CN1444567A - Imidazole derivatives - Google Patents

Imidazole derivatives Download PDF

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Publication number
CN1444567A
CN1444567A CN01813397A CN01813397A CN1444567A CN 1444567 A CN1444567 A CN 1444567A CN 01813397 A CN01813397 A CN 01813397A CN 01813397 A CN01813397 A CN 01813397A CN 1444567 A CN1444567 A CN 1444567A
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cyclobutyl
base
imidazoles
cis
compound
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M·K·艾利亚尼安
C·B·库博
C·J·赫劳
L－F·劳
F·S·美尼逖
M·A·萨尼尔
P·A·瑟莫尔
A·维拉罗波斯
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Pfizer Products Inc
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Pfizer Products Inc
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Abstract

The invention provides compounds of formula (1), wherein R<1>, R<2>, R<3>, and R<4> are as defined, and their pharmaceutically acceptable salts. Compounds of formula (1) are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula (1) for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula (1) for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

Description

Imdazole derivatives
Technical field
The present invention relates to imdazole derivatives, contain the pharmaceutical composition of such derivative, use the method for such derivatives for treatment abnormal cell growth and some central nervous system diseases and illness.The compounds of this invention plays the inhibitor of cyclin dependant protein kinase cdk5 (cyclin dependant protein kinase 5) and cdk2 (cyclin dependant protein kinase 2).The compounds of this invention still is the inhibitor of enzyme GSK-3 (glycogen synthase kinase-3).
Background technology
Serine/threonine kinase cdk5 is relevant with neurodegenerative disease together with its cofactor p25 (or longer cofactor p35), so cdk5/p25 (or cdk5/p35) inhibitor can be used for treating neurodegenerative disease for example Alzheimer, Parkinson's disease, apoplexy or huntington's chorea.Following discovery has been supported to use the such neurodegenerative disease of cdk5 inhibitor for treating: cdk5 relates to the phosphorylation (J.Biochem, 117,741-749 (1995)) of tau protein.Cdk5 also with the phosphorprotein (DARPP-32) of Dopamine HCL and ring AMP-regulation and control in Threonine 75 phosphorylations, and therefore in the dopaminergic nerve transmission, work (Nature, 402,669-671 (1999)).
Serine/threonine kinase cdk2 is essential for the normal cell cycle, and plays a crucial role in the illness by the common trait of abnormal cells cycle-many tumour illnesss-cause.Therefore, the cancer that cdk2 can be used for treating number of different types and other disease relevant with abnormal cell growth or illness (Meijer waits the people, The character of cell cycle protein dependent kinase chemical inhibitor With possible application, Pharmacology ﹠amp; Therapeutics, 82 (2-3), 279-284 (1999); Sausville waits the people, Cell cycle protein dependent kinase: Develop new treatment target Initial methods, Pharmacology ﹠amp; Therapeutics 82 (2-3) 285-292 (1999)).
GSK-3 is a serine/threonine protein kitase.It is that (Embi waits the people to one of several protein kinases of phosphorylation Glycogensynthase, Eur.J.Biochem.107:519-527 (1980); Hemmings waits the people, Eur.J.Biochem.119:443-451 (1982)).GSK-3 is present in the vertebrates with two kinds of isotype α and β, it is reported the monomer structure that has 49kD and 47kD respectively.These two kinds of isotypes are phosphorylation muscle Glycogensynthase (Cross waits the people, Biochemical Journal 303:21-26 (1994)) all.It is reported that the amino acid consistence of GSK-3 class homologue in catalytic domain surpassed 98% (Plyte waits the people, Biochim.Biophys.Acta 1114:147-162) (1992)).Because kind be high conservative in composing, the someone has proposed the basic role of GSK-3 in cell processes.
Existing people proposes GSK-3 and relates to multiple different disease and illness.For example, Chen waits the people to propose in Diabetes 43:1234-1241 (1994), and the active increase of GSK-3 may be very important in diabetes B.Yet also to be that the Glycogensynthase that exists in the diabetes B is active weaken and the reason (Nikoulina waits the people, Diabetes 49:263-271 (2000)) of skeletal muscle insulin resistance in the expression increase of GSK-3 in diabetic subject's muscle.And, the greater activity of the 1 type phosphoprotein phosphatase that detects in immotile sperm is the active reason of higher GSK-3, and show its mobility influential (Vijayaraghavan waits people Biology of Reproduction 54:709-718 (1996)) to the sperm that keeps being detected.People such as Vijayaraghavan point out that such result provides biochemical basis for development and regulation and control sperm motility, and phosphatase 1/inhibitor 2/GSK-3 system has been proposed possible physiological action.GSK-3 active with Alzheimer and emotional handicap bipolar disorder relevant (WO97/41854) for example.In the middle of other illness, GSK-3 also relates to alopecia, schizophrenia and neurodegeneration, comprises chronic neurodegenerative disease (for example above-mentioned Alzheimer) and neural wound for example apoplexy, traumatic brain injury and spinal cord injuries receptor.
Summary of the invention
The invention provides Shi 1 compound and pharmaceutically acceptable Yan thereof
Figure A0181339700091
Qi Zhong R1Shi Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8) alkynyl, (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5-C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 14) aryl or (5-14 Yuan) heteroaryl; Qi Zhong R1But Ren Xuan is independently selected from Xia the Qu of row for basic R by 1-65Qu generation: F, Cl, Br, I, Xiao base, Qing be basic ,-CF3、-NR 7R 8、 -NR 7C(＝O)R 8、-NR 7C(＝O)OR 8、-NR 7C(＝O)NR 8R 9、-NR 7S(＝O) 2R 8、 -NR 7S(＝O) 2NR 8R 9、-OR 7、-OC(＝O)R 7、-OC(＝O)OR 7、-C(＝O)OR 7、 -C(＝O)R 7、-C(＝O)NR 7R 8、-OC(＝O)NR 7R 8、-OC(＝O)SR 7、-SR 7、-S(＝O)R 7、 -S(＝O) 2R 7、-S(＝O) 2NR 7R 8、-O-S(＝O) 2R 7、-N 3And R7； R 2Shi H, F, CH3, CN or C (=O) OR7； R 3Shi-C (=O) NR9-、-C(＝O)O-、-C(＝O)(CR 10R 11) n-or-(CR10R 11) n-； R 4Shi Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8Alkynyl), (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5- C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 14) aryl or (5-14 Yuan) heteroaryl; Qi Zhong R4But Ren Xuan is independently selected from Xia the Qu of row for basic R by 1-36Qu generation: F, Cl, Br, I, Xiao base, Qing be basic ,-CF3、-NR 7R 8、 -NR 7C(＝O)R 8、-NR 7C(＝O)OR 8、-NR 7C(＝O)NR 8R 9、-NR 7S(＝O) 2R 8、 -NR 7S(＝O) 2NR 8R 9、-OR 7、-OC(＝O)R 7、-OC(＝O)OR 7、-C(＝O)OR 7、 -C(＝O)R 7、-C(＝O)NR 7R 8、-OC(＝O)NR 7R 8、-OC(＝O)SR 7、-SR 7、-S(＝O)R 7、 -S(＝O) 2R 7、-S(＝O) 2NR 7R 8, or R7； R 7、R 8, and R9Be independently selected from respectively H, Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8Alkynyl), (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5-C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 14) aryl and (5-14 Yuan) heteroaryl, Qi Zhong R7、R 8, and R9Respectively independently the Ren Xuan Qu that is independently selected from Xia row by 1-6 for basic Qu generation: F, Cl, Br, I, NO2、-CN、-CF 3、-NR 10R 11、-NR 10C(＝O)R 11、-N 10C(＝O)OR 11、 -NR 10C(＝O)NR 11R 12、-NR 10S(＝O) 2R 11、-NR 10S(＝O) 2NR 11R 12、-OR 10、 OC(＝O)R 10、-OC(＝O)OR 10、-OC(＝O)NR 10R 11、-OC(＝O)SR 10、-SR 10、 -S(＝O)R 10、-S(＝O) 2R 10、-S(＝O) 2NR 10R 11、-C(＝O)R 10、-C(＝O)OR 10、 -C(＝O)NR 10R 11, and R10 Or work as R7And R8Zai NR7R 8Zhong Shi, but Ta Ren Xuan connects the NR that Yi is connected Yu Qi Suo7R 8Nitrogen Xing become 3-7 Yuan Za cycloalkyl, but Suo Shu Za cycloalkyl Ren Xuan comprises 1 or 2 other Za Yuan that is independently selected from N, O and S; R10、R 11, and R12Be independently selected from respectively H, Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8Alkynyl), (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5-C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 4) aryl and (5-14 Yuan) heteroaryl, Qi Zhong R10、R 11, and R12Respectively independently the Ren Xuan Qu that is independently selected from Xia row by 1-6 for basic Qu generation: F, Cl, Br, I, NO2、-CN、-CF 3、-NR 13R 14、-NR 13C(＝O)R 14、-NR 13C(＝O)OR 14、 -NR 13C(＝O)NR 14R 15、-NR 13S(＝O) 2R 14、-NR 13S(＝O) 2NR 14R 15、-OR 13、 OC(＝O)R 13、-OC(＝O)OR 13、-OC(＝O)NR 13R 14、-OC(＝O)SR 13、-SR 13、 -S(＝O)R 13、-S(＝O) 2R 13、-S(＝O) 2NR 13R 14、-C(＝O)R 13、-C(＝O)OR 13、 -C(＝O)NR 13R 14, and R13； R 13、R 14, and R15Be independently selected from respectively H, Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8Alkynyl), (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5-C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 14) aryl and (5-14 Yuan) heteroaryl, Qi Zhong R13、R 14, and R15Respectively independently the Ren Xuan Qu that is independently selected from Xia row by 1-6 for basic Qu generation: F, Cl, Br, I, NO2、-CN、-CF 3、-NR 16R 17、-NR 16C(＝O)R 17、-NR 16C(＝O)OR 17、 -NR 16C(＝O)NR 17R 18、-NR 16S(＝O) 2R 17、-NR 16S(＝O) 2NR 17R 18、-OR 16、 OC(＝O)R 16、-OC(＝O)OR 16、-OC(＝O)NR 16R 17、-OC(＝O)SR 16、-SR 16、 -S(＝O)R 16、-S(＝O) 2R 16、-S(＝O) 2NR 16R 17、-C(＝O)R 16、-C(＝O)OR 16、 -C(＝O)NR 16R 17, and R16； R 16、R 17, and R18Be independently selected from respectively H, Zhi chain or Zhi chain (C1-C 8) Wan base, Zhi chain or Zhi chain (C2-C 8) alkenyl, Zhi chain or Zhi chain (C2-C 8Alkynyl), (C3-C 8) cycloalkyl, (C4-C 8) cycloalkenyl group, (3-8 Yuan) Za cycloalkyl, (C5-C 11) bicyclic alkyl, (C7-C 11) bicycloenyl, (5-11 Yuan) Za bicyclic alkyl, (C6-C 14) aryl and (5-14 Yuan) heteroaryl; N Shi 0,1,2 or 3; Qi Zhong is multiple for Mei Chong of n ,-C (=O) (CR10R 11) n-and-(CR10R 11) nThe R of-Zhong10And R11All define as Shang Suo independently.
Formula 1 compound of the present invention is for example inhibitor of cdk5 and cdk2 of serine/threonine kinase inhibitor, especially cell cycle protein dependent kinase, and can be used for treating neurodegenerative disease and other CNS illness, and abnormal cell growth, comprises cancer.Formula 1 compound can be used in particular for suppressing cdk5.Formula 1 compound also can be used as the GSK-3 inhibitor.
Except as otherwise noted, otherwise term used herein " alkyl " comprises the saturated univalence hydrocarbyl with straight or branched part.The example of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.
Except as otherwise noted, otherwise term used herein " alkenyl " comprises the alkyl with at least one carbon-to-carbon double bond, and wherein said alkyl as defined above.Non-limiting examples of alkenyls includes but not limited to vinyl and propenyl.
Except as otherwise noted, otherwise term used herein " alkynyl " comprises the alkyl with at least one carbon-to-carbon triple bond, and wherein said alkyl as defined above.The example of alkynyl includes but not limited to ethynyl and 2-propynyl.
Except as otherwise noted, otherwise term used herein " cycloalkyl " comprises non-aromatics saturated cyclic alkyls, and wherein said alkyl as defined above.The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl." bicyclic alkyl " is the non-aromatics saturated carbon ring base that is made of two rings, and wherein said ring is shared one or two carbon atom.For the object of the invention, and except as otherwise noted, bicyclic alkyl comprises volution group and fused rings group.The example of bicyclic alkyl includes but not limited to two ring-[3.1.0] hexyls, norborneol alkyl, spiral shell [4.5] decyl, spiral shell [4.4] nonyl, spiral shell [4.3] octyl group and spiral shell [4.2] heptyl." cycloalkenyl group " and " bicycloenyl " is meant non-as defined above aromatic carbocyclic cycloalkyl and bicyclic alkyl, but comprises the unitary carbon-to-carbon double bond of one or more connection carbocyclic rings (" in the ring " two keys) and one or more carbon-to-carbon double bonds (" ring is outer " two keys) that are connected carbocyclic ring unit and adjacent acyclic carbon.The example of cycloalkenyl group includes but not limited to cyclopentenyl and cyclobutene base, and the limiting examples of bicycloenyl has norbornene.Cycloalkyl, cycloalkenyl group, bicyclic alkyl and bicycloenyl also comprise the group that is replaced by one or more oxo bases.Examples of groups with oxo base has oxo cyclopentyl, oxo cyclobutyl, oxo cyclopentenyl and Norcamphor base.
Except as otherwise noted, otherwise term " aryl " comprise by remove the organic group that a hydrogen obtains, for example phenyl, naphthyl, indenyl and fluorenyl from aromatic hydrocarbons.
Similar terms such as term used herein " heterocyclic radical ", " Heterocyclylalkyl " are meant and contain one or more heteroatomss, preferred 1-4 heteroatomic non-aromatics cyclic group that is selected from O, S and N respectively." assorted bicyclic alkyl " is non-aromatics bicyclic ring shape group, and wherein said ring is shared one or two atom, and at least one ring contains heteroatoms (O, S or N).For the object of the invention, and except as otherwise noted, assorted bicyclic alkyl comprises volution group and fused rings group.In one embodiment, each ring in the assorted bicyclic alkyl contains and is up to 4 heteroatomss (be 0-4 heteroatoms, condition is to have at least a ring to contain at least one heteroatoms).Heterocyclic group of the present invention can also comprise the ring system that is replaced by one or more oxo bases.The example of non-aromatic heterocycle has the ethylenimine base, azetidinyl, pyrrolidyl, piperidyl, the azatropylidene base, piperazinyl, 1,2,3, the 6-tetrahydro pyridyl, Oxyranyle, oxetanyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholino, thiomorpholine is for thioxane base, pyrrolinyl, indolinyl, the 2H-pyranyl, the 4H-pyranyl, the dioxane base, 1,3-dioxolane base, pyrazolinyl, dihydro pyranyl, the dihydro-thiophene base, the dihydrofuran base, pyrazolidyl, imidazolinyl, imidazolidyl, 3-azabicyclic [3.1.0] hexyl, 3-azabicyclic [4.1.0] heptane base, quinolizinyl, quinuclidinyl, 1,4-dioxo spiro [4.5] decyl, 1,4-dioxo spiro [4.4] nonyl, 1,4-dioxo spiro [4.3] octyl group, with 1,4-dioxo spiro [4.2] heptyl.
" heteroaryl " used herein is meant and comprises one or more heteroatomss (O, S or N), preferred 1-4 heteroatomic aryl.Wherein at least one ring be containing of aromatic ring one or more heteroatomic many cyclic groups are " heteroaryls ".Heteroaryl of the present invention can also comprise the ring system that is replaced by one or more oxo bases.The example of heteroaryl has pyridyl, pyridazinyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazyl, furyl, thienyl isoxazolyl, thiazolyl oxazolyl, isothiazolyl, pyrryl, indyl, benzimidazolyl-, benzofuryl, the cinnolines base, indazolyl, the indolizine base, phthalazinyl, triazinyl, pseudoindoyl, purine radicals oxadiazole base, thiadiazolyl group, the furazan base, benzo furazan base, benzothienyl, the benzotriazole base, benzothiazolyl benzoxazolyl, quinazolyl, quinoxalinyl, naphthyridinyl, the dihydroquinoline base, tetrahydric quinoline group, the dihydro-isoquinoline base, tetrahydro isoquinolyl, benzofuryl, the furo pyridyl, pyrrolo-pyrimidine radicals, and azaindolyl.
Above-mentioned group derived from compound listed above can be that C-connects or N-connects, as long as such connection is possible.For example, the group derived from the pyrroles can be pyrroles-1-base (N-connection) or pyrroles-3-base (C-connection).The term that relates to group also comprises all possible tautomer.
In one embodiment, the invention provides formula 1 compound, wherein R 3Be C (=O) NR 9-or-C (=O) (CR 10R 11) n-.In another embodiment, for each repetition of n ,-C (=O) (CR 10R 11) n-in R 10And R 11All be hydrogen.In another embodiment ,-C (=O) NR 9-R 9Be hydrogen.In another embodiment, R 3Be-C (=O) NR 9-or-C (=O) (CR 10R 11) n-, and R 2Be hydrogen.
In another embodiment of the present invention, provide formula 1 compound, wherein R 1Be the optional (C that replaces 3-C 8) cycloalkyl or the optional (C that replaces 5-C 11) bicyclic alkyl.Embodiment preferred is such, wherein R 1Be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norborneol alkyl, optional respectively being substituted as mentioned above of described group (is promptly chosen wantonly by 1-6 and is independently selected from following substituent R 5Replace: F, Cl, Br, I, nitro, cyano group ,-CF 3,-NR 7R 8,-NR 7C (=O) R 8,-NR 7C (=O) OR 8,-NR 7C (=O) NR 8R 9,-NR 7S (=O) 2R 8,-NR 7S (=O) 2NR 8R 9,-OR 7,-OC (=O) R 7,-OC (=O) OR 7,-C (=O) OR 7,-C (=O) R 7,-C (=O) NR 7R 8,-OC (=O) NR 7R 8,-OC (=O) SR 7,-SR 7,-S (=O) R 7,-S (=O) 2R 7,-S (=O) 2NR 7R 8, and R 7).In a more preferred embodiment, R 1Be (C 3-C 8) cycloalkyl or the optional (C that replaces 5-C 11) bicyclic alkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norborneol alkyl, and optionally be independently selected from following substituting group by 1-3 and replace: F, Cl, Br, I, nitro, cyano group ,-CF 3,-NR 7R 8,-NR 7C (=O) R 8,-OR 7,-C (=O) OR 7,-C (=O) R 7, and R 7More preferably, R 1Be (C 3-C 8) cycloalkyl or the optional (C that replaces 5-C 11) bicyclic alkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norborneol alkyl, and R 1Quilt-NR 7C (=O) R 8, (C 6-C 14) aryl, (3-8 unit) Heterocyclylalkyl or (5-14 unit) heteroaryl replace, wherein said aryl, Heterocyclylalkyl and heteroaryl be optional independently respectively to be independently selected from following substituting group by 1-6 and to replace: F, Cl, Br, I, NO 2,-CN ,-CF 3,-NR 10R 11,-NR 10C (=O) R 11,-NR 10C (=O) OR 11,-NR 10C (=O) NR 11R 12,-NR 10S (=O) 2R 11,-NR 10S (=O) 2NR 11R 12,-OR 10, OC (=O) R 10,-OC (=O) OR 10,-OC (=O) NR 10R 11,-OC (=O) SR 10,-SR 10,-S (=O) R 10,-S (=O) 2R 10,-S (=O) 2NR 10R 11,-C (=O) R 10,-C (=O) OR 10,-C (=O) NR 10R 11, and R 10In another embodiment of the present invention, R 1Be two ring [3.1.0] hexyls, and optional being substituted as mentioned above (promptly chosen wantonly by 1-6 and is independently selected from following substituent R 5Replace: F, Cl, Br, I, nitro, cyano group ,-CF 3,-NR 7R 8,-NR 7C (=O) R 8,-NR 7C (=O) OR 8,-NR 7C (=O) NR 8R 9,-NR 7S (=O) 2R 8,-NR 7S (=O) 2NR 8R 9,-OR 7,-OC (=O) R 7,-OC (=O) OR 7,-C (=O) OR 7,-C (=O) R 7,-C (=O) NR 7R 8,-OC (=O) NR 7R 8,-OC (=O) SR 7,-SR 7,-S (=O) R 7,-S (=O) 2R 7,-S (=O) 2NR 7R 8, and R 7).
In another embodiment of the present invention, provide formula 1 compound, wherein R 1Be the optional straight or branched (C that replaces 1-C 6) alkyl or the optional straight or branched (C that replaces 2-C 8) alkenyl.
In another embodiment of the present invention, provide formula 1 compound, wherein R 2Be hydrogen.In another embodiment, R 2Be hydrogen, and R 1As the further definition of the previous paragraph institute.
In another embodiment, the invention provides formula 1 compound, wherein R 4Be (C 6-C 14) aryl or (5-14 unit) heteroaryl, described group is optional respectively to be substituted.In embodiment preferably, R 4Be optional phenyl that replaces or the optional pyridyl that replaces.In another embodiment preferred, R 4Be optional respectively naphthyl, quinolyl or the isoquinolyl that replaces.In another embodiment, R 4Be naphthyl, quinolyl or isoquinolyl, and be unsubstituted.
In another embodiment, provide formula 1 compound, wherein R 2Be hydrogen, and R 4As the further definition of the previous paragraph institute.
Preferred formula 1 examples for compounds is: N-(1-cyclobutyl-1H-imidazol-4 yl)-2-quinoline-6-base-ethanamide; N-(1-cyclopentyl-1H-imidazol-4 yl)-2-(4-methoxyl group-phenyl)-ethanamide; N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4 yl]-2-quinoline-6-base-ethanamide; (1-cyclobutyl-1H-imidazol-4 yl)-phenyl carbamate; 1-(1-cyclobutyl-1H-imidazol-4 yl)-3-isoquinoline 99.9-5-base-urea; N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide; 6-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; 1H-imidazoles-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; 6-hydroxyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; 3-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides; 2-pyridin-3-yl-thiazole-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides; 6-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl formamyl }-nicotinic acid methyl ester; Pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides; N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide; 5-methyl-pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides; N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-isobutyramide; 6-chloro-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; Quinoline-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides; 1H-pyrroles-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides; N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl-2-between tolyl-ethanamide; Pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides; 2-(3-hydroxyl-phenyl)-N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-ethanamide; Piperidines-4-formic acid (cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-amide hydrochloride; N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-2-base-ethanamide; N-{ cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide; And pyridine-2-formic acid cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; Pharmacologically acceptable salt with above-claimed cpd.
Other concrete formula 1 examples for compounds of the present invention is: cis-N-(1-two ring [3.1.0] oneself-3-base-1H-imidazol-4 yl)-2-quinoline-6-base-ethanamide; Cis-N-{1-[is trans-6-(pyridine-2-carbonyl)-two rings [3.1.0] oneself-the 3-yl]-the 1H-imidazol-4 yl-2-quinoline-6-base-ethanamide; N-{1-[cis-3-(2-methoxyl group-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-quinoline-6-base-ethanamide; N-{1-[cis-3-(2-fluoro-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-quinoline-6-base-ethanamide; N-{1-[cis-3-(4-methoxyl group-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-quinoline-6-yl acetamide; 2-quinoline-6-base-N-[1-(cis-3-p-methylphenyl-cyclobutyl)-1H-imidazol-4 yl]-ethanamide; N-{1-[cis-3-(2-oxyethyl group-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-quinoline-6-base-ethanamide; N-{1-[cis-3-(3-methoxyl group-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-quinoline-6-base-ethanamide; Pharmacologically acceptable salt with above-claimed cpd.
