CN1145610C - Quinazolinone and benzoxazine derivatives as progesterone receptor modulators - Google Patents
Quinazolinone and benzoxazine derivatives as progesterone receptor modulators Download PDFInfo
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- CN1145610C CN1145610C CNB008070792A CN00807079A CN1145610C CN 1145610 C CN1145610 C CN 1145610C CN B008070792 A CNB008070792 A CN B008070792A CN 00807079 A CN00807079 A CN 00807079A CN 1145610 C CN1145610 C CN 1145610C
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Abstract
This invention provides compounds which are agonists and antagonists of the progesterone receptor having general structure (I): wherein R1 and R2 are independently selected from H, CORA, or NRBCORA, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclic moieties; or R1 a nd R2 are fused to form: 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic rings; RA is H or optionally substituted alkyl, aryl, alkoxy, o r aminoalkyl groups; RB is H, C1 to C3 alkyl or substituted C1 to C3 alkyl; R3 is H, OH, NH2, CORC or optionally substituted alkyl, alkenyl, or alkynyl; RC is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R4 is H, halogen, CN, NO2, or optionally substituted alkyl, alkynyl, alkoxy, amino or aminoalkyl; R5 is an optionally substituted benzene or five or six membered ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2 or NR6; R6 is H or C1 to C3 alkyl; G1 is O, NR7, or CR7R8; G2 is CO, CS, or CR7R8; provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8; R7 and R8 are H or an optionally substituted alkyl, aryl, or heterocyclic moiety; or pharmaceutically acceptable salt thereof, and methods using these compounds in mammals as agonists or antagonists of the progesterone receptor.
Description
Technical field
The present invention relates to compound as progesterone receptor agonist and antagonist, and their preparation and purposes.
Technical background
Intracellular receptor (IR) forms the relevant generegulation agent of a class formation, is called " ligand dependent transcription factor " (R.M.Evans, Science, 240,889,1988).Steroid receptor family is a subclass of IR family, comprises progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and mineralcorticoid receptor (MR).
For PR, natural hormone or part are the steroid Progesterone, but have also prepared synthetic compound such as medroxyprogesterone acetate or Levonorgestrel, and they can be used as part.In case have part in the pericellular liquid, part is just by the passive film that diffuses through, and combines with IR and to produce the receptor/ligand mixture.The specific gene promoter that exists in this mixture and the cell DNA combines.In case be incorporated into DNA, mixture is with regard to the proteinic generation of regulating mRNA and this genes encoding.
The compound that is incorporated into IR and the effect of simulation natural hormone is called agonist, and the compound of inhibitory hormone effect is called antagonist.
Known, PR agonist (natural and synthetic) plays an important role in WomanHealth.The PR agonist can be used for the Birth control preparation, usually when having the ER agonist.The ER agonist can be used for treating the syndromes in climacteric, but with the outgrowth effect in uterus, this can cause suffering from the rising of uterus carcinoma danger.Use the PR agonist simultaneously and can reduce or eliminate this danger.
The PR antagonist can be used for contraception.In this case, they can give (people such as Ulmann, Ann.N.Y.Acad.Sci., 261 separately, 248,1995), also can with the coupling of PR agonist (people such as Kekkonen, Fertilityand Sterility, 60,610,1993) or with part ER antagonist (as tamoxifen) coupling (WO 96/19997A1, on July 4th, 1996).
The PR antagonist can be used for the treatment of hormonal dependent mammary cancer (people such as Horwitz, Horm.Cancer, 283, the Birkhaeuser of publisher, Boston, Mass., editor Vedeckis), and uterus carcinoma and ovarian cancer.The PR antagonist also can be used for treating non-pernicious chronic disease such as fibroma (people such as Murphy, J.Clin.Endo.Metab., 76,513,1993) and endometriosis (people such as Kettel, Fertility and Sterility, 56,402,1991).
The PR antagonist also can be used for hormone replacement therapy, treats postclimacteric patient (United States Patent (USP) 5719136) with part ER antagonist (as tamoxifen) coupling.
Show that in hormonal dependent prostate cancer model, PR antagonist (as mifepristone and onapristone (onapristone)) is effective, show that they can be used for treating this class disease of the male sex (people such as Michna, Ann.N.Y.Acad.Sci., 761,224,1995).
People such as Jones (U.S. Patent No. 5,688,810) have described PR antagonist dihydroquinoline 1.
People such as Jones have described the enol ether 2 (U.S. Patent No. 5,693,646) as the PR part.
People such as Jones have described the compound 3 (U.S. Patent No. 5,696,127) as the PR part.
People such as Zhi have described the lactone 4,5 and 6 (J.Med.Chem., 41,291,1998) as the PR antagonist.
People such as Zhi have described the ether 7 (J.Med.Chem., 41,291,1998) as the PR antagonist.
People such as Combs disclose the acid amides 8 (J.Med.Chem., 38,4880,1995) as the PR part.
People such as Perlman have described the novel vitamin D analogues 9 (Tet.Letters, 35,2295,1994) as the PR part.
People such as Hamann have described PR antagonist 10 (Ann.N.Y.Acad.Sci., 761,383,1995).
People such as Chen have described PR antagonist 11 (people such as Chen, POI-37,16
ThInt.Cong.Het.Chem., Montana, 1997).
People such as Kurihari have described PR ligand 12 (J.Antibiotics, 50,360,1997).
A large amount of publications have been reported the method for making and the purposes of benzodiazine ketone (benzodiazinones) and benzoxazine.Yet, in the document, do not have example to contain and make compound become the required substituting group of activated progesterone receptor modulators.In the document, comprise people's such as Kubla patent (US 4666913), claim that wherein the compound such as A and B can be used as cardiac tonic.People such as Ning have reported the synthetic of quinazolinone such as C.
The document that other prior aries relevant with the present invention are open benzoxazines.In these documents, people such as Gromaehevskaya (Chem.Heterocycl.Compd. (N.Y.), 33 (10), 1209-1214 (1998)) have studied the bromination process of some benzoxazine such as Compound D.The claimed compounds such as E of people such as Kobzina (U.S. Patent No. 3,917,592) is as the purposes of weedicide.
People such as Pflegel (Pharmazie, 37 (10), 714-717 (1982)) disclose quinazoline-2-thioketones in the polarography research of heterogeneous ring compound, as compound F 17-hydroxy-corticosterone.Do not mention the activity of compound F 17-hydroxy-corticosterone.
Summary of the invention
Compound of the present invention also shows the competitive inhibitor that can be used as the Progesterone that is incorporated into PR, and all can be used as agonist in the functional model in vitro and in vivo and/or antagonist works.These compounds can be used for contraception, in treatment fibroma, endometriosis, mammary cancer, uterus carcinoma, ovarian cancer and the prostate cancer, and are used for hormone replacement therapy after the menopause.
Compound of the present invention contains aromatics and replaces side group.These aromatic substituents have proved that it is vital having the progesterone receptor modulators activity for the compound that makes formation, and the structure diversity of wide model is arranged, and can comprise the heteroaryl groups of aryl, heteroaryl or the replacement of aryl, replacement.
The invention provides formula I compound, or its pharmacy acceptable salt:
In the formula:
R
1, R
2Be the independent substituting group that is selected from down group: H, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
2-C
6Alkenyl, the C of replacement
2-C
6Alkenyl, C
2-C
6Alkynyl, the C of replacement
2-C
6Alkynyl, C
3-C
8Cycloalkyl, the C of replacement
3-C
8Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, COR
A, or NR
BCOR
A
Or R
1And R
2Condense formation:
A) the optional 3-8 unit spirocyclane basic ring that replaces;
B) the optional 3-8 unit volution alkenyl that replaces; Or
C) the optional 3-8 unit heterocycle that replaces, it contains 1-3 heteroatoms that is selected from down group: O, S and N; A), b) and c) volution, it can be randomly be selected from down 1-4 group replacement of group: fluorine, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylthio ,-CF
3,-OH ,-CN, NH
2,-NH (C
1-C
6Alkyl), or-N (C
1-C
6Alkyl)
2
R
ABe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, the C of replacement
1-C
3Aminoalkyl,
R
BBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl,
R
3Be H, OH, NH
2, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
3-C
6Alkenyl, the C of replacement
1-C
6Alkenyl, alkynyl, or the alkynyl that replaces, COR
C,
R
CBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, the C of replacement
1-C
3Aminoalkyl,
R
4Be H, halogen, CN, NO
2, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, alkynyl, or the alkynyl that replaces, C
1-C
6Alkoxyl group, the C of replacement
1-C
6Alkoxyl group, amino, C
1-C
6Aminoalkyl, the C of replacement
1-C
6Aminoalkyl,
R
5Be the trisubstituted benzene ring that contains substituent X, Y and Z as follows:
X is selected from down group: halogen, CN, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, alkynyl, or the alkynyl that replaces, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Thio alkoxy, the C of replacement
1-C
3Thio alkoxy, amino, C
1-C
3Aminoalkyl, the C of replacement
1-C
3Aminoalkyl, NO
2, C
1-C
3Perfluoroalkyl contains 1-3 heteroatomic 5 or 6 yuan of rings, COR
D, OCOR
D, or NR
ECOR
D
R
DBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, or the C that replaces
1-C
3Aminoalkyl;
R
EBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl;
Y and Z are the independent substituting groups that is selected from down group: H, halogen, CN, NO
2, amino, aminoalkyl, C
1-C
3Alkoxyl group, C
1-C
3Alkyl, or C
1-C
3Thio alkoxy;
Perhaps
R
5Be to contain 1,2 or 3 heteroatomic 5 or 6 yuan of ring: O that are selected from down group, S, SO, SO
2Or NR
6, and contain 1-2 independent substituting group that is selected from down group: H, halogen, CN, NO
2, amino, and C
1-C
3Alkyl, C
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, COR
F, or NR
GCOR
F
R
FBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, or the C that replaces
1-C
3Aminoalkyl;
R
GBe H, C
1-C
3Alkyl, or the C that replaces
1-C
3Alkyl;
R
6Be H or C
1-C
3Alkyl;
G
1Be O, NR
7, or CR
7R
8
G
2Be CO, CS, or CR
7R
8
Condition is to work as G
1When being O, G
2Be CR
7R
8, and G
1And G
2Can not be CR simultaneously
7R
8
R
7And R
8Be the independent substituting group that is selected from down group: H or the optional alkyl that replaces, aryl, or heterocyclic moiety.
Preferred compound is those formulas I compound, or its pharmacy acceptable salt:
In the formula:
R
1Be H, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
3-C
8Cycloalkyl, the C of replacement
3-C
8Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, COR
A, or NR
BCOR
A
R
2Be H, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
2-C
6Alkenyl, the C of replacement
2-C
6Alkenyl, C
3-C
8Cycloalkyl, the C of replacement
3-C
8Cycloalkyl, aryl, the aryl of replacement, heterocycle, the heterocycle of replacement, COR
A, or NR
BCOR
A
Perhaps
R
1And R
2Condense and form the optional 3-8 unit spiro cycloalkyl group that replaces, alkenyl or contain 1-3 and be selected from down the heteroatomic heterocycle of organizing: O, S and N, as mentioned above;
R
ABe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, or the C that replaces
1-C
3Aminoalkyl;
R
BBe H, C
1-C
3Alkyl, or the C that replaces
1-C
3Alkyl,
R
3Be H, OH, NH
2, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
3-C
6Alkenyl, the C of replacement
1-C
6Alkenyl, alkynyl, or the alkynyl that replaces, COR
C
R
CBe H, C
1-C
4Alkyl, the C of replacement
1-C
4Alkyl, aryl, the aryl of replacement, C
1-C
4Alkoxyl group, the C of replacement
1-C
4Alkoxyl group, C
1-C
4Aminoalkyl, or the C that replaces
1-C
4Aminoalkyl;
R
4Be H, halogen, CN, NO
2, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl, C
1-C
6Alkoxyl group, the C of replacement
1-C
6Alkoxyl group, amino, C
1-C
6Aminoalkyl, the C of replacement
1-C
6Aminoalkyl,
R
5Be the trisubstituted benzene ring that contains substituent X, Y and Z as follows:
X is selected from: halogen, CN, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Thio alkoxy, the C of replacement
1-C
3Thio alkoxy, amino, C
1-C
3Aminoalkyl, the C of replacement
1-C
3Aminoalkyl, NO
2, C
1-C
3Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, COR
D, OCOR
D, or NR
ECOR
D
R
DBe H, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, aryl, the aryl of replacement, C
1-C
3Alkoxyl group, the C of replacement
1-C
3Alkoxyl group, C
1-C
3Aminoalkyl, or the C that replaces
1-C
3Aminoalkyl;
R
EBe H, C
1-C
3Alkyl, or the C that replaces
1-C
3Alkyl;
Y and Z are the independent substituting groups that is selected from down group: H, halogen, CN, NO
2, C
1-C
3Alkoxyl group, C
1-C
3Alkyl, or C
1-C
3Thio alkoxy;
Perhaps
R
5Be to contain 1,2 or 3 heteroatomic 5 or 6 yuan of ring: O that are selected from down group, S, SO, SO
2Or NR
6, and contain 1-2 independent substituting group that is selected from down group: H, halogen, CN, NO
2, amino, and C
1-C
3Alkyl, C
1-C
3Alkoxyl group;
R
6Be H, or C
1-C
3Alkyl;
G
1Be O, NR
7, or CR
7R
8
G
2Be CO, CS, or CR
7R
8, condition is to work as G
1When being O, G
2Be CR
7R
8, and G
1And G
2Can not all be CR
7R
8
R wherein
7And R
8Be the independent substituting group that is selected from down group: H, alkyl, the alkyl of replacement, aryl, the aryl of replacement, heterocycle, or the heterocycle that replaces.
In addition, preferred compound is those formulas I compound, or its pharmacy acceptable salt:
In the formula:
R
1=R
2And be selected from C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl, or by condensing R
1And R
2Form the spiro cycloalkyl group that 3-6 unit volution is constituted;
R
3Be H, OH, NH
2, C
1-C
6Alkyl, the C of replacement
1-C
6Alkyl ,-COH ,-CO (C
1-C
4Alkyl) or-CO (C
1-C
4Alkoxyl group);
R
4Be H, halogen, NO
2, C
1-C
3Alkyl, the C of replacement
1-C
3Alkyl,
R
5Be the disubstituted benzenes ring that contains substituent X and Y as follows:
X is selected from down group: halogen, CN, C
1-C
3Alkoxyl group, C
1-C
3Alkyl, NO
2, C
1-C
3Perfluoroalkyl contains 1-3 heteroatomic 5 yuan of heterocycles, C
1-C
3Thio alkoxy,
Y be 4 ' or 5 ' position on being selected under the substituting group of group: H, halogen, CN, NO
2, C
1-C
3Alkoxyl group, C
1-C
4Alkyl, C
1-C
3Thio alkoxy,
Perhaps
R
5Be 5 yuan of rings with following formula structure:
U is O, S, or NR
6,
R
6Be H, or C
1-C
3Alkyl, C
1-C
4CO
2Alkyl,
X ' is selected from down group: halogen, CN, NO
2, C
1-C
3Alkyl and C
1-C
3Alkoxyl group;
Y ' is selected from down group: H and C
1-C
4Alkyl
Perhaps
R
5Be 6 yuan of rings with following formula structure:
X
1Be N or CX
2,
X
2Be halogen, CN, alkoxyl group, or NO
2,
G
1Be O, NR
7, or CR
7R
8
G
2Be CO, CS, or CR
7R
8
Condition is to work as G
1When being O, G
2Be CR
7R
8, and G
1And G
2Can not all be CR
7R
8
R wherein
7And R
8Be the independent substituting group that is selected from down group: H, alkyl, the alkyl of replacement, aryl, the aryl of replacement, heterocycle, or the heterocycle that replaces.
