CN1771249A - Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. - Google Patents

Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Download PDF

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CN1771249A
CN1771249A CNA2004800094639A CN200480009463A CN1771249A CN 1771249 A CN1771249 A CN 1771249A CN A2004800094639 A CNA2004800094639 A CN A2004800094639A CN 200480009463 A CN200480009463 A CN 200480009463A CN 1771249 A CN1771249 A CN 1771249A
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oxo
phenyl
diformamide
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W·梅德尔斯基
C·察克拉基迪斯
D·多尔施
B·切赞尼
J·格莱茨
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Merck Patent GmbH
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Abstract

The invention relates to the novel compounds of formula (I), wherein R1, R2 ,and R3 are defined as in claim 1. The inventive compounds inhibit coagulation factor Xa and can be used in the prophylaxis and/or therapy of thrombo-embolic diseases and for treating tumors.

Description

Be used for the treatment of thrombotic 1-N-phenyl-2-N-Phenylpyrrolidine-1,2-dicarboxamide derivatives as coagulation factor xa inhibitors
The present invention relates to formula I compound and pharmaceutically available derivative, salt, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Figure A20048000946300171
Wherein
R represent H, A, A-CO-, Hal ,-C ≡ C-H ,-C ≡ C-A or-C ≡ C-C (=O)-A,
R 1Expression H ,=O, Hal, A, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 2Expression H, Hal or A,
R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA, CN, (CH 2) nOH, (CH 2) nHal, NR 4R 5,=NH ,=N-OH ,=N-OA and/or ketonic oxygen (=O),
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also expression has the alkylidene chain of 3,4 or 5 carbon atoms together, described alkylidene chain also can by A, Hal, OA and/or ketonic oxygen (=CO) replace,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
Target of the present invention is to find the novel cpd with valuable character, and particularly those can be used for preparing the compound of medicine.
Discoverable type I compound and salt thereof have of great value pharmacological property and have good tolerance.Particularly, they show the Xa factor inhibition activity and therefore can be used for opposing and prevention of thromboembolic disorders, for example restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty and intermittent claudication.
Formula I compound of the present invention still is the inhibitor of the proconvertin a factor, the IXa factor and zymoplasm in the blood coagulation cascade.
In EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO 00/71516 aromatic Amidine derivatives with anti-thrombosis function is disclosed for example.The ring-type guanidine that is used for the treatment of thrombotic disease has for example been described in WO 97/08165.For example in WO 96/10022, disclose and had the inhibiting aromatic heterocycle compounds of Xa factor.N-[(amino imino methyl as the replacement of Xa factor inhibitor has been described in WO 96/40679) phenylalkyl] the azaheterocyclyl acid amides.
Other carboxamides derivatives as can be known from WO 02/48099 and WO 02/57236 has been described other pyrrolidin derivatives in WO 02/100830.
Other Hete rocyclic derivatives as can be known from WO 03/045912.
The antithrombotic of compound of the present invention forms and anti-freezing acts on admittedly owing to the restraining effect to the activation blood coagulating protein enzyme that is called Xa factor, or to other the inhibition of activation serine protease (for example the VIIa factor, the IXa factor or zymoplasm).
Xa factor is one of proteolytic enzyme that participates in complicated blood coagulation process.Xa factor promotes that thrombogen is converted into zymoplasm.Zymoplasm is split into fibrin monomer with Fibrinogen, and these monomers are tentatively facilitated thrombosis after crosslinked.The activation of zymoplasm can cause the generation of thrombotic disease.But the inhibition of zymoplasm can suppress to participate in thrombotic fibrinous formation.
For example can be by G.F.Cousins etc. at Circulation 1996,94, the method among the 1705-1712 is measured the restraining effect of zymoplasm.
Therefore, the inhibition of Xa factor can prevent the formation of zymoplasm.
Formula I compound of the present invention and salt thereof are by suppressing the formation that Xa factor participates in the process of setting of blood and therefore suppresses thrombus.
Compound of the present invention is to the inhibition of Xa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example J.Hauptmann etc. is at Thrombosis and Haemostasis1990, and 63, a kind of suitable method has been described among the 220-223.
The inhibition of Xa factor can be by T.Hara for example etc. at Thromb.Haemostas.1994, and 71, the method among the 314-319 is measured.
Proconvertin a is with after tissue factor combines, and starts the exogenous part of coagulation cascade and impels the activation of the X factor and obtain Xa factor.Therefore the formation of the inhibition of VIIa factor prevention Xa factor and the formation of ensuing zymoplasm.
Compound of the present invention is to the inhibition of the VIIa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example H.F.Ronning etc. is at Thrombosis Research1996, and 84, the ordinary method of measuring the inhibition of the VIIa factor has been described among the 73-81.
Factor IXa produces in the inherent coagulation cascade, participates in the activation of the X factor equally and obtains Xa factor.Therefore, the inhibition of the IXa factor can prevent the formation of Xa factor in a different manner.
Compound of the present invention is to the inhibition of the IXa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example J.Chang etc. is at Journal of Biological Chemistry1998, and 273, a kind of suitable method has been described among the 12089-12094.
Compound of the present invention also can be used for treating tumour, tumor disease and/or metastases.T.Taniguchi and N.R.Lemoine are in Biomed.Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer (molecular pathogenesis of carcinoma of the pancreas)) have pointed out the dependency between the development of the tissue factor TF/VIIa factor and various types of cancers among the 57-59.
The publication of below listing has been described TF-VII and the Xa factor inhibitor antitumor action to all kinds tumour:
K.M.Donnelly etc. are at Thromb.Haemost.1998; 79:1041-1047;
E.G.Fischer etc. are in J.Clin.Invest.104:1213-1221 (1999);
B.M.Mueller etc. are in J.Clin.Invest.101:1372-1378 (1998);
M.E.Bromberg etc. are at Thromb.Haemost.1999; 82:88-92.
Formula I compound can be used as active constituents of medicine in people and veterinary drug, especially for treatment and prevention of thromboembolic disorders, for example the restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty, intermittent claudication, venous thrombosis, pulmonary infarction, artery thrombosis, myocardial ischemia, based on thrombotic unsettled angina and apoplexy.
Compound of the present invention also can be used for treatment or the atherosis disease of prevention of arterial, for example coronary artery disease, cerebral arterial disease or peripheral arterial disease.Described compound also can with other thrombolytics combined utilization in myocardial infarction, further prevent inaccessible again after thrombolysis, Percutaneous Transluminal Angioplasty (PTCA) and the crown by-pass operation.
Compound of the present invention also is used for prevention and forms thrombus once more in microsurgery, in addition also as the antithrombotics relevant with artificial organ or in hemodialysis as antithrombotics.
Described compound also is used to clean catheter and the intravital medical assistor of patient, or is used for external preservation blood, blood plasma and other blood products as antithrombotics.Compound of the present invention also can be used for the disease that wherein blood coagulation plays an important role to the process of this disease or represents the pathological root of secondary disease, for example cancer (comprising transfer), inflammatory diseases (comprising sacroiliitis) and diabetes.
