CN101468958B - Novel ethylene diamine derivative - Google Patents

Novel ethylene diamine derivative Download PDF

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Publication number
CN101468958B
CN101468958B CN2008100420604A CN200810042060A CN101468958B CN 101468958 B CN101468958 B CN 101468958B CN 2008100420604 A CN2008100420604 A CN 2008100420604A CN 200810042060 A CN200810042060 A CN 200810042060A CN 101468958 B CN101468958 B CN 101468958B
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compound
dimethyl
dialkylene
xin
diamantane
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CN101468958A (en
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孟庆义
陈义朗
刘亦斌
罗会兵
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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Priority to PCT/CN2009/073417 priority patent/WO2010022634A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates

Abstract

The invention relates to ethylenediamine compounds of which the structural formula is as shown in a formula (I), pharmaceutically acceptable salts, a preparation method thereof and application of the ethylenediamine compounds in preparing medicines for treating infectious diseases caused by tubercle bacillus and particularly infectious diseases caused by multidrug resistant tubercle bacillus. Thecompounds of which the structural formula is shown in the (I) have good in vitro tubercle bacillus resistant activity and good in vivo pharmacokinetics property.

Description

Ethylene diamine derivative
Technical field
The invention belongs to field of pharmacology; Relate to pharmaceutical chemistry, pharmacology and pharmacokinetics field; More specifically, relate to anti-mycobacterium tuberculosis medicine and preparation method thereof and the purposes in the infectious disease medicament that preparation treatment infection, particularly tubercule bacillus cause.
Background technology
White plaque is infected by mycobacterium tuberculosis (Mycobacterium tuberculosis) and causes, is one of ancient disease of the mankind.In people's paratuberculosis, modal is pulmonary tuberculosis.Even to this day, pulmonary tuberculosis still serious harm human beings'health, is to cause one of maximum communicable disease of death toll at present.According to the statistics of WHO, the world has 1/3 people to infect tubercule bacillus approximately, and only in 2005, the whole world has 1,600,000 people and dies from tuberculosis.Pulmonary tuberculosis also is to cause one of AIDS patient's main causes of death.
The method of several kinds one line medicines such as vazadrine, Rifampin, Tibutol and pyrazinoic acid amide drug combination is mainly adopted in the treatment of tuberculosis disease at present.There is following shortcoming in this treat-ment: treatment cycle is long, need usually more than 1 year, this be the tubercule bacillus of latent to medicine insensitive due to; Untoward reaction is comparatively serious, might cause serious hepatopathy like Rifampin and vazadrine drug combination, and Tibutol can cause optic nerve lesion; Particularly existing medicine is very poor even invalid to multidrug resistance tubercule bacillus (MDR-TB) result of treatment of rapid spread.
In view of above situation, press at present and develop novel antitubercular agent.This novel medicament should have following characteristic: to resistant organism, particularly the multidrug resistance bacterium is effective; The course of treatment can be shortened; To latent period tubercule bacillus effective; With a line antitubercular agent of present use can drug combination; Can oral administration.
Tibutol is the antitubercular agent of being developed in nineteen fifties by Lederle Laboratories, is one of widely used antitubercular agent clinically.Yet Tibutol is higher to the minimum inhibitory concentration (MIC) of mycobacterium tuberculosis, is about 5 μ g/mL, and the life-time service Tibutol also can cause damage to optic nerve, so people never stop the structure of Tibutol is transformed.
Tibutol
The Sequella company of the U.S. has synthesized a series of Tibutol verivates, and therefrom SQ109 has been found in screening
Figure G2008100420604D00022
SQ109
It is active that the compound that US20040019117 provided has the tuberculosis stronger than Tibutol, particularly chemical sproof tubercule bacillus had fine activity.Yet SQ109 causes its oral administration biaavailability very low [British Journal of Pharmacology, 2006,1-10 because first pass effect is serious; Current Medicinal Chemi stry, 2008,15,809-825], seriously limited the prospect of its clinical application.
Therefore, this area presses for the active good and high medicinal compound of bioavailability of exploitation tuberculosis.
Summary of the invention
The purpose of this invention is to provide the active good and high medicinal compound of bioavailability of one type of tuberculosis.
In first aspect of the present invention, the compound shown in a kind of formula (I) is provided, or its crystal formation, pharmacy acceptable salt, hydrate or solvate:
Figure G2008100420604D00023
Wherein, R is for have the substituting group of 3 Sauerstoffatoms at least.
In another preference, the R in the formula is:
Figure G2008100420604D00031
In the formula, R 1And R 2Can be independently be hydrogen, unsubstituted or have a 1-3 substituent C 1-C 6Alkyl, wherein said substituting group is selected from: halogen, amino or hydroxyl.
In another preference, R 1And R 2Be H or unsubstituted C independently 1-C 6Branched-chain or straight-chain alkyl.
In another preference, R 1Be H or C 1-C 3Alkyl; And/or R 2Be unsubstituted C 3-C 6Alkyl.
More preferably, described compound is selected from down group:
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester (I-a);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester PHENRAMINE MALEATE (I-b);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester mesylate (I-c);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester phosphoric acid salt (I-d);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester (I-e);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester PHENRAMINE MALEATE (I-f);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester mesylate (I-g);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester phosphoric acid salt (I-h);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester (I-i);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester PHENRAMINE MALEATE (I-j);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester (I-k);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester PHENRAMINE MALEATE (I-1); Or
(E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-((5-methyl isophthalic acid, 3-dioxo cyclopentenes-2-ketone-4-yl) methyl)-N '-(diamantane-2-yl)-ethane-1,2-diamines PHENRAMINE MALEATE (I-m).
