CN1206006A - Novel hexahydro-1,4-diazepine derivative and its salt - Google Patents

Novel hexahydro-1,4-diazepine derivative and its salt Download PDF

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CN1206006A
CN1206006A CN 98116701 CN98116701A CN1206006A CN 1206006 A CN1206006 A CN 1206006A CN 98116701 CN98116701 CN 98116701 CN 98116701 A CN98116701 A CN 98116701A CN 1206006 A CN1206006 A CN 1206006A
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hydrogen
salt
acid
diaza
compound
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古盐裕之
平山复志
石原司
舩津雅志
川崎富久
松本祐三
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

Provided is a compound inhibits anticoagulation based on the acitve coagulation X factor, can be used as preventive and therapeutical agent for the disease caused by coagulation inhibitor, thrombosis or embolism. The compound is hexahydro-1,4-diazepine derivative and its salt represent by the follow formula I, wherein A: phenylene, pyridylene, R1: hydrogen or -C double bonds NH-lower alkyls, X: -CO- or SO2-, Y: bond or lower alkylidenes, R2: -COOH or lower alkyls.

Description

Novel six hydrogen-1,4-diaza _ derivative or its salt
The present invention relates to as medicine, particularly as effective six hydrogen-1,4-diaza _ derivative or its salt that activate blood coagulation X factor inhibitors.
In recent years,, just progressively increase with the thrombotic disease headed by myocardial infarction, cerebral thrombosis, the peripheral arterial thrombosis disease along with Occidentalizing and the aging of population of living habit, in the society to the understanding of the importance for the treatment of these diseases also in raising.
The solid therapy of anti-freezing is the treatment of radiotherapy, anti-platelet therapy and thrombosis and the part in the medical treatment method in the prevention, especially for the anticoagulant of the prevention of thrombosis must show security when the long term administration and suitable anti-freezing solid active.
But, the warfarin potassium that is widely used in the world as unique per os anticoagulant, people are difficult to from control its anti-freezing solidity energy (J.Clinical Pharmacology based on the characteristic of its mechanism of action, 32,196-209,1992/N.Eng.J.Med., 324 (26), 1865-1875,1991), be a kind of medicine that is difficult to use clinically.
Zymoplasm makes Fibrinogen be converted into scleroproein in the final stage of solidifying, to hematoblastic activation with condense very big influence is arranged.But present peroral administration bioavailability is lower, considers (Biomed.Biochim.Acta, 44,1201-1210,1985) from the security aspect, and also not selling on the market can peroral administration thrombin inhibitors.
On the other hand, the activation blood coagulation X factor is to be positioned at exogenous and endogenous solidifies the key enzyme of the junction of two streams of classification successive reaction, it is more effective than Trombin inhibiting to suppress this factor, and has possibility (the THROMBOSIS RESEARCH (19) that suppresses coagulation system specifically, 339-349,1980).
As compound with the effect of the activation blood coagulation X factor, known have amidino groups naphthyl benzene derivative or its a salt (JP-A-5-208946/Thrombosis Haemostasis, 71 (3), 314-319,1994/ThrombosisHaemostasis, 72 (3), 393-396,1994), in addition, WO96/16940 has disclosed amidino groups naphthyl derivatives or its salt that following general formula is represented.
Figure 9811670100031
(in the formula, B is a low-grade alkylidene etc., R 1For hydrogen atom or-A-W-R 4(A is-SO the group of expression 2-etc., W is a singly-bound etc., R 4For can substituted low alkyl group etc.), R 2Be low alkyl group, R 3Be hydrogen atom etc., n is 0 or 1).
Present inventors find, at amidino groups naphthyl methyl with above-claimed cpd constitutional features by in nitrogen-atoms and the structure that phenyl or pyridyl are connected, when this phenyl or pyridyl directly with six hydrogen-1, when the nitrogen-atoms of 4-diaza _ ring connects, six hydrogen-1 that promptly following logical formula I is represented, 4-diaza _ derivative or its salt show good inhibition effect to the activation blood coagulation X factor, thereby have finished the present invention.
That is to say, six hydrogen-1 that the present invention represents about following logical formula I, 4-diaza _ derivative or its salt, and be the medical composition of effective constituent with them, particularly activate blood coagulation X factor inhibitors.
Figure 9811670100041
(symbol has following implication in the formula:
A is phenylene or pyridylidene, R 1For hydrogen atom or-C (=NH)-low alkyl group, X is-CO-or-SO 2-, Y is key or low-grade alkylidene, R 2For-COOH or-the COO-low alkyl group)
In the structure of The compounds of this invention, six hydrogen-1,4-diaza _ basic phenyl (or pyridyl) is connected with the amidino groups naphthyl methyl by nitrogen-atoms, and in the structure of aforementioned known compound, pyrrolidyl (or piperidyl) oxygen phenyl is connected with the amidino groups naphthyl methyl by nitrogen-atoms, and both have significant difference in this.