In addition, preferred compound is those formulas I compound, and pharmacy acceptable salt:
In the formula:
R
1=R
2And be selected from down group: CH
3With by condensing R
1And R
2The spiro cycloalkyl group that forms 6 yuan of volutions and constitute,
R
3Be H, OH, NH
2, CH
3, the methyl of replacement, COR
C,
R
CBe H, C
1-C
3Alkyl, C
1-C
4Alkoxyl group,
R
4Be H, halogen, C
1-C
3Alkyl,
R
5Be the disubstituted benzenes ring that contains substituent X and Y as follows:
X is selected from down group: halogen, CN, methoxyl group, NO
2, the 2-thiazole,
Y be 4 ' or 5 ' position on being selected under the substituting group of group: H and F,
Perhaps
R
5Be 5 yuan of rings with following formula structure:
U is O, S, or NH,
X ' is selected from down group: halogen, CN, NO
2,
Y ' is selected from down group: H and C
1-C
4Alkyl
G
1Be O, NR
7, or CR
7R
8
G
2Be CO, CS, or CR
7R
8
Condition is to work as G
1When being O, G
2Be CR
7R
8, and G
1And G
2Can not all be CR
7R
8
R
7And R
8Be the independent substituting group that is selected from down group: H, alkyl, the alkyl of replacement, aryl, the aryl of replacement, heterocycle, or the heterocycle that replaces.
Compound of the present invention can contain unsymmetrical carbon, and compounds more of the present invention can contain one or more asymmetric centers, and therefore optical isomer and diastereomer can be arranged.Though formula I does not show with stereochemistry, the present invention includes these optical isomers and diastereomer; And racemic and the enantiomer-pure R that disassembles and the steric isomer of S; And other mixtures of R and S steric isomer and their pharmacy acceptable salts.One skilled in the art will appreciate that by condensing R
1And R
2And form listed substituent number in volution or the assorted volution, can determine by the size of volution.
Term used herein " alkyl " refers to straight or branched aliphatic hydrocarbon group saturated, that contain 1-8 carbon atom; " alkenyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon-carbon double bond and 2-8 carbon atom; " alkynyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon carbon triple bond and 2-8 carbon atom.
Term " alkyl of replacement ", " alkenyl of replacement " and " alkynyl of replacement " refer to by the one or more abovementioned alkyl that substituting group replaced, alkenyl and alkynyls that are selected from down group: halogen, CN, OH, NO
2, amino, aryl, heterocycle, the aryl of replacement, the heterocycle of replacement, alkoxyl group, aryloxy, the alkoxyl group of replacement, alkyl-carbonyl, alkyl carboxyl, alkylamino, arylthio.These substituting groups can be connected on any carbon atom of alkyl, alkenyl or alkynyl group, but condition is this stable chemical structure part that connects and composes.
The term of this paper " aryl " refers to aromatic systems, can be monocycle or originally condensed or many aromatic rings of linking together, thereby at least a portion is condensed or the formation conjugated virtue system of shack.Aromatic yl group comprises (but being not restricted to): phenyl, naphthyl, xenyl, anthryl, tetralyl, phenanthryl.
Term " aryl of replacement " refers to by 1-4 the above-mentioned aryl that group replaced that is selected from down group: halogen, CN, OH, NO
2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl group, aryloxy, replacement alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or arylthio.
Term used herein " heterocycle " refers to stable 4-7 unit's monocycle or stable many rings heterocycle, this heterocycle can be saturated, part is undersaturated or undersaturated, and by carbon atom be selected from a following 1-4 heteroatoms and constitute: N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any many rings, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.This heterocycle also can be connected in any heteroatoms or carbon atom, but condition is that the structure that is generated must be chemically stable.These heterocyclic groups comprise: for example, and tetrahydrofuran (THF), piperidyl, piperazinyl, 2-oxo-piperidine base, azepines base, pyrrolidyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, quinolyl, thienyl, furyl, benzofuryl, benzothienyl, thio-morpholinyl, thio-morpholinyl sulfoxide and isoquinolyl.
Term used herein " heterocycle of replacement " refers to by following 1-4 the above-mentioned heterocycle that substituting group replaced: halogen, CN, OH, NO
2, amino, alkyl, replacement alkenyl, alkynyl, alkoxyl group, aryloxy, alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or the arylthio of replacement of alkyl, cycloalkyl, alkenyl, replacement.Term " alkoxyl group " refers to the OR group, and wherein R is the alkyl of alkyl or replacement.Term " aryloxy " refers to the OR group, and wherein R is the aryl of aryl or replacement.Term " alkyl-carbonyl " refers to the RCO group, and wherein R is the alkyl of alkyl or replacement.Term " alkyl carboxyl " refers to the COOR group, and wherein R is the alkyl of alkyl or replacement.Term " aminoalkyl " refers to secondary amine or tertiary amine, wherein contains the alkyl of 1-8 carbon atom or the alkyl of replacement, can be identical or different, and tie point is on nitrogen-atoms.Term " halogen " refers to Cl, Br, F and I element.
Compound of the present invention is prepared by flow process shown in following:
Flow process I
Shown in flow process I, can prepare compound of the present invention as committed step by utilizing suitable linked reaction usually.In inert atmosphere such as argon gas or nitrogen,-78 ℃ to room temperature, the suitable neighbour-benzaminic acid or derivatives thereof that replaces is as ethyl ester (X=Br, I, Cl, or potential coupling precursor are as alkoxyl group, it can be converted into OTf group suitable in the linked reaction), with suitable organometallic reagent (as Grignard reagent), in suitable non-protonic solvent (nonprotic solvents) (including, but are not limited to THF or ether), handle, form neighbour-amino methanol 2.Comprise Suzuki reaction and Stille reaction with various linked reactions, can realize the arylation of amino methanol 2, thereby form compound 3.These reactions are carried out in the presence of transition-metal catalyst usually, for example, usually and phosphine ligand (as Ph
3P, dppf, dppe) palladium of Xing Chenging and nickel composite, or the catalyzer such as acid chloride.Under this catalytic condition, suitably nucleophilic reagent (as aryl boric acid, aryl stannane or aryl zn cpds) that replaces and amino methanol 2 couplings generate 3.If need alkali in the reaction, normally used alkali comprises (but being not restricted to): sodium bicarbonate, yellow soda ash, potassiumphosphate, barium carbonate, cesium fluoride or potassium acetate.The most frequently used solvent comprises in these reactions: the mixture of benzene, DMF, Virahol, ethanol, DME, ether, acetone or arbitrary above-mentioned solvent and water.Usually in inert atmosphere (as nitrogen or argon gas),, carry out linked reaction under the temperature of room temperature to 95 ℃.Can be in the presence of suitable acid catalyst (as tosic acid), in suitable solvent such as toluene, benzene, in inert atmosphere (as argon gas or nitrogen) in room temperature to reflux temperature, handle amino methanol 3 with suitable ketone, thereby make compound 4 of the present invention.
Flow process II has described the preparation procedure that has the benzoxazine of two different substituents at 4.When in protic solvent (as ethanol or Virahol), under inert atmosphere (as argon gas or nitrogen) and reflux temperature, use N-, when O-dimethyl hydroxyl amine hydrochlorate is handled, can make Weinreb acid amides 6 from the isatoic acid acid anhydride of suitable replacement.With acid amides 6 and aryl electrophilic reagent such as aryl boric acid or the coupling of aryl stannane to form 7, can be by adopting typical linked reaction (as Suzuki, Stille coupling program), by carrying out with the similar fashion described in the preparation compound 3.Under inert atmosphere (as argon gas or nitrogen),-78 ℃ of temperature ranges, in non-protonic solvent (as THF or ether), use organometallic compound (as lithium alkylide, alkynyl lithium, lithium aryl to room temperature, or their Grignard counterpart) handles Weinreb acid amides 7, generate keto-amine 8.Under inert atmosphere (as argon gas or nitrogen) ,-78 ℃ of temperature ranges to room temperature in non-protonic solvent (as THF or ether), handle 8 with organometallic reagent (as alkyl, alkynyl or aryl Grignard reagent), ketone 8 can be changed into methyl alcohol 9.Also can be under inert atmosphere, 0 ℃ of temperature range to solvent boiling point, in suitable solvent (as THF, ether or dehydrated alcohol), be reduced into 9 methyl alcohol part with the ketone groups of suitable reductive agent (as lithium aluminum hydride, sodium borohydride), thereby ketone 8 is changed into methyl alcohol 98.Also can in flow process I, prepare compound 4, change The compounds of this invention into 9.
Flow process II
Perhaps, shown in flow process III, also can be under inert atmosphere (as argon gas or nitrogen),-78 ℃ of temperature ranges to room temperature, in suitable solvent (THF or ether), handle neighbour-aminobenzonitrile 11 with organometallic compound (as organic lithium reagent or Grignard reagent), thereby make adjacent keto-amine 8.By the mode similar,, can make benzonitrile 11 easily from the benzonitrile (as bromo benzonitrile 10) of suitable replacement with suitable linked reaction (as Stille or Suzuki flow process) to preparation Weinreb acid amides 7.
Flow process III
Flow process IV has described 3,4-dihydroquinazoline-2-ketone synthetic.Under inert atmosphere (as argon gas or nitrogen),-78 ℃ of temperature ranges to room temperature, in non-protonic solvent (as THF or ether), 2-aminobenzonitrile 11 with organometallic compound such as organolithium or the replacement of Grignard agent treated, thereby form the imino-intermediate, this intermediate carries out in-situ treatment again at 0-60 ℃ with suitable carbonic ether (as diethyl carbonate or methylcarbonate), forms quinazoline-2-ketone 12.Under inert atmosphere (as argon gas or nitrogen); 0 ℃ of temperature range to room temperature; at suitable solvent (as DMF; or the mixture of THF and DMF solvent) in; by handling 12 with suitable alkali such as potassium hydride KH, potassium tert.-butoxide or sodium hydride; add protective material then as to the methoxy-benzyl muriate, can realize protection with suitable blocking group (as right-methoxybenzyl base section) to quinazoline-2-ketone 12.Can be under inert atmosphere (as argon gas or nitrogen); 0 ℃ of temperature range to room temperature; in non-protonic solvent (as THF or ether); in the presence of suitable Lewis acid such as trifluoromethanesulfonic acid magnesium; with suitable organometallic compound such as organolithium or Grignard reagent; join in shielded quinazoline-2-ketone 12, by the Michael mode to produce 13.
Flow process IV
Remove blocking group; can be by realizing with the suitable protective material processing of going; for example; for right-methoxy-benzyl blocking group; can be at inert atmosphere (as argon gas or nitrogen), 0 ℃ to room temperature, in suitable solvent (as methylene dichloride); with protonic acid such as TFA, or handle 13 and be removed with ceric ammonium nitrate (ceric ammonium nitrate).Before removing blocking group; appropriate base such as sodium hydride, potassium hydride KH or the potassium tert.-butoxide that can be used in the suitable solvent (as DMF) handle 13; then at inert atmosphere (as argon gas or nitrogen); 0 ℃ to room temperature; with organic iodide or organic triflate (triflate) as methyl iodide cancellation reaction soln, thereby realize the alkylation of 3-nitrogen.When blocking group is removed by suitable agent; just can make compound 14 of the present invention; for example for right-methoxy-benzyl blocking group; can be at inert atmosphere (as argon gas or nitrogen); 0 ℃ to room temperature; in suitable solvent (as methylene dichloride), use protonic acid such as TFA, or be removed with ceric ammonium nitrate (ceric ammoniumnitrate) processing 13.
Change compound 14 into 3,4-dihydroquinazoline-2-thioketones 15 can pass through at inert atmosphere (as argon gas or nitrogen), under refluxing, in non-protonic solvent (as o-Xylol, chlorobenzene or toluene), with suitable sulphur reagent such as Lawesson agent treated 14 and realize.
Shown in flow process V, by several different methods compound 14 or 15 is further derived at 1, cause forming various new derivatives, comprising the 1-carboxy derivatives of the 1-carbonyl of the 1-alkyl of 1-alkyl, replacement, 1-carbonyl, replacement, 1-carboxyl, replacement.For example, under the inert atmosphere (as argon gas or nitrogen), in appropriate solvent (as DMF), by handling carbamate 14 or 15 with suitable alkali (as sodium hydride), add suitable electrophilic reagent then (as the alkyl of alkyl or replacement, bromide, iodide or triflate), can make the alkyl of alkyl or replacement, derivative 16 or 17.Two-phase condition shown in the also available flow process V changes into 16 or 17 at 1 with 14 or 15, wherein uses two-phase catalyzer (as the bromination tributyl ammonium) to carry out alkylation in appropriate solvent (as acetonitrile).Another example of this 1 modification comprises (but being not restricted to): the example shown in flow process V, wherein heat with triethyl orthoformate 14 or 15, thereby generate the derivative that 14 or 15 1-replaces.
Flow process V
Under the inert atmosphere (as argon gas or nitrogen); when in appropriate solvent (as acetonitrile), having suitable basic catalyst (as DMAP); handle 14 or 15 with suitable acylating agent or carboxylating agent (as Di-tert butyl pyrocarbonate); easily realize acidylate or carboxylation, thereby generate compound 18 or 19 in the 1-position of compound 14 or 15.In The suitable solvent (as THF or diethyl ether), when having suitable alkali such as sodium hydride, with suitable aminating agent (as ammonia chloride), press (the people .J.Org.Chem.30 such as Metlesics of the flow process described in the reference, 1311 (1965)), 1 amination of compound 14 or 15 can be generated compound 20 or 21.
According to flow process VI, in suitable non-protonic solvent, when having alkali, suitable aniline (as 4-bromaniline 22) and acrylate chloride 23 reactions can be formed acid amides 24.Alkali is preferably highly basic such as sodium hydride or hexamethyl dimethyl silanyl acid amides sodium (sodium hexamethyldisilylamide) or hexamethyl dimethyl silanyl acid amides potassium, at inert atmosphere (argon gas or nitrogen), 0 ℃ to the reflux temperature of solvent, adopt THF as solvent.
Flow process VI
Then, at inert atmosphere (as argon gas or nitrogen), 0 ℃ to the solvent refluxing temperature, under strong acid condition, acid amides 24 and sulfuric acid, boron trifluoride etherate or more preferably with aluminum chloride (perhaps as molten mass, or in inert solvent (dichlorobenzene)) reaction, form cyclic amide 25.Then, compound 25 and aryl or heteroaryl boric acid, boron trioxide or the reaction of trialkyl stannane produce required aryl-linking compound 26.Reaction can be in inert atmosphere (as argon gas or nitrogen), 0 ℃ to the solvent refluxing temperature, in solvent such as acetone, ethanol, benzene, toluene or THF, close in the presence of palladium (O) or the acid chloride as four (triphenylphosphines) at palladium catalyst and to carry out, and may be such as the additive yellow soda ash, cesium fluoride or the potassiumphosphate.
Change compound 26 into thioamides 27, can be in inert atmosphere (as argon gas or nitrogen), under refluxing, in non-protonic solvent (as o-Xylol, chlorobenzene or toluene), realize with suitable sulphur reagent such as Lawesson agent treated.
Flow process VII
According to flow process VII, allow sodium hydride reaction among suitable cyclic amide (as 25) and the THF, form anionic species, add benzyl halide then, change raw material into N-shielded amide product 28.Close in the presence of palladium (O) or the acid chloride as four (triphenylphosphines) at palladium catalyst, 28 with aryl boric acid (boronic acid) reaction, thereby make two kinds of aromatic substances couplings form 29.This reaction is carried out under the two-phase condition usually.That is, water uses with appropriate organic solvent such as toluene or DMF usually.Palladium catalyst normally adds at last, and reaction mixture refluxes in the presence of rare gas element such as nitrogen.Product Grignard reagent, magnesium alkyl halide is handled in THF, adds ammonium chloride solution then to form enamine derivates 30.The reduction of two keys and removal blocking group can be realized in single step in 30, and promptly in the Parr hydrogenation equipment, the palladium that carries with gac carries out catalytic reduction reaction, thereby form target compound 31.