Other example of concrete formula 1 compound is: N-{1-[3-(2-hydroxyl-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; N-{1-[3-(3-hydroxyl-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; N-{1-[3-(2-amino-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; N-{1-[3-(3-amino-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; N-{1-[3-(3-amino methyl-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; N-{1-[3-(3-dimethylaminomethyl-phenyl)-cyclobutyl]-the 1H-imidazol-4 yl }-2-(4-methoxyl group-phenyl)-ethanamide; And 2-(4-methoxyl group-phenyl)-N-{1-[3-(1-methyl isophthalic acid H-pyrazole-3-yl)-cyclobutyl]-the 1H-imidazol-4 yl }-ethanamide; Pharmacologically acceptable salt with above-claimed cpd.
The salt of formula 1 compound can be by obtaining with any acidity or the basic group formation salt that are present on formula 1 compound.The example of the pharmacologically acceptable salt of formula 1 compound be hydrochloride, tosilate, fumarate, Citrate trianion, succinate, salicylate, oxalate, hydrobromate, phosphoric acid salt, mesylate, tartrate, maleate, two pairs of toluyl tartrates, acetate, vitriol, hydriodate, mandelate, sodium salt, sylvite, magnesium salts, calcium salt and lithium salts.
Formula 1 compound can have rotophore, therefore can exist with different enantiomorphs and other steric isomer configuration.The present invention includes all enantiomorphs, diastereomer and other steric isomer of such formula 1 compound, and racemic modification and composition thereof.
The present invention also comprises isotope-labeled compound, and they are identical with formula 1 compound, but the atom that has one or more atoms to be had to be different from common atomic mass of occurring in nature or total mass number substitutes.Can be incorporated into the isotropic substance that the interior isotopic example of The compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, for example 3H, 11C, 14C, 18F, 123I and 125I.Containing other the isotopic The compounds of this invention of above-mentioned isotropic substance and/or other atom and the pharmacologically acceptable salt of described compound is included in the scope of the present invention.Isotope-labeled The compounds of this invention for example for example mixes radio isotope 3H and 14The The compounds of this invention of C can be used for medicine and/or the analysis of substrate tissue distribution.Tritium, promptly 3H and carbon-14, promptly 14The C isotropic substance is owing to be easy to preparation and detection but particularly preferred. 11C and 18The F isotropic substance can be used in particular for PET (positron emission tomography method), 125The I isotropic substance can be used in particular for SPECT (single photon emission computerized tomography(SPECT)), and they all can be used for the brain imaging.In addition, promptly with heavier isotropic substance 2H replaces can obtain some by the treatment advantage that stronger metabolic stability brings, and for example increases transformation period or the essential dosage of reduction in the body, is preferred in some cases therefore.Isotope-labeled formula of the present invention 1 compound generally can be undertaken that disclosed method makes in reaction scheme and/or embodiment by replace the heterotope labelled reagent with the isotope-labeled reagent that is easy to obtain.
The present invention also provides and has been used for the treatment of the disease that comprises abnormal cell growth in the Mammals or the pharmaceutical composition of illness, wherein contains formula 1 compound and pharmaceutically acceptable carrier of suppressing the abnormal cell growth significant quantity.
The present invention also provides and has been used for the treatment of the disease that comprises abnormal cell growth in the Mammals or the pharmaceutical composition of illness, wherein contains formula 1 compound and pharmaceutically acceptable carrier of suppressing the active significant quantity of cdk2.
The present invention also provides in the treatment Mammals and has comprised the disease of abnormal cell growth or the method for illness, comprises formula 1 compound that suppresses the abnormal cell growth significant quantity to described administration.
The present invention also provides in the treatment Mammals and has comprised the disease of abnormal cell growth or the method for illness, comprises formula 1 compound that suppresses the active significant quantity of cdk2 to described administration.
Comprise in the pharmaceutical composition or method of the disease of abnormal cell growth or illness in treatment, in one embodiment, comprise that the disease of abnormal cell growth or illness are cancers.Described cancer can be a cancer, for example bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer small cell lung cancer, esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, uterus carcinoma, thyroid carcinoma, prostate cancer or skin carcinoma squamous cell cancer for example for example; Lymphatic system hematopoiesis tumour, for example leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, He Jiejin lymphomas, non_hodgkin lymphoma, hairy cell lymphoma or Burkett ' s lymphoma; Myeloid lineage hematopoiesis tumour, for example acute and chronic lymphocytic leukemia, myelodysplastic syndrome or promyelocyte leukemia; Between the tumour of matter origin, for example fibrosarcoma or rhabdosarcoma; Maincenter or peripheral nervous system tumour be astrocytoma, neuroblastoma, neurospongioma or schwannoma for example; Melanoma; Spermocytoma; Teratoma; Osteosarcoma; Xeroderma pitmentosum (xenoderoma pigmentoum); Keratoacanthoma; Thyroid follcular carcinoma; Or Kaposi.
In another embodiment, comprise that the disease of abnormal cell growth or illness are benign.Such disease or illness comprise benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pnemnofibrosis, sacroiliitis, psoriasis, glomerulonephritis, restenosis, loose cicatrization, inflammatory bowel, transplant rejection, fungi infestation and endotoxin shock.
The present invention also provides the pharmaceutical composition that is used for the treatment of neurodegenerative disease in the Mammals or illness, wherein contains formula 1 compound and pharmaceutically acceptable carrier of described disease of treatment or illness significant quantity.
The present invention also provides the pharmaceutical composition that is used for the treatment of neurodegenerative disease in the Mammals or illness, wherein contains formula 1 compound and pharmaceutically acceptable carrier of suppressing the active significant quantity of cdk5.
The present invention also provides the method for neurodegenerative disease in the treatment Mammals or illness, comprises formula 1 compound that suppresses the active significant quantity of cdk5 to described administration.
The present invention also provides the method for neurodegenerative disease in the treatment Mammals or illness, comprises formula 1 compound for the treatment of described disease or illness significant quantity to described administration.
In an embodiment of the present invention, neurodegenerative disease of being treated or illness are selected from huntington's chorea, apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, the dementia that virus causes is the dementia that causes of AIDS for example, the neurodegeneration relevant with infectation of bacteria, migraine, hypoglycemia, the urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer, Alzheimers type senile dementia, mild cognitive weakens, the cognitive decline relevant with the age, vomiting, corticobasal degeneration, boxer's dementia, Tang Shi (Down ' s) syndrome, myotonia atrophica, Niemann (Niemann-Pick) disease, Pick's disease, prion disease with entanglement, stein-leventhal syndrome, low funiculus lateralis sclerosis, with the subacute sclerosing panencephalitis that causes.
The present invention also provides and has been used for the treatment of its treatment in the Mammals and can be undertaken or the pharmaceutical composition of promoted disease or illness by the neurotransmission that changes the Dopamine HCL mediation, wherein contains cdk5 inhibitor and pharmaceutically acceptable carrier of described disease of treatment or illness significant quantity.
The present invention also provides and has been used for the treatment of its treatment in the Mammals and can be undertaken or the pharmaceutical composition of promoted disease or illness by the neurotransmission that changes the Dopamine HCL mediation, wherein contains cdk5 inhibitor and pharmaceutically acceptable carrier of suppressing the cdk5 significant quantity.
The present invention also provides its treatment in the treatment Mammals to be undertaken or the method for promoted disease or illness by the neurotransmission that changes the Dopamine HCL mediation, comprises the cdk5 inhibitor that suppresses the active significant quantity of cdk5 to described administration.
The present invention also provides its treatment in the treatment Mammals to be undertaken or the method for promoted disease or illness by the neurotransmission that changes the Dopamine HCL mediation, comprises the cdk5 inhibitor for the treatment of described disease or illness significant quantity to described administration.
In an embodiment of the present invention, described its treatment can be undertaken or promoted disease or illness are selected from: Parkinson's disease by the neurotransmission that changes the Dopamine HCL mediation; Schizophrenia; Schizophrenia-like disorder; Schizophreniform affective disorder, for example delusional type or depressive type; Paranoea; The psychosis that material causes, for example psychosis that causes of alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; Paranoia's template personality disorder; Schizophrenia template personality disorder; Drug habit, for example narcotic (for example heroine, opium and morphine), Cocaine and alcohol addiction; Medicine is given up, and comprises narcotic, Cocaine and alcohol withdrawal; Obsessional idea and behavior disorder; Tourette's syndrome; Dysthymia disorders; The mood outbreak that major depressive episode, manic or chaotic mental state are shown effect, extremely frivolous hot-tempered mental state is shown effect, has atypical characteristics or had melancholy feature or paralepsy, the postpartum of catatonia feature are initial; Schizophrenia dysthymia disorders before the apoplexy retarded depression, severe depression, dysthymic disorder, mild depression, menstruation after anxiety disorder, the psychosis, with mental case such as paranoea or schizophrenia eclipsed severe depression, two-phase mental case such as two-phase I psychosis, two-phase II psychosis, cyclothymia; Anxiety; Attention is not enough and the hyperaction obstacle; With the not enough obstacle of attention.
In another embodiment, its treatment of treatment can be undertaken by the neurotransmission that changes the Dopamine HCL mediation or the method or composition of promoted disease or illness in, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the pharmaceutical composition that is used for the treatment of in the Mammals by active promoted disease of cdk5 or illness, wherein contains formula 1 compound and pharmaceutically acceptable carrier of suppressing the active significant quantity of cdk5.
The present invention also provides the method that is used for the treatment of in the Mammals by active promoted disease of cdk5 or illness, comprises formula 1 compound that suppresses the active significant quantity of cdk5 to described administration.
We find that also formula 1 compound has the activity that suppresses GSK3.Therefore, expectation formula 1 compound can be used for treating its treatment can be undertaken or promoted disease and illness by suppressing GSK-3.Its treatment can be by suppressing that GSK-3 carries out or promoted disease and illness comprise neurodegenerative disease and illness.Neurodegenerative disease and illness were above being discussed, and include but not limited to Alzheimer, Parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, apoplexy, cerebral ischemia, the dementia relevant, the neurodegeneration relevant with infectation of bacteria with AIDS, to infarct dementia, traumatic brain injury and spinal cord injuries receptor.Therefore, formula 1 compound can be treated active and active neurodegenerative disease of GSK-3 and illness based on cdk5 effectively.
Its treatment can be by suppressing that GSK-3 carries out or promoted disease and illness comprise mental disorder and illness, for example schizophrenia, schizophrenia-like disorder; Schizophreniform affective disorder, for example delusional type or depressive type; Paranoea; The psychosis that material causes, for example psychosis that causes of alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; Paranoia's template personality disorder; With schizophrenia template personality disorder.Such disease and treatment of conditions can also be undertaken or promote by the neurotransmission that changes the Dopamine HCL mediation.Therefore, formula 1 compound can be treated active and active such disease of GSK-3 and illness based on cdk5 effectively.
Its treatment can be by suppressing that GSK-3 carries out or promoted other disease and illness comprise mood disorder and mental state outbreak, for example major depressive episode, the outbreak of manic or chaotic mental state, extremely frivolous hot-tempered mental state outbreak, has atypical characteristics or have melancholy feature or mood outbreak that paralepsy, the postpartum of catatonia feature are initial; Schizophrenia dysthymia disorders before the apoplexy retarded depression, severe depression, dysthymic disorder, mild depression, menstruation after anxiety disorder, the psychosis, with mental case such as paranoea or schizophrenia eclipsed severe depression, two-phase mental case such as two-phase I psychosis, two-phase II psychosis and cyclothymia.The such mood disorder and the treatment of outbreak can also be undertaken or promote by the neurotransmission that changes the Dopamine HCL mediation.Therefore, formula 1 compound can be treated active and more active mood disorders of GSK-3 and mental state outbreak based on cdk5 effectively.
Its treatment can be by suppressing that GSK-3 carries out or promoted other disease and illness have male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute sarcopenia for example fixes with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; Immune deficiency; And cancer.
Therefore, the present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals that comprises the people: male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute myatrophy (sarcopenia) is for example fixed with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; And immune deficiency, wherein said composition comprises formula 1 compound of pharmaceutically acceptable carrier and described disease of treatment or illness significant quantity.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals that comprises the people: male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute myatrophy is for example fixed with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; And immune deficiency, wherein said composition comprises pharmaceutically acceptable carrier and suppresses formula 1 compound of GSK-3 significant quantity.
The present invention also provides to be used for the treatment of and has been selected from the following disease or the method for illness in the Mammals that comprises the people: male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute myatrophy is for example fixed with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; And immune deficiency, described method comprises formula 1 compound for the treatment of described disease or illness significant quantity to described administration.
The present invention also provides to be used for the treatment of and has been selected from the following disease or the method for illness in the Mammals that comprises the people: male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute myatrophy is for example fixed with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; And immune deficiency, described method comprises formula 1 compound that suppresses the GSK-3 significant quantity to described administration.
The present invention also provides the method that suppresses GSK-3 in comprising people's Mammals, and described method comprises formula 1 compound that suppresses the GSK-3 significant quantity to described administration.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following illness in the Mammals: Alzheimer, mild cognitive weaken and the cognitive decline relevant with the age, wherein contain cdk5 inhibitor and the COX-II inhibitor and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the method that is selected from following illness in the treatment Mammals: Alzheimer, mild cognitive weaken and the cognitive decline relevant with the age, described method comprises that to described administration cdk5 inhibitor and COX-II inhibitor, wherein the combined amount of cdk5 inhibitor and COX-II inhibitor can be treated described illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Cdk5 inhibitor and COX-II inhibitor can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
In addition, the cdk5 inhibitor for example the pharmacologically acceptable salt of formula 1 compound or formula 1 compound can be used for the treatment of or prevent the antidepressive or the antianxiety agent administration of dysthymia disorders and/or anxiety or be mixed with pharmaceutical composition with one or more.
Therefore, the present invention also provides the pharmaceutical composition that is used for the treatment of dysthymia disorders in the Mammals or anxiety, wherein contains cdk5 inhibitor and nk 1 receptor antagonist and pharmaceutically acceptable carrier of treatment dysthymia disorders or anxiety significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the method for dysthymia disorders in the treatment Mammals or anxiety, comprise that to described administration cdk5 inhibitor and nk 1 receptor antagonist, wherein the combined amount of cdk5 inhibitor and nk 1 receptor antagonist can be treated dysthymia disorders or anxiety effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Cdk5 inhibitor and nk 1 receptor antagonist can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides the pharmaceutical composition that is used for the treatment of dysthymia disorders in the Mammals or anxiety, wherein contains the cdk5 inhibitor and the 5HT of treatment dysthymia disorders or anxiety significant quantity 1DReceptor antagonist and pharmaceutically acceptable carrier.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the method for dysthymia disorders in the treatment Mammals or anxiety, comprises to described administration cdk5 inhibitor and 5HT 1DReceptor antagonist, wherein cdk5 inhibitor and 5HT 1DThe combined amount of receptor antagonist can be treated dysthymia disorders or anxiety effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Cdk5 inhibitor and 5HT 1DReceptor antagonist can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides the pharmaceutical composition that is used for the treatment of dysthymia disorders in the Mammals or anxiety, wherein contains cdk5 inhibitor and SSRI and pharmaceutically acceptable carrier of treatment dysthymia disorders or anxiety significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the method for dysthymia disorders in the treatment Mammals or anxiety, comprises that to described administration cdk5 inhibitor and SSRI, wherein the combined amount of cdk5 inhibitor and SSRI can be treated dysthymia disorders or anxiety effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Cdk5 inhibitor and SSRI can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides and has been used for the treatment of schizoid pharmaceutical composition in the Mammals, wherein contain the cdk5 inhibitor of treatment schizophrenia significant quantity and be selected from following tranquilizer: ziprasidone, olanzapine, Risperidone, L-745870, sonepiprazole, RP62203, NGD941, balaperidone, flesinoxan and gepirone hydrochloride, and pharmaceutically acceptable carrier.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides and has been used for the treatment of schizoid method in the Mammals, described method comprises to described administration cdk5 inhibitor and is selected from following tranquilizer: the Lars leads to (ziprasidone), olanzapine (olanzapine), Risperidone, L-745870, Song Pila azoles (sonepiprazole), RP62203, NGD 941, Ba Lapi ketone (balaperidone), flesinoxan (flesinoxan) and gepirone hydrochloride now, and wherein the combined amount of cdk5 inhibitor and tranquilizer can be treated schizophrenia effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Described cdk5 inhibitor and tranquilizer can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following illness in the Mammals: Alzheimer, mild cognitive weaken and the cognitive decline relevant with the age, wherein contain cdk5 inhibitor and the acetylcholinesterase depressant and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides the method that is selected from following illness in the treatment Mammals: Alzheimer, mild cognitive weaken and the cognitive decline relevant with the age, described method comprises that to described administration cdk5 inhibitor and acetylcholinesterase depressant, wherein the combined amount of cdk5 inhibitor and acetylcholinesterase depressant can be treated described illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Cdk5 inhibitor and acetylcholinesterase depressant can be administered to described Mammals simultaneously and/or at different time.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, wherein contain cdk5 inhibitor and the TPA (tissue plasminogen activator is ACTIVASE for example) and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides and has been selected from the following disease or the method for illness in the treatment Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, described method comprises cdk5 inhibitor and the TPA that treats described illness significant quantity to described administration, and wherein the combined amount of cdk5 inhibitor and TPA can be treated described disease or illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Described cdk5 inhibitor and TPA can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, wherein contain cdk5 inhibitor and the NIF (neutrophil supressor) and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides and has been selected from the following disease or the method for illness in the treatment Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, described method comprises cdk5 inhibitor and the NIF that treats described illness significant quantity to described administration, and wherein the combined amount of cdk5 inhibitor and NIF can be treated described disease or illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Described cdk5 inhibitor and NIF can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals: huntington's chorea, apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, the dementia that virus causes is the dementia that causes of AIDS for example, migraine, hypoglycemia, the urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer, Alzheimers type senile dementia, mild cognitive weakens, the cognitive decline relevant with the age, vomiting, corticobasal degeneration, boxer's dementia, Down ' s syndrome, myotonia atrophica, the Niemann-Pick disease, Pick's disease, prion disease with entanglement, stein-leventhal syndrome, low funiculus lateralis sclerosis, with the subacute sclerosing panencephalitis that causes, wherein contain cdk5 inhibitor and the nmda receptor antagonist and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides and has been selected from the following disease or the method for illness in the treatment Mammals: huntington's chorea, apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, amyotrophic lateral sclerosis, pain, the dementia that virus causes is the dementia that causes of AIDS for example, migraine, hypoglycemia, the urinary incontinence, cerebral ischemia, multiple sclerosis, Alzheimer, Alzheimers type senile dementia, mild cognitive weakens, the cognitive decline relevant with the age, vomiting, corticobasal degeneration, boxer's dementia, Down ' s syndrome, myotonia atrophica, the Niemann-Pick disease, Pick's disease, prion disease with entanglement, stein-leventhal syndrome, low funiculus lateralis sclerosis, with the subacute sclerosing panencephalitis that causes, described method comprises the cdk5 inhibitor and the nmda receptor antagonist for the treatment of described illness significant quantity to described administration, and wherein the combined amount of cdk5 inhibitor and nmda receptor antagonist can be treated described disease or illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Described cdk5 inhibitor and nmda receptor antagonist can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
The present invention also provides and has been used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, wherein contain cdk5 inhibitor and the potassium channel modulating agents and the pharmaceutically acceptable carrier for the treatment of described illness significant quantity.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.
The present invention also provides and has been selected from the following disease or the method for illness in the treatment Mammals: apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia, described method comprises the cdk5 inhibitor and the potassium channel modulating agents for the treatment of described illness significant quantity to described administration, and wherein the combined amount of cdk5 inhibitor and potassium channel modulating agents can be treated described disease or illness effectively.In one embodiment, described cdk5 inhibitor is formula 1 compound or pharmaceutically acceptable salt thereof.Described cdk5 inhibitor and potassium channel modulating agents can be administered to described Mammals simultaneously and/or at different time.In addition, they can be in single pharmaceutical composition or the pharmaceutical composition separated in administration together.
Term " smelting treatment " etc. is meant reverse, alleviates or suppresses progress or such disease or one or more symptoms of illness of applied disease of this term or illness.According to patient's illness, these terms used herein also are included in the beginning of the symptom of suffering from preventing disease before described disease or the illness or illness or disease or illness, comprise palliating a disease or the severity of illness or the symptom relevant with it.Prevention or alleviate is meant The compounds of this invention is administered to the individuality of not suffering from described disease or illness when the administration before like this ill." prevention " also comprises the recurrence of preventing disease or illness or the symptom relevant with it.
Except as otherwise noted, otherwise " Mammals " used herein is meant any Mammals.Term mammal " comprise such as but not limited to dog, cat and people.
" abnormal cell growth " used herein is meant pernicious (for example in cancer) or the benign cell growth of the normal regulation mechanism that is independent of (for example losing contact inhibition).The example of optimum proliferative disease has psoriasis, benign prostatauxe, human papillomavirus (HPV) and restenosis.
" neurodegenerative disease " used herein is meant and neuron sex change diseases associated and illness.Its character is that the illness and the disease of neuropathic is that those skilled in the art are known usually.
Mentioned when describing disease and illness in this article " its treatment can be undertaken or promotes by the neurotransmission that changes the Dopamine HCL mediation " is meant the disease or the illness that are caused by the Dopamine HCL neurotransmission to small part, or cause unusual Dopamine HCL neurotransmission, bring the symptom of disease or illness or the disease or the illness of performance thus.
Mentioned when describing disease and illness in this article " its treatment can be undertaken or promotes by reducing the cdk5 activity " is meant the disease or the illness that are caused by the cdk5 activity to small part, or cause unusual cdk5 activity, bring the symptom of disease or illness or the disease or the illness of performance thus.
" suppressing the active significant quantity of cdk5 " used herein is meant that the amount of compound is enough to combine with enzyme cdk5 and realization reduces the active effect of cdk5.
" suppressing the active significant quantity of cdk2 " used herein is meant that the amount of compound is enough to combine with enzyme cdk5 and realization reduces the active effect of cdk2.
Detailed Description Of The Invention
Above-mentioned formula 1 compound and pharmacologically acceptable salt thereof can make according to following reaction scheme and discussion.Except as otherwise noted, otherwise R 1, R 2, R 3, and R 4As defined above.The separation of product and purifying are undertaken by chemical field standard method known to the skilled.
Word used herein " reaction-inert solvent " is meant that wherein component do not bring the mode and the interactional solvent systems of raw material, reagent or intermediate product of disadvantageous effect with the productive rate of giving required product.
Opinion in office is stated during the synthesis program, may need and/or wish sensitivity or reactive group on any relevant molecule are protected.This available GPF (General Protection False base, for example at T.W.Greene, Protective Groups in Organic Chemistry, John Wiley ﹠amp; Sons, 1981; With T.W.Greene and P.G.M.Wuts, Protective Groupsin Organic Chemistry, John Wiley ﹠amp; Sons, the protecting group of describing in 1991 realizes.