Compound of the present invention also can be used for migrainous treatment (F.Morales-Asin etc., Headache, 40,2000,45-47).
In described treatment of diseases, compound of the present invention also with other thrombolysis activity compound combined utilization, for example with t-PA, streptokinase or the urokinase combined utilization of " the former activator of tissue plasminogen " t-PA, modification.Compound of the present invention in described other materials, before or after give.
The recurrence preferred especially and acetylsalicylic acid administration simultaneously forms with the prevention clot.
Compound of the present invention also can be used with platelet glycoprotein acceptor (IIb/IIIa) antagonist combination of anticoagulant.
The present invention relates to formula I compound and salt thereof, relate to the formula I compound of preparation claim 1-10 and the method for available derivative, solvate and steric isomer pharmaceutically thereof, the method is characterized in that:
A) with formula II compound
Wherein R has specified meaning in the claim 1,
Obtain the intermediate carbamate derivative with the chloroformate derivative reaction,
React with formula III-1 compound subsequently,
Wherein
R 1, R 2And R 3Have specified meaning in the claim 1,
And if R 1Expression OH, then described OH group is optional if desired, removes described OH-blocking group subsequently with protected form,
Or
B) with formula IV compound
Figure A20048000946300221
R wherein 2And R 3Have specified meaning in the claim 1,
Obtain the intermediate carbamate derivative with the chloroformate derivative reaction,
React with formula III-2 compound subsequently,
Wherein R and R 1Have specified meaning in the claim 1,
And if R 1Expression OH, then described OH group is optional if desired, removes described OH-blocking group subsequently with protected form,
And/or
Alkali or the sour a kind of salt that is converted into it with formula I.
The invention still further relates to optically active form (steric isomer), enantiomer, racemoid, diastereomer and the hydrate and the solvate of these compounds.The solvate of term compound means the inert solvent molecule and adds and be incorporated on the described compound, and this form is owing to their power that attracts each other.Solvate is for example monohydrate, dihydrate or alcohol adduct.
Term pharmaceutically available derivative means for example salt and the so-called preceding drug compound of The compounds of this invention.
The term prodrug derivant for example means by the formula I compound of alkyl or carboxyl groups, sugar or oligopeptides modification, their in organism rapidly cracking obtain active compound of the present invention.Int.J.Pharm.115 for example, described in the 61-67 (1995), these prodrug derivants also comprise the biodegradable polymer derivant of The compounds of this invention.
The invention still further relates to the mixture of formula I compound of the present invention, the mixture of two kinds of diastereomers for example, for example ratio is the mixture of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000.These are the mixture of particularly preferred Stereoisomeric compounds.
For all appearance group more than once, A for example, their implication is independent of each other.
Unless otherwise indicated, otherwise in context, group or parameters R, R 2And R 3Has specified meaning among the formula I.
A is expressed as the alkyl of branching (straight chain) not or branching, has 1,2,3,4,5,6,7,8,9 or 10 carbon atom.A preferably represents methyl, be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl in addition, also be amyl group, 1-, 2-or 3-methyl butyl, 1 in addition, 1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group, preference is as being trifluoromethyl in addition.
A very particularly preferably represents to have the alkyl of 1,2,3,4,5 or 6 carbon atom, be preferably methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1, the 1-trifluoroethyl.A is the representative ring alkyl also.
The preferred representative ring propyl group of cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.
Alkylidene group is preferably represented methylene radical, ethylidene, propylidene, butylidene, pentylidene or hexylidene, also represents the alkylidene group of branching.
R preferably represent Hal or-C ≡ C-H,
R 1Preferred expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-or cycloalkyl-(CH 2) n-COO-, preferred especially H ,=O or OH.
R 2Preferred expression H, Cl, F or have the alkyl of 1-6 carbon atom, for example methyl, ethyl, propyl group, butyl or trifluoromethyl,
R 3Preferred expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA ,=NH and/or ketonic oxygen (=O), perhaps R 3Also represent CONR 4R 5
R 3Preferred especially expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine (oxazinan)-3-base, 4H-1,4-oxazine-4-base, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl oxadiazole base, thiadiazolyl group, pyridazinyl, pyrazinyl, or CONR 4R 5
In another embodiment, R 3Preferred expression optional by Hal and/or A single-or two replace 2-oxo-piperidine-1-bases, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base.
R3 very particularly preferably represents 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base.
At CONR 4R 5In, NR 4R 5In preferred expression methylamino, dimethylamino, ethylamino, diethylamino, tetramethyleneimine-1-base or piperidino-(1-position only).
Described formula I compound can have one or more chiral centres and therefore occur with multiple stereoisomeric forms in any ratio.Formula I comprises all these forms.
Therefore, The present invention be more particularly directed to the formula I compound that at least one described group wherein has a kind of preferred implication of pointing out above.Several groups of preferred compounds can be expressed as the compound of following minor Ia-Ih and pharmaceutically available derivative, salt, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, these minors are consistent with formula I and wherein do not have more detailed specified group to have meaning specified in formula I, but wherein
In Ia, R represent Hal or-C ≡ C-H;
In Ib, R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA ,=NH and/or ketonic oxygen (=O),
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together;
In Ic, R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl oxadiazole base, thiadiazolyl group, pyridazinyl or pyrazinyl
Or
CONR 4R 5，
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together;
In Id, R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl;
In Ie, R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl oxadiazole base, thiadiazolyl group, pyridazinyl or pyrazinyl
Or
CONR 4R 5，
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together;
In If, R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base;
In Ig, R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base;
In Ih, R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
Formula I compound and preparation raw material thereof are by known method preparation itself, as document (for example in standard textbook, as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry (organic chemistry method)], Georg-Thieme-Verlag, Stuttgart) described in, under the reaction conditions of known and suitable described reaction, carry out exactly.Changing method that also can the known method of use itself carries out, but in this narration in more detail.
If desired, but also thereby original position forms described raw material and need not to separate from reaction mixture, but further be converted into formula I compound immediately.
The starting compound of some formula II, III-1, III-2 and IV is a novel cpd.
Preferred through type II or IV compound and chloroformate derivative (for example chloroformic acid 4-nitro phenyl ester) prepared in reaction formula I compound obtain intermediate carbamate, and react with formula III-1 or III-2 compound subsequently.
Usually in the presence of acid binding agent, in inert solvent, carry out this reaction, described acid binding agent is preferably oxyhydroxide, carbonate, the supercarbonate of basic metal or alkaline-earth metal, or other salt of faintly acid of basic metal or alkaline-earth metal (preferred potassium, sodium, calcium or caesium).It also is favourable adding the phenol composition of organic bases (for example triethylamine, xylidine, pyridine or quinoline), excessive formula II or the alkyl derivative of formula III.According to the condition of using, the reaction times can be several minutes-14 days, and temperature of reaction is about 0 ℃-150 ℃, is generally 20 ℃-130 ℃.
