CN1835921A - N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors - Google Patents
N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors Download PDFInfo
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- CN1835921A CN1835921A CNA2004800172229A CN200480017222A CN1835921A CN 1835921 A CN1835921 A CN 1835921A CN A2004800172229 A CNA2004800172229 A CN A2004800172229A CN 200480017222 A CN200480017222 A CN 200480017222A CN 1835921 A CN1835921 A CN 1835921A
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to an N- pyrrolidine-3-group- amide derivant which can be used as 5-hydroxytryptamine and noradrenaline reuptake inhibitor, as formula (1) which can be used as drug and/or veterinary drug. Wherein, R[1]is H, C[1-6] is acroleic acid, -C(X)Y, C[3-8] is cycloalkyl, arylamine, het, arylamine-C[1-4] is acroleic acid or het-C[1-4] is acroleic acid, while at least one of cycloalkyl, arylamine or het group is replaced by at least one of C[1-8] acroleic acid, C[1-8] alkoxylation catalyst, OH, halogenated, CF[3], OCF[3], SCF[3], hydroxyl group-C[1-6]acroleic acid, C[1-4]alkoxylation catalyst-C[1-6]acroleic acid and C[1-4]acroleic acid-S-C[1-4]acroleic acid; R[2] is arylamine or foreignarylamine, while each of them is replaced by at least one replace group of C[1-8]acroleic acid , C[1-8] alkoxylation catalyst , OH, halogenated , CF[3], OCF[3] SCF[3], hydroxyl group -C[1-6] acroleic acid , C[1-4] alkoxylation catalyst -C[1-6] acroleic acid and C[1-4] acroleic acid -S-C[1-4] acroleic acid; R[3] is C[1-6] acroleic acid , C[3-8] cycloalkyl , C[3-8] cycloalkyl -C[1-6] acroleic acid, arylamine , het, arylamine-C[1-4] acroleic acid or het-C[1-4] acroleic acid, wherein, cycloalkyl, arylamine, or het group is replaced by the replace group of at least one of C[1-6] acroleic acid , C[1-6] alkoxylation catalyst , OH, halogenated , CF[3], OCF[3], SCF[3], hydroxyl group -C[1-6] acroleic acid , C[1-4]alkoxylation catalyst -C[1-6]acroleic acid and C[1-4] acroleic acid -S-C[1-4] acroleic acid ; X is S or O; Y is H, C[1-6]acroleic acid , arylamine, het, arylamine -C[1-4] acroleic acid or het-C[1-4] acroleic acid; n is 1 or 2; when n=1, m=0 or 1; when n=2, m=0, * means the chirality center. The invention can be used in wider application as incontinence of urine.
Description
The present invention relates to suppress the new amide compound of monoamine re-uptake, their preparation method, the pharmaceutical composition that contains them and their purposes in medicine.
Compound exhibits of the present invention is as the activity of serotonin and NRI, thereby in various treatments field purposes arranged all.For example, compound of the present invention is used for the treatment of and wherein relates to the disease that monoamine translocator function is regulated, more specifically, treatment wherein relates to the disease of the re-uptake inhibition of serotonin or norepinephrine, especially treatment wherein relates to the disease that serotonin and norepinephrine suppress, for example urinary incontinence simultaneously.
According to first aspect, the invention provides formula (I) compound:
With its medicine and/or veterinary drug (veterinarily) acceptable derivates,
Wherein
R
1Be H, C
1-6Alkyl ,-C (X) Y, C
3-8Cycloalkyl, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl, wherein cycloalkyl, aryl or het group are optional is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
R
2Be aryl or heteroaryl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
R
3Be C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkyl-C
1-6Alkyl, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl, wherein cycloalkyl, aryl or het group are optional is independently selected from C by at least one
1-6Alkyl, C
1-6Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
X is S or O;
Y is H, C
1-6Alkyl, C
1-6Alkoxyl group, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl;
N is 1 or 2, and its prerequisite is when n is 1, and m is 0 or 1 and when n is 2, and m is 0, if wherein m is 0, then * represents chiral centre;
Aryl is phenyl, naphthyl, anthryl or phenanthryl;
Heteroaryl is fragrant 5-or 6-element heterocycle, and it contains at least one N, O or S heteroatoms, optional condensing in aryl;
Het is fragrance or non-fragrant 4-, 5-or 6-element heterocycle, and it contains at least one N, O or S heteroatoms, optional condense in 5-or 6-person's carbocyclic ring or contains at least one N, O or S heteroatomic second 4-, 5-or 6-element heterocycle.
In an embodiment of the present invention, R
1Be H and R
2, R
3With m be as defined above.
In another embodiment of the present invention, m is 0, R
1, R
2And R
3Be as defined above.When m was 0, * represented R or S enantiomorph configuration.Therefore, in another embodiment, m is 0, R
1, R
2And R
3Be as defined above, * represents the S enantiomorph.
In another embodiment, R
1, R
3With m be as defined above, R
2Be phenyl, naphthyl or quinolyl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces; In another embodiment, substituting group can be selected from halo, OH, C
1-4Alkyl, C
1-4Alkoxyl group and CF
3Phenyl, naphthyl or quinolyl can be chosen wantonly by 1,2 or 3 substituting group and replace, and each is independently selected from halo, OH and C
1-4Alkyl.In another embodiment, R
2Be phenyl, be selected from chlorine, fluorine, OH and C by two
1-4The substituting group of alkyl replaces.In another embodiment, R
2It is dichlorophenyl.
In another embodiment, R
1, R
2With m be as defined above, R
3Be C
1-6Alkyl, C
3-8Cycloalkyl or C
3-8Cycloalkyl-C
1-6Alkyl.In another embodiment, R
3Be C
1-6Alkyl, C
3-6Cycloalkyl or C
3-6Cycloalkyl-C
1-4Alkyl.
In another embodiment of the present invention, provide formula II compound:
With its medicine and/or veterinary drug acceptable derivates,
Wherein
R
4Be phenyl, naphthyl or quinolyl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
R
5Be C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkyl-C
1-6Alkyl, aryl or aryl-C
1-4Alkyl, wherein cycloalkyl and aryl are optional is independently selected from C by at least one
1-6Alkyl, C
1-6Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces; With
M is 0 or 1, and wherein when m was 0, then * represented R or S enantiomorph.
In another embodiment, R
5With m be as defined above, R
4Be phenyl, 1-naphthyl or 2-naphthyl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces.Described substituting group can be chosen wantonly and be selected from C
1-6Alkyl, C
1-6Alkoxyl group, OH, halo and CF
3Phenyl or naphthyl can be replaced by 1,2 or 3 substituting group.In an embodiment, phenyl or naphthyl is replaced by two substituting groups.In another embodiment, phenyl or naphthyl is independently selected from chlorine, fluorine, C by two
1-4The substituting group of alkyl and OH replaces.In another embodiment, phenyl or naphthyl is replaced by two cl radicals.
In another embodiment, R
4With m be as defined above, R
5Be C
1-6Alkyl, C
3-6Cycloalkyl or C
3-6Cycloalkyl-C
1-4Alkyl.
In another embodiment, R
4And R
5Be as defined above, m is 0.In this embodiment, * represents R or S enantiomorph.In another embodiment, m be 0 and * represent the S enantiomorph.
In another embodiment, provide the formula III compound
With its medicine and/or veterinary drug acceptable derivates,
Wherein
R
6Be phenyl, naphthyl or quinolyl, each is chosen wantonly and is independently selected from halo, OH, C by at least one
1-6Alkyl, C
1-6Alkoxyl group and CF
3Substituting group replace;
R
7Be C
1-6Alkyl, C
3-6Cycloalkyl, C
3-6Cycloalkyl-C
1-4Alkyl, aryl or aryl-CH
2-, wherein cycloalkyl and aryl are optional is independently selected from halo, OH, C by at least one
1-4Alkyl, C
1-4Alkoxyl group and CF
3Group replace; With
* represent R or S enantiomorph.
In another embodiment, R
7With * be as defined above, R
6Be phenyl, 1-naphthyl or 2-naphthyl, each is chosen wantonly and is independently selected from halo, OH, C by at least one
1-6Alkyl, C
1-6Alkoxyl group and CF
3Substituting group replace; Described substituting group can be chosen wantonly and be selected from chlorine, fluorine, C
1-4Alkyl, OMe and OH.Phenyl and naphthyl can be replaced by 1,2 or 3 substituting group.In another embodiment, phenyl and naphthyl are independently selected from fluorine and cl radical replacement by 1,2 or 3.
In another embodiment, R
6With * be as defined above, R
7Be C
1-6Alkyl, C
3-6Cycloalkyl or C
3-6Cycloalkyl-C
1-4Alkyl.In another embodiment, R
7Be C
1-6Alkyl, optional C
3-6Alkyl.Work as R
7Be C
3-6During alkyl, it can be side chain C
3-6Alkyl.
In another embodiment, R
6And R
7Be as defined above, * represents the S enantiomorph.
In another embodiment, provide formula IV compound:
With its medicine and/or veterinary drug acceptable derivates,
Wherein
R
8Be phenyl, optional by 1-3 halo substituting group replacement;
R
9Be C
1-6Alkyl; With
* represent R or S enantiomorph.
R
8Optional is dichlorophenyl, R
9Be C
3-4Branched-chain alkyl and * represent the S enantiomorph.R
9It can be isobutyl-.
In another embodiment, the invention provides and be selected from following compound:
2,3-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
2,4-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
2-chloro-3-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-fluoro-2-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-methoxyl group-2-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-chloro-N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl] benzamide;
4-chloro-N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3,4-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
N-(2-naphthyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
N-(2-naphthyl methyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide;
The N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl]-the 2-naphthoamide;
The N-butyl-N-[(3S)-tetramethyleneimine-3-yl]-the 1-naphthoamide;
4-chloro-N-(3, the 4-dichloro benzyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide;
4-chloro-N-(2, the 3-dichloro benzyl)-N[(3R)-tetramethyleneimine-3-yl] benzamide;
With its medicine and/or veterinary drug acceptable derivates,
In addition, the unrestricted example of compound within the scope of the invention comprises:
N-tetramethyleneimine-3-base-N-(5,6,7,8-naphthane-1-ylmethyl)-benzamide;
N-(2,4-two chloro-benzyls)-N-tetramethyleneimine-3-base-benzamide;
N-(3-chloro-4-methyl-benzyl)-2-fluoro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-2-carboxylic acid butyl-tetramethyleneimine-3-base-acid amides;
Naphthalene-2-carboxylic acid isobutyl--tetramethyleneimine-3-base-acid amides;
Naphthalene-2-carboxylic acid (2,2-dimethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
3-chloro-N-isobutyl--4-methyl-N-tetramethyleneimine-3-base-benzamide;
N-isobutyl--2,3-dimethyl-N-tetramethyleneimine-3-base-benzamide;
3-chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2-chloro-4-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
2-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-chloro-2-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-chloro-4-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
N-butyl-2,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-methyls-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2-ethyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-isobutyl-s-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid isobutyl--tetramethyleneimine-3-base-acid amides;
2,4-two chloro-5-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(2,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(1,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(1,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclohexyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid sec-butyl-tetramethyleneimine-3-base-acid amides;
N-sec-butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
N-sec-butyl-2,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(1-ethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(1-ethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (1-ethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
2,3-two chloro-N-cyclobutyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclobutyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-tetramethyleneimine-3-base-N-(1,2,2-trimethylammonium-propyl group)-benzamide;
The N-tertiary butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid cyclopentyl-tetramethyleneimine-3-base-acid amides;
2,3-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
3-chloro-N-isobutyl--2-methyl-N-tetramethyleneimine-3-base-benzamide;
N-butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
N-butyl-3,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-2-carboxylic acid cyclobutylmethyl-tetramethyleneimine-3-base-acid amides;
Naphthalene-1-carboxylic acid cyclobutylmethyl-tetramethyleneimine-3-base-acid amides;
3,4-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
4-chloro-N-isobutyl--2-methoxyl group-N-tetramethyleneimine-3-base-benzamide;
4-chloro-N-isobutyl--3-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-isobutyl-s-3-methyl-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (3-methyl-butyl)-tetramethyleneimine-3-base-acid amides;
Naphthalene-1-carboxylic acid (2,2-dimethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
3,4-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(4-fluoro-phenyl)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(4-fluoro-phenyl)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-tetramethyleneimine-3-base-acid amides;
N-butyl-2,3,4-three chloro-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
N-tetramethyleneimine-3-base-N-(3-trifluoromethyl-benzyl)-benzamide;
2,4-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-(2,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid phenyl-tetramethyleneimine-3-base-acid amides;
2,3,4-three chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
2-bromo-4-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
4-chloro-2-oxyethyl group-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-bromo-4-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-isobutyl-s-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-3-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3-two chloro-4-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3-two chloro-5-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,4,5-three chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,5-two chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,5-two chloro-4-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3,5-three chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,3-two chloro-6-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
3,4-two chloro-6-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
3,4-two chloro-2-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2-chloro-3,6-two fluoro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,4-two chloro-5-fluoro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
With its medicine and/or veterinary drug acceptable derivates.
