and the residue triturated with ethyl acetate/pentane/dichloromethane (90: 10: 1) to provide the title compound as a white solid in quantitative yield 350 g.
1H NMR(400MHz，CDCl3)δ：3.19(m，2H)，3.75(m，2H)，4.45(m，1H)，4.78(m，1H)，6.60(m，1H)，6.83(m，1H)，7.14(m，1H)，7.18-7.50(m，10H)
Preparation of 79: 3- (2-chloro-4-fluorophenoxy) azetidine hydrochloride
A solution of preparation 78 (5g, 13.59mmol) and 1, 8-bis (dimethylamino) naphthalene (2.91g, 13.59mmol) in dichloroethane (50mL) was treated with chloroethyl chloroformate (4.08g, 28.54mmol) and the mixture was then heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (60mL), washed with 2N hydrochloric acid (2 × 30mL), dried over sodium sulfate and concentrated in vacuo. The residue was then azeotroped with toluene and dichloromethane, triturated with ether and purified by HPLC using a Phenomenex Luna C18 system eluting with water/acetonitrile/trifluoroacetic acid (5: 95: 0.1) to acetonitrile (95: 5 to 5: 95) to provide the title compound in 52% yield of 1.69 g.
1H NMR(400MHz，CDCl3)δ：4.22(m，2H)，4.58(m，2H)，5.18(m，1H)，6.92(m，1H)，7.04(m，1H)，7.30(m，1H)；LRMS ESI m/z202[M+H]+
Preparation 80: 3- (2-chloro-4-fluorophenoxy) -N- (6-methoxypyridin-3-yl) azetidine-1-thiocarboxamide
N-methylmorpholine (16.6mL, 150.8mmol) and 5-isothiocyanato-2-methoxypyridine [ (20.9g, 125.7mmol), J.Org.chem. (1980), 45, 4219] were added portionwise to an ice-cooled suspension of preparation 79 (29.93g, 125.7mmol) in tetrahydrofuran (150mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was recrystallized from water. The resulting solid was filtered, washed with water and ether, and dried under vacuum at 45 ℃ for 18 hours to provide the title compound as a solid in 74% yield of 34 g.
LRMS APCI m/z 368[M+H]+
Preparation 81: 3- (2-chloro-4-fluorophenoxy) -N- (6-methoxypyridin-3-yl) azetidine-1-thiocarbonylimide methyl ester
The title compound was prepared in quantitative yield from preparation 80 and potassium tert-butoxide using the same method as described for preparation 3. LRMS APCI M/z 382[ M + H ]]+
Preparation 82: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1.2, 4-triazol-3-yl ] azetidin-3-ol
A mixture of preparation 4 (1g, 2.95mmol) and 2M sodium hydroxide solution (10mL) in ethanol (20mL) was heated at reflux for 24 h. The reaction mixture was then cooled to room temperature, acidified to pH 6 with hydrochloric acid and extracted with dichloromethane. The organic solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 50: 50) to afford the title compound as a brown oil in 26% yield 200 mg.
1H NMR(400MHz，CDCl3)δ：2.17(s，3H)，3.80(m，2H)，3.95(m，2H)，4.03(s，3H)，4.57(m，1H)，6.88(d，7.52(dd，1H)，8.11(d，1H)；LRMS ESI m/z 262[M+H]+
Preparation 83: 3-methoxy-4- [ (3R) -pyrrolidin-3-yloxy ] benzonitrile
4-hydroxy-3-methoxybenzonitrile (12g, 80.2mmol) and triphenylphosphine (21g, 80.2mmol) were added portionwise to an ice-cooled solution of tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (15g, 80.2mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2g, 80.2mmol) in tetrahydrofuran (100mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water (100mL), and the combined aqueous solutions were washed with ethyl acetate (2 × 150mL), basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (2 × 250 mL). The combined organic solutions were washed with brine (100mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a cream solid in 67% yield of 11.8 g. LRMSESI M/z 219[ M + H [ ]]+
Preparation 84: (3R) -3- (2-chlorophenoxy) pyrrolidine hydrochloride
Diisopropyl azodicarboxylate (21mL, 107mmol) and 4-hydroxy-3-chlorophenol (11.1mL, 107mmol) were added in portions to tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (20 g)107mmol) and triphenylphosphine (28.1g, 107mmol) in tetrahydrofuran (320mL) and the mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (400mL) and water (400 mL). The organic layer was separated and washed with water (100mL), and the combined aqueous solutions were washed with ethyl acetate (2 × 300mL), basified to pH 9 with solid potassium carbonate and extracted with ethyl acetate (2 × 400 mL). The combined organic solutions were then washed with water (3 × 300mL), dried over magnesium sulfate and concentrated in vacuo. The residual oil was dissolved in diethyl ether (60mL), treated dropwise with hydrochloric acid (4M in dioxane, 25mL) and the resulting precipitate was filtered off, washed with diethyl ether and dried to afford the title compound as a white solid in 55% yield 13.69 g. LRMS APCI M/z 198[ M + H ]]+
Preparation 85: (3R) -3- (2-methoxyphenoxy) pyrrolidine hydrochloride
The title compound was prepared as a white solid in 45% yield from tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate and 2-methoxyphenol using the same method as described for preparation 84. Microanalysis: experimental values (%) C (57.43), H (7.05), N (6.08); c11H15NO2The following needs are: (%) C (57.50), H (6.96), N (6.09).
Preparation 86: (3R) -3- (2-methylphenoxy) pyrrolidine hydrochloride
(3S) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester using the same method as described for preparation 84Butyl and o-cresol the title compound was prepared as a pale pink solid in 54% yield. LRMSAPCIm/z178[ M + H ]]+
Preparation 87: 2- [ (3R) -pyrrolidin-3-yloxy ] benzonitrile maleate
2-Hydroxybenzonitrile (9.5g, 80.2mmol) and triphenylphosphine (21g, 80.2mmol) were added portionwise to an ice-cooled solution of tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (15g, 80.2mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2g, 80.2mmol) in tetrahydrofuran (100mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, the organic layer was separated and washed with water (100mL), and the combined aqueous solution was washed with ethyl acetate (2 × 150mL), basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (2 × 250 mL). The combined organic solutions were washed with brine (100mL), dried over magnesium sulfate and concentrated in vacuo. The residue was diluted with ethyl acetate and treated with a solution of maleic acid (6.5g) in ethyl acetate (200mL) and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was then filtered off, washed with ethyl acetate and dried to provide the title compound as a cream solid in 49% yield 12 g. LRMS ESI M/z 189[ M + H ]]+
Preparation 88: 4- [ (3R) -pyrrolidin-3-yloxy ] benzonitrile maleate
4-hydroxybenzene is reacted withNitrile (9.5g, 80.2mmol) and triphenylphosphine (21g, 80.2mmol) were added portionwise to an ice-cooled solution of tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (15g, 80.2mmol) in tetrahydrofuran (225 mL). A solution of diisopropyl azodicarboxylate (16.2g, 80.2mmol) in tetrahydrofuran (100mL) was then added dropwise and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was treated with hydrochloric acid (4M in dioxane, 250 mL). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with water (100mL), and the combined aqueous solutions were washed with ethyl acetate (2 × 150mL), basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (2 × 250 mL). The combined organic solutions were washed with brine (100mL), dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (97: 3: 1 to 90: 10: 1). The appropriate fractions were evaporated under reduced pressure and the residue was diluted with ethyl acetate and treated with a solution of maleic acid (5g) in ethyl acetate (140 mL). The resulting precipitate was then filtered off, washed with ethyl acetate and dried to provide the title compound as a cream solid in 65% yield 9.87 g. LRMS ESI M/z 189[ M + H ]]+
Preparation 89: (3R) -3- (4-fluorophenoxy) pyrrolidine
Diethyl azodicarboxylate (60.5mL, 384mmol) was added to an ice-cooled mixture of (S) - (-) -1-benzyl-3-pyrrolidinol (56.72g, 320mmol), 4-fluorophenol (39.45g, 352mmol) and triphenylphosphine (100.7g, 384mmol) in tetrahydrofuran (500mL) and the mixture was stirred for 18 h while the temperature was raised to ambient temperature. The reaction mixture was then concentrated in vacuo and the residue was dissolved in pentane: dichloromethane (90: 10). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was then washed by washing with dichloromethanePurifying by silica gel column chromatography. The appropriate fractions were evaporated under reduced pressure and part of the residue (5g) was dissolved in methanol (100 mL). 10% Pd/C (0.5g) and ammonium formate (5.8g, 92mmol) were added and the mixture was stirred at room temperature for 3 hours. Then the mixture is passed throughFiltration and the filtrate concentrated in vacuo and purified by column chromatography on silica gel eluting with methylene chloride: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) to afford the title compound as a colorless oil.1H NMR(400MHz，DMSO-d6)δ：2.03(m，2H)，3.10-3.29(m，3H)，3.36(m，1H)，5.01(m，1H)，6.96(m，2H)，7.08(m，2H).