In second aspect of the present invention, the method for the compound shown in a kind of preparation formula (I) is provided, said method comprises step:
(a) in anhydrous inert solvent, at-10 ℃ to reflux temperature and under the alkaline condition, with formula 1 compound and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1, the 2-diamines is the SQ109 reaction, forms the compound of formula (I)
Figure G2008100420604D00041
In the formula, the definition of R1 and R2 is the same;
Perhaps said method comprises:
(a) in inert solvent, under the alkaline condition, geranyl chloride and the reaction of 2-monoethanolamine obtain 2-(the 6-dialkylene is amino for (E)-3,7-dimethyl--Xin-2) ethanol, and promptly compound 2;
Figure G2008100420604D00042
(b) in inert solvent, under the alkaline condition, formula I compound and compound 2 reactions form compound 3,
Figure G2008100420604D00043
In the formula, R 1And R 2Definition the same;
(c) in inert solvent, with compound 3 oxidations, obtain compound 4,
In the formula, R 1And R 2Definition the same;
(d) in inert solvent, compound 4 and 2-amantadine are carried out reductive amination process, form the compound of formula (I);
Perhaps, said method comprises step:
In inert solvent ,-10 ℃ to reflux temperature and alkaline condition, 4-brooethyl-5-methyl isophthalic acid; 3-dioxo-cyclopentenes-2-ketone and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1; The 2-diamines is the SQ109 reaction, forms formula (I) compound;
Figure G2008100420604D00052
In another preference, described method also comprises step: with formula (I) compound and the acid-respons that form, form pharmacy acceptable salt.More preferably, with formula (I) compound that forms and toxilic acid reaction, thereby form PHENRAMINE MALEATE.
In the third aspect of the invention, a kind of pharmaceutical composition is provided, it contains pharmaceutically acceptable carrier and above-mentioned formula (I) compound of the present invention, or its crystal formation, pharmacy acceptable salt, hydrate or solvate.
In fourth aspect of the present invention; Formula of the present invention (I) compound is provided; Or the purposes of its crystal formation, pharmacy acceptable salt, hydrate or solvate, they are used to prepare the anti-mycobacterium tuberculosis medicine, perhaps be used to prepare the treatment infection medicine.
In another preference, described infection comprises the infection that tubercule bacillus causes, the infection that more preferably causes for the multidrug resistance tubercule bacillus.
Provided by the invention suc as formula novel ethylene diamine derivative and the pharmacy acceptable salt thereof shown in (I); Has good pharmacokinetic property; Comparing the SQ109 oral administration biaavailability improves a lot; Having overcome restriction SQ109 becomes the clinical serious hindrance that makes medicament, and therefore, The compounds of this invention can be used for preparing the medicine of the infection that treatment tuberculosis bacillus infectious disease, particularly multidrug resistance tubercule bacillus cause.
Embodiment
The inventor is through extensive and deep research; Screened a large amount of compounds in vitro and in vivo; It is active that discoverable type (I) compound not only has the Tuberculosis in vitro nuclear bacillus similar or more excellent with SQ109 first; The more important thing is that novel derivative of the present invention has than SQ109 better medicament metabolisming property, therefore higher oral administration biaavailability is particularly suitable for as novel antimycobacterial drug.The inventor has accomplished the present invention on this basis.
Activeconstituents
As used herein, term " The compounds of this invention " refers to the compound shown in the formula (I).This term also comprises and various crystalline forms, pharmacy acceptable salt, hydrate or the solvate of formula (I) compound.
As used herein, term " pharmacy acceptable salt " refers to the formed salt that is suitable as medicine of The compounds of this invention and acid or alkali.Pharmacy acceptable salt comprises inorganic salt and organic salt.One type of preferred salt is The compounds of this invention and the sour salt that forms.Being fit to the salifiable acid of shape includes, but are not limited to: mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, Hydrocerol A, TNP, methylsulfonic acid, Phenylsulfonic acid; And acidic amino acid such as aspartic acid, L-glutamic acid.
As used herein, term " alkyl " comprises the straight or branched alkyl, also comprises naphthenic base.Representational alkyl comprises (but being not limited to): methyl, ethyl, propyl group (like n-propyl and sec.-propyl), butyl, amyl group, hexyl etc.
The preparation method
The preparation method of formula of the present invention (I) structural compounds is more specifically described below; But these concrete grammars do not constitute any restriction to the present invention; In addition, reaction conditions, for example the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc. are not limited to following explanation.
The compounds of this invention can also be chosen various compound methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
In flow process of the present invention, each reaction in inert solvent, is carried out under room temperature to reflux temperature (as 0 ℃～80 ℃, preferred 0 ℃～50 ℃) usually.Reaction times was generally 0.1 hour-60 hours, preferably was 0.5-48 hour.
In a preference, formula of the present invention (I) compound can be by following flow preparation:
Flow process 1
Figure G2008100420604D00071
Preferred reagent and reaction conditions comprise: Et 3N, THF, 0 ℃, 3h
Flow process 1 is described below more specifically:
By known class like the method [WO2006050472] of reaction to replace or unsubstituted methyl-chloroformate (R 1And R 2Definition as preceding) is raw material, makes compound 1.
Compound 1 is in-30 ℃～solvent refluxing temperature, and in anhydrous inert solvent, under the alkaline condition, with N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1, the 2-diamines is the SQ109 reaction, obtains the compound of structural formula (I), R 1And R 2The definition as before.
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, chloroform, methylene dichloride, toluene or benzene; The alkali that is fit to is organic bases such as triethylamine, pyridine or N, the N-lutidine; Reaction preferably is controlled at-10 ℃ to room temperature.Top condition is that THF is a solvent, and triethylamine is an alkali, and-10 ℃ are arrived room temperature reaction 3 hours.
As required, aforesaid method obtains formula (I) structural compounds and can in organic solvent, react with organic acid or mineral acid and form pharmacy acceptable salt.One of preferred condition is that formula (I) structural compounds reacts the PHENRAMINE MALEATE that forms formula (I) structural compounds with toxilic acid in Virahol.
