CN101654437A - Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds - Google Patents
Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds Download PDFInfo
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Abstract
The present invention relates to a compound of the general formula(I)wherein: R1 is a selected from the group consisting of (C1-C6)alkoxy(C1-C6)alkyl which may be substituted by a (C1-C6)alkoxy, phenyl-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl, (C1-C6)alkoxy or halogen, and naphtyl-(C1-C6)-alkyl,R2 and R3 are both independently hydrogenor halogen,R4 is a biolabile ester forming group,as a pharmaceutically acceptable metal salt, characterized in that the salt is selected from the group consisting of the lithium salt and bivalent metal ion salts such as magnesium, calcium and zinc salts. The invention further relates to a method for the preparation of the above salts, to a pharmaceutical composition comprising the salts of the invention, to the use of these salts in the treatment of hart disorders or hypertension, in the improvement of gastrointestinal blood flow or in the treatment and prophylaxis of cardiac damages induced by adriamycin and comparable anti-cancer drugs and to crystalline S-a-methylbenzylamine salts of the compounds of formula (I) that are useful as an intermediate in the production of the above mentionedsalts.
Description
The application is to be on January 15th, 2003 applying date, application number is 03802391.1 (PCT/EP03/00515), and denomination of invention is divided an application for the Chinese patent application of " solid salt of benzo-aza cycloheptatriene compound and the application in preparation of pharmaceutical compounds thereof ".
The present invention relates to the new salts of one group of following formula: compound,
And their application in preparation of pharmaceutical compounds.
Benzo-aza cycloheptatriene with following formula has been disclosed in EP 0733642, and EP 0830863, WO00/48601 and WO01/03699.EP 0733642 relates to the compound and the acceptable salt of their physiology of formula (I), and relates to the application of described compound aspect Cardiac Insufficiency.EP 0830863, and WO00/48601 and WO01/03699 relate separately to above-claimed cpd and improving the stomach and intestine blood flow, treating hypertension and the application aspect Zorubicin and the caused heart damage of similar cancer therapy drug in treatment and prevention.
Preferred benzo-aza cycloheptatriene is R wherein
1Be styroyl or 1-naphthyl ethyl, R
2And R
3All be hydrogen, R
4It is the compound of biolabile ester group.The proper group that forms biolabile ester comprises (C
1-C
6)-alkyl, on phenyl ring by (C
1-C
6)-alkyl or be connected two (C on the adjacent carbons
2-C
6Optional phenyl or the phenyl-(C that replaces of)-alkylidene chain
1-C
6)-alkyl, on dioxolane by (C
1-C
6)-alkyl is chosen the dioxolane methyl of replacement wantonly or quilt (C on the oxygen methyl
1-C
6Optional (the C that replaces of)-alkyl
2-C
6)-alkyloyloxyethyl methyl.Work as R
4Group is (C
1-C
6During)-alkyl, it is (the C of non-branching preferably
1-C
4)-alkyl.In most preferred, R
4It is ethyl.
In further medicine and clinical development process, found that most preferred has important disadvantages, promptly this compound is a solid foam.Have reproducible, constant bioavailability in order to ensure the active ingredient from solid dosage forms, it is important using all even reproducible variant of active compound.Therefore, for being derived from common uneven material, for example the reproducibility of the compound of solid foam and constant bioavailability always exist query.
It is evident that equally the separate solid foams are very difficult on technical scale.In addition, described compound is water-soluble hardly, and the preparation that therefore prepares the described compound that can be used in intravenous injection (IV) is very difficult.Before the present invention, can only prepare IV preparation (seeing the example II of EP0733642) by corresponding diacid.This means that the compound that is used for the IV preparation must be different from the compound that is used for oral preparations, and this is undesirable for a medical compounds.In further performance history, found that the sodium salt and the solvability of sylvite in water of single acid is far better, but these salt also can only be with the isolated in form of solid foam.