Preparation 90: (3S) -3- (2-methoxyphenoxy) pyrrolidine hydrochloride
The title compound was prepared from tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate and 2-methoxyphenol in 40% yield as a pale pink solid using the same method as described for preparation 84. LCMSIPCI M/z 194[ M + H ]]+
Preparation 91: (3S) -3- (2-chlorophenoxy) pyrrolidine hydrochloride
The title compound was prepared in 54% yield as a pale pink solid from tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate and 2-chlorophenol using the same method as described for preparation 84. LCMS APCIm/z 198[ M + H ]]+
Preparation 92: (3S) -3- (2-methylphenoxy) pyrrolidine hydrochloride
The title compound was prepared as a white solid in 40% yield from tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate and 2-cresol using the same method as described for preparation 84. LCMS APCI M/z178[ M + H ]]+
Preparation 93: (3S) -3-hydroxy-N- (6-methoxypyridin-3-yl) pyrrolidine-1-thiocarboxamide
The title compound was prepared in 99% yield from (S) -3-hydroxypyrrolidine and 5-isothiocyanato-2-methoxypyridine (j.org.chem. (1980), 45, 4219) using the same method as described for preparation 35.
1H NMR(400MHz，CD3OD)δ：1.91-2.22(m，2H)，3.69-3.81(m，4H)，3.88(s，3H)，4.40-4.52(m，1H)，6.78(d，1H)，7.69(dd，1H)，8.00(m，1H)；LCMS m/z 254[M+H]+
Preparation 94 to 100
The following compounds of the general formula shown below were prepared using the same procedure as described for preparation 35, using the product of preparation 83-89 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219).
NMR Spectroscopy at 400MHz in CDCl3Middle run
Preparation 101: (3S) -3- (2-methoxyphenoxy) -N- (6-methoxypyridin-3-yl) pyrrolidine-1-thiocarboxamide
The title compound was prepared in 90% yield from the product of preparation 90 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) using the same method as described for preparation 35.
LRMS APCI m/z 360[M+H]+
Preparation 102: (3S) -3-hydroxy-N- (6-methoxypyridin-3-yl) pyrrolidine-1-thiocarbonylimide methyl ester
The title compound was prepared from the product of preparation 93 and methyl p-toluenesulfonate using the same method as described for preparation 3. The crude compound was recrystallized from ether/cyclohexane to afford the desired product as a solid in 94% yield.1H NMR(400MHz，CD3OD)δ：1.91-2.20(m，2H)，2.01(s，3H)，3.58(m，1H)，3.63-3.75(m，3H)，3.83(s，3H)，4.40(m，1H)，6.77(d，1H)，7.34(dd，1H)，7.68(m，1H)；LCMS m/z 268[M+H]+
Preparation 103 to 109
The following compounds of the general formula shown below were prepared using the same method as described in preparation 3, using the products of preparations 94 to 100 and methyl p-toluenesulfonate.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Preparation 110: (3S) -1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] pyrrolidin-3-ol
The title compound was prepared from the product of preparation 102 and acethydrazide using the same method as described for preparation 4. The crude compound was triturated with pentane to provide the desired product in 44% yield.1H NMR(400MHz，CD3OD)δ：1.78-1.87(m，1H)，1.90-2.02(m，1H)，2.15(s，3H)，3.03(m，1H)，3.18-3.30(m，3H)，4.01(s，3H)，4.33(m，1H)，6.98(d，1H)，7.78(dd，1H)，8.23(m，1H)；LCMS m/z 276[M+H]+
Preparation 111: 2- (benzyloxy) -6-fluoropyridine
Benzyl alcohol (1.88g, 17.38mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 458mg, 19.11mmol) in tetrahydrofuran (15mL) and the mixture was heated at 50 ℃ for 45 min. The reaction mixture was then cooled to room temperature, a solution of 2, 6-difluoropyridine (2g, 17.38mmol) in tetrahydrofuran (4mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ethyl acetate, concentrated in vacuo and the residue was partitioned between ethyl acetate (50mL) and water (20 mL). The organic layer was separated, washed with brine (20mL), dried over magnesium sulfate and concentrated in vacuo. The residue was then concentrated in vacuo from dichloromethane to afford the title compound as a clear oil in 98% yield 3.48 g.
LRMS APCI m/z 204[M+H]+
Preparation of 112: 4- { [6- (benzyloxy) pyridin-2-yl ] oxy } piperidine-1-carboxylic acid tert-butyl ester
A solution of 1-boc-4-hydroxypiperidine (501mg, 2.49mmol) in tetrahydrofuran (10mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 65mg, 2.74mmol) and the mixture was heated at 55 ℃ for 1 hour. The reaction mixture was then cooled to room temperature, a solution of the product of preparation 111 (506mg, 2.49mmol) in tetrahydrofuran (3mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes and at 70 ℃ for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate (20mL) and water (10mL), the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (100: 0 to 90: 10) to provide the title compound as a white solid in 49% yield of 470 mg. LRMS APCI M/z 385[ M + H ]]+
Preparation 113: 4- [ (6-keto-1, 6-dihydropyridin-2-yl) oxy ] piperidine-1-carboxylic acid tert-butyl ester
The title compound was prepared in 96% yield from the product of preparation 112 using the same method as described for preparation 17.
LRMS APCI m/z 295[M+H]+
Preparation of 114: 4- [ (1-methyl-6-keto-1, 6-dihydropyridin-2-yl) oxy ] piperidine-1-carboxylic acid tert-butyl ester
Sodium hydride (60% dispersion in mineral oil, 27mg, 1.12mmol) was added to a solution of preparation 113's product (276mg, 0.93mmol) in tetrahydrofuran (4mL) and the mixture was stirred at room temperature for 30 minutes. Methyl p-toluenesulfonate (192mg, 1.03mmol) was then added and the mixture was stirred at room temperature for 18 hours. Methyl p-toluenesulfonate (87.3mg, 0.47mmol) was additionally added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (10mL) and water (5 mL). The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 97: 3) to give the title compound in 59% yield 170 mg. LRMS APCI M/z 309[ M + H ]]+
Preparation 115: 1-methyl-6- (piperidin-4-yloxy) pyridin-2 (1H) -one hydrochloride
The title compound was prepared in quantitative yield as a solid from the product of preparation 114 using the same method as described for preparation 50.
LRMS APCI m/z 209[M+H]+
Preparation 116: n- (6-methoxypyridin-3-yl) -4- [ (1-methyl-6-oxo-1, 6-dihydropyridin-2-yl) oxy ] piperidine-1-thiocarboxamide
The title compound was prepared in 50% yield from the product of preparation 115 and 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) using the same method as described for preparation 35.
LRMS APCI m/z 375[M+H]+
Preparation 117: 1- [ 5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4H- [1, 2, 4] triazol-3-yl ] -pyrrolidin-3-ol
The title compound was prepared from the product of preparation 102 and the compound of preparation 5 using the same method as described for preparation 4. The crude compound was triturated with pentane to afford the desired product in 58% yield. LCMS M/z 306[ M + H ]]+
Preparation 118: 1- [ 5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4H- [1, 2, 4] triazol-3-yl ] -azetidin-3-ol
The title compound was prepared in 68% yield from the compound of preparation 6 using the same procedure as described for preparation 82.
LRMS ESI m/z 292[M+H]+
Example 1: 5- {3- [3- (4-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine
Sodium hydride (60% dispersion in mineral oil, 12mg, 0.3mmol) was added to a solution of 4-fluorophenol (33mg, 0.3mmol) in N, N-dimethylformamide (2mL) and the mixture was stirred at room temperature until bubbling ceased. The product of preparation 4 (50mg, 0.15mmol) was then added and the mixture was heated at 100 ℃ for 40 h. The cooled reaction mixture was then partitioned between water and dichloromethane and the organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to give the title compound in 41% yield 21.8 mg.1H NMR(400MHz，CDCl3)δ：2.18(s，3H)，3.91(m，2H)，3.99(s，3H)，4.12(m，2H)，4.84(m，1H)，6.63(m，2H)，6.91(m，3H)，7.50(dd，1H)，8.10(d，1H)；LRMS ESI m/z 356[M+H]+
Examples 2 to 31
The following compounds of the general formula shown below were prepared using the same method as described in example 1 using the products of preparation 4 (examples 2-14) or preparation 6 (15-31) and commercial phenols or compounds known in the literature as outlined below.