In another preference, formula of the present invention (I) compound can be by following flow preparation:
Flow process 2
Figure G2008100420604D00081
Preferred reagent and reaction conditions comprise: a) 2-monoethanolamine, and salt of wormwood, Soiodin, THF refluxes 24h; B) compound 1, Et 3N, THF, 0 ℃, 2h; C) oxalyl chloride, DMSO, CH 2Cl 2,-60 ℃, 30min, Et then 3N, 15min; D) 2-amantadine, sodium triacetoxy borohydride, 1,2-ethylene dichloride, room temperature, 0.5h
Flow process 2 is described below more specifically:
(1) in organic solvent, under the alkaline condition, geranyl chloride and the reaction of 2-monoethanolamine obtain 2-(the 6-dialkylene is amino for (E)-3,7-dimethyl--Xin-2) ethanol, and promptly compound 2.
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, methyl alcohol, ethanol, chloroform, methylene dichloride, toluene or benzene; The alkali that is fit to is mineral alkali such as salt of wormwood, yellow soda ash etc., organic bases such as triethylamine, pyridine or N, N-dimethyl aminopyridine etc.; Catalyzer is potassiumiodide or Soiodin; Temperature of reaction is controlled at 0 ℃ of temperature to solvent refluxing.Top condition is that THF is a solvent, and salt of wormwood is alkali, and Soiodin is a catalyzer, back flow reaction 24 hours.
(2) in inert organic solvents, under the alkaline condition, compound 2 and compound 1 reaction obtain compound 3, R 1And R 2The definition as before.
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, chloroform, methylene dichloride, toluene or benzene; The alkali that is fit to is mineral alkali such as salt of wormwood, yellow soda ash etc., organic bases such as triethylamine, pyridine or N, N-dimethyl aminopyridine etc.; Temperature of reaction is controlled at-20 ℃ of temperature to solvent refluxing.Top condition is that THF is a solvent, and triethylamine is an alkali, and 0 ℃ was reacted 2 hours.
(3) in organic solvent, with compound 3 oxidations, obtain compound 4, R with suitable oxygenant 1And R 2The definition as before.
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, chloroform, methylene dichloride, toluene or benzene; The oxygenant that is fit to is chromium trioxide, pyridinium dichromate, pyridinium chloro-chromate, adjacent iodoxybenzene formic acid, Dess-Martin oxygenant, methyl-sulphoxide etc.; Can add oxalyl chloride, N when making oxygenant with methyl-sulphoxide, N '-dicyclohexyl carbimide, sulfur trioxide pyridine complex etc. are made activating reagent; Temperature of reaction is controlled at-78 ℃ of temperature to solvent refluxing.Top condition is that methylene dichloride is a solvent, and methyl-sulphoxide is an oxygenant, and oxalyl chloride is an activating reagent, and-60 ℃ were reacted 0.5 hour.
(4) in organic solvent, compound 4 carries out reductive amination process with the 2-amantadine, obtains the compound R of structural formula (I) 1And R 2The definition as before.
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, chloroform, methylene dichloride, 1,2-ethylene dichloride, toluene, benzene, acetonitrile, methyl alcohol or ethanol etc.; The reductive agent that is fit to is sodium triacetoxy borohydride or sodium cyanoborohydride etc.; Can add protonic acids such as catalytic amount to stoichiometric formic acid, acetate quickens reaction; Temperature of reaction is controlled at-20 ℃ of temperature to solvent refluxing.Top condition is 1, and the 2-ethylene dichloride is a solvent, and sodium triacetoxy borohydride is a reductive agent, room temperature reaction 0.5 hour.
As required, aforesaid method obtains formula (I) structural compounds and can in organic solvent, react with organic acid or mineral acid and form pharmacy acceptable salt.One of preferred condition is that formula (I) structural compounds reacts the PHENRAMINE MALEATE that forms formula (I) structural compounds with toxilic acid in Virahol.
In another preference, formula of the present invention (I) compound can be by following flow preparation:
Flow process 3
Figure G2008100420604D00091
Preferred reagent and reaction conditions comprise: K 2CO 3, THF refluxes 10h
Flow process 3 is described below more specifically:
In organic solvent, under the alkaline condition, 4-brooethyl-5-methyl isophthalic acid; 3-dioxo-cyclopentenes-2-ketone and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1; The 2-diamines is the SQ109 reaction, obtains the compound of structural formula of the present invention (I).
The solvent that is fit in the above-mentioned reaction is THF, dioxane, ether, chloroform, methylene dichloride, 1,2-ethylene dichloride, toluene, benzene, acetonitrile, N, dinethylformamide, methyl alcohol or ethanol etc.; The alkali that is fit to is mineral alkali such as salt of wormwood, yellow soda ash etc., organic bases such as triethylamine, pyridine or N, N-dimethyl aminopyridine etc.; Can use catalyzer such as potassiumiodide or Soiodin that reaction is quickened; Temperature of reaction is controlled at 0 ℃ of temperature to solvent refluxing.Top condition is that THF is a solvent, and salt of wormwood is alkali, back flow reaction 10 hours.
As required, aforesaid method obtains formula (I) structural compounds and can in organic solvent, react with organic acid or mineral acid and form pharmacy acceptable salt.One of preferred condition is that formula (I) structural compounds reacts the PHENRAMINE MALEATE that forms formula (I) structural compounds with toxilic acid in Virahol.