Formula (I), (II), (III) or (IV) compound or any (directly or indirectly) formula (I), (II), (III) or (IV) any medicine of other compound of compound or its active metabolite or residue or the salt or solvate of the acceptable salt of veterinary drug, solvate, ester or acid amides or this ester or acid amides of can providing to patient's administration the time are provided for medicine and/or veterinary drug acceptable derivates.
For medicine or veterinary drug purposes, aforesaid salt will be medicine or the acceptable salt of veterinary drug, but other salt can find the purposes in for example preparation formula (I), (II), (III) or compound (IV) and its medicine or veterinary drug acceptable salt.
The acceptable salt of said medicine or veterinary drug comprises its acid salt and alkali salt.
The appropriate acid additive salt is formed by the acid that forms non-toxic salt.Example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, d-camphorsulfonic acid salt, Citrate trianion, ethanedisulphonate, half ethanedisulphonate, esilate, fumarate, gluceptate, gluconate, glucuronate, oxybenzene acyl benzoate, hydrochloride/muriate, Hydrogen bromide/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, saccharate, stearate, succinate, tartrate and mesylate.
Suitable alkali salt is formed by the alkali that forms non-toxic salt.Example comprises ammonium, arginine, benzyl star, calcium, choline, diethylamine, diethanolamine, Padil, Methionin, magnesium, meglumine, thanomin, potassium, sodium, Trometamol and zinc salt.
To the summary of acceptable acid addition salts, referring to " Handbook of Pharmaceutical Salts:Properties, Selection, and Use ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Formula (I), (II), (III) or pharmacologically acceptable salt (IV) can be easily by the solution of the described compound of mixing and required as required acid or alkali preparations.Described salt can maybe can be reclaimed by evaporating solvent by filtering to collect by solution precipitation.Can change to almost nonionicization by complete ionization in salt intermediate ion degree.
Pharmaceutically useful solvate of the present invention comprises formula (I), (II), (III) or (IV) hydrate and the solvate of compound.
Being included in equally in the scope of the invention is title complex, for example clathrate compound, medicine-host's inclusion complex, and wherein opposite with above-mentioned solvate, medicine and host exist with stoichiometry or nonstoichiometry.Comprise equally in the present invention be that to contain can be stoichiometry or non-stoichiometric two or more pharmaceutical complex organic and/or inorganic component.The title complex ionizable, partial ionization or the nonionicization that obtain, to the summary of this title complex, referring to J Pharm Sci,
64(8), 1269-1288, Haleblian (August, 1975).
Formula (I), (II), (III) or (IV) compound can be in any functional group of this compound modification so that medicine or veterinary drug acceptable derivates to be provided.The example of this derivative is at Drugs of Today, Volume19, Number 9,1983, pp 499-538, Topics in Chemistry, Chapter 31, pp 306-316 and " Design of Prodrugs " H.Bundgaard, Elsevier, 1985, describe among the Chapter 1 (its content is incorporated herein by reference), comprising: ester, carbonic ether, half ester, phosphoric acid ester, nitro ester, sulfuric ester, sulfoxide, acid amides, sulphonamide, carbamate, nitrogenous compound, phosphamide, join sugar, ether, acetal and ketal.
What those skilled in the art will be further understood that is, some part that is called " preceding-part " in the prior art, for example as H.Bundgaard " Design of Prodrugs " (ibid) described in, when appropriate functional group is present in the compound of the present invention, can be placed in this functional group.
Because R
1-R
9Some implication (for example sec-butyl) definition unsymmetrical carbon or because the numerical value of integer m, formula (I), (II), (III) or (IV) compound can contain one or more chiral centres, there are many stereoisomeric forms in any ratio (for example a pair of optically active isomer or enantiomeric form) in this compound.All isomer that the present invention comprises The compounds of this invention be should understand, all how much, change and optically-active form and their mixture (for example change or racemic mixture) comprised.
Can there be one or more tautomers in compound of the present invention, and its all tautomers and their mixture are included in the scope of the present invention, and for example claimed 2 hydroxy pyrimidine base has also covered its tautomer α-pyridyl.
Should understand the formula of the present invention includes (I), (II), (III) or radioisotope labeled compound (IV).
Formula (I), (II), (III) or (IV) and its medicine and veterinary drug acceptable derivates also can exist and surpass a kind of crystallized form, a kind of characteristic that is called heteromorphism, all these polycrystalline forms (" polymorphic form ") within the scope of the present invention.Heteromorphism usually can produce in response to temperature or pressure or both changes, also can be produced by the variation of crystallization method.Polymorphic form can be distinguished with different physical features, and X-ray diffractogram, solvability and the fusing point of compound are used to distinguish polymorphic form usually.
Except as otherwise noted, any alkyl can be a straight or branched, is 1-8 carbon atom, for example 1-6 carbon atom or 1-4 carbon atom, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or the tertiary butyl.When alkyl contained above a carbon atom, it can be undersaturated.Therefore, term C
1-6Alkyl comprises C
2-6Thiazolinyl and C
2-6Alkynyl.Equally, term C
1-8Alkyl comprises C
2-8Thiazolinyl and C
2-8Alkynyl, term C
1-4Alkyl comprises C
2-4Thiazolinyl and C
2-4Alkynyl.
Term halogen is used to represent fluorine, chlorine, bromine or iodine.
Except as otherwise noted, term het comprises any fragrance, saturated or undersaturated 4,5 or 6 yuan of heterocycles, and it contains maximum 4 heteroatomss that are selected from N, O and S.The example of this heterocyclic group comprises furyl, thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, dioxolanyl oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyranyl, pyridyl, piperidyl, dioxacyclohexyl, morpholino, the dithia cyclohexyl, thiomorpholine generation, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, the tetramethylene sulfone base, tetrazyl, triazinyl, the azepines base, oxygen azepine heptan is because of base, sulphur azepine heptan is because of base, diaza heptan is because of base and thiazolinyl.In addition, the term heterocycle comprises the annelated heterocycles group, for example benzimidazolyl-, benzoxazolyl, imidazopyridyl, benzoxazinyl, benzothiazine Ji, oxazole and pyridyl, benzofuryl, quinolyl, quinazolyl, quinoxalinyl, dihydroquinazoline base (dihydroquinazdinyl), benzothiazolyl, phthalimido, benzodiazepines base, indyl and pseudoindoyl.Term het, heterocyclic radical and heterocycle should be explained equally.
For avoiding query, except as otherwise noted, being meant by the group of one or more definition that term replaces replaces.Group is optional under the situation of many selectable groups therein, and the group of selection can be identical or different.In addition, term is meant that independently those substituting groups can be identical or different when surpassing a substituting group and be selected from many possible substituting groups.
Hereinafter, formula (I), (II), (III) or (IV) analogue, above-mentioned isomer and the above-mentioned polymorphic form of compound and its medicine and veterinary drug acceptable derivates, above-mentioned labelled with radioisotope all are called " compound of the present invention ".
In one embodiment of the invention, compound of the present invention is formula (I), (II), (III) or (IV) medicine and the veterinary drug acceptable derivates of compound, for example, formula (I), (II), (III) or (IV) medicine of compound or the acceptable salt of veterinary drug or solvate (for example formula (I), (II), (III) or (IV) medicine or the acceptable salt of veterinary drug of compound).
In another embodiment of the invention, it provides compound of the present invention, and it is to have SRI or NRI IC
50The inhibitor that value is taken in for 200nM or following serotonin and/or norepinephrine monoamine again.In another embodiment, compound has 100nM or following SRI and/or NRI IC
50Value.In another embodiment, compound has 50nM or following SRI or NRIIC
50Value.In another embodiment more, compound has 25nM or following SRI and NRI IC
50Value.
According to diagram 1, the formula V compound can by formula (VI) compound by with aldehyde R
3 'The CHO reaction is subsequently with acid or acyl chlorides R
2COX (wherein X is OH or halogen) reaction and the preparation of deprotection base.
Diagram 1
In above-mentioned diagram, R
2With m be as defined above, PG is a blocking group, group-CH
2R
3 'Satisfy R
3Definition.
(a)-reduction amination
It is reduction amination that 1 amine (VI) and aldehyde reaction form 2 amine (VII), wherein after the dehydration of amine and aldehyde by the imines that forms with the metal hydride reagent reduction or in suitable solvent hydrogenation at room temperature carry out.
In this reaction, the amine of equimolar amount and aldehyde are used sodium triacetoxy borohydride (STAB), NaCN (BH) usually
3Or NaBH
4(for example DCM, THF) at room temperature handled 1-24 hour at suitable solvent.Perhaps in amine and aldehyde mixing after 1-18 hour, be added in excessive reductant in the suitable solvent (for example THF, MeOH, EtOH) (NaBH for example
4, LiAlH
4, STAB), choose wantonly in the presence of siccative (for example molecular sieve) or remove with suitable solvent (for example toluene, dimethylbenzene) and anhydrate with the Dean-Stark device.Another kind method is included in palladium or nickel catalyzator (for example Pd/C, RaneyNi) existence is following under hydrogen atmosphere, chooses under high temperature and high pressure catalytic hydrogenation in suitable solvent (for example EtOH) wantonly.
The more specifically example of reduction amination comprises with amine or in the presence of 10%Pd/C, chooses wantonly in the presence of triethylamine and at room temperature handles aldehyde 18 hours or at room temperature handled amine 6 hours in methyl alcohol in the presence of excessive sodium borohydride at about 415kPa (about 60psi) hydrogen in ethanol.
(b)-acid amides formation
The formation of peptide bond can be carried out with the following method between acid or carboxylic acid halides and amine (VII):
(i) carboxylic acid halides and amine (VIII) are used the excess acid accepting agent, in suitable solvent, or
(ii) acid is chosen wantonly and is used conventional coupler, and amine (VII), chooses wantonly in the presence of catalyzer, uses the excess acid accepting agent, in suitable solvent.
The example of this reaction is as follows:
(i) acyl chlorides (optional generation on the spot) and excess amine (VII) are optional with excessive 3 amine, for example Et
3N, Hunig alkali or NMM, in DCM Huo diox, optional at high temperature the reaction 1-24 hour;
(ii) acid, WSCDI/DCCl/TBTU and HOBT/HOAT and excess amine (VII) and excessive NMM, Et
3N, Hunig alkali at room temperature reacted in THF, DCM or EtOAc 4-48 hour; Or
(iii) acid and PYBOP /PyBrOP /Mukaiyama reagent and excess amine (VII) and excessive NMM, Et
3N, Hunig alkali at room temperature reacted in THF, DCM or EtOAc 4-24 hour.