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 2 | 3-OCH | H | δ：2.18(s，3H)，3.76(s，3H)，3.91(m，2H)，3.99(s，3H)，4.18(m，2H)，4.88(m，1H)，6.23(m，2H)，6.52(dd，1H)，6.88(d，1H)，7.16(m，1H)，7.54(dd，1H)，8.13(d，1H)；ESI m/z 367[M+H] | 27％ |
| 3 | 2-CH、4-CN | H | δ：1.77(s，3H)，2.10(s，3H)，3.96(m，2H)，4.00(s，3H)，4.16(m，2H)，4.95(m，1H)，6.40(d，1H)，6.90(m，1H)，7.39(m，2H)，7.48(dd，1H)，8.12(d，1H)；ESI m/z 376[M+H] | 40％ |
| 4 | 2-CH、4-F | H | δ：2.17(s，3H)，2.20(s，3H)，3.92(m，2H)，3.99(s，3H)，4.08(m，2H)，4.83(m，1H)，6.30(d，1H)，6.74(m，1H)，6.85(dd，1H)，6.89(d，1H)，7.49(dd，1H)，8.12(d，1H)；ESI m/z 370[M+H] | 45％ |
| 5 | 4-CH | H | δ：2.18(s，3H)，2.24(s，3H)，3.93(m，2H)，4.00(s，3H)，4.11(m，2H)，4.86(m，1H)，6.58(d，2H)，6.89(d，1H)，7.03(d，2H)，7.50(dd，1H)，8.10(d，1H)；ESI m/z 352[M+H] | 41％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 6 | 2-CH、5-F | H | δ：2.16(s，3H)，2.21(s，3H)，3.95(m，2H)，4.02(s，3H)，4.14(m，2H)，4.84(m，1H)，6.11(d，1H)，6.57(m，1H)，6.90(dd，1H)，7.04(d，1H)，7.49(dd，1H)，8.12(d，1H)；ESI m/z 370[M+H] | 35％ |
| 7 | 4-Cl | H | δ：2.19(s，3H)，3.93(m，2H)，4.00(s，3H)，4.12(m，2H)，4.84(m，1H)，6.60(d，2H)，6.87(d，1H)，7.19(d，2H)，7.48(dd，1H)，8.10(d，1H)；ESIm/z 372[M+H] | 23％ |
| 8 | 3-F | H | ESI m/z 356[M+H] | 35％ |
| 9 | 3-F、5-F | H | ESI m/z 374[M+H] | 10％ |
| 10 | 2-Cl | H | δ：2.20(s，3H)，4.00(m，5H)，4.16(m，2H)，4.94(m，1H)，6.53(d，1H)，6.90(m，2H)，7.14(m，1H)，7.35(d，1H)，7.52(dd，1H)，8.11(d，1H)；ESIm/z 372[M+H] | 32％ |
| 11 | 2-CN | H | ESI m/z 363[M+H] | 31％ |
| 12 | 2-Cl、4-F | H | δ：2.20(s，3H)，4.02(m，5H)，4.14(m，2H)，4.88(m，1H)，6.53(d，1H)，6.88(m，2H)，7.11(m，1H)，7.52(dd，1H)，8.13(d，1H)；ESI m/z 390[M+H] | 20％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 13 | 2-F、6-F | H | ESI m/z 374[M+H] | 27％ |
| 14 | 2-F、4-F | H | ESI m/z 374[M+H] | 54％ |
| 15 | 3-F、4-F | OCH | δ：3.27(s，3H)，3.94(m，2H)，4.01(s，3H)，4.18(m，2H)，4.32(s，2H)，4.85(m，1H)，6.38(m，1H)，6.54(m，1H)，6.85(d，1H)，7.03(m，1H)，7.59(dd，1H)，8.10(d，1H)；LCMS m/z 368[M+H] | 48％ |
| 16 | 3-CH | OCH | δ：2.17(s，3H)，3.30(s，3H)，3.97(m，2H)，4.00(s，3H)，4.18(m，2H)，4.32(s，2H)，4.90(m，1H)，6.45(m，2H)，6.52(dd，1H)，6.78(d，1H)，7.14(m，1H)，7.59(dd，1H)，8.21(d，1H)；ESI m/z 382[M+H] | 53％ |
| 17 | 3-OCH | OCH | δ：3.28(s，3H)，3.76(s，3H)，3.94(m，2H)，3.99(s，3H)，4.16(m，2H)，4.31(s，2H)，4.90(m，1H)，6.23(m，2H)，6.53(dd，1H)，6.85(d，1H)，7.14(m，1H)，7.58(dd，1H)，8.19(d，1H)；ESI m/z 398[M+H] | 54％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 18 | 3-Cl | OCH | δ：3.27(s，3H)，3.95(m，2H)，3.99(s，3H)，4.22(m，2H)，4.31(s，2H)，4.92(m，1H)，6.56(dd，1H)，6.68(m，1H)，6.86(d，1H)，6.95(dd，1H)，7.18(m，1H)，7.64(dd，1H)，8.02(d，1H)；ESIm/z 402[M+H] | 38％ |
| 19 | 3-CF | OCH | δ：3.30(s，3H)，3.97(m，2H)，3.99(s，3H)，4.20(m，2H)，4.32(m，2H)，4.96(m，1H)，6.85(m，2H)，6.94(s，1H)，7.25(m，1H)，7.37(m，1H)，7.60(dd，1H)8.22(d，1H)；ESI m/z 436[M+H] | 57％ |
| 2O | 3-F | OCH | δ：3.32(s，3H)，3.97(m，2H)，4.02(s，3H)，4.18(m，2H)，4.34(m，2H)，4.95(m，1H)，6.42(m，1H)，6.44(m，1H)，6.68(m，1H)，6.86(d，1H)，7.19(m，1H)，7.60(dd，1H)，8.21(d，1H)；ESI m/z 408[M+Na] | 49％ |
| 21 | 4-F | OCH | δ：3.29(s，3H)，3.96(m，2H)，3.99(s，3H)，4.14(m，2H)，4.32(m，2H)，4.86(m，1H)，6.62(m，2H)，6.85(d，1H)，6.92(m，2H)，7.59(dd，1H)，8.19(d，1H)；ESI m/z 386[M+H] | 51％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 22 | 2-Cl | OCH | δ：3.30(s，3H)，3.99(s，3H)，4.05(dd，2H)，4.18(dd，2H)，4.32(s，2H)，4.95(m，1H)，6.52(m，1H)，6.86(d，1H)，6.92(m，1H)，7.15(m，1H)，7.36(dd，1H)，7.60(dd，1H)，8.21(d，1H)；APCIm/z 402/404[M+H] | 48％ |
| 23 | 2-CN | OCH | APCI m/z 393[M+H] | 70％ |
| 24 | 2-F、4-F | OCH | APCI m/z 404[M+H] | 53％ |
| 25 | 2-Cl、4-F | OCH | δ：3.29(s，3H)，3.99(s，3H)，4.05(dd，2H)，4.24(dd，2H)，4.31(s，2H)，4.92(m，1H)，6.50(m，1H)，6.77(m，1H)，6.87(d，1H)，7.12(dd，1H)，7.65(dd，1H)，8.22(d，1H)；APCI m/z 420/422[M+H] | 28％ |
| 26 | 2-F、6-F | OCH | APCI m/z 404[M+H] | 83％ |
| 27 | 2-CH、5-Cl | OCH | δ：2.13(s，3H)，3.29(s，3H)，3.99(dd，2H)，4.00(s，3H)，4.23(dd，2H)，4.31(s，2H)，4.91(m，1H)，6.34(d，1H)，6.84(dd，1H)，6.88(d，1H)，7.03(d，1H)，7.64(d，1H)，8.22(d，1H)；APCI m/z 416/418[M+H] | 57％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of the product |
| 28 | 2-CH、3-CH | OCH | δ：2.10(s，3H)，2.24(s，3H)，3.29(s，3H)，3.99-4.01(m，5H)，4.19(dd，2H)，4.31(s，2H)，4.90(m，1H)，6.23(d，1H)，6.78(d，1H)，6.86(d，1H)，6.96(m，1H)，7.61(dd，1H)，8.20(d，1H)；APCI m/z 396[M+H] | 70％ |
| 29 | 2-CH、6-CH | OCH | δ：2.15(s，6H)，3.29(s，3H)，4.00(s，3H)，4.06(dd，2H)，4.13(dd，2H)，4.31(s，2H)，4.57(m，1H)，6.85-6.92(m，2H)，6.95-6.99(m，2H)，7.63(dd，1H)，8.22(d，1H)；APCI m/z 396[M+H] | 45％ |
| 30 | 2-CHCH | OCH | δ：1.16(t，3H)，2.60(q，2H)，3.29(s，3H)，3.98-4.00(m，5H)，4.22(dd，2H)，4.31(s，2H)，4.95(m，1H)，6.38(d，1H)，6.86(d，1H)，6.90(m，1H)，7.07(m，1H)，7.14(m，1H)，7.63(dd，1H)，8.21(d，1H)；APCI m/z 396[M+H] | 70％ |
| 31 | 2-CH、3-OCH | OCH | APCI m/z 412[M+H] | 76％ |
NMR Spectroscopy at 400MHz in CDCl3Carrying out medium operation; except for example 15 (LCMS)
Example 3: 4-hydroxy-3-methyl-benzonitrile can be exemplified by j.med.chem.; 1999, 42, 3572
Example 31: 3-methoxy-2-methyl-phenol can be prepared as described in J.org.chem., 1990, 55(5), 1466-71
Example 25A (crystallization example 25)
The compound of example 25 was dissolved in hot ethyl acetate and cooled to room temperature with gentle stirring. The crystalline material was isolated by filtration.