Compound preferably of the present invention is R 1For-C (=NH)-compound of low alkyl group.
The present invention more relates to and comprises six hydrogen-1, the salt that allows on 4-diaza _ derivative or its pharmacopedics, and the medical composition of the carrier that allows on the pharmacopedics, particularly activation blood coagulation X factor inhibitors wherein.
Below, The compounds of this invention (I) is elaborated.
There is no particular limitation to " rudimentary " in the definition of group in this specification sheets general formula, and expression has a straight chain shape or a chain carbochain of 1～6 carbon atom.
So " low alkyl group " is that carbonatoms is 1～6 alkyl, specifically is meant methyl, ethyl, propyl group, butyl, amyl group, hexyl or their isomer such as sec.-propyl etc., be preferably carbonatoms and be 1～4 alkyl, be more preferably methyl and ethyl.
" low-grade alkylidene " is that carbonatoms is 1～6 a straight chain shape or a chain alkylidene group, specifically be meant methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene or their isomer, be preferably carbonatoms and be 1～3 alkylidene group, be more preferably methylene radical and ethylidene.
The compounds of this invention is according to the difference of substituting group kind, has the geometrical isomer and the tautomer of suitable-anti-(or (E) body and (Z) body) sometimes, sometimes because of having chiral carbon and exist (R) body and (S) body optically active isomer.The present invention includes the mixture of these geometrical isomers, tautomer, optically active isomer and their list from thing.
The compounds of this invention (I) forms acid salt sometimes or forms salt according to the difference of substituting group kind and alkali.Described salt is meant the salt that allows on the pharmacopedics, specifically comprise and mineral acids such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid the acid salt that organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, aspartic acid, L-glutamic acid form; With mineral alkalis such as sodium, potassium, magnesium, calcium, aluminium, salt that organic basess such as methylamine, ethamine, thanomin, Methionin, ornithine form or ammonium salt etc.
And the present invention also comprises various hydrates, solvate and the polymorphic material of The compounds of this invention (I) and salt thereof.
In addition, the present invention is not limited only to the compound of following examples record certainly, comprises all six hydrogen-1,4-diaza _ derivative or its salt that logical formula I is represented.
(preparation method)
Below, the representational preparation method that possesses of The compounds of this invention (I) is described.
Figure 9811670100051
(in the formula, A, R 2, X, Y as previously mentioned, Alk represents low alkyl group, P represents amino blocking group)
The blocking group of the amino that P represents is to be generally used for protecting amino group, and there is no particular limitation to it, for example ,-COO-low alkyl group ,-COO-low alkyl group-aryl, acyl group, low alkyl group ,-low alkyl group-aryl ,-SO 2-Ji etc.
(steps A)
R in the The compounds of this invention 1For the compound (Ia) of hydrogen atom can be by changing nitrile into imido-ester, make itself and amine condensation then and make.
In the presence of hydrogen chloride gas, in-40 ℃～0 ℃ temperature range, make alcohols such as methyl alcohol, ethanol act on nitrile (III), make it change imido-ester into, then, make amine or ammonium salt reactions such as ammonia, volatile salt, ammonium chloride, ammonium acetate.Solvent can use reacting favourable solvent or inert solvent.Inert solvent comprises tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, benzene,toluene,xylene, ethyl acetate, acetone, acetonitrile, methylene dichloride, ethylene dichloride, chloroform, methyl alcohol, ethanol, Virahol or their mixed solvent etc.
Change in the reaction of amidino groups at nitrile, the blocking group of the amino of representing with P is not cut off sometimes.In this case, utilize appropriate means to cut off this blocking group and obtain The compounds of this invention (Ia).
(step B)
R in the The compounds of this invention 1For-C (=NH)-compound (Ib) of low alkyl group can be by in the presence of alkali, the The compounds of this invention (Ia) that abovementioned steps 1 is made reacts with imidate compound and makes.
Previous reaction can be carried out being cooled under the heating condition, can use aforementioned inert solvent.And, as alkali, can use organic basess such as N-methylmorpholine, triethylamine, Trimethylamine 99, pyridine, picoline, lutidine, accelerine, mineral alkalis such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydroxide.
And, compound (Ib) with-when the COO-alkyl combines, as required, can by under the alkaline condition, acidic conditions down or the hydrolysis reaction under the neutrallty condition change carboxyl into.
In the aforementioned hydrolysis reaction, under alkaline condition, can use alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta, can use acid such as Lewis acids such as hydrochloric acid, sulfuric acid, boron trichloride, tosic acid under the acidic conditions, neutrallty condition can use the enzymes such as an alkali metal salt, Iodotrimethylsilane and esterase of halogen ion, mercaptan and selenol of lithium iodide and lithiumbromide etc. and so on down.