Flow process VIII
3-fluoro-5-(2,4,4-trimethylammonium-1,2,3,4-hydrogen-quinolyl)-benzonitrile (compound 35) can be by flow process VIII preparation, and this is a flow process similar to flow process VII.According to flow process VIII, compound 28 and Grignard reagent, magnesium alkyl halide reacts in THF, adds ammonium chloride solution then to form enamine derivates 32.Can form reductive derivative 33 with the two keys of cyano group sodium borohydride reduction.Blocking group is removed with strong acid (as trifluoromethanesulfonic acid (triflic acid) or sulfuric acid); form de-protected compound 34; close in the presence of palladium (O) or the acid chloride as four (triphenylphosphines) at palladium catalyst then; compound 34 and the phenyl-boron dihydroxide coupling that suitably replaces, thus make two kinds of aromatic substances couplings form 35.This reaction is carried out under the two-phase condition usually.That is, water uses with appropriate organic solvent such as toluene or DMF usually.
Compound of the present invention can with pharmaceutically or the acceptable acid of physiology or alkali deutero-salt form use.These salt include, but is not limited to the salt that forms with following mineral acid: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the salt that forms with organic acid, organic acid then refers to acetate, oxalic acid, Succinic Acid and toxilic acid.Other salt comprise the salt that forms with basic metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), with the form (when with this form administration, can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.
The present invention also comprises pharmaceutical composition and methods of treatment, and it comprises one or more above-claimed cpds as the progesterone receptor antagonist to the administration medicine effective quantity, wherein G
2Be C=O.The present invention also provides similar method and composition, and they adopt the agonist of one or more compounds of this paper as progesterone receptor, wherein G
2Be C=S.In addition, the present invention also provides similar method and composition, and they adopt one or more compounds of this paper, wherein G
1=O and G
2=CR
7CR
8The time be the agonist of progesterone receptor, work as G
1=CR
7CR
8And G
2=CR
7CR
8It is the agonist of progesterone receptor.
Single with or coupling progesterone receptor antagonist of the present invention, can be used for practising contraception and treat and/or prevent optimum and method malignant tumour.The concrete purposes of compound of the present invention and pharmaceutical composition comprises: treat and/or prevent myometrium fibroma, endometriosis, benign prostatauxe; The cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, pituitary gland and gland cancer, meningioma and other hormone-dependent tumors.Other purposes of progesterone receptor antagonist of the present invention comprise: the synchronization that domestic animal oestruses.When progesterone receptor antagonist of the present invention is used to practise contraception, can be individually with every day the 1-500 milligram the successive administration mode use, perhaps be used for different schemes, this scheme after using 21 days progestogen with progesterone receptor antagonist for treating 2-4 days.In this scheme, the progestogen of first usefulness 0.1-500 milligram dosage every day (for example, Levonorgestrel, trimegestone (trimegestone), gestodene, the Norethisterone acetic ester, norgestimate or encircle the third Progesterone acetic ester), use the progesterone receptor antagonist of the present invention of 0.1-500 milligram dosage every day then.
Single using or coupling progesterone receptor antagonist of the present invention also can be used for treating and/or preventing optimum and method malignant tumour.The concrete purposes of compound of the present invention and pharmaceutical composition comprises: treat and/or prevent myometrium fibroma, endometriosis, benign prostatauxe; The cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, pituitary gland and gland cancer, meningioma and other hormone-dependent tumors.Other purposes of progesterone receptor antagonist of the present invention comprise: the synchronization that domestic animal oestruses.
Single using or coupling progesterone receptor agonist of the present invention can be used for contraception and treats and/or prevents hemorrhage of functional disorder, leiomyoma of uterus, endometriosis; Polycystic ovary syndrome, uterine mucosa, ovary, mammary gland, colon, prostatic cancer and gland cancer.Other purposes of progesterone receptor agonist of the present invention comprise: promote to ingest.
When being used to practise contraception, progesterone receptor agonist of the present invention should with oestrogenic hormon agonist (as lynoral) coupling, or use successively.The preferred dose of progesterone receptor agonist is the 0.01-500 mg/day.
When compound is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, thinner etc.; and can be with following form oral administration: tablet, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing the 20-50% ethanol of having an appointment), perhaps carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment in the medium waiting to ooze).For example, these pharmaceutical preparations can contain and the about 25-90% of carrier blended, are about the activeconstituents of 5%-60% (weight) usually.
The effective dose of used activeconstituents can change with the severity of the pattern of used specific compound, administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 1-100mg, preferably is about 2-80mg.Be applicable to dosage form for oral administration, comprise active compound with the pharmaceutically acceptable solid-state or about 0.5-500mg of liquid carrier blended.Can regulate this dosage replys so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
These active compounds can be by oral and intravenously, intramuscular or subcutaneous route administration.Solid-state carrier comprises: starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and white bole, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be fit to the characteristic of activeconstituents and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, and for example seasonings, pigment, sanitas and antioxidant are as vitamin-E, vitamins C, BHT and BHA.
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The oral administration of compound is preferred.
But these active compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare these active compounds (as free alkali or pharmacy acceptable salt).Also can in glycerine, liquid, polyoxyethylene glycol and the mixture in oil thereof, prepare dispersion liquid.Under routine storage and working conditions, contain sanitas in these preparations to prevent microorganism growth.
The medicament forms that is adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (being used for preparing aseptic injectable solution or dispersion liquid) temporarily.In all situations, these forms must be aseptic and must be that fluid is discharged fluid to be easy to syringe.Under manufacturing and condition of storage must be stable, and must be able to prevent the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, wherein contains just like water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
Embodiment
The following embodiment that does not play the qualification effect has set forth the preparation of The compounds of this invention.
Embodiment 1
1-(4-amino-3 '-chloro-xenyl-3-yl)-ethane ketone
To 2-amino-5-bromo-N-methoxyl group-N-methyl-benzamide (7.78g, 30mmol), the 3-chlorophenylboronic acid (5.63g, 36mmol), four (triphenylphosphines) close palladium (O) (1.73g, 1.5mmol), and yellow soda ash (7.63g, 72mmol), the mixture in DME and water (150mL/30mL) mixed solvent, outgas to remove oxygen, under nitrogen, heated 3 hours then at 85 ℃.Reaction mixture is cooled to room temperature, and handles with salt solution (30mL) and ethyl acetate (100mL).Separate organic layer, (3 * 40mL) extract water layer with ethyl acetate.The blended organic layer is with the salt water washing and use dried over mgso.After removing solvent, residue purified by flash chromatography (silica gel, hexane: ethyl acetate/1: 1), obtain 5-(3-chloro-phenyl-)-N-methoxyl group-N-methyl-benzamide, be brown oil (5g, 57%).Under nitrogen, in-78 ℃, to this benzamide (5g, 17.2mmol) anhydrous THF solution drip lithium methide diethyl ether solution (1.4M, 28.6mL, 40mL).Stir after 30 minutes, reaction mixture with saturated aqueous ammonium chloride solution (50mL)-78 ℃ of processing.Add ethyl acetate (100mL), separate organic layer, (3 * 20mL) extract water layer with ethyl acetate.The organic layer that merges is through washing (salt solution) and dry (MgSO
4).After removing solvent, residue is with purified by flash chromatography (silica gel, hexane: ethyl acetate/2: 1), obtain 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethane ketone (ethanone), be yellow solid (2g, 47%): mp 89-90 ℃;
1H-NMR (CDCl
3) δ 7.89 (d, 1H, J=2.0Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268 ([M+Na]+, 60%); C
14H
12The analytical value of ClNO: C, 68.44, H, 4.92, N, 5.70. measured value: C, 68.40, H, 4.89, N, 5.61.
Embodiment 2
1-(4-amino-3 '-chloro-xenyl-3-yl)-dimethyl-methyl alcohol
To 1-(4-amino-3 '-chloro-xenyl-3-yl)-ethane ketone (.55g, anhydrous THF solution 2.2mmol), under nitrogen and 0 ℃, add methylmagnesium-bromide (3.0M, in ether, 1mL, 3mmol).Mixture slowly is warming up to room temperature and continues under nitrogen and stirred 18 hours.Mixture is handled with 10 milliliters of saturated aqueous ammonium chloride solutions, adds ethyl acetate (50mL).Separate organic layer, (3 * 15mL) extract water layer with ethyl acetate.The organic layer that merges washs with salt solution (20mL), and dry (MgSO
4).After removing solvent, residue is by purified by flash chromatography (silica gel, hexane: ethyl acetate/2: 1), obtain title compound, be beige solid: 186-188 ℃ of (hydrochloride) .C
15H
17Cl
2The analytical value of NO: C, 60.42, H, 5.75, N, 4.7. measured value: C, 60.51, H, 5.62, N, 4.56.
Embodiment 3
6-(3-chloro-phenyl)-2,4,4-trimethylammonium-2-Trifluoromethyl-1,4-dihydro-2H-benzo [d] [1,3] oxazine
Under blanket of nitrogen, stir (4-amino-3 '-chloro-xenyl-3-yl)-dimethyl-methyl alcohol (0.25g, 0.95mmol), trifluoromethyl acetone (0.16g, 1.43mmol), and tosic acid (0.01g, 0.05mmol) mixture in dry toluene (5mL) is 48 hours.Reaction is removed toluene after finishing, and residue is by purified by flash chromatography (silica gel, 10% ethyl acetate/hexane), form 6-(3-chloro-phenyl)-2,4,4-trimethylammonium-2-Trifluoromethyl-1,4-dihydro-2H-benzo [d] [1,3]-oxazines (0.22g, 65%) are clean oil.This oil is dissolved in the ether (78 ℃), handles with the diethyl ether solution of 1N HCl then, form the hydrochloride of title compound, be white solid:
1H-NMR (DMSO-d
6) δ 7.67 (bs, 1H), 7.58 (d, 1H, J=7.88Hz), 7.42 (m, 3H), 7.32 (d, 1H, J=7.96Hz), 6.84 (d, 1H, J=8.03Hz), 1.52 (s, 3H), 1.5 (s, 6H); MS (APCI) m/z 354 ([M-H]
-, 100%); C
18H
17ClF
3The analytical value of NO: C, 55.12; H, 4.62; N, 3.57. measured value: C, 54.97; H, 4.59; N, 3.41.
Embodiment 4
6-(3-chloro-phenyl)-2,2,4,4-tetramethyl--1,4-dihydro-2H-benzo [d] [1,3] oxazine
(4-amino-3 '-chloro-xenyl-3-yl)-dimethyl-methyl alcohol (0.46g, 1.8mmol), acetone (0.16g, 2.7mmol), and tosic acid (0.017g, 0.09mmol) mixture in dry toluene (6mL), at 33 ℃, heated overnight under blanket of nitrogen.Reaction is removed toluene after finishing, and compound forms 6-(3-chloro-phenyl)-2,2,4 by purified by flash chromatography (silica gel, 15% ethyl acetate/hexane), 4-tetramethyl--1, and [1,3] oxazine (0.36g, 68%) is yellow oil to 4-dihydro-2H-benzo [d].This oil is dissolved in the ether (78 ℃), handles with the diethyl ether solution of 1N HCl then, forms the hydrochloride of title compound, is yellow solid:
1H-NMR (DMSO-d
6) δ 7.70 (bs, 1H), 7.61 (d, 1H, J=7.82Hz), 7.52 (bs, 1H), 7.44 (m, 2H), 7.33 (d, 1H, J=8.21Hz), 6.87 (d, 1H, J=7.85Hz), 1.5 (s, 6H), 1.4 (s, 6H); MS (ESI) m/z 302 ([M+H]
+, 100%); C
18H
20The analytical value of ClNO: C, 63.91; H, 6.26; N, 4.14. measured value: C, 64.08; H, 6.43; N, 4.14.
Embodiment 5
6-(3-nitro-phenyl)-2,2,4 ,-trimethylammonium-1,4-dihydro-2H-benzo [d] [1,3] oxazine
Press embodiment 4 same way as, usefulness 1-(4-amino-3 '-nitro-xenyl-3-yl)-ethanol and acetone preparation.Yellow solid: mp 188-189 ℃; C
17H
18N
2O
30.35H
2The analytical value of O: C, 67.02; H, 6.19; N, 9.20. measured value: C, 66.7; H, 5.89; N, 9.03.
Embodiment 6
4-amino-3 '-chloro-xenyl-3-formonitrile HCN
To 2-amino-5-bromobenzyl nitrile (10g, 50mmol), and the 3-chlorophenylboronic acid (9.5g, 60mmol), four (triphenylphosphines) close palladium (O) (3.5g, 3mmol), and yellow soda ash (13g, 120mmol) mixture in DME and water (100mL/25mL) mixed solvent, outgas, to remove oxygen, under blanket of nitrogen, be heated to 85 ℃ then, 5 hours.Reaction mixture is cooled to room temperature, and with saturated aqueous ammonium chloride solution (80mL) cancellation.Add ethyl acetate (200mL), separate organic layer, (3 * 40mL) extract water layer with ethyl acetate.The organic layer that merges is with the salt water washing and use dried over mgso.Vacuum is removed solvent, residue with flash chromatography on silica gel method purifying (hexane: ethyl acetate/4: 1) obtain 4-amino-3 '-chloro-xenyl-3-formonitrile HCN, be beige solid (8g, 87%): mp 118-119 ℃;
1H-NMR (DMSO-d
6) δ 7.80 (d, 1H, J=2.3Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J=8.0Hz), 7.42 (t, 1H, J=7.9Hz), 7.31 (m, 1H), 6.87 (d, 1H, J=8.7Hz), 6.29 (br, 2H); C
13H
9ClN
2Analytical value: C, 68.28, H, 3.97, N, 12.25. measured value: C, 67.68, H, 4.06, N, 11.89.
Embodiment 7
6-(3-chloro-phenyl-)-4-cyclopropyl-1H-quinazoline-2-ketone
With the similar program described in the document (people J.Med.Chem. such as Tucker, 1994,37,2437-2444) preparation.Under nitrogen and 50 ℃, to magnesium (0.9g, 37mmol) and Cyclopropyl Bromide (3.2mL, in the anhydrous THF solution of the brominated propyl group magnesium that 40mmol) makes, adding 4-amino-3 '-chloro-xenyl-3-formonitrile HCN (2.3g, anhydrous THF solution 10mmol).After the adding, reaction mixture kept 30 minutes under nitrogen at 50 ℃, handled with methylcarbonate in the dropping mode then.Under nitrogen, reaction soln is cooled to room temperature then in 50 ℃ of stirrings 30 minutes.Add saturated aqueous ammonium chloride solution (30mL), add ethyl acetate (80mL) then.Separate organic layer, (3 * 40mL) extract water layer with ethyl acetate.The organic layer that merges is with the salt water washing and use dried over mgso.After removing solvent, residue is by purified by flash chromatography (silica gel, methylene dichloride: methyl alcohol/25: 1), form 6-(3-chloro-phenyl-)-4-cyclopropyl-1H-quinazoline-2-ketone, be light yellow solid (0.55g, 18%): mp 189-190 ℃;
1H-NMR (DMSO-d
6) δ 11.71 (D2O is tradable for s, 1H), 8.56 (d, 1H, J=1.3Hz), 8.09 (dd, 1H, J=8.6,1.6Hz), 7.92 (s, 1H), 7.77 (d, 1H, J=7.7Hz), 7.52 (t, 1H, J=7.9Hz), 7.45 (d, 1H, J=8.1Hz), 7.36 (d, 1H, J=8.6Hz), 3.15 (m, 1H), 1.20 (m, 4H); MS (CI) m/z 297 ([M+H]
+, 100%); C
17H
13ClN
2The analytical value of O: C, 69.98, H, 4.49, N, 9.23. measured value: C, 67.98, H, 4.46, N, 9.10.