The purpose of this invention is to provide the salt of a kind of general formula (I) compound, the salt of this compound should satisfy following requirement:
It is a) easy on the commercial production scale by crystallization or the pure solid chemical compound of precipitate and separate,
B) sufficiently high solvability is arranged so that make the IV preparation in physiological fluid,
C) have the solid state properties that allows to be prepared into pharmaceutical preparation with standard ancillary compound and standard equipment,
D) the preferred preparation process can significantly not lost chirality and chemical purity.
This purpose can realize that wherein metal ion is lithium ion or divalent-metal ion by the metal-salt of preparation above-mentioned general formula (I) compound.Preferred divalent metal salt is a calcium, magnesium and zinc salt.Calcium salt most preferably.Astoundingly, found that sodium salt and the sylvite mentioned among these salt and the EP0733642 are opposite, have in demand character, can be as them with solid (amorphous) isolated in form, and pH 7.4 etc. the solvability in the seepage flow body higher at least 10 times than corresponding acid.And can prepare divalent salts and can racemize.
In another aspect of this invention, provide a kind of preparation metal-salt, preferred Li
+Or divalence Ca
2+, Mg
2+Or Zn
2+The method of salt.
Astoundingly, have been found that at room temperature that the lithium salts of formula I compound and the divalent metal salt solvability in the low-pole aprotic solvent such as hexanaphthene, toluene, methyl tertiary butyl ether and ethyl acetate is very good.
By the oxyhydroxide of required metal or suitable salt are mixed with the solution or the slurries of formula I compound in above-mentioned low-pole aprotic solvent, can easily obtain salt of the present invention.Perhaps, when the solubleness of the oxyhydroxide of required metal or salt is not enough to begin to react, can in the solution of described organic solvent or slurries, add a spot of water, and added water can be removed by component distillation.In this case, necessary selection and water form the apolar aprotic solvent of azeotrope.For the very bad metal of oxyhydroxide solvability, can be with this metal with b-oxide (Mg (OEt) for example
2) or mixed hydroxides/carbonate (3Zn (OH)
22ZnCO
3) form add.Preferred solvent is methyl tertiary butyl ether or ethyl acetate in the aforesaid method.When in solution, having obtained described salt, can separate as follows: at first remove still the water that exists, subsequently and precipitant mix by component distillation.Precipitant is defined as second kind of liquid, and this liquid is added in the solution to reduce the solubleness of dissolved compound, causes the precipitation/crystallization of this compound and makes the productive rate maximization of product.It is necessary that these two kinds of liquid (original solvents and added precipitation agent) can dissolve each other each other fully with arbitrary proportion.(this method also is used for reducing inorganic salt in the solubleness of the aqueous solution (ALFASSI Z.B. etc., AlChE J.1984, by adding the organic solvent that dissolves each other with water
30, 874-6; MYDLARZ J. etc., J.Chem.Eng.Data 1989,
34, 124-6; MULLIN J.W. etc., Chem.Eng.Process.1989,
26, 93-9).The example of the precipitation agent in the scope of the invention is a linear hydrocarbons.Preferred precipitation agent is linear C
4-C
10Hydrocarbon.Most preferred precipitation agent is a normal hexane.
As if because described in all cases salt all is isolating with the non-crystalline state precipitated form, this throw out all is uniformly in all cases, need to carry out real crystallisation step sometimes to improve the purity that must satisfy the active compound of being strict with.Surprisingly, have been found that the S-α-Jia Jibianji amine salt of formula I compound is suitable for the purifying of these compounds very much, for example described salt is crystal, and can carry out recrystallization with high yield from organic solvent, and described organic solvent is preferably pure as ethanol or Virahol.Therefore, the invention still further relates to the S-α-Jia Jibianji amine salt of formula I compound.Because S-α-Jia Jibianji amine seems toxicity and can not use too greatly, therefore described salt only is suitable as the intermediate in the purification step.
Can come the S-α-Jia Jibianji amine salt of preparation I compound by adding S-α-Jia Jibianji amine in the solution of formula I compound in ethanol or Virahol or other suitable alcohols.After the cooling of this solution left standstill, described salt will crystallize out from solution (according to concentration).