When carboxylic acid halides was acyl chlorides (being X=Cl), it can produce on the spot by standard method, reacted 90 minutes at 70 ℃ in methylene dichloride with amine (VII) and triethylamine subsequently.
(c)-the deprotection base
When PG is suitable amine protecting group group; when preferred BOC, trifluoroacetic acid base or benzyl; remove PG by (VII) and form unprotected amine (V) by the method for blocking group selection is carried out; as " Protective Groups in Organic Synthesis ", the 3rd edition are described in following document; TW Greene andPGM Wuts.John Wiley and Sons; Inc., 1999, classify this paper reference as.
The example of this deprotection reaction is as follows:
When PG was BOC, the deprotection base comprises with excessive strong acid (for example hydrochloric acid, TFA) at room temperature handled (VII) in suitable solvent (for example DCM, EtOAc, diox).
When PG was the trifluoroacetic acid base, the deprotection base comprised with alkali (K for example
2CO
3, Na
2CO
3, NH
3, Ba (OH)
2) in alcoholic solvent (for example MeOH, EtOH), optional water and optional at high temperature handle (VII).
When PG was Bz, the deprotection base comprised or with transition metal or transition metal salt hydrogenation catalyst (for example Pd/C, Pd (OH)
2) at hydrogen donor (NH for example
4 +HCO
2 -) exist down in polar solvent (for example tetrahydrofuran (THF), ethanol, methyl alcohol), choose wantonly and under high temperature and/or high pressure, carry out transfer hydrogenation, perhaps in the presence of palladium or nickel catalyzator (for example Pd/C, Raney Ni) under hydrogen atmosphere, choose under high temperature and high pressure catalytic hydrogenation in suitable solvent wantonly.
More specifically:
When PG was BOC, the deprotection base comprised or with at room temperature handling 18 hours or at room temperature handled in DCM 4.5 hours with TFA in the excessive 4M hydrochloric acid Zai diox.
When PG was the trifluoroacetic acid base, the deprotection base comprises used K
2CO
3At methyl alcohol: water mixture (5: 1-10: at room temperature handled 1) 18 hours.
When PG was Bz, the deprotection base comprises used NH
4 +HCO
2 -Under gentle reflux, handled 6-20 hour in ethanol with 10%Pd/C.
According to diagram 2, formula (IX) compound can by formula (VI) compound by with R
3-L is prepared in reaction under conditions suitable, and wherein L is a leavings group.The formula that obtains (IX) compound subsequently can be by the method described in the diagram 1 forms acid amides and the deprotection base is converted into formula (II) compound to be similar to.
Diagram 2
In above-mentioned diagram, R
2, R
3With m be as defined above, PG is that suitable blocking group and L is leavings group, its implication especially will depend on the character of reaction and the concrete reaction conditions that is adopted.Suitable leavings group is significantly to those of skill in the art, in many standard organic chemistry books, describes, for example: " Advanced Organic Chemistry ", Jerry March, the 3rd edition, Wiley (1985), classifies this paper reference as by the 587th page; They comprise halogen (for example Br) and sulphonate (for example methanesulfonates or triflate).
Easily, R
3Be aryl, L is that Br and reaction (d) are at high temperature carried out in the presence of palladium catalyst in suitable solvent.The catalytic aryl aminating reaction of this palladium is well known by persons skilled in the art.
The more specifically example of diagram 2 methods comprises with formula (IV) amine and closes two palladiums, 2 at three (dibenzalacetones), 2 '-two (diphenylphosphino)-1, and 1 '-dinaphthalene and sodium tert-butoxide exist down handled aryl bromides 18 hours at 100 ℃ in toluene.
According to diagram 3, formula (IX) compound can by the ketone of formula (XII) by with primary amine R
3-NH
2Prepared in reaction under conditions suitable.The formula that obtains (IX) compound subsequently can be by the method described in the diagram 1 forms acid amides and the deprotection base is converted into formula (II) compound to be similar to.
Diagram 3
In such scheme, R
2, R
3With m be as defined above, PG is suitable blocking group.
Primary amine R
3-NH
2With the reaction (e) of ketone (XII) reduction amination suitably, wherein can be after the dehydration of amine and ketone by the imines reduction that will generate, for example with metal hydride reagent or under conditions suitable hydrogenation carry out.
Easily, being reflected among the THF of amine and ketone at room temperature carried out 18 hours in the presence of three titanium isopropylates (IV), and the excessive sodium borohydride that is used in subsequently in the methyl alcohol at room temperature reduced 5 hours.
The person skilled in the art can select required formula (I), (II), (III) or the only synthetic method of compound (IV), and certainly, above-mentioned diagram can improve as required according to those skilled in the art's the common knowledge.
For example, person skilled in the art's hydrogen (according to the numerical value of m) of certainly understanding being connected in the acid amides (II) of deprotection base or piperidines (V) or tetramethyleneimine nitrogen can use usually as required conventional synthetic method with other group replace with form n wherein be 1 and m be 0 or 1 formula (I) compound.
In addition, wherein n be 2 and m be that 0 formula (I) compound can use the suitable feedstock preparation with being similar to above-mentioned method.
To those skilled in the art clearly, one or more responsive functional groups formula (I), (II), (III) or (IV) compound will need protected and the deprotection base in synthetic.This can realize by routine techniques, for example as " Protective Groups in Organic Synthesis ", and the 3rd edition, TW Greene and PGMWuts.John Wiley and Sons, Inc., 1999, classify this paper reference as, it has also described the method for removing this group.
To it will be apparent to one skilled in the art that; the derivative of some protection of the The compounds of this invention for preparing before the final deprotection base stage itself can not have pharmaceutical activity; but in some cases; can oral or administered parenterally, metabolism has the compound of the present invention of pharmaceutical activity with formation in vivo subsequently.Therefore, this derivative can be described as prodrug.In addition, some compound of the present invention can be used as the prodrug of other compound of the present invention.
Therefore, according to a further aspect in the invention, it provides preparation formula (I), (II), (III) or (IV) method of compound, and it comprises makes formula (X) compound:
R wherein
3, n and m be as defined above, Y is R
1Or blocking group, with acid or carboxylic acid halides: R
2COX reaction, wherein X is OH or halogen and deprotection base as required.
Work as R
3When comprising the methylene moiety that is bonded directly to nitrogen-atoms, formula (X) compound can be by making formula (XXI) compound and aldehyde R
3 'CHO (wherein-CH
2R
3 'Satisfy R
3Definition) prepared in reaction.
Use another kind of method, formula (X) compound can be by making formula (XXI) compound and compound R
3-L prepared in reaction, wherein L is a leavings group, is selected from halogenide, methanesulfonates and triflate.
In addition, formula (X) compound can be by making formula (XXII) compound and compound R
3-NH
2Prepared in reaction:
Above-mentioned some intermediate is a new compound, should understand all new intermediates and constitute another aspect of the present invention.
Racemic compound can use preparation HPLC to separate with the post that has chiral stationary phase, or splits to obtain independent enantiomorph with method known to those skilled in the art.In addition, chiral intermediate is detachable and be used to prepare chipal compounds of the present invention.
According to a further aspect in the invention, it provides one or more metabolites that compound of the present invention forms in vivo.
Compound of the present invention can have following advantage, they are more effective, have longer acting duration, have wideer field of activity, be more stable, have less side effect or more selectively or than the compound of prior art have other more useful properties.
Compound of the present invention is useful, has pharmacological activity in the human body because they Mammals, comprise.Therefore they are used for the treatment of or prevent wherein to be used to relate to the disease of monoamine translocator function adjusting, more specifically, treatment wherein relates to the disease of taking in inhibition again of serotonin or norepinephrine, especially treats the disease that wherein relates to serotonin and norepinephrine inhibition.
Therefore, compound of the present invention is used for the treatment of the urinary incontinence, for example real stress incontinence (GSI), stress incontinence (USI) or the old urinary incontinence; Hyperactivity hyperkinesia bladder (OAB), detrusor hyperactivity hyperkinesia that comprises congenital detrusor instability (di), causes because of nervous system disease (for example Parkinson's disease, multiple sclerosis, the damage of vertebra funiculus lateralis and shock) and bladder flow out the detrusor hyperactivity hyperkinesia of blocking (for example benign prostatic hyperplasia (BPH), urethrostenosis or narrow) and causing, night eneuresis, because the urinary incontinence (for example real stress incontinence that is associated with the hyperactivity hyperkinesia bladder) and urinary disorders, for example frequent micturition and the urgent urination that the combination of above-mentioned disease causes.
Because above-mentioned pharmacological activity, compound of the present invention also is used for the treatment of dysthymia disorders, for example major depression, send out dysthymia disorders after dysthymia disorders, single incident dysthymia disorders, inferior syndrome dysthymia disorders, cancer patients's dysthymia disorders, disturbances in patients with Parkinson disease dysthymia disorders, the myocardial infarction, paediatrics dysthymia disorders, the dysthymia disorders that child abuse causes, infertile women's dysthymia disorders, post-natal depression, premenstrual dysphoric and short-tempered old man's syndromes again.
Because above-mentioned pharmacological activity, compound of the present invention also is used for the treatment of cognitive illnesses, for example dull-witted, especially degenerated dementia (comprising senile dementia, presenile dementia, pik disease, Huntington chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (comprising that many infractions are dull-witted) and with head in space hold infringement, wound, infection and relative disease (comprising the HIV infection), metabolism, toxin, the anoxic dementia relevant with the VITAMIN defective; The mild cognitive damage relevant with the age, especially relevant memory impairment (AAMI), amnesia and the cognitive decline (ARCD) of being correlated with the age with the age; Mental disorder, for example schizophrenia and mania; Stress disease after the anxiety disorder, for example generalization anxiety disorder, phobia (for example agoraphobia, social phobia and simple phobias), Phobias, obsessional idea and behavior disease, wound, mix anxiety with depressed; Personality disease, for example avoiding reaction individual character disease and distractibility hyperkinetic syndrome (ADHD); Sexual dysfunction, for example premature ejaculation, male erectile dysfunction (MED) and Female sexual dysfunction (FSD) (for example the women excites disease (FSAD)); Premenstrual syndrome; Seasonal emotion disease (SAD); Eating disorder, for example anorexia nervosa and nervosa bulimia; Fat; Appetite inhibiting; The chemical that is caused by drug addiction or substance abuse relies on the Nicotine of for example wallowing in, alcohol, Cocaine, heroine, sedative hypnotics and benzodiazepines addiction; Disconnected addiction syndromes for example relies on the syndromes that causes by above-mentioned chemical; Headache, for example migraine, string headache, chronic sudden migraine, the headache relevant with vascular disease, with chemical dependence or relevant headache and the tension headache of disconnected addiction syndromes that cause by the chemical dependence; Pain; Parkinson's disease, for example Parkinson's neurological dysfunction and the slow dyskinesia that cause of the dementia in the Parkinson's disease, Antipsychotic drug); Endocrinopathy, for example hyperprolactinemia; Vasospasm is for example in the cerebral blood vessel system; The cerebellum disorder; Tourette syndrome; Dial the hair addiction; Kleptomania; Emotional instability; The pathologic shout; Sleeping eyes disease (for example fainting) and shock.