Novel ethylene diamine derivative shown in formula provided by the invention (I) structure, representative compound title and structural formula are seen table 1
Figure G2008100420604D00101
The representational compound of table 1 the present invention
Figure G2008100420604D00102
Figure G2008100420604D00111
Figure G2008100420604D00121
Pharmaceutical composition and application process
Because The compounds of this invention has the active and better oral administration biaavailability of excellent tuberculosis bar; So The compounds of this invention and various crystal formation thereof; Pharmaceutically acceptable inorganic or organic salt; Hydrate or solvate, and to contain The compounds of this invention be that the pharmaceutical composition of main active ingredient can be used for treating, preventing and alleviates the infection that the infection that is caused by tubercule bacillus, especially multidrug resistance tubercule bacillus cause.
Pharmaceutical composition of the present invention comprises on The compounds of this invention or its pharmacology in the safe and effective weight range acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-1000mg The compounds of this invention/agent, more preferably, contains 10-200mg The compounds of this invention/agent.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as each component ability and compound of the present invention and blending each other between them in the compsn, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has Mierocrystalline cellulose and verivate thereof (like Xylo-Mucine; TKK 021 sodium; Vladipor UAM 500 etc.); Gelatin; Talcum; Solid lubricant is (like Triple Pressed Stearic Acid; Magnesium Stearate); Calcium sulfate; Vegetables oil is (like soya-bean oil; Til; Peanut oil; The olive wet goods); Polyvalent alcohol is (like Ucar 35; Glycerine; N.F,USP MANNITOL; Sorbyl alcohol etc.); Emulsifying agent (as telling
Figure G2008100420604D00131
); Wetting agent (like sodium lauryl sulphate); Tinting material; Seasonings; Stablizer; Inhibitor; Sanitas; Apirogen water etc.
When using The compounds of this invention, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages; Active compound mixes with at least a conventional inert excipient (or carrier), like Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material; For example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, PVP K120, sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca(flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example Tego Alkanol 16 and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, like casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this compsn certain part in digestive tube.The instance of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension-s, syrup or tincture.Except the active ingredient beyond the region of objective existence; Liquid dosage form can comprise the conventional inert diluent that adopts in this area, like water or other solvent, solubilizing agent and emulsifying agent; Example is known; The mixture of ethanol, Virahol, ethyl-carbonate, ETHYLE ACETATE, Ucar 35,1,3 butylene glycol, N and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and til or these materials etc.
Except these inert diluents, compsn also can comprise auxiliary agent, like wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension-s can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and SPAN, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The compsn that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension-s or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that possibly need in case of necessity is mixed together.
The compounds of this invention can be individually dosed, perhaps with other pharmaceutically acceptable compound administation of combination.
When making pharmaceutical composition; Be the Mammals (like the people) that the The compounds of this invention of safe and effective amount is applicable to the needs treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using is for the people of 60kg body weight; Day dosage is generally 1～1000mg, preferred 20～500mg.Certainly, concrete dosage is factor such as considered route of administration, patient health situation also, and these all are within the skilled practitioners skill.
Major advantage of the present invention comprises:
Compound provided by the present invention or its pharmacy acceptable salt not only have the Tuberculosis in vitro nuclear bar activity similar or more excellent with SQ109, the more important thing is that novel derivative of the present invention has the better oral administration biaavailability than SQ109.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Among all embodiment, fusing point is measured with MEL-TEMP fusing point appearance, and TM is not proofreaied and correct; 1H-NMR is with Varian Mercury400 NMR record, and chemical shift is represented with δ (ppm); Mass spectrum is measured with Tianjin, island LC-MS2010EV; Separate and use silica gel, the undeclared 200-300 order that is.
Embodiment 1: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester (compound I-a)
Method one
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1; (700mg 2.12mmol) is dissolved among the 20mL THF 2-diamines, adds triethylamine (642mg; 6.36mmol) ice bath is cooled to 0 ℃; (413mg 2.12mmol), drips Bi Huifu stirring at room 2h to drip chloroformic acid (pivaloyl oxygen base) methyl ester.Add 75mL water, ethyl acetate extraction (50mL * 2), saturated common salt washing, dried over sodium sulfate.Concentrate column chromatography (sherwood oil: ETHYLE ACETATE=3:1), get weak yellow liquid (543mg, yield 52.5%) behind the filtering siccative.
1H?NMR(400MHz?CDCl 3)δ：1.18(s，9H)，1.42-1.47(m，3H)，1.58(s，3H)，1.62-1.70(m，9H)，1.72-1.84(m，6H)，1.85-2.08(m，6H)，2.60-2.75(m，3H)，3.28(t，J＝6.59Hz，1H)，3.36(t，J＝6.59Hz，1H)，3.88(d，J＝6.58Hz，1H)，3.96(d，J＝6.58Hz，1H)，5.05-5.16(m，2H)，5.77(s，2H)
Method two
2-(the 6-dialkylene is amino for (E)-3,7-dimethyl--Xin-2) ethanol (compound 2)
The 2-monoethanolamine (6.36g 104.4mmol) is dissolved among the 100mL THF, add geranyl chloride (6g, 34.8mmol), salt of wormwood (9.6g, 70mmol), Soiodin (100mg, 0.66mmol), temperature rising reflux.Stop heating behind the backflow 24h, the filtering insolubles, filtrating concentrates back column chromatography (CH 2Cl 2: MeOH=10:1), get weak yellow liquid (4.1g, yield 60%).
1H?NMR(400MHzCDCl 3)δ：1.57(s，3H)，1.61(s，3H)，1.65(s，3H)，1.95-2.09(m，4H)，2.89(t，J＝5.2Hz，2H)，3.21(d，J＝6.8Hz，2H)，3.59(t，J＝5.2Hz，2H)，5.03-5.08(m，1H)，5.19-5.24(m，1H)
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-hydroxyethyl)-carboxylamine (pivaloyl oxygen base) methyl ester (compound 3-a, R 1=H, R 2=the tertiary butyl)
(197mg 1mmol) is dissolved among the 10mL exsiccant THF compound 2, adds Et 3N (202mg, 2mmol), ice bath is cooled to 0 ℃, dropping chloroformic acid (pivaloyl oxygen base) methyl ester (194mg, 1mmol).Feed intake finish after, stirring at room 30min.Add entry (30mL), MTBE (30mL), separatory.Organic phase is with washing (30mL * 1), and saturated common salt is washed (30mL * 1), dried over sodium sulfate.Filtering siccative, filtrating concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=2:1), get weak yellow liquid (210mg, yield 59%).