Can prepare pharmacologically acceptable salts of the present invention according to the Recipe of prior art.Can use common dosage forms, for example tablet, capsule or suppository.These pharmaceutical preparations can prepare with known method, for example directly compression, granulation, extrude, molded, adopt conventional solid excipient, for example weighting agent such as Mierocrystalline cellulose, lactose and starch, tackiness agent such as Mierocrystalline cellulose and Polyvinylpyrolidone (PVP) (pvp), disintegrating agent such as starch and crosslinked pvp, antiseize paste (glidiants) is as colloid silica, lubricant such as Magnesium Stearate, perhaps Chang Gui liquid and semisolid excipient, for example polyoxyethylene glycol, castor oil derivative, triglyceride level and paraffin.Can add sanitas in addition, for example parabens and emulsifying agent such as polysorbate.
The acceptable salt of medicine of the present invention is suitable as large mammal, particularly Ren Lei medication, be used for the treatment of heart failure and promote urinating and the natriuresis drainage of patient particularly in heart failure, be used to improve the stomach and intestine blood flow, the heart damage that treatment hypertension and treatment and prevention are caused by Zorubicin and similar cancer therapy drug.For realizing this purpose, can be with administered parenterally, particularly intravenous injection, medicament forms oral or the suppository administration uses compound of the present invention.Used dosage can vary with each individual, and changes according to the character of the situation of being treated, used predetermined substance and administering mode.For large mammal, particularly human, be that the medicament forms administration of single agent 1～800mg generally is suitable with activity substance content.
Following embodiment is just in order to illustrate the present invention in more detail, so these embodiment are in office, and where face does not constitute limitation of the scope of the invention.
Embodiment
The general procedure of embodiment 1, preparation I compound metal-salt.
The active substance of about 15mmol acid form is dissolved or suspended in the 40ml low-pole aprotic solvent.Add about 1.2 normal metal reagents, in the water-soluble or identical solvent of this reagent with the active compound solvent for use.In some cases, must add entry to start reaction.Remove by component distillation and to anhydrate.When metal reagent is not oxyhydroxide or b-oxide, solvent is all removed, then be dissolved in again in the original low-pole aprotic solvent of 40～160ml, subsequent filtration is to remove unreacted metal reagent and optional formed other salt.Filtrate is added in the hexane, when forming solid product, collect product with strainer.When forming tar or oily matter, most of solvent is toppled over away gently, and evaporate residual solvent to obtain solid foam.
The preparation of the different salt of table 1, two kinds of active substances
| The changeization thing ＊ | Metal in the salt | Metal reagent M | Solvent | The quantity of M (g) (mmo) | Quantity of solvent (ml) | Hexane amount (ml) | Productive rate (%) | The result |
| ??I | ??Ca 2+ | ??Ca(OH) 2 | ??MTBE | ??0.67(9.0) | ??40 | ??80 | ??95 | Pressed powder |
| ??I | ??Mg 2+ | ??Mg(OEt) 2 | ??MTBE | ??1.25(10.9) | ??40 | ??130 | ??103 | The solid powder |
| ??I | ??Zn 2+ | ??3Zn(OH) 2·??2Zn(CO 3) 2 | ??MTBE | ??1.05(10.9) | ??115 | ??235 | ??95 | Pressed powder |
| ??I | ??Li + | ??LiOH | ??MTBE | ??0.4(16.7) | ??160 | ??130 | ??85 | Pressed powder |
| ??I | ??K + | ??KOH | ??MTBE | ??1.02(18.3) | ??95 | ??235 | ??98 | Solid foam |
| ??I | ??Na + | ??NaOH | ??MTBE | ??1.02(17.8) | ??95 | ??235 | ??89 | Solid foam |
| ??II | ??Ca 2+ | ??Ca(OH) 2 | ??EtOAc | ??0.56(7.6) | ??75 | ??235 | ??87 | Pressed powder |
*Compound I=(3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
*Compound I I=[S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-2-oxygen-1H-1-benzo-aza cycloheptatriene-1-acetate.