The example of suitable inert solvent has alkane (hexane for example, sherwood oil, benzene, toluene or dimethylbenzene), hydrochloric ether (trieline for example, 1, the 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride), alcohol (methyl alcohol for example, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol), ether (Anaesthetie Ether for example, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox), glycol ethers (for example ethylene glycol monomethyl ether or single ether, glycol dimethyl ether (diglyme)), ketone (for example acetone or butanone), acid amides (ethanamide for example, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF)), nitrile (for example acetonitrile), sulfoxide (for example dimethyl sulfoxide (DMSO) (DMSO)), dithiocarbonic anhydride, carboxylic acid (for example formic acid or acetate), nitro-compound (for example Nitromethane 99Min. or oil of mirbane), the mixture of ester (for example ethyl acetate) or described solvent.
Also can be by removing the blocking group preparation I compound of formula I compound with OH-or NH-blocking group.
The preferred raw material that is used to remove blocking group is consistent with formula I for those; but have corresponding protected amino and/or oh group; rather than the compound of one or more free amine groups and/or oh group; preferred those compounds that have the amido protecting group rather than be connected to the hydrogen atom on the nitrogen-atoms; particularly those have the compound of R '-N group (wherein R ' expression amido protecting group) rather than HN group; and/or those have the compound of the hydrogen atom on hydroxy-protective group rather than the oh group; for example those are consistent with formula I, but have-OR " or-COOR " group (wherein R " expression hydroxy-protective group) rather than-OH or-compound of COOH group.
Also can there be a plurality of identical or different protected amino and/or oh groups in the molecule of raw material.If the blocking group that exists differs from one another, they are optionally removed in many cases.
Term " amido protecting group " is known as general term, relates to being suitable for protection (blocking-up) amino group to avoid chemical reaction, still the group of having removed easily after carry out in the other places of this molecule at required chemical reaction.This type of group generally is specially acyl group, aryl, aralkoxy methyl or aromatic alkyl group unsubstituted or that replace.Because described amido protecting group is removed after required reaction (or serial reaction), their type and size are not vital; But preferably those have 1-20, particularly the group of 1-8 carbon atom.Term " carboxyl groups " should be understood on the wide significance relevant with present method.It comprises by aliphatic series, araliphatic, aromatics or heterocyclic carboxylic acid or sulfonic acid derives and next carboxyl groups, is specially alkoxy carbonyl, aryloxycarbonyl, particularly aromatic alkoxy carbonyl group.The example of this type of carboxyl groups has alkyloyl (for example ethanoyl, propionyl, butyryl radicals), aralkanoyl (for example phenyl acetyl), aroyl (for example benzoyl or tolyl (tolyl)), aryloxy group alkyl acyl group (for example POA), alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl, 2; 2,2-trichlorine ethoxy carbonyl, BOC (tert-butoxycarbonyl) and 2-iodine ethoxy carbonyl), aromatic alkoxy carbonyl (for example CBZ (" carbobenzoxy-(Cbz) "), 4-methoxyl group benzyloxy base carbonyl and FMOC) and aryl sulfonyl (for example Mtr).Preferred amido protecting group is BOC and Mtr, also has CBZ, Fmoc, benzyl and ethanoyl in addition.
Equally, term " hydroxy-protective group " is known as general term, relates to being suitable for protecting oh group to avoid chemical reaction, still the group of having removed easily after carry out in the other places of this molecule at required chemical reaction.This type of group is generally aryl, aralkyl or the carboxyl groups of above-mentioned unsubstituted or replacement, also has alkyl group or alkyl silyl blocking group in addition.Because described hydroxy-protective group is removed behind required reaction or serial reaction, their type and size are not vital; Preferred those have 1-20, particularly the group of 1-10 carbon atom.The example of hydroxy-protective group is in particular benzyl, 4-methoxy-benzyl, p-nitrophenyl formyl radical, p-toluenesulfonyl, the tertiary butyl and ethanoyl, the wherein preferred especially benzyl and the tertiary butyl.If R 1Expression OH, then t-butyldimethylsilyl blocking group very particularly preferably.
According to used blocking group; for example use strong acid (preferably using TFA or perchloric acid), also can use other strong inorganic acid (for example hydrochloric acid or sulfuric acid), strong organic carboxyl acid (for example trichoroacetic acid(TCA)) or sulfonic acid (for example Phenylsulfonic acid or tosic acid) from formula I compound functions derivative, to discharge formula I compound.Also can there be other inert solvents, but always not necessary.The suitable preferred organic solvent of inert solvent, for example carboxylic acid (for example acetate), ether (for example tetrahydrofuran (THF) or diox), acid amides (for example DMF), halohydrocarbon (for example methylene dichloride), in addition pure (for example methyl alcohol, ethanol or Virahol) and water.Be suitable for the mixture of above-mentioned solvent in addition.Preferred excessive use TFA and need not to add other solvents, and perchloric acid preferably uses with the form of mixtures of 9: 1 ratio of acetate and 70% perchloric acid.Described cracked temperature of reaction is preferably about 0 ℃-Yue 50 ℃, is preferably 15-30 ℃ (room temperature).
BOC, OBut and Mtr group can be for example, preferably under 15-30 ℃, use the dichloromethane solution of TFA or use about 3-5N HCl De dioxane solution to remove, and the FMOC group can use the DMF solution of dimethylamine, diethylamine or the piperidines of about 5-50% to remove under 15-30 ℃.
Alkyl silyl blocking group (for example t-butyldimethylsilyl blocking group) for example can use the tetra-n-butyl Neutral ammonium fluoride to remove.
But the blocking group that hydrogenolysis is removed (for example CBZ, benzyl or amidino groups discharge Cong Qi oxadiazole derivative) can be for example, removes by handling with hydrogen under the existence of catalyzer (for example noble metal catalyst (as palladium) is preferably on the carrier (as carbon)).The suitable solvent here is those solvents of pointing out above, and concrete example is as being alcohol (for example methyl alcohol or ethanol) or acid amides (for example DMF).Described hydrogenolysis is preferably carried out under 20-30 ℃, 1-10 crust usually under the pressure of about 0-100 ℃ temperature and about 1-200 crust.The hydrogenolysis of CBZ group for example in the methyl alcohol of 5-10%Pd/C or use ammonium formiate (replacement hydrogen) in methyl alcohol/DMF of Pd/C, is carried out in 20-30 ℃ well.
The example of suitable inert solvent has alkane (hexane for example, sherwood oil, benzene, toluene or dimethylbenzene), hydrochloric ether (trieline for example, 1, the 2-ethylene dichloride, tetrachloromethane, trifluoromethylbenzene, chloroform or methylene dichloride), alcohol (methyl alcohol for example, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol), ether (Anaesthetie Ether for example, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox), glycol ethers (for example ethylene glycol monomethyl ether or single ether, glycol dimethyl ether (diglyme)), ketone (for example acetone or butanone), acid amides (ethanamide for example, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone (NMP) or dimethyl formamide (DMF)), nitrile (for example acetonitrile), sulfoxide (for example dimethyl sulfoxide (DMSO) (DMSO)), dithiocarbonic anhydride, carboxylic acid (for example formic acid or acetate), nitro-compound (for example Nitromethane 99Min. or oil of mirbane), the mixture of ester (for example ethyl acetate) or described solvent.