Use aforementioned inert solvent, reaction is carried out usually at ambient temperature, but requires sometimes to react under cooling conditions or under the heating condition.In a word, suitably select common method to react.
The above-mentioned The compounds of this invention that makes can pass through known method, for example, extraction, precipitation, partition chromatography, fractional crystallization, recrystallization etc. single from, refining, can make desirable salt by salt-forming reaction commonly used.
In addition, when The compounds of this invention has chiral carbon, have optically active isomer, but these optically active isomers can be by to carry out common methods such as the fractional crystallization of recrystallization and vapor-phase chromatography separated with suitable salt.
(preparation method of starting compound)
Below, the representative preparation method of the starting compound of The compounds of this invention (I) is described.
(in the formula, A, R 2, X, Y and P as previously mentioned, W represents halogen atom or organic sulfonic acid residue, Q represents aldehyde radical)
Method for making 1
This reaction is to make six hydrogen-1, and 4-diaza _ (IV) and oil of mirbane or nitropyridine derivative (V) react, the reaction of synthetic compound (VI).This reaction is identical with common replacement(metathesis)reaction, in solvent-free or aforementioned inert organic solvents, carries out to heating condition or under the reflux condition in room temperature, if necessary, can carry out under the condition that aforementioned mineral alkali exists.And, import amino blocking group again by appropriate means, just can synthesize the compound (VI) that P is the blocking group of amino.
Method for making 2
This reaction is the reaction from the synthetic amine body (VII) of nitro-body (VI).This reaction can be undertaken by the reduction method in the common method, specifically can adopt metals such as having used zinc and tin method, used LiAlH 4Deng the method for metal hydride, used the process of contact reduction of palladium-carbon etc.These reactions can be carried out to heating condition in room temperature in aforementioned inert solvent.
Method for making 3
This reaction is the reductive amination process that compound (VII) and its corresponding aldehyde (VIII) and reductive agent are reacted.Described reductive agent can use sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride etc.This reaction can be in alcohol or aforementioned inert solvent, carries out being cooled under the heating condition (backflows) stirring.
Method for making 4
(a) preparation method of amide compound (IIIa)
X synthesizes for the amination reaction that-amide compound (IIIa) that CO-represents can pass through the reactive derivative (for example, acyl chlorides) of amine (IX) and carboxylic acid in the starting compound (III).Usually, previous reaction can be in aforementioned inert solvent, carries out being cooled under the room temperature, according to the difference of amination reaction kind, can carry out under anhydrous condition, if necessary, also can carry out under the condition that aforementioned bases exists.
(b) preparation method of amine compound (IIIb)
X in the starting compound (III) 1For-SO 2The amine compound (IIIb) of-expression generally can be in the presence of aforementioned bases, reacts by amine (IX) and halo sulfonyl derivative and sulphonic acid anhydride and synthesizes.Previous reaction can be in aforementioned inert solvent, carries out being cooled under the reflux conditions, is preferably the method that suitable selection is suitable for.
Utilize starting compound that aforesaid method makes shown in reference example.
Reference example 1
4-tert-butoxycarbonyl-1-(4-nitrophenyl) six hydrogen-1H-1, the 4-diaza _
Reference example 2
4-tert-butoxycarbonyl-1-(5-nitro-2-pyridyl) six hydrogen-1H-1, the 4-diaza _
Reference example 3
7-[[4-(4-tert-butoxycarbonyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) anilino] methyl]-2-naphthalene nitrile
Reference example 4
[N-[4-(4-tert-butoxycarbonyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-cyano group-2-naphthyl) methyl] sulphonamide] ethyl acetate
Reference example 5
N-[4-(4-tert-butoxycarbonyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-cyano group-2-naphthyl) methyl] ammonia carbonyl ethyl propionate
Reference example 6
[N-[6-(4-tert-butoxycarbonyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) the 3-pyridyl]-N-[(7-cyano group-2-naphthyl) methyl] sulphonamide] ethyl acetate
The compounds of this invention can suppress to activate the blood coagulation X factor specifically, has very strong anti-freezing and acts on admittedly.So as the blood coagulation inhibitor, the prevention and treatment of diseases agent that thrombus or embolism cause is very effective.
In addition, can confirm the inhibition activity of the good activation blood coagulation X factor that The compounds of this invention possesses by test method shown below.
(1) people's activation blood coagulation X factor time of setting test method
People's the activation blood coagulation X factor (コ ス モ バ イ オ company) is dissolved in the 0.05M Tris hydrochloride buffer (pH=7.40), makes 0.05 unit/ml.Take a blood sample with 1/10 volumetrical, 3.8% Trisodium Citrate, with 3000rpm centrifugal treating 10 minutes, in blood plasma 90 μ l that pass through isolating people and physiological saline, add and solidify X factor solution 50 μ l through the medicament 10 μ l and the above-mentioned activation blood coagulation of dissolved dilution, in 37 ℃ of heating 3 minutes, add 20mM CaCl then 2Solution 100 μ l carry out the mensuration of setting time.