Single crystal X-ray diffraction experiments
The crystal structure was determined by single crystal X-ray diffraction at room temperature and ambient relative humidity using a Bruker SMART APEX single crystal X-ray diffractometer and MoK α radiation. The intensity of exposures from multiple series were integrated (SMART V5.622 (control) and SAINT V6.02 (integrated) software, Bruker AXS inc., Madison, WI 1994), with each exposure covering 0.3 ° in ω, exposure time 30 seconds and total dataset greater than spherical. The absorbed data was corrected using a multiple scan method (SADABS, program for scaling and correcting the area detector data, g.m. sheldrag, University of gottingen, 1997 (methods based on r.h. blanking, Acta cryst.1995, a51, 33-38)).
Crystal Structure the space group P was directly mapped to the space group P using SHELXS-97(SHELXS-97, a program for crystal structure resolution, G.M. SHELdrick, University of Gottingen, Germany, 1997, 97-2)1Was successfully resolved and improved to a final improved R-coefficient of 5.16% (I > 3 σ 1) using SHELXL-97(SHELXL-97, program for crystal structure improvement, g.m. sheldrick, University of Gottingen, Germany, 1997, 97-2) with a least squares approach.
Powder X-ray diffraction
X-ray diffraction data were collected at room temperature using a Bruker AXS D4 powder X-ray diffractometer (Cu ka radiation) equipped with an automatic sample changer, a theta-theta goniometer, an automatic beam divergence slit, a secondary monochromator, and a scintillation counter. The powder was mounted on a 12mm diameter silicon wafer sample holder. The sample was rotated while being irradiated with copper K α 1X-ray (wavelength: 1.5406 angstroms) with the X-ray tube operating at 40kV/40 mA. The analysis was performed with a goniometer operating in continuous mode, set to step 5 seconds per 0.02 ° across a 2 θ range of 2 ° to 55 °. The PXRD pattern of example 25A exhibits the following characteristic diffraction peaks.
| 2θ±0.1(/°) |
| 23.7 |
| 24.6 |
| 10.7 |
| 16.2 |
| 14.1 |
| 18.3 |
| 2θ±0.1(/°) |
| 8.5 |
Calculation of powder X-ray diffraction patterns from the Crystal Structure
The 2 theta angle, d-spacing and relative intensity were calculated from the single crystal structure of example 25A using the "reflective powder diffraction" module of Accelrys MS modeling [ version 3.0 ] (Table I).
The relevant simulation parameters are:
wavelength 1.5406 angstrom (Cu K alpha)
Polarization coefficient of 0.5
Pseudo-Voigt profile (U ═ 0.01, V ═ 0.001, W ═ 0.002)
The calculated pattern represents the phase-pure pattern of example 25A, as it originates from a single crystal structure. A comparison of the measured and calculated patterns is shown in figure I and confirms that the host is represented by a single crystal structure. The small difference between the peak intensities may be attributed to the preferred orientation effect in the measured pattern.
Example 32: 1- [ 5-isopropyl-4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl methanesulfonate
The title compound was prepared from the product of preparation 7 and 3-fluorophenol using a method analogous to example 1. After 16 hours (40 hours in comparative example 1), tlc analysis showed the reaction was complete, providing 38% yield of the desired product.
1H NMR(400MHz，CDCl3)δ：1.23(d，6H)，2.67(m，1H)，3.92(m，2H)，4.00(s，3H)，4.12(m，2H)，4.85(m，1H)，6.38(d，1H)，6.44(dd，1H)，6.66(m，1H)，6.91(d，1H)，7.18(m，1H)，7.49(dd，1H)，8.11(d，1H)；LRMS ESI m/z 384[M+H]+
Example 33: 3- {3- [3- (5-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -6-methoxy-2-methylpyridine
Sodium hydride (60% dispersion in mineral oil, 22.4mg, 0.56mmol) was added to a solution of 5-fluorophenol (62.8mg, 0.56mmol) in N, N-dimethylformamide (2mL) and the mixture was stirred at room temperature until foaming ceased. The product of preparation 16 (100mg, 0.28mmol) was then added and the mixture was heated at 100 ℃ for 18 h. Then sodium hydride (60% dispersion in mineral oil, 11.2mg, 0.28mmol) and 5-fluorophenol (31.4mg, 0.28mmol) were added and heating continued for another 24 hours. The cooled reaction mixture was then diluted with water (20mL) and brine (40mL) and extracted with ethyl acetate (2X 30 mL). The combined organic solutions were then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to give the title compound in 27% yield 30 mg.
1H NMR(CDCl3，400MHz)δ：2.15(s，3H)，2.24(s，3H)，3.92(m，2H)，3.98(s，3H)，4.14(m，1H)，4.19(m，1H)，4.90(m，1H)，6.40(m，1H)，6.44(d，1H)，6.70(m，2H)，7.20(m，1H)，7.41(d，1H)；LRMS ESI+m/z 369[M+H]+
Example 34: 3- {3- [3- (4-fluoro-2-methylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -6-methoxy-2-methylpyridine
The title compound was prepared in 34% yield from the product of preparation 16 and 4-fluoro-3-cresol using the same method as described in example 33.
1H NMR(CDCl3，400MHz)δ：2.13(s，3H)，2.18(s，3H)，2.24(s，3H)，3.91(m，1H)，3.96(m，1H)，3.99(s，3H)，4.04(m，1H)，4.14(m，1H)，4.85(m，1H)，6.32(m，1H)，6.75(m，2H)，6.84(m，1H)，7.39(d，1H)；LRMS ESI+m/z 383[M+H]+
Example 35: 5- {3- [3- (3-fluorophenoxy) -3-methylazetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine
A solution of preparation 12 (75mg, 0.2mmol), acethydrazide (44.4mg, 0.6mmol) in ethanol (3mL) was filteredThe molecular sieve was heated at 50 ℃ for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 95: 5) to provide the title compound in 26% yield.
1H NMR(CDCl3，400MHz)δ：1.65(s，3H)，2.21(s，3H)，3.82(d，2H)，4.04(s，3H)，4.18(d，2H)，6.40(m，2H)，6.66(t，1H)，6.92(d，1H)，7.19(m，1H)，7.59(m，1H)，8.16(d，1H)；LRMS ESI+m/z 369[M+H]+
Example 36: 5- [3- [3- (3-fluorophenoxy) -3-methylazetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine
The title compound was prepared in 27% yield from the products of preparations 12 and 5 using the same method as described for example 35.
1H NMR(CDCl3，400MHz)δ：1.63(s，3H)，3.30(s，3H)，3.84(d，2H)，3.99(s，3H)，4.18(d，2H)，4.30(s，2H)，6.38(m，2H)，6.65(t，1H)，6.86(d，1H)，7.17(m，1H)，7.62(m，1H)，8.21(d，1H)；LRMS ESI+m/z 400[M+H]+
Example 37: 5- {3- [4- (3, 4-Difluorophenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine
The product of preparation 21 (67.4mg, 0.23mmol) and 3, 4-difluorophenol (50.85mg, 0.47mmol) were added to a mixture of polymer-supported triphenylphosphine (403mg, 0.61mmol) and di-tert-butyl azodicarboxylate (107mg, 0.47mmol) in dichloromethane (2mL) and the mixture was stirred at room temperature for 4 h. Trifluoroacetic acid (0.78mL) was then added and the mixture was stirred for an additional 1 hour. The reaction mixture was basified with 2M sodium hydroxide solution (5mL) and the organic layer was separated and concentrated in vacuo. Purification by HPLC using a Phenomenex Luna C18 system eluting with water/acetonitrile/trifluoroacetic acid (5: 95: 0.1) to acetonitrile (95: 5 to 5: 95) afforded the title compound as a gum in 32% yield of 29.8 mg.