Ester can be for example under 0-100 ℃ with acetate or saponification in water, water/THF or water/diox with sodium hydroxide or potassium hydroxide.
The free amino group can further pass through conventional method with acyl chlorides or acid anhydrides acidylate, perhaps with haloalkane alkylation or and CH unsubstituted or that replace 3-C (=NH)-and the OEt reaction, reaction is preferably in the inert solvent (for example methylene dichloride or THF) and/or in the presence of alkali (for example triethylamine or pyridine) to be carried out in-60 ℃-+30 ℃.
The alkali usable acid of formula I compound is converted into relevant acid salt, for example the alkali and acid reaction in inert solvent (for example ethanol), evaporation subsequently by making equivalent.The acid of suitable this reaction is in particular the acid that obtains acceptable salt on those physiology.Therefore, can use mineral acid, for example sulfuric acid, nitric acid, haloid acid (for example hydrochloric acid or Hydrogen bromide), phosphoric acid (for example ortho-phosphoric acid), thionamic acid; Also can use organic acid, be specially aliphatic, alicyclic, araliphatic, aromatics or heterocycle monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, Succinic Acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid, ethyl sulfonic acid, ethionic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene list sulfonic acid, naphthalene disulfonic acid, lauryl sulfate.The salt (for example picrate) that forms with unacceptable acid on the physiology can be used for separating and/or purifying formula I compound.
On the other hand, formula I compound available bases (for example sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood) is converted into corresponding metal salt, particularly an alkali metal salt or alkaline earth salt, or makes and be converted into corresponding ammonium salt.
Also can use acceptable organic bases, for example thanomin on the physiology.
Unless otherwise indicated, otherwise following formula III-1, III-2 and the preferred implication of the group of VI compound are consistent with above-mentioned formula I compound.
The invention still further relates to midbody compound and the isomer and the salt of formula III-1,
Figure A20048000946300321
Wherein
R 1Expression H ,=O, Hal, A, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, o-allyl group, o-propargyl, o-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 2Expression H, Hal or A,
R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA, CN, (CH 2) nOH, (CH 2) nHal, NR 4R 5,=NH ,=N-OH ,=N-OA and/or ketonic oxygen (=O),
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also expression has the alkylidene chain of 3,4 or 5 carbon atoms together, described alkylidene chain also can by A, Hal, OA and/or ketonic oxygen (=CO) replace,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
The present invention preferably relates to midbody compound and the isomer and the salt of formula III-1, wherein
R 1Expression H ,=O, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-or cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
The present invention especially preferably relates to midbody compound and the isomer and the salt of formula III-1, wherein
R 1Expression H ,=O or OR 6,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base
R 6Expression alkyl silyl blocking group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
The invention still further relates to midbody compound and the isomer and the salt of formula III-2,
Wherein
R represent H, A, A-CO-, Hal ,-C ≡ C-H ,-C ≡ C-A or-C ≡ C-C (=O)-A,
R 1Expression H ,=O, Hal, A, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4,
Wherein, if R 1Expression H, then R does not represent chlorine.
The present invention also preferably relates to midbody compound and the isomer and the salt of formula III-2,
Wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-or cycloalkyl-(CH 2) n-COO-,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4,
Wherein, if R 1Expression H, then R does not represent chlorine.
The present invention also especially preferably relates to midbody compound and the isomer and the salt of formula III-2,
Wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O or OR 6,
R 6Expression alkyl silyl blocking group,
Hal represents F, Cl, Br or I,
Wherein, if R 1Expression H, then R does not represent chlorine.
In J.Heterocyclic Chem. (1993), 30 (6) 1641-4 and in Pharmazie (1991), 46 (6), compound N-(4-chlorophenyl)-1-pyrrolidine formamide has been described among the 418-22.
The precursor of preparation formula III-1 or III-2 compound is a formula VI compound,
Figure A20048000946300361
Wherein
R 1Have specified meaning among formula III-1 and the III-2,
With
R 7Expression amido protecting group.
Described amido protecting group is preferably represented tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
Prepare wherein R 1The formula VI compound of expression H, for example the pyrrolidine compound of formula VI-1 and VI-2 can adopt the tert-butyl carbazate (tert-butyl carbazane) and 1 of known preparation method from the Z-protection, and the 3-dibromopropane carries out (Dutta, AS. with two-step approach; Morley, J.S.J.Chem.Soc.Perkin Trans 1 1975,1712).
Formula VI compound is a novel cpd, wherein
R 1Expression OH or OR 6,
R 6Expression silyl blocking group,
R 7Expression BOC or Z.
Therefore, the invention still further relates to midbody compound and the isomer thereof of formula VI,
Wherein
R 1Expression OH or OR 6,
R 6Expression silyl blocking group,
R 7Expression tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
Special preferred formula VI compound, wherein
R 6The expression t-butyldimethylsilyl.
Be similar to following flow process, can be directly by 1 of tert-butyl carbazate and silyl protection, 3-two bromo-2-propyl alcohol prepare described compound with single stage method.Free OH compound can not successfully carry out this reaction.
If desired, adopt known method to remove the silyl blocking group, for example use the tetra-n-butyl Neutral ammonium fluoride.
The invention still further relates to the method for preparation formula VI compound and isomer thereof,
Wherein
R 1Expression OH or OR 6,
R 6Expression silyl blocking group,
R 7Expression tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z),
Can be by formula VII compound
R 7-NHNH 2 VII
R wherein 7Expression BOC or Z,
With 1 of silyl protection, 3-two bromo-2-propyl alcohol prepared in reaction,
And optional this blocking group of removing subsequently.
The method of special preferred preparation formula VI compound, wherein
R 6The expression t-butyldimethylsilyl.
Therefore formula I compound of the present invention different enantiomeric forms can occur because their molecular structure can be chirality.Therefore they can exist with racemic form or with the form of optically active form.
Because the racemic modification of compound of the present invention or the pharmaceutical active of steric isomer may be different, may need to use these enantiomers.In these cases, end product or even intermediate can by chemistry well-known to those skilled in the art or physical method for separation be the enantiomerism compound or even former state be used to synthesize.
Under the situation of racemic amines, by forming diastereomer by described mixture with the reaction of optically-active resolving agent.The example of suitable resolving agent has opticity acid; the for example R and the S form of the amino acid (for example N-benzoyl proline(Pro) or N-benzenesulfonyl proline(Pro)) of tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, suitable N-protected, or various opticity camphorsulfonic acid.Be preferably in also that chromatography splits the enantiomerism liquid solution under the help of optically-active resolving agent (for example other derivatives of dinitrobenzoyl phenylglycocoll, cellulosic triacetate or carbohydrate or be fixed on chirality deutero-methacrylate polymers on the silica gel).The eluent of suitable this purpose is water or alcoholic solvent mixture, hexane/isopropyl alcohol/acetonitrile for example, and for example ratio is 82: 15: 3.