1H?NMR(400MHz?CDCl 3)δ：1.21(s，9H)，1.58(s，3H)，1.63(s，6H)，1.98-2.11(m，4H)，3.34(t，J＝5.2Hz，1H)，3.41(t，J＝5.2Hz，1H)，3.66(s，1H)，3.75(s，1H)，3.90(d，J＝7.2Hz，1H)，3.98(d，J＝7.2Hz，1H)，5.03-5.06(m，1H)，5.09-5.17(m，1H)，5.77(s，2H)
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-aldehyde-base-carboxylamine (pivaloyl oxygen base) methyl ester (compound 4-a, R 1=H, R 2=the tertiary butyl)
(143mg 1.12mmol) is dissolved in 10mL exsiccant CH to oxalyl chloride 2Cl 2In, be cooled to-60 ℃, and adding DMSO (87mg, 1.12mmol), temperature control stirs 15min, and (200mg 0.56mmol), continues temperature control and stirs 30min, dropping Et to add compound 3-a 3(113mg 1.12mmol), continues temperature control and stirs 10min N, rises to room temperature.Add entry (10mL), separatory, organic phase is with washing (10mL * 1), and saturated common salt is washed (10mL * 1), and dried over sodium sulfate concentrates behind the filtering siccative, gets colourless liquid (169mg, yield 85%).
1H?NMR(400MHz?CDCl 3)δ：1.20(s，4.5H)，1.22(s，4.5H)，1.59-1.68(m，9H)，1.99-2.06(m，4H)，3.90-4.05(m，4H)，5.01-5.08(m，2H)，5.74(s，1H)，5.81(s，1H)，9.50(s，0.5H)，9.55(s，0.5H)
(E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester (compound I-a)
Under the argon shield, and compound 4-a (160mg, 0.45mmol), (68mg 0.45mmol) is dissolved in 15mL exsiccant 1 to the 2-amantadine, in the 2-ethylene dichloride, adds NaBH (OAc) 3(144mg, 0.68mmol), stirring at room 30min adds saturated NaHCO 3The aqueous solution (20mL), separatory, organic phase is with washing (20mL * 1), and saturated common salt is washed (20mL * 1), dried over sodium sulfate.(the sherwood oil: ETHYLE ACETATE=2:1), get weak yellow liquid (187mg, yield 85%) of column chromatography behind the filtering siccative.
1H?NMR(400MHz?CDCl 3)δ：1.18(s，9H)，1.42-1.47(m，3H)，1.58(s，3H)，1.62-1.70(m，9H)，1.72-1.84(m，6H)，1.85-2.08(m，6H)，2.60-2.75(m，3H)，3.28(t，J＝6.59Hz，1H)，3.36(t，J＝6.59Hz，1H)，3.88(d，J＝6.58Hz，1H)，3.96(d，J＝6.58Hz，1H)，5.05-5.16(m，2H)，5.77(s，2H)
Embodiment 2: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester PHENRAMINE MALEATE (compound I-b)
Compound I-a (250mg) is dissolved in the 5mL Virahol, adds toxilic acid (59mg).Stirring at room 0.5h concentrates, and gets white solid (310mg, yield 100%).
Mp：164-166℃； 1H?NMR(400MHz?DMSO)δ：1.44(s，9H)，1.56-1.74(m，15H)，1.84-2.09(m，12H)，3.01-3.09(m，2H)，3.45-3.51(m，3H)，3.83-3.90(m，2H)，5.06-5.11(m，2H)，5.71(s，2H)，6.03(s，2H)，8.31(brs，2H)；MS(ESI)：489
Embodiment 3: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester mesylate (compound I-c)
Compound I-a (250mg) is dissolved in the 5mL Virahol, adds methylsulfonic acid (49mg).Stirring at room 0.5h concentrates, and gets white solid (293mg, yield 98%).
Mp：173-175℃；MS(ESI)：489
Embodiment 4: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester phosphoric acid salt (compound I-d)
Compound I-a (100mg) is dissolved in the 5mL Virahol, adds phosphoric acid (20mg).Stirring at room 0.5h concentrates, and gets white solid (112mg, yield 93%).
Mp：147-148℃；MS(ESI)：489
Embodiment 5: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester (compound I-e)
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-hydroxyethyl)-carboxylamine (isobutyl acyloxy) methyl ester (compound 3-b, R 1=H, R 2=sec.-propyl)
(197mg 1mmol) is dissolved among the 10mL exsiccant THF compound 2, adds Et 3N (202mg, 2mmol), ice bath is cooled to 0 ℃, dropping chloroformic acid (isobutyl acyloxy) methyl ester (180mg, 1mmol).Feed intake finish after, stirring at room 30min.Add entry (30mL), MTBE (30mL), separatory.Organic phase is with washing (30mL * 1), and saturated common salt is washed (30mL * 1), dried over sodium sulfate.Filtering siccative, filtrating concentrate back column chromatography (sherwood oil: ETHYLE ACETATE=2:1), get weak yellow liquid (197mg, yield 58%).