Reaction scheme 1 has illustrated and has been suitable for preparing wherein R 3Be-C (=O) NH-,-C (=O) O-or-C (=O) (CR 10R 11) n-the method for formula 1 compound.Referring to reaction scheme 1, with 1,4-dinitrobenzene imidazoles (J.Phys.Chem. (1995) Vol.99, pp.5009-1015) in methyl-sulphoxide (DMSO), pyridine-water, water, acetonitrile-water, alcohol or alcohol-water solvent system, preferably lower alcohol for example the solution in the methyl alcohol in-20 ℃-Yue 50 ℃ approximately, preferred approximately-5 ℃-35 ℃ handle with primary alkyl or arylamines, obtained that formula 21-N-replaces-the 4-nitroimidazole.1,4-dinitrobenzene imidazoles is high energy, semistable material, should preserve in refrigerator when not using always.Thermodynamics is measured and to be shown, under adiabatic condition in 35 ℃ its may produce enough energy to bring heavy explosion.Using between this matter era high degree of care always.The reaction of formula 2 a nitro-compounds reduction accepted way of doing sth 3 amine can be carried out like this: with formula 2 compounds and noble metal catalyst solvent for example the mixture in ethyl acetate, tetrahydrofuran (THF), dioxane or its mixture be exposed under the atmospheric hydrogen pressure of about 1-100, wherein preferably hydrogen pressure is about 10 normal atmosphere of about 1-.Palladium is preferred noble metal catalyst.For the purpose of convenient, can be with metal suspension at inert solid carrier for example on the charcoal.After formula 2 compounds have reacted completely, this mixture is filtered exist side by side soon gained formula 3 amine and acyl chlorides ClC (=O) (CR 10R 11) nR 4, acid anhydrides (R 4(CR 10R 11) nC (=O)) 2O or activatory carboxylic acid derivative XC (=O) (CR 10R 11) nR 4At alkali for example triethylamine, diisopropylethylamine, pyridine or 2, the 6-lutidine exists down in-78 ℃ of-40 ℃ of reactions approximately.1-propane phosphonic acid cyclic anhydride and triethylamine are preferred combinations.The activatory carboxylic acid derivative is by carboxylic acid HOC (=O) (CR 10R 11) nR 4For example dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, the inferior phosphonyl chloride of chloroformic acid alkyl or aryl ester, two (2-oxo-3-oxazolidinyl), benzotriazole-(dimethylamino) Phosphonium hexafluorophosphate or any other such normative document reagent make 1-base oxygen base-three with known activating reagent.Obtained wherein R by this method 3Be-C (=O) (CR 10R 11) n-formula 1B compound.
Perhaps, after the filtration, can be at-78 ℃-40 ℃ approximately, preferred-78 ℃--40 ℃ with alkali for example triethylamine, diisopropylethylamine, pyridine or 2, and 6-lutidine and chloroformic acid alkyl or aryl ester processing formula 3 amine are to obtain wherein R 3Be-C (=O) O-and R 4It is the formula 1A compound of phenyl.Diisopropylethylamine and phenyl chloroformate are preferred combinations.For example handle formula 1A phenyl carbamate with uncle or secondary amine in about 40 ℃-90 ℃ in dioxane, dimethyl formamide or the acetonitrile at solvent then, obtained wherein R 3Be-C (=O) NR 9-and R 4Be the corresponding urea product 1C of phenyl or heteroaryl.1: 1 mixture of dioxane-dimethyl formamide and 70 ℃ are preferred.
Reaction scheme 1
Prepare wherein R 1By R 5Replace, and R 5Be NHC (=O) R 8The method of formula 1 compound shown in reaction scheme 2.At reaction-inert solvent for example tetrahydrofuran (THF), methylene dichloride or chloroform, in the preferred chloroform, in-10 ℃-Yue 30 ℃ approximately, at alkali for example triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, preferred triethylamine, with catalytic 4-N, the N-dimethyl aminopyridine exists down, wherein R 5Formula 4 compounds of=OH alkyl-or aryl-SULPHURYL CHLORIDE, preferred Tosyl chloride (TosO) is handled, and has obtained wherein R 5Be CH 3(C 6H 4) SO 3(TosO) formula 5 compounds.At the polar solvent mixture of dimethyl formamide, methyl-sulphoxide, lower alcohol, water or these solvents for example, in preferred alcohol-water mixture, in about 20 ℃-130 ℃, preferred 90 ℃ of-110 ℃ of an alkali metal salts with trinitride, preferred sodiumazide is handled formed tosylate, has obtained wherein R 5Be N 3Formula 6 compounds.
Under the selective reduction condition, for example trialkyl or triaryl phosphine and water, triphenylphosphine at solvent for example tetrahydrofuran (THF), dioxane, acetonitrile or its mixture, is handled the gained trinitride in the preferred tetrahydrofuran (THF), has obtained wherein R 5Be NH 2Formula 7 compounds.Can be by reacting the formula 7 compound (R that will form thus with chloro-formic ester, isocyanic ester, urea chloride, acyl chlorides, acid anhydrides or activatory carboxylic acid derivative 5=NH 2) the primary amino derivatize.The activatory carboxylic acid derivative is by carboxylic acid and known activating reagent dicyclohexylcarbodiimide for example, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, alkyl chloroformate, the inferior phosphonyl chloride of two (2-oxos-3-oxazolidinyl), benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium hexafluorophosphate, or any other such normative document reagent, preferred 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, if necessary at amine alkali triethylamine for example, diisopropylethylamine, pyridine, or 2, the 6-lutidine exists down, in-78 ℃-80 ℃ approximately, preferred 0 ℃-40 ℃ make.Tetrahydrofuran (THF) and methylene dichloride are preferred solvents.
The wherein R that can will form thus by following method 5Be-NHC (=O) R 8Formula 8 compounds transform accepted way of doing sth 1D compound (R 5Be NHC (=O) R 8R 3Be C (=O) (CR 10R 11) nR 4) (wherein palladium is preferred noble metal catalyst to ∷ with formula 8 compounds and noble metal catalyst, and for the purpose of convenient, can be with metal suspension at inert solid carrier for example on the charcoal) solvent for example the mixture in ethyl acetate, tetrahydrofuran (THF), dioxane or its mixture be exposed under the atmospheric hydrogen pressure of about 1-100, wherein preferred hydrogen pressure is about 10 normal atmosphere of about 1-.After formula 8 compounds have reacted completely; this mixture is filtered; exist side by side and be about to gained amine and acyl chlorides, acid anhydrides or activatory carboxylic acid derivative; if suitably at alkali for example triethylamine, diisopropylethylamine, pyridine or 2; the 6-lutidine exists down in-78 ℃ of-40 ℃ of reactions approximately; wherein 1-propane phosphonic acid cyclic anhydride and triethylamine are preferred combinations, have obtained the N-acylate of formula 1D.The activatory carboxylic acid derivative be by carboxylic acid and known activating reagent for example dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, the inferior phosphonyl chloride of alkyl chloroformate, two (2-oxo-3-oxazolidinyl), benzotriazole-(dimethylamino) Phosphonium hexafluorophosphate or any other such normative document reagent make 1-base oxygen base-three.
In above-mentioned acidylate,, then obtain aryl carbamate 1E if use chloroformic acid aryl ester or chloroformic acid heteroaryl ester to replace acyl chlorides, acid anhydrides or activatory carboxylic acid derivative.Can be at solvent for example dioxane, dimethyl formamide or acetonitrile, in 1: 1 mixture of preferred dioxane-dimethyl formamide, handle gained aryl carbamate 1E (R with amine in about 40 ℃-90 ℃, preferred 70 ℃ 3Be C (=O) O-, and R 4Be aryl or heteroaryl), obtained the corresponding urea product of formula 1F (R 3Be-C (=O) NR 9-, R 4Be aryl or heteroaryl).
Reaction scheme 2
Figure A0181339700341
Prepare wherein R 5Be-NHC (=O) R 8Formula 1 compound in addition-method is shown in reaction scheme 3.At reaction-inert solvent for example tetrahydrofuran (THF), methylene dichloride or chloroform, in the preferred methylene dichloride, in-10 ℃-Yue 30 ℃ approximately, at amine alkali for example triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and 4-N, N-dimethyl aminopyridine exist down, with alkyl-or aryl-SULPHURYL CHLORIDE, preferred Tosyl chloride (TosCI) is handled wherein R 5Be the compound 4 of OH, obtained wherein R 5Be CH 3(C 6H 4) SO 3(TosO) formula 5 compounds.Triethylamine is preferred amine alkali.By following method with formula 5 compound (R 5Be TosO) conversion accepted way of doing sth 1G compound (R 5Be TosO, R 3Be C (=O) (CR 10R 11) nR 4): with formula 5 compound (R 5Be TosO) with noble metal catalyst solvent for example the mixture in ethyl acetate, tetrahydrofuran (THF), dioxane or its mixture be exposed under the atmospheric hydrogen pressure of about 1-100, wherein the pressure of hydrogen is preferably about 10 normal atmosphere of about 1-.Palladium is preferred noble metal catalyst.For the purpose of convenient, can be with metal suspension at inert solid carrier for example on the charcoal.After formula 5 compounds have reacted completely; this mixture is filtered; exist side by side and be about to gained amine and acyl chlorides, acid anhydrides or activatory carboxylic acid derivative; if suitably at alkali for example triethylamine, diisopropylethylamine, pyridine or 2; the 6-lutidine exists down in-78 ℃ of-40 ℃ of reactions approximately; wherein 1-propane phosphonic acid cyclic anhydride and triethylamine are preferred combinations, have obtained formula 1G N-acylate.The activatory carboxylic acid derivative be by carboxylic acid and known activating reagent for example dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, the inferior phosphonyl chloride of alkyl chloroformate, two (2-oxo-3-oxazolidinyl), benzotriazole-(dimethylamino) Phosphonium hexafluorophosphate or any other such normative document reagent make 1-base oxygen base-three.
At the polar solvent mixture of dimethyl formamide, methyl-sulphoxide, lower alcohol, water or these solvents for example, in preferred alcohol-water mixture, in about 20 ℃-130 ℃, preferred 90 ℃ of-110 ℃ of an alkali metal salts with trinitride, preferred sodiumazide is handled formula 1G compound (R 5Be TosO, R 3Be-C (=O) (CR 10R 11) n-), obtained wherein R 5Be N 3Formula 1H compound.Then by following method with formula 1H trinitride (R 5Be N 3) reduction: with formula 1H trinitride (R 5Be N 3) (wherein palladium is preferred noble metal catalyst with noble metal catalyst, and for the purpose of convenient, can be with metal suspension at inert solid carrier for example on the charcoal) solvent for example the mixture in ethyl acetate, tetrahydrofuran (THF), dioxane or its mixture be exposed under the atmospheric hydrogen pressure of about 1-100, wherein preferred hydrogen pressure is about 10 normal atmosphere of about 1-.
Perhaps, formula 1H trinitride (R 5Be N 3) reduction can be by at solvent for example tetrahydrofuran (THF), dioxane or acetonitrile, with trialkyl or triaryl phosphine and water, triphenylphosphine is handled and is carried out in the preferred tetrahydrofuran (THF).Can be by reacting formula 1I compound (R with chloro-formic ester, isocyanic ester, urea chloride, acyl chlorides, acid anhydrides or activatory carboxylic acid derivative 5Be NH 2) the primary amino derivatize, wherein said activatory carboxylic acid derivative is by carboxylic acid and known activating reagent dicyclohexylcarbodiimide for example, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, alkyl chloroformate, the inferior phosphonyl chloride of two (2-oxos-3-oxazolidinyl), benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium hexafluorophosphate, or any other such normative document reagent, preferred 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, if necessary at amine alkali triethylamine for example, diisopropylethylamine, pyridine, or 2, the 6-lutidine exists down, in-78 ℃-80 ℃ approximately, preferred 0 ℃-40 ℃ make.Tetrahydrofuran (THF) and methylene dichloride are preferred solvents.
Reaction scheme 3
R wherein 3Be-(CR 10R 11) n-formula 1 compound can make according to reaction scheme 4.Referring to reaction scheme 4, be in or be not in for example tetrabutylammonium chloride of phase-transfer catalyst, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, benzyl trimethyl ammonium chloride, benzyltrimethylammonium bromide, or the benzyl trimethyl Neutral ammonium fluoride exists down, at reaction-inert solvent tetrahydrofuran (THF) for example, 1, the 4-dioxane, N, dinethylformamide, methyl-sulphoxide, or in the toluene, in-20 ℃-150 ℃ approximately, preferred 20 ℃-100 ℃, with alkali sodium hydride for example, potassium hydride KH, lithium hydride, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium diisopropylamine, sodium amide, hexamethyldisilazane base (hexamethyldisilazide) potassium, hexamethyldisilazane base sodium, sodium tert-butoxide, or potassium tert.-butoxide is handled the solution of 4-bromine imidazoles, add alkyl then, allyl group, or benzyl muriate, bromide, iodide, alkyl sulfonic ester, aromatic yl sulphonate, or triflate, obtained that 1-replaces-4-bromine imidazoles (9) replaces with 1--and the mixture of 5-bromine imidazoles (10), can use the method known to those skilled in the art it is separated.
Perhaps, at palladium catalyst palladium (O) four (triphenylphosphine) for example, acid chloride (II), allyl group chlorination target dipolymer, three (dibenzalacetones), two palladiums (O), three (dibenzalacetones), two palladiums (O) chloroform affixture, Palladous chloride (II), preferred palladium four (triphenylphosphine) or acid chloride (II) exist down, be in or be not in for example triphenylphosphine of phosphine part, the tri-o-tolyl phosphine, tri-butyl phosphine, 1,2-two (diphenylphosphino) ethane, or 1,3-two (diphenylphosphino) propane exists down, at reaction-inert solvent tetrahydrofuran (THF) for example, 1, the 2-ethylene dichloride, 1, the 4-dioxane, methyl-sulphoxide or N, dinethylformamide, in the preferred tetrahydrofuran (THF), in about 0 ℃-100 ℃, preferred 50 ℃-80 ℃, use the allyl group fluorochemical, allyl chloride, allyl group iodate thing, allyl acetate, or allyl carbonate, preferred allyl carbonate is handled 4-bromine imidazoles, obtained that 1-replaces-4-bromine imidazoles (9) and 1-replacement-mixture of 5-bromine imidazoles (10).
At reaction-inert solvent toluene, 1 for example, in 4-dioxane or the tetrahydrofuran (THF), in about 0 ℃-150 ℃, preferred 20 ℃-110 ℃, usefulness-NH 2(CR 10R 11) nR 4Intermediate and palladium catalyst be acid chloride (II) for example, allyl group chlorination target dipolymer, three (dibenzalacetones), two palladiums (O), three (dibenzalacetones), two palladiums (O) chloroform affixture, or Palladous chloride (II), preferred acid chloride (II), three (dibenzalacetones), two palladiums (O), with three (dibenzalacetones), two palladiums (O) chloroform affixture, with phosphorus part BINAP for example, 2-xenyl dicyclohexylphosphontetrafluoroborate, 2-xenyl di-t-butyl phosphine, or 2-N, N-dimethylamino-2 '-diphenylphosphino biphenyl, preferred 2-N, N-dimethylamino-2 '-diphenylphosphino biphenyl and alkali is sodium tert-butoxide for example, cesium carbonate, or potassiumphosphate (K 3PO 4), preferably phosphoric acid potassium processing 1-replaces-4-bromine imidazoles (9), has obtained coupled product 1.
Reaction scheme 4
R wherein 3Be-C (=O) (CR 10R 11) n-another synthetic method of formula 1 compound shown in reaction scheme 5.For example in propyl carbinol, n-propyl alcohol, Virahol or the ethanol, perhaps do not use solvent at solvent,, use primary amine R in about 23 ℃-Yue 200 ℃, preferred about 60 ℃-Yue 150 ℃ 1-NH 2Handle 2-isocyano--3-N, N-dimethylamino ethyl propenoate (11) has obtained formula 12 imidazoles.1, handle N with trimethyl aluminium in the 2-ethylene dichloride, O-dimethyl hydroxyl amine hydrochlorate adds 12 then, and about 30 ℃-Yue 80 ℃, preferred about 50 ℃ of heating, has obtained imidazoles 13.At-50 ℃-Yue 30 ℃ approximately, preferred-20 ℃-Yue 0 ℃ approximately, for example add organometallic reagent M-(CR in the solution in tetrahydrofuran (THF), methylene dichloride or the ether at solvent to imidazoles 13 10R 11) nR 4, wherein M is lithium or magnesium halogenide, preferably magnesium halogenide, has obtained compound 14.At about 23 ℃, compound 14 is added in hydroxy amine hydrochloric acid salt and the mixture of salt of wormwood in lower alcohol solvent, preferred alcohol, obtained oxime 15, be isomer mixture.At about 0 ℃, handle the acetone soln of oxime 15 successively with aqueous sodium hydroxide solution and Tosyl chloride, extract aftertreatment after, obtained the mixture of O-sulfonyl compound.Crude product is dissolved in non-polar solvent for example benzene, hexane or toluene, in the preferred toluene, is applied on the alumina post, use chloroform-methanol (about 10: 1) wash-out then, after about 5 minutes, the regional isomer that has obtained compound lB and formed by Beckmann rearrangement.
Reaction scheme 5
Formula 1J compound also can make by the method shown in the reaction scheme 6.Being used for a kind of critical materials of this synthetic is the compound (formula X compound) that contains two keys, and this compound is by ER 5With the individual R that is selected from of 1-3 5Group replace (X), wherein ER 5Be to be selected from following electron-withdrawing group: C (=O) R 7, C (=O) OR 7, C (=O) NR 7R 8, S (=O) 2R 7, S (=O) 2NR 7R 8, S (=O) 2OR 7, cyano group and heteroaryl.Perhaps, formula X compound can be such, wherein ER 5With a R 5Link to each other, perhaps directly link to each other and encircle, and therefore comprise compound for example 2-cyclopentenes-1-ketone and 2-tetrahydrobenzene-1-ketone to form with the two keys of carbon one carbon.Perhaps, wherein X is Cl, Br, I, OC (=O) R 7, or OS (=O) 2R 7Formula X compound can be used as raw material; Such examples for compounds is 3-chloro-1-cyclopentanone, 3-acetoxyl group-1-cyclobutanone.Therefore, referring to reaction scheme 6, at solvent for example acetonitrile, methylene dichloride, 1,2-ethylene dichloride or chloroform are in the preferred acetonitrile, in-60 ℃-Yue 50 ℃ approximately, preferred-20 ℃-23 ℃, with the salt of intermediate 16 or 17 processing, 4 (5)-nitroimidazoles, wherein said salt is sodium salt, sylvite, cesium salt, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) or tetraalkylammonium salt, tetra-n-butyl ammonium salt and DBU are preferred salt, have obtained formula 2A adduct.Can nitro-compound 2A be reduced by following method: (wherein palladium is preferred noble metal catalyst with 2A and noble metal catalyst, and for the purpose of convenient, can be with metal suspension at inert solid carrier for example on the charcoal) solvent for example the mixture in ethyl acetate, tetrahydrofuran (THF), dioxane or its mixture be exposed under the atmospheric hydrogen pressure of about 1-100, wherein preferred hydrogen pressure is about 10 normal atmosphere of about 1-.After 2A reacts completely, this mixture is filtered exist side by side soon gained amine and acyl chlorides ClC (=O) (CR 10R 11) nR 4, acid anhydrides (R 4(CR 10R 11) nC (=O)) 2O or activatory carboxylic acid derivative XC (=O) (CR 10R 11) nR 4At alkali for example triethylamine, diisopropylethylamine, pyridine or 2, the 6-lutidine exists down in-78 ℃-Yue 40 ℃ of reactions approximately, and wherein 1-propane phosphonic acid cyclic anhydride and triethylamine are preferred combinations, have obtained the 1J compound.The activatory carboxylic acid derivative is by carboxylic acid HOC (=O) (CR 10R 11) nR 4For example dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, carbonyl dimidazoles, 1-propane phosphonic acid cyclic anhydride, the inferior phosphonyl chloride of chloroformic acid alkyl or aryl ester, two (2-oxo-3-oxazolidinyl), benzotriazole-(dimethylamino) Phosphonium hexafluorophosphate or any other such normative document reagent make 1-base oxygen base-three with known activating reagent.
Perhaps, after the filtration, can be at-78 ℃-40 ℃ approximately, preferred-78 ℃--40 ℃ with alkali for example triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine and chloroformic acid alkyl or aryl ester are handled gained amine intermediate, wherein diisopropylethylamine and phenyl chloroformate are preferred combinations, have obtained 1K.
Then at solvent for example dioxane, dimethyl formamide or acetonitrile, handle 1K with uncle or secondary amine in about 40 ℃-90 ℃, preferred about 70 ℃ in 1: 1 mixture of preferred dioxane-dimethyl formamide, obtained corresponding urea product 1L.
Use method known to those skilled in the art to transform compound 2A, 1J, 1K and 1L then, with other formula 1 compound that obtains to describe in this application.
R wherein 2Formula 1 compound that is not hydrogen can transform wherein R as herein described by using the well-known method of those skilled in the art 2Formula 1 compound that is hydrogen makes.For example, R wherein 2Formula 1 compound that is F can make like this: in toluene, dimethylbenzene or dioxane, in about room temperature-Yue 150 ℃, preferred about 100 ℃-Yue 120 ℃, handle wherein R with N-fluorobenzene sulfimide 2Be formula 1 compound of hydrogen, formula 1A, 1B and the 1C compound of in reaction scheme 1 above, mentioning for example.
Reaction scheme 6
Figure A0181339700421
The pharmacologically acceptable salt of formula 1 compound can make by solution or suspension with 1 stoichiometric pharmaceutically acceptable acid or corresponding free alkali of alkaline purification or acid in a usual manner.Can adopt conventional concentrate or crystallization technique separates these salt.The example of suitable acid has acetate, lactic acid, succsinic acid, toxilic acid, tartrate, citric acid, gluconic acid, xitix, phenylformic acid, styracin, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, thionamic acid, sulfonic acid for example methylsulfonic acid, Phenylsulfonic acid, tosic acid and relevant acid.The example of alkali has sodium, potassium and calcium.
The compounds of this invention can with single dose or multiple doses be individually dosed or with pharmaceutically acceptable carrier administration.Suitable pharmaceutical carrier comprises inert solid diluent, aseptic aqueous solution and multiple organic solvent.Can be by formula 1 compound or pharmaceutically acceptable salt thereof is mixed the pharmaceutical composition that makes with for example administrations easily such as tablet, pulvis, lozenge, syrup, injection solution of multiple different dosage form.If necessary, these pharmaceutical compositions can contain other component for example correctives, tackiness agent, vehicle etc.Therefore, for oral administration, contain different vehicle for example Trisodium Citrate, lime carbonate and calcium phosphate tablet can with different disintegrating agents for example starch, methylcellulose gum, alginic acid and some composition silicates and tackiness agent for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic use together.In addition, lubricant for example operate through being usually used in film-making by Magnesium Stearate, sodium lauryl sulphate and talcum powder.The solids composition of similar type can also use in soft hard filling gelatine capsule as weighting agent.For this, preferable material comprises lactose or toffee and high molecular weight polyethylene glycol.When needs aqeous suspension or elixir come oral administration, can be with essential active ingredient and different sweeting agent or correctives, tinting material or dyestuffs wherein, and for example water, ethanol, propylene glycol, glycerine and combine mixing of emulsifying agent or suspension agent and thinner if necessary.