That the mensuration of setting time is used is the KC4A of Amelung company.Setting time when setting time 2 times of prolongations consumption (slightly being called CT2) replaces medicament by interpolation 10 μ l physiological saline is calculated.Its result is as shown in table 1.
(2) thrombin of beef time of setting test method
People's Fibrinogen (freeze-dried preparation, シ ゲ マ company) is dissolved in the Tris hydrochloride buffer (pH=7.40) of 0.05M, makes 6mg/ml.Thrombin of beef (the 500IU/ pipe is held the field pharmacy) is dissolved in the physiological saline, makes the thrombin solution of various concentration.In the above-mentioned fibrinogen solution of 100 μ l, add 100 μ l physiological saline, after 3 minutes, add the above-mentioned thrombin solution of 100 μ l, carry out the mensuration of setting time, measure the concentration of the zymoplasm that solidifies in the time of about 20 seconds in 37 ℃ of heating.
Then, in the above-mentioned fibrinogen solution of 100 μ l, add medicament 100 μ l, carry out the mensuration of setting time through the physiological saline dilution.That the mensuration of setting time is used is the KC4A of Amelung company.2 times of setting times prolong the setting time of consumption (slightly being called CT2) when adding 100 μ l physiological saline and calculate.Its result is as shown in table 1.
More than the measurement result of (1) and (2) can confirm that The compounds of this invention can suppress people's the activation blood coagulation X factor specifically, prolong setting time at low concentration, show good blood coagulation resisting function.
Table 1
The embodiment numbering The time of setting test test CT2 (μ M) of people's the activation blood coagulation X factor Thrombin of beef time of setting test test CT2 (μ M)
5 0．111 7．3
8 0．098 35．1
9 0．069 13．3
10 0．089 13．0
Control compound 0．590 ＞100
* Japanese Patent discloses the compound of the flat 5-208946 of communique number embodiment 52
(3) used the external time of setting test method (oral administration) of cynomolgus monkey to utilize stomach tube to make male cynomolgus monkey (3-6kg through fasting more than 12 hours, Ha system リ-) force orally to be dissolved in physiological saline or to be suspended in medicament in 0.5% methocel solution, under no narcosis, sentence 1/10 volumetrical, 3.8% Trisodium Citrate blood sampling 3ml after a period of time from the thigh vein, with 3000rpm centrifugal treating 10 minutes, make separating plasma.Use this blood plasma, by following (a) and method (b) carry out external source be setting time (PT) and endogenous be the mensuration of setting time (APTT).
(a) external source is setting time (PT)
(54mg/ pipe, freeze-dried preparation, オ Le ソ company) is dissolved in the 2.5ml distilled water with tissue thrombokinase, in 37 ℃ of preheatings.Make the above-mentioned blood plasma heating of 50 μ l 1 minute at 37 ℃, add the above-mentioned cytozyme solution of 50 μ l then, carry out the mensuration of setting time.That the mensuration of setting time is used is the KC4A of Amelung company.Setting time when adding 50 μ l physiologic saline for substitute medicines in contrast, this control value is that 1 o'clock relative value is exactly the activity of medicine.
(b) endogenous is setting time (APTT)
At 37 ℃ of active ト ロ Application ボ Off ア ッ Network ス (オ Le ソ company) of heating 50 μ l and the above-mentioned blood plasma of 50 μ l, be added on the 20mM CaCl of 37 ℃ of preheatings then 2Solution 50 μ l carry out the mensuration of setting time.That the mensuration of setting time is used is the KC4A of Amelung company.Setting time when adding the physiologic saline for substitute medicine in contrast, this control value is that 1 o'clock relative value is exactly the activity of medicine.In addition, change dosage and blood sampling time, the dose-dependent of the antagonism solidification that uses the same method and through the time change and measure.
If the oral The compounds of this invention of the results verification of this test has good setting time prolongation effect.
The salt that allows on the The compounds of this invention of representing with logical formula I more than a kind or 2 kinds and its pharmacopedics is that the medical composition of effective constituent has used formulation carrier and vehicle and other additives commonly used, can be modulated into tablet, powder, granula subtilis, granule, capsule, pill, solution, injection, suppository, ointment and patch etc., but per os or non-oral administration.
Human clinical's dosage of The compounds of this invention can be according to patient's decisions such as symptom, body weight, age and sex, and the oral administration amount of being grown up usually 1 day is 0.1～500mg, and non-oral administration amount is 0.01～100mg, can 1 administration also can divide administration several times.