Embodiment 8
6-(3-chloro-phenyl-)-4-cyclopropyl-1-(4-methoxy-benzyl)-1H-quinazoline-2-ketone
Under room temperature and nitrogen, to 6-(3-chloro-phenyl-)-4-cyclopropyl-1H-quinazoline-2-ketone (0.5g, the 1.68mmol) suspension in dry DMF, add hexamethyl silyl acid amides potassium (0.45g, 2.1mmol).Reaction mixture at room temperature stirred 30 minutes, and (0.35mL 2.5mmol) handles, then 55 ℃ of heating 5 hours with right-methoxy-benzyl chlorine.Then, mixture is cooled to room temperature, uses saturated aqueous ammonium chloride solution (10mL) cancellation then.Add methylene dichloride (50mL), separate organic layer.(2 * 20mL) extract water layer, the salt water washing of the organic layer of merging, and dry (MgSO with methylene dichloride
4).After removing solvent, residue flash chromatography (silica gel, hexane: ethyl acetate/1: 1) separate, obtain 6-(3-chloro-phenyl-)-4-cyclopropyl-1-(4-methoxy-benzyl)-1H-quinazoline-2-ketone, be beige solid: mp 173-174 ℃;
1H-NMR (DMSO-d
6) δ 8.65 (d, 1H, J=1.8Hz), 8.10 (dd, 1H, J=8.9,1.8Hz), 7.93 (d, 1H, J=1.6Hz), 7.79 (d, 1H, J=7.6Hz), 7.53 (d, 2H, J=8.4Hz), 7.46 (t, 1H, J=8.1Hz), 7.21 (d, 2H, J=8.6Hz), 6.88 (d, 2H, J=8.6Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, 1H), 1.18-1.27 (m, 4H); MS (CI) m/z 417 ([M+H]
+, 100%); C
25H
21ClN
2O
2Analytical value: C, 72.02, H, 5.08, N, 6.72. measured value: C, 71.88, H, 4.91, N, 6.70.
Acquisition is beige solid: mp 158-159 ℃ as 6-(3-chloro-phenyl-)-4-cyclopropyl-2-(4-methoxy-benzyl oxygen) quinazoline of by product;
1H-NMR (DMSO-d
6) δ 8.75 (d, 1H, J=1.7Hz), 8.26 (dd, 1H, J=8.8,1.8Hz), 8.01 (s, 1H), 7.84 (m, 2H), 7.56 (t, 1H, J=7.9Hz), 7.45 (m, 3H), 6.96 (d, 2H, J=8.6Hz), 5.38 (s, 2H), 3.75 (s, 3H), 3.24 (m, 1H), 1.25 (m, 4H); MS (CI) m/z417 ([M+H]
+, 100%); C
25H
21ClN
2O
2Analytical value: C, 72.02, H, 5.08, N, 6.72. measured value: C, 72.19, H, 4.91, N, 6.65.
Embodiment 9
6-(3-chloro-phenyl-)-4-cyclopropyl-4-methyl-3,4-dihydro-1H-quinazoline-2-ketone
Under room temperature and nitrogen, to 6-(3-chloro-phenyl-)-4-cyclopropyl-1-(4-methoxy-benzyl)-1H-quinazoline-2-ketone (0.25g, 0.6mmol) anhydrous ether solution in, add trifluoromethanesulfonic acid magnesium (magnesium triflate) (0.78g, 2.4mmol).Mixture stirred 30 minutes, with diethyl ether solution (3.0M, 1.0mL, 3.0mmol) processing of methylmagnesium-bromide.Reaction mixture was placed 3 hours in room temperature under nitrogen, used saturated aqueous ammonium chloride solution (10mL) and the cancellation of 1N aqueous hydrochloric acid (5mL) mixture then.Mixture at room temperature stirred 20 minutes, added ethyl acetate (40mL).Separate organic layer, (3 * 10mL) extract water layer with ethyl acetate.The organic layer salt water washing that merges, and dry (MgSO
4).Remove solvent, half residue is dissolved in TFA (3mL), stirs 72 hours under room temperature at nitrogen then.Solution is poured on the frozen water, filters and collect white depositions.Solid washes with water, uses flash chromatography (methylene dichloride: methyl alcohol/25: 1, silica gel) purifying then, forms 6-(3-chloro-phenyl-)-4-cyclopropyl-4-methyl-3, and 4-dihydro-1H-quinazoline-2-ketone is beige solid (40mg, 43%): mp 125-127 ℃;
1H-NMR (DMSO-d
6) δ 9.21 (s, 1H), 7.71 (s, 1H), 7.61 (d, 1H, J=7.8Hz), 7.55 (d, 1H, J=1.6Hz), 7.47 (dd, 1H, J=8.3,1.8Hz), 7.45 (t, 1H, J=7.8Hz), 7.36 (d, 1H, J=8.1Hz), 6.84 (d, 1H, J=8.2Hz), 6.79 (s, 1H), 1.54 (s, 3H), 1.11 (m, 1H), 0.42 (m, 1H), 0.15-0.20 (m, 3H); MS (ESI) mz 313 ([M+H]
+, 100%).
Embodiment 10
6-(3-chloro-phenyl-)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-1H-quinazoline-2-ketone
Under nitrogen and room temperature, dry DMF (5mL) solution of half the thick affixture that makes to embodiment 9, add sodium hydride (25mg, 0.63mmol).Mixture at room temperature stirred 30 minutes, handled with methyl-iodide (0.5mL, excessive).Stir after 3.5 hours, the mixture of saturated aqueous ammonium chloride and 1N aqueous hydrochloric acid (10mL/5mL) is added to reaction mixture.Add ethyl acetate (30mL), separate organic layer.(3 * 10mL) extract water layer, the salt water washing of the organic layer of merging, and dry (MgSO with ethyl acetate
4).Remove and desolvate, residue is dissolved in the mixed solvent of methylene dichloride and TFA (2mL/2mL).Stir after 3 hours, solution is poured on the frozen water, make its neutralization by adding saturated sodium bicarbonate aqueous solution.Add ethyl acetate (30mL), separate organic layer.(3 * 10mL) extract water layer with ethyl acetate.The organic layer salt water washing that merges, and dry (MgSO
4).Vacuum is removed solvent, and residue is by flash chromatography (silica gel, hexane: ethyl acetate/1: 1) purifying, obtain 6-(3-chloro-phenyl-)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-1H-quinazoline-2-ketone, be white solid (11mg, 11%, 3 step): mp 193-194 ℃;
1H-NMR (DMSO-d
6) δ 9.51 (s, 1H), 7.68 (s, 1H), 7.59 (d, 1H, J=8.0Hz), 7.57 (d, 1H, J=1.6Hz), 7.51 (dd, 1H, J=8.3,1.7Hz), 7.46 (t, 1H, J=7.8Hz), 7.35 (d, 1H, J=8.1Hz), 6.87 (d, 1H, J=8.3Hz), 3.02 (s, 3H), 1.51 (s, 3H), 1.25 (m, 1H), 0.32-0.51 (m, 3H), 0.25 (m, 1H); MS (CI) m/z 327 ([M+H]
+, 100%) and .C
19H
19ClN
2O0.3H
2The analytical value of O: C, 68.69, H, 5.95, N, 8.43. measured value: C, 68.69, H, 5.70, N, 8.18.
Embodiment 11
6-(3-chloro-phenyl-)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-
Under nitrogen, and sodium hydride (1.16g, ca 29mmol, 60%, in oil) with hexane (* 3) washing, place anhydrous THF (50mL) then.In this slurry, drip 4-bromaniline (5.0g, anhydrous THF (100ml) solution 29mmol).After 0.5 hour, mixture is cooled to 0 ℃, use 3 then, anhydrous THF (30ml) solution-treated of 3-dimethyl acryloyl chloride.After 4 hours, mixture is used extracted with diethyl ether then with saturated aqueous ammonium chloride solution cancellation.Organic layer water, salt water washing, and dry (Na
2SO
4) and evaporation.Then, residue ethyl acetate/hexane crystallization obtains N-(3,3 '-dimethyl allene acyl)-4-bromaniline (3.36g, 13.22mmol, 46%), is white solid:
1H NMR (CDCl
3) δ 7.42 (s, 4H), 7.06 (s, 1H), 5.68 (s, 1H), 2.21 (s, 3H), 1.09 (s, 3H); MS (EI) m/z 253[M+].
(4.0g 15.38mmol) to about 130-140 ℃, melts solid to heat N-(3,3 '-dimethyl allene acyl)-4-bromaniline under nitrogen.(3.07g 23mmol), and continues heating to add aluminum chloride.After 1 hour, cooling mixture, water cancellation carefully, and with methylene dichloride (3 * 60mL) extraction.The organic layer that merges washes with water, dry (MgSO
4) and evaporation.Then, residue is carried out column chromatography (SiO
2, the ethyl acetate/hexane gradient elution), obtain 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(1.69g, 6.6mmol, 47%) is white solid:
1H-NMR (CDCl
3) δ 8.82 (s, 1H), 7.39 (d, 1H, J=2Hz), 7.29 (dd, 1H, J=8.3,2.0Hz), 6.71 (d, 1H, J=8.0Hz), 2.47 (s, 2H), 1.32 (s, 6H).
Under nitrogen, to the above-mentioned compound of mentioning at last (0.5g, the 1.96mmol) solution in glycol dimethyl ether (15mL), add four (triphenylphosphines) close palladium (O) (0.11g, 0.09mmol).After 15 minutes, (0.6g 3.9mmol), adds salt of wormwood (1.62g, aqueous solution 11.7mmol) (7.5mL) again to add the 3-chlorophenylboronic acid.Reflux after 1.5 hours, mixture is cooled, filters and use ethyl acetate extraction.Organic layer washes with water, dry (MgSO
4) and evaporation.Then, residue is carried out column chromatography (SiO
2, ethyl acetate: hexane/3: 1), use the dichloromethane/hexane crystallization, obtain 6-(3-chloro-phenyl-)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(0.21g, 0.73mmol, 37%) is white solid; Mp.211-215 ℃;
1H-NMR (CDCl
3) δ 8.48 (s, 1H), 7.53 (s, 1H), 7.47 (d, 1H, J=2.0Hz), 7.44-7.29 (m, 4H), 6.87 (1H, d, J=2.0Hz), 2.54 (s, 2H), 1.39 (s, 6H); MS ((-) ES) m/z 284[M-H]
-.
Embodiment 12-
Pharmacology
Compound of the present invention is tested with correlation test as described below, in vitro tests their scope of validity be 0.01nM to 5 μ M, be 0.001 to 300mg/kg in vivo in the test.Below selected example is listed in:
Table 1
Compound R 1 R2 R3 hPR CV-1
IC
50(nM)
1 Me Me Cl 10.0
2 CF
3 Me Cl 50.0
3 Me H NO
2 1675
R＝H，hPR?CV-1，IC
50＝1075nM hPR?CV-1，IC
50＝1075nM
R＝Me，hPR?CV-1，IC
50＝580nM
A. extracorporeal biology
Measure extracorporeal biology by the following method: (1) competitive radioligand combination: with having the A type people progesterone receptor of Progesterone as radioligand; (2) cotransfection test can provide with agonist EC
50With antagonist IC
50The functional vigor that value is expressed; (3) T47D cell proliferation, this provides the another kind of functional trial of agonist and antagonist data; (4) T47D cell alkaline phosphatase test, this also is a kind of functional trial that agonist and antagonist data are provided.
1.hPR in conjunction with testing: with reference to Pathirana, C.; Stein, R.B.; Berger, T.S.; Fenical, W.; Ianiro, T.; Mais, D.E.; Torres, A.; Glodman, M.E., " from the non-steroid class people progesterone receptor modulators of marine alga cymoplia barbata ", and J.Steroid Biochem.Mol.Biol., 1992,41,733-738 carries out.
2.CV-1 the test of the PRE-luciferase in the cell
The purpose of this test is based on compound influence to PRE-luciferase reporter activity in the CV-1 cell of personnel selection PR and PRE-luciferase plasmids cotransfection, determines the progestogenic or the anti-pregnant effect of compound.Material used in this test is as follows:
A. substratum: growth medium is as follows: contain 10% (v/v) foetal calf serum (hot deactivation), 0.1mM MEM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, DMEM BRL) (Bio Whittaker).Test medium is as follows: foetal calf serum (hot deactivation), 0.1mM MEM non-essential amino acid, 100U/ml penicillin, 100mg/ml Streptomycin sulphate and the 2mM GlutaMax (GIBCO, no phenol red DMEM BRL) (Bio Whittaker) that contain the desorb of 10% (v/v) activated carbon.
B. the cultivation of cell, transfection, processing and luciferase test
CV-1 cell stoste is maintained in the growth medium.With 1.2 * 10
7The calf thymus DNA that individual cell, 5mg pLEM plasmid (inserting hPR-B at Sph1 and BamH1 site), 10mg pGL3 plasmid (two PRE are arranged in the luciferase sequence upstream) and 50mg supersound process are crossed carries out cotransfection as carrier DNA (250ml).In 260V and 1,000mF carries out electroporation with Biorad Gene Pulser II.Behind the electroporation, cell is resuspended to growth medium, and on 96 orifice plates, inoculates with 40,000 cells/well (200 μ l).After the overnight incubation, change substratum into test medium.In test medium, handle these cells then with contrast or test compounds.In the presence of the 3nM Progesterone, measure the contraception activity of compound.Handle after 24 hours, discard substratum, (GIBCO BRL) washs these cells 3 times with D-PBS.Each hole adds 50 μ l cell lysis buffer solution, and (WI), dull and stereotyped (Lab Line Instrument Inc) goes up vibration 15 minutes at the titration oscillator plate for Promega, Madison.Measure the activity of luciferase with the luciferase reagent of Promega.
C. interpretation of result
Various processing repeat 4 times at least.Be matched with the variance and the non-linear dose response curve of agonist and antagonist pattern with the data analysis of logarithm conversion.Reduce the influence of outlier (outlier) with the Huber weighted method.With the numerical evaluation EC that converts again
50Or IC
50In two one-way analysises of variance and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
D. control compound
Progesterone and trimegestone be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all tested in full dose response curve, and calculate EC
50Or IC
50Value.
The expectation EC of contrast progestogen in three independent studies of table 2.
50, standard deviation (SE) and 95% fiducial interval (CI)
EC
50 95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
Progesterone 1 0.616 0.026 0.509 0.746
2 0.402 0.019 0.323 0.501
3 0.486 0.028 0.371 0.637
Trimegestone 1 0.0075 0.0002 0.0066 0.0085
2 0.0081 0.0003 0.0070 0.0094
3 0.0067 0.0003 0.0055 0.0082
The expectation IC of antiprogestin RU486 in three independent studies of table 3.
50, standard deviation (SE) and 95% fiducial interval (CI)
IG
50
95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
RU486 1 0.028 0.002 0.019 0.042
2 0.037 0.002 0.029 0.048
3 0.019 0.001 0.013 0.027
Progestogenic activity: compare with control vector, the compound that makes the PRE-uciferase activity significantly increase (p＜0.05) is thought activated.
Anti-pregnant activity: the compound that significantly reduces the activity (p＜0.05) of 3nM Progesterone inductive PRE-luciferase.
EC
50: in the time of increasing the peaked semiactive of PRE-uciferase activity, compound concentrations (being defaulted as " nM ") and standard deviation.
IC
50: in the time of reducing the peaked semiactive of 3nM Progesterone inductive PRE-uciferase activity, compound concentrations (being defaulted as " nM ") and standard deviation.
3.T47D the proliferation experiment of cell
The purpose of this experiment is to measure progestogenic and anti-pregnant effectiveness with the cell proliferation experiment of T47D cell.Measure compound to DNA synthetic effect in the T47D cell.Below be this experiment used material and method:
A. growth medium: be supplemented with 10% (v/v) foetal calf serum (not heat inactivation), 100U/ml penicillin, 100mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, DEME BRL): F12 (1: 1) (GIBCO, BRL).
B. handle substratum: be supplemented with 0.5% activated carbon desorb foetal calf serum, 100U/ml penicillin, 200mg/ml Streptomycin sulphate and 2mM GlutaMax (GIBCO, no phenol red minimum essential medium (MEM) BRL) (#51200-038 GIBCO, BRL).