For parenteral administration, can use the solution that in sesame oil or peanut oil, aqueous propylene glycol or aseptic aqueous solution, contains The compounds of this invention or its pharmacologically acceptable salt.If necessary, such aqueous solution should suitably cushion, and at first with enough salt solution or glucose liquid diluent etc. is oozed.These specific aqueous solution are particularly suited for intravenously, intramuscular, subcutaneous and intraperitoneal administration.Used aseptic aqueous medium all is easy to obtain by standard technique well known by persons skilled in the art.
Formula 1 compound or pharmaceutically acceptable salt thereof Orally-administrable, transdermal administration (for example using patch), parenteral administration (for example intravenous administration), rectal administration or topical.Generally speaking, treatment neurodegenerative disease or illness or its treatment can be undertaken or the per daily dose of promoted disease or illness is generally the patient's that the about 10.0mg/kg of about 0.0001-treated body weight by the neurotransmission that changes the Dopamine HCL mediation.Treatment cancer or relate to the disease of optimum abnormal cell growth or the per daily dose of illness is generally the patient's that the about 500mg/kg of about 0.0001-treated body weight.For example, formula 1 compound or pharmaceutically acceptable salt thereof can with about 0.01mg to be up to about 1000mg/ days, preferably the about 500mg/ of about 0.1-days dosage is treated neurodegenerative disease to adult's administration of mean body weight (about 70kg), such per daily dose once gives or gives in batches (promptly being divided into multidose gives).Treatment diabetes, sperm motility, alopecia, maybe can be generally the patient's that the about 10.0mg/kg of about 0.0001-treated body weight by the per daily dose that suppresses any other disease that GSK-3 treats or illness.Consider known facts for example body weight, age, the people's that treated healthy state, the severity and the selected specific administration approach of disease, the doctor can make change according to above-mentioned dosage range.
Formula 1 compound and pharmacologically acceptable salt thereof can also be selected from the material administration of anti-angiogenic agent, signal conduction depressant drug and antiproliferative or be mixed with pharmaceutical composition with a certain amount of one or more, and the amount of wherein said active substance can suppress abnormal cell growth together effectively.
Anti-angiogenic agent for example MMP-2 (matrix-metalloprotease 2) inhibitor, MMP-9 (matrix-metalloprotease 9) inhibitor and COX-II (cyclo-oxygenase II) inhibitor can with formula 1 compound at treatment abnormal cell growth as herein described, comprise Combined Preparation in method for cancer and the pharmaceutical composition.The example of useful COX-II inhibitor comprises CELEBREX TM(celecoxib), valdecoxib and rofecoxib.The case description of useful matrix metalloprotease is in following document: WO96/33172 (publication on October 24th, 1996), WO96/27583 (publication on March 7th, 1997), european patent application 97304971.1 (submission on July 8th, 1997), european patent application 99308617.2 (submission on October 29th, 1999), WO98/07697 (publication on February 26th, 1998), WO98/03516 (publication on January 29th, 1998), WO98/34918 (publication on April 13rd, 1998), WO98/34915 (publication on August 13rd, 1998), WO98/33768 (on April 6th, 1998), WO98/30566 (publication on July 16th, 1998), European patent publication 606,046 (publication on July 13rd, 1994), European patent publication 931,788 (publication on July 28th, 1999), WO90/05719 (May 31 nineteen ninety), WO99/52910 (publication on October 21st, 1999), WO99/52889 (publication on October 21st, 1999), WO99/29667 (on June 17th, 1999), PCT International Application PCT/IB98/01113 (submission on July 21st, 1998), european patent application 99302232.1 (submission on March 25th, 1999), UK Patent Application 9912961.1 (on June 3rd, 1999), U.S. Provisional Application 60/148,464 (on Augusts 12nd, 1999), United States Patent (USP) 5,863,949 (publication on January 26th, 1999), United States Patent (USP) 5,861,510 (publication on January 19th, 1999), with European patent publication 780,386 (publication on June 25th, 1997), all these documents are all introduced the present invention with for referencial use in full.Preferred L MP-2 and MMP-9 inhibitor be the inhibition activity to MMP-1 very little or without any suppress active those.More preferably can optionally suppress those of MMP2 and/or MMP-9 with respect to other matrix-metalloprotease (being MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).
Some specific examples that is used for MMP inhibitor of the present invention is AG-3340, RO32-3555, RS13-0830 and following compounds: 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-cyclopentyl)-amino]-propionic acid; Outside the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-formic acid oxyamide; (2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 4-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-cyclobutyl)-amino]-propionic acid; 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-4-formic acid oxyamide; (R) 3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-pyrans-3-formic acid oxyamide; (2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic acid oxyamide; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(1-hydroxyl amino formyl radical-1-methyl-ethyl) amino]-propionic acid; 3-[[4-(4-fluoro-phenoxy group)-benzenesulfonyl]-(4-hydroxyl amino formyl radical-tetrahydrochysene-pyrans-4-yl)-amino]-propionic acid; Outside the 3--3-[4-(4-chloro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-formic acid oxyamide; In the 3--3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-8-oxa--two ring [3.2.1] octane-3-formic acid oxyamide; (R) 3-[4-(4-fluoro-phenoxy group)-benzenesulfonyl amino]-tetrahydrochysene-furans-3-formic acid oxyamide; Pharmacologically acceptable salt and solvate with described compound.
Other anti-angiogenic agent comprises that other COX-II inhibitor and other MMP inhibitor also can be used for the present invention.
With the cdk5 inhibitor for example the formula 1 compound significant quantity of uniting the COX-II inhibitor of use generally can determine by those skilled in the art.For uniting the COX-II inhibitor of use with the cdk5 inhibitor, the per daily dose of recommendation is the about 25mg/kg body weight of about 0.1-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, uniting the amount of COX-II inhibitor of use and/or the amount of cdk5 inhibitor may be lower than in order to obtain the amount of the required independent use of identical required inhibition abnormal cell growth effect.
Formula 1 compound can also be united use with the signal conduction depressant drug, for example can suppress the agent of EGFR (EGF-R ELISA) reactive activity, for example EGFR antibody, EGF antibody and be the molecule of EGFR inhibitor; VEGF (vascular endothelial growth factor) inhibitor; With the erbB2 acceptor inhibitor, for example in conjunction with the organic molecule of erbB2 acceptor or antibody HERCEPTIN for example TM(Genentech, Inc.of South San Francisco, California, USA).Such cooperative programs can be used for treating and preventing abnormal cell growth as described herein, comprise cancer.
The EGFR inhibitor is described in for example WO95/19970 (publication on July 27 nineteen ninety-five), WO98/14451 (publication on April 9th, 1998), WO98/02434 (publication on January 22nd, 1998) and United States Patent (USP) 5,747, in 498 (publication on May 5th, 1998), and such material can as described hereinly be used for the present invention.The EGFR inhibitor comprises but is not limited to monoclonal antibody C225 and anti-EGFR 22Mab (ImClone SystemsIncorporated of New York, New York, USA), compound ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.of Annandale, New Jersey, USA) and OLX-103 (Merck ﹠amp; Co.of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc.ofHopkinton, Massachusettes).These and other EGFR inhibitor can be used for the present invention.
The VEGF inhibitor for example SU-5416 and SU-6668 (Sugen Inc.of SouthSan Francisco, California USA) also can unite use with formula 1 compound.The VEGF inhibitor is described in for example following document: WO99/24440 (publication on May 20th, 1999), PCT International Application PCT/IB99/00797 (submission on May 3rd, 1999), WO95/21613 (publication on August 17 nineteen ninety-five), WO99/61422 (publication on December 2nd, 1999), United States Patent (USP) 5,834,504 (publication on November 10th, 19998), WO98/50356 (publication on November 12nd, 1998), United States Patent (USP) 5,883,113 (publication on March 16th, 1999), United States Patent (USP) 5,886,020 (publication on March 23rd, 1999), United States Patent (USP) 5,792,783 (publication on August 11st, 1998), WO99/10349 (publication on March 4th, 1999), WO97/32856 (publication on September 12nd, 1997), WO97/22596 (publication on June 26th, 1997), WO98/54093 (publication on December 3rd, 1998), WO98/02438 (publication on January 22nd, 1998), WO99/16755 (publication on April 8th, 1999), and WO-98/02437 (publication on January 22nd, 1998), all these documents are all introduced the present invention with for referencial use in full.Other example that can be used for some concrete VEGF inhibitor of the present invention be IM862 (Cytran Inc.of Kirkland, Washington, USA); Genentech, Inc.of South San Francisco, the anti-VEGF monoclonal antibody of California; And angiozyme-a kind of derive from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, synthetic ribozyme California).These and other VEGF inhibitor can as described hereinly be used for the present invention.
The ErbB2 acceptor inhibitor is GW-282974 (Glaxo Welcome pic) for example, with monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc.of TheWoodlands, Texas, USA) also can unite use with 2B-1 (Chiron) with formula 1 compound, those that in following document, describe: WO98/02434 (publication on January 22nd, 1998) for example, WO99/35146 (publication on July 15th, 1999), WO99/35132 (publication on July 15th, 1999), WO98/02437 (publication on January 22nd, 1998), WO97/13760 (publication on April 17th, 1997), WO95/19970 (publication on July 27 nineteen ninety-five), United States Patent (USP) 5,587,458 (publication on December 24th, 1996), with United States Patent (USP) 5,877,305 (publication on March 2nd, 1999), described document are all introduced the present invention with for referencial use in full.Be used for ErbB2 acceptor inhibitor of the present invention and also be described in U.S. Provisional Application of submitting on January 27th, 1,999 60/117,341 and the U.S. Provisional Application of submitting on January 27th, 1,999 60/117,346, these two pieces of applications are all introduced the present invention with for referencial use in full.Other compound and the material that are described in erbB2 acceptor inhibitor compound and the material in PCT application, U.S. patent and the U.S. provisional application and suppress the erbB2 acceptor can be united use with formula 1 compound of the present invention.
Formula 1 compound can also be united use with other promoting agent that is used for the treatment of abnormal cell growth or cancer, the material that these promoting agents include but not limited to strengthen anti tumor immune response is CTLA4 (cytotoxic lymphocyte 4) antibody and can block other material of CTLA4 for example; And antiproliferative method Buddhist nun protein transferase inhibitor for example.Can be used for concrete CTLA4 antibody of the present invention and be included in those that describe in the U.S. Provisional Application 60/113,647 (submission on December 23rd, 1998), this application is introduced the present invention in full with for referencial use, yet other CTLA4 antibody also can be used for the present invention.
Formula 1 compound can be united the method that is used to suppress the Mammals abnormal cell growth with radiotherapy.The technology of using radiotherapy is known in the art, and these technology can be used in the combination therapy as herein described.The compounds of this invention using in this combination therapy can as described hereinly be determined.
For example formula 1 compound can also weaken with treatment Alzheimer, mild cognitive with COX-II inhibitor Combined Preparation the Cdk5 inhibitor or the relevant cognitive decline with the age.The specific examples of the COX-II inhibitor that can be used for this aspect of the present invention above is provided, has wherein described to unite and used COX-II inhibitor and formula 1 compounds for treating abnormal cell growth.With the cdk5 inhibitor for example the formula 1 compound significant quantity of uniting the COX-II inhibitor of use generally can determine by those skilled in the art.For uniting the COX-II inhibitor of use with the cdk5 inhibitor, effective per daily dose of recommendation is the about 25mg/kg body weight of about 0.1-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, the amount of uniting the amount of COX-II inhibitor of use and/or cdk5 inhibitor may be lower than for obtain identical required treatment Alzheimer, mild cognitive weakens or the amount of the independent use that the cognitive decline effect relevant with the age is required.
Cdk5 inhibitor for example formula 1 compound can also be treated dysthymia disorders or anxiety with the administration of nk 1 receptor antagonist combination.The reaction that NK1 receptor antagonist as described herein is can the antagonism nk 1 receptor, suppress the tachykinin mediation thus is the material of the reaction of P material mediation for example.Various nk 1 receptor antagonist is known in the art, and can be as described herein with the cdk5 inhibitor for example formula 1 compound unite use.The nk 1 receptor antagonist is described in for example following document: United States Patent (USP) 5,716,965 (publication on February 10th, 1998); United States Patent (USP) 5,852,038 (publication on December 22nd, 1998); WO90/05729 (May 31 nineteen ninety international publishing day); United States Patent (USP) 5,807,867 (publication on September 15th, 1998); United States Patent (USP) 5,886,009 (publication on March 23rd, 1999); United States Patent (USP) 5,939,433 (publication on August 17th, 1999); United States Patent (USP) 5,773,450 (publication on June 30th, 1998); United States Patent (USP) 5,744,480 (publication on April 28th, 1998); United States Patent (USP) 5,232,929 (publication on August 3rd, 1993); United States Patent (USP) 5,332,817 (publication on June 26th, 1994); United States Patent (USP) 5,122,525 (publication on June 16th, 1992); United States Patent (USP) 5,843,966 (publication on December 1st, 1998); United States Patent (USP) 5,703,240 (publication on December 30th, 1997); United States Patent (USP) 5,719,147 (publication on February 17th, 1998); With United States Patent (USP) 5,637,699 (publication on June 10th, 1997).The PCT international application of each above-mentioned U.S. patent and above-mentioned publication is all introduced the present invention with for referencial use in full.The compound of describing in described reference with nk 1 receptor antagonistic activity can be used for the present invention.Yet other nk 1 receptor antagonist also can be used for the present invention.
With the cdk5 inhibitor for example the formula 1 compound significant quantity of uniting the nk 1 receptor antagonist of use generally can determine by those skilled in the art.For uniting the nk 1 receptor antagonist of use with the cdk5 inhibitor, effective per daily dose of recommendation is the about 21mg/kg body weight of about 0.07-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, uniting the amount of nk 1 receptor antagonist of use and/or the amount of cdk5 inhibitor may be lower than in order to obtain the amount of the required independent use of identical required treatment dysthymia disorders or anxiety effect.
The present invention also provides the cdk5 inhibitor that is used for the treatment of dysthymia disorders or anxiety for example formula 1 compound and 5HT 1DThe cooperative programs of receptor antagonist.5HT as described herein 1DReceptor antagonist is antagonism 5HT 1DThe material of hypotype serotonin receptor.Any such material can be as described herein with the cdk5 inhibitor for example formula 1 compound unite use.Concrete 5HT 1DThe material of receptor antagonist activity can be determined by those skilled in the art.For example, 5HT 1DReceptor antagonist is described in the following document: WO98/14433 (April 9 1998 international publishing date); WO97/36867 (October 9 1997 international publishing date); WO94/21619 (September 29 1994 international publishing date); United States Patent (USP) 5,510,350 (publication on April 23rd, 1996); United States Patent (USP) 5,358,948 (publication on October 25th, 1994); And GB2276162A (publication on September 21st, 1994).These and other 5HT 1DReceptor antagonist can be used for the present invention.The patent application of above-mentioned publication and full patent texts are introduced the present invention with for referencial use.
With the cdk5 inhibitor for example formula 1 compound unite the 5HT of use 1DThe significant quantity of receptor antagonist generally can be determined by those skilled in the art.For uniting the 5HT of use with the cdk5 inhibitor 1DReceptor antagonist, effective per daily dose of recommendation is the about 40mg/kg body weight of about 0.01-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, the 5HT that unites use 1DThe amount of the amount of receptor antagonist and/or cdk5 inhibitor may be lower than in order to obtain the amount of the required independent use of identical required treatment dysthymia disorders or anxiety effect.
The present invention also provides the pharmaceutical composition and the method for dysthymia disorders in the treatment Mammals or anxiety, wherein comprises cdk5 inhibitor for example formula 1 compound and SSRI.Can with the cdk5 inhibitor for example formula 1 compound and pharmacologically acceptable salt thereof the example of uniting the SSRI that is used for described method or pharmaceutical composition include but not limited to fluoxetine, paroxetine, house Rayleigh and fluvoxamine.Other SSRI can with cdk5 inhibitor for example formula 1 compound or pharmaceutically acceptable salt thereof combination or Combined Preparation.Can for example other antidepressive and/or the neuroleptics of formula 1 compound combination or Combined Preparation comprise WELLBUTRIN, SERZONE and EFFEXOR with the cdk5 inhibitor.
With the cdk5 inhibitor for example the formula 1 compound significant quantity of uniting the SSRI of use generally can determine by those skilled in the art.For uniting the SSRI of use with the cdk5 inhibitor, effective per daily dose of recommendation is the about 500mg/kg body weight of about 0.01-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, uniting the amount of SSRI of use and/or the amount of cdk5 inhibitor may be lower than in order to obtain the amount of the required independent use of identical required treatment dysthymia disorders or anxiety effect.
The cdk5 inhibitor for example formula 1 compound or pharmaceutically acceptable salt thereof can also with one or more major tranquilizers for example the dopaminergic agent unite use can be to treat its treatment by changing that the Dopamine HCL neurotransmission is carried out or promoted disease or illness schizophrenia for example.The example that can unite the major tranquilizer of use comprises ziprasidone (5-(2-(4-(1,2-benzisothiazole-3-yl)-1-piperazinyl) ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one; U.S. patent 4,831,031 and U.S. patent 5,312,925); Olanzapine (2-methyl-4-(4-methyl isophthalic acid-piperazinyl-10H-thieno-(2,3b) (1,5) benzodiazepine ; U.S. patent 4,115,574 and U.S. patent 5,229,382); Risperidone (3-[2-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] ethyl]-6,7,8,9-tetrahydrochysene-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one; U.S. patent 4,804, and 663); L-745870 (3-(4-(4-chloro-phenyl-) piperazine-1-yl) methyl isophthalic acid H-pyrrolo-(2,3-b) pyridine; U.S. patent 5,432, and 177); Sonepiprazole (S-4-(4-(2-(heterochromatic full-1-yl) ethyl) piperazine-1-yl) benzsulfamide; U.S. patent 5,877, and 317); RP62203 (fananserin; 2-(3-(4-(4-fluorophenyl)-1-piperazinyl) propyl group) naphtho-(1,8-c, d) isothiazole-1,1-dioxide; U.S. patent 5,021, and 420); NGD941 (U.S. patent 5,633,376 and U.S. patent 5,428,165); Balaperidone ((1 α, 5 α, 6 α)-3-(2-(6-(4-fluorophenyl)-3-azabicyclic (3.2.0) heptan-3-yl) ethyl)-2,4 (1H, 3H)-quinazoline diones; U.S. patent 5,475, and 105); Flesinoxan ((+)-4-fluoro-N-[2-[4-5-(2-hydroxymethyl-1,4-benzo dioxane base)]-the 1-piperazinyl] ethyl] benzamide; U.S. patent 4,833, and 142); And gepirone hydrochloride (4,4-dimethyl-1-(4-(4-(2-pyrimidyl)-1-piperazinyl) butyl)-2,6-dioxopiperidine; U.S. patent 4,423, and 049).The patent of describing in this paragraph is introduced the present invention with for referencial use respectively in full.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.With the cdk5 inhibitor for example the formula 1 compound amount of uniting the above-mentioned major tranquilizer of use generally be the psychotic amount that is used for the treatment of known in the art.Yet, in some cases, unite the amount of major tranquilizer of use and/or the amount of cdk5 inhibitor and may be lower than in order to obtain the amount of the required independent use of identical required treatment dysthymia disorders or anxiety effect.It is also understood that the present invention also comprises cdk5 inhibitor for example formula 1 compound and the major tranquilizer except listing above or the cooperative programs of Dopamine HCL agent.
For example in the cooperative programs of formula 1 compound, the recommended dose of sonepiprazole is the about 50mg/kg weight in patients of about 0.005-/sky at above-mentioned and cdk5 inhibitor.In such cooperative programs, the recommended dose of RP62203 is the about 6mg/kg weight in patients of about 0.20-/sky.In such cooperative programs, the recommended dose of NGD941 is the about 140mg/kg body weight/day of about 0.1-.In such cooperative programs, the recommended dose of balaperidone is the about 100mg/kg body weight/day of about 1-.In such cooperative programs, the recommended dose of flesinoxan is the about 1.6mg/kg body weight/day of about 0.02-.In such cooperative programs, the recommended dose of gepirone hydrochloride is the about 2mg/kg body weight/day of about 0.01-.In such cooperative programs, the recommended dose of L-745870 is the about 250mg/kg body weight/day of about 0.01-, the preferred about 100mg/kg body weight/day of about 0.05-.In such cooperative programs, the recommended dose of Risperidone is the about 50mg/kg body weight/day of about 0.05-.In such cooperative programs, the recommended dose of olanzapine is the about 0.6mg/kg body weight/day of about 0.0005-.In such cooperative programs, the recommended dose of ziprasidone is the about 10mg/kg body weight/day of about 0.05-.Yet for each above-mentioned cooperative programs, in some cases, the amount of each concrete component may be lower than in order to obtain the amount of the required independent use of identical required treatment psychosis effect in the cooperative programs.
The present invention also provides treatment Alzheimer, mild cognitive to weaken or the pharmaceutical composition and the method for the cognitive decline relevant with the age, wherein comprises cdk5 inhibitor for example formula 1 compound and acetylcholinesterase depressant.Acetylcholinesterase depressant is known in the art, and any such acetylcholinesterase depressant all can be used for aforementioned pharmaceutical compositions or method.The example that can be used for acetylcholinesterase depressant of the present invention is ARICEPT (donepezil; U.S. patent 4,895, and 841); EXELON (rivastigmine ((S)-[N-ethyl-3-[1-(dimethylamino) ethyl] phenylcarbamate); U.S. patent 5,603,176 and U.S. patent 4,948,807); Trichlorphon ((2,2,2-three chloro-1-hydroxyethyls) dimethyl phosphonate; U.S. patent 2,701,225 and U.S. patent 4,950,658); Lycoremine (U.S. patent 4,663,318); Physostigmine (Forest, USA); Tacrine (1,2,3,4-tetrahydrochysene-9-acridine amine; U.S. patent 4,816, and 456); Selagine (5R-(5 α, 9 β, 11E))-5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-first ring suffering (b) pyridine-2-(1H)-ketone); And icopezil (5, and 7-dihydro-3-(2-(1-(phenyl methyl)-4-piperidyl) ethyl)-6H-pyrrolo-(3,2-f)-1,2-benzoisoxazole-6-ketone; U.S. patent 5,750,542 and WO92/17475).Patent of describing in this paragraph and patent application are introduced the present invention with for referencial use respectively in full.
With the cdk5 inhibitor for example the formula 1 compound significant quantity of uniting the acetylcholinesterase depressant of use generally can determine by those skilled in the art.For uniting the acetylcholinesterase depressant of use with the cdk5 inhibitor, effective per daily dose of recommendation is the about 10mg/kg body weight of about 0.01-.Effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.In some cases, the amount of uniting the amount of acetylcholinesterase depressant of use and/or cdk5 inhibitor may be lower than for obtain identical required treatment Alzheimer, mild cognitive weakens or the amount of the independent use that the cognitive decline effect relevant with the age is required.