Peroral administration solids composition of the present invention can adopt tablet, powder and granule etc.In these solids compositions, the active substance more than a kind or a kind will mix with a kind of inert diluent at least, for example, and lactose, mannitol, glucose, hydroxypropylcellulose, Microcrystalline Cellulose, starch, polyvinylpyrrolidone, silicic acid, magnesium aluminate.According to common method, except inert diluent, also can comprise other additives in the composition, for example, lubricants such as Magnesium Stearate, disintegrating agents such as glycolic cellulose calcium, stablizers such as lactose, solubilizing agent or solubility promoters such as L-glutamic acid or aspartic acid.If necessary, also can be in gastric solubility or enteric film such as tablet or pill coated outside gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalates.
Peroral administration liquid composition comprises the opacifying agent that allows on the pharmacopedics, solution, suspensoid, syrup, elixir etc., and the general inert diluent that uses comprises Purified Water, ethanol.Except inert diluent, also can comprise auxiliary agent, sweeting agent, correctives, perfume compound, sanitass such as solubilizing agent or solubility promoter, wetting agent suspensoid in the said composition.
Para-oral injection comprises sterile aqueous or non-aqueous solution agent, suspensoid, opacifying agent.The thinner of aqueous solution agent and suspensoid comprises injection distilled water and physiological saline.Water-insoluble solution, suspensoid comprise propylene glycol, polyoxyethylene glycol, olive wet goods vegetables oil, alcohols such as ethanol, polysorbate 80 (trade(brand)name) etc.Also can comprise additives such as isotonic agent, sanitas, wetting agent, emulsifying agent, dispersion agent, stablizer, solubilizing agent or solubility promoter in these compositions.
Below disclosed the preparation example of The compounds of this invention, the preparation method of The compounds of this invention has been specifically described.
Embodiment 1
[N-[4-(4-tert-butoxycarbonyl six hydrogen-1H-1 with reference example 4 gained, the 4-diaza _-the 1-yl) phenyl]-N-[(7-cyano group-2-naphthyl) methyl] sulphonamide] ethyl acetate 5.19g is dissolved in 9ml chloroform and the 9ml alcoholic acid mixing solutions, under stirring this solution is cooled to-20 ℃, import hydrogenchloride then, make solution saturated.After 23 hours, boil off reaction solution in 5 ℃ of stirring reaction liquid.Be dissolved in the 18ml ethanol residue obtained, add the 6.6g ammonium acetate then therein, in stirring at room 28 hours.Boil off reaction solution, refining residue obtained with the ODS column chromatography, used elutriant is an ethanol: water (10: 90).Then, add the hydrochloric acid of a small amount of 1N, lyophilize makes 1.02g[N-[(7-amidino groups-2-naphthyl) methyl]-N-[4-(six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl] sulphonamide] ethyl acetate 2 hydrochlorides.
Operation can make the compound of following examples 2～4 similarly to Example 1.
Embodiment 2
N-[(7-amidino groups-2-naphthyl) methyl]-N-[4-(six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl] malonamic acid ethyl ester 2 hydrochlorides
Embodiment 3
N-[(7-amidino groups-2-naphthyl) methyl]-N-[4-(six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl] ammonia carbonyl ethyl propionate 2 hydrochlorides
Embodiment 4
[N-[(7-amidino groups-2-naphthyl) methyl]-N-[6-(six hydrogen-1H-1, the 4-diaza _-the 1-yl)-the 3-pyridyl] sulphonamide] ethyl acetate 2 hydrochlorides
Embodiment 5
[N-[(7-amidino groups-2-naphthyl) methyl]-N-[4-(six hydrogen-1H-1 that embodiment 1 is made, the 4-diaza _-the 1-yl) phenyl] sulphonamide] ethyl acetate 2 hydrochloride 590mg are dissolved in the 22ml ethanol, (hydrochloride and the 555mg triethylamine of エ チ Le ア セ ト イ ミ デ-ト) were in stirring at room 15 hours to add 680mg second imido acid ethyl ester then.Boil off reaction solution, refining residue obtained with the ODS column chromatography, used elutriant is an ethanol: water (10: 90).Acquisition 118mg[N-[4-(4-acetylimino six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] sulphonamide] ethyl acetate 2 hydrochlorides.
Operation can obtain the compound of following examples 6 and 7 similarly to Example 5.
Embodiment 6
[N-[4-(4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] malonamic acid ethyl ester 2 hydrochlorides
Embodiment 7
[N-[4-(4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] ammonia carbonyl ethyl propionate 2 hydrochlorides
Embodiment 8
The N-[4-that embodiment 5 is made (4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] sulphonamide] ethyl acetate 2 hydrochloride 450mg are dissolved in the 8ml concentrated hydrochloric acid, in stirring at room 14 hours.Boil off reaction solution, be dissolved in the 8ml concentrated hydrochloric acid, in stirring at room 4 hours residue obtained.