Because above-mentioned pharmacological activity, compound of the present invention also is used for the treatment of many other illnesss or disease, comprises ypotension; Gastrointestinal tract disease (comprising that mobility and excretory change), irritable bowel syndrome (IBS), intestinal obstruction (intestinal obstruction, gastroparesis (for example diabetic gastroparesis), ulcer of digestive system, the gastro-esophageal reflux disease (GORD when post operative ileus and Sepsis for example for example, or its synonym GERD), flatulence and other functional bowel disease, for example maldigestion (for example non-ulcer maldigestion (NUD)) and non-heart thoracic cavity pain (NCCP) and fibromyalgia syndrome.
Because above-mentioned pharmacological activity, compound of the present invention also can be used for treating pain.For example, pull/sprain pain after the pain that causes, postoperative pain (pain after any kind surgical operation), the wound, burn, myocardial infarction, acute pancreatitis and renal colic.Also usually because treatment interacts the relevant syndromes that has an intense pain of cancer that for example chemotherapy toxicity, immunotherapy, hormonotherapy and radiation treatment produce.Other example comprise the pain (for example skeleton pain, headache and face ache, visceral pain) relevant with tumour or with cancer therapy relevant pain (for example syndromes, chronic postoperative pain syndromes, radiation back syndromes after the chemotherapy), have a back ache, it may be because hernia or disruptive intervertebral disk or central plane joint (lumber facet joint), sacrum osteoarthrosis, vertically ligament is unusual to ridge paraspinal muscle or back.
In addition, compound of the present invention also can be used for treating neurodynia.This is defined as the pain (IASP definition) that is caused or caused by main infringement or dysfunction in the neural system.Nervous lesion can be caused by wound and disease, so term ' neuropathic pain ' comprises the disease with different causes of disease.They comprise, but be not limited to neuropathy or VITAMIN deficiency that the neuropathy of the neuropathy of diabetes, the neurodynia after the bleb, backache, cancer, the neuropathy that chemotherapy causes, HIV neuropathy, phantom limb pain, Carpal Tunnel syndromes, chronic alcoholism, thyroid function decline, trigeminal neuralgia, uremia, wound cause.
The pain of other type includes, but are not limited to:
-inflammatory pain, for example arthrodynia comprises rheumatoid arthritis (RA) and osteoarthritis (OA) and inflammatory bowel disease (IBD);
-muscle-skeletal diseases includes, but are not limited to ostalgia, fibromyalgia, spondylitis, seronegativity (non-rheumatoid) joint disease, non-rheumatic arthritis, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis;
-nervus centralis pain or ' thalamic pain ' are defined as the pain that caused by nervous system damage or dysfunction, include, but are not limited to pain after the nervus centralis apoplexy, multiple sclerosis, the damage of vertebra funiculus lateralis, Parkinson's disease and epilepsy;
-heart and blood vessel pain include but not limited to, angina, myocardial infarction, left atrioventricular valve are narrow, pericarditis, Raynaud phenomenon, sclerodoma, skeletal muscle local asphyxia;
-visceral pain and gastrointestinal illness comprise the pain relevant with dysmenorrhoea, pelycalgia, urocystitis and pancreatitis;
-headache includes, but are not limited to migraine, migraine, string headache, the tension-type headache of migraine, the absence of aura of tendency is arranged; With
-actinal surface pain includes, but are not limited to toothache, temporomandibular joint myofascial pain.
The disease that cherishes a special interest comprises the urinary incontinence, for example mix incontinence, GSI and USI, pain, depressed disease, anxiety disorder, for example stress disease after obsessional idea and behavior disease and the wound, personality disease, for example ADHD, sexual dysfunction and chemical rely on and are relied on by chemical the disconnected addiction syndromes that causes.
Therefore, according on the other hand, the invention provides:
I) be used for the compound of the present invention of people or veterinary drug;
Ii) be used for the treatment of and wherein relate to the disease that monoamine translocator function is regulated, for example compound of the present invention of the urinary incontinence;
Iii) The compounds of this invention is used for the treatment of purposes in the medicine that wherein relates to the disease that monoamine translocator function regulates in preparation;
The The compounds of this invention that iv) is used for the treatment of the disease that wherein relates to serotonin or norepinephrine adjusting;
V) The compounds of this invention is used for the treatment of purposes in the medicine that wherein relates to the disease that serotonin or norepinephrine regulate in preparation;
The The compounds of this invention that vi) is used for the treatment of the disease that wherein relates to serotonin and norepinephrine adjusting;
Vii) The compounds of this invention is used for the treatment of purposes in the medicine that wherein relates to the disease that serotonin and norepinephrine regulate in preparation;
Viii) be used for the treatment of the urinary incontinence, for example the The compounds of this invention of GSI or USI;
Ix) The compounds of this invention is used for the treatment of the urinary incontinence in preparation, for example the purposes in the medicine of GSI or USI;
X) treatment wherein relates to the method for the disease of monoamine translocator function adjusting, and it comprises the compound of the present invention to patient's drug treatment significant quantity of this treatment of needs;
Xi) treatment wherein relates to the method for the disease of serotonin or norepinephrine adjusting, and it comprises the compound of the present invention to patient's drug treatment significant quantity of this treatment of needs;
Xii) treatment wherein relates to the method for the disease of serotonin and norepinephrine adjusting, and it comprises the compound of the present invention to patient's drug treatment significant quantity of this treatment of needs;
Xiii) the treatment urinary incontinence, the method for GSI or USI for example, it comprises the compound of the present invention to patient's drug treatment significant quantity of this treatment of needs.
Should be appreciated that all treatments of mentioning of this paper comprise healing, alleviate and prophylactic treatment, except as otherwise noted.
Compound of the present invention can be individually or as the part administration of combination therapy, if administration combination therapy medicine, then activeconstituents can be successively or simultaneously with separately or the formula of medicine administration of associating.
The example that is used for the suitable drug of assisting therapy comprises:
Estrogen agonist or selective estrogen receptor modulators (for example HRT treatment or Lasofoxifene);
Alpha adrenergic receptor agonists, for example Phenylpropanolamine or R-450;
Alpha-adrenergic aceptor antagonist (for example fragrant appropriate Lamine, Doxazosin, tamsulosin, terazosin and Prazosin (prazasin)) comprises selectivity α
1L-adrenoceptor antagonists (for example WO98/30560 embodiment 19);
Beta-adrenergic agonist (for example clenbuterol);
Muscarinic receptor antagonists (for example, tolterodine or Oxybutynin) comprises muscarine M3 receptor antagonist (for example, darifenacin);
Cox inhibitor, for example Cox-2 inhibitor (for example, celecoxib, rofecoxib, cut down ground former times cloth, Parecoxib or rely on former times cloth);
Tachykinin receptor antagonists, for example neurokinin (for example, NK1, NK2 or NK3 antagonist);
Beta 3 receptor agonist;
5HT
1Part (for example, buspirone);
5HT
1Agonist, for example Qu Tan (for example, sumatriptan or naratriptan);
Dopamine-receptor stimulant (for example, Apomorphine can find in US-A-5945117 as the instruction of medicine) comprises d2 dopamine receptor agonist (for example, premiprixal, Pharmacia Upjohn compound number PNU95666 or Ropinirole);
Black adrenal cortical hormone receptor agonist (for example melanotan II);
The PGE receptor antagonist;
PGE1 agonist (for example, Prostaglandin E1);
Other monoamine transporter inhibitors, for example norepinephrine reuptake inhibitors (for example, Reboxetine), serotonin reuptake inhibitors (for example Sertraline, fluoxetine or paroxetine) or Dopamine HCL reuptake inhibitors;
5-HT3 receptor antagonist (for example, ondansetron, granisetron, tropisetron, azasetron, dolasetron or Lotronex);
Phosphodiesterase (PDE) inhibitor, for example the PDE2 inhibitor (for example, the embodiment 100 of red-9-(2-hydroxyl-3-nonyl)-VITAMIN B4 or EP 0771799, classify this paper reference as), PDE5 inhibitor (for example, 'Xiduofeng ', 1-{[3-(3 especially, 4-dihydro-5-methyl-4-oxo-7-propyl imidazole also [5,1-f]-as-triazine-2-yl)-the 4-ethoxyl phenenyl] alkylsulfonyl }-the 4-ethyl piperazidine, promptly Vardenafil is also referred to as BayerBA 38-9456; Or Icos Lilly ' s IC351, referring to following structure).
IC351(Icos Lilly)
Therefore, on the other hand, the invention provides the combination medicine that contains The compounds of this invention and other medicine.
Use for human body, compound of the present invention can be individually dosed, but in human body therapy, usually will with according to the suitable drug excipient of required route of administration and standard drug choice of practice, the mixture administration of diluent or carrier.
For example, compound of the present invention can contain tablet, capsule (comprising soft gel capsule), vaginal suppository (ovule), elixir, solution or the form of suspension of seasoning or tinting material oral, suck or sublingual administration, described formulation is used for immediately, delay, modification, lasting, dual, controlled release or pulse delivery application.But also interior (intracavernosal) administration of via intranasal application of compound of the present invention, compound of the present invention also can be through quick dispersion or rapid-dissolve dosage form administration.
This tablet can contain vehicle, for example Microcrystalline Cellulose, lactose, Trisodium Citrate, lime carbonate, secondary calcium phosphate, Padil and starch (preferred corn, potato or tapioca (flour)), disintegrating agent, for example Explotab, croscarmellose sodium and some composition silicate and Granulating Bonding Agent, for example Polyvinylpyrolidone (PVP), Vltra tears (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and Sudan Gum-arabic.In addition, can comprise lubricant, for example Magnesium Stearate, stearic acid, mountain Yu acid glycerol base ester and talcum.
The solids composition of similar type is also as the filler in the gelatine capsule, and in this respect, preferred vehicle comprises lactose, starch, Mierocrystalline cellulose, toffee or high molecular weight polyethylene glycol.For aq suspension and/or elixir, compound of the present invention and its pharmaceutically useful salt can with various sweeteners or seasonings, coloring material or dyestuff, with emulsifying agent and/or suspension agent and and thinner, for example water, ethanol, propylene glycol and glycerine or its combined hybrid.
Improved release and pulsed release dosage form can contain vehicle, for example those that immediate release dosage form is described in detail and additional vehicle, and it is as the rate of release improving agent, and they are coated on the device and/or are included in the device body.The rate of release improving agent comprises, but not exclusively be limited to Vltra tears, methylcellulose gum, carboxymethyl cellulose, ethyl cellulose, rhodia, polyethylene oxide, xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin, Cellacefate, Hydroxypropyl Methylcellulose Phathalate, Sipacril 2739OF and their mixture.Improve to discharge and pulsed release dosage form can contain a kind of rate of release and improves the combination that vehicle or multiple rate of release are improved vehicle, rate of release improvement vehicle can be present in the formulation, promptly in the substrate and/or on formulation, promptly on surface or coating.
Disperse or dissolve form formula (FDDF) fast and can contain following composition: aspartame, Sunnett, citric acid, croscarmellose sodium, polyvinylpolypyrrolidone, two xitix, ethyl propenoate, ethyl cellulose, gelatin, Vltra tears, Magnesium Stearate, N.F,USP MANNITOL, methyl methacrylate, peppermint seasonings, polyoxyethylene glycol, fumed silica, silicon-dioxide, Explotab, stearyl-sodium fumarate, Sorbitol Powder, Xylitol.Be used for the term that this paper describes FDDF and disperse or dissolve the solvability that depends on employed drug substance, promptly when drug substance does not dissolve, can prepare the fast-dispersing type, when drug substance dissolves, can prepare rapid-dissolve dosage form.
But compound of the present invention is administered parenterally also, for example in the intravenously, intra-arterial, intraperitoneal, sheath, in the ventricle, in the urethra, in the breastbone, in the skull, intramuscular or subcutaneous, or they can pass through the infusion techniques administration.For administered parenterally, they preferably use with the aseptic aqueous solution form, and it contains other material, and for example enough salt or glucose are with preparation and the isoosmotic solution of blood.If desired, the aqueous solution should be suitable buffered (preferred 3-9pH).The suitable parenteral administration of preparation is finished with standard pharmaceutical technology well known by persons skilled in the art easily under aseptic condition.