C. cell cultures
T47D cell stoste is maintained in the growth medium.BrdU is mixed experiment, the amount (in growth medium) of cell with 10,000 cells/well is inoculated in 96 orifice plates (Falcon, Becton DickinsonLabware).After the overnight incubation, change substratum into the processing substratum, before processing, cultivated these cells again 24 hours.Compound stoste is dissolved in appropriate carriers (in 100% ethanol or 50% ethanol/50%DMSO), with handling the substratum dilution, adds to cell then.Progestogen and antiprogestin control compound are all tested in full dose-response curve mode.The final concentration of carrier is 0.1%.In control wells, cell is only accepted carrier.In the presence of 0.03nM trimegestone (contrast progestogen agonist), measure antiprogestin.Handle after 24 hours, discard substratum, with 10mM BrdU (Amersham Life Science, Arlington Heights, IL) labeled cell 4 hours in handling substratum.
D. cell proliferation experiment
When the BrdU mark finishes, discard substratum, by supplier's explanation, measure mixing of BrdU with cell proliferation ELISA test kit (#RPN 250, Amersham Life Science).In brief, cell is fixed 30 minutes in containing the ethanol of fixing agent, in the damping fluid of blockading, cultivate 30 minutes then to reduce background.The anti-BrdU antibody of peroxidase labelling is added in the hole, cultivated 60 minutes.With PBS rinsing cell 3 times, with 3,3 ', 5,5 '-tetramethyl benzidine (TMB) substrate cultivation 10-20 minute (effectiveness that depends on the compound of being tested).Add 25 μ l 1M sulfuric acid then and react with color development stopping in each hole, inherent 450nm place read optical density(OD) with plate reader in 5 minutes.
E. interpretation of result
With the data that square root converts, analyze the variance and the non-linear dose response curve that are matched with agonist and antagonist pattern.Reduce the influence of outlier with the Huber weighted method.By the numerical evaluation EC that converts again
50Or IC
50In the single dose and dose response analysis of variance and the analysis of non-linear dose response, and use JMP software (SAS Institute, Inc.).
F. control compound
Trimegestone and medroxyprogesterone acetate (MPA) be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are tested in full dose response curve mode, and calculate EC
50Or IC
50Value.
Expectation EC in each research of table 4.
50, standard deviation (SE) and 95% fiducial interval (CI)
EC
50 95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
Trimegestone 1 0.017 0.003 0.007 0.040
2 0.014 0.001 0.011 0.017
3 0.019 0.001 0.016 0.024
MPA 1 0.019 0.001 0.013 0.027
2 0.017 0.001 0.011 0.024
The expectation IC of table 5. antiprogestin RU486
50, standard deviation (SE) and 95% fiducial interval (CI)
IC
50 95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
RU486 1 0.011 0.001 0.008 0.014
2 0.016 0.001 0.014 0.020
3 0.018 0.001 0.014 0.022
EC
50: can increase BrdU incorporation maximum value one half compound concentrations and standard deviation;
IC
50: can make 0.1 trimegestone inductive BrdU incorporation reduce maximum value one half compound concentrations and standard deviation.
4.T47D cell alkaline phosphatase experiment
The purpose of this experiment is by measuring the effect of compound to T47D cell neutral and alkali Phosphoric acid esterase enzymic activity, identifying progestogen or antiprogestin.Below be this experiment used material and method.
A. substratum: be supplemented with the desorb of 5% (v/v) activated carbon foetal calf serum (not heat inactivation), 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates and 2mM GlutaMax (GIBCO, DMEM BRL): F12 (1: 1) (GIBCO, BRL).
B. alkaline phosphatase is tested damping fluid:
I.0.1M Tris-HCl, pH9.8 contains 0.2%Triton X-100
II.0.1M Tris-HCl, pH9.8, contain 4mM phosphoric acid right-nitro phenyl ester (Sigma)
C. cell cultures and processing:
Refrigerated T47D cell is thawed in 37 ℃ of water-baths, and be diluted to 280,000 cell/ml with substratum.The cell suspending liquid that in each hole of 96 orifice plates (Falcon, Becton Dickinson Labware), adds 180 μ l dilution.In each hole, add contrast or the test compounds of 20 μ l then with the substratum dilution.When the test progesterone antagonist is active, in the presence of the 1nM Progesterone, add contrast antiprogestin or test compounds.At 37 ℃, 5%CO
2Cultivated these cells 24 hours in the/moistening atmosphere.
D. alkaline phosphatase enzyme experiment
When processing finishes, discard the substratum in the flat board, in each hole, add 50 μ l experiment damping fluid I.These flat boards were vibrated 15 minutes on the titer plate vibrator.Then 150 μ l experiment damping fluid II is added in each hole.At 405nM place test wavelength, be measuring space optical density(OD) totally 30 minutes with 5 minutes.
E. interpretation of result: analyze the dosage reply data
To reference and test compounds, the speed (slope) (Y-axle) of enzyme reaction is drawn dose response curve with dosage (X-axle).With the data that square root converts, analyze the variance and the non-linear dose response curve that are matched with agonist and antagonist pattern.Reduce the influence of outlier with the Huber weighted method.By the numerical evaluation EC that converts again
50Or IC
50In the single dose and dose response analysis of variance and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
F. control compound
Progesterone and trimegestone be progestogen in contrast, and RU486 is antiprogestin in contrast.All control compounds are all tested in full dose response curve mode, and calculate EC
50Or IC
50Value.
The expectation EC of contrast progestogen in three independent experiments of table 6.
50, standard deviation (SE) and 95% fiducial interval (CI)
EC
50 95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
Progesterone 1 0.839 0.030 0.706 0.996
2 0.639 0.006 0.611 0.669
3 1.286 0.029 1.158 1.429
Trimegestone 1 0.084 0.002 0.076 0.091
2 0.076 0.001 0.072 0.080
3 0.160 0.004 0.141 0.181
The expectation IC of contrast antiprogestin RU486 in three independent experiments of table 7.
50,
Standard deviation (SE) and 95% fiducial interval (CI)
IC
50 95％CI
Compound
Experiment
(nM)
SE
Lower limit
The upper limit
RU486 1 0.103 0.002 0.092 0.115
2 0.120 0.001 0.115 0.126
3 0.094 0.007 0.066 0.134
B. biology in the body
Carry out testing in the initial body with rat decidua model, it can be used for measuring the gestagenic action of agonist and antagonist.Experiment is to suppress model with the rat ovulation to carry out in the secondary body, therefore fails to obtain flow process because this model still also is in the development phase.
1. rat decidua experiment: the purpose of this flow process is the effect to the rat uterus deciduaization of assessment progestogen and antiprogestin, and the relative effectivenes of various test compounds is compared.Below be used material and method:
A. method: test compounds is dissolved in 100% ethanol, and mixes with Semen Maydis oil (carrier).Then by heating (～80 ℃) this mixture evaporating ethanol, thereby preparation is at oil (Mazola
TM) in test compounds stoste.Subsequently before handling animal, with 100% Semen Maydis oil or 10% ethanol (in Semen Maydis oil) dilution test compounds.When these two kinds of carriers are compared, do not find the difference of decidua between replying.
B. animal (RACUC flow process #5002)
After operation, (Taconic Farms NY) obtains the ovariectomized female Sprague-Dawley rat (～60 day age and 230g) that grows up from Taconic.Before processing, carried out oophorectomize to reduce the sex steroid in the recycle system at least 10 days.These animals passes are supported in the room of 12 hours light/dark cycle, and feed with standard rat feed and feedwater arbitrarily.
C. handle
Before processing, rat is weighed and random packet 4 or 5 every group.With the nape of the 0.2ml carrier subcutaneous injection rat that contains test compounds, or carry out with the 0.5ml carrier with gavage.Handle these animals every day 1 time, totally 7 days.In test during antiprogestin, at preceding 3 days animals received test compounds handling and EC
50The Progesterone of dosage (5.6mg/kg).After decidua stimulated, animal was still accepted Progesterone and dissected corpse after 4 day.
D. dosage
By preparing dosage based on mg/kg average group body weight.In all researchs, comprise the control group of only accepting carrier.Determine dose response curve (as 0.1,0.3,1.0,3.0mg/kg) with the semilog increased value.
E. decidua is brought out
The injection back is about 24 hours for the third time, by anti-uterine veil (antimesometrial) the chamber endothelium of swiping with the 21G pin, thereby brings out decidua at an angle in uterus.Thereby do not swipe as unprovoked contrast in the diagonal angle.After about 24 hours, pass through CO in final processing
2Suffocate and put to death rat, measure body weight.Take out the uterus, clean out fat.Weigh respectively decidua (D-angle) and the contrast (C-angle) horn of uterus.
F. interpretation of result
Calculate the increase of decidua horn of uterus weight by D-angle/C-angle, and use normality and the homogeneity maximization that number conversion is made variance.Reduce the influence of viewed improper conversion value in dose response curve match and the variance one-way analysis with Huber M-estimated value.In unidirectional ANOVA and non-linear response analysis, and use JMP software (SAS Institute, Inc.).
G. control compound
All progestogen control compounds are all tested in full dose response curve mode, and calculating is for the EC of uterus weight in wet base
50Value.
The expectation EC of each experiment of table 8.
50, standard deviation (SE) and 95% fiducial interval (CI)
EC
50 95％CI
Compound
Experiment
(mg/kg, s.c.)
SE
Lower limit
The upper limit
Progesterone 1 5.50 0.77 4.21 7.20
2 6.21 1.12 4.41 8.76
3-ketone desogestrel 1 0.11 0.02 0.07 0.16
(3-Ketodesogestrel)?2 0.10 0.05 0.11 0.25
3 0.06 0.03 0.03 0.14
Levonorgestrel 1 0.08 0.03 0.04 0.16
2 0.12 0.02 0.09 0.17
3 0.09 0.02 0.06 0.13
4 0.09 0.02 0.06 0.14
MPA 1 0.42 0.03 0.29 0.60
2 0.39 0.05 0.22 0.67
3 0.39 0.04 0.25 0.61
Estimated average EC in the dose response curve of three kinds of control compounds of table 9.
50,
Standard deviation and 95% fiducial interval
EC50
95％CI
Compound
(mg/kg, s.c.)
SE
Lower limit
The upper limit
Progesterone 5.62 0.62 4.55 7.00
3-ketone desogestrel 0.10 0.02 0.07 0.14
Levonorgestrel 0.10 0.01 0.08 0.12
The expectation IC of table 10. antiprogestin RU486
50, standard deviation and 95% fiducial interval
IC
50 95％CI
Compound
Experiment
(mg/kg, p.o.)
SE
Lower limit
The upper limit
RU486 1 0.21 0.07 0.05 0.96
2 0.14 0.02 0.08 0.27
Concentration: compound concentrations in the experiment (is defaulted as: the mg/kg body weight)
Administration path: the path that gives the animalizing compound.
Body weight: the average overall of animal is heavy (to be defaulted as: kg).
The D-angle: the weight in wet base of decidua horn of uterus (is defaulted as: mg).
The C-angle: the weight in wet base of contrast horn of uterus (is defaulted as: mg).
Decidua is replied: [(D-C)/C] * 100%
Progestogenic activity: compare with control vector, the compound that energy remarkable (p＜0.05) brings out the decidua effect is considered to activated.
Anti-pregnant activity: significantly reduce EC
50The compound of the decidua effect that Progesterone brought out (p＜0.05).
The EC of uterus weight
50: make decidua reply the compound concentration (being defaulted as mg/kg) that maximum value increases by a half.
The IC of uterus weight
50: make EC
50The compound concentration (being defaulted as mg/kg) that maximum value reduces a half is replied in the decidua that Progesterone brings out.
Embodiment 13
5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN
Under nitrogen and-78 ℃, (10g, (3.0M, 90mL 270mmol) handle anhydrous THF (200mL) solution 46mmol) 2-amino-5-bromo-benzoic acid with the diethyl ether solution of methylmagnesium-bromide.Under nitrogen, reaction mixture is warming up to room temperature lentamente, continues to stir 48 hours, pours cold 0.5N aqueous hydrochloric acid (300mL) then into.With 1N aqueous sodium hydroxide solution neutralise mixt, add ethyl acetate (300mL) then.Separate organic layer, (3 * 100mL) extract water layer with ethyl acetate.The organic layer salt water washing that merges, dry (MgSO
4).After vacuum is removed solvent, residue by the silica gel rapid column chromatography (hexane: ethyl acetate/3: 2) purifying, form 2-(2-amino-5-bromophenyl) propan-2-ol, be beige solid (6g, 57%): mp 62-63 ℃;
1H-NMR (CDCl
3) δ 7.19 (d, 1H, J=2.3Hz), 7.12 (dd, 1H, J=8.4,2.3Hz), 6.51 (d, 1H, J=8.4Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).
Under blanket of nitrogen, in room temperature, to 2-(2-amino-5-bromophenyl) propan-2-ol (27g, add in anhydrous toluene solution 125mmol) acetyl aldehyde (acetylaldehyde) (10.5mL, 187mmol).After 10 minutes, mixture is by silica-gel plate, and filtrate is concentrated, and produces 6-bromo-2,4,4-trimethylammonium-1, and 4-dihydro-2H-3, the 1-benzoxazine is beige solid (25g, 78%):
1H-NMR (DMSO-d
6) δ 7.22 (d, 1H, J=2.2Hz), 7.08 (dd, 1H, J=8.6,2.3Hz), 6.51 (d, 1H, J=8.6Hz), 6.36 (s, 1H), 4.72 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (d, 3H, J=5.5Hz).
To 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3, the 1-benzoxazine (3.6g, 14mmol), two (tetramethyl ethylene ketone ester group) two boron [bis (pinacolato) diboron] (5g, 19.7mmol), potassium acetate (4g, 41mmol), and chlorination [1,1 '-two (diphenylphosphine) ferrocene] (1: 1 is compound with methylene dichloride to close palladium (II), 0.4g the 0.5mmol) mixture in DMF (80mL) carries out malleation nitrogen wind drift, to remove oxygen, under blanket of nitrogen, heated 18 hours then at 85 ℃.Allow reaction mixture be cooled to room temperature, with 5-bromo-2-thiophene formonitrile HCN (4g, 21mmol), chlorination [1,1 '-two (diphenylphosphine) ferrocene] (1: 1 is compound with methylene dichloride, 0.4g to close palladium (II), 0.5mmol) and aqueous sodium carbonate (2M, 35mL 70mmol) handles, and heats 3 hours at 85 ℃ under the nitrogen then.Allow reaction mixture be cooled to room temperature, add salt solution (100mL) and ethyl acetate (150mL).Separate organic layer, (3 * 50mL) extract water layer with ethyl acetate.The organic layer that the merges (MgSO that is dried
4), and concentrate.Residue by quick silica gel column chromatography (THF: purifying hexane/1: 4), obtain title compound, be beige solid (1g, 25%): mp172-173 ℃;
1H-NMR (DMSO-d
6) δ 7.88 (d, 1H, J=4.0Hz), 7.47 (d, 1H, J=4.0Hz), 7.43 (d, 1H, J=2.0Hz), 7.32 (dd, 1H, J=8.36,2.4Hz), 6.77 (s, 1H), 6.60 (d, 1H, J=8.4Hz), 4.83 (m, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.28 (d, 3H, J=5.6Hz); MS (ESI) m/z 283[M-H]
-.
Embodiment 14
3-fluoro-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) benzonitrile
According to the program of embodiment 13, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine and the preparation of 3-bromo-5-fluorine benzonitrile.Be white solid: mp 163-164 ℃;
1H-NMR (DMSO-d
6) δ 8.02 (t, 1H, J=1.5Hz), 7.87 (dt, 1H, J=10.6,2.2Hz), 7.65 (m, 1H), 7.55 (d, 1H, J=2.2Hz), 7.44 (dd, 1H, J=8.4,2.2Hz), 6.63 (d, 1H, J=8.4Hz), 6.58 (s, 1H), 4.82 (m, 1H), 1.52 (s, 3H), 1.50 (s, 3H), 1.28 (d, 3H, J=5.1Hz); MS (ESI) m/z 295[M-H]
-.
Embodiment 15
4-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN
According to the program of embodiment 13, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine and the preparation of 4-bromo-2-thiophene formonitrile HCN.Be beige solid: mp 175-176 ℃;
1H-NMR (DMSO-d
6) δ 8.39 (d, 1H, J=1.5Hz), 8.13 (d, 1H, J=1.5Hz), 7.47 (d, 1H, J=1.9Hz), 7.36 (dd, 1H, J=8.4,1.9Hz), 6.59 (d, 1H, J=8.4Hz), 6.41 (s, 1H), 4.78 (m, 1H), 1.51 (s, 3H), 1.47 (s, 3H), 1.28 (d, 3H, J=5.4Hz); MS (ESI) m/z 285[M+H]
+.