Boil off reaction solution, refining residue obtained with the ODS column chromatography, used elutriant is an acetonitrile: water (10: 90).After adding the hydrochloric acid of a small amount of 1N, lyophilize, acquisition 302mg[N-[4-(4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] sulphonamide] acetate 2 hydrochlorides.
Operation can obtain the compound of following examples 9 and 10 similarly to Example 8.
Embodiment 9
N-[4-(4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl) phenyl]-N-[(7-amidino groups-2-naphthyl) methyl] succinamic acid 2 hydrochlorides
Embodiment 10
[N-[6-(4-imido ethyl six hydrogen-1H-1, the 4-diaza _-the 1-yl)-the 3-pyridyl]-N-[(7-amidino groups-2-naphthyl) methyl] sulphonamide] acetate 2 hydrochlorides
Below, the structure of table 2 expression embodiment compound, the physical and chemical character of table 3 expression reference example compound, the physical and chemical character of table 4 and table 5 expression embodiment compound.
Symbol has following implication in the table:
Rf is the reference example numbering, and Ex is the embodiment numbering, and NMR is a nuclear magnetic resonance spectrum, and MS is the mass spectroscopy value, and Et is an ethyl, and Ph is a phenyl, and Py is a pyridyl.
Table 2
Figure 9811670100131
?Ex ?R 1 ?X ?Y ?R 2 A
?1 ?H -SO 2- -CH 2- -COOEt ?Ph
?2 ?H -CO- -CH 2- -COOEt ?Ph
?3 ?H -CO- -CH 2CH 2- -COOH ?Ph
?4 ?H -SO 2- -CH 2- -COOH ?Py
?5 -C(=NH)-CH 3 -SO 2- -CH 2- -COOEt ?Ph
?6 -C(=NH)-CH 3 -CO- -CH 2- -COOEt ?Ph
?7 -C(=NH)-CH 3 -CO- -CH 2CH 2- -COOEt Ph
?8 -C(=NH)-CH 3 -SO 2- -CH 2- -COOH ?Ph
?9 -C(=NH)-CH 3 -CO- -CH 2CH 2- -COOH ?Ph
?10 -C(=NH)-CH 3 -SO 2- -CH 3- -COOH ?Py
Table 3
?Rf Data
1 ?NMR(CDCl 3)δ:1.40(9H,s),1?85-2.10(2H,m),3.19-3.35(2H,m), ????3.58-3.72(6H,m),6.71(2H,d,J=9.5Hz),8.12(2H,d,J=9.5Hz)
2 ?NMR(CDCl 3)δ:1.40(4H,s),1.42(5H,s),1.94-2.00(2H,m),3,27-3.40(2H,m), ????3.57-3.62(2H,m),3.71-3.93(4H,m),6.50(1H,d,J=9.5Hz), ????8.20(1H,dd,J=2.6Hz,9.5Hz),9.04(1H,d,J=2.6Hz)
3 ?NMR(CDCl 3)δ:1.42(9H,s),1.80-2.09(2H,m),3.07-3.55(8H,m),4.47(2H,s), ????6.61(4H,s),7.50-7.71(2H,m),7.82-7.94(3H,m),8.17(1H,s)???????????????????????????
4 ?NMR(CDCl 3)δ:1.26(3H,t,J=7.3Hz),1.31(4H,s),1.39(5H,s),1.75-2.01(2H,m),???????????? ????3.13-3.31(2H,m),3.45-3.57(6H,m),4.04(2H,s),4.35(2H,q,J=7.3Hz), ????5.02(2H,s),6.55(2H,d,J=9.0Hz),7.20(2H,d,J=9,0Hz),7.50-7.92(5H,m), ????8.13(1H,s)
5 ?NMR(CDCl 3)δ:1.26(3H,t,J=7.4Hz),1.35(4H,s),1.41(5H,s),1.86-1.95(2H,m), ????2.40(2H,t,J=6.6Hz),2.64(2H,t,J=6.6Hz),3.20-3.26(1H,m), ????3.29-3.35(1H,m),3.47-3.56(6H,m),4.15(2H,q,J=7.4Hz),5.00(2H,s), ????6.57(2H,d,J=8.8Hz),6.63-6.68(2H,m),7.58(1H,dd,J=1.5Hz,8.5Hz),?????????????????? ????7.59(1H,dd,J=1.5Hz,8.5Hz),7.69(1H,s),7.82(1H,d,J=8.5Hz),??????????????????????? ????7.88(1H,d,J=8．5Hz),8.15(1H,s)