MS(ESI)：342
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-aldehyde-base-carboxylamine (isobutyl acyloxy) methyl ester (compound 4-b, R 1=H, R 2=sec.-propyl)
(127mg 1mmol) is dissolved in 10mL exsiccant CH to oxalyl chloride 2Cl 2In, be cooled to-60 ℃, and adding DMSO (78mg, 1mmol), temperature control stirs 15min, and (170mg 0.5mmol), continues temperature control and stirs 30min, dropping Et to add compound 3-b 3(113mg 1.12mmol), continues temperature control and stirs 10min N, rises to room temperature.Add entry (10mL), separatory, organic phase is with washing (10mL * 1), and saturated common salt is washed (10mL * 1), and dried over sodium sulfate concentrates behind the filtering siccative, gets colourless liquid (141mg, yield 83%).
MS(ESI)：340
(E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester (compound I-e)
Under the argon shield, and compound 4-b (141mg, 0.42mmol), (63mg 0.42mmol) is dissolved in 15mL exsiccant 1 to the 2-amantadine, in the 2-ethylene dichloride, adds NaBH (OAc) 3(144mg, 0.68mmol), stirring at room 30min adds saturated NaHCO 3The aqueous solution (20mL), separatory, organic phase is with washing (20mL * 1), and saturated common salt is washed (20mL * 1), dried over sodium sulfate.(the sherwood oil: ETHYLE ACETATE=2:1), get weak yellow liquid (180mg, yield 90%) of column chromatography behind the filtering siccative.
1H?NMR(400MHz?CDCl 3)δ：1.15(d，J＝7.1Hz，6H)，1.42-1.47(m，2H)，1.58(s，3H)，1.63-1.68(m，10H)，1.78-1.83(m，6H)，1.90-1.93(m，2H)，1.99-2.06(m，4H)，2.55-2.58(m，1H)，2.66-2.71(m，3H)，3.28-3.36(m，2H)，3.88(d，J＝6.9Hz，1H)，3.96(d，J＝6.9Hz，1H)，5.00-5.09(m，2H)，5.76(s，2H)
Embodiment 6: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester PHENRAMINE MALEATE (compound I-f)
With reference to the method that becomes PHENRAMINE MALEATE among the embodiment 2, (180mg, 0.38mmol) (44mg, 0.38mmol) reaction obtains compound I-f to compound I-e, is white solid (220mg, yield 98%) with toxilic acid.
Mp：151-153℃； 1H?NMR(400MHz?DMSO)δ：1.09(d，J＝7.0Hz，6H)，1.56-1.60(m，5H)，1.64-1.74(m，10H)，1.85(s，4H)，1.90-2.12(m，8H)，2.55-2.61(m，1H)，3.05-3.10(m，3H)，3.43-3.53(m，2H)，3.83-3.90(m，2H)，5.06-5.11(m，2H)，5.71(s，2H)，6.01(s，2H)，8.20-8.40(brs，2H)；MS(ESI)：475
Embodiment 7: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester mesylate (compound I-g)
With reference to the method that becomes mesylate among the embodiment 3, (60mg, 0.13mmol) (12.5mg, 0.13mmol) reaction obtains compound I-g to compound I-e, is white solid (72mg, yield 99%) with methylsulfonic acid.
Mp：160-161℃；MS(ESI)：475
Embodiment 8: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester phosphoric acid salt (compound I-h)
With reference to becoming phosphatic method among the embodiment 4, (60mg, 0.13mmol) (12.7mg, 0.13mmol) reaction obtains compound I-h to compound I-e, is white solid (70mg, yield 96%) with phosphoric acid.
Mp：137-138℃；MS(ESI)：475
Embodiment 9: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester (compound I-i)
With reference to the method among the embodiment 1, (E)-N-(3,7-dimethyl--Xin-2; The 6-dialkylene)-and N '-(diamantane-2-yl)-ethane-1, (330mg is 1mmol) with chloroformic acid-1-(pivaloyl oxygen base) ethyl ester (208mg for the 2-diamines; 1mmol) reaction; Obtain compound I-i, be weak yellow liquid (248mg, yield 50%).
1H?NMR(400MHz?CDCl 3)δ：1.17(s，9H)，1.23-1.27(m，2H)，1.44-1.49(m，5H)，1.66-1.69(m，10H)，1.76(s，1H)，1.83(s，6H)，1.91-2.01(m，4H)，2.04-2.09(m，3H)，2.71-2.76(m，3H)，3.25-3.35(m，2H)，3.87-3.95(m，2H)，5.04-5.07(m，1H)，5.13-5.16(m，1H)，6.78-6.82(m，1H)
Embodiment 10: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester PHENRAMINE MALEATE (compound I-j)
With reference to the method that becomes PHENRAMINE MALEATE among the embodiment 2, compound I-i (200mg, 0.4mmol) and toxilic acid (46mg is a raw material 0.4mmol), obtains I-j (246mg, yield 100%).
Mp：151-153℃； 1H?NMR(400MHz?DMSO)δ：1.13(s，9H)，1.43(s，3H)，1.56-1.60(m，5H)，1.64(s，3H)，1.67(s，3H)，1.71-1.74(m，4H)，1.85(s，4H)，1.89-2.00(m，4H)，2.03-2.10(m，4H)，3.07(s，2H)，3.35-3.38(m，1H)，3.86-3.88(m，2H)，5.05-5.07(m，1H)，5.11-5.13(m，1H)，6.03(s，2H)，6.64-6.65(m，1H)，8.25-8.40(brs，2H)；MS(ESI)：503
Embodiment 11: (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester (compound I-k)
With reference to the method among the embodiment 1, (E)-N-(3,7-dimethyl--Xin-2; The 6-dialkylene)-and N '-(diamantane-2-yl)-ethane-1, (330mg is 1mmol) with chloroformic acid-1-(isobutyl acyloxy) ethyl ester (194mg for the 2-diamines; 1mmol) reaction; Obtain compound I-k, be weak yellow liquid (241mg, yield 49%).