Be used for the oral and administered parenterally to people patient, the dosage level of compound or its salt of the present invention or solvate is generally 10-500mg (single or separate dosage).
Therefore, the tablet of compound or its salt for example of the present invention or solvate or capsule can contain 5mg-250mg active compounds single or two or more administrations simultaneously as required.Under any circumstance the clinician will determine to be suitable for most the actual dose of any individual patient, will be with concrete patient's age, body weight and reactions change.Above-mentioned dosage is giving an example under the average case, has the discrete situation certainly, uses higher or lower dosage range, and they within the scope of the invention.The person skilled in the art will understand, and in treatment some disease (comprising PE), compound of the present invention can adopt the single dose based on " needs " (promptly need or require).
The tablet formulation example
Usually tablet formulation can the typical case contain the 0.01mg-500mg that has an appointment compound of the present invention (or its salt), and tablet supply weight is 50mg-1000mg.The example that is used for the 10mg tablet formulation is described:
Composition %w/w
Compound free alkali or salt 10.000
*
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium Stearate 1.500
*This quantity is regulated according to pharmaceutical activity, based on free alkali weight.
But compound of the present invention also in the nose or by inhalation, is carried with Foradil Aerolizer formoterol fumarate or by the aerosol spray of pressurizing vessel, pump, sprinker or atomizer easily, uses suitable propelling agent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, hydro fluoroalkanes, for example 1,1,1, the 2-Tetrafluoroethane (HFA 134A[trade mark]) or 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227EA[trade mark]), carbonic acid gas or other suitable gas.Under the pressurized aerosol situation, dosage device can be determined by the valve that conveying and metering quantity is provided.Pressurizing vessel, pump, sprinker or atomizer can contain the solution or the suspension of active compound, and the mixture that for example uses ethanol and propelling agent is as solvent, and it also can contain lubricant, for example sorbitan trioleate.The capsule and the cartridge case (by for example gelatin preparation) that are used for sucker or insufflator can be mixed with and contain compound of the present invention and suitable powder matrix, for example powdered mixture of lactose or starch.
Aerosol or dry powder formulations preferably set and make each dosing or " spray (puff) " contain the 1-50mg compound of the present invention that oriented patient carries.Aerocolloidal whole per daily dose will be 1-50mg, and it can the single dose administration or more common dosed administration to separate in a day.
Compound of the present invention also can be prepared and be used for through the atomizer administration.The preparation that is used for sprayer device can contain following composition: solubilizing agent, emulsifying agent or suspension agent: water, ethanol, glycerine, propylene glycol, low molecular poly, sodium-chlor, hydrofluoric ether, polyglycol ether, sorbitan trioleate, oleic acid.
Perhaps, compound of the present invention can suppository or vaginal suppository form administration, or they can gel, hydrogel, washing lotion, solution, emulsifiable paste, ointment or the topical application of face powder form.Compound of the present invention also can use by using the skin plaster through skin or subcutaneous administration.They also can pass through eyes, lung or rectum administration.
Use for ophthalmology, The compounds of this invention can be mixed with isoosmotic, the suspension of the molecule in the Sterile Saline of pH regulator, or preferably be mixed with isoosmotic, the solution in the Sterile Saline of pH regulator, optional and sanitas, for example benzalkonium chloride mixes.On the other hand, they can for example be prepared in the paraffin at ointment.
Topical application for skin, compound of the present invention can be prepared suitable ointment, and it contains and suspends or for example be dissolved in active compound with the mixture of one or more following materials: mineral oil, whiteruss, white paraffin, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Perhaps, they can be mixed with suspension or be dissolved in for example suitable washing lotion or the emulsifiable paste of the mixture of one or more following materials: mineral oil, sorbitan monostearate, polyoxyethylene glycol, whiteruss, polysorbate60, hexadecyl ester, paraffin, stearyl alcohol, 2-Standamul G, benzyl alcohol and water.
Compound of the present invention also can be used in combination with cyclodextrin.Known cyclodextrin and drug molecule form and comprise or the non-title complex that comprises.The formation of drug-cyclodextrin title complex can improve solvability, dissolution rate, bioavailability and/or the stability of drug molecule.The drug-cyclodextrin title complex is generally used for most of formulations and route of administration.As the alternative that directly cooperates with medicine, cyclodextrin can be used as supplementary additive, for example as carrier, thinner or solubilizing agent.α-, β-and γ-Huan Hujing be the most normal use, suitable example is described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
For the oral or administered parenterally to people patient, the dosage level of formula (I) compound and its pharmaceutically useful salt is 0.01-30mg/kg (single or divide equally dosage), is preferably 0.01-5mg/kg.Therefore, tablet will contain the 1mg-0.4g compound, as required, be used for single or two or more administrations simultaneously.Under any circumstance the clinician will determine to be suitable for most the actual dose of any particular patient, will be with age, body weight and the reactions change of particular patient.Certain above-mentioned dosage only is giving an example under the average case, has the situation of using higher or lower dosage, and they within the scope of the invention.
The preferred oral administration.
Use for veterinary drug, according to common veterinary drug practice, with suitable acceptable preparation administration, the structive sursery doctor will determine dosage and route of administration to compound of the present invention, to be suitable for most particular animals according to common animal doctor's practice.
Therefore, according on the other hand, the invention provides the pharmaceutical preparation that contains compound of the present invention and pharmaceutically useful auxiliary material, diluent or carrier.
Also can be easily use about above-mentioned combination medicine (combination), therefore contain pharmaceutical preparation formation another aspect of the present invention of combination medicine and pharmaceutically useful auxiliary material, diluent or carrier as defined above with pharmaceutical dosage forms.The pharmaceutical preparation that each component of this combination medicine can be independent or the pharmaceutical preparation of associating are successively or administration simultaneously.
Unite when using when compound of the present invention and second kind of medicine, the dosage that every kind of compound dosage can be different from compound when using separately, suitable dose those skilled in the art can easily know.
The present invention illustrates with following unrestricted embodiment, wherein uses following abbreviation and definition:
The APCI atmospheric chemical ionization
Arbacel filtering medium
Br is wide
The BOC tert-butoxycarbonyl
The CDI carbonyl dimidazoles
The δ chemical shift
The d doublet
The Δ heating
The DCCI dicyclohexylcarbodiimide
The DCM methylene dichloride
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
ES
+Electron spray ionisation just scans
ES
-The negative scanning of electron spray ionisation
H hour
HOAT 1-hydroxyl-7-azepine benzotriazole
HOBT 1-hydroxyl-7-benzotriazole
The HPLC high pressure liquid chromatography
The m/z mass spectra peak
The min branch
The MS mass spectrum
The NMM N-methylmorpholine
The NMR nucleus magnetic resonance
The q quartet
S is unimodal
The t triplet
TBTU 2-(1-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate
The Tf trifluoromethane sulfonyl group
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The TLC tlc
TS
+Thermospray ionization just scans
WSCDI 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
Be prepared as follows example and embodiment and illustrate the present invention, but do not limit the present invention in any way.All temperature are ℃, and flash column chromatography carries out with Merck silica gel 60 (9385), and Solid-Phase Extraction (SPE) chromatography is carried out under the 15mmHg vacuum with Varian Mega Bond Elut (Si) cylinder (Anachem).Tlc (TLC) is carried out with Merck silica gel 60 plates (5729).Fusing point is measured with the GallenkampMPD350 device, does not proofread and correct.NMR carries out with Varian-Unity Inova 400MHz nmr spectrometer or Varian Mercury 400MHz nmr spectrometer.Mass spectrum carries out with single four utmost point electrospray mass spectrometers of Finnigan Navigator or Finnigan aQa APCI mass spectrograph.
Preparation example 1
(3R)-1-(trifluoroacetyl group) tetramethyleneimine-3-aminocarbamic acid tertiary butyl ester
With (3R)-3-tert-butoxycarbonyl amino) (3.87mL 48.3mmol) is dissolved in the methylene dichloride (55mL), and reaction mixture stirred 1 hour at 0 ℃ under nitrogen for tetramethyleneimine (3.0g, 16.1mmol are obtained by Flurochem on the market) and pyridine.(2.74mL, 32.2mmol) solution in methylene dichloride (5mL) makes reaction mixture be warming to room temperature, stirs 2 hours to drip trifluoroacetic anhydride in 10 minutes in reaction mixture.Reaction mixture is with methylene dichloride (100mL) dilution, with saturated sodium bicarbonate solution, water and salt water washing.Separate organic layer, use dried over mgso, vacuum concentration.(2 * 30mL) component distillations obtain title product to crude product with toluene.
1HNMR(DMSO-D
6，400MHz)：1.40(s，9H)，1.82(dd，1H)，2.08(dd，1H)，3.33(m，1H)，3.46(m，1H)，3.59-3.77(brm，2H)，4.06(m，1H)，7.22(m，1H)。
MS ES+m/z 281[MH]
+。
Preparation example 2
(3R)-1-(trifluoroacetyl group) tetramethyleneimine-3-amine hydrochlorate
(4.59g 16.1mmol) is dissolved in the methylene dichloride (100mL), and reaction mixture stirred 1 hour at 0 ℃ with the amine of the Boc of preparation example 1 protection.The hydrogen chloride gas bubbling makes reaction mixture be warming to room temperature by the solution that obtains 10 minutes subsequently.Bubbling was by solution 15 and 10 minutes respectively with hydrogen chloride gas and nitrogen, and the reaction mixture vacuum concentration obtains title product.
1HNMR(CDCl
3，400MHz)：1.27(m，2H)，1.65(m，1H)，1.81(m，1H)，2.10(m，2H)，3.32(m，2H)，3.61(m，1H)。
MS ES+ m/z 183[MH]
+。
Preparation example 3
(3S)-3-(isobutylamino) tetramethyleneimine-1-carboxylic acid tertiary butyl ester
With (3S) 3-amino-tetramethyleneimine-1-carboxylic acid tertiary butyl ester (3g, 16.1mmol) adding isobutyric aldehyde (1.61mL, 17.7mmol) and the solution of 10%Pd/C (360mg) in ethanol (60mL) in, reaction mixture under about 415kPa (about 60psi) hydrogen 18 hours.Reaction mixture filters by Arbocel , uses the ethyl acetate thorough washing.Filtrate vacuum concentration, crude product silica gel column chromatography purifying, with 1: 1 ethyl acetate: the pentane wash-out obtained title product 2.8g, (73%).
1HNMR(CDCl
3，400MHz)：0.92(d，6H)，1.44(s，9H)，1.63(m，2H)，2.00(m，1H)，2.39(m，2H)，3.02(m，1H)，3.25(m，2H)，3.48(m，2H)，3.60(m，1H)。
MS APCI+243[MH
+]。
Preparation example 4
(3S)-N-butyl-1-(trifluoroacetyl group) tetramethyleneimine-3-amine
With triethylamine (1.9mL, 13.72mmol) and butyraldehyde (1.3mL 14.41mmol) adds (S)-1-(trifluoroacetyl group) tetramethyleneimine-3-base amine (3.0g; 13.72mmol) (J.Med.Chem., 1996,39 (14); 2771 pages, No.6) in the solution in ethanol (60mL).Reaction mixture is handled with 10%Pd/C (300mg), at room temperature places 18 hours in about 415kPa (about 60psi) hydrogen.Reaction mixture filters by Arbocel , uses the ethyl acetate thorough washing.Filtrate is washed with saturated sodium bicarbonate solution, uses dried over mgso, vacuum concentration.Crude product silica gel column chromatography purifying, with 25: 75: 0 to 100: 0: 0 to 99: 0: 1 ethyl acetate: pentane: the triethylamine wash-out obtained title product.