The invention still further relates on formula I compound and/or its physiology acceptable salt at preparation medicine (medicinal compositions), particularly prepare purposes in the medicinal compositions by method non-chemically.They can change into suitable formulation with at least a solid, liquid and/or semi-fluid vehicle or auxiliary at this, and can be used in combination one or more other activeconstituentss if desired.
The invention still further relates to and contain at least a formula I compound and/or its pharmaceutically available derivative, solvate and steric isomer and the optional vehicle and/or the medicine of auxiliary, described steric isomer comprises the mixture of its all ratios.
These compositions can be used for people or veterinary drug.Suitable vehicle for (for example oral), parenteral or topical in the suitable intestines not with the organic or inorganic thing of described novel cpd reaction, for example water, vegetables oil, phenylcarbinol, aklylene glycol, polyoxyethylene glycol, triacetin, gelatin, carbohydrate (for example lactose or starch), Magnesium Stearate, talcum, Vaseline.The formulation of suitable for oral administration administration is in particular tablet, pill, coating tablet, capsule, powder, granule, syrup, fruit juice agent or drops, the formulation of suitable rectal administration is a suppository, the formulation of suitable parenteral admin is a solution, preferred oil-based or aqueous solution agent, also have suspensoid, emulsion or implant, and the formulation of suitable topical application is ointment, emulsifiable paste, powder or also is nasal spray.But also lyophilize and the lyophilize thing of gained is used for for example preparing injection formulations of described novel cpd.Above-mentioned composition can be sterilized and/or be comprised auxiliary, the for example salt of lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, adjusting osmotic pressure, cushion, tinting material, seasonings and/or multiple other activeconstituentss, for example one or more VITAMIN.
Acceptable salt can be used for opposing and prevention of thromboembolic disorders, for example restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty, intermittent claudication, migraine, tumour, tumor disease and/or metastases on formula I compound and the physiology thereof.
Usually, preferably with the about 1-500mg of every dose unit, the dosage that is in particular 5-100mg gives material of the present invention at this.Per daily dose is preferably about 0.02-10mg/kg body weight.But, each patient's concrete dosage depends on many factors, for example depends on effect, age, body weight, general health situation, sex, diet, the number of times of administration and the seriousness of method, discharge rate, drug combination and the applied disease specific of this treatment of the particular compound of use.The preferred oral administration.
The invention still further relates to and contain pharmaceutically medicine of available derivative, solvate and steric isomer and at least a other drug activeconstituents of at least a formula I compound and/or its, described steric isomer comprises the mixture of its all ratios.
The invention still further relates to the packed medicament of forming by the independent packing of following substances (kit) (set (kit)):
(a) pharmaceutically available derivative, salt, solvate and steric isomer of the formula I compound of significant quantity and/or its, described steric isomer comprises the mixture of its all ratios,
With
(b) the other drug activeconstituents of significant quantity.
Described packed medicament comprises suitable container, for example box, independent bottle, sack or ampoule.This packed medicament can for example comprise independent a plurality of ampoules, each ampoule contains the formula I compound of significant quantity and/or its pharmaceutically available derivative, salt, solvate and steric isomer and the dissolving of significant quantity or the other drug activeconstituents of lyophilized form, and described steric isomer comprises the mixture of its all ratios.
The invention still further relates to pharmaceutically available derivative, salt, solvate and steric isomer purposes in the medicine of the following disease of preparation treatment of the formula I compound that is used in combination with at least a other drug activeconstituents and/or its: the restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty, intermittent claudication, migraine, tumour, tumor disease and/or metastases, described steric isomer comprises the mixture of its all ratios.
In context, all temperature are all ℃ to provide.In following examples, " conventional aftertreatment " means and adds entry when needing, regulate pH to 2-10 when needing, composition according to end product, with ethyl acetate or the described mixture of dichloromethane extraction, separate each phase, organic phase is also evaporated through dried over sodium sulfate, and by chromatography and/or recrystallization purifying product on silica gel.Rf value on silica gel; Eluent: ethyl acetate/methanol is 9: 1.
Mass spectrum (MS): EI (Electron Impactionization) M +
ESI (electron spray ionisation) (M+H) +(unless otherwise indicated)
Embodiment 1
The 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide (" A1 ")
Step 1
2-[3-chloro-4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-1-t-butyl formate:
340mg (1.5mmol) 4-(4-amino-2-chlorophenyl) morpholine-3-ketone is dissolved in the 10ml methylene dichloride (DCM), then add 302mg (1.5mmol) chloroformic acid 4-nitro phenyl ester and 121 μ l (1.5mmol) pyridines successively, this mixture at room temperature stirred 1 hour subsequently.In this reaction mixture, add 300.0mg (0.7mmol) tetramethyleneimine-1-t-butyl formate and 0.765mg (4.5mmol) N-ethyl diisopropylamine.After at room temperature stirring 20 hours, this mixture is carried out conventional aftertreatment, obtain the product of 420mg (57.3%) step 1; MS (FAB) m/e=425/427 (M+H) +
Step 2
N-[3-chloro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1-methane amide:
The product of 410mg (0.84mmol) step 1 is dissolved in the 5ml diox, adds 5ml (20mmol) 4M HCl De dioxane solution subsequently.Stir after 5 hours under the room temperature, this mixture is carried out conventional aftertreatment, obtain the product of 330mg (productive rate Y=91.5%) step 2.MS(FAB)m/e＝325/327(M+H) +。
Step 3
84.3mg (0.7mmol) 4-ethynyl aniline is dissolved among the 10ml DCM, then adds 140.7mg (0.7mmol) chloroformic acid 4-nitro phenyl ester and 56.4 μ l (0.7mmol) pyridines successively, this mixture at room temperature stirred 1 hour subsequently.The product and 0.475ml (2.8mmol) the N-ethyl diisopropylamine that in this reaction mixture, add 300.0mg (0.7mmol) step 2.After the stirring at room 20 hours, this mixture is carried out conventional aftertreatment.Residue EA recrystallization, obtaining 170mg (productive rate Y=50.6%) is crystalline " A1 "; MS (FAB) m/e=468/470 (M+H) +
Prepare following compound similarly:
1) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide (" A2 "), M+H +478,480;
2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +438,440;
3) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +458,460;
4) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +462,464;
5) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +472,474;
6) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +502,504;
7) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-oxo-pyrrolidine base) phenyl] tetramethyleneimine-1, the 2-diformamide;
8) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-oxo-tetramethyleneimine-1, the 2-diformamide;
9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-piperidine) phenyl] tetramethyleneimine-1,2-diformamide, M+H +442,444;
10) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +444,446;
11) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +462,464;
12) 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +536,538;
13) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +468,470;
14) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1,3-oxa-piperidine-3-yl) phenyl] tetramethyleneimine-1,2-diformamide, M+H +444,446;
15) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
16) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
17) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1,2-diformamide (" A3 "), M+H +483.