The present invention also provides for example cooperative programs of nmda receptor antagonist of the cdk5 inhibitor for the treatment of following disease and neuroprotective: huntington's chorea; apoplexy; spinal cord injuries receptor; traumatic brain injury; multi-infarct dementia; epilepsy; amyotrophic lateral sclerosis; pain; the dementia that virus causes is the dementia that causes of AIDS for example; migraine; hypoglycemia; the urinary incontinence; cerebral ischemia; multiple sclerosis; Alzheimer; Alzheimers type senile dementia; mild cognitive weakens; the cognitive decline relevant with the age; vomiting; corticobasal degeneration; boxer's dementia; Down ' s syndrome; myotonia atrophica; the Niemann-Pick disease; Pick's disease; prion disease with entanglement; stein-leventhal syndrome; low funiculus lateralis sclerosis; with the subacute sclerosing panencephalitis that causes.The example that can be used for nmda receptor antagonist of the present invention comprises (1S, 2S)-1-(4-hydroxy phenyl)-2-(4-hydroxy-4-phenyl piperidine-1-yl)-1-propyl alcohol (U.S. patent 5,272,160), eliprodil (U.S. patent 4,690,931) and gavestenel (U.S. patent 5,373,018).Also can be used for other nmda receptor antagonist of the present invention is described in the following document: U.S. patent 5,373,018; U.S. patent 4,690, and 931; U.S. patent 5,272, and 160; U.S. patent 5,185, and 343; U.S. patent 5,356, and 905; U.S. patent 5,744, and 483; WO97/23216; WO97/23215; WO97/23214; WO96/37222; WO96/06081; WO97/23458; WO97/32581; WO98/18793; WO97/23202; With U.S. application 08/292,651 (submission on August 18th, 1994).Above-mentioned patent and patent application are introduced the present invention with for referencial use respectively in full.
With the cooperative programs of nmda receptor antagonist in, effective per daily dose of cdk5 inhibitor is generally the about 10mg/kg body weight of about 0.0001-.Be used for the cdk5 inhibitor for example formula 1 compound unite use with treat any above-mentioned illness for example the amount of the nmda receptor antagonist of Alzheimer serve as about 0.02mg/kg/ days-Yue 10mg/kg/ days.Yet, in some cases, unite the amount of nmda receptor antagonist of use and/or the amount of cdk5 inhibitor and may be lower than in order to obtain the amount of the required independent use of the described illness effect of identical required treatment.
The present invention also provides for example cooperative programs of TPA, NIF or potassium channel modulating agents such as BMS-204352 of cdk5 inhibitor and some materials that can treat apoplexy or traumatic brain injury.Such cooperative programs can be used for treating neurodegenerative disease for example apoplexy, spinal cord injuries receptor, traumatic brain injury, multi-infarct dementia, epilepsy, pain, Alzheimer and senile dementia.
For above-mentioned combination therapy and pharmaceutical composition, the significant quantity of The compounds of this invention and other promoting agent can for example be determined in above-mentioned patent and the middle amount of describing of patent application (introducing among the present invention) according to the significant quantity of compound as herein described and the known or described significant quantity of other promoting agent known in the art by those skilled in the art.For such treatment and composition, preparation and route of administration can be based on as herein described about the information of The compounds of this invention as the information of the composition of unique promoting agent and treatment and other promoting agent of uniting use with it of being provided be provided.
Can use bioanalysis well known by persons skilled in the art for example to determine that in following mensuration concrete formula 1 compound suppresses the activity of cdk2, cdk5 or GSK-3.
The given activity of formula 1 compound inhibition cdk5 or cdk2 can for example use the analysis of the obtainable material of those skilled in the art to confirm by following:
Enzymic activity can be used as that (Amersham, cat.no.AH-9968) [33P] that is incorporated in the biotinylated peptide substrates PKTPKKAKKL measures from γ-phosphoric acid ester of [33P] ATP.In such mensuration, reaction is to contain 50mM Tris-HCl, pH8.0; 10mMMgCl 2, 0.1mM Na 3VO 4With carry out in the damping fluid of 1mM DTT.The final concentration of ATP is about 0.5 μ M (final specific activity is 4uCi/nmol), and the ultimate density of substrate is 0.75 μ M.Can carry out about 60 minutes in room temperature by adding the reaction that cdk5 and activator p25 or cdk2 and activator cyclin E begin.The 0.6 volume damping fluid that contains following component (final concentration) by adding comes termination reaction: 2.5mM EDTA, 0.05%Triton-X100, the SPA pearl (Amersham cat.no.RPNQ0007) of 100uM ATP and 1.25mg/ml streptavidin bag quilt.By the radioactivity on the scintillation counting quantitative assay pearl.
Formula 1 compound suppress GSK-3 given activity can do not contain cell and based on the mensuration of cell in determine that these two kinds of methods were all described (referring to for example WO99/65897) in the prior art.Not celliferous mensuration generally can be by with GSK-3 and peptide substrates, radiolabeled ATP (γ for example 33P-or γ 32-P-ATP derives from Amersham, ArlingtonHeights, Illinois), magnesium ion and test compounds cultivate together and carry out.This mixture cultivation for some time is incorporated into radiolabeled phosphoric acid ester in the peptide substrates with the activity by GSK-3.Generally be with all or a part of enzyme reaction mixture transfer to contain unified amount can the binding peptide substrate the Kong Zhonghou of part, wash this reaction mixture to remove unreacted radiolabeled ATP.After the washing, quantitative assay is retained in each hole 33P or 32The amount of P is to determine to be incorporated into the amount of the radio-labeled phosphoric acid ester in the peptide substrates.Observed restraining effect, it shows as the minimizing that is incorporated into the radio-labeled phosphoric acid ester in the peptide substrates compared with the control.The example that is used for the suitable GSK-3 of this mensuration is the crosslinked CREB peptide sequence of SGSG-, and it is conjugated protein that it is derived from CREB DNA, is described in Wang, waits the people, and Anal.Biochem. is among the 220:397-402 (1994).The GSK-3 of the purifying that is used to measure can for example derive from personnel selection GSK-3 β expression plasmid cells transfected, and such plasmid is described in for example Stambolic, waits the people, among the Current Biology 6:1664-68 (1996).WO99/65897; Wang waits the people, and Stambolic, waits people's document to introduce the present invention with for referencial use.
It is as follows to be similar to another example that the GSK-3 that describes in the preceding paragraph measures: enzymic activity is as (Amersham cat.no.AH-9968) is incorporated into that [33P] in the biotinylated peptide substrates PKTPKKAKKL measure from γ-phosphoric acid ester of [33P] ATP.In such mensuration, reaction is to contain 50mM Tris-HCl, pH8.0; 10mM MgCl 2, 0.1mMNa 3VO 4With carry out in the damping fluid of 1mM DTT.The final concentration of ATP is about 0.5 μ M (final specific activity is 4 μ Ci/nmol), and the ultimate density of substrate is 0.75 μ M.Can carry out about 60 minutes in room temperature by the reaction that the adding enzyme begins.The 0.6 volume damping fluid that contains following component (final concentration) by adding comes termination reaction: 2.5mM EDTA, 0.05%Triton-X100, the SPA pearl (Amersham cat.no.RPNQ0007) of 100uM ATP and 1.25mg/ml streptavidin bag quilt.By the radioactivity on the scintillation counting quantitative assay pearl.
When foundation said determination method is measured the cdk5 inhibition, the IC of the title compound inhibiting peptide substrate phosphorylation of all following embodiment 50All be lower than about 50 μ M.
Use assay method for example said determination method is measured the inhibition of the title compound of several following embodiment to GSK-3, and the compound of all tests suppresses the IC of GSK-3 β 50All be lower than about 50 μ M.
The following example is for example understood the present invention.Yet, should be appreciated that fully that describe in this article and the present invention that narrate is not subjected to the restriction of following embodiment in claims.
Embodiment preparation example 11-cyclobutyl-4-nitro-1H-imidazoles
23 ℃ with 1,4-dinitrobenzene imidazoles (237mg, 1.5mmol, J.Phys.Chem.1995,99, (107mg is 1.5mmol) in the solution in methyl alcohol (10mL) 5009-5015) to be added to cyclobutyl amine.This reaction mixture was stirred 16 hours, and solvent removed in vacuo by silica gel chromatography purifying gained resistates (1: 1 hexane-ethyl acetate), has obtained 230mg (productive rate is 92%) 1-cyclobutyl-4-nitro-1H-imidazoles then;
1H?NMR(400MHz，CDCl 3)δ7.81(s，1H)，7.45(s，1H)，4.64(m，1H)，2.6(m，2H)，2.4(m，2H)，2.0(m，2H)；MS(AP/Cl)：168.2(M+H) +.
Attention: 1,4-dinitrobenzene imidazoles is high energy, semistable material, should preserve in refrigerator when not using always.Thermodynamics is measured and to be shown, under adiabatic condition in 35 ℃ its may produce enough energy to bring heavy explosion.Using between this matter era high degree of care always.Preparation example 21-cyclopentyl-4-nitro-1H-imidazoles
This reaction is the method cyclopentyl amine and 1 according to preparation example 1, and 4-dinitrobenzene imidazoles carries out, and has obtained 205mg (productive rate is 75%) 1-cyclopentyl-4-nitro-1H-imidazoles; 1H NMR (400MHz, CDCl 3) δ 7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H), 2.0-1.7 (m, 6H); MS (AP/Cl): 182.2 (M+H) +. preparation example 34-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazoles
This reaction is with cis-(J.Med.Pharm.Chem 1960,2,687-691 for 3-benzyl ring butylamine according to the method for preparation example 1; ACIEE 1981,20, and 879-880) with 1,4-dinitrobenzene imidazoles carries out, and has obtained 46mg (productive rate is 46%) 4-nitro-1-(cis-3-phenyl-cyclobutyl)-1H-imidazoles;
1H?NMR(300MHz，CDCl 3)δ7.9(s，1H)，7.55(s，1H)，7.4-7.2(m，5H)，4.73(m，1H)，3.48(m，1H)，3.12(m，2H)，2.54(m，2H)；MS(AP/Cl)：244(M+H) +.
Embodiment 1N-(1-cyclobutyl-1H-imidazol-4 yl)-2-quinoline-6-base-ethanamide
(preparation example 1,150mg 0.9mmol) and ethyl acetate (10mL), add 10% palladium carbon (250mg) then to add 1-cyclobutyl-4-nitro-1H-imidazoles in Parr hydrogenation bottle.This reaction mixture is placed on the Parr hydrogenation apparatus, and under 50psi hydrogen in 23 ℃ of reactions.The content of this hydrogenation bottle is filtered via short Celite pad, under nitrogen atmosphere, wash in the flame-dried flask with anhydrous methylene chloride (25mL).Add Et 3(626 μ L 4.5mmol), and are cooled to 10 ℃ with this reaction soln to N.(168mg 0.9mmol) and tripropyl phosphonic acid anhydride (530 μ L, the solution of 1.7M in ethyl acetate), and stirs this mixture 2 hours at-10 ℃ to add 6-quinolyl acetate then.This solution is diluted with methylene dichloride (50mL), and wash (2 *) with water.Water layer with dichloromethane extraction (3 *), is merged organic layer, and with salt water washing (1 *).Solvent removed in vacuo, resistates is adsorbed onto on the silica gel, and use Biotage Flash 12 systems that connect SIM to carry out chromatogram purification (40: 1 methylene chloride-methanols), obtained 130mg (productive rate is 47%) N-(1-cyclobutyl-1H-imidazol-4 yl)-2-quinoline-6-base-ethanamide (this title compound);
1H?NMR(300MHz，CDCl 3)δ9.48(s，1H)，8.87(dd，J＝1.6，4.3Hz，1H)，8.11(m，2H)，7.76(d，J＝1.8Hz，1H)，7.67(dd，J＝2.0，8.7Hz，1H)，7.44(d，J＝1.6Hz，1H)，7.38(m，1H)，7.25(d，J＝1.6Hz，1H)，4.5(m，1H)，3.90(s，2H)，2.4(m，2H)，2.3(m，2H)，1.85(m，2H)；MS(AP/Cl)：307.1(M+H) +.
Embodiment 2N-(1-cyclopentyl-1H-imidazol-4 yl)-2-(4-methoxyl group-phenyl)-ethanamide
Carry out the method for embodiment 1 with homoanisic acid and 1-cyclopentyl-4-nitro-1H-imidazoles (preparation example 2), the productive rate with 32% (26.5mg) has made N-(1-cyclopentyl-1H-imidazol-4 yl)-2-(4-methoxyl group-phenyl)-ethanamide;
1H?NMR(400MHz，CDCl 3)δ8.54(s，1H)，7.35(s，1H)，7.24(m，2H)，6.87(d，J＝1.7Hz)，4.36(m，1H)，3.78(s，3H)，3.64(s，2H)，2.1(m，2H)，1.8(m，4H)，1.6(m，2H)；MS(AP/Cl)：300.3(M+H) +.
Embodiment 3N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4 yl]-2-quinoline-6-base-ethanamide
Carry out the method for embodiment 1 with 6-quinolyl acetate and 4-nitro-1-(cis-3-benzyl ring butyl)-1H-imidazoles (preparation example 3), have 38% productive rate to make N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4 yl]-2-quinoline-6-base-ethanamide;
1H?NMR(300MHz.CDCl 3)δ8.93(m，1H)，8.12(m，2H)，7.79(d，J＝1.5Hz，1H)，7.71(m，1H)，7.55(d，J＝1.5Hz，1H)，7.41(dd，J＝4.3，8.4Hz，1H)，7.37-7.22(m，5H)，4.57(m，1H)，3.96(s，2H)，3.33(m，1H)，2.95(m，2H)，2.49(m，2H)；MS(AP/Cl)：383.0(M+H) +.
Embodiment 4 (1-cyclobutyl-1H-imidazol-4 yl)-phenyl carbamate
(preparation example 1,3g 18mmol) and ethyl acetate (70mL), add 10% palladium carbon then to add 1-cyclobutyl-4-nitro-1H-imidazoles under nitrogen atmosphere in Parr hydrogenation bottle.With this mixture under 50psi hydrogen in 23 ℃ of hydrogenations 6 hours.Then this mixture is filtered via Celite pad, and wash in the flame-dried flask with anhydrous methylene chloride (140mL).Gained solution is cooled to-78 ℃, add diisopropylethylamine (2.3g, 18mmol), drip then phenyl chloroformate (2.5g, 16.2mmol).After 30 minutes, add the methyl alcohol (9mL) that contains acetate (1.8mmol).This reaction mixture is transferred in the separating funnel,, and washed with water (2 *) with ethyl acetate (200mL) dilution.With ethyl acetate (2 * 10mL) aqueous layer extracted.Merge organic layer, with salt water washing (2 *), dry then (MgSO 4), filter and vacuum concentration.Crude product is adsorbed onto on the silica gel,, has obtained 3g (productive rate is 65%) (1-cyclobutyl-1H-imidazol-4 yl) phenyl carbamate by silica gel chromatography purifying (1: 1 hexane-ethyl acetate);
1H NMR (400MHz, CDCl 3) δ 7.4-7.3 (m, 2H), 7.22-7.18 (m, 3H), 4.5 (m, 1H), 2.46-2.30 (m, 4H), 1.83 (m, 2H); MS (AP/Cl): 258.2 (M+H) +. embodiment 51-(1-cyclobutyl-1H-imidazol-4 yl)-3-isoquinoline 99.9-5-base-urea
In 1 drachm bottle, add with nut at interval (1-cyclobutyl-1H-imidazol-4 yl) phenyl carbamate (embodiment 4,50mg, 0.19mmol), the 5-aminoisoquinoline (30mg, 0.21mmol) and 1: 1 dioxane-DMF (1mL).This reaction mixture was heated 2 hours at 70 ℃.This reaction mixture is adsorbed onto on the silica gel, and, has obtained 30mg (52% productive rate) 1-(1-cyclobutyl-1H-imidazol-4 yl)-3 isoquinoline 99.9-5-base-urea by silica gel chromatography purifying (40: 1 chloroform-methanols);
1H NMR (400MHz, CD 3OD) δ 9.21 (d, J=1.7Hz, 1H), 8.45 (d, J=6.2Hz, 1H), 8.24 (d, J=7.5Hz, 1H), 7.98 (d, J=5.4Hz, 1H), 7.84 (dd, J=2.3,8.3Hz, 1H), 7.66 (m, 1H), 7.54 (s, 1H), 7.12 (brs, 1H), 4.66 (m, 1H), 2.5-2.3 (m, 4H), 1.9 (m, 2H); MS (AP/Cl): 308.0 (M+H) +. preparation example 4 N-[1-(cis-3-azido--cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide step 1
With 3-benzyloxy cyclobutyl amine (43.4g, 245mmol, Chem.Ber.1957,90,1424-1432) be dissolved in hydrogen chloride methanol solution (saturated, 450mL) in, add 10% palladium carbon (4g) then.With the hydrogenation 6 hours under 50psi hydrogen of this reaction mixture.This mixture is filtered, and vacuum concentration has obtained about 35g oily matter.This oily matter is placed methyl alcohol (600mL), be cooled to 0 ℃, and (13.7g 245mmol) handles with potassium hydroxide.When pH=10, add 1,4-dinitrobenzene imidazoles (42.7g, 270mmol) solution in methyl alcohol (200mL) (by at 0 ℃ with 1,4-dinitrobenzene imidazoles is dissolved in and makes in the methyl alcohol) (note: 1,4-dinitrobenzene imidazoles is high energy, semistable material, should preserve in refrigerator when not using always.Thermodynamics is measured and to be shown, under adiabatic condition in 35 ℃ its may produce enough energy to bring heavy explosion.Using between this matter era high degree of care always).The gained organic suspension liquid is warmed to 23 ℃ lentamente, keeps spending the night.Solvent removed in vacuo by the silica gel plug purifying gained resistates (20: 1 chloroform-methanols) of flowing through big, has obtained 19g (42% productive rate) 3-(4-nitro-imidazoles-1-yl)-cyclobutanol, is 1: 1 mixture of cis-trans isomer;
1H NMR (400MHz, CD 3OD) δ 8.29 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 5.02 (m, 1H), 4.53 (m, 1H), 4.37 (m, 1H), 4.10 (m, 1H), 2.95 (m, 2H), 2.7 (m, 2H), 2.5 (m, 2H), 2.3 (m, 2H); MS (AP/Cl): 184.0 (M+H) +Step 2
With 3-(4-nitro-imidazoles-1-yl)-cyclobutanol (preparation example 4, step 1; 4g 22mmol) uses Et 3(7.7mL 55mmol) handles in methylene dichloride (150mL) N, and (5g, 26.4mmol) and 4-N, (268mg 2.2mmol) handles N-dimethyl aminopyridine (DMAP) to use Tosyl chloride (TsCI) then.With the gained mixture stirring at room 24 hours.Thin-layer chromatographic analysis shows two new points.This reaction mixture is diluted with methylene dichloride, and water (1 *) and salt solution (1 *) washing.With organic layer drying (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying (1: 1-2: 1 hexane-ethyl acetate) separate trans and the cis diastereomer.First wash-out point (high Rf) is a trans-isomer(ide), trans-toluene-4-sulfonic acid 3-(4-nitro-imidazoles-1-yl)-cyclobutyl ester (2.7g, 37% productive rate);
1H NMR (400MHz, CDCl 3) δ 7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=1.7Hz, 1H), 7.36 (dd, J=0.5,8.0Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/Cl): 338.1 (M+H) +. second wash-out point is cis-isomeride, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazoles-1-yl)-cyclobutyl ester (2.9g, 39% productive rate);
1H NMR (400 MHz, CDCl 3) δ 7.8 (m, 3H), 7.43 (d, J=1.4Hz, 1H), 7.36 (dd, J=0.6,8.5Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6-2.5 (m, 2H), 2.45 (s, 3H); MS (AP/Cl): 338.1 (M+H) +. relative configuration is determined by measuring nuclear Overhauser effect.Step 3
With trans-toluene-4-sulfonic acid 3-(4-nitro-imidazoles-1-yl)-cyclobutyl ester (preparation example 4, step 2; 590mg 1.75mmol) mixes in ethyl acetate (30mL) with 10% palladium on carbon (500mg).Then with this mixture under 50psi hydrogen in room temperature reaction 6 hours.With this mixture via diatomite filtration in the dry flask of flame that remains under the nitrogen atmosphere.Add Et 3N (1.22mL, 8.75mmol), add then the 1-naphthyl acetic acid (326mg, 1.75mmol) and the tripropyl phosphonic acid anhydride (1.1mL, the 1.7M solution in ethyl acetate, 1.75mmol).With this mixture stirring at room 1 hour, then with the ethyl acetate dilution, and water and salt water washing.With organic layer drying (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying gained resistates (50: 1 chloroform-methanols), obtained trans-toluene-4 sulfonic acid 3-[4-of 600mg (72% productive rate) (2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl ester;
1H NMR (400MHz, CDCl 3) δ 7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J=8.3Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/Cl): 476.2 (M+H)+. step 4
With trans-toluene-4-sulfonic acid 3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl ester (preparation example 4, step 3; 593mg, 1.25mmol) (813mg 12.5mmol) mixes in ethanol (15mL), water (5mL) and chloroform (5mL) with sodiumazide.Under agitation this mixture heating up was refluxed 96 hours then.Solvent removed in vacuo, the dilute with water resistates, and use dichloromethane extraction.With organic layer drying (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying (50: 1 chloroform-methanols), obtained 340mg (79% productive rate) N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide;
1H?NMR(400MHz，CDCl 3)δ8.41(s，1H)，7.98(d，J＝6.4?Hz，1H)，7.87(m，1H)，7.82(m，1H)，7.5(m，2H)，7.45(m，3H)，7.08(d，J＝1.7Hz，1H)，4.2(m，3H)，3.75(m，1H)，2.85(m，2H)，2.35(m，2H)；MS(AP/Cl)：347.2(M+H)+.
Embodiment 6N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide
With N-[1-(cis-3-azido--cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide (preparation example 4, step 4; 330mg, 0.95mmol) with triphenylphosphine (301mg, 1.15mmol) in tetrahydrofuran (THF) (10mL) and water (1mL) in 23 ℃ of processing.With this solution stirring at room 18 hours.Solvent removed in vacuo by silica gel chromatography purifying gained resistates (20: 1: 0.5 chloroform-methanol-ammonium hydroxide), has obtained 289mg (productive rate is 95%) N-(1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl)-2-naphthalene-1-base-ethanamide;
1H?NMR(400MHz，CD3OD)δ8.05(d，J＝7.5Hz，1H)，7.87(d，J＝7.9Hz，1H)，7.79(d，J＝9.0Hz，1H)，7.45(m，5H)，7.35(s，1H)，4.26(m，1H)，4.16(s，2H)，3.29(m，2H)，3.16(m，1H)，2.75(m，2H)，2.1(m，2H)；MS(AP/Cl)：321.3(M+H)+.