1HNMR(CDCl
3，400MHz)：1.01(t，3H)，1.38(m，2H)，1.47(m，2H)，1.86-2.09(m，2H)，2.62(m，2H)，3.38-3.87(brm，6H)。
MS APCI+m/z 239[MH]
+。
Preparation example 5
(3S)-N-isobutyl--1-(trifluoroacetyl group) tetramethyleneimine-3-amine
Use tertiary butyl aldehyde, employing is similar to the method described in the preparation example 4 and prepares this compound.
1HNMR(CDCl
3，400MHz)：0.91(t，6H)，1.26(d，2H)，1.47(m，2H)，1.72(m，1H)，2.42(m，2H)，3.39(m，2H)，3.77(m，1H)，4.09(m，1H)。
MS APCI+m/z 239[MH]
+。
Preparation example 6
(3S)-1-benzyl-N-(2-menaphthyl) tetramethyleneimine-3-amine
With the 3-naphthaldehyde (2.0g, 12.8mmol) and (3S)-(2.37g, 13.4mmol) solution in methyl alcohol (30mL) at room temperature stirred under nitrogen 6 hours 1-benzyl-3-amino-tetramethyleneimine.(969mg, 25.6mmol), reaction mixture was at room temperature placed 18 hours to add sodium borohydride.The reaction mixture dilute with water extracts with ethyl acetate (x3), merges organic layer, with dried over mgso and vacuum concentration.Crude product silica gel column chromatography purifying, with 100: 0 to 97: 3 methylene dichloride: methanol-eluted fractions obtained title product 4.01g.
1HNMR(CDCl
3，400MHz)：1.62(m，1H)，2.19(m，1H)，2.48(m，2H)，2.80(m，2H)，3.42(m，1H)，3.63(s，2H)，3.92(m，2H)，7.26(m，5H)，7.44(m，3H)，7.78(m，4H)。
MS APCI+m/z 317[MH]
+。
Preparation example 7
(3R)-1-benzyl-N-(2-naphthyl methyl) tetramethyleneimine-3-amine
With (3R)-1-benzyl-3-amino-tetramethyleneimine, employing is similar to the method described in the preparation example 6 and prepares this compound.
1HNMR(CDCl
3，400MHz)：1.65(m，1H)，2.18(m，1H)，2.51(m，2H)，2.78(m，2H)，3.41(m，1H)，3.63(m，2H)，3.94(s，2H)，7.22(m，1H)，7.28(m，4H)，7.43(m，3H)，7.79(m，4H)。
MS APCI+m/z 317[MH]
+。
Preparation example 8
(3R)-N-(3, the 4-dichloro benzyl)-1-(trifluoroacetyl group) tetramethyleneimine-3-amine
With the amine and 3 of preparation example 2,4-dichlorobenzaldehyde, employing is similar to the method described in the preparation example 6 and prepares this compound.
1HNMR(DMSO-D
6，400MHz)：1.88(m，2H)，2.63(m，1H)，3.36-3.78(m，7H)，7.32(m，1H)，7.59(m，2H)。
MSAPCI+m/z 341[MH]
+。
Preparation example 9
(3R)-N-(2, the 3-dichloro benzyl)-1-(trifluoroacetyl group) tetramethyleneimine-3-amine
With the amine and the 2,3 dichloro benzaldehyde of preparation example 2, employing is similar to the method described in the preparation example 6 and prepares this compound.
1HNMR(DMSO-D
6，400MHz)：1.92(m，2H)，3.29-3.74(m，7H)，3.83(m，1H)，7.27(m，1H)，7.51(m，2H)。
MS APCI+m/z 341[MH]
+。
Preparation example 10-12
With suitable carboxylic acid RCO
2H (1mmol) is dissolved in the ice bath refrigerative methylene dichloride (5mL), and (0.248mL, 2.5mmol) with 1 N, handle by dinethylformamide with oxalyl chloride for refrigerative solution.Remove deicing, reaction mixture is warming to room temperature, at room temperature stirs 2 hours.The reaction mixture vacuum concentration, with product add triethylamine (0.229mL, 1.64mmol) and the amine of preparation example 3 (200mg is 0.83mmol) in the solution in the Zai diox (10mL).Reaction mixture be heated to 70 ℃ 45 minutes, cool to room temperature then.Reaction mixture vacuum concentration, product are dissolved in the methylene dichloride, with 10% citric acid solution and the washing of 2M sodium hydroxide solution.Separate organic layer, vacuum concentration.Crude product silica gel column chromatography purifying, with 100: 0-98: 2 methylene dichloride: methanol-eluted fractions obtains title product.
Preparation example 13
(3S)-and 3-[(2,3-dichloro-benzoyl base) (isobutyl-) amino] tetramethyleneimine-1-carboxylic acid tertiary butyl ester
(200mg, (0.229mL, 1.652mmol) in the solution in the Zai diox (5mL), reaction mixture is with 2,3-dichloro-benzoyl base chlorine (207mg, 0.99mmol) processing 0.826mmol) to add triethylamine with the amine of preparation example 3.Reaction mixture is heated to 70 ℃, stirs 90 minutes, and reaction mixture vacuum concentration, product are dissolved in the methylene dichloride with 2M sodium hydroxide and the washing of 10% citric acid solution.Separate organic layer, vacuum concentration, crude product silica gel column chromatography purifying obtains title product 278mg with the methylene dichloride wash-out, (81%).
MS APCI+m/z 315[MH]
+。
Preparation example 14-17
The following compound of above-mentioned general formula is similar to the method preparation described in the preparation example 13 with the amine of preparation example 3 and suitable acyl chlorides, employing:
Preparation example 18
N-[(3S)-1-benzyl-pyrrole alkane-3-yl]-N-(2-naphthyl methyl) benzamide
With benzoyl chlorine (0.12mL, 1.043mmol) add preparation example 6 amine (300mg, 0.948mmol) and triethylamine (0.26gel, 1.896mmol) in the solution in methylene dichloride (5mL), reaction mixture was at room temperature placed under nitrogen 18 hours.Reaction mixture water and salt water washing obtain title product 380mg with dried over mgso and vacuum concentration.
1HNMR(CDCl
3，400MHz)：1.83-2.62(brm，4H)，2.84(m，2H)，3.62(m，2H)4.56(m，1H)，5.05(m，2H)，7.24(m，4H)，7.31-7.60(m，9H)，7.78(m，4H)
MS ES+m/z 421[MH]
+
Preparation example 19
N-[(3R)-1-benzyl-pyrrole alkane-3-yl]-N-(2-naphthyl methyl) benzamide
With the amine of preparation example 7, employing is similar to the method described in the preparation example 18 and prepares title compound.
1HNMR(CDCl
3，400MHz)：1.94-2.58(brm，6H)，2.86(m，2H)，3.62(m，1H)，5.08(m，2H)，7.23(m，4H)，7.34-7.60(m，9H)，7.79(m，4H)
MS APCI+m/z 421[MH]
+
Preparation example 20
The N-butyl-N-[(3S)-1-(trifluoroacetyl group) tetramethyleneimine-3-yl]-the 1-naphthoamide
With the amine and the 1-naphthoyl chlorine of preparation example 4, employing is similar to the method described in the preparation example 18 and prepares this compound.
1HNMR(CDCl
3，400MHz)：0.61(m，2H)，0.98(m，3H)，1.32-1.60(brm，4H)，3.06(m，2H)，3.27-3.76(m，4H)，5.28(m，1H)，7.39(m，1H)，7.45(m，3H)，7.72(m，1H)，7.89(m，2H)。
MS APCI+m/z 393[MH]
+。
Preparation example 21
The N-tertiary butyl-N-[(3S)-1--(trifluoroacetyl group) tetramethyleneimine-3-yl]-the 2-naphthoamide
With the amine of 1-naphthoyl chlorine and preparation example 3, employing is similar to the method described in the preparation example 18 and prepares this compound.
1HNMR(CDCl
3，400MHz)：0.84(m，8H)，2.00(m，1H)，3.25(m，2H)，3.93(m，2H)，4.38(brm，1H)，5.31(m，2H)，7.24(m，2H)，7.38-7.62(m，5H)。
MS APCI+m/z 393[MH]
+。
Preparation example 22
4-chloro-N-(3, the 4-dichloro benzyl)-N-[(3R)-1-(trifluoroacetyl group) tetramethyleneimine-3-yl] benzamide
(180mg 0.58mmol) is dissolved in the methylene dichloride (3mL), and (0.16mL 1.16mmol) handles reaction mixture with triethylamine with the amine of preparation example 8.Reaction mixture is cooled to 0 ℃, and dropping 4-chlorobenzene formacyl chlorine (0.08mL, 0.63mmol).Reaction mixture stirred 18 hours under nitrogen, and reaction mixture with the methylene dichloride dilution, washes with water again.The organic layer dried over mgso, vacuum concentration.Crude product silica gel column chromatography purifying, with 100: 0 to 95: 5 methylene dichloride: methanol-eluted fractions obtained title product.
1HNMR(DMSO-D
6，400MHz)：2.02(m，2H)，3.37-3.72(m，4H)，4.61(m，2H)，5.68(m，1H)，7.22-7.59(m，7H)。
MS APCI+m/z 479[MH]
+。
Preparation example 23
4-chloro-N-(2, the 3-dichloro benzyl)-N-[(3R)-1-(trifluoroacetyl group) tetramethyleneimine-3-yl] benzamide
With the amine of preparation example 9, employing is similar to the method described in the preparation example 22 and prepares this compound.
1HNMR(DMSO-D
6，400MHz)：2.04(m，2H)，3.37-3.76(m，4H)，4.46-4.76(m，3H)，7.22-7.58(brm，7H)。
MS APCI+m/z 479[MH]
+。
Embodiment 1
2,3-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] the benzamide Citrate trianion
(10.55g 25.4mmol) is dissolved under the nitrogen in methylene dichloride (20mL), and (20mL 260.5mmol) handles reaction mixture with trifluoroacetic acid with the product of the Boc of preparation example 13 protection.Reaction mixture is at room temperature gone up subsequently and was stirred 4.5 hours.Reaction mixture vacuum concentration, resistates are dissolved in the methylene dichloride (200mL), with 1M sodium hydroxide solution (100mL) washing.Separate organic phase, with dried over mgso and vacuum concentration.Resistates ethyl acetate (10x) component distillation, vacuum-drying subsequently obtains the free alkali colorless oil of title product, 7.281g (91%).A part product (3.327g, 10.56mmol) with citric acid (2.028g, the 10.56mmol) solution-treated in methyl alcohol, vacuum concentration, high vacuum dry obtains title product pink solid 4.71g.
1HNMR(MeOD，400MHz)：0.80(t，6H)，1.89(m，2H)，2.11(brm，2H)，2.53(m，2H)，2.68-2.91(m，4H)，3.59(m，1H)，3.82(m，2H)，4.37(m，1H)，7.40(m，2H)，7.61(m，1H)。
MS APCI+m/z 315[MH
+]。
Embodiment 2
2,4-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide hydrochloride salt
(157mg 0.561mmol) is added in the solution of 4M hydrochloric acid in methylene dichloride (5mL) in the diox (1mL), and reaction mixture at room temperature stirred 18 hours with the BOC of preparation example 14 protection product.The reaction mixture vacuum concentration, product obtains title product 103.3mg, (87%) with the ether development subsequently with methylene dichloride and ether component distillation.