Embodiment 2
The 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide (" B1 ")
Step 1
(2-bromo-1-brooethyl oxyethyl group)-tertiary butyl dimethylsilane:
With 26.7g (122.4mmol) 1,3-two bromo-2-propyl alcohol are dissolved among the 150ml DCM, add 18.35g (269.59mmol) imidazoles subsequently.The 150ml DCM solution that dropwise adds 18.47g (122.54mmol) TERT-BUTYL DIMETHYL CHLORO SILANE subsequently.This mixture was at room temperature stirred 18 hours, carry out conventional aftertreatment, obtain the colorless oil of crude product 39.1g (productive rate Y=95.9%) step 1, be directly used in step 2.
Step 2
4-(t-butyldimethylsilyloxy base) tetramethyleneimine-1-t-butyl formate:
9.87g (246.6mmol) sodium hydride (60%) is suspended among the 50ml DMF.The 100ml DMF solution (a large amount of foams are arranged) that dropwise adds 15.5g (117.4mmol) tert-butyl carbazate subsequently.After the stirring at room 2 hours, dropwise add the product of 39.0g (117.5mmol) step 1, this mixture at room temperature stirred 18 hours subsequently.Carry out conventional aftertreatment, the brown that obtains 30.2g (productive rate Y=85%) step 2 is slightly oily, is directly used in step 3.
Step 3
4-(t-butyldimethylsilyloxy base)-2-(4-chlorophenyl formamyl) tetramethyleneimine-1-t-butyl formate:
The product of 30.1g (99.8mmol) step 2 is dissolved among the 200ml DCM, adds 15.3g (99.8mmol) isocyanic acid 4-chloro phenyl ester subsequently, this mixture at room temperature stirred 5 hours subsequently.This thick product washes with water, uses dried over sodium sulfate, and this solid of filtering is evaporated to this mixture dried subsequently.Obtain the product (productive rate Y=51%) of 23.4g step 3 with the PE/EA=8/2 silica gel column chromatography.
Step 4
N-(4-chlorophenyl)-4-(t-butyldimethylsilyloxy base) tetramethyleneimine-1-methane amide:
25.0ml (13.0mmol) trifluoroacetic acid is dropwise added in the 50ml DCM solution of product of 10.2g (22.4mmol) step 3, this mixture at room temperature stirred 1 hour subsequently.Carry out conventional aftertreatment, obtain the product of 7.8g (98%) step 4; MS (FAB) m/e=356/358 (M+H) +
Step 5
The 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-(t-butyldimethylsilyloxy base) tetramethyleneimine-1, the 2-diformamide:
145.3mg (0.68mmol) 1-(4-aminophenyl)-2H-pyridin-2-ones is dissolved among the 2mlDCM, then add 157.2mg (0.78mmol) chloroformic acid 4-nitro phenyl ester and 62.96 μ l (0.78mmol) pyridines successively, this mixture at room temperature stirred 1 hour subsequently.The product, 0.4ml (2.3mmol) N-ethyl diisopropylamine and the 2ml THF that in this reaction mixture, add 277.6mg (0.78mmol) step 4.After the stirring at room 18 hours, this mixture is carried out conventional aftertreatment, obtain the product of 330mg (productive rate Y=74.5%) step 5; MS (FAB) m/e=568/570 (M+H) +
Step 6
“B1”：
The product of 330mg (0.58mmol) step 5 is dissolved among the 4.0ml THF, adds 250.0mg (0.8mmol) tetra-n-butyl Neutral ammonium fluoride subsequently under the stirring at room, under this temperature, continue subsequently to stir 1 hour.This mixture dilute with water adds 1N HCl solution subsequently.Vacuumize down the precipitation of this deposit of filtering, washing is also dry, obtains the crystal " B1 " of 190mg (productive rate Y=72%); MS (FAB) m/e=454/456 (M+H) +
Prepare following compound similarly:
1) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +460,462;
2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-piperidine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +458,460;
3) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +474,476;
4) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-oxo-pyrrolidine base) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +458,460;
5) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +478,480;
6) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +494,496;
7) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(2-oxo-pyrrolidine base) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +478,480;
8) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +488,490;
9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +488,486;
10) 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +552,553;
11) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1,2-diformamide, M+H +518,520;
12) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
13) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
14) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
15) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
16) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
17) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
18) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
19) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
20) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
21) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
22) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
23) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide.
Embodiment 3
With 1 normal following oxy-compound:
1) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
2) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
3) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
4) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
5) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
6) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
7) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
8) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
9) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
10) in DCM, react under the room temperature with under the normal required acyl chlorides room temperature of 1.1-1.5,, obtain following compound through after the conventional aftertreatment:
11) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-acetoxyl group tetramethyleneimine-1, the 2-diformamide,
12) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-benzyloxycarbonyl group oxygen base tetramethyleneimine-1, the 2-diformamide,
13) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-benzoyloxy tetramethyleneimine-1, the 2-diformamide,
14) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-tertiary butyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
15) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-isobutyl-ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
16) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclohexyl methyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
17) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclopentylcarbonyl oxygen base tetramethyleneimine-1, the 2-diformamide,
18) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-cyclopropyl methyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
19) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclobutyl carbonyl oxygen base tetramethyleneimine-1, the 2-diformamide.
14. the embodiment of preparation midbody compound
14.1 with all compounds of following formula VI (wherein R=H or methyl; N=3,4 or 5) can carry out according to following flow process.