Embodiment 16
4-methyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN
According to the program of embodiment 13, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophene formonitrile HCN preparation.Be light yellow solid: mp 145-146 ℃;
1H-NMR (DMSO-d
6) δ 7.79 (s, 1H), 7.18 (d, 1H, J=2.0Hz), 7.13 (dd, 1H, J=8.4,2.0Hz), 6.68 (s, 1H), 6.54 (d, 1H, J=8.3Hz), 4.83 (m, 1H), 2.26 (s, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.28 (d, 3H, J=5.5 Hz); MS (ESI) m/z 299[M+H]
+.
Embodiment 17
3-[(2R, 4S)-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-5-fluorine benzonitrile
Under nitrogen and 0 ℃, to 2-amino-4-bromobenzyl nitrile (5g, anhydrous THF solution 25mmol), add phenyl-magnesium-bromide (3M, in the ether, 25mL, 75mmol).Allow mixture be warming up to room temperature, under nitrogen, stirred 15 hours, handle with 2N aqueous hydrochloric acid (100mL).The aqueous solution was heated to 50 ℃ of for 3 hours, was cooled to room temperature, with cold saturated sodium bicarbonate solution neutralization.Add ethyl acetate (100mL), separate organic layer, (3 * 40mL) extract water layer with ethyl acetate.The organic layer that the merges (MgSO that is dried
4), and evaporation.Residue by rapid column chromatography (silica gel, hexane: ethyl acetate/4: 1) purifying obtain (2-amino-5-bromophenyl) (phenyl) ketone, is yellow crystals (2.13g, 31%): MS (ESI) m/z 276/278[M+H]
+
Under nitrogen and room temperature, to (2-amino-5-bromophenyl) (phenyl) ketone (1g, anhydrous THF (15mL) solution 3.6mmol), add methylmagnesium-bromide (the 3M diethyl ether solution, 3mL, 9mmol).After 3 hours, mixture is handled with saturated ammonium sulfate solution (30mL) and ethyl acetate (50mL).Separate organic layer, dry (MgSO
4), and evaporation.Then, residue is dissolved in the dry toluene, under nitrogen and room temperature, handles with acetyl aldehyde (2mL).After 2 minutes, remove solvent, residue is by column chromatography (silica gel, hexane: ethyl acetate/4: 1) purifying, obtain 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3, the 1-benzoxazine is light yellow solid (0.8g, 70%): MS (ESI) m/z 318/320[M+H]
+.
To 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3, the 1-benzoxazine (0.6g, 1.9mmol), 3-cyano group-5-fluorobenzoic boric acid (0.45g, 2.7mmol), four (triphenylphosphines) close palladium (O) (0.2g, 0.17mmol), yellow soda ash (0.6g, 5.7mmol) mixture in DME and water (20/5mL) mixed solvent, carry out malleation nitrogen wind drift, to remove oxygen, under blanket of nitrogen, be heated to then 85 ℃ 2 hours.Allow reaction mixture be cooled to room temperature, add salt solution (30mL) and ethyl acetate (100mL).Separate organic layer, (3 * 30mL) extract water layer with ethyl acetate.The organic layer that the merges (MgSO that is dried
4), and evaporation.Residue by silica gel column chromatography (hexane: ethyl acetate/4: 1) purifying, obtain title compound, be beige solid (0.09g, 13%): mp128-129 ℃;
1H-NMR (DMSO-d
6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7,1.9Hz), 7.71 (d, 1H, J=2.0Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8,2.4Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6Hz), 6.69 (d, 1H, J=8.3Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5Hz); MS (ESI) m/z 357[M-H]
-.
Embodiment 18
Tertiary butyl 2-cyano group-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-
The 1-carboxylicesters
The tertiary butyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-1-carboxylicesters, be according to the coupling program among the embodiment 17, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine and 1-tert-butoxycarbonyl pyrroles-2-ylboronic acid preparation.Under nitrogen and-78 ℃, to the tertiary butyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-1-carboxylicesters (1g, 2.9mmol) anhydrous THF (20mL) solution, add Sulfuryl chloride isocyanate (0.35mL, 4.0mmol).Mixture continues down to stir 2 hours in nitrogen at-78 ℃, handles with dry DMF (5mL), rises to room temperature then.Add ammoniumsulphate soln (50mL) and ethyl acetate (100mL), separate organic layer, dry (MgSO
4), and evaporation.Residue by silica gel column chromatography (hexane: ethyl acetate/4: 1) purifying, obtain title compound, be white solid (0.019g, 1.78%):
1H-NMR (DMSO-d
6) δ 7.48 (d, 1H, J=2.0Hz), 7.36 (dd, 1H, J=8.3,2.0Hz), 7.32 (d, 1H, J=3.6Hz), 7.14 (d, 1H, J=8.3Hz), 6.46 (d, 1H, J=4.0Hz), 5.35 (q, 1H, J=5.2Hz), 1.58 (d, 3H, J=5.6Hz), 1.56 (s, 3H), 1.51 (s, 3H), 1.38 (s, 9H); MS (ESI) m/z 366[M-H]
-.
Embodiment 19
9H-fluorenes-9-ylmethyl-6-[1-(tertbutyloxycarbonyl)-5-cyano group-1H-pyrroles-2-yl]-2,4, the 4-trimethylammonium-
2H-3,1-benzoxazine-1 (4H)-carboxylicesters
With the tertiary butyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-1-carboxylicesters (1.7g, 4.96mmol), chloroformic acid 9-fluorenyl methyl esters (1.92g, 7.5mL), yellow soda ash (4g, 37mmol) the mixture in Zai diox (50mL) and the water (50mL) at room temperature stirred 6 hours under blanket of nitrogen.Add ethyl acetate (100mL), separate organic layer, dry (MgSO
4), and evaporation.Residue by silica gel column chromatography (hexane: ethyl acetate/6: 1) purifying obtains 9H-fluorenes-9-ylmethyl-6-[1-(tertbutyloxycarbonyl)-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters is clarification oily matter.
Use the program of embodiment 18, with 9H-fluorenes-9-ylmethyl-6-[1-(tertbutyloxycarbonyl)-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters (1.2g, 2.1mmol) and Sulfuryl chloride isocyanate (0.28mL, 3.1mmol) preparation title compound (0.8g, 65%).White solid: mp 135-136 ℃;
1H-NMR (DMSO-d
6) δ 7.90 (t, 2H, J=6.7Hz), 7.64 (d, 1H, J=7.5Hz), 7.59 (d, 1H, J=7.1Hz), 7.40 (td, 2H, J=7.2,2.0Hz), 7.31-7.34 (m, 3H), 7.29 (d, 1H, J=1.2Hz), 7.04-7.09 (m, 2H), 6.44 (d, 1H, J=3.57Hz), 5.30 (q, 1H, J=5.6Hz), 4.86 (dd, 1H, J=10.7,5.2Hz), 4.64 (dd, 1H, J=10.8,5.2Hz), 4.33 (t, 1H, J=4.7Hz) .1.50 (s, 3H), 1.30 (s, 9H), 1.20 (s, 3H), 1.03 (d, 3H, J=5.6Hz); MS (ESI) m/z 590[M+H]
+
Embodiment 20
5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-2-formonitrile HCN
Under blanket of nitrogen, at 160 ℃ of heating 9H-fluorenes-9-ylmethyl-6-[1-(tertbutyloxycarbonyl)-5-cyano group-1H-pyrroles-2-yls]-2,4,4-trimethylammonium-2H-3, (0.5g 0.84mmol), no longer produces until gas 1-benzoxazine-1 (4H)-carboxylicesters.After being cooled to room temperature, obtain 9H-fluorenes-9-ylmethyl-6-[5-cyano group-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters is white solid (0.4g, 97%).
Under nitrogen and room temperature, stir 9H-fluorenes-9-ylmethyl-6-[5-cyano group-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3, (0.1g, 0.2mmol) solution in the DMF of 20% piperidines (5mL) solution is 10 minutes for 1-benzoxazine-1 (4H)-carboxylicesters.Pour mixture into saturated ammoniumsulphate soln (30mL), with ether (3 * 30mL) extractions.The organic layer that the merges (MgSO that is dried
4), and evaporation.Residue by silica gel column chromatography (hexane: ethyl acetate/3: 1) purifying, obtain title compound, be white solid (0.03g, 56%): mp 201-202 ℃;
1H-NMR (DMSO-d
6) δ 12.27 (s, 1H), 7.44 (d, 1H, J=2.1Hz), 7.32 (dd, 1H, J=8.3,1.1Hz), 6.92 (dd, 1H, J=4.1,2.6Hz), 6.57 (d, 1H, J=8.3Hz), 6.50 (dd, 1H, J=4.2,2.6Hz), 6.40 (s, 1H), 4.77-4.80 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.7Hz); MS (ESI) m/z 266[M-H]
-.
Embodiment 21
9H-fluorenes-9-ylmethyl 6-(5-cyano group-1-methyl isophthalic acid H-pyrroles-2-yl)-2,4,4-trimethylammonium-2H-' 3,1-benzene
Bing oxazine-1 (4H)-carboxylicesters
To 9H-fluorenes-9-ylmethyl-6-[5-cyano group-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters (0.4g, 0.8mmol) and the mixture of salt of wormwood (1.5g) in dry DMF, under blanket of nitrogen, at room temperature use methyl iodide (1.5mL, excessive) to handle.Stirred the mixture 30 minutes.Add saturated ammonium sulphate solution (50mL) and ethyl acetate (50mL).Separate organic layer, (3 * 15mL) extract water layer with ethyl acetate.The organic layer that the merges (MgSO that is dried
4), evaporation obtains title compound, is white solid (0.35g, 87%): mp 63-64 ℃;
1H-NMR (DMSO-d
6) δ 7.90 (m, 2H), 7.62 (d, 1H, J=7.7Hz), 7.58 (d, 1H, J=7.7Hz), 7.40 (m, 2H), 7.29-7.32 (m, 3H), 7.14 (dd, 1H, J=8.1,1.9Hz), 7.01-7.04 (m, 2H), 6.33 (d, 1H, J=4.3Hz), 5.31 (q, 1H, J=5.8Hz), 4.88 (dd, 1H, J=10.8,5.0Hz), 4.65 (dd, 1H, J=10.8,4.6Hz), 4.34 (t, 1H, J=4.6Hz), 3.71 (s, 3H), 1.52 (s, 3H), 1.21 (s, 3H), 1.06 (d, 3H, J=5.4Hz); MS (ESI) m/z 504[M+H]
+.
Embodiment 22
1-methyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-2-formonitrile HCN
According to the program of embodiment 20, with 9H-fluorenes-9-ylmethyl 6-(5-cyano group-1-methyl isophthalic acid H-pyrroles-2-yl)-2,4,4-trimethylammonium-2H-' 3,1-benzoxazine-1 (4H)-carboxylicesters (0.3g, 0.6mmol) and the DMF formulations prepared from solutions of 20% piperidines.White solid (0.07g, 42%): mp 195-196 ℃;
1H-NMR (DMSO-d
6) δ 7.16 (d, 1H, J=2.8Hz), 7.08 (dd, 1H, J=8.1,1.9Hz), 6.98 (d, 1H, J=4.1Hz), 6.63 (d, 1H, J=8.5Hz), 6.61 (s, 1H), 6.20 (d, 1H, J=4.1Hz), 4.79-4.81 (m, 1H), 3.67 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.27 (d, 3H, J=5.5Hz); MS (ESI) m/z 282[M+H]
+.
Embodiment 23
5-(the 2-methylspiro [4H-3,1-benzoxazine-4,1 '-pentamethylene]-the 6-yl)-4 methyl-2-thiophene formonitrile HCN
With preparation 6-bromo-2,4 among the embodiment 13,4-trimethylammonium-1,4-dihydro-2H-3, the same program of 1-benzoxazine, preparation 2-methyl-6-bromine spiral shell [4H-3,1-benzoxazine-4,1 '-pentamethylene].
Press the program of embodiment 13, with 2-methyl-6-bromine spiral shell [4H-3,1-benzoxazine-4,1 '-pentamethylene] and 5-bromo-4-methyl-2-thiophene formonitrile HCN prepare title compound.Light yellow solid: mp 58-60 ℃;
1H-NMR (DMSO-d
6) δ 7.79 (s, 1H), 7.16 (d, 1H, J=1.9Hz), 7.12 (dd, 1H, J=8.4,2.2Hz), 6.66 (s, 1H), 6.63 (d, 1H, J=8.4Hz), 4.75 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 6H), 1.32 (d, 3H, J=5.5Hz).
Embodiment 24
4-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-pentamethylene]-the 6-yl)-2-thiophene formonitrile HCN
According to the program of embodiment 13, with 2-methyl-6-bromine spiral shell [4H-3,1-benzoxazine-4,1 '-pentamethylene] and 4-bromo-2-thiophene formonitrile HCN be prepared.Beige solid: mp 103-104 ℃.
Embodiment 25
5-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-hexanaphthene]-the 6-yl)-4-methyl-2-thiophene formonitrile HCN
With preparation 6-bromo-2,4 among the embodiment 13,4-trimethylammonium-1,4-dihydro-2H-3, the program that the 1-benzoxazine is identical prepare 2-methyl-6-bromine spiral shell [2H-3,1-benzoxazine-4,1 '-hexanaphthene].
Press the program of embodiment 13, with 2-methyl-6-bromine spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene] and 5-bromo-4-methyl-2-thiophene formonitrile HCN prepare title compound.Brown solid:
1H-NMR (DMSO-d
6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8Hz), 7.14 (dd, 1H, J=8.4,2.2Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=8.2Hz), 4.74 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 (d, 3H, J=5.3Hz); MS (ESI) m/z 337[M-H]
-.
Embodiment 26
4-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-hexanaphthene]-the 6-yl) 2-thiophene formonitrile HCN
According to the program of embodiment 13, with 2-methyl-6-bromine spiral shell [4H-3,1-benzoxazine-4,1 '-hexanaphthene] and 4-bromo-2-thiophene formonitrile HCN be prepared.Brown solid: mp 111-112 ℃;
1H-NMR (DMSO-d
6) δ 8.42 (s, 1H), 8.14 (s, 1H), 7.47 (s, 1H), 7.35 (dd, 1H, J=8.3,1.1Hz), 6.58 (d, 1H, J=8.4Hz), 6.38 (s, 1H), 4.72 (m, 1H), 1.92-2.16 (m, 2H), 1.35-1.75 (m, 8H), 1.31 (d, 3H, J=5.3Hz); MS (ESI) m/z 325[M+H]
+.
Embodiment 27
6-(3-fluorophenyl)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine
Press the coupling program of embodiment 17, with 3-fluorophenyl boric acid and 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3, the 1-benzoxazine is prepared.Yellow solid: mp 139-140 ℃;
1H-NMR (CDCl
3) δ 7.40-7.19 (m, 6H), 7.01-6.94 (m, 1H), 6.72 (d, 1H, J=8.24Hz), 4.90 (q, 1H, J=5.48Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5Hz); MS (ES) m/z 272 ([M+H]
+).
Embodiment 28
6-(3-chloro-phenyl-)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine
Press the coupling program of embodiment 17, with 3-chlorophenylboronic acid and 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3, the 1-benzoxazine is prepared.Orange solids: mp 144-146 ℃;
1H-NMR (CDCl
3) δ 7.50 (t, 1H, J=1.78 Hz), 7.40 (dt, 1H, J=7.61,1.45Hz), 7.33 (t, 1H, J=7.76Hz), 7.29-7.22 (m, 4H) 6.72 (d, 1H, J=8.24Hz), 4.90 (q, 1H, J=5.45Hz), 1.62 (s, 3H), 1.59 (s, 3H), 1.46 (d, 3H, J=5.5Hz); MS (ES) m/z 288/290 ([M+H]
+).