Embodiment 7a6-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides
(9.4mg, 0.07mmol) solution in methylene dichloride is handled with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (84mg) and DMAP (2mg) with 6-picoline formic acid at 23 ℃.Stir after 10 minutes, add N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2 naphthalenes-1-base-ethanamide (embodiment 6,20mg, 0.06mmol).Then the gained mixture was stirred 3 hours.Add entry, this solution is adjusted to neutrality, and use ethyl acetate extraction with the NaOH aqueous solution.With organic layer drying (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying (20: 1 CHCl 3-MeOH), obtained 26mg (productive rate is 95%) 6-methyl-pyridine-2-formic acid { 3-[4-(2-naphthalene-1-base acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides;
1H?NMR(400MHz，CDCl 3)δ9.15(s，1H)，8.28(d，J＝8.3Hz，1H)，8.01(d，J＝7.5Hz，1H)，7.96(d，J＝7.5Hz，1H)，7.97(d，J?7.5Hz，1H)，7.81(dd，J＝2.4，6.6Hz，1H)，7.72(m，1H)，7.5(m，5H)，7.2(m，1H)，7.16(s，1H)，4.45(m，1H)，4.25(m，1H)，4.18(s，2H)，2.98(m，2H)，2.60(s，3H)，2.40(m，2H)；MS(AP/Cl)：440.3(M+H)+.
Embodiment 7b1H-imidazoles-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz.CD3OD)δ8.06(d，J＝7.9Hz，1H)，7.87(m，1H)，7.80(d，J＝7.5Hz，1H)，7.7(s，1H)，7.64(s，1H)，7.5(m，6H)，4.44(m，1H)，4.32(m，1H)，4.18(s，2H)，2.9(m，2H)，2.45(m，2H)；MS(AP/Cl)：415.3(M+H)+.
Embodiment 7c6-hydroxyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ8.02(d，J＝7.9Hz，1H)，7.84(d，J＝7.9Hz，1H)，7.79(d，J＝7.5Hz，1H)，7.65(s，1H)，7.60(m，1H)，7.45(m，6H)，7.14(brs，1H)，6.71(d，J＝8.7Hz，1H)，4.4(m，1H)，4.32(m，1H)，4.17(s，2H)，2.93(m，2H)，2.5(m，2H)；MS(AP/Cl)：442.3(M+H)+.
Embodiment 7d3-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(CD3OD，400MHz)δ8.39(d，J＝4.2Hz，1H)，8.06(d，J＝8.3?Hz，1H)，7.87(d，J＝7.5Hz，1H)，7.80(d，J＝7.5Hz，1H)，7.69(d，J＝7.9Hz，1H)，7.5(m，7H)，4.5(m，1H)，4.3(m，1H)，4.17(s，2H)，2.92(m，2H)，2.54(s，3H)，2.46(m，2H)；MS(AP/Cl)：440.3(M+H)+.
Embodiment 7e2-pyridin-3-yl-thiazole-4-formic acid cis-3-[4-(2-naphthalene-1-base acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)9.21(d，J＝2.5?Hz，1H)，8.61(d，J＝5.0Hz，1H)，8.41(dd，J＝1.7，7.9Hz，1H)，8.26(s，1H)，8.06(d，J＝7.9Hz，1H)，7.86(d，J＝7.5Hz，1H)，7.79(d，J＝7.9Hz，1H)，7.5(m，7H)，4.44(m，2H)，4.17(s，2H)，2.9(m，2H)，2.6(m，2H)；MS(AP/Cl)：509.3(M+H)+.
Embodiment 7f6-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl formamyl }-nicotinic acid methyl ester
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD/CDCl 3)δ9.15(d，J＝1.6Hz，1H)，9.12(d，J＝8.0Hz，1H)，8.45(dd，J＝2.0，8.4Hz，1H)，8.16(d，J＝8.0Hz，1H)，8.02(d，J＝8.4Hz，1H)，7.85(d，J＝8.0Hz，1H)，7.80(d，J＝7.8Hz，1H)，7.48(m，6H)，4.45(m，2H)，3.96(s，3H)，2.94(m，2H)，2.58(m，2H)；MS(AP/Cl)：484.3(M+H)+.
Embodiment 7g pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ9.23(d，J＝2.0Hz，1H)，9.03(d，J＝8.0Hz，1H)，8.73(d，J＝2.4Hz，1H)，8.63(d，J＝1.6，2.4Hz，1H)，8.02(d，J＝8.4Hz，1H)，7.85(d，J＝8.0Hz，1H)，7.79(d，J＝8.0Hz，1H)，7.49(m，6H)，4.44(m，2H)，4.16(s，2H)，2.95(m，2H)，2.56(m，2H)；MS(AP/Cl)：427.3(M+H)+.
Embodiment 7hN-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ8.05(d，J＝8.3Hz，2H)，7.99(d，J＝7.1Hz，1H)，7.86(d，J＝7.5Hz，1H)，7.80(J＝7.1Hz，2H)，7.45(m，8H)，4.47(m，1H)，4.37(m，1H)，4.17(s，2H)，2.90(m，2H)，2.47(m，2H)；MS(AP/Cl)：425.0(M+H)+.
Embodiment 7i5-methyl-pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ9.07(d，J＝1.2Hz，1H)，8.5(d，J＝0.8Hz，1H)，8.02(d，J＝8.0Hz，1H)，7.85(d，J＝7.6Hz，1H)，7.79(d，J＝7.6Hz，1H)，7.45(m，6H)，4.40(m，2H)，4.16(s，2H)，2.93(m，2H)，2.61(s，3H)，2.54(m，2H)；MS(AP/Cl)：441.3(M+H)+.
Embodiment 7jN-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-isobutyramide
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ8.01(d，J＝7.9Hz，1H)，7.84(d，J＝7.5Hz，1H)，7.78(d，J＝7.5Hz，1H)，7.45(m，6H)，4.35(m，1H)，4.15(s，2H)，4.11(m，2H)，2.84(m，2H)，2.35(m，1H)，2.28(m，2H)，1.06(d，J＝6.6Hz，6H)；MS(AP/Cl)：391.1(M+H)+.
Embodiment 7k6-chloro-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is to make by the method that is similar to embodiment 7a;
1H?NMR(400MHz，CD3OD)δ8.07(d，J＝7.9Hz，1H)，8.03(d，J＝7.5Hz，1H)，7.94(m，1H)，7.87(d，J＝7.9Hz，1H)，7.81(d，J＝7.9Hz，1H)，7.61(d，J＝7.1Hz，1H)，7.58(s，1H)，7.5(m，5H)，4.45(m，1H)，4.39(m，1H)，4.18(s，2H)，2.89(m，2H)，2.63(m，2H)；MS(AP/Cl)：460.2，462.2(M+H)+.
Embodiment 8
According to following operation with different carboxylic acids with N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide (embodiment 6) acidylate, purifying then: to the carboxylic acid (RCO in 1 drachm nut 2H, 1 equivalent, 0.075mmol) middle N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl that adds]-2-naphthalene-1-base-ethanamide (0.33equiv, 8mg, 0.025mmol) solution in methylene dichloride (1mL).Add then the PS-carbodiimide (Argonaut Technologies, 0.5 equivalent, 39mg, 0.038mmol, 1mmol/g).With this mixture 23 ℃ of joltings 24 hours.Attention: be insoluble in the methylene dichloride as tartaric acid, then add N, dinethylformamide (0.5mL).Each reaction mixture is transferred in the 3mL SPE cartridge case (20 microns frits) with the fixed 2 drachm bottles of scale to collect solvent with methylene dichloride (0.5mL).Solvent is pressurizeed via frit, and polymkeric substance is washed with THF (0.5mL), methylene dichloride (0.5mL), THF (0.5mL) and methylene dichloride (0.5mL).This solution is concentrated under nitrogen atmosphere, by lcms analysis crude product (post: 3.9 * 150mm Waters Symmetry C 18, 5 μ M; Flow velocity=1.0ml/ minute; Solvent systems: the A=0.1%TFA aqueous solution; The B=acetonitrile; The 10-100%B linear gradient was with 10 minutes).If observe parent ion (M+H), by this thick reaction mixture of preparation HPLC purifying (post: 30 * 150mm Waters Symmetry C 185 μ M; Flow velocity=20mL/ minute; Solvent systems: the A=0.1%TFA aqueous solution; The B=acetonitrile; The 10-100%B linear gradient was with 15 minutes), determine suitable fraction by online mass spectrograph.By analyzing the activatory purity (post: 2.1 * 150mm WatersSymmetry C that HPLC measures chromatogram purification 185 μ M; Flow velocity=0.5mL/ minute; Solvent systems: the A=0.1%TFA aqueous solution; The B=acetonitrile; The 10-100%B linear gradient was with 10 minutes), use UV:254nM and diode to arrange and detect.
Sequence Table <110> Biot · Maili You Company (BIOMERIEUX) <120> control the microbiological quality of the water phase medium method and kit <130> AQUAGENE B05B3650 <140> <141> <150> FR00-08839 <151> 200-07-06 <160> 104 <170> PatentIn Ver.2.1 <210> 1 <211> 39 <212> DNA <213> Campylobacter (Campylobacter coli) <400> 1 tttgtgaaat ctaatggctt aaccattaaa ctgcttgag 39 <210> 2 <211> 29 <212> DNA <213> Campylobacter (Campylobacter coli) <400> 2 atccgtagag atcaccaaga atacccatt 29 <210> 3 <211> 54 <212> DNA <213> Campylobacter jejuni (Campylobacter jejuni) <400> 3 gtctcttgtg aaatctaatg gcttaaccat taaactgctt gggaaactga tagt 54 <210> 4 <211> 24 <212> DNA <213> Campylobacter jejuni (Campylobacter jejuni) <400> 4 ggaactcaac tgacgctaag gcgc 24 <210> 5 <211> 24 <212> DNA <213> Pseudomonas aeruginosa (Pseudomonas aeruginosa) <400> 5 gtggttcagc aagttggatg tgaa 24 <210> 6 <211> 27 <212> DNA <213> Pseudomonas aeruginosa (Pseudomonas aeruginosa) <400> 6 aaactactga gctagagtac ggtagag 27 <210> 7 <211> 35 <212> DNA <213> Pseudomonas fluorescens (Pseudomonas fluorescens) <400> 7 tgttttgacg ttaccgacag aataagcacc ggcta 35 <210> 8 <211> 27 <212> DNA <213> Pseudomonas fluorescens (Pseudomonas fluorescens) <400> 8 tagagtatgg tagagggtgg tggaatt 27 <210> 9 <211> 21 <212> DNA <213> Legionella bacteria (Legionella) <400> 9 atactgacac tgaggcacga a 21 <210> 10 <211> 23 <212> DNA <213> invasion of Legionella pneumophila (Legionel1a pneumophila) <400> 10 ttactgggcg tcaagggtgc gta 23 <210> 11 <211> 23 <212> DNA <213> invasion of Legionella pneumophila (Legionella pneumophila) <400> 11 ttaacctggg acggtcagat aat 23 <210> 12 <211> 27 <212> DNA <213> Acinetobacter baumannii (Acinetobacter baumannii) <400> 12 gcgtaggcgg cttattaagt cggatgt 27 <210> 13 <211> 27 <212> DNA <213> Acinetobacter baumannii (Acinetobacter baumannii) <400> 13 cattcgatac tggtgagcta gagtatg 27 <210> 14 <211> 47 <212> DNA <213> E. coli Shigella species (Escherichia Coli Shigella Species) <400> 14 cggggaggaa gggagtaaag ttaatacctt tgctcattga cgttacc 47 <210> 15 <211> 22 <212> DNA <213> Salmonella (Salmonella) <400> 15 gaggaaggtg ttgtggttaa ta 22 <210> 16 <211> 32 <212> DNA <213> guinea Aeromonas (Aeromonas cayiae) <400> 16 cagtagctaa tatctgctgg ctgtgacgtt ac 32 <210> 17 <211> 32 <212> DNA <213> hydrophila and Aeromonas (Aeromonas hydrophi1a) <400> 17 acgcaggcgg ttggataagt tagatgtgaa ag 32 <210> 18 <211> 20 <212> DNA <213> hydrophila and Aeromonas (Aeromonas hydrophila) <400> 18 aattgcattt aaaactgtcc 20 <210> 19 <211> 35 <212> DNA <213> mild Aeromonas (Aeromonas sobria) <400> 19 gaaaggttgg cagctaatat ctgtcagctg tgacg 35 <210> 20 <211> 26 <212> DNA <213> mild Aeromonas (Aeromonas sobria) <400> 20 aattgctgtt cagctagagt cttgta 26 <210> 21 <211> 53 <212> DNA <213> Vibrio cholera (Vibrio cholerae) <400> 21 cagtagggag gaaggtggtt aagttaatac cttaatcatt tgacgttacc tac 53 <210> 22 <211> 48 <212> DNA <213> Vibrio cholera (Vibrio cholerae) <400> 22 tcaacctagg aatcgcattt gaaactgaca agctagagta ctgtagag 48 <210> 23 <211> 37 <212> DNA <213> Staphylococcus aureus (Staphylococcus aureus) <400> 23 gttattaggg aagaacatat gtgtaagtaa ctgtgca 37 <210> 24 <211> 37 <212> DNA <213> Staphylococcus epidermidis (Staphylococcus epidermatitis) <400> 24 tattagggaa gaacaaatgt gtaagtaact atgcacg 37 <210> 25 <211> 23 <212> DNA <213> Streptococcus bovis horse intestines (streptococcus boyis streptococcus equinus) <400> 25 ttggaaactg ttagacttga gtg 23 <210> 26 <211> 43 <212> DNA <213> Enterococcus faecalis (Enterococcus faecalis) <400> 26 aagaacaagg acgttagtaa ctgaacgtcc cctgacggta tct 43 <210> 27 <211> 27 <212> DNA <213> feces, small intestine, durable enterococci (Enterococcus faecium, hirae, durans) <400> 27 agagtaactg ttcatccctt gacggta 27 <210> 28 <211> 29 <212> DNA <213> Clostridium perfringens (Clostridium perfringens) <400> 28 agcgtaggcg gatgattaag tgggatgtg 29 <210> 29 <211> 22 <212> DNA <213> Clostridium perfringens (Clostridium perfringens) <400> 29 gtgctgcatt ccaaactggt ta 22 <210> 30 <211> 24 <212> DNA <213> mycobacteria (Mycobacterium sp.) <400> 30 gcgtgcgggc gatacgggca gact 24 <210> 31 <211> 25 <212> DNA <213> Bird, M. intracellulare (Mycobacterium avium, intracellulare) <400> 31 aaggtccggg ttttctcgga ttgac 25 <210> 32 <211> 29 <212> DNA <213> Kansas mycobacteria (Mycobacterium kansasii) <400> 32 gtccgggttc tctcggattg acggtaggt 29 <210> 33 <211> 22 <212> DNA <213> Gordon mycobacteria (Mycobacterium gordonae) <400> 33 gttttctcgg gctgacggta gg 22 <210> 34 <211> 24 <212> DNA <213> Mycobacterium marinum (Mycobacterium marinum) <400> 34 aggttcgggt tttctcggat tgac 24 <210> 35 <211> 20 <212> DNA <213> toad mycobacteria (Mycobacterium xenopi) <400> 35 ctttcagcct cgacgaagct 20 <210> 36 <211> 22 <212> DNA <213> toad mycobacteria (Mycobacterium xenopi) <400> 36 gtgacggtag gggcagaaga ag 22 <210> 37 <211> 42 <212> DNA <213> gladioli Burkholderia (Burkholderia gladioli) <400> 37 ccggaaagaa atcctgaggg ctaatatcct tcggggatga cg 42 <210> 38 <211> 25 <212> DNA <213> Onions Burkholderia (Burkholderia cepacia) <400> 38 actgcattgg tgactggcag gctag 25 <210> 39 <211> 39 <212> DNA <213> addicted maltose Stenotrophomonas bacteria (Stenotrophomonas maltophilia) <400> 39 gaggaacatc catggcgaag gcagctacct ggaccaaca 39 <210> 40 <211> 23 <212> DNA <213> Cryptosporidium (Cryptosporidium) <400> 40 cagttatagt ttacttgata atc ​​23 <210> 41 <211> 20 <212> DNA <213> Cryptosporidium (Cryptospori dium) <400> 41 ttattagata aagaaccaat 20 <210> 42 <211> 27 <212> DNA <213> Cryptosporidium (Cryptosporidium) <400> 42 acctatcagc tttagacggt agggtat 27 <210> 43 <211> 27 <212> DNA <213> Cryptosporidium (Cryptosporidium) <400> 43 tgccttgaat actccagcat ggaataa 27 <210> 44 <211> 37 <212> DNA <213> Cryptosporidium (Cryptospori dium) <400> 44 agagattgga ggttgttcct tactccttca gcacctt 37 <210> 45 <211> 35 <212> DNA <213> short Cryptosporidium (Cryptosporidium parvum) <400> 45 tcattataac agttatagtt tacttgataa tcttt 35 <210> 46 <211> 43 <212> DNA <213> short Cryptosporidium (Cryptospori dium parvum) <400> 46 attggaatga gttaagtata aaccccttta caagtatcaa ttg 43 <210> 47 <211> 29 <212> DNA <213> short Cryptosporidium (Cryptosporidium parvum) <400> 47 tagttggatt tctgttaata atttatata 29 <210> 48 <211> 36 <212> DNA <213> short Cryptosporidium (Cryptospori dium parvum) <400> 48 atatttatat aatattaaca taattcatat tactat 36 <210> 49 <211> 41 <212> DNA <213> short Cryptosporidium (Cryptosporidium parvum) <400> 49 tttcgaagga aatgggtaat cttttgaata tgcatcgtga t 41 <210> 50 <211> 382 <212> DNA <213> adenovirus 40 L19443 (Adenovirus 40 L19443) <400> 50 ctaaagggaa ctgccagtgt aaagcataac atgatttgtg gcggtggtca ctctcagctg 60 ctaacctgtg cagatggaaa ctgtcaggct ctgagagtgt ttcacgtagt atctcatccc 120 cgccgcccct ggcctgtttt tgagcacaac atgcttatgc gctgtactgt gcatttggga 180 gctcgtcgtg gcatgttttc tccataccag agtaactttt gccacactaa agttttaatg 240 gaaactgatg ctttttctcg ggtatggtgg aacggggtat ttgatttaac catggagcta 300 tttaaagtgg tgaggtatga tgagtcaaag gttcgttgtc gcccctgtga gtgtggagct 360 aatcatatta ggttatatcc ag 382 <210> 51 <211> 382 <212> DNA <213> adenovirus 41 bis M18289 (Adenovirus 41 bis M18289) <400> 51 ctgaagggaa ctgccagtgt taagcataat atgatttgtg gcactggtca ctctcagctg 60 ctaacttgcg cagatggaaa ctgtcagact ctaaaagtga ttcatgtggt ttcccatcag 120 cgccgcccct ggcctgtttt tgagcataac atgcttatgc gttgtaccat gcatttgggg 180 gctcgtcgtg gcatgttttc tccatatcag agtaattttt gccatactaa agttttaatg 240 gaaactgatg ctttttcgcg ggtgtggtgg agcggggtgt ttgatttgac catagagctg 300 tataaagtgg tgagatatga tgagttaaag gctcgttgtc gcccctgtga gtgtggagcc 360 aatcacatca ggttatatcc ag 382 <210> 52 <211> 67 <212> DNA <213> Astroviruses HtAstV-1-2 L23513 (Astrovirus HAstV-1-2 L23513) <400> 52 agggtacagc ttccttcttt tctgtctctg tttagattat tttaatcacc atttaaaatt 60 gatttaa 67 <210> 53 <211> 521 <212> DNA <213> poliovirus X00595 (Poliovirus X00595) <400> 53 cggtaccttt gtgcgcctgt tttatactcc cctcccgcaa cttagaagca cgaaaccaag 60 ttcaatagaa gggggtacaa accagtacca ctacgaacaa gcacttctgt ttccccggtg 120 acattgcata gactgctcac gcggttgaaa gtgatcgatc cgttacccgc ttgtgtactt 180 cgaaaagcct agtatcgcct tggaatcttc gacgcgttgc gctcagcacc cgaccccggg 240 gtgtggctta ggctgatgag tctggacatt cctcaccggt gacggtggtc taggctgcgt 300 tggcggccta cctatggcta acgccatagg acgttagatg tgaacaaggt gtgaagagcc 360 tattgagcta cataagagtc ctccggcccc tgaatgcggc taatcctaac cacggaacag 420 gcggtcgcga accagtgact ggcttgtcgt aacgcgcaag tctgtggcgg aaccgactac 480 tttgggtgtc cgtgtttcct gttattttta tcatggctgc t 521 <210> 54 <211> 520 <212> DNA <213> Coxsackie virus D00538 (Coxsackievirus D00538) <400> 54 aggtaccttt gtacgcctgt tttatatccc ttcccccgta actttagaag cttatcaaaa 60 gttcaatagc aggggtacaa gccagtacct ctacgaacaa gcacttctgt ttccccggtg 120 aaatcatata gactgtaccc acggtcaaaa gtgattgatc cgttatccgc ttgagtactt 180 cgagaagcct agtatcgcct tggaatcttc gacgcgttgc gctcaacact ctgccccgag 240 tgtagcttag gctgatgagt ctgggcactc cccaccggcg acggtggccc aggctgcgtt 300 ggcggcctac ccatggctga tgccgtggga cgctagttgt gaacaaggtg tgaagagcct 360 attgagctac tcaagagtcc tccggcccct gaatgcggct aatcctaacc acggagcaat 420 cgctcacgac ccagtgagta ggttgtcgta atgcgtaagt ctgtggcgga accgactact 480 ttgggtgtcc gtgtttccct ttatattcat actggctgct 520 <210> 55 <211> 525 <212> DNA <213> echovirus X77708 (Echovirus X77708) <400> 55 cggtaccttt gtgcgcctgt tttatatacc ctcccctcag taacctagaa gttcatcaca 60 aatgatcaat agttagctca acaaaccagt tgagcctaga tcaagcactt ctgttacccc 120 gggctgagta tcaataagct gttgacacgg ctgaaggaga aaacgcccgt tacccgacca 180 gctacttcgg agaacctagt atcaccatag aggttgcgta gcgtttcgct ccgcacaacc 240 ccagtgtaga tcaggtcgat gagtcaccgc gttccccaca ggcgactgtg gcggtggctg 300 cgttggcggc ctgcccatgg ggttacccat gggacgcttc aatactgaca tggtgtgaag 360 agttgactga gctagctggt agtcctccgg cccctgaatg cggctaatcc taactgtgga 420 gcaagtgccc acaacccagt gggtggcttg tcgtaatggg caactctgca gcggaaccga 480 ctactttggg tgaccgtgtt tctctttatt cttatattgg ctgct 525 <210> 56 <211> 981 <212> DNA <213> Rotavirus U36242 (Rotavirus U36242) <400> 56 atgtatggta ttgaatatac cacaattctg accattttga tatttatcat attattgaat 60 tatatattaa