Figure A20048000946300481
For example synthetic 1-(4-amino-2-methyl phenyl) piperidines-2-ketone:
14.2 the Phenylpiperidine ketone unit of synthetic no methyl group:
Preparation 1-as follows (4-amino-2-methyl phenyl) piperidines-2-ketone:
Figure A20048000946300493
14.3 1-(4-aminophenyl)-1H-pyrazine-2-ketone
Figure A20048000946300501
14.4 1-(4-amino-2,5-3,5-dimethylphenyl)-piperidines-2-ketone
Figure A20048000946300502
14.5 1-(4-amino-3-aminomethyl phenyl) piperidines-2-ketone
14.6 1-(5-aminopyridine-2-yl) piperidines-2-ketone
14.7 1-(4-aminomethyl phenyl) piperidines-2-ketone
14.8 2-(4-aminophenyl)-2-azabicyclic [2.2.2] suffering-3-ketone
14.9 1-(3-amino-6-ethylphenyl) pyrrolidin-2-one
Figure A20048000946300522
14.10 2-(4-amino-2-trifluoromethyl)-2-azabicyclic [2.2.2] suffering-3-ketone
Figure A20048000946300531
14.11 1-(4-amino-3-chlorophenyl) pyrrolidin-2-one
Figure A20048000946300532
14.12 1-(4-amino-2-trifluoromethyl) piperidines-2-ketone
Figure A20048000946300541
14.13 3-(4-amino-2-methyl phenyl)-1,3-oxa-piperidine-2-ketone
Figure A20048000946300542
14.14 4-(4-aminophenyl) morpholine-3-ketone
Figure A20048000946300551
14.15 1-(4-aminophenyl) pyridin-2-ones
14.16 1-(4-amino-2-methyl phenyl) piperidines-2-ketone
Figure A20048000946300553
14.17 1-(4-aminophenyl)-1H-pyridine-4-ketone
Figure A20048000946300561
14.18 1-(4-aminophenyl)-4-tert-butoxycarbonyl piperazine-2-ketone
14.19 1-(3-aminophenyl) piperidines-2-ketone
Figure A20048000946300563
14.20 1-(4-aminophenyl)-2-hexanolactam
Figure A20048000946300571
14.21 1-(4-amino-3-fluorophenyl) piperidines-2-ketone
Figure A20048000946300572
14.22 1-(4-amino-2-fluorophenyl) piperidines-2-ketone
Figure A20048000946300573
14.23 1-(4-amino-2-fluorine)-2-hexanolactam
Figure A20048000946300581
Pharmacology data
Avidity to acceptor
Table 1
Compound number FXa-IC 50[nM] TF/FVIIa-IC 50[M]
“A1” 75.0 160.0
“A2” 120.0 250.0
“A3” 55.0 120.0
Following examples relate to medicinal compositions:
Embodiment A: injection phial agent
With 2N hydrochloric acid with the activeconstituents of 100g formula I and 5g Sodium phosphate dibasic the solution in 3 liters of distilled waters regulate pH to 6.5, sterile filtration is transferred in the injection phial, lyophilize and in sealed under aseptic conditions under aseptic condition.Each injection phial contains the 5mg activeconstituents.
Embodiment B: suppository
With the mixture fusion of activeconstituents and 100g soybean lecithin and the 1400g theobroma oil of 20g formula I, in the impouring mould and make its cooling.Each suppository contains the 20mg activeconstituents.
Embodiment C: solution
Activeconstituents, 9.38g NaH with 1g formula I 2PO 42H 2O, 28.48g Na 2HPO 412H 2O and 0.1g benzalkonium chloride prepare solution in the 940ml distilled water.Regulate pH to 6.8 and make solution reach 1L, pass through irradiation sterilization.This solution can be used as eye drops.
Embodiment D: ointment
Activeconstituents with 500mg formula I under aseptic condition mixes with 99.5g Vaseline.
Embodiment E: tablet
The mixture of suppressing activeconstituents, 4kg lactose, 1.2kg yam starch, 0.2kg talcum and the 0.1kg Magnesium Stearate of 1kg formula I with the method for routine obtains tablet, makes every to contain the 10mg activeconstituents.
Embodiment E: coated tablet
Be similar to the embodiment E compressed tablets, the method by routine is carried out dressing with the dressing material of sucrose, yam starch, talcum, tragacanth and dyestuff subsequently.
Embodiment G: capsule
With the method for routine the activeconstituents of 2kg formula I is packed in the hard gelatin capsule, make every capsules contain the 20mg activeconstituents.
Embodiment H: ampulla
With the solution sterile filtration of activeconstituents in 60 liters of distilled waters of 1kg formula I, transfer in the ampoule lyophilize and under aseptic condition in sealed under aseptic conditions.Every ampoule contains the 10mg activeconstituents.

Claims (26)

1. formula I compound and pharmaceutically available derivative, salt, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Figure A2004800094630002C1
Wherein
R represent H, A, A-CO-, Hal ,-C ≡ C-H ,-C ≡ C-A or-C ≡ C-C (=O)-A,
R 1Expression H ,=O, Hal, A, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 2Expression H, Hal or A,
R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA, CN, (CH 2) nOH, (CH 2) nHal, NR 4R 5,=NH ,=N-OH ,=N-OA and/or ketonic oxygen (=O),
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also expression has the alkylidene chain of 3,4 or 5 carbon atoms together, described alkylidene chain also can by A, Hal, OA and/or ketonic oxygen (=CO) replace,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
2. the compound of claim 1 and pharmaceutically available derivative, salt, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R represent Hal or-C ≡ C-H.
3. claim 1 or 2 compound and pharmaceutically available derivative, salt, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by Hal, A, OA ,=NH and/or ketonic oxygen (=O) single-, two-or three replacements,
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together.
4. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-3, described steric isomer comprises the mixture of its all ratios, wherein
R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl oxadiazole base, thiadiazolyl group, pyridazinyl or pyrazinyl
Or
CONR 4R 5，
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together.
5. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-4, described steric isomer comprises the mixture of its all ratios, wherein
R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl.
6. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-5, described steric isomer comprises the mixture of its all ratios, wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base, furyl, thienyl, pyrryl, imidazolyl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, triazolyl, tetrazyl oxadiazole base, thiadiazolyl group, pyridazinyl or pyrazinyl
Or
CONR 4R 5，
R 4, R 5Independent separately expression H or A,
R 4And R 5Also represent to have the alkylidene chain of 3,4 or 5 carbon atoms together.
7. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-6, described steric isomer comprises the mixture of its all ratios, wherein
R 3Expression optional by Hal and/or A single-or dibasic 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base.
8. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-7, described steric isomer comprises the mixture of its all ratios, wherein
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base.
9. one or multinomial compound and pharmaceutically available derivative, salt, solvate and steric isomer among the claim 1-8, described steric isomer comprises the mixture of its all ratios, wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OH, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
10. the compound of claim 1, described compound are selected from the compound of following formula and pharmaceutically available derivative, salt, solvate and steric isomer, and described steric isomer comprises the mixture of its all ratios,
1) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
2) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
3) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
4) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
5) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-piperidine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
6) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl)]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
7) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-oxo-pyrrolidine base) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
8) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
9) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
10) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(2-oxo-pyrrolidine base) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
11) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
12) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
13) 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
14) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
15) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
16) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
17) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
18) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
19) 1-N-[(4-chlorophenyl)]-2-N-{[3-chloro-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
20) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-oxo-pyrrolidine base) phenyl] tetramethyleneimine-1, the 2-diformamide,
21) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-oxo-pyrrolidine-1, the 2-diformamide,
22) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-piperidine) phenyl] tetramethyleneimine-1, the 2-diformamide,
23) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
24) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
25) 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
26) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-azabicyclic [2.2.2] suffering-3-ketone-2-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
27) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1,3-oxa-piperidine-3-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
28) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
29) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
30) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
31) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
32) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
33) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
34) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
35) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
36) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
37) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
38) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
39) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-acetoxyl group tetramethyleneimine-1, the 2-diformamide,
40) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-benzyloxycarbonyl group oxygen base tetramethyleneimine-1, the 2-diformamide,
41) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-benzoyloxy tetramethyleneimine-1, the 2-diformamide,
42) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine 4-yl) phenyl]-4-tertiary butyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
43) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-isobutyl-ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
44) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclohexyl methyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
45) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclopentylcarbonyl oxygen base tetramethyleneimine-1, the 2-diformamide,
46) 1-N-[(4-ethynyl phenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-cyclopropyl methyl ketonic oxygen base tetramethyleneimine-1, the 2-diformamide,
47) 1-N-[(4-ethynyl phenyl)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-4-cyclobutyl carbonyl oxygen base tetramethyleneimine-1, the 2-diformamide,
48) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl] tetramethyleneimine-1, the 2-diformamide,
49) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4-hydroxyl pyrrolidine-1, the 2-diformamide,
50) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(S)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide,
51) 1-N-[(4-bromophenyl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and 4-hydroxyl pyrrolidine-1, the 2-diformamide.