Embodiment 29
6-(3-chloro-4-fluorophenyl)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine
With 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3, and the 1-benzoxazine (3.0g, 11.7mmol), 3-chloro-4-fluorobenzoic boric acid (3.1g, 17.6mmol), four (triphenylphosphines) close palladium (O) (0.67g, 0.59mmol), and yellow soda ash (3.72g, the 35.1mmol) mixture in DME (80mL) and water (40mL) is in 50 ℃, with nitrogen wind drift 15 minutes, then under nitrogen in 85 ℃ of heating 1 hour.Reaction is cooled to room temperature, adds ethyl acetate (200mL).Organic layer, also concentrates with dried over sodium sulfate with salt solution (50mL) washing 1 time with aqueous ammonium chloride solution (50mL) washing 2 times, obtains yellow solid.This solid grinds with ether (25mL) and hexane (25mL), collects by strainer, and dry, form 6-(3-chloro-4-fluorophenyl)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine (1.87g, 35%) is a yellow solid: mp 173-175 ℃;
1H-NMR (DMSO-d
6) δ 7.79 (dd, 1H, J=6.84,2.14Hz), 7.60-7.57 (m, 1H), and 7.43-7.39 (m, 2H), 7.29 (dd, 1H, J=8.12,2.14Hz), 6.62 (d, 1H, J=8.54Hz), 6.40 (s, 1H), 4.79 (q, 1H, J=5.55Hz), 1.53 (s, 3H), 1.48 (s, 3H), 1.28 (d, 3H, J=5.55Hz); MS (ES) m/z 306/308 ([M+H]
+).
Embodiment 30
2-fluoro-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) benzonitrile
Press the coupling program of embodiment 13, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3, the fluorine-based benzonitrile preparation of 1-benzoxazine and 5-bromo-2-.White solid 184-186 ℃;
1H-NMR (DMSO-d
6) δ 8.17 (dd, 1H, J=5.86,3.42Hz), 8.00-7.98 (m, 1H), 7.52 (t, 1H, J=9.28Hz), 7.45 (d, 1H, J=1.95Hz), 7.34 (dd, 1H, J=8.30,1.95Hz), 6.63 (d, 1H, J=8.3Hz), 6.45 (d, 1H), 4.8 (q, 1H, J=5.37Hz), 1.53 (s, 3H), 1.49 (s, 3H), 1.29 (d, 3H, J=5.37Hz); MS (ES) m/z 297 ([M+H]
+).
Embodiment 31
4-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-2-furans formonitrile HCN (furonitrile)
Press the coupling program of embodiment 13, with 6-bromo-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyano group furans are prepared.Light brown solid: mp 116-118 ℃;
1H-NMR (DMSO-d
6) δ 8.43 (s, 1H), 8.06 (s, 1H), 7.38 (d, 1H, J=1.98Hz), 7.25 (dd, 1H, J=7.93,1.98Hz) 6.58 (d, 1H, J=7.93Hz), 6.37 (s, 1H), 4.77 (q, 1H, J=5.55Hz), 1.50 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.55Hz); MS (ES) m/z 269 ([M+H]
+C
16H
16N
2O
2Analytical value: C, 71.62; H, 6.01, N, 10.44. measured value: C, 71.55; H, 6.26, N, 10.17.
Embodiment 32
3-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-5-fluorine benzonitrile
Under nitrogen, in 80 ℃ the heating 2-(2-amino-5-bromo-phenyl)-propan-2-ols (5g, 21.7mmol), trifluoro acetaldehyde methyl hemiacetal (5mL), and the mixture of sal epsom (10g) in toluene (75mL).After raw material disappeared, by silica-gel plate filtering reaction thing, filtrate was used dried over sodium sulfate, and concentrated, and formed 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1, and 4-dihydro-2H-3, the 1-benzoxazine is amorphous solid:
1H-NMR (DMSO-d
6) δ 7.31 (d, 1H, J=1.99Hz), 7.19 (dd, 1H, J=8.73,2.38Hz), 6.88 (s 1H), 6.74 (d, 1H, J=8.33Hz), 5.32 (m, 1H), 1.52 (s, 6H).
With 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine (0.5g, 1.61mmol), 3-cyano group-5-fluorobenzoic boric acid (0.39g, 1.8mmol), four (triphenylphosphines) close palladium (O) (0.2g, 0.161mmol), and yellow soda ash (0.5g, 4.83mmol) mixture in DME (50mL) and water (25mL), 50 ℃ with nitrogen wind drift 15 minutes, then under nitrogen in 85 ℃ of heating 1 hour.Reaction mixture is cooled to room temperature, adds ethyl acetate (200mL).Organic layer with salt solution (20mL) washing once, is used dried over sodium sulfate, and is concentrated with aqueous ammonium chloride solution (20ml) washing 2 times, obtains yellow solid.By rapid column chromatography (silica gel, 5% ethyl acetate/hexane) purifying, obtain 3-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-5-fluorine benzonitrile (0.396g, 73%), be white solid: mp 102-103 ℃;
1H-NMR (DMSO-d
6) δ 8.07 (s, 1H), 7.91 (d, 1H, J=10.7Hz), 7.7 (d, 1H, J=10.7Hz) 7.62 (d, 1H, J=1.98Hz), 7.53 (dd, 1H, J=8.33,1.98Hz), 7.05 (s, 1H), 6.87 (d, 1H, J=8.33Hz), 5.39-5.37 (m, 1H), 1.61 (s, 3H), 1.59 (s, 3H); MS (ES) m/z 349 ([M-H]
-).
Embodiment 33
4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] thiophene-2-formonitrile HCN
Press the coupling program of embodiment 13, with 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and the preparation of 4-bromo-2-thiophene formonitrile HCN.Yellow solid:
1H-NMR (DMSO-d
6) δ 8.43 (s, 1H), 8.19 (s, 1H), 7.54 (d, 1H, J=1.98Hz), 7.46 (dd, 1H, J=8.33,1.98Hz), 6.90 (s, 1H), 6.83 (d, 1H, J=8.33Hz), 5.35 (d, 1H, J=3.57Hz), 1.59 (s, 3H), 1.57 (s, 3H); MS (ES) m/z 337 ([M-H]
-).
Embodiment 34
4-[1-ethanoyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] thiophene
Fen-2-formonitrile HCN
With 4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] (0.25g 0.74mmol) is dissolved among the DMF (10mL) thiophene-2-formonitrile HCN, adds NaH (0.09g, 2.22mmol), stirred the mixture 30 minutes, add then Acetyl Chloride 98Min. (0.079mL, 1.11mmol).After raw material disappears, pour reaction mixture into salt solution (100mL), with ether (150mL) extraction product, with dried over sodium sulfate and concentrated.Residue obtains 4-[1-ethanoyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl by rapid column chromatography (silica gel, 25% ethyl acetate/hexane) purifying] thiophene-2-formonitrile HCN (0.1g, 36%), be amorphous solid:
1H-NMR (DMSO-d
6) δ 8.58 (s, 1H), 8.5 (s, 1H), 7.83-7.80 (m, 2H), 7.64 (d, 1H, J=8.74Hz), 6.42 (q, 1H, J=10Hz), 2.24 (s, 3H), 1.73 (s, 3H), 1.42 (s, 3H).
Embodiment 35
(6 (5-cyano thiophenes-3-yl)-4,4-dimethyl-2-(trifluoromethyl)-2H-3,1-benzoxazine-1 (4H)-yl)
The methyl pivalate
With 4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] (0.30g 0.89mmol) is dissolved among the DMF (10mL) thiophene-2-formonitrile HCN, adds NaH (0.065g, 2.7mmol), stirred the mixture 30 minutes, add then chloroacetic acid tert-butyl ester (0.19mL, 1.3mmol).After raw material disappears, pour reaction mixture into salt solution (100mL), with ether (150mL) extraction product, with dried over sodium sulfate and concentrated.Behind the rapid column chromatography (silica gel, 8% ethyl acetate/hexane), obtain (1-benzoxazine-1 (4H)-yl) methyl pivalate (0.127g, 32%) is amorphous solid for 6 (5-cyano thiophenes-3-yl)-4,4-dimethyl-2-(trifluoromethyl)-2H-3:
1H-NMR (CDCl
3) δ 7.82 (s, 1H), 7.58 (s, 1H), 7.41 (dd, 1H, J=8.33,1.98Hz), 7.25 (d, 1H, J=1.98Hz) 7.10 (d, 1H, J=8.33Hz), 6.79 (d, 1H, J=8.33Hz), 5.66 (d, 1H, J=11.9Hz), 5.38 (d, 1H, J=11.9Hz), 1.72 (s, 3H), 1.55 (s, 3H), 1.18 (s, 9H).
Embodiment 36
3-fluoro-5-(2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine-6-yl) benzonitrile
Press the coupling program of embodiment 13, with 6-bromo-2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine and the preparation of 3-bromo-5-fluorine benzonitrile.White solid:
1H-NMR (DMSO-d
6) δ 8.03 (s, 1H), 7.87 (d, 1H, J=10.7Hz), 7.65 (d, 1H, J=10.7Hz), 7.57 (d, 1H, J=1.98Hz) 7.45 (dd, 1H, J=8.33,1.98Hz), 6.65 (d, 1H, J=8.33Hz), 6.42 (s, 1H), 1.52 (s, 6H), 1.34 (s, 6H); MS (ES) m/z311 ([M+H]
+).
Embodiment 37
4-(2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN
Press the coupling program among the embodiment 13, with 6-bromo-2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyano thiophene are prepared.The amorphous orange solids:
1H-NMR (DMSO-d
6) δ 8.4 (d, 1H, J=1.69Hz), 8.14 (d, 1H, J=1.69Hz), 7.49 (d, 1H, J=2.20Hz), 7.38 (dd, 1H, J=8.43,2.02Hz), 6.61 (d, 1H, J=8.43Hz), 6.26 (s, 1H), 1.49 (s, 6H), 1.32 (s, 6H); MS (ES) m/z 299 ([M+H]
+).
Embodiment 38
5-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-the 4-thiotolene-
The 2-formonitrile HCN
Press the coupling program of embodiment 13, with 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-4-methyl-2-thiophene-formonitrile HCN preparation.Light yellow solid: mp 97-98 ℃;
1H-NMR (DMSO-d
6) δ 7.82 (s, 1H), 7.26 (d, 1H, J=1.7Hz), 7.21 (dd, 1H, J=8.1,2.1Hz), 7.16 (s, 1H), 6.88 (d, 1H, J=8.1Hz), 5.40 (m, 1H), 2.27 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H); MS (ESI) m/z 351[M-H]
-.
Embodiment 39
6-(3-chloro-phenyl-)-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine
Press the coupling program of embodiment 17, with 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and the preparation of 3-chlorophenylboronic acid.Light yellow solid: mp 108-109 ℃;
1H-NMR (DMSO-d
6) δ 7.69 (t, 1H, J=1.7Hz), 7.59 (d, 1H, J=7.8Hz), 7.35-7.50 (m, 3H), 7.32 (dt, 1H, J=8.1,1.1Hz), 6.91 (s, 1H), 6.87 (d, 1H, J=8.4Hz), 5.35 (m, 1H), 1.60 (s, 3H), 1.59 (s, 3H); MS (ESI) m/z 340[M-H]
-.
Embodiment 40
6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-ketone
Use four (triphenylphosphines) of catalytic amount to close palladium (O) and spend the night in the reflux in toluene that contains the water-soluble salt of wormwood of equivalent, with 3-fluorophenyl boric acid and equivalent 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-coupling and finish preparation.Operation is carried out recrystallization with ethanol then in the usual way, obtains gray solid: mp 190-192 ℃.
1H-NMR (DMSO-d
6) δ 10.27 (s, 1H), 7.57 (s, 1H), 7.50 (m, 4H), 7.15 (m, 1H), 6.95 (d, 1H J=8.2Hz), 2.39 (s, 2H), 1.29 (s, 6H); MS (APCI (-)) m/z 268[M-H]
-C
17H
16FNO0.25H
2The analytical value of O: C, 74.57, H, 6.07, N, 5.12. measured value: C, 74.86, H, 5.97, N 5.06.
Embodiment 41
3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-5-fluorine benzonitrile
Allow 6-bromo-4, the coupling in the DMF that refluxes of two (tetramethyl ethylene ketone ester group) two boron [bis (pinacolato) diboron] of 4-quinoline-2-one-and equivalent contains the equivalent yellow soda ash that is dissolved in the minimal amount of water and four (triphenylphosphines) of catalytic amount and closes palladium (O) in DMF.After backflow is spent the night, add equivalent 3-bromo-5-fluorine benzonitrile.And then add the yellow soda ash of another part equivalent, add the same catalyst of additional quantity subsequently.After a few hours of refluxing, filter reaction mixture, and vacuum-drying.Residue is extracted into ethyl acetate, and solution dried over mgso is then filtered, to the filtrate evaporation of circling round once more, formation solid residue.Use ethyl alcohol recrystallization, obtain title compound, be gray solid: mp 249-250 ℃.
1H-NMR (DMSO-d
6) δ 10.32 ((s, 1H), 8.09 (t, 1H, J=1.6Hz), 7.93 (d, 1H, J=12.7Hz) 7.77, (d, 1H, J=8.1Hz), 7.70 (s, 1H), 7.61 (d, 1H J=8.9Hz), 6.95 (d, 1H, J=8.3Hz), 2.40 (s, 2H), 1.30 (s, 6H); MS (APCI (-)) m/z 293[M-H]
-C
18H
15FN
2O1.5H
2The analytical value of O: C, 67.28, H, 5.65, N, 8.72. measured value: C, 67.36, H, 4.90, N s8.44.
Embodiment 42
3-(4,4-dimethyl-2-oxo-1,2,3,4 ,-tetrahydroquinoline-6-yl) benzonitrile
Preparation is by in the usual way, four (triphenylphosphines) of use catalytic amount close palladium (O) and spend the night as catalyzer and in the reflux in toluene that contains the water-soluble salt of wormwood of equivalent, make 3-cyano-phenyl boric acid and equivalent 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-coupling.Carry out recrystallization with ethanol then, obtain gray solid: mp.190-192 ℃;
1H-NMR (DMSO-d
6) δ 10.29 ((s, 1H), 8.17 (s, 1H), 8.00 (d, 1H, J=7.9Hz), 7.77 (d, 1H, J=6.4Hz), 7.65 (m, 2H), 7.55 (d, 1H, J=8.2Hz), 6.97 (d, 1H, J=8.3Hz), 2.40 (s, 2H), 1.30 (s, 6H); MS (APCI (-)) m/z 275[M-H]
-C
18H
16N
2O0.25H
2The analytical value of O: C, 75.77, H, 6.01, N, 9.82. measured value: C, 75.45, H, 5.65, N 9.20.
Embodiment 43
6-(3-chloro-phenyl-)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-thioketones
By to 6-(3-chloro-phenyl-)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-ketone and the equivalent thiophosphoric anhydride mixture in pyridine stirs and reflux spends the night, and is prepared.After vacuum was removed pyridine, with 6N salt acid treatment residue, residue is recrystallization in ethanol, obtains product, is yellow solid: mp.197-198 ℃.
1H-NMR (DMSO-d
6) δ 12.34 (s, 1H), 7.75 (m, 1H), 7.64 (m, 2H), 7.57 (dd, 1H J=9.3 and 2.1Hz), 7.48 (t, 1H, J=7.7Hz), 7.41 (m, 1H), 7.20 (d, 1H, J=8.3 Hz), 3.34 (s, 2H), 1.26 (s, 6H); MS (APCI (-)) m/z 300[M-H]
-C
17H
16The analytical value of ClNS: C, 67.65, H, 5.34, N, 4.64. measured value: C, 67.77, H, 5.57, N 4.54.
Embodiment 44
6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-thioketones
By to 6-(3-fluorophenyl)-4,4-dimethyl-3, the mixture of 4-dihydroquinoline-2 (1H)-ketone and equivalent thiophosphoric anhydride stirs in pyridine, and reflux spends the night and is prepared.Embodiment operates by the front, obtains yellow solid, mp 209-211 ℃.