Table 2 has been summed up the character of prepared salt.Compounds content is measured (MACHEREY-NAGEL Nucleosil 100-5C with the HPLC method
18-HD post uses the gradient system from 5%B to 100%B, and elutriant A is the phosphoric acid buffer of pH=5.1, and elutriant B is and 10% elutriant A blended acetonitrile).For calcium, metal content is measured with the disodium EDTA complexometry, and for other metal, metal content is measured with atomic emission spectrum (AES).
The performance of the salt of table 2, table 1 preparation
| Compound ＊ | Metal in the salt | Compounds content (%rel) | Metal content (%W/W) | Theoretical metal content (% W/W) | Solubleness in the low-pole aprotic organic solvent | Solvability in the water |
| ??I | ??Ca 2+ | ??99.8 | ??3.8 | ??3.6 | Solvable | Solvable |
| ??I | ??Mg 2+ | ??99.6 | ??2.4 | ??2.2 | Solvable | Solvable |
| ??I | ??Zn 2+ | ??99.9 | ??7.0 | ??5.8 | Solvable | Solvable |
| ??I | ??Li + | ??88.0 | ??1.6 | ??1.3 | Solvable | Yi Rong |
| ??I | ??K + | ??78.4 | ??7.5 | ??6.8 | Insoluble | Yi Rong |
| ??I | ??Na + | ??84.7 | ??4.3 | ??4.1 | Insoluble | Yi Rong |
| ??II | ??Ca 2+ | ??n.d. | ??3.4 | ??3.3 | Solvable | Solvable |
*Compound I=(3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
*Compound I I=[S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
The n.d.=undetermined
As can be seen from Table 2, the Li that separates as pressed powder, Ca, Mg and Zn salt may be dissolved in the low-pole aprotic solvent.The example of these solvents has ethyl acetate, toluene, hexanaphthene and methyl tertiary butyl ether.These compounds also may be dissolved in the polar aprotic solvent, THF for example, acetone, acetonitrile, DMF and DMSO.The a little higher than theoretical amount of the metal content that records in the salt, but this is in the aftertreatment of these types be normal in analyzing.With the salifiable process of monovalence strong basicity oxyhydroxide in, the degraded of active substance can take place, cause the low compounds content in the final salt.
Embodiment 2, (3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4, the preparation of the S-α-Jia Jibianji amine salt of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate
With 18g (3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate is dissolved in the 90ml dehydrated alcohol.Add 4.1g S-α-Jia Jibianji amine down at 20～25 ℃.Naturally the crystal slurries that form are heated to 40 ℃, and stirred 1 hour.To be cooled after 0～5 ℃, restir 4 hours filter to be collected crystal, and is with the cold absolute ethanol washing of 40ml, dry in vacuum drying oven under 45 ℃.First collects 19g (3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4, the S-α-Jia Jibianji amine salt of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
Embodiment 3, (3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4, the preparation of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate calcium salt
To 30g (3S)-3-[[[1-(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4, in the solution of S-α-Jia Jibianji amine salt in 120ml methyl tertiary butyl ether (MTBE) of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate, add the 100ml1M aqueous hydrochloric acid, the mixture of stirring gained 10 minutes.Separate each layer, and, be higher than 5 until pH with 15ml water washing organic layer at least 3 times.Add 2g 95%Ca (OH)
2, reflux mixture to 55 ℃.When the not obvious minimizing of rear suspension liquid quantity in 30 minutes, add 0.5ml water.By water trap (Dean-Stark equipment) backflow mixture 2 hours.After 2 hours, distillate is clarified fully and reaction mixture has a bit muddy.Mixture is cooled to 30-35 ℃, and within 30 minutes, is added in the 240ml hexane by pot strainer.The filtering separation solid product, and use the 50ml hexane wash.Dry back obtains the free-pouring powder of 25.6g canescence.