1H?NMR(400MHz?CDCl 3)δ：1.15(d，J＝7.0Hz，6H)，1.25(s，2H)，1.43-1.50(m，8H)，1.59(s，3H)，1.66-1.70(m，8H)，1.78(s，1H)，1.82(s，4H)，1.91-2.10(m，5H)，2.48-2.56(m，1H)，2.69-2.77(m，3H)，3.28-3.33(m，2H)，3.88-3.93(m，2H)，5.06-5.08(m，1H)，5.15-5.16(m，1H)，6.80-6.83(m，1H)
Embodiment 12: (E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester PHENRAMINE MALEATE (compound I-1)
With reference to the method that becomes PHENRAMINE MALEATE among the embodiment 2, (200mg, 0.41mmol) (48mg, 0.41mmol) reaction obtains compound I-1 to compound I-k, is white solid (237mg, yield 96%) with toxilic acid.
Mp：131-133℃； 1H?NMR(400MHz?DMSO)δ：1.07(d，J＝6.6Hz，6H)，1.45(s，3H)，1.55-1.61(m，5H)，1.62-1.75(m，10H)，1.84(s，4H)，1.90-2.01(m，4H)，2.03-2.11(m，4H)，3.08(s，3H)，3.50-3.61(m，3H)，3.84(s，2H)，5.05-5.15(m，2H)，6.01(s，2H)，6.65(q，J＝5.3Hz，1H)，8.23-8.50(brs，2H)；MS(ESI)：489
Embodiment 13: (E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-((5-methyl isophthalic acid, 3-dioxo cyclopentenes-2-ketone-4-yl) methyl)-N '-(diamantane-2-yl)-ethane-1,2-diamines PHENRAMINE MALEATE (compound I-m)
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1; (500mg 1.51mmol), is dissolved among the 30mL THF 2-diamines; (625mg 4.53mmol), adds 4-brooethyl-5-methyl isophthalic acid again to add salt of wormwood; 3-dioxo-cyclopentenes-2-ketone (292mg, 1.51mmol), temperature rising reflux 12h.Be cooled to room temperature, the filtering insolubles, filtrating concentrates.Obtain compound (E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-((5-methyl isophthalic acid, 3-dioxo cyclopentenes-2-ketone-4-yl) methyl)-N '-(diamantane-2-yl)-ethane-1, the crude product of 2-diamines.This crude product is added in the 5mL Virahol, and (175mg 1.51mmol), stirs 15min, adds the 3mL methyl tert-butyl ether, and 0 ℃ of placement is spent the night, and crosses to filter red solid to add toxilic acid again.With mixed solvent (methyl tert-butyl ether: the recrystallization of Virahol=10:1), compound I-m, be red solid (270mg, yield 32%).
Mp：98-99℃；1H?NMR(400MHz?DMSO)δ：1.56(s，3H)，1.61-1.64(m，7H)，1.71(s，5H)，1.85-1.95(m，6H)，1.99-2.15(m，9H)，2.73(t，J＝6.0Hz，2H)，3.01-3.13(m，5H)，3.49(s，2H)，5.05(m，1H)，5.08(m，1H)，6.01(s，?2H)；MS(ESI)：443
Embodiment 14: the experiment of Tuberculosis in vitro nuclear bacillus
Experiment material: bacterial strain: mycobacterium tuberculosis type strain H37Rv is from the China national culture presevation.Liquid nutrient medium Middlebrook 7H9 liquid nutrient medium (containing 10% nutritional additive), self-control.
Experiment is diluted to required experimental concentration with liquid nutrient medium after medicine is dissolved as 5mg/ml with DMSO, the final concentration of DMSO in nutrient solution 0.01%, the growth of tubercule bacillus there is not influence.
Experimental technique: medicine to be detected and positive control medicine SQ109 add respectively with continuous twice extent of dilution (4-0.0625 μ g/ml concentration) and contain in the cultivation bottle of liquid nutrient medium; Plant the mycobacterium tuberculosis type strain H37Rv of certain bacterium amount then; Cultivated 14 days for 37 ℃; Observe the minimum inhibitory concentration (MIC) of each medicine to mycobacterium tuberculosis, it is parallel that same experimental group is established three pipes.
Experimental result: experimental result is seen table 2
Table 2 representative compound antibacterial activity in vitro of the present invention
Compound MIC(μg/ml)
I-a 0.5
I-b 0.5
I-f 0.25
I-1 0.5
I-m 0.25
SQ109 0.5
Can know that by table 2 compound of the present invention has the tubercle bacillus resistant activity stronger than SQ109, can be used as better antitubercular agent.
In addition, the The compounds of this invention of salt-independent shape (is generally liquid like compound I-a), though therefore its tubercle bacillus resistant activity is close with its salt form, preferably uses the salt form (for example PHENRAMINE MALEATE) of The compounds of this invention when being used to prepare medicine.
Embodiment 15: drug disposition metabolism experiment
Animal and animal rearing condition: 36 of regular grade SD rats, 150～200g, male and female half and half.Laboratory animal plant provides by Green Dragon mountain, and environmental compatibility experimentized after 3 days.Feed: granulated feed, supply with by Green Dragon mountain laboratory animal plant.Raising condition: air-conditioned room, temperature 18-24 ℃, relative humidity 70%.
Experimental technique
1. dosage setting
SQ109: irritate stomach and give dosage 1.5mg/kg and 13mg/kg; Intravenous injection gives dosage 1.5mg/kg;
Compound I-b: irritate stomach and give dosage 1.5mg/kg and 13mg/kg; Intravenous injection gives dosage 1.5mg/kg.
Compound I-f: irritate stomach and give dosage 1.5mg/kg and 13mg/kg; Intravenous injection gives dosage 1.5mg/kg.