1H NMR(CDCl3，400MHz)δ：1.69-1.80(m，2H)，1.89-1.95(m，2H)，2.31(s，3H)，3.02-3.12(m，2H)，3.31-3.40(m，2H)，4.01(s，3H)，4.30-4.80(m，1H)，6.52-6.60(m，1H)，6.64-6.70(m，1H)，6.80(d，1H)，6.98-7.02(m，1H)，7.56(dd，1H)，8.08(s，1H)；LRMS ESIm/z 402[M+H]+
Examples 38 to 53
The following compounds of the general formula shown below were prepared from the product of preparation 21 (examples 38-45) and the product of preparation 42 (examples 39-53) and the appropriate commercial phenols or phenols known in the literature as outlined below using the same method as described in example 37.
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of |
| 38 | 2-CH、6-CH | H | δ：1.69-1.80(m，2H)，1.88-1.97(m，2H)，2.03(s，6H)，2.09(s，3H)，2.85-2.96(m，2H)，3.38-3.45(m，2H)，3.82-3.91(m，1H)，4.01(s，3H)，6.87-7.01(m，4H)，7.59(d，1H)，8.18(s，1H)；APCI m/z 394[M+H] | 10％ |
| 39 | 2-CH、3-OCH | H | δ：1.71-1.81(m，2H)，1.86-1.97(m，2H)，2.07(s，3H)，2.25(s，3H)，3.00-3.10(m，2H)，3.00-3.39(m，2H)，3.80(s，3H)，4.00(s，3H)，4.36-4.42(m，1H)，6.46-6.51(m，2H)，6.90(d，1H)，7.01-7.10(m，1H)，7.59(dd，1H)，8.16(m，1H)；APCI m/z 410[M+H] | 36％ |
| 40 | H | H | δ：1.68-1.76(m，2H)，1.89-1.96(m，2H)，2.25(s，3H)，2.97-3.03(m，2H)，3.30-3.36(m，2H)，3.99(s，3H)，4.37-4.42(m，1H)，6.85-6.94(m，4H)，7.22-7.27(m，2H)，7.54(dd，1H)，8.12(m，1H)；APCIm/z 366[M+H] | 22％ |
| 41 | 2-F、3-F | H | APCI m/z 402[M+H] | 19％ |
| 42 | 3-F、5-F | H | HRMS m/z Experimental value 402.1736; cHFNORequires 402.1726[ M + H] | 7％ |
| 43 | 2-CH、4-F | H | HRMS m/z Experimental value 398.1967; cHFNORequires 398.1987[ M + H] | 18％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of |
| 44 | 2CH、5-CN | H | HRMS m/z Experimental value 405.2034; cHNORequires 405.2017[ M + H] | 15％ |
| 45 | 2CH、3-F | H | HRMS m/z Experimental value 398.1974; cHFNORequires 398.1987[ M + H] | 14％ |
| 46 | 2-CH、5-CN | OCH | ESI m/z 435[M+H] | 5％ |
| 47 | 2-CH、5-F | OCH | ESI m/z 428[M+H] | 7％ |
| 48 | 2-CH、3-F | OCH | ESI m/z 428[M+H] | 5％ |
| 49 | 2-CH、4-F | OCH | ESI m/z 428[M+H] | 13％ |
| 50 | 2-CH、5-OCH | OCH | ESI m/z 439[M+H] | 7％ |
| 51 | 2-CH、4-CN | OCH3 | ESI m/z 435[M+H] | 7％ |
| 52 | 3-F、5-F | OCH | ESI m/z 432[M+H] | 12％ |
| Numbering | X′ | R | Data (LRMS and/orH NMR) | Yield of |
| 53 | 3-F、4-F | OCH | δ：1.71-1.81(m，2H)，1.90-1.99(m，2H)，3.14-3.22(m，2H)，3.31(s，3H)，3.39-3.48(m，2H)，4.00(s，3H)，4.30-4.39(m，3H)，6.58(m，1H)，6.63-6.69(m，1H)，6.80(d，1H)，7.00-7.09(m，1H)，7.77(dd，1H)，8.29(m，1H)；ESI m/z 432[M+H] | 21％ |
NMR Spectroscopy at 400MHz in CDCl3Carrying out medium operation; examples 42-45(HRMS) except
Example 40: use of diisopropyl azodicarboxylate instead of di-tert-butyl azodicarboxylate
Example 43: the crude product was purified by HPLC using a Phenomenex Luna C18 system eluted with 0.1% formic acid (aqueous) to 0.1% formic acid/acetonitrile (100: 0 to 2: 98)
Example 44: 3-hydroxy-4-methyl-benzonitrile can be prepared as described in WO 96/24609, page 20
Example 45: 3-fluoro-2-methyl-phenol can be prepared as described on page 32 of EP 511036
Examples 46 to 52: the crude compound was purified by HPLC using a Phenomenex Luna C18 system eluted with 0.1% formic acid (aqueous) to 0.1% formic acid/acetonitrile (100: 0 to 2: 98)
Example 54: 2-methoxy-5- {3- [4- (2-methoxyphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } pyridine
Diisopropyl azodicarboxylate (176 μ L, 0.69mmol) in tetrahydrofuran (2mL) was added to an ice-cooled mixture of the product of preparation 21 (200mg, 0.69mmol), 2-methoxyphenol (86mg, 0.69mmol), and polymer-supported triphenylphosphine (238mg, 0.83mmol) in tetrahydrofuran (2 mL)/dichloromethane (0.6mL) and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted with dichloromethane, basified with 2M sodium hydroxide solution and passed through a phase separation tube. The organic solution was concentrated in vacuo and the residue was purified by column chromatography on silica eluting with dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5: 0.5). The appropriate eluate was evaporated under reduced pressure and the residue was further purified by HPLC using a Phenomenex Luna C18 system eluting with water/acetonitrile/trifluoroacetic acid (5: 95: 0.1) to acetonitrile (95: 5 to 5: 95). The appropriate fractions were evaporated under reduced pressure and the residue was washed with sodium bicarbonate solution and extracted with dichloromethane. The organic solution was then dried over sodium sulfate and concentrated in vacuo to give an oil. The oil was triturated to give the title compound as a solid in 21% yield 58 mg.
1H NMR(CDCl3，400MHz)δ：1.70-1.79(m，2H)，1.90-1.97(m，2H)，2.25(s，3H)，2.94-3.00(m，2H)，3.34-3.40(m，2H)，3.82(s，3H)，4.00(s，3H)，4.29-4.35(m，1H)，6.82-6.96(m，5H)，7.55(dd，1H)，8.12(m，1H)；LRMS APCI m/z 396[M+H]+
Example 55: 3- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -2-methylpyridine
Potassium tert-butoxide (31mg, 0.28mmol) was added to a solution of preparation 24 (90.1mg, 0.25mmol) in tetrahydrofuran (3mL) and the reaction was stirred at room temperature for 30 min. Methyl p-toluenesulfonate (51.4mg, 0.28mmol) was then added and the mixture was stirred for 3 hours. The reaction mixture was then concentrated in vacuo and redissolved in dichloromethane. The organic solution was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was redissolved in tetrahydrofuran (3mL) and trifluoroacetic acid (one drop) and acetohydrazide (42mg, 0.56mmol) were added and the mixture was heated at reflux for 4 hours. The reaction mixture was then concentrated in vacuo and redissolved in dichloromethane. The organic solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to afford an oil. The oil was purified by column chromatography on silica gel eluting with methylene chloride: methanol (90: 10) to provide 46.5mg of the title compound as a red oil in 52% yield.
1H NMR(DMSO-d6，400MHz)δ：1.69-1.81(m，2H)，1.90-2.02(m，2H)，2.25(s，3H)，2.50(s，3H)，3.00-3.10(m，2H)，3.30-3.39(m，2H)，4.00(s，3H)，4.40(m，1H)，6.90(d，1H)，7.12(m，2H)，7.55(d，1H)，8.10(m，1H)，8.15(m，1H)；LRMS APCI m/z 381[M+H]+
Examples 56 to 63
The following compounds of the general formula shown below were prepared using the same method as that described in example 55. The products of preparations 37, 47 and 51 were treated with acethydrazide to afford examples 56 to 58. Likewise, the products of preparations 35, 37, 47, 48 and 51 were treated with 2-methoxyacetohydrazide (preparation 5) to afford examples 59 to 63.