6 ?NMR(CDCl3)δ:1.34-1.41(12H,m),1.84-1.91(2H,m),3.20-3.34(2H,m), ????3.48-3.61(4H,m),3.68-3.72(2H,m),4.06(2H,s),4.35(2H,q,J=6,9Hz), ????5.00(2H,s),6.36(1H,d,J=9.2Hz),7.27-7.39(1H,m), ????7.58(1H,dd,J=1.7Hz,8.6Hz),7.65-7.70(2H,m),7.85(1H,d,J=8.1Hz),????????????????? ????7.88(1H,d,J=8.1Hz),8.13-8.15(2H,m)
Table 4
?Ex Data
?1 ?NMR(DMSO-d 6)δ:1.27(3H,t,J=7.0Hz),2.01-2.07(2H,m),3.03-3.06(2H,m), ????3.11-3.15(2H,m),3.41(2H,t,J=6.0Hz),3,62-3.65(2H,m), ????4.24(2H,q,J=7.0Hz),4.36(2H,s),5.01(2H,s),6.68(2H,d,J=9.2Hz),??????????????????????? ????7.20(2H,d,J=9.2Hz),7.66(1H,dd,J=1.7Hz,8.6Hz), ????7.82(1H,dd,J=1.7Hz,8.6Hz),7.90(1H,s),8.02(1H,d,J=8.6Hz), ????8.10(1H,d,J=8.6Hz),8.49(1H,s),9.27(2H,br),9.31(2H,s),9.52(2H,s)
?2 ?NMR(DMSO-d 6)δ:1.16(3H,t,J=7.0Hz),2.02-2.09(2H,m),3.01-3.06(2H,m), ????3.10-3.15(2H,m),3.28(2H,s),3.43(2H,t,J=7.0Hz),3.63-3.67(2H,m), ????4.04(2H,q,J=7.0Hz),5.03(2H,s),6.69(2H,d,J=9.1Hz),7.00(2H,d,J=9.1Hz), ????7.63(1H,dd,J=1.6Hz,9.6Hz),7.81(1H,dd,J=1.6Hz,8.6Hz),7.87(1H,s), ????8.04(1H,d,J=8.6Hz),8.12(1H,d,J=8.6Hz),8.45(1H,s),9.29(4H,s), ????9.53(2H,s)
?3 ?NMR(DMSO-d 6)δ:1.18(3H,t,J=7.0Hz),1.89-1.96(2H,m),2.35(2H,t,J=7.0Hz), ????2.53(2H,t,J=7.0Hz),2.89(2H,t,J=5.6Hz),3.02(2H,t,J=5.2Hz), ????3.44(2H,t,J=6.2Hz),3.56(2H,t,J=5.2Hz),4.06(2H,q,J=7.0Hz),4.99(2H,s), ????6.67(2H,d,J=9.2Hz),6.99(2H,d,J=9.2Hz),7.61(1H,dd,J=1.6Hz,8.2Hz), ????7.79(1H,dd,J=1.6Hz,8.2Hz),7.84(1H,s),8.01(1H,d,J=8.6Hz), ????8.11(1H,d,J=8.6Hz),8.44(1H,s),9.52(6H,br)
Table 5
?Ex Data
?4 ?NMR(DMSO-d 6)δ:1.27(3H,t,J=7.2Hz),1.92-2.04(2H,m),3.08-3.18(4H,m), ????3.56-3.61(2H,m),3.81-3.85(2H,m),4.24(2H,q,J=7.2Hz),4.47(2H,s), ????5.04(2H,s),6.68(1H,d,J=8.8Hz),7.60(1H,d,J=8.8Hz), ????7.67(1H,dd,J=1.6Hz,8.8Hz),7.81(1H,dd,J=1.6Hz,8.4Hz),7.95(1H,s), ????8.02-8.06(2H,m),8.11(1H,d,J=8.8Hz),8.48(1H,s),8.98(2H,br),9.15(2H,s), ????9.46(2H,s)
?5 ?NMR(DMSO-d 6)δ:1.25-1.29(3H,m),1.79-1.85(2H,m),2.03(2H,s),2.25(1H,s), ????3.47-3.75(8H,m),4.21-4.27(2H,m),4.37(2H,s),5.00(2H,s), ????6.68-6.73(2H,m),7.17-7.21(2H,m),7.62-7.66(1H,m),7.82(1H,d,J=8.8Hz), ????7.90(1H,s),8.03(1H,dd,J=4.0Hz,8.8Hz),8.10(1H,d,J=8.8Hz),8.49(0.4H,s) ????8.51(0.6H,s),8,64(0.6H,s),8.76(0.4H,s),9.29(2H,s),9.33(1H,s), ????9.53(2H,s) MS(m/z):565(M-2HCl+1) +
?6 ?NMR(DMSO-d 6)δ:1.13-1.18(3H,m),1.78-1.85(2H,m),2.03(2H,s), ????2.25(1H,s),3.26(1.4H,s),3.28(0.6H,s),3.48-3.54(4H,m),3.58-3.72(4H,m), ????4.00-4.07(2H,m),5.02(2H,s),6.69-6.73(2H,m),6.69-7.01(2H,m), ????7.60-7.63(1H,m),7.80-7.83(1H,m),7.86(0.7H,s),7.88(0.3H,s), ????8.04(1H,d,J=8.4Hz),8.12(1H,d,J=8.4Hz),8.45(0.3H,s),8.48(0.7H,s), ????8.60(0.7H,bs),8.74(0.3H,bs),9.24(2H,br),9.28(1H,br),9.52(2H,s) MS(m/z):529(M-2HCl+1) +