2. biological specimen collection and processing
Water 12h is can't help in fasting before the animals administer.36 rats are divided into 9 groups at random by body weight, sex; Every group 4; Male and female half and half; Be respectively 2 and receive (iv) three dose groups of reagent compound I-b and compound I-f and each 1.5mg/kg of positive control medicine SQ109 (ig), 13mg/kg (ig) and 1.5mg/kg, to carry out the Plasma Concentration test experience.5min before administration and after the administration, 10min, 15min, 30min, 1h; 2h, 3h, 5h, 7h, 10h; 24h is through rat eye rear vein beard extracting vein blood 0.5ml, the centrifugal 8min of 4000rpm, and separated plasma is measured the compound concentration in the blood plasma with the LC-MS method, and calculates its medicine for parameter by ordinary method.
The drug metabolism parameter of experimental result: compound I-b and compound I-f and positive control medicine SQ109 is seen table 3, table 4 and table 5.
Table 3 SQ109 is in the moving parameter of the intravital medicine of rat
Figure G2008100420604D00221
Table 4 give with compound I-b after SQ109 in the moving parameter of the intravital medicine of rat
Figure G2008100420604D00231
Table 5 give with compound I-f after SQ109 in the moving parameter of the intravital medicine of rat
Figure G2008100420604D00232
From seeing that table 3, table 4 and table 5 can know that The compounds of this invention is compared with SQ109, oral administration biaavailability is greatly improved, and is far superior to the positive control medicine, has approximately improved 2-3 doubly.
Embodiment 16 pharmaceutical compositions
Compound I-b 20g
Starch 140g
Microcrystalline Cellulose 60g
Press ordinary method, after above-mentioned substance was mixed, the common gelatine capsule of packing into obtained 1000 capsules.
Embodiment 17 pharmaceutical compositions
Compound I-f 50g
Starch 400g
Microcrystalline Cellulose 200g
Press ordinary method, after above-mentioned substance was mixed, the common gelatine capsule of packing into obtained 1000 capsules.
The compounds of this invention has good pharmacokinetic property; Overcome restriction SQ109 and become the clinical serious hindrance that makes medicament; Therefore, The compounds of this invention can be used for preparing the medicine of the infection that treatment tuberculosis bacillus infectious disease, particularly multidrug resistance tubercule bacillus cause.
All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Claims (8)

1. the compound shown in the formula (I) or its pharmacy acceptable salt:
Figure FSB00000667852500011
Described compound is selected from down group:
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester (I-a);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester PHENRAMINE MALEATE (I-b);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester mesylate (I-c);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (pivaloyl oxygen base) methyl ester phosphoric acid salt (I-d);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester (I-e);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester PHENRAMINE MALEATE (I-f);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester mesylate (I-g);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine (isobutyl acyloxy) methyl ester phosphoric acid salt (I-h);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester (I-i);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(pivaloyl oxygen base) ethyl ester PHENRAMINE MALEATE (I-j);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester (I-k);
(E)-N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-(2-(diamantane-2-base is amino) ethyl)-carboxylamine 1-(isobutyl acyloxy) ethyl ester PHENRAMINE MALEATE (I-1); Or
(E)-and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N-((5-methyl isophthalic acid, 3-dioxo cyclopentenes-2-ketone-4-yl) methyl)-N '-(diamantane-2-yl)-ethane-1,2-diamines PHENRAMINE MALEATE (I-m).
2. method for preparing the compound shown in the formula as claimed in claim 1 (I) is characterized in that said method comprises step:
(a) in anhydrous inert solvent, at-10 ℃ to reflux temperature and under the alkaline condition, with formula 1 compound and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1, the 2-diamines is the SQ109 reaction, forms the compound of formula (I)
Figure FSB00000667852500021
In the formula, the definition of R1 and R2 is the same;
Perhaps said method comprises:
(a) in inert solvent, under the alkaline condition, geranyl chloride and the reaction of 2-monoethanolamine obtain 2-(the 6-dialkylene is amino for (E)-3,7-dimethyl--Xin-2) ethanol, and promptly compound 2;
Figure FSB00000667852500022
(b) in inert solvent, under the alkaline condition, formula I compound and compound 2 reactions form compound 3,
Figure FSB00000667852500023
In the formula, R 1And R 2Definition the same;
(c) in inert solvent, with compound 3 oxidations, obtain compound 4,
In the formula, R 1And R 2Definition the same;
(d) in inert solvent, compound 4 and 2-amantadine are carried out reductive amination process, form the compound of formula (I);
Perhaps, said method comprises step:
In inert solvent ,-10 ℃ to reflux temperature and alkaline condition, 4-brooethyl-5-methyl isophthalic acid; 3-dioxo-cyclopentenes-2-ketone and N-(3,7-dimethyl--Xin-2,6-dialkylene)-N '-(diamantane-2-yl)-ethane-1; The 2-diamines is the SQ109 reaction, forms formula (I) compound;
Figure FSB00000667852500032
3. preparation method as claimed in claim 2 is characterized in that, described method also comprises step: with formula (I) compound and the acid-respons that form, form pharmacy acceptable salt.
4. preparation method as claimed in claim 3 is characterized in that, with the toxilic acid reaction, thereby forms PHENRAMINE MALEATE.
5. a pharmaceutical composition is characterized in that, it contains pharmaceutically acceptable carrier and the described compound of claim 1 or its pharmacy acceptable salt.
6. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, is used to prepare the anti-mycobacterium tuberculosis medicine.
7. the purposes of the described compound of claim 1 or its pharmacy acceptable salt is characterized in that, is used to prepare the medicine of the infection that the treatment tubercule bacillus causes.
8. purposes as claimed in claim 7 is characterized in that, the infection that described infection causes for the multidrug resistance tubercule bacillus.
CN2008100420604A 2008-08-26 2008-08-26 Novel ethylene diamine derivative Expired - Fee Related CN101468958B (en)

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