aaactataac taatacgatg gactatatag tttttaaatt tttgctacta 120 atcgctctga tgtcaccatt tgtaaggacg caaaattatg gcatgtattt accaataaca 180 ggatcactag acgctgtata cacaaattca actagtggag aatcatttct aacttcaacg 240 ctatgtttat actatccaac agaagctaaa aatgagattt cagataatga atgggaaaat 300 actctatcag aattattttt aactaaagga tggccggctg gatcagttta ttttaaagac 360 tacaatgata ttactacatt ttctatgaat ccacaactgt attgtgatta taatgtagta 420 ttgatgagat atgataatac atctgaatta gatgcatcgg agttagcaga tcttatattg 480 aacgaatggc tgtgcaatcc tatggatata tcactttact attatcaaca aaatagcgaa 540 tcaaacaaat ggatatcaat cggaacagac tgtacggtaa aagtttgtcc actcaataca 600 caaactctag gaattggatg caaaactacg gacgtggata catttgagat tgttgcgtcg 660 tctgaaaaat tggtaattac tgatgttgta aatggtgtaa accataaaat aaatatttca 720 ataagtacat gtactatacg taattgtaat aaactaggac cacgagaaaa tgttgctata 780 attcaagttg gtggaccgaa cgcactagat atcactgctg atccaacaac agttccacag 840 gttcaaagaa ttatgcgagt aaattggaaa aaatggtggc aagtgtttta tacagtagtt 900 gactatatta accaaattat acaagttatg tccaaacggt caagatcatt agacacagct 960 gctttttatt atagaattta g 981 <210> 57 <211> 981 <212> DNA <213> Rotavirus M86834 (Rotavirus M86834) <400> 57 atgtatggta ttgaatatac cacagttcta ttttatttga tatcgttcgt tcttgtgagt 60 tacattttaa aaaccataac gaaaatgatg gactatatta tttatagagt aacttttata 120 attgttgtat tatcagtact gtctaatgcg caaaattatg gaataaattt gccaattact 180 ggatctatgg atacagcgta cgctaattcg acgcaaaatg gaaatttcct gtcttcaact 240 ctatgtctat attatccatc tgaggctcca actcaaatta gtgataacga atggaaagat 300 acattatctc agttgttttt gactaaggga tggccaacag gttcagttta ttttaatgaa 360 tattcgaatg ttctggattt ttcaattgac ccaaaattat actgtgatta taatattgta 420 ttaattaaat ttgcttctgg agaggagttg gatatatctg aactagctga tctgatacta 480 aatgaatggt tgtgtaatcc aatggatata acgctatatg attatcaaca aactggagaa 540 gcaaataaat ggatatcaat gggatcatct tgtactgtca aagtgtgccc attaaatacg 600 caaactttag gaattggctg ccaaacaacg aatgtagcta cttttgaaat ggtggctgac 660 agtgaaaaac tagcgatagt tgatgttgtt gataatgtaa atcataaatt agatattaca 720 tctacaacgt gtacaatacg aaattgtaag aaattaggtc caagagaaaa tgtggctata 780 atacaggttg gtggttctaa tatactagat ataacggctg atcccacgac ttcaccgcaa 840 acggaacgaa tgatgcgtgt taattggaag aaatggtggc aagtatttta cactgtagtt 900 gattatatta atcagatagt acaaatgatg tccaaaagat cgaggtcgct agattcatcc 960 tctttttatt atagagtata g 981 <210> 58 <211> 981 <212> DNA <213> Rotavirus U26395 (Rotavirus U26395) <400> 58 atgtatggta ttgaatatac cacaattcta atctttctga tatcaatcat cctactcaac 60 tatatattaa aatcagtgac ccgaataatg gactacatta tatatagatt tttattaatt 120 tctgtagcat tatttgcctt aactaaagct cagaactatg gacttaatat accaataaca 180 ggatcaatgg acactgttta ctccaactct actcaagaag gaatatttct aacatccaca 240 ttatgtttgt attatccaac tgaagcaagt actcaaatca gtgatggtga ttggaaagac 300 tcattatcac aaatgtttct tacaaaaggt tggccaacag gatcagtcta ttttaaagag 360 tactcaaata ttgttgactt ttccgttgat ccacaattat attgtgatta taacttagta 420 ctaatgaagt atgatcaaaa tcttgaacta gatatgtcag aattagctga tttgatattg 480 aatgaatggc tatgtaatcc aatggatata acattatatt attatcaaca atcgggagaa 540 tcaaataagt ggatatcaat gggatcatca tgtactgtga aagtgtgtcc actgaataca 600 caaacgttag gaataggttg tcaaacaacg aatgtagact catttgaaac ggttgctgaa 660 aatgaaaaat tagctatagt ggatgtcgtt gatgggatca atcataaaat aaatttgaca 720 actacgacat gtactattcg aaattgtaag aagttaggtc caagagagta tgtagctatc 780 atacaagttg gtggctctaa tatattagac ataacagcgg atccagcgac taatccacaa 840 attgagagaa tgatgagagt gaattggaaa agatggtggc aagtatttta taccatagta 900 gattatatta atcagattgt acaggtgatg tccaaaagat caagatcatt aaattctgca 960 gctttttatt atagagtata g 981 <210> 59 <211> 398 <212> DNA <213> Novo g virus M87661 (Norwalk virus M87661) <400> 59 ataaaagttg gcatgaacac aatagaagat ggccccctca tctatgctga gcatgctaaa 60 tataagaatc attttgatgc agattataca gcatgggact caacacaaaa tagacaaatt 120 atgacagaat ccttctccat tatgtcgcgc cttacggcct caccagaatt ggccgaggtt 180 gtggcccaag atttgctagc accatctgag atggatgtag gtgattatgt catcagggtc 240 aaagaggggc tgccatctgg attcccatgt acttcccagg tgaacagcat aaatcactgg 300 ataattactc tctgtgcact gtctgaggcc actggtttat cacctgatgt ggtgcaatcc 360 atgtcatatt tctcatttta tggtgatgat gagattgt 398 <210> 60 <211> 247 <212> DNA <213> hepatitis A virus M14707 (Hepatite A M14707) <400> 60 gttttgctcc tctttatcat gctatggatg ttactacaca agttggagat gattctggag 60 gtttttcaac aacagtttct acagaacaga atgttccaga tccccaagtt ggtataacaa 120 ccatgaaaga tttgaaagga aaagctaaca gagggaaaat ggatgtttca ggagtacaag 180 cacctgtggg agctatcaca acaattgagg atccagtttt agcaaagaaa gtacctgaga 240 catttcc 247 <210> 61 <211> 54 <212> DNA <213> Enterococcus faecalis (Enterococcus faecalis) <400> 61 tctcaatcac tggacgtggt actgttgcta caggacgtgt tgaacgtggt gaag 54 <210> 62 <211> 53 <212> DNA <213> E. coli (Escherichia coli) <400> 62 tctccatctc cggtcgtggt accgttgtta ccggtcgtgt agaacgcggt atc 53 <210> 63 <211> 21 <212> DNA <213> short Cryptosporidium (Cryptosporidium parvum) <400> 63 tcctacgtct aacttcacgt g 21 <210> 64 <211> 21 <212> DNA <213> short Cryptosporidium (Cryptosporidium parvum) <400> 64 tgtgattggt aaaaagtata g 21 <210> 65 <211> 164 <212> DNA <213> sucking Giardia lamblia (Giardia lamblia) <400> 65 ggaatgtctt gtaggcgccc gcccccaccg cgcgccggat gcgtccctgc cccttgtaca 60 caccgcccgt cgctcctacc gactgggcgc ggcggcgagc gccccggacg cgcgaagggc 120 cgcgagcccc cgcgcctgga ggaaggagaa gtcgtaacaa ggta 164 <210> 66 <211> 23 <212> DNA <213> E. coli (Escherichia coli) <400> 66 tacctttgct cattgacgtt acc 23 <210> 67 <211> 24 <212> DNA <213> Enterococcus faecalis (Enterococcus faecalis) <400> 67 actgaacgtc ccctgacggt atct 24 <210> 68 <211> 51 <212> DNA <213> E. coli (Escherichia coli) 0157: H7 <400> 68 tggatcgcga aaactgtgga attgagcagc gttggtggga aagcgcgtta c 51 <210> 69 <211> 81 <212> DNA <213> E. coli (Escherichia coli) <400> 69 tgtgggcatt cagtctggat cgcgaaaact gtggaattga gcagcgttgg tgggaaagcg 60 cgttacaaga aagccgggca a 81 <210> 70 <211> 30 <212> DNA <213> polio virus type 2 (Poliovirus type 2) <400> 70 ctccggcccc tgaatgcggc taatcctaac 30 <210> 71 <211> 20 <212> DNA <213> polio virus type 2 (Poliovirus type 2) <400> 71 accagtgact ggcttgtcgt 20 <210> 72 <211> 30 <212> DNA <213> Ho Saatchi virus A21 (Coxsackievirus A21) <400> 72 tccggcccct gaatgcggct aatcctaacc 30 <210> 73 <211> 20 <212> DNA <213> Coxsackie virus A21 (Coxsackievirus A21) <400> 73 ccagtgagta ggttgtcgta 20 <210> 74 <211> 30 <212> DNA <213> echovirus 12 (Echovirus 12) <400> 74 agtcctccgg cccctgaatg cggctaatcc 30 <210> 75 <211> 20 <212> DNA <213> echovirus 12 (Echovirus 12) <400> 75 acaacccagt gggtggcttg 20 <210> 76 <211> 1061 <212> DNA <213> rotavirus (Rotavirus) <400> 76 ggctttaaaa gagagaattt ccgtttggct agcggttagc tccttttaat gtatggtatt 60 gaatatacca caattctaac ctttctgata tcaatagttt tattgaacta tatattaaaa 120 tcactaacta gtgcgatgga ctttataatt tatagatttc ttttacttat tgttattgca 180 tcaccttttg ttaaaacaca aaattatgga attaatttac cgatcactgg ctccatggat 240 acagcatatg caaattcatc acagcaagaa acatttttga cttcaacgct atgcttatat 300 tatcctacag aagcgtcaac tcaaattgga gatacagaat ggaaggatac tctgtcccaa 360 ttattcttga ctaaagggtg gccaactgga tcagtctatt ttaaagaata caccgatatc 420 gcttcattct caattgatcc gcaactttat tgggattata atgttgtact gatgaagtat 480 gattcaacgt tagagctaga tatgtctgaa ttagctgatt taattctaaa tgaatggtta 540 tgtaacccaa tggatataac attatattat tatcagcaaa cagatgaagc gaataaatgg 600 atatcgatgg gacagtcttg taccataaaa gtatgtccat tgaatacgca gactttagga 660 ataggttgta ttaccacaaa tacagcgaca tttgaagagg tggctacaag tgaaaaatta 720 gtaataaccg atgttgttga tggtgtgaac cataaacttg atgtgactac aaatacctgt 780 acaattagga attgtaagaa gttgggacca agagaaaatg tagcgattat acaagtcggt 840 ggctcagatg tgttagatat tacagcggat ccaactactg caccacaaac tgaacgtatg 900 atgcgagtaa attggaagaa atggtggcaa gttttctata cagtagtaga ttatattaat 960 cagattgtgc aagttatgtc caaaagatca cggtcattaa attcagcagc tttttactat 1020 agggtttgat atatcttaga ttagaattgt atgatgtgac c 1061 <210> 77 <211> 30 <212> DNA <213> rotavirus (Rotavirus) <400> 77 tttttaaatt tttgctacta atcgctctga 30 <210> 78 <211> 21 <212> DNA <213> rotavirus (Rotavirus) <400> 78 aatacatctg aattagatgc a 21 <210> 79 <211> 19 <212> DNA <213> rotavirus (Rotavirus) <400> 79 caaacaaatg gatatcaat 19 <210> 80 <211> 45 <212> DNA <213> rotavirus (Rotavirus) <400> 80 ggttcaaaga attatgcgag taaattggaa aaaatggtgg caagt 45 <210> 81 <211> 20 <212> DNA <213> rotavirus (Rotavirus) <400> 81 ctttttatta tagaatttag 20 <210> 82 <211> 30 <212> DNA <213> rotavirus (Rotavirus) <400> 82 tttatagagt aacttttata attgttgtat 30 <210> 83 <211> 21 <212> DNA <213> rotavirus (Rotavirus) <400> 83 tctggagagg agttggatat a 21 <210> 84 <211> 19 <212> DNA <213> rotavirus (Rotavirus) <400> 84 caaataaatg gatatcaat 19 <210> 85 <211> 45 <212> DNA <213> rotavirus (Rotavirus) <400> 85 aacggaacga atgatgcgtg ttaattggaa gaaatggtgg caagt 45 <210> 86 <211> 20 <212> DNA <213> rotavirus (Rotavirus) <400> 86 ctttttatta tagagtatag 20 <210> 87 <211> 30 <212> DNA <213> rotavirus (Rotavirus) <400> 87 tatatagatt tttattaatt tctgtagcat 30 <210> 88 <211> 21 <212> DNA <213> rotavirus (Rotavirus) <400> 88 caaaatcttg aactagatat g 21 <210> 89 <211> 19 <212> DNA <213> rotavirus (Rotavirus) <400> 89 caaataagtg gatatcaat 19 <210> 90 <211> 45 <212> DNA <213> rotavirus (Rotavirus) <400> 90 aattgagaga atgatgagag tgaattggaa aagatggtgg caagt 45 <210> 91 <211> 20 <212> DNA <213> rotavirus (Rotavirus) <400> 91 ctttttatta tagagtatag 20 <210> 92 <211> 30 <212> DNA <213> rotavirus (Rotavirus) <400> 92 tttatagatt tcttttactt attgttattg 30 <210> 93 <211> 21 <212> DNA <213> rotavirus (Rotavirus) <400> 93 tcaacgttag agctagatat g 21 <210> 94 <211> 19 <212> DNA <213> rotavirus (Rotavirus) <400> 94 cgaataaatg gatatcgat 19 <210> 95 <211> 45 <212> DNA <213> rotavirus (Rotavirus) <400> 95 aactgaacgt atgatgcgag taaattggaa gaaatggtgg caagt 45 <210> 96 <211> 20 <212> DNA <213> rotavirus (Rotavirus) <400> 96 ctttttacta tagggtttga 20 <210> 97 <211> 64 <212> DNA <213> hepatitis A virus (Hepatitis A virus) <400> 97 atggatgttt caggagtaca agcacctgtg ggagctatca caacaattga ggatccagtt 60 ttag 64 <210> 98 <211> 551 <212> DNA <213> Sapporo virus (Sapporo Virus) <400> 98 tgtgatgctg ccaccacgct tatagccacc gcggctttta aggccgtggc taccaggcta 60 caggtggtga caccaatgac accagttgct gttggcatta acatggactc tgttcagatg 120 caagtgatga atgactcttt aaaggggggt gttctttact gtttggatta ttccaaatgg 180 gattccacac aaaaccctgc agtgacagca gcctccctgg caatattgga gagatttgct 240 gagccccatc caattgtgtc ttgtgccatt gaggctcttt cctcccctgc agagggctat 300 gtcaatgata tcaaatttgt gacacgcggc ggcctaccat ctgggatgcc atttacatct 360 gtcgtcaatt ctatcaacca tatgatatac gtggcggcag ccatcctgca ggcatacgaa 420 agccacaatg tcccatatac tggaaacgtc ttccaagtgg agaccgttca cacgtatggt 480 gatgattgca tgtacagcgt gtgccctgcc actgcatcaa ttttccacac tgtgcttgca 540 aacctaacgt c 551 <210> 99 <211> 382 <212> DNA <213> Sosa Templeton virus (Southampton Virus) <400> 99 tcaaagttgg aatgaattca attgaggatg ggccactgat ctatgcagaa cattcaaaat 60 ataagtacca ctttgatgca gattacacag cttgggactc aactcaaaat aggcaaatca 120 tgacagagtc attttcaatc atgtgtcggc taactgcatc acccgaacta gcttcggtgg 180 tggctcaaga cttgctcgca ccctcagaga tggatgttgg cgactacgtc ataagagtga 240 aggaaggcct cccatctggt ttcccatgca catcacaagt taatagtata aaccattggt 300 taataactct gtgcgccctt tctgaagtga ctggcctgtc gccagacgtt atccaatcca 360 tgtcatattt ctctttctat gg 382 <210> 100 <211> 312 <212> DNA <213> Desert Screen Virus (Desert Shield Virus) <400> 100 tttgatgctg attacacggc ctgggattcc actcaaaaca gggaaatcat gatggagtcc 60 tttaacatca tgtgtaaact cactgccaac ccttccctgg ctgcggtagt ggcacaagac 120 ttactttctc cttctgaaat ggatgttgga gattatgtaa tcagtgtgaa agacggcctg 180 ccatcaggct tcccgtgtac ctcacaagtc aacagcataa atcactggat tctcaccctg 240 tgtgcattgt cagaagtcac cgggctctcc ccagatgtgt tgcagtcaca gtcgtatttt 300 tccttctatg gg 312 <210> 101 <211> 362 <212> DNA <213> Toronto virus (Toronto Virus) <400> 101 aatgaagatg gtcccataat atttgagaaa cattccagat acagatacca ctatgatgca 60 gattactccc gctgggactc cacgcagcag cgggcagtgc tggcagcagc acttgaaatc 120 atggtgaggt tctctgctga accacagcta gcacaaatag tagctgaaga cctgctagca 180 ccaagtgtgg ttgatgtggg tgacttcaag atcaccatta atgaaggcct accttctggt 240 gtgccttgca cctcacagtg gaactccatt gcccactggt tgcttactct gtgtgccctt 300 tctgaagtta caggactagg ccccgacatc atacaagcta attctatgta ctctttctat 360 gg 362 <210> 102 <211> 364 <212> DNA <213> Snow Virus (Snow Mountain Virus) <400> 102 tgaatgagga tggacccata atttttgaaa agcactccag gttctcatac cactatgatg 60 cagattactc acgctgggac tcaacccaac agagggcagt gctagctgca gccttggaaa 120 tcatggtaaa attctcacca gaaccacatt tggcccaaat tgttgcagag gatctcctag 180 cccccagtgt gatggatgta ggtgatttca aaataacaat taatgaggga ctgccctcgg 240 gagtaccctg cacatcacag tggaattcca tcgcccactg gctcctcaca ctctgtgcac 300 tatctgaagt cacaaacctg gctcctgaca tcatacaagc taactccttg ttctctttct 360 atgg 364 <210> 103 <211> 376 <212> DNA <213> Hawaii virus (Hawai ivirus) <400> 103 tcagagttgg tatgaacatg aatgaggatg gccccattat ctttgagaaa cactccaggt 60 ataaatatca ttaagattat tctcgatggg actcaacaca gcagagagcc gtactagctg 120 cagccctaga gatcatggtc aaattctccc cagagccaca cttggcccag gtagttgcag 180 aagaccttct ttcccccagt gtgatggatg tgggtgactt caagatatca atcaacgagg 240 gtcttccctc tggggtgccc tgcacctcgc aatggaactc catcacccac tggctcctca 300 ctctttgtgc actctctgaa gtcacggacc tgtcccctga catcattcaa gccaattcct 360 tattctcttt ctatgg 376 <210> 104 <211> 382 <212> DNA <213> Bristol virus (Bristol Virus) <400> 104 tcagagttgg catgaatatg aatgaggatg gccccatcat cttcgagaga cactccagat 60 acaagtatca ctatgatgct gactactctc ggtgggattc aacacaacaa agggccgtgt 120 tagcagcagc cctagaaatc atggttaaat tctccccaga accgcatttg gcccagatag 180 ttgcagaaga ccttctatct cctagtgtga tggatgtggg tgacttcaaa atatcaatca 240 atgagggcct tccctctggt gtgccctgca cctctcaatg gaattccatc gcccactggc 300 tcctcactct ctgtgcactc tctgaagtta caaacctgtc ccctgacatc atacaggcta 360 attccctctt ttccttctat gg 382 ...
Table 1
Acylate, correlation reserved time and mass-spectrometric data
Retention time Shi Shi example is analyzed (M+H) the standby routine 54-3-[4-of 8a 7.68 8.79 476.28b 6.97 7.96 414.28c 7.45 8.56 453.28d 6.84 6.68 426.28e 6.75 7.77 455.2 Zhi (2-Nai-1-base-Yi Xian base is amino)-Mi Zuo-1-yl of HPLC (between Shi) LCMS (between Shi)]-the cyclobutyl carbamoyl }-Pai Ding-1-formic acid 9H-Wu-9-base methyl esters step 1
With the 4-piperidine carboxylic acid (129mg, 1mmol) with sodium hydroxide (80mg, 2mmol) water/dioxane (1: 1, handle in 10mL).After 30 minutes, (259mg 1mmol), stirs this reaction soln 4 hours the chloroformic acid 9-fluorenyl methyl esters of dropping in dioxane (2mL) then in stirring at room.Solvent removed in vacuo, and dilute with water.With HCl (1N) with pH regulator to 1, with this aqueous solution of ethyl acetate extraction.With organic layer drying (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying (50: 1: 0.5 chloroform-methanol-acetate), obtained 340mg (productive rate is 97%) N-1-(fluorenyl methoxy carbonyl)-4-piperidyl formic acid;
1H NMR (400MHz, CDCl 3) d7.75 (d, J=7.1Hz, 2H), 7.55 (d, J=7.5Hz, 2H), 7.39 (m, 2H), 7.30 (m.2H), 4.4 (brs, 2H), 4.23 (t, J=6.5Hz, 1H), 3.9 (brd, 2H), 2.9 (brs, 2H), 2.52 (m, 1H), 1.90 (brs, 2H), 1.62 (brs, 2H); MS (AP/Cl): 352.0 (M+H)+steps 2
With N-1-(fluorenyl methoxy carbonyl)-4-piperidyl formic acid (preparation example 5, step 1; 77mg) solution in methylene dichloride is handled with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (84mg) and DMAP (5mg).Stir after 30 minutes, add N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide (embodiment 6).Then the gained mixture was stirred 4 hours.Add entry, this solution is adjusted to neutrality, and use ethyl acetate extraction.With organic layer drying (MgSO 4), filter and vacuum concentration.By silica gel chromatography purifying (20: 1 chloroform-methanols), obtained 101mg (productive rate is 77%) 4-{3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl formamyl)-piperidines-1-formic acid 9H-fluorenes-9-base methyl esters;
1H?NMR(400MHz，CD3OD)δ8.0(d，J＝8.3Hz，1H)，7.83(m，1H)，7.78(dd，J＝2.07，7.5Hz，1H)，7.73(d，J＝7.5Hz，2H)，7.53(d，J＝6.6Hz，2H)，7.44(m，5H)，7.35(m，3H)，7.27(m，2H)，4.4(brs，2H)，4.2(m，1H)，4.15(m，5H)，2.85(m，4H)，2.25(m，3H)，1.7(brs，2H)，1.5(brs，2H)；MS(AP/Cl)：654.8(M+H)+.