1HNMR(MeOD，400MHz)：0.80(m，6H)，1.89(m，1H)，2.51(m，2H)，2.90(m，1H)，3.20(m，2H)，3.52(m，1H)，3.78(m，2H)，4.30(m，1H)，7.40(m，1H)，7.46(d，1H)，7.58(s，1H)。
MS APCI+m/z 315[MH
+]。
Embodiment 3-8
The following compound of above-mentioned general formula be similar to embodiment 2 described methods prepare shown in the hydrochloride of compound:
Embodiment 9
N-(2-naphthyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide hydrochloride salt
Under nitrogen with the product of the benzyl protection of preparation example 18 (370mg, 88mmol), ammonium formiate (555mg, 8.798mmol) and the solution of 10%Pd/C (40mg) in ethanol (5mL) refluxed 6 hours.Reaction mixture filters by Arbocel , uses the ethanol thorough washing, the filtrate vacuum concentration.Crude product silica gel column chromatography purifying is with 100: 0: 0 to 90: 10: 1 methylene dichloride: methyl alcohol: 0.88 ammoniacal liquor wash-out.Product is dissolved in the solution of minimum dilute hydrochloric acid in methylene dichloride vacuum concentration.Product is developed with ether (x3), and vacuum-drying obtains title product 120mg, (36%).
1HNMR(DMSO-D
6，400MHz)：2.06(m，2H)，2.98(brs，1H)，3.79(m，3H)，4.43(m，1H)，4.71(m，2H)，7.25-7.59(m，9H)，7.78(m，1H)，7.93(m，3H)。
MSAPCI+m/z 331[MH]
+。
Embodiment 10
N-(2-naphthyl methyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide hydrochloride salt
, adopt to be similar to the method described in the embodiment 9 and to prepare title compound as raw material with the product of the preparation example 19 of benzyl protection, collect 160mg, (47%) title compound.
1HNMR(DMSO-D
6，400MHz)：2.11(m，2H)，3.00(m，1H)，3.35(brm，3H)，4.44(m，1H)，4.78(m，2H)，7.28-7.56(brm，9H)，7.81(m，1H)，7.96(m，3H)。
MS ES+m/z 331[MH]
+。
Embodiment 11
The N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl]-2-naphthoamide hydrochloride
(92mg, 0.66mmol) (130mg, 0.33mmol) in the solution in water (0.5mL) and methyl alcohol (5mL), reaction mixture at room temperature stirred 18 hours the product of the trifluoroacetic acid base protection of adding preparation example 21 with salt of wormwood.With the reaction mixture vacuum concentration, crude product is dissolved in 1: 1 10% solution of potassium carbonate: in the ethyl acetate mixture (25mL).The organic layer dried over mgso, vacuum concentration.Crude product is dissolved in the ethyl acetate, is used in the 1M salt acid treatment in the ether, at room temperature stirs 1 hour.The reaction mixture vacuum concentration obtains title product.
1HNMR(MeOD，400MHz)：0.79(d，6H)，1.93(m，1H)，2.56(m，2H)，3.25(m，3H)，3.55(t，1H)，3.80(m，2H)，4.36(m，1H)，7.48(d，1H)，7.59(m，2H)，7.96(m，4H)。
MS ES+m/z 298[MH
+]。
Embodiment 12
The N-butyl-N-[(3S)-tetramethyleneimine-3-yl]-2-naphthoamide hydrochloride
, adopt to be similar to embodiment 11 described methods and to prepare this compound as raw material with the product of the trifluoroacetic acid base of preparation example 20 protection.
1HNMR usefulness (MeOD, 400MHz): 0.62 (m, 3H), 1.04 (m, 2H), 1.72 (m, 2H), 2.65 (m, 2H), 3.07 (m, 2H), 3.21 (m, 1H), 3.59 (m, 1H), 3.87 (m, 2H), 4.42 (m, 1H), 7.30 (s, m, 1H), 7.57 (m, 3H), 7.78 (m, 1H), 8.00 (m, 2H).
MS ES+m/z 297[MH]
+。
Embodiment 13
4-chloro-N-(3, the 4-dichloro benzyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide hydrochloride salt
, adopt to be similar to embodiment 11 described methods and to prepare this compound as raw material with the product of the trifluoroacetic acid base of preparation example 22 protection, collect title product, 75mg, (47%).
1HNMR(DMSO-D
6，400MHz)：1.58(m，1H)，1.83(m，1H)，2.60(m，1H)，2.81(m，2H)，3.42(m，2H)，4.61(m，2H)，7.25(m，1H)，7.39-7.59(m，7H)。
Embodiment 14
4-chloro-N-(2.3-dichloro benzyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide hydrochloride salt
, adopt to be similar to embodiment 11 described methods and to prepare this compound as raw material with the product of the trifluoroacetic acid base of preparation example 23 protection, collect title product, 90mg (52%).
1HNMR(DMSO-D
6，400MHz)：1.62(m，1H)，1.88(m，1H)，2.61(m，2H)，2.85(m，2H)，4.28(m，1H)，4.59(t，2H)，7.24(m，1H)，7.36(m，1H)，7.42-7.58(m，6H)。
MS ES+m/z 385[MH]
+。
Embodiment 15
2,4-two chloro-5-fluoro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide hydrochloride salt
With the amine and 2 of preparation example 3,4-two chloro-5-fluoro benzoyl chlorine adopt to be similar to preparation example 13 described method preparation (3S)-3-[(2,4-two chloro-5-fluoro benzoyls) (isobutyl-) amino] tetramethyleneimine-1-carboxylic acid tertiary butyl ester, obtain required product 340mg.
MS ES+m/z 455[MNa]
+。
2,4-two chloro-5-fluoro-N-isobutyl-s-N[(3S)-tetramethyleneimine-3-yl] benzamide hydrochloride salt by above-claimed cpd with being similar to the method preparation described in the embodiment 2 to obtain title product pale solid, 100mg.
MS APCI+m/z 333[MH]
+。
Experimental value: C, 47.22; H, 5.87; N, 7.08%.C
15H
19Cl
2FN
2O.HCl.0.7H
2O calculated value: C, 47.17; H, 5.64; N, 7.33%.
Embodiment 16
The NRI IC of following mensuration embodiment 1-14 compound
50With SRI IC
50, the results are shown in the table 1.
Biological activity
Following with compound inhibition people's serotonin and/or the serotonin of norepinephrine transporter and/or the biological activity of the aptitude tests compound that norepinephrine is taken in again.
(i) cell cultures
Personnel selection serotonin transporter (hSERT), (cell is being added 10% dialysis foetal calf serum (FCS) at 37 ℃ under the 5%CO2 to the human embryonic kidney cell (HEK-293) of norepinephrine transporter (hNET) or dopamine transporter (hDAT) stable transfection with the standard cell lines culture technique, Dulbecco ' s Modified Eagle ' sMedium (DMEM) substratum of 2mM L-glutaminate and 250 μ g/ml Geneticins (hSERT and hNET cell) or add 5%FCS, 5% newborn calf serum, grow in the DMEM-substratum of 2mM L-glutaminate and 2.5mg/ml tetracycline (hDAT cell)) cultivate.Before test,, be suspended in (referring to as follows) in the standard test damping fluid again with 750,000 cells/ml survivaling cell density by dissociating and centrifugal cell harvesting with cell dissociation solution (sigma).
(ii) inhibitor effectiveness is measured
All test compounds are dissolved among the 100%DMSO with 4mM, are diluted with water to 1%DMSO and obtain suitable test concentration.Test is carried out on 96 hole filter membrane base plates.Express the cell (75 of suitable human transport protein, 000 cell/test holes) in the standard test damping fluid that contains test compound, standard inhibitor (over against shining) or compound carrier (DMSO in water, final DMSO concentration is 0.1% in each test holes), cultivated 5 minutes in advance at 25 ℃.By adding
3The H-5-hydroxy-tryptamine,
3The H-norepinephrine or
3H-Dopamine HCL matrix begins reaction, and all are reflected under 25 ℃ carries out in Shaking Incubators.To hSERT and hDAT test incubation time is 5 minutes, and test is 15 minutes to hNET.By adding ice-cold wash buffer (referring to as follows) stopped reaction, use vacuum manifold filtration test mixture subsequently, wash rapidly with ice-cold lavation buffer solution, quantitatively participate in cell subsequently
3The quantity of H-matrix.Filtration/washing test plate adds scintillating liquid 45 ℃ of dryings 1 hour, measures radioactivity with scintillation counting.The effectiveness of test compound quantitatively is IC
50Value (suppressing the required test compound concentration of the specific absorption cell of 50% radio-labeling matrix) with respect to maximum (only compound carrier) and minimum (being suppressed fully) response by the standard inhibitor.
(iii) the standard test damping fluid is formed:
Three (hydroxymethyl) aminomethane hydrochloride (26mM)
NaCl(124mM)
KCl(4.5mM)
KH
2PO
4(1.2mM)
MgCl
2.6H
2O(1.3mM)
Xitix (1.136mM)
Glucose (5.55mM)
pH 7.40
CaCl
2(2.8mM)
Pargyline (100 μ M)
Annotate: the pH of damping fluid is adding CaCl
2Be adjusted to 7.40 with 1MnaOH before the Pargyline.
Lavation buffer solution is formed:
Three (hydroxymethyl) aminomethane hydrochloride (26mM)
NaCl(124mM)
KCl(4.5mM)
KH
2PO
4(1.2mM)
MgCl
2.6H
2O(1.3mM)
Xitix (1.136mM)
7.40,4 ℃ of pH use 6MHCl.
(iv) test parameter is summarized
| The HSERT test | The HDAT test | The HNET test | |
| Every test holes cell | 75,000 | 75,000 | 75,000 |
| Substrate concn | 3H-5HT (50nM) | 3H-Dopamine HCL (200nM) | 3H-norepinephrine (200nM) |
| Incubation time (minute) | 5 | 5 | 15 |
Table 1
| Compound | SRI IC 50(nM) | NRI IC 50(nM) |
| Embodiment 1 | 13.9 | 14.1 |
| Embodiment 2 | 9.7 | 28.5 |
| Embodiment 3 | 22.3 | 21.2 |
| Embodiment 4 | 18.8 | 45.9 |
| Embodiment 5 | 10.9 | 32.9 |
| Embodiment 6 | 45.2 | 56.9 |
| Embodiment 7 | 5.7 | 55.4 |
| Embodiment 8 | 7.5 | 16.7 |
| Embodiment 9 | 5.7 | 14.0 |
| Embodiment 10 | 7.6 | 7.7 |
| Embodiment 11 | 3.2 | 17.0 |
| Embodiment 12 | 21.5 | 26.3 |
| Embodiment 13 | 8.8 | 3.1 |
| Embodiment 14 | 43.0 | 57.1 |
| Embodiment 15 | 17.5 | 71.6 |
Compound of the present invention is handled easily with free alkali form and is separated, but the pharmaceutically useful acid salt of The compounds of this invention can use the ordinary method preparation.The solvate of compound of the present invention (for example, hydrate) can form in the treating processes of one of above-mentioned processing step.
When compound prepared with the described method of the foregoing description, the person skilled in the art will understand still must maybe need to adopt different processing or purification condition.
Claims (24)
1, formula (I) compound:
With its medicine and/or veterinary drug acceptable derivates,
Wherein
R
1Be H, C
1-6Alkyl ,-C (X) Y, C
3-8Cycloalkyl, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl, wherein cycloalkyl, aryl or het group are optional is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
R
2Be aryl or heteroaryl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
R
3Be C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkyl-C
1-6Alkyl, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl, wherein cycloalkyl, aryl or het group are optional is independently selected from C by at least one
1-6Alkyl, C
1-6Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces;
X is S or O;
Y is H, C
1-6Alkyl, aryl, het, aryl-C
1-4Alkyl or het-C
1-4Alkyl;
N is 1 or 2, and its prerequisite is when n is 1, and m is 0 or 1 and when n is 2, and m is 0, if wherein m is 0, then
*The expression chiral centre;
Aryl is phenyl, naphthyl, anthryl or phenanthryl;
Heteroaryl is fragrant 5-or 6-element heterocycle, and it contains at least one N, O or S heteroatoms, optional condensing in aryl;
Het is fragrance or non-fragrant 4-, 5-or 6-element heterocycle, and it contains at least one N, O or S heteroatoms, optional condense in 5-or 6-person's carbocyclic ring or contains at least one N, O or S heteroatomic second 4-, 5-or 6-element heterocycle.