1H-NMR: δ=7.29 (1H, dd, J=2.2 and 8.1), 7.28 (1H, ddd, J=2.0,6.6,8.1), 7.25 (1H, dd, J=2.0 and 7.6), 7.19 (1H, ddd, J=2.2,6.6,7.6), 7.19 (2H, dddd, J=0.6,1.7,7.5,7.8), 7.13 (1H, dd, J=1.3 and 7.5), (7.10 2H, ddd, J=1.3,2.1,7.8), 4.39 (1H, d, J=16.9), 4.28 (1H, dd, J=8.1 and 11.7), 4.28 (1H, d, J=16.9), 4.07 (1H, dd, J=7.2 and 10.8), 4.01 (1H, dd, J=7.1 and 10.8), (3.33 1H, ddd, J=8.0,13.2,13.7), (2.57 1H, ddd, J=1.2,7.1,13.7), (2.52 1H, dd, J=5.9 and 9.6), 2.49 (1H, dd, J=6.7 and 9.4), 2.31 (1H, dddd, J=3.3,5.1,9.2,9.3), 2.29 (1H, dddd, J=7.1,8.1,13.1,13.2), 2.03 (1H, dddd, J=1.2,8.0,11.7,13.1), 2.0 (1H, dd, J=9.3 and 14.2), 1.82 (1H, dd, J=3.3 and 14.2), (1.82 1H, ddd, J=5.9,9.4,13.6), (1.70 1H, ddd, J=6.7,9.6,13.6), 2.02-1.42 (8H, m), 1.21 (3H, dd, J=7.1 and 7.2).
Embodiment 4, Compound I I i.e. [S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4, the preparation of the S-α-Jia Jibianji amine salt of 5-tetrahydrochysene-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate
With 21g Compound I I is [S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4,5-tetrahydrochysene-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate is dissolved among the 190ml MTBE.Add 45ml ethanol and 4.5g S-α-Jia Jibianji amine.4 ℃ stored 4 days and stirred every day once after, filter and collect crystal, with 80ml MTBE washing, in vacuum drying oven in 45 ℃ of dryings.First collects the i.e. [S-(R of 19g Compound I I
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4, the S-α-Jia Jibianji amine salt of 5-tetrahydrochysene-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
Embodiment 5, [S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4, the preparation of 5-tetrahydrochysene-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate calcium salt
Under agitation, in 15 minutes, to 10g[S-(R
*, S
*)]-3-[[[1-[2-(ethoxycarbonyl)-4-(1-naphthyl) butyl] cyclopentyl] carbonyl] amino]-2,3,4, add the aqueous hydrochloric acid of 4.4ml 36% in the multiphase mixture that the S-α-Jia Jibianji amine salt of 5-tetrahydrochysene-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate forms in 80ml methyl tertiary butyl ether (MTBE) and 60ml water, at room temperature stirred the gained mixture 1.5 hours.Separate each layer, twice of 50ml water washing of organic layer.Organic layer is condensed into oil, adds the 15ml ethyl acetate, gained solution is condensed into oil once more.Dissolve this oil once more with the 80ml ethyl acetate, and add 2ml water.Add 0.56g 95%Ca (OH)
2, by water trap (Dean-Stark equipment) backflow mixture 4 hours.Filtering solution, and liquor capacity reduced to 40ml.Solution is cooled to 30-35 ℃, in 30 minutes, is added in the cold hexane of 250ml (10 ℃), 10 ℃ of following restir 30 minutes.The filtering separation solid product is used twice of 10ml hexane wash.Vacuum-drying (18 hours, 50 ℃, 120 millibars) after, obtain the free-pouring powder of 7.4g.