NMR Spectroscopy at 400MHz in CDCl3Or DMSO-d6(examples 56 and 60)
Example 58: after heating at reflux for 2 hours, the other trifluoroacetic acid (few drops) and 2.0eq acethydrazide.
Example 63: after heating at reflux for 2 hours, the other trifluoroacetic acid (few drops) and 2.0eq 2-methoxyacetohydrazide (preparation 5).
Examples 64 to 72
The following compounds of the general formula shown below were prepared using the same method as described in example 4. The products of preparations 38, 39, 41, 58 and 61 were treated with acethydrazide to afford examples 64 to 68. Likewise, the products of preparations 38, 41, 58 and 61 were treated with 2-methoxyacethydrazide (preparation 5) to afford examples 69 to 72.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Example 73: n- {1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } -N-methylpyrimidin-2-amine
A mixture of preparation 57 (101mg, 0.33mmol), 2-chloropyrimidine (46mg, 0.40mmol) and N, N-diisopropylethylamine (87. mu.L, 0.5mmol) in dimethylsulfoxide (2mL) was heated at 100 ℃ for 2 hours. Additional 2-chloropyrimidine (46mg, 0.4mmol) and N, N-diisopropylethylamine (87. mu.L, 0.5mmol) were added and heating continued at 100 ℃ for 4 hours and at 120 ℃ for 12 hours. The reaction mixture was then partitioned between dichloromethane and water and the organic layer was separated and washed with 10% citric acid (2 × 5 mL). The aqueous solution was basified with sodium bicarbonate solution and extracted with dichloromethane (3 × 10 mL). The combined organic solutions were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1 to 95: 5: 0.5) to provide the title compound as a foam in 56% yield 70 mg.
LRMS APCI 381[M+H]+
Examples 74 to 108
The following compounds of the general formula shown below were prepared using the same procedure as described in example 1 using the product of preparation 4 (examples 74-91) or preparation 6 (examples 92-108) and 3 to 5 equivalents of a commercially available phenol or a compound known in the literature as outlined below.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Example 84: 3-methoxy-2-methyl-phenol can be prepared as described in J.Med.chem.1990, 33, 614
Examples 95 to 98: grinding the crude compound with diethyl ether
Example 106: 1, 5-dimethyl-1H-pyrazol-3-ol can be prepared as described in Tetrahedron, 1998, 54, 9393
Example 109: 4- ({1- [4- (6-methoxy-2-methylpyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] azetidin-3-yl } oxy) -3-methylbenzonitrile
The title compound was prepared as a light brown solid in 51% yield from the products of preparations 16 and 70 using the same method as described in example 1.
1H NMR(400MHz，CDCl3)δ：2.12(s，3H)，2.18(s，3H)，2.23(s，3H)，3.88(s，1H)，3.95(s，4H)，4.06(s，4.15(s，1H)，4.93(s，1H)，6.41(d，1H)，6.69(d，1H)，7.37(d，1H)，7.40(m，2H)
Example 110: 2-methoxy-5- [ 3-methyl-5- (3-phenoxyazetidin-1-yl) -4H-1, 2, 4-triazol-4-yl ] pyridine
The title compound was prepared in 89% yield from the product of preparation 65 and acethydrazide using the same method as described for preparation 4.
LRMS ESI m/z 358[M+H]+
Example 111: [5- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] methanol
A mixture of preparation 81 (300mg, 0.8mmol) and preparation 80 (360mg, 4mmol) in butanol (5mL) was heated at reflux for 18 h. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue purified by HPLC using a Phenomenex Luna C18 system eluting with water/acetonitrile/trifluoroacetic acid (5: 95: 0.1) acetonitrile (95: 5 to 5: 95) to afford the title compound as a clear oil in 6% yield.
LRMS ESI m/z 406[M+H]+
Example 112: 5- [3- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine
Potassium tert-butoxide (4g, 35.42mmol) was added portionwise to an ice-cooled solution of preparation 80 (10.86g, 29.52mmol) in tetrahydrofuran (100mL) and the reaction was stirred at room temperature for 20 minutes. Methyl p-toluenesulfonate (51.4mg, 0.28mmol) was then added and the mixture was stirred for 40 minutes. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate (150mL) and water (50 mL). The organic layer was separated and washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was redissolved in tetrahydrofuran (75mL) and trifluoroacetic acid (1.2mL), 2-methoxyacetohydrazide (preparation 5, 6.15g, 59.04mmol) was added and the mixture was heated at reflux for 90 min. The reaction mixture was then concentrated in vacuo and redissolved in ethyl acetate. The organic solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give an oil. The oil was then triturated with ether to give the title compound as a solid in 52% yield 6.5 g.
1H NMR(400MHz，CDCl3)δ：3.29(s，3H)，3.99(s，3H)，4.05(dd，2H)，4.18(m，2H)，4.31(s，2H)，4.92(m，1H)，6.50(m，1H)，6.85(m，2H)，7.15(dd，1H)，7.61(dd，1H)，8.22(d，1H)；LRMS APCIm/z 420/422[M+H]+
Examples 113 to 124
A mixture of the appropriate phenol (commercially available, (1eq) unless specified below), cesium carbonate (4eq) and the product of preparation 4 (1eq) or the product of preparation 6 (1eq) in acetonitrile (2mL) under a nitrogen atmosphere was heated at reflux for 24 hours. The crude mixture was then partitioned between dichloromethane and water and passed through a phase separation tube. The organic solution was concentrated in vacuo and the residue was purified by HPLC using a Phenomenex Luna C18 system eluting with water/0.1% formic acid: acetonitrile/0.1% formic acid (95: 5 to 5: 95) to provide the title compound.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Example 120: 3, 5-difluoro-2-methylphenol is prepared as described in preparation 68
Example 121: 2-chloro-3-hydroxybenzonitrile was prepared as described in preparation 72
Example 122: 3-chloro-4-hydroxybenzonitrile was prepared as described in preparation 71
Example 123: 3-fluoro-2- (trifluoromethyl) phenol was prepared as described in preparation 73
Example 125: 1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] azetidin-3-ol
A mixture of preparation 82 (135mg, 0.52mmol) and 3, 4, 5-trichloropyridine (94mg, 0.52mmol) in dimethylsulfoxide (5mL) was stirred at room temperature for 24 hours. The reaction mixture was then partitioned between dichloromethane and water and the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to provide the title compound as a crystalline solid in 43% yield of 90 mg.
1H NMR(400MHz，CDCl3)5：2.21(s，3H)，4.00(s，3H)，4.07(m，2H)，4.14(m，2H)，4.96(m，1H)，6.88(d，1H)，7.50(dd，1H)，8.10(d，1H)；LRMS ESI m/z 409[M+H]+
Examples 126 to 128
The following compounds of the general formula shown below were prepared using the same procedure as described in example 125, using the product of preparation 82 and a commercially available phenol or a compound known in the literature as outlined below.
Example 127: the crude compound was triturated with diethyl ether twice
Examples 129 to 138
The following compounds of the general formula shown below were prepared from the product of preparation 21 (example 129-133) and the product of preparation 42 (example 134-138) and 1 to 2 equivalents of the appropriate commercial phenol (or phenol known in the literature as outlined below) using the same procedure as described in example 37.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Example 129: 3-hydroxy-2-methylbenzonitrile was prepared as described in preparation 74
Example 131: 3-hydroxy-2-methylbenzamide was prepared as described in preparation 75
Examples 132 and 135: 3-hydroxy-N, N, 2-trimethylbenzamide prepared as described in preparation 76
Example 133: 2- (methoxymethyl) phenol was prepared as described in preparation 77
Example 136: 2- (dimethylamino) -4-methyl-5-pyrimidineol is prepared as described in EP 138464, page 22
Example 139: 5- {3- [ (3S) -3- (2-chlorophenoxy) pyrrolidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine
A mixture of preparation 110 (200mg, 0.73mmol), 2-chlorophenol (112mg, 0.87mmol), di-tert-butyl azodicarboxylate (235mg, 1.02mmol) and polymer-supported triphenylphosphine (610mg, 1.83mmol) in dichloromethane (10mL) was stirred at room temperature for 18 h. The reaction mixture was then filtered, concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 92: 8) to provide the title compound as a glass in 74% yield 209 mg.