Embodiment 9 piperidines-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-amide hydrochloride
Will be at the 4-{3-[4-among the DMF (5mL) (2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl formamyl } piperidines-1-formic acid 9H-fluorenes-9-base methyl esters (preparation example 5; 100mg; 0.15mmol) handle with piperidines (0.5mL), and stirring at room 2 hours.Solvent removed in vacuo by silica gel chromatography purifying resistates (4: 1: 0.08 chloroform-methanol-ammonium hydroxide), has obtained free alkali.This free alkali is dissolved in the ether,, has obtained hydrochloride (64mg, productive rate are 91%) with the solution-treated of 1N HCl in methyl alcohol, piperidines-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-amide hydrochloride;
1H NMR (400MHz, CD3OD) δ 8.01 (d, J=8.0Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 7.43 (m, 4H), 7.36 (s, 2H), 4.34 (m, 1H), 4.15 (s, 2H), 4.10 (m, 1H), 3.03 (m, 2H), 2.83 (m, 2H), 2.54 (m, 2H), 2.24 (m, 3H), 1.69 (m, 2H), 1.55 (m, 2H); MS (AP/Cl): 432 (M+H)+. preparation example 6 isoquinoline 99.9-5-base-acetate step 1
(5.0g 34.7mmol) mixed 15 minutes with the 48%HBr aqueous solution (65mL) with the 5-aminoisoquinoline at-78 ℃.The Sodium Nitrite of dropping in water (6mL) (3.1g, 45mmol).After 15 minutes, this mixture is warmed to 0 ℃-78 ℃ of stirrings.Add copper powder (0.3g) very lentamente to prevent excess foaming.After adding fully, give reaction vessel fit on reflux exchanger, and this mixture was heated 4 hours at 100 ℃.This mixture is poured on the ice (about 200g), and be adjusted to alkalescence (pH=10) with KOH.With this aqueous mixture of ethyl acetate extraction, with the organic layer salt water washing that merges, dry (MgSO 4), filter, and vacuum concentration.By silica gel chromatography purifying (10: 1 hexane-ethyl acetate), obtained 3.8g (productive rate is 53%) 5-bromo-isoquinoline;
1H NMR (400MHz, CD3OD) δ 9.25 (s, 1H), 8.57 (d, J=6.2Hz, 1H), 8.1 (m, 3H), 7.60 (m, 1H); MS (AP/Cl): 208.0,210.0 (M+H)+. step 2
Under nitrogen atmosphere, with the 5-bromo-isoquinoline (preparation example 6, step 1,1.04g, 5.0mmol) with allyl tributyltin (1.7mL, 5.5mmol) and palladium chloride two (triphenylphosphine) (176mg, 0.25mmol) in toluene (20mL) the mixing.This mixture heating up was refluxed 16 hours.After being cooled to room temperature, under agitation add saturated potassium fluoride aqueous solution (20mL), formed precipitation.Stir after 15 minutes, this mixture is filtered, organic layer and water layer are separated, vacuum concentration, and, obtained 778mg (productive rate is 92%) 5-allyl group isoquinoline 99.9 by silica gel chromatography purifying (6: 1 hexane-ethyl acetate); 1H NMR (400MHz, CDCl 3) δ 9.25 (s, 1H), 8.54 (d, J=5.8Hz, 1H), 7.85 (m, 1H), 7.79 (d, J=5.8Hz, 1H), 7.56 (m, 2H), 6.1 (m, 1H), 5.15 (m, 1H), 5.05 (m, 1H), 3.81 (d, J=6.2Hz, 2H); MS (AP/Cl): 170.1 (M+H)+. step 3
Will be in 5-allyl group isoquinoline 99.9 (preparation example 6, the step 2 in methylene dichloride (2mL), acetate (0.5mL) and the water (0.5mL); 169mg, (100mg is 0.2mmol) in 23 ℃ of processing for Mn ca.500,95uL 1.0mmol) to be used in dimethyl polyethylene glycol in the methylene dichloride (1mL).This mixture is cooled to 0 ℃, adds KMnO in batches 4(521mg 3.3mmol), remains on the temperature below 30 ℃ to powder.After the vigorous stirring 18 hours, solvent removed in vacuo, (10mL 1N), refluxes this mixture 4 hours to add hydrogen chloride methanol solution.Vacuum is removed methyl alcohol, the dilute with water resistates, with yellow soda ash with this mixture alkalization (pH=9).With this mixture of ethyl acetate extraction, with the salt water washing of gained organic layer, dry (MgSO 4), filter, vacuum concentration, and, obtained isoquinoline 99.9-5-base-methyl acetate by silica gel chromatography purifying (2: 1 hexane-ethyl acetate);
1H?NMR(400MHz.CDCl 3)δ9.28(brs，1H)，8.58(d，J＝6.2Hz，1H)，7.95(d，J＝7.9Hz，1H)，7.80(d，J＝5.8Hz，1H)，7.66(d，J＝5.8Hz，1H)，7.59(t，J＝7.6Hz，1H)，4.06(s，2H)，3.70(s，3H)；MS(AP/Cl)：202.1(M+H)+.
Attention: have 5-isoquinolyl formaldehyde impurity (about 20%) behind the silica gel chromatography purifying.Step 4
With isoquinoline 99.9-5-base-methyl acetate (preparation example 6, step 3; 9mg, 0.448mmol) (4N 3mL) handles, and heats 4 hours at 50 ℃ with aqueous sodium hydroxide solution.This solution is cooled to 0 ℃, drips acetate (2mL), formed precipitation.This mixture is spent the night 0 ℃ of maintenance (about 15 hours), via removing by filter precipitation, and wash with water.Solid is air-dry, obtained 35mg (productive rate is 47%) isoquinoline 99.9-5-base-acetate;
1H NMR (400MHz, CD3OD) δ 9.24 (s, 1H), 8.47 (d, J=6.2Hz, 1H), 8.04 (d, J=7.9Hz, 1H), 7.96 (d, J=6.2Hz, 1H), 7.74 (d, J=6.6Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 4.11 (s, 2H); MS (AP/Cl): 188.3 (M+H)+. preparation example 7N-[cis-3-(4-nitro-imidazoles-1H-yl) cyclobutyl] ethanamide step 1
With trans-toluene-4-sulfonic acid 3-(4-nitro-imidazoles-1-yl)-cyclobutyl ester (preparation example 1, step 2; 3.6g 10.7mmol) (7g 107mmol) mixes in ethanol (100mL), water (35mL) and chloroform (20mL) with sodiumazide.This mixture heating up was refluxed 24 hours.Vacuum is removed ethanol and chloroform, with gained mixture dilute with water, and uses ethyl acetate extraction.With organic layer salt water washing, dry (MgSO 4), filter and vacuum concentration.By silica gel chromatography purifying (1: 1-3: 1 ethyl acetate-hexane), obtained 2.2g (99%) 1-(3-cis-azido--cyclobutyl)-4-nitro-1H-imidazoles;
1H NMR (400MHz, CDCl 3) δ 7.85 (s, 1H), 7.49 (s, 1H), 4.42 (m, 1H), 3.91 (m, 1H), 3.07 (m, 2H), 2.43 (m, 1H); MS (AP/Cl): 208.5 (M+H)+. step 2
Will be in the 1-among the THF (100mL) (3-cis-azido--cyclobutyl)-4-nitro-1H-imidazoles (preparation example 7, step 1; 2.2g, 10.7mmol) with triphenylphosphine (3.36g, 12.8mmol) and water (10mL) processing.With this solution stirring at room 18 hours.Solvent removed in vacuo by silica gel chromatography purifying resistates (20: 1: 0.4 chloroform-methanol-ammonium hydroxide), has obtained 1.95g (100% productive rate) 1-(3-cis-amino-cyclobutyl)-4-nitro-1H-imidazoles;
1H NMR (400MHz, CD3OD) δ 8.32 (s, 1H), 7.81 (s, 1H), 4.46 (m, 1H), 3.29 (m, 1H), 2.87 (m, 2H), 2.17 (m, 2H); MS (AP/Cl): 183.1 (M+H)+. step 3
With 1-(3-cis-amino-cyclobutyl)-4-nitro-1H-imidazoles (preparation example 7, step 2; 500mg 2.75mmo1) with the acetate coupling, and as purifying as described in the embodiment 7, has obtained 594mg (96% productive rate) N-[cis-3-(4-nitro-imidazoles-1H-yl) cyclobutyl] ethanamide;
1H NMR (400MHz, CD3OD) δ 8.30 (s, 1H), 7.82 (s, 1H), 4.58 (m, 1H), 4.17 (m, 1H), 2.95 (m, 2H), 2.39 (m, 2H), 1.93 (s, 3H); MS (AP/Cl): 225.1 (M+H)+. preparation example 8N-[cis-3-(4-nitro-imidazoles-1-yl)-cyclobutyl]-benzamide
N-[cis-3-(4-nitro-imidazoles-1-yl)-cyclobutyl]-benzamide is to make according to the method that is similar to preparation example 7 products;
1H NMR (400MHz, CD3OD) δ 8.36 (s, 1H), 7.85 (m, 3H), 7.55 (m, 1H), 7.47 (m, 2H), 4.65 (m, 1H), 4.44 (m, 1H), 3.05 (m, 2H), 2.60 (m, 2H); MS (AP/Cl): 287.3 (M+H)+. preparation example 9 pyridines-2-formic acid [cis-3-(4-nitro-imidazoles-1-yl)-cyclobutyl]-acid amides
[cis-3-(4-nitro-imidazoles-1-yl)-cyclobutyl]-acid amides is to make according to the method that is similar to preparation example 7 products to pyridine-2-formic acid;
1H?NMR(400MHz，CDCl 3)：δ8.55(m，1H)，8.35(d，J＝7.0Hz，1H)，8.19(d，J＝7.9Hz，1H)，8.01(s，1H)，7.88(td，J＝1.65，7.9Hz；1H)，7.57(s，1H)，7.47(m，1H)，4.5(m，2H)，3.17(m，2H)，2.72(m，2H)；MS(AP/Cl)：288.1(M+H)+.
Embodiment 9aN-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-2-base-ethanamide
According to the method for embodiment 1 with N-[cis-3-(4-nitro-imidazoles-1H-yl) cyclobutyl] ethanamide (preparation example 7; 50mg, 0.22mmol) hydrogenation also with 2-naphthyl acetic acid acidylate, has obtained 35mg (productive rate is 44%) N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-2-base-ethanamide;
1H?NMR(400MHz，CD3OD)δ8.05(d，J＝8.0Hz，1H)，7.87(d，J＝7.6Hz，1H)，7.81(d，J＝6.4Hz，1H)，7.46(m，5H)，7.37(s，1H)，4.41(m，1H)，4.17(s，2H)，4.12(m，1H)，2.84(m，2H)，2.27(m，2H)，1.89(s，3H)；MS(AP/Cl)：363.3(M+H)+.
Embodiment 9bN-{ cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide
This title compound is according to the method that is similar to embodiment 9a, uses preparation example 8 products and isoquinoline 99.9-5-guanidine-acetic acid (preparation example 6) to make;
1H NMR (400MHz, CD3OD) δ 9.24 (s, 1H), 8.45 (d, J=6.2Hz, 1H), 8.05 (d, J=7.9Hz, 1H), 8.02 (J=6.2Hz, 1H), 7.82 (m, 3H), 7.67 (m, 1H), 7.52 (m, 2H), 7.45 (m, 3H), 4.5 (m, 1H), 4.4 (m, 1H), 4.21 (s, 2H), 2.95 (m, 2H), 2.50 (m, 2H); MS (AP/Cl): 426.3 (M+H)+. embodiment 9c pyridine-2-formic acid (cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides
This title compound is according to the method that is similar to embodiment 9a, uses preparation example 9 products and isoquinoline 99.9-5-guanidine-acetic acid (preparation example 6) to make;
1H?NMR(400MHz，CD3OD)δ9.23(s，1H)，8.60(m，1H)，8.44(d，J＝5.8Hz，1H)，8.03(m，3H)，7.92(dt，J＝1.7，7.5Hz，1H)，7.78(d，J＝7.1Hz，1H)，7.66(m，1H)，7.58(s，1H)，7.5(m，1H)，7.46(s，1H)，4.45(m，1H)，4.40(m，1H)，4.20(s，2H)，2.85(m，2H)，2.6(m，2H)；MS(AP/Cl)：427.2(M+H)+.
Embodiment 10N-{ cis-3-[4-(3-naphthalene-1-base-urea groups)-imidazoles-1-yl]-cyclobutyl }-ethanamide
As described in the embodiment 4 with N-[cis-3-(4-nitro-imidazoles-1H-yl) cyclobutyl] (preparation example 7,50mg is 0.22mmol) with the phenyl chloroformate reaction for ethanamide.Obtained indissociable carboxylamine one-and two-phenylester mixture of products by (20: 1: 0.2 chloroform-methanol-ammonium hydroxide) behind the silica gel chromatography purifying, it has been dissolved in (1: in the 1DMF/ dioxane (500uL).Add the 1-ALPHA-NAPHTHYL AMINE (31mg, 0.22mmol), and with this mixture 70 ℃ of heating 16 hours.Behind silica gel chromatography purifying twice (20: 1: 0.02 chloroform-methanol-ammonium hydroxide), obtained 4.4mg (5% productive rate) N-{ cis-3-[4-(3-naphthalene-1-base-urea groups)-imidazoles-1-yl]-cyclobutyl }-ethanamide; 1H NMR (400MHz, CD3OD) δ 8.06 (d, J=8.0Hz, 1H), 7.97 (d, J=8.8Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 7.51 (m, 4H), 7.16 (s, 1H), 4.46 (m, 1H), 4.15 (m, 1H), 2.89 (m, 2H), 2.33 (m, 2H), 1.92 (s, 3H); MS (AP/Cl): 364.0 (M+H)+.

Claims (13)

1. formula 1 compound and pharmacologically acceptable salt thereof
Figure A0181339700021
R wherein 1Be straight or branched (C 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8) alkynyl, (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl or (5-14 unit) heteroaryl; R wherein 1Can choose wantonly by 1-6 and be independently selected from following substituent R 5Replace: F, Cl, Br, I, nitro, cyano group ,-CF 3,-NR 7R 8,-NR 7C (=O) R 8,-NR 7C (=O) OR 8,-NR 7C (=O) NR 8R 9,-NR 7S (=O) 2R 8,-NR 7S (=O) 2NR 8R 9,-OR 7,-OC (=O) R 7,-OC (=O) OR 7,-C (=O) OR 7,-C (=O) R 7,-C (=O) NR 7R 8,-OC (=O) NR 7R 8,-OC (=O) SR 7,-SR 7,-S (=O) R 7,-S (=O) 2R 7,-S (=O) 2NR 7R 8,-O-S (=O) 2R 7,-N 3And R 7
R 2Be H, F, CH 3, CN or C (=O) OR 7
R 3Be-C (=O) NR 9-,-C (=O) O-,-C (=O) (CR 10R 11) n-or-(CR 10R 11) n-;
R 4Be straight or branched (C 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8Alkynyl), (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl or (5-14 unit) heteroaryl; R wherein 4Can choose wantonly by 1-3 and be independently selected from following substituent R 6Replace: F, Cl, Br, I, nitro, cyano group ,-CF 3,-NR 7R 8,-NR 7C (=O) R 8,-NR 7C (=O) OR 8,-NR 7C (=O) NR 8R 9,-NR 7S (=O) 2R 8,-NR 7S (=O) 2NR 8R 9,-OR 7,-OC (=O) R 7,-OC (=O) OR 7,-C (=O) OR 7,-C (=O) R 7,-C (=O) NR 7R 8,-OC (=O) NR 7R 8,-OC (=O) SR 7,-SR 7,-S (=O) R 7,-S (=O) 2R 7,-S (=O) 2NR 7R 8, or R 7
R 7, R 8, and R 9Be independently selected from H, straight or branched (C respectively 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8Alkynyl), (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl and (5-14 unit) heteroaryl, wherein R 7, R 8, and R 9Choose wantonly independently respectively by 1-6 and be independently selected from following substituting group replacement: F, Cl, Br, I, NO 2,-CN ,-CF 3,-NR 10R 11,-NR 10C (=O) R 11,-NR 10C (=O) OR 11,-NR 10C (=O) NR 11R 12,-NR 10S (=O) 2R 11,-NR 10S (=O) 2NR 11R 12,-OR 10, OC (=O) R 10,-OC (=O) OR 10,-OC (=O) NR 10R 11,-OC (=O) SR 10,-SR 10,-S (=O) R 10,-S (=O) 2R 10,-S (=O) 2NR 10R 11,-C (=O) R 10,-C (=O) OR 10,-C (=O) NR 10R 11, and R 10Or
Work as R 7And R 8At NR 7R 8In the time, they can choose wantonly connection with its NR that is connected 7R 8Nitrogen form 3-7 unit Heterocyclylalkyl, described Heterocyclylalkyl can be chosen wantonly and comprise 1 or 2 other heteroatoms that is independently selected from N, O and S;
R 10, R 11, and R 12Be independently selected from H, straight or branched (C respectively 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8Alkynyl), (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl and (5-14 unit) heteroaryl, wherein R 10, R 11, and R 12Choose wantonly independently respectively by 1-6 and be independently selected from following substituting group replacement: F, Cl, Br, I, NO 2,-CN ,-CF 3,-NR 13R 14,-NR 13C (=O) R 14,-NR 13C (=O) OR 14,-NR 13C (=O) NR 14R 15,-NR 13S (=O) 2R 14,-NR 13S (=O) 2NR 14R 15,-OR 13, OC (=O) R 13,-OC (=O) OR 13,-OC (=O) NR 13R 14,-OC (=O) SR 13,-SR 13,-S (=O) R 13,-S (=O) 2R 13,-S (=O) 2NR 13R 14,-C (=O) R 13,-C (=O) OR 13,-C (=O) NR 13R 14, and R 13
R 13, R 14, and R 15Be independently selected from H, straight or branched (C respectively 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8Alkynyl), (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl and (5-14 unit) heteroaryl, wherein R 13, R 14, and R 15Choose wantonly independently respectively by 1-6 and be independently selected from following substituting group replacement: F, Cl, Br, I, NO 2,-CN ,-CF 3,-NR 16R 17,-NR 16C (=O) R 17,-NR 16C (=O) OR 17,-NR 16C (=O) NR 17R 8,-NR 16S (=O) 2R 17,-NR 16S (=O) 2NR 17R 18,-OR 16, OC (=O) R 16,-OC (=O) OR 16,-OC (=O) NR 16R 17,-OC (=O) SR 16,-SR 16,-S (=O) R 16,-S (=O) 2R 16,-S (=O) 2NR 16R 17,-C (=O) R 16,-C (=O) OR 16,-C (=O) NR 16R 17, and R 16
R 16, R 17, and R 18Be independently selected from H, straight or branched (C respectively 1-C 8) alkyl, straight or branched (C 2-C 8) alkenyl, straight or branched (C 2-C 8Alkynyl), (C 3-C 8) cycloalkyl, (C 4-C 8) cycloalkenyl group, (3-8 unit) Heterocyclylalkyl, (C 5-C 11) bicyclic alkyl, (C 7-C 11) the assorted bicyclic alkyl of bicycloenyl, (5-11 unit), (C 6-C 14) aryl and (5-14 unit) heteroaryl;
N is 0,1,2 or 3;
Wherein for each repetition of n ,-C (=O) (CR 10R 11) n-and-(CR 10R 11) n-in R 10And R 11All independently as defined above.
2. the compound of claim 1, wherein R 3Be-C (=O) NH-or-C (=O) (CR 10R 11) n-.
3. the compound of claim 1, wherein R 1Be the optional (C that replaces 3-C 8) cycloalkyl or the optional (C that replaces 5-C 11) bicyclic alkyl.
4. the compound of claim 4, wherein R 1Be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norborneol alkyl or two ring-[3.1.0] hexyls, described group is optional respectively to be substituted.
5. the compound of claim 1, wherein R 1Be the optional straight or branched (C that replaces 1-C 8) alkyl or the optional straight or branched (C that replaces 2-C 8) alkenyl.
6. the compound of claim 1, wherein R 4Be (C 6-C 14) aryl or (5-14 unit) heteroaryl, described group is optional respectively to be substituted.
7. the compound of claim 6, wherein R 4Be phenyl, pyridyl, naphthyl, quinolyl or isoquinolyl, described group is optional respectively to be substituted.
8. each compound of claim 1-7, wherein R 2Be hydrogen.
9. the compound of claim 1, wherein said compound is selected from:
N-(1-cyclobutyl-1H-imidazol-4 yl)-2-quinoline-6-base-ethanamide;
N-(1-cyclopentyl-1H-imidazol-4 yl)-2-(4-methoxyl group-phenyl)-ethanamide;
N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4 yl]-2-quinoline-6-base-ethanamide;
(1-cyclobutyl-1H-imidazol-4 yl)-phenyl carbamate;
1-(1-cyclobutyl-1H-imidazol-4 yl)-3-isoquinoline 99.9-5-base-urea;
N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-1-base-ethanamide;
6-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides;
1H-imidazoles-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides;
6-hydroxyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides;
3-methyl-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides;
2-pyridin-3-yl-thiazole-4-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides;
6-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-the cyclobutyl formamyl }-nicotinic acid methyl ester;
Pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides;
N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide;
5-methyl-pyrazine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino) imidazoles-1-yl]-cyclobutyl }-acid amides;
N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-isobutyramide;
6-chloro-pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides;
Quinoline-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides;
1H-pyrroles-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides;
N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl]-cyclobutyl-2-between tolyl-ethanamide;
Pyridine-2-formic acid cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-acid amides;
2-(3-hydroxyl-phenyl)-N-{ cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-ethanamide;
Piperidines-4-formic acid (cis-3-[4-(2-naphthalene-1-base-acetylamino)-imidazoles-1-yl] cyclobutyl }-amide hydrochloride;
N-[1-(cis-3-acetylamino-cyclobutyl)-1H-imidazol-4 yl]-2-naphthalene-2-base-ethanamide;
N-{ cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-benzamide; With
Pyridine-2-formic acid cis-3-[4-(2-isoquinoline 99.9-5-base-acetylamino)-imidazoles-1-yl]-cyclobutyl }-acid amides; With
The pharmacologically acceptable salt of above-claimed cpd.
10. treat the pharmaceutical composition that comprises disease or illness or the neurodegenerative disease or the illness of abnormal cell growth in the Mammals, wherein contain compound and pharmaceutically acceptable carrier of the claim 1 of described disease of treatment or illness significant quantity.
11. its treatment can be undertaken or the pharmaceutical composition of promoted disease or illness by the neurotransmission that changes the Dopamine HCL mediation in the treatment Mammals, wherein contains described disease of treatment or illness significant quantity or suppresses cdk5 inhibitor and pharmaceutically acceptable carrier of the active significant quantity of cdk5.
12. be used for the treatment of the pharmaceutical composition that is selected from following disease or illness in the Mammals: male fertility and sperm motility; Diabetes; Impaired glucose tolerance; Metabolism syndrome or syndrome X; Polycystic ovary syndrome; Lipogenesis and obesity; Flesh generates and is weak, for example relevant with age physical appearance decline; Acute myatrophy is for example fixed with burn, bed, four limbs or big relevant amyotrophy and/or the emaciation of chest, abdomen and/or plastic surgery; Sepsis; Spinal injury; Alopecia, hair is thin and bald; And immune deficiency, wherein said composition comprises compound and pharmaceutically acceptable carrier of the claim 1 of described disease of treatment or illness significant quantity.
13. pharmaceutical composition wherein comprises the cdk5 inhibitor and is selected from following second kind of active ingredient and pharmaceutically acceptable carrier: SSRI, nk 1 receptor antagonist, 5HT 1DAntagonist, for example BMS-204352 and nmda receptor antagonist of logical, the olanzapine in Lars, Risperidone, L-745870, Song Pila azoles, RP62203, NGD941, Ba Lapi ketone, flesinoxan, gepirone hydrochloride, acetyl cholinesterase enzyme inhibitors, TPA, NIF, potassium channel modulating agents now, wherein said cdk5 inhibitor and second kind of active ingredient exist with significant quantity together.
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CN1934091B (en) * 2004-03-23 2012-02-08 辉瑞产品公司 imidazole compounds for the treatment of neurodegenerative disorders
CN111018840A (en) * 2017-10-25 2020-04-17 西南大学 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof
CN111018840B (en) * 2017-10-25 2022-09-09 西南大学 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof
CN114450300A (en) * 2019-06-12 2022-05-06 Ip2Ipo创新有限公司 Novel compounds
CN112250636A (en) * 2020-11-09 2021-01-22 广西科技大学 5-aminoimidazole compound and synthesis method thereof

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