1H-NMR (DMSO-d
6) δ 12.34 (s, 1H), 7.65 (d, 1H J=2.2Hz), 7.57 (dd, 1H J
1=8.24 J
2=2.2Hz), 7.51 (m, 3H), 7.18 (m, 2H), 2.84 (s, 2H), 1.26 (s, 6H) .MS m/z 284[M-H]
-C
17H
16FINS:C, 71.55, H, 5.65, N, 4.91. measured value: C, 71.18, H, 5.59, N
4.82.
Embodiment 45
3-(4,4-dimethyl-2-sulfo--1,2,3,4 ,-tetrahydroquinoline-6-yl) benzonitrile
Preparation is by to 3-(4,4-dimethyl-2-oxo-1,2,3,4 ,-tetrahydroquinoline-6-yl) benzonitrile and equivalent thiophosphoric anhydride stirring the mixture in pyridine, carries out reflux and spends the night.Embodiment operates by the front, obtains yellow solid: mp 220-223 ℃ dec.
1H-NMR (DMSO-d
6) δ 12.35 (s, 1H), 8.21 (s, 1H), 8.10 (d, 1H, J=6.0Hz), 7.80 (d, 1H, J=7.9Hz), 7.72 (s, 1H), 7.65 (m, 2H), 7.21 (d, 1H, J=8.4Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS (APCI (-)) m/z 291[M-H]
-C
18H
16N
2S3H
2The analytical value of O: C, 62.40, H, 6.40, N, 8.09. measured value: C, 62.12, H, 4.88, N 7.77.
Embodiment 46
3-(4,4-dimethyl-2-sulfo--1,2,3,4-tetrahydroquinoline-6-yl)-5-fluorine benzonitrile
Preparation is by to 3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-5-fluorine benzonitrile and equivalent thiophosphoric anhydride stirring the mixture in pyridine, carries out reflux and spends the night.Embodiment operates by the front, obtains yellow solid: mp.240-242 ℃ of dec.;
1H-NMR (DMSO-d
6) δ 12.37 (s, 1H), 8.13 (s, 1H), 7.98 (dt, 1H, J=10.4 and 5.4Hz), 7.81 (d, 1H, J=8.4Hz), 7.7 (d, 1H, J=1.8Hz), 7.68 (dd, 1H, J=8.3 and 1.9Hz), 7.22 (d, 1H, J=8.3Hz), 2.85 (s, 2H), 1.27 (s, 6H); MSm/z 309[M-H]
-C
18H
15FN
2S0.10H
2The analytical value of O: C, 69.25, H, 4.91, N, 8.97. measured value: C, 69.15, H, 4.74, N 8.75.
Embodiment 47
6-(3-fluoro-phenyl)-2,4,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline
6-bromo-1-(4-methoxyl group-benzyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.
To 6-bromo-4,4-dimethyl-3, (0.5g in THF 1.97mmol) (25mL) solution, adds 60%NaH (0.12g, mineral oil suspension 2.95mmol) to 4-dihydro-1H-quinoline-2-one-.The reaction mixture that forms at room temperature stirred 30 minutes, added 4-methoxy-benzyl chlorine (0.34g, 2.17), reflux 20 hours.Reaction is cooled to room temperature, water cancellation lentamente.After with ethyl acetate extraction, the organic layer (MgSO that is dried
4), evaporation, residue is by chromatography (SiO
23: 7 ethyl acetate/hexane) purifying.Obtain white crystals product (0.35g, 48%); Mp 118-119 ℃,
1H NMR (DMSO-d
6) δ 1.23 (s, 6H), 2.59 (s, 2H), 3.70 (s, 3H), 3.72 (s, 1H), 4.41 (d, 1H, J=5.86Hz), 5.09 (s, 1H), 6.87 (m, 2H), 7.01 (d, 1H, J=8.78Hz), 7.17 (d, 1H, J=8.98Hz), 7.23 (d, 1H, J=8.79), 7.34 (dd, 1H, J=6.59 and 2.2Hz), 7.43 (d, 1H, J=2.2Hz); MS (APCI (+)) [M+H]
+=374/376.
6-(3-fluoro-phenyl)-1-(4-methoxyl group-benzyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-.
To 6-bromo-1-(4-methoxyl group-benzyl)-4 in the ethylene glycol dimethyl ether (50mL), 4-dimethyl-3,4-dihydro-1H-quinoline-2-one-(2.9g, 7.75mmol), K
2CO
3(1.18g, four (triphenylphosphines) of (5.0mL) solution of water 8.53mmol) and catalytic amount close the mixture of palladium, and reflux spends the night.After being cooled to room temperature, mixture ethyl acetate extraction, organic phase NaHCO
3MgSO is used in solution and salt water washing
4Drying concentrates, and uses alcohol crystal, obtains product, is white crystalline material (1.8g, 60%): mp 159-162 ℃,
1H NMR (DMSO-d
6) δ 1.32 (s, 6H), 2.63 (s, 2H), 3.70 (s, 3H), 5.15 (s, 2H), 6.89 (d, 2H, J=11.72Hz), 7.14 (m, 2H), 7.22 (d, 2H, J=8.8Hz), 7.53 (m, 4H), 7.60 (d, 1H, J=2.2Hz); MS (APCI (+)) [M+H]
+=390.
6-bromo-1-(4-methoxyl group-benzyl)-2,4,4-trimethylammonium-1,4-dihydro-quinoline
At room temperature, to 6-(3-fluoro-phenyl)-1-(4-methoxyl group-benzyl)-4,4-dimethyl-3, (1.16g, THF 2.99mmol) (15mL) solution add 1.4M methylmagnesium-bromide (2.6mL to 4-dihydro-1H-quinoline-2-one-, 12.56mmol) solution, the reaction mixture that stirring forms 6 hours.Ethyl acetate extraction is used in the solution with water cancellation, handles with ammonium chloride solution, uses the salt water washing, uses MgSO
4Drying, and concentrate.Product, with 2: 8 hexane/ethyl acetate purifying mixtures and uses below by column chromatography.
To 6-(3-fluoro-phenyl)-1-(4-methoxyl group-benzyl)-2,4,4-trimethylammonium-1,2,3, (0.15g, ethanol 0.39mmol) (35mL) solution add 10%Pd/C to the 4-tetrahydroquinoline, and hydrogenation is 10 hours under 40psi.Remove catalyzer by diatomite filtration, product passes through chromatography purification.Obtain blush liquid.
1H?NMR(DMSO-d
6)δ1.15(d，3H，J＝6.73Hz)，1.21(s，3H)，1.34(m，4H)，1.60(dd，1H，J
1＝10.1，J
2＝2.69，Hz)，3.40(m，1H)，5.95(s，1H)，6.55(d，1H，J＝8.08Hz)，7.01(m，1H)，7.21(dd，1H，J
1＝5.78?J
2＝2.02Hz)，7.35(m，4H)；MS(FI?Pos)[M+H]
+＝270.
Other compounds, comprise 5-(2,4,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-1H-pyrroles-2-formonitrile HCN, 1-methyl-5-(2,4,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-1H-pyrroles-2-formonitrile HCN and 3-fluoro-5-(2,4,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline-6-yl)-benzonitrile etc., can use method for preparing.
Claims (14)
1. following formula: compound, or its pharmacy acceptable salt is characterized in that,
In the formula:
R
1, R
2Be the independent substituting group that is selected from down group: H, C
1-C
6Alkyl, and C
3-C
8Cycloalkyl;
Perhaps R
1And R
2Condense formation:
The saturated volution of 3-8 unit based on carbon;
R
3Be the C that H, 4-p-methoxy-phenyl replace
1-C
6Alkyl or COR
C
R
CBe C
1-C
4Alkyl, or carboxyl-9H-fluorenes-9-base-methyl;
R
4Be H;
R
5Be selected from: (i) or (ii):
(i) have the substituted benzene ring of following structure:
X is selected from down group: halogen, CN or NO
2
Y and Z are the independent substituting groups that is selected from down group: H, halogen, CN or NO
2Or
(ii) skeleton contains 1 heteroatomic 5 yuan of ring: O that are selected from down group, S, or NR
6, and contain 1-2 independent substituting group that is selected from down group: H, CN and C
1-C
3Alkyl;
Condition is the carbon atom connections of these 6 yuan of rings by these 6 yuan of rings;
R
6Be H, COR
FOr C
1-C
3Alkyl; R
FBe C
1-C
4Alkoxyl group;
G
1Be O, NR
7, or CR
7R
8
G
2Be CO, CS, or CR
7R
8
Wherein,
(iii) work as G
1When being O, G
2Be CR
7R
8And
(iv) G
1And G
2Can not all be CR
7R
8
R
7And R
8Be independently selected from: H, C
1-C
6Alkyl, the C that halogen replaces
1-C
6Alkyl.
2. compound as claimed in claim 1 is characterized in that having following formula:
In the formula:
R
1=R
2And be C
1-C
3Alkyl, or R
1And R
2Condense the 3-6 unit saturated volution of formation based on carbon, X is selected from down group: halogen, CN or NO
2
Y be 4 ' or 5 ' position on being selected under the substituting group of group: H, halogen, CN or NO
2
3. compound as claimed in claim 2 is characterized in that, X be CN and Y be 5 '-fluorine.
4. compound as claimed in claim 1 is characterized in that having following formula:
In the formula:
R
1=R
2And being selected from is C
1-C
3Alkyl, or R
1And R
2Condense the 3-6 unit saturated volution of formation based on carbon,
U is O, S, or NR
6,
X ' is selected from CN;
Y ' is selected from H or CH
3
5. compound as claimed in claim 4 is characterized in that U is S, and X ' is that CN and Y ' are H or CH
3
6. compound as claimed in claim 1 is characterized in that, is selected from down group:
6-(3-chloro-phenyl)-2,4,4-trimethylammonium-2-Trifluoromethyl-1,4-dihydro-2H-benzo [d] [1,3] oxazine;
6-(3-chloro-phenyl)-2,2,4,4-tetramethyl--1,4-dihydro-2H-benzo [d] [1,3] oxazine;
6-(3-nitro-phenyl)-2,2,4 ,-trimethylammonium-1,4-dihydro-2H-benzo [d] [1,3] oxazine;
5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN;
3-fluoro-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-benzonitrile;
4-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN;
4-methyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN;
3-[(2R, 4S)-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-5-fluorine benzonitrile;
5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-2-formonitrile HCN;
9H-fluorenes-9-ylmethyl-6-(5-cyano group-1-methyl isophthalic acid H-pyrroles-2-yl)-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters;
1-methyl-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-2-formonitrile HCN;
5-(the 2-methylspiro [4H-3,1-benzoxazine-4,1 '-pentamethylene]-the 6-yl)-4 methyl-2-thiophene formonitrile HCN;
4-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-pentamethylene]-the 6-yl)-2-thiophene formonitrile HCN;
5-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-hexanaphthene]-the 6-yl)-4-methyl-2-thiophene formonitrile HCN;
4-(the 2-methylspiro [2H-3,1-benzoxazine-4,1 '-hexanaphthene]-the 6-yl) 2-thiophene formonitrile HCN;
6-(3-fluorophenyl)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine;
6-(3-chloro-phenyl-)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine;
6-(3-chloro-4-fluorophenyl)-2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine;
2-fluoro-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl) benzonitrile;
4-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-2-furans formonitrile HCN;
3-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-5-fluorine benzonitrile;
4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] thiophene-2-formonitrile HCN;
4-[1-ethanoyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl] thiophene-2-formonitrile HCN;
(6-(5-cyano thiophene-3-yl)-4,4-dimethyl-2-(trifluoromethyl)-2H-3,1-benzoxazine-1 (4H)-yl) methyl pivalate;
3-fluoro-5-(2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine-6-yl) benzonitrile;
4-(2,2,4,4-tetramethyl--1,4-dihydro-2H-3,1-benzoxazine-6-yl) thiophene-2-formonitrile HCN;
5-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine-6-yl]-4-thiotolene-2-formonitrile HCN;
6-(3-chloro-phenyl-)-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine;
Or its pharmacy acceptable salt.
7. compound as claimed in claim 1 is characterized in that, is selected from down group:
6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-ketone;
3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)-5-fluorine benzonitrile;
3-(4,4-dimethyl-2-oxo-1,2,3,4 ,-tetrahydroquinoline-6-yl) benzonitrile;
6-(3-chloro-phenyl-)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-thioketones;
6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2 (1H)-thioketones;
3-(4,4-dimethyl-2-sulfo--1,2,3,4 ,-tetrahydroquinoline-6-yl) benzonitrile;
3-(4,4-dimethyl-2-sulfo--1,2,3,4-tetrahydroquinoline-6-yl)-5-fluorine benzonitrile;
6-(3-fluoro-phenyl)-2,4,4-trimethylammonium-1,2,3,4-tetrahydrochysene-quinoline;
6-(3-chloro-phenyl-)-4-cyclopropyl-1H-quinazoline-2-ketone;
6-(3-chloro-phenyl-)-4-cyclopropyl-1-(4-methoxy-benzyl)-1H-quinazoline-2-ketone;
6-(3-chloro-phenyl-)-4-cyclopropyl-4-methyl-3,4-dihydro-1H-quinazoline-2-ketone;
6-(3-chloro-phenyl-)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-1H-quinazoline-2-ketone;
6-(3-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-1H-quinoline-2-one-;
Or its pharmacy acceptable salt.
8. compound as claimed in claim 1 is characterized in that, is selected from down group:
Tertiary butyl 2-cyano group-5-(2,4,4-trimethylammonium-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrroles-1-carboxylicesters; With 9H-fluorenes-9-ylmethyl-6-[1-(tertbutyloxycarbonyl)-5-cyano group-1H-pyrroles-2-yl]-2,4,4-trimethylammonium-2H-3,1-benzoxazine-1 (4H)-carboxylicesters, or its pharmacy acceptable salt.
9. a pharmaceutical composition is characterized in that, it contains the described compound of claim 1 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier or vehicle.
10. the purposes of the described compound of claim 1 or its acceptable salt is characterized in that, is used to prepare medicine, and this medicine is applied to mammalian object as contraceptive bian.
11. the purposes of the described compound of claim 1 or its acceptable salt is characterized in that, is used to prepare medicine, this medicine is used for the treatment of or prevents the optimum or malignancy disease by the progesterone receptor mediation of mammalian object, wherein G
2Be C=O or CR
7R
8
12. purposes as claimed in claim 11 is characterized in that, described optimum or malignancy disease is selected from: myometrium fibroma, endometriosis, benign prostatauxe; The cancer of uterine mucosa, ovary, mammary gland, colon, prostate gland, pituitary gland and gland cancer, meningioma and other hormone-dependent tumors.
13. the purposes of the described compound of claim 1 or its acceptable salt is characterized in that, is used to prepare medicine, this medicine is used for the treatment of or prevents uterine mucosa, ovary, mammary gland, colon or prostatic cancer and gland cancer, the wherein G of mammalian object
2Be C=S.
14. the purposes of the described compound of claim 1 or its acceptable salt is characterized in that, is used to prepare medicine, this medicine is used to be applied to mammalian object to carry out hormone replacement therapy after the menopause.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30455199A | 1999-05-04 | 1999-05-04 | |
| US09/304,551 | 1999-05-04 | ||
| US09/552,629 | 2000-04-19 | ||
| US09/552,629 US6358948B1 (en) | 1999-05-04 | 2000-04-19 | Quinazolinone and benzoxazine derivatives as progesterone receptor modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1349508A CN1349508A (en) | 2002-05-15 |
| CN1145610C true CN1145610C (en) | 2004-04-14 |
Family
ID=26974097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008070792A Expired - Fee Related CN1145610C (en) | 1999-05-04 | 2000-05-01 | Quinazolinone and benzoxazine derivatives as progesterone receptor modulators |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1145610C (en) |
-
2000
- 2000-05-01 CN CNB008070792A patent/CN1145610C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1349508A (en) | 2002-05-15 |
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