1H NMR(400MHz，CDCl3)δ：2.10(m，5H)3.20(m，1H)，3.40(m，1H)，3.50(m，2H)，4.00(s，3H)，4.80(m，1H)，6.80(m，3H)，7.15(m，1H)，7.30(d，1H)，7.50(d，1H)，8.10(s，1H)；LRMS APCIm/z 386[M+H]+
Example 140: 2-methoxy-5- { 3-methyl-5- [ (3S) -3- (2-methylphenoxy) pyrrolidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine
The title compound was prepared from the product of preparation 110 and 2-cresol using the same method as described for example 139. The crude compound was purified by HPLC using a Phenomenex Luna C18 system eluted with water/acetonitrile/trifluoroacetic acid (5: 95: 0.1) to acetonitrile (95: 5 to 5: 95) to provide the desired product in 31% yield.
LRMS APCI m/z 367[M+H]+
Example 141: 3- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) phthalonitrile
Potassium tert-butoxide (42mg, 0.57mmol) was added to a solution of preparation 21's product (150mg, 0.52mmol) in tetrahydrofuran (5mL) and the mixture was stirred at room temperature for 30 min. 3-fluorobenzonitrile (76mg, 0.52mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to provide the title compound as a solid in 37% yield of 79 mg.
1H NMR(400MHz，CDCl3)δ：1.80(m，2H)2.10(m，2H)，2.25(s，3H)，3.10(m，2H)，3.40(m，2H)，4.00(s，3H)，4.60(m，1H)，6.95(d，1H)，7.20(m，1H)，7.35(d，1H)，7.60(m，2H)，8.15(s，1H)；LRMS APCI m/z 416[M+H]+
Example 142: 3- ({1- [5- (methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) phthalonitrile
The title compound was prepared as an oil in 31% yield from the product of preparation 42 and 3-fluorobenzonitrile using the same method as described in example 141.
LRMS APCI m/z 446[M+H]+
Example 143: 6- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -1-methylpyridin-2 (1H) -one
The title compound was prepared as a solid in 76% yield by successive treatment of preparation 116 with potassium tert-butoxide and acetohydrazide using the same procedure as described for example 55.
LRMS APCI m/z 397[M+H]+
Example 144: 6- ({1- [5- (methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -1-methylpyridin-2 (1H) -one
The title compound was prepared in 62% yield as a solid by successive treatment of preparation 116 with potassium tert-butoxide and 2-methoxyacetohydrazide (preparation 5) using the same procedure as described for example 55.
LRMS APCI m/z 427[M+H]+
Examples 145 to 157
The following compounds of the general formula shown below were prepared using the same method as described for preparation 4. The products of preparation 103-109 were treated with acethydrazide to provide examples 145-150 and 2-methoxyacethydrazide (preparation 5) to provide examples 151-157.
NMR Spectroscopy at 400MHz in CDCl3Middle run
Examples 158 to 159
The following compounds of the general formula shown below were prepared using the same method as that described in example 55. The product of preparation 101 was treated continuously with potassium tert-butoxide and acetohydrazide to provide example 158 or with potassium tert-butoxide and 2-methoxyacetohydrazide (preparation 5) to provide example 159. The crude compound was triturated with ether to afford the desired product.
Example 160: 5- [3- [ (3S) -3- (2-chlorophenoxy) pyrrolidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine
5-isothiocyanato-2-methoxypyridine [ (306mg, 1.84mmol), J.org.chem. (1980), 45, 4219] was added to a solution of preparation 91's product (387mg, 1.95mmol) and N, N-diisopropylethylamine (0.32mL, 1.84mmol) in dichloromethane (5mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (5mL), saturated citric acid solution (5mL) and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. Potassium tert-butoxide (217mg, 1.93mmol) was added to a solution of the residue in tetrahydrofuran (6mL) and the reaction was stirred at room temperature for 15 minutes. Methyl p-toluenesulfonate (360mg, 1.93mmol) was then added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane. The organic solution was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was redissolved in tetrahydrofuran (10mL), trifluoroacetic acid (67 μ L) and 2-methoxyacetohydrazide (183mg, 1.76mmol) were added and the mixture was heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate and water. The organic solution was separated, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene chloride: methanol (100: 0 to 95: 5) to give the title compound in 25% yield of 191 mg.
1H NMR(400MHz，CDCl3)δ：2.00-2.10(m，2H)，3.20-3.60(m，7H)，3.98(s，3H)，4.25(s，2H)，4.85-4.90(m，1H)，6.78-6.90(m，3H)，7.10-7.18(m，1H)，7.30-7.35(d，1H)，7.55-7.60(d，1H)，8.20(s，1H)；APCI m/z 416[M+H]+
Example 161: 2-methoxy-5- {3- (methoxymethyl) -5- [ (3S) -3- (2-methylphenoxy) pyrrolidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine
The title compound was prepared in 52% yield as a foam from the product of preparation 92, 5-isothiocyanato-2-methoxypyridine (j. org. chem. (1980), 45, 4219) and 2-methoxyacethydrazide (preparation 5) using the same method as the one described for example 160.
LRMS APCI m/z 396[M+H]+
Example 162: 5- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -4-methylpyrimidine
The title compound was prepared in 41% yield from the product of preparation 21 and 4-methylpyrimidin-5-ol [ chem.heterocyclic.comp. (engl.trans), 1989, 25, 530] using the same method as described for example 37.
LRMS APCI m/z 382[M+H]+
Example 163: 5- ({1- [5- (methoxymethyl) -4- (6-methoxypyridin-3-yl) -4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -4-methylpyrimidine
The title compound was prepared in 24% yield from the product of preparation 42 and 4-methylpyrimidin-5-ol [ chem.heterocyclic.comp. (engl.trans), 1989, 25, 530] using the same method as described for example 37.
1H NMR(400MHz，CDCl3)δ：1.78-1.90(m，2H)，1.95-2.10(m，2H)，2.45(s，3H)，3.12-3.25(m，2H)，3.32(s，3H)，3.38-3.50(m，2H)，4.00(s，3H)，4.35(s，2H)，4.50-4.62(m，1H)，6.88-6.92(d，1H)，7.70-7.76(d，1H)，8.18(s，1H)，8.25-8.30(s，1H)，8.70(s，1H)；LRMS APCI m/z 412[M+H]+
Example 164: 5- {3- [4- (3, 5-difluoro-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine
The title compound was prepared in 48% yield from the products of preparations 21 and 68 using the same method as described for example 37.
1H NMR(400MHz，CDCl3)δ：1.70-1.85(m，2H)，1.90-2.00(m，2H)，2.05(s，3H)，2.25(s，3H)，3.00-3.08(m，2H)，3.28-3.38(m，2H)，4.00(s，3H)，4.35-4.40(m，1H)，6.30-6.42(m，2H)，6.88-6.92(d，1H)，7.50-7.55(d，1H)，8.12(s，1H)；LRMS APCI m/z 416[M+H]+
Example 165: 5- [3- [4- (3, 5-difluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine
The title compound was prepared in 32% yield from the products of preparations 42 and 68 using the same method as described for example 37.
1H NMR(400MHz，CDCl3)δ：1.72-1.85(m，2H)，1.90-2.00(m，2H)，2.05(s，3H)，3.05-3.12(m，2H)，3.30-3.40(m，5H)，4.00(s，3H)，4.35(s，2H)，4.38-4.42(m，1H)，6.30-6.42(m，2H)，6.87(d，1H)，7.67(d，1H)，8.25(s，1H)；LRMS APCI m/z 446[M+H]+
Examples 166 to 171
The following compounds of the general formula shown below were prepared using the same method as that described in example 139, using the product of preparation 117 and a commercially available phenol.
Example 172: 4-chloro-6- {1- [ 5-methoxymethyl-4- (6-methoxy-pyridin-3-yl) -4H- [1, 2, 4] triazol-3-yl ] -azetidin-3-yloxy } -5-methyl-pyrimidine
The title compound was prepared in 100% yield from the product of preparation 118 and 4, 6-dichloro-5-methylpyrimidine using the same method as described for example 55.
LRMS APCI m/z 418[M+H]+
Examples 173 to 177
The following compounds of the general formula shown below were prepared using the same method as described in example 139, using the product of preparation 110 and a commercially available phenol.
Example 178: 5- {3- [3- (2-chloro-4-fluoro-phenoxy) -azetidin-1-yl ] -5-methoxymethyl- [1, 2, 4] triazol-4-yl } -pyridin-2-ol
Trimethyliodosilane (86 μ L, 0.29mmol) was added to a solution of the product of example 25 (100mg, 0.24mmol) in acetonitrile (5mL) at room temperature. The reaction mixture was then heated at 70 ℃ for 18 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc (20mL) and washed with 2N (aqueous) HCl (10mL) and brine. By reaction with dichloromethane: methanol (100: 0 to 95: 5) followed by pure MeOH followed by dichloromethane: methanol: NH3(100: 10: 1) the residue was purified by column chromatography on silica gel to give the title compound in 15% yield 15 mg.