1H-NMR: δ=7.99 (1H, wide bimodal, J=8), 7.88 (1H, dd, J=1.5 and 8), 7.73 (1H, wide bimodal, J=8), 7.56-7.44 (2H, m), 7.37 (1H, t, J=8) ,～7.36 (NH, d, J=8), (7.31 1H, dd, J=1.5 and 8), 7.29 (1H, d, J=8), 7.24 (1H, triple bimodal, J=1.5,8,8), 7.21 (1H, dd, J=1.5 and 8), 7.13 (1H, triple bimodal, J=1.5,8,8), 4.48 (1H, d, J=16), 4.23 (1H, two triplets, J=8,8,12), and 4.14-3.99 (3H, m), 3.56 (1H, triple bimodal, J=8,13,13), 3.02-2.96 (2H, m), and 2.5-2.34 (2H, m), 2.2-1.74 (8H, m), 1.6-1.24 (6H, m), 1.20 (3H, t, J=6).
Claims (14)
1, be selected from (3S)-3-[[[1-[(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] cyclopentyl] carbonyl] amino]-2,3,4, lithium salts, calcium salt, magnesium salts and the zinc salt of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate.
2, the described salt of claim 1, wherein said salt is calcium salt.
3, the preparation method of the salt of claim 1, this method comprises the solution of the oxyhydroxide of lithium, calcium, magnesium or zinc or slurries and (3S)-3-[[[1-[(2R)-2-(ethoxycarbonyl)-4-phenyl butyl] and cyclopentyl] carbonyl] amino]-2,3,4, solution or the slurries of 5-tetrahydrochysene-2-oxo-1H-1-benzo-aza cycloheptatriene-1-acetate in the low-pole aprotic solvent mix, and produce the homogeneous solution of this salt in described low-pole aprotic solvent.
4, the method for claim 3, wherein said low-pole aprotic solvent is methyl tertiary butyl ether or ethyl acetate.
5, claim 3 or 4 method also comprise as follows going out described salt with isolated in solid form:
I) randomly azeotropic removes water, then
Ii) by making described salt crystallization or precipitation in the solution and the precipitant mix of the described salt in the low-pole aprotic solvent.
6, the method for claim 5, wherein said precipitation agent are linear (C
4-C
10)-hydrocarbon.
7, the method for claim 6, wherein said precipitation agent is a normal hexane.
8, contain the salt of at least a claim 1 or 2 and the pharmaceutical composition of pharmaceutical carrier or auxiliary.
9, the pharmaceutical composition of claim 8, wherein said composition are the forms that is fit to intravenous administration.
10, claim 1 or 2 the salt application in making pharmaceutical composition, this pharmaceutical composition is used for the treatment of by the treatable cardiac conditions of said composition.
11, claim 1 or 2 salt are used for improving the application of the composition of stomach blood flow in manufacturing.
12, claim 1 or 2 the salt application in making pharmaceutical composition, this pharmaceutical composition is used for the treatment of by the treatable hypertension of said composition.
13, claim 1 or 2 salt are used for the treatment of and prevent by the application in the composition of the caused heart damage of cancer therapy drug in manufacturing.
14, the application of claim 13, wherein said cancer therapy drug is a Zorubicin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02075621 | 2002-01-16 | ||
| EP02075621.9 | 2002-01-16 | ||
| NL1019762 | 2002-01-17 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN03802391A Division CN100591689C (en) | 2002-01-16 | 2003-01-15 | Solid salts of benzazepine compounds and its uses in preparing pharmaceutical compound containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101654437A true CN101654437A (en) | 2010-02-24 |
Family
ID=35161101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910141767A Pending CN101654437A (en) | 2002-01-16 | 2003-01-15 | Solid salts benzazepine compounds and their use in the preparation of pharmaceuticals compounds |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101654437A (en) |
| AR (1) | AR038128A1 (en) |
| UA (1) | UA78013C2 (en) |
| ZA (1) | ZA200405263B (en) |
-
2003
- 2003-01-13 AR ARP030100083 patent/AR038128A1/en unknown
- 2003-01-15 CN CN200910141767A patent/CN101654437A/en active Pending
- 2003-01-15 UA UA20040806857A patent/UA78013C2/en unknown
-
2004
- 2004-07-01 ZA ZA200405263A patent/ZA200405263B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR038128A1 (en) | 2004-12-29 |
| UA78013C2 (en) | 2007-02-15 |
| ZA200405263B (en) | 2005-06-24 |
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