?7 ?NMR(DMSO-d 6)δ:1.18(3H,t,J=7.0Hz),1.81-1.86(2H,m),2.01(2H,s), ????2.25(1H,s),2.29-2.36(2H,m),2.52-2.57(2H,m),3.50-3.56(3H,m), ????3.58-3.62(1H,m),3.65-3.76(4H,m),4.06(2H,q,J=7.0Hz),4.99(2H,s), ????6.71-6.76(2H,m),6.97-7.02(2H,m),7.56-7.58(1H,m),7.79-7.85(2H,m), ????8.02(1H,d,J=8.6Hz),8.11(1H,d,J=8.6Hz),8.46(0.3H,s),8.49(0.7H,s), ????8.62(0.7H,s),8.76(0.3H,s),9.27(2H,s),9.37(1H,s),9.52(2H,s) MS((m/z):543(M-2HCl+1) +
?8 ?NMR(DMSO-d 6)δ:1.79-1.86(2H,m),2.03(2H,s),2.26(1H,s),3.49-3.79(8H,m), ????4.26(2H,s),5.00(1.4H,s),5.01(0.6H,s),6.70-6.74(2H,m),7.18-7.22(2H,m), ????7.63-7.67(2H,m),7.84-7.90(1H,m),8.02(0.3H,d,J=8.4Hz), ????8.03(0.7H,d,J=8.4Hz),8.10(1H,d,J=8.4Hz),8.54(0.3H,s),8.57(0.7H,s), ????8.75(0.7H,s),8.92(0.3H,s),9.45(2H,s),9.48(1H,s),9.62(0.6H,s), ????9.63(1.4H,s) MS(m/z):537(M-2HCl+1) +
?9 ?NMR(DMSO-d 6)δ:1.80-1.82(2H,m),2.04(2H,s),2.25(1H,s),2.26-2.33(2H,m), ????2.46-2.52(2H,m),3.48-3.75(8H,m),4.99(2H,s),6.71-6.74(2H,m), ????6.99-7.06(2H,m),7.56-7.59(1H,m),7.95-7.82(1H,m),7.86(1H,br), ????8.00(1H,d,J=9.2Hz),8.12(1H,d,J=9.2Hz),8.44(0.3H,s),8.45(0.7H,s), ????8?53(0.7H,br),8.65(0.3H,br),9.17(3H,br),9.47(2H,s),??????????????????????????????????? MS(m/z):515(M-2HCl+1) +
10 ?NMR(DMSO-d 6)δ:1.79-1.83(2H,m),2.12(1.8H,s),2.25(1.2H,s), ????3.53-3.60(2H,m),3.64-3.70(3H,m),3.73-3.82(2H,m),3.84-3.88(1H,m), ????4.39(2H,s),5.04(2H,s),6.79-6.86(1H,m),7.64-7.69(2H,m), ????7.84(1H,dd,J=2.0Hz,10.2Hz),7.94(1H,s),8.01-8.06(2H,m), ????8.12(1H,d,J=11.3Hz),8.53(0.6H,s),8.54(0.4H,s),8.73(0.6H,s), ????8.82(0.4H,s),9.36(2H,s),9.41(0.4H,s),9.43(0.6H,s),9.57(2H,s) MS(m/z):538(M-2HCl+1) +

Claims (3)

1. six hydrogen-1, the salt that allows on 4-diaza _ derivative or its pharmacopedics is characterized in that, represents by following logical formula I,
Figure 9811670100021
Symbol has following implication in the formula:
A represents phenylene or pyridylidene,
R 1The expression hydrogen atom or-C (=NH)-low alkyl group,
X represents-CO-or-SO 2-,
Y represents key or low-grade alkylidene,
R 2Expression-COOH or-the COO-low alkyl group.
2. a medical composition is characterized in that, comprises described six hydrogen-1 of claim 1, the salt that allows on 4-diaza _ derivative or its pharmacopedics, and the carrier that allows on the pharmacopedics.
3. medical composition as claimed in claim 2, its feature also are, are activation blood coagulation X factor inhibitors.
CN 98116701 1997-07-23 1998-07-23 Novel hexahydro-1,4-diazepine derivative and its salt Pending CN1206006A (en)

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JP197587/97 1997-07-23
CN 98116701 CN1206006A (en) 1997-07-23 1998-07-23 Novel hexahydro-1,4-diazepine derivative and its salt

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