1H NMR(400MHz，CDCl3)δ：3.35(s，3H)，4.10-4.20(m，2H)，4.30-4.40(m，4H)，4.95-5.00(m，1H)，6.50-6.60(m，1H)，6.70-6.75(m，1H)，6.85-6.95(m，1H)，7.10-7.20(m，1H)，7.50-7.55(m，1H)，7.65-7.80(m，1H)，8.10-8.15(s，1H)；APCI m/z 406[M+H]+
[ brief description of drawings ]
Figure 1 shows a comparison of measured and calculated powder X-ray diffraction patterns for a compound according to example 25A of the present invention.
Claims (25)
1. A compound of formula (I):
wherein:
m is 1 or 2 and n is 1 or 2;
x is selected from O, NH and N (C)1-C6) An alkyl group;
R1selected from:
(i) a phenyl ring or a naphthyl ring;
(ii) 5-to 6-membered aromatic heterocycles containing 1 to 3N heteroatoms and N-oxides thereof;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、NH(C1-C6) Alkyl, N ((C)1-C6) Alkyl radical)2、CO(C1-C6) Alkyl, C (O) NH (C)1-C6) Alkyl, C (O) N ((C)1-C6) Alkyl radical)2And C (O) NH2；
R2Selected from:
(i) h and hydroxy;
(ii)(C1-C6) Alkyl optionally substituted by O (C)1-C6) Alkyl or phenyl substitution;
(iii)O(C1-C6) Alkyl optionally substituted by O (C)1-C6) Alkyl substitution; and
(iv) a 5-to 7-membered N-linked heteroaromatic ring containing 1 to 3N atoms, which ring is optionally substituted by one or more groups selected from CN, halogen and (C)1-C6) Radical substitution of alkyl;
R3selected from H, (C)1-C6) Alkyl and (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
R4is H or (C)1-C6) An alkyl group;
R5selected from H, hydroxy, (C)1-C6) Alkyl and O (C)1-C6) An alkyl group;
R6and R7Are all H; while
R8Is H or (C)1-C6) An alkyl group;
a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
2. The compound of claim 1, wherein m and n are both 1, or m and n are both 2, or m is 1 and n is 2.
3. The compound of claim 1, wherein X is O or NCH3。
4. A compound of claim 1, wherein R1Selected from:
(i) a phenyl ring; and
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2。
5. A compound of claim 4, wherein R1Selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、N((C1-C6) Alkyl radical)2、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2。
6. A compound of claim 5, wherein R1Selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyrazolyl, each of which is optionally substituted with one to three substituents independently selected from chloro, fluoro, methyl, ethyl, isopropyl, methoxy, cyano, CF3、N(CH3)2、C(O)N(CH3)2And C (O) NH2。
7. A compound of claim 1, wherein R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution;
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution; and
(iv) a 5-to 6-membered N-linked heteroaromatic ring containing 1 to 3 nitrogen atoms.
8. A compound of claim 7, wherein R2Selected from:
(i) h or hydroxy;
(ii)(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution; and
(iii)O(C1-C3) Alkyl optionally substituted by O (C)1-C3) Alkyl substitution.
9. A compound of claim 8, wherein R2Selected from H, hydroxy, methyl, methoxy and ethoxy.
10. A compound of claim 1, wherein R3Is H or (C)1-C3) An alkyl group.
11. The compound of claim 10, wherein R3Is H or CH3。
12. A compound of claim 1, wherein R4Is H or methyl; r5Is hydroxy or methoxy; and R is6And R7Both are H.
13. A compound according to claim 1, which isIn R8Selected from the group consisting of H, methyl, ethyl and isopropyl.
14. The compound of claim 13, wherein R8Is H or methyl.
15. A compound according to claim 1 selected from:
5- [3- [4- (3-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
2-methoxy-5- {3- (methoxymethyl) -5- [4- (2-methylphenoxy) piperidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine;
5- [3- [4- (5-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (3-fluoro-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [4- (2-chlorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
3- {3- [3- (4-fluoro-2-methylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -6-methoxy-2-methylpyridine;
5- [3- [4- (4-fluoro-2-methylphenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (4-fluoro-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
2-methoxy-5- { 3-methyl-5- [4- (2-methylphenoxy) piperidin-1-yl ] -4H-1, 2, 4-triazol-4-yl } pyridine;
5- {3- [4- (2-chlorophenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [4- (3, 4-difluorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [3- (2-ethyl-4-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [4- (3, 5-difluorophenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- [3- [3- (2, 3-dimethylphenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- [3- [4- (3, 5-difluorophenoxy) piperidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine;
5- {3- [3- (4-fluoro-2-methylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
5- {3- [3- (2, 3-dimethylphenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
2-methoxy-5- (3- (methoxymethyl) -5- {3- [3- (trifluoromethyl) phenoxy ] azetidin-1-yl } -4H-1, 2, 4-triazol-4-yl) pyridine;
5- {3- [3- (2-chloro-4-fluorophenoxy) azetidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } -2-methoxypyridine;
3- ({1- [4- (6-methoxypyridin-3-yl) -5-methyl-4H-1, 2, 4-triazol-3-yl ] piperidin-4-yl } oxy) -2-methylbenzonitrile;
2-methoxy-5- {3- [4- (3-methoxy-2-methylphenoxy) piperidin-1-yl ] -5-methyl-4H-1, 2, 4-triazol-4-yl } pyridine; and
5- [3- [3- (3-chlorophenoxy) azetidin-1-yl ] -5- (methoxymethyl) -4H-1, 2, 4-triazol-4-yl ] -2-methoxypyridine; a tautomer thereof; and
pharmaceutically acceptable salts of these compounds or tautomers.
16. A compound of formula (I):
wherein:
m is 1 or 2 and n is 1 or 2;
x is selected from O and N (C)1-C6) An alkyl group;
R1is selected from
(i) A phenyl ring; and
(ii) a 5-to 6-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms;
each of which is optionally substituted with one or more substituents independently selected from halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, cyano, CF3、C(O)N((C1-C6) Alkyl radical)2And C (O) NH2；
R2Selected from H, hydroxy, (C)1-C6) Alkyl and O (C)1-C6) An alkyl group;
R3is selected from H and (C)1-C6) An alkyl group;
R4is H or (C)1-C6) An alkyl group;
R5selected from H, hydroxy, (C)1-C6) Alkyl and O (C)1-C6) An alkyl group;
R6and R7Are all H; while
R8Is H or (C)1-C6) An alkyl group;
a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
17. A compound of the formula:
a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
19. A pharmaceutical composition comprising a compound according to claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
20. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, in the manufacture of a medicament for the treatment of a disease or condition in which inhibition of oxytocin is known or may be shown to produce a beneficial effect.
21. The use of claim 20, wherein the disease or condition is selected from the group consisting of sexual dysfunction, male sexual dysfunction, female sexual dysfunction, hypoactive sexual disorder, sexual arousal disorder, orgasm disorder, dyspareunia disorder, premature ejaculation, prenatal labor, complications of labor, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder and neuropsychiatric disorders.
22. The use of claim 21, wherein the disease or condition is selected from the group consisting of sexual arousal disorder, orgasmic disorder, pain disorder during sexual intercourse, and premature ejaculation.
23. Use of a compound according to claim 17 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition in which inhibition of oxytocin is known or may be shown to produce a beneficial effect.
24. The use of claim 23, wherein the disease or condition is selected from the group consisting of sexual dysfunction, male sexual dysfunction, female sexual dysfunction, hypoactive sexual disorder, sexual arousal disorder, orgasm disorder, dyspareunia disorder, premature ejaculation, prenatal labor, complications of labor, appetite and eating disorders, benign prostatic hyperplasia, premature labor, dysmenorrhea, congestive heart failure, arterial hypertension, liver cirrhosis, renal hypertension, ocular hypertension, obsessive-compulsive disorder and neuropsychiatric disorders.
25. The use of claim 24, wherein the disease or condition is selected from the group consisting of sexual arousal disorder, orgasmic disorder, pain disorder during sexual intercourse, and premature ejaculation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0501190.3A GB0501190D0 (en) | 2005-01-20 | 2005-01-20 | Novel pharmaceuticals |
| GB0501190.3 | 2005-01-20 | ||
| PCT/IB2006/000118 WO2006077496A1 (en) | 2005-01-20 | 2006-01-11 | Substituted triazole derivatives as oxytocin antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1113927A1 HK1113927A1 (en) | 2008-10-17 |
| HK1113927B true HK1113927B (en) | 2011-04-29 |
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