11. one kind prepares the formula I compound of claim 1-10 and the method for available derivative, solvate and steric isomer pharmaceutically thereof, its characteristics are:
A) with formula II compound
Figure A2004800094630010C1
Wherein R has specified meaning in the claim 1,
Obtain the intermediate carbamate derivative with the chloroformate derivative reaction,
Compound with formula III-1 reacts subsequently,
Figure A2004800094630010C2
Wherein
R 1, R 2And R 3Have specified meaning in the claim 1,
And if R 1Expression OH, then described OH group is optional if desired, removes described OH-blocking group subsequently with protected form,
Or
B) with formula IV compound
R wherein 2And R 3Have specified meaning in the claim 1,
Obtain the intermediate carbamate derivative with the chloroformate derivative reaction,
React with formula III-2 compound subsequently,
Figure A2004800094630011C2
Wherein R and R 1Have specified meaning in the claim 1,
And if R 1Expression OH, then described OH group is optional if desired, removes described OH-blocking group subsequently with protected form,
And/or
Alkali or the sour a kind of salt that is converted into it with formula I.
12. one or multinomial compound among the claim 1-10, described compound is as inhibitors of coagulation factor Xa.
13. one or multinomial compound among the claim 1-10, described compound is as the inhibitor of proconvertin a.
14. comprise among at least a claim 1-10 one or multinomial formula I compound and/or its pharmaceutically available derivative, salt, solvate and steric isomer and the optional vehicle and/or the medicine of auxiliary, described steric isomer comprises the mixture of its all ratios.
15. comprise among at least a claim 1-10 pharmaceutically medicine of available derivative, salt, solvate and steric isomer and at least a other drug activeconstituents of or multinomial formula I compound and/or its, described steric isomer comprises the mixture of its all ratios.
16. acceptable salt and the purposes of solvate in the medicine of the following disease of preparation treatment on one or multinomial compound and/or its physiology among the claim 1-10: the restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty, intermittent claudication, migraine, tumour, tumor disease and/or metastases.
17. the packed medicament of forming by the independent packing of following substances (kit):
(a) pharmaceutically available derivative, salt, solvate and steric isomer of or multinomial formula I compound and/or its among the claim 1-10 of significant quantity, described steric isomer comprises the mixture of its all ratios,
With
(b) the other drug activeconstituents of significant quantity.
18 unite among the claim 1-10 of use pharmaceutically available derivative, salt, solvate and steric isomer purposes in the medicine of the following disease of preparation treatment of or multinomial formula I compound and/or its with at least a other drug activeconstituents: the restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty, intermittent claudication, migraine, tumour, tumor disease and/or metastases, described steric isomer comprises the mixture of its all ratios.
19. the midbody compound of formula III-1 and isomer thereof and salt,
Wherein
R 1Expression H ,=O, Hal, A, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 2Expression H, Hal or A,
R 3Expression has saturated, the unsaturated or aromatic heterocycle of monocycle of 1-4 N, O and/or S atom, can not replace or by following group list-, two-or three replacements: Hal, A, OA, CN, (CH 2) nOH, (CH 2) nHal, NR 4R 5,=NH ,=N-OH ,=N-OA and/or ketonic oxygen (=O),
Or CONR 4R 5,
R 4, R 5Independent separately expression H or A,
R 4And R 5Also expression has the alkylidene chain of 3,4 or 5 carbon atoms together, described alkylidene chain also can by A, Hal, OA and/or ketonic oxygen (=CO) replace,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
20. the midbody compound of claim 19 and isomer thereof and salt,
Wherein
R 1Expression H ,=O, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-or cycloalkyl-(CH 2) n-COO-,
Ph represents unsubstituted phenyl,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
21. the midbody compound of claim 20 and isomer thereof and salt,
Wherein
R 1Expression H ,=O or OR 6,
R 2Expression H, Hal or A,
R 3Expression 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base, 4H-1,4-oxazine-4-base
R 6Expression alkyl silyl blocking group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4.
22. the midbody compound of formula III-2 and isomer thereof and salt,
Wherein
R represent H, A, A-CO-, Hal ,-C ≡ C-H ,-C ≡ C-A or-C ≡ C-C (=O)-A,
R 1Expression H ,=O, Hal, A, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-, cycloalkyl-(CH 2) n-COO-, A-CONH-, A-CONA-, Ph-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH ,=N-OA or=CF 2,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4,
Wherein, if R 1Expression H, then R does not represent chlorine.
23. the midbody compound of claim 22 and isomer thereof and salt,
Wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O, OR 6, OA, A-COO-, Ph-(CH 2) n-COO-or cycloalkyl-(CH 2) n-COO-,
Ph represent not replace or by A, OA or Hal single-, two-or trisubstd phenyl,
R 6The expression hydroxy-protective group,
A represents to have not branching, branching or the cyclic alkyl of 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine and/or chlorine,
Hal represents F, Cl, Br or I,
N represents 0,1,2,3 or 4,
Wherein, if R 1Expression H, then R does not represent chlorine.
23. the midbody compound of claim 22 and isomer thereof and salt,
Wherein
R represent Hal or-C ≡ C-H,
R 1Expression H ,=O or OR 6,
R 6Expression alkyl silyl blocking group,
Hal represents F, Cl, Br or I,
Wherein, if R 1Expression H, then R does not represent chlorine.
24. the midbody compound of formula VI and isomer thereof,
Figure A2004800094630016C1
Wherein
R 1Expression OH or OR 6,
R 6Expression silyl blocking group,
R 7Expression tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
25. the method for preparation formula VI compound and isomer thereof,
Figure A2004800094630016C2
Wherein
R 1Expression OH or OR 6,
R 6Expression silyl blocking group,
R 7Expression tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z),
Described compound can be by formula VII compound
R 7-NHNH 2 VII
R wherein 7Expression BOC or Z,
With 1 of silyl protection, the reaction of 3-two bromo-2-propyl alcohol is optionally subsequently removed described blocking group and is obtained.
CNA2004800094639A 2003-04-03 2004-03-09 Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Pending CN1771249A (en)

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