2, the compound of claim 1, wherein R
1Be H.
3, claim 1 or 2 compound, wherein m is 0,
*Expression R or S enantiomorph.
4, the compound of claim 3, wherein
*Expression S enantiomorph.
5, the compound of above-mentioned arbitrary claim, wherein R
2Be phenyl, naphthyl or quinolyl, each is chosen wantonly and is independently selected from C by at least one
1-8Alkyl, C
1-8Alkoxyl group, OH, halo, CF
3, OCF
3, SCF
3, hydroxyl-C
1-6Alkyl, C
1-4Alkoxy-C
1-6Alkyl and C
1-4Alkyl-S-C
1-4The substituting group of alkyl replaces.
6, the compound of claim 5, wherein R
2Be phenyl or naphthyl, each is chosen wantonly and is independently selected from halo, OH, C by 1,2 or 3
1-4Alkyl and CF
3Substituting group replace.
7, the compound of above-mentioned arbitrary claim, wherein R
3Be C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Cycloalkyl-C
1-4Alkyl or aryl-C
1-4Alkyl.
8, the compound of claim 7, wherein R
3Be C
1-6Alkyl, C
3-6Cycloalkyl, C
3-6Cycloalkyl-C
1-2Alkyl, phenyl-CH
2-or naphthyl-CH
2-.
9, the compound of claim 1, wherein
R
1Be H;
R
2Be phenyl or naphthyl, each is chosen wantonly and is independently selected from halo, OH, C by 1,2 or 3
1-4Alkyl and CF
3Substituting group replace;
R
3Be C
1-6Alkyl, C
3-6Cycloalkyl, C
3-6Cycloalkyl-C
1-3Alkyl, phenyl-CH
2-or naphthyl-CH
2-and
M is 0.
10, the compound of claim 1, it is selected from:
2,3-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
2,4--two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
2-chloro-3-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-fluoro-2-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-methoxyl group-2-methyl-N-isopropyl butyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3-chloro-N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl] benzamide;
4-chloro-N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl] benzamide;
3,4-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
N-(2-naphthyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide;
N-(2-naphthyl methyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide;
The N-isobutyl--N-[(3S)-tetramethyleneimine-3-yl]-the 2-naphthoamide;
The N-butyl-N-[(3S)-tetramethyleneimine-3-yl]-the 1-naphthoamide;
4-chloro-N-(3, the 4-dichloro benzyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide;
N-tetramethyleneimine-3-base-N-(5,6,7,8-naphthane-1-ylmethyl)-benzamide;
N-(2,4-two chloro-benzyls)-N-tetramethyleneimine-3-base-benzamide;
N-(3-chloro-4-methyl-benzyl)-2-fluoro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-2-carboxylic acid butyl-tetramethyleneimine-3-base-acid amides;
Naphthalene-2-carboxylic acid isobutyl--tetramethyleneimine-3-base-acid amides;
Naphthalene-2-carboxylic acid (2,2-dimethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
3-chloro-N-isobutyl--4-methyl-N-tetramethyleneimine-3-base-benzamide;
N-isobutyl--2,3-dimethyl-N-tetramethyleneimine-3-base-benzamide;
3-chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2-chloro-4-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
2-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-chloro-2-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-chloro-4-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
N-butyl-2,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-methyls-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2-ethyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-isobutyl-s-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid isobutyl--tetramethyleneimine-3-base-acid amides;
2,4-two chloro-5-fluoro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(2,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(1,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(1,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-cyclohexyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid sec-butyl-tetramethyleneimine-3-base-acid amides;
N-sec-butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
N-sec-butyl-2,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(1-ethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(1-ethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (1-ethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
2,3-two chloro-N-cyclobutyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclobutyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-cyclopentyl-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-tetramethyleneimine-3-base-N-(1,2,2-trimethylammonium-propyl group)-benzamide;
The N-tertiary butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid cyclopentyl-tetramethyleneimine-3-base-acid amides;
2,3-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-(2,2-dimethyl-propyl group)-2-methyl-N-tetramethyleneimine-3-base-benzamide;
3-chloro-N-isobutyl--2-methyl-N-tetramethyleneimine-3-base-benzamide;
N-butyl-2,3-two chloro-N-tetramethyleneimine-3-base-benzamide;
N-butyl-3,4-two chloro-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-2-carboxylic acid cyclobutylmethyl-tetramethyleneimine-3-base-acid amides;
Naphthalene-1-carboxylic acid cyclobutylmethyl-tetramethyleneimine-3-base-acid amides;
3,4-two chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
4-chloro-N-isobutyl--2-methoxyl group-N-tetramethyleneimine-3-base-benzamide;
4-chloro-N-isobutyl--3-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-isobutyl-s-3-methyl-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (3-methyl-butyl)-tetramethyleneimine-3-base-acid amides;
Naphthalene-1-carboxylic acid (2,2-dimethyl-propyl group)-tetramethyleneimine-3-base-acid amides;
3,4-two chloro-N-(3-methyl-butyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(4-fluoro-phenyl)-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-N-(4-fluoro-phenyl)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-tetramethyleneimine-3-base-acid amides;
N-butyl-2,3,4-three chloro-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-cyclobutylmethyls-N-tetramethyleneimine-3-base-benzamide;
N-tetramethyleneimine-3-base-N-(3-trifluoromethyl-benzyl)-benzamide;
2,4-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
3,4-two chloro-N-phenyl-N-tetramethyleneimine-3-base-benzamide;
2,3,4-three chloro-N-(2,2-dimethyl-propyl group)-N-tetramethyleneimine-3-base-benzamide;
Naphthalene-1-carboxylic acid phenyl-tetramethyleneimine-3-base-acid amides;
2,3,4-three chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
2,3-two chloro-N-(2-cyclopropyl-ethyl)-N-tetramethyleneimine-3-base-benzamide;
2-bromo-4-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
4-chloro-2-oxyethyl group-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
3-bromo-4-chloro-N-isobutyl--N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-5-fluoro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide;
3,4-two chloro-N-isobutyl-s-2-methyl-N-tetramethyleneimine-3-base-benzamide;
2,4-two chloro-3-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3-two chloro-4-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3-two chloro-5-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,4,5-three chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,5-two chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,5-two chloro-4-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2,3,5-three chloro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide;
2,3-two chloro-6-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
3,4-two chloro-6-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
3,4-two chloro-2-fluoro-N-isobutyl--N-[tetramethyleneimine-3-yls] benzamide;
2-chloro-3,6-two fluoro-N-isobutyl-s-N-[tetramethyleneimine-3-yl] benzamide; With
4-chloro-N-(2, the 3-dichloro benzyl)-N-[(3R)-tetramethyleneimine-3-yl] benzamide;
Or its medicine and/or veterinary drug acceptable derivates.
11, the compound of claim 10, it is 2,3-two chloro-N-isobutyl-s-N-[(3S)-and tetramethyleneimine-3-yl] benzamide or its medicine and/or veterinary drug acceptable derivates.
12, pharmaceutical composition, it contains among the claim 1-11 any one compound and pharmaceutically useful auxiliary material, diluent or carrier.
13, as any one compound among the claim 1-11 of medicine.
14, the compound of any one is used for the treatment of purposes in the medicine that relates to the disease that monoamine translocator function in the Mammals regulates in preparation among the claim 1-11.
15, the compound of any one is used for the treatment of purposes in the medicine that relates to the disease that serotonin in the Mammals or norepinephrine regulate in preparation among the claim 1-11.
16, the purposes of claim 15 wherein relates to the adjusting of serotonin and norepinephrine.
17, the compound of any one is used for the treatment of purposes in the medicine of urethral disease in the Mammals, depression, pain, premature ejaculation, ADHD or fibromyalgia in preparation among the claim 1-11.
18, the purposes of claim 17 is used for treating the urinary incontinence Mammals, for example GSI or USI.
19, treatment wherein relates to the method for the disease that monoamine translocator function regulates, and it comprises in the claim 1-11 of patient's drug treatment significant quantity of this treatment of needs the compound of any one.
20, treatment wherein relates to the method for the disease that serotonin or norepinephrine regulate, and comprises in the claim 1-11 of patient's drug treatment significant quantity of this treatment of needs the compound of any one.
21, the method for claim 20 wherein relates to the adjusting of serotonin and norepinephrine.
22, the method for treatment urethral disease, depression, pain, premature ejaculation, ADHD or fibromyalgia comprises in the claim 1-11 of patient's drug treatment significant quantity of this treatment of needs any one compound.
23, the method for claim 22, wherein urethral disease is the urinary incontinence, for example GSI or USI.
24, the method for preparing any one compound among the claim 1-11 comprises making formula (X) compound:
R wherein
3, n and m be as defined above, Y is R
1Or blocking group, with acid or carboxylic acid halides: R
2COX reaction, wherein X is OH or halogen and as required or require the deprotection base.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0314048.0 | 2003-06-17 | ||
| GBGB0314048.0A GB0314048D0 (en) | 2003-06-17 | 2003-06-17 | Novel compounds |
| US60/493,126 | 2003-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1835921A true CN1835921A (en) | 2006-09-20 |
Family
ID=27636730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800172229A Pending CN1835921A (en) | 2003-06-17 | 2004-06-07 | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
Country Status (9)
| Country | Link |
|---|---|
| CN (1) | CN1835921A (en) |
| GB (1) | GB0314048D0 (en) |
| GT (1) | GT200400121A (en) |
| NO (1) | NO20060190L (en) |
| OA (1) | OA13178A (en) |
| RS (1) | RS20050924A (en) |
| TN (1) | TNSN05321A1 (en) |
| UA (1) | UA80338C2 (en) |
| ZA (1) | ZA200509132B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952280B (en) * | 2007-12-19 | 2014-04-23 | 大日本住友制药株式会社 | Bicyclic heterocyclic derivative |
-
2003
- 2003-06-17 GB GBGB0314048.0A patent/GB0314048D0/en not_active Ceased
-
2004
- 2004-06-07 CN CNA2004800172229A patent/CN1835921A/en active Pending
- 2004-06-07 OA OA1200500363A patent/OA13178A/en unknown
- 2004-06-07 RS YUP-2005/0924A patent/RS20050924A/en unknown
- 2004-06-15 GT GT200400121A patent/GT200400121A/en unknown
- 2004-07-06 UA UAA200511011A patent/UA80338C2/en unknown
-
2005
- 2005-11-11 ZA ZA200509132A patent/ZA200509132B/en unknown
- 2005-12-16 TN TNP2005000321A patent/TNSN05321A1/en unknown
-
2006
- 2006-01-12 NO NO20060190A patent/NO20060190L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952280B (en) * | 2007-12-19 | 2014-04-23 | 大日本住友制药株式会社 | Bicyclic heterocyclic derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| UA80338C2 (en) | 2007-09-10 |
| GB0314048D0 (en) | 2003-07-23 |
| RS20050924A (en) | 2008-04-04 |
| NO20060190L (en) | 2006-01-12 |
| GT200400121A (en) | 2005-03-03 |
| ZA200509132B (en) | 2007-02-28 |
| TNSN05321A1 (en) | 2007-07-10 |
| OA13178A (en) | 2006-12-13 |
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