CN103172619A - 4-(substituted benzyl)-1(2H)-2,3-phthalazinone derivatives, and preparation methods, medicinal compositions and uses thereof - Google Patents
4-(substituted benzyl)-1(2H)-2,3-phthalazinone derivatives, and preparation methods, medicinal compositions and uses thereof Download PDFInfo
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Abstract
The invention relates to 4-(substituted benzyl)-1(2H)-2,3-phthalazinone derivatives, and preparation methods, medicinal compositions and uses thereof, and concretely relates to compounds of formula I or isomers thereof, and pharmaceutically acceptable salts, solvates, chemical protection types and prodrugs thereof. R1, R2, R3, R4, R5 and R6 in the formula I are defined in the specification and the claim in the invention. The compounds are effective poly(ADP-ribose)polymerase (PARP) inhibitors.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the new 4-of a class (substituted benzyl)-1 (2H)-2,3-naphthyridine ketones derivant and preparation method thereof, its pharmaceutical composition and purposes, this compound have Poly ADP-Ribose Polymerase (PARP) and suppress active.
Background technology
Poly ADP-Ribose Polymerase (also is known as poly-ADP-ribose synthase and poly-ADP-ribosyltransferase, so-called PARP) family comprises approximately 18 kinds of protein now, although these protein have certain homology on catalyst structure domain, but its cell function is different (Ame etc., Bioessays.J., 342,249-268 (1999)).At present, only find that PARP-1 and PARP-2 are its active enzyme of catalysis by the DNA splitting of chain occurs.PARP-1 is the enzyme that extensively is present in Mammals, is many structures and the protein of a kind of 113-kDa of having, and PARP can identify strand or double-stranded breach and the combination quick with it of DNA, thereby participates in the signal conduction of DNA damage.(D ' Amours etc., 1999, Biochem.J.342:249-268)
At present, the conclusion that can draw is, PARP can coordinate DNA and repair and apoptosis, keep the complete and stable of DNA, PARP participates in the functions such as DNA relevant gene amplification, cell fission and differentiation, apoptosis, DNA base excision reparation, and affect telomere length and chromosome stability (d ' Adda di Fagagna etc., 1999, Nature Gen., 23 (1): 76-80).Also there is report to find that the interior PARP content of tumour cell and activity are all higher than normal cell.(shiobara M etc., J Gastroentero Hepatol, 2001,16:338-344)
Also have report the PARP inhibitor have the effect of angiogenesis inhibitor (Rajesh etc., Biochem.Biophys.Res.Comm..350:1056-1062).
In some vascular disease, septic shock, ischemia injury, septic shock, neurotoxicity, hemorrhagic shock, macular degeneration (AMD), pigment retina in the oxidative damage of visual correlation and organ-graft refection's pathogenic process, PARP-1 has also played effect (Cantoni etc., Biochim.Biophys.Acta, 1989,1014:1-7; Liaudet etc., Proc.Natl.Acad.Sci.U.S.A., 97 (3), 2000,97 (3): 10203-10208).Proved that the PARP inhibitor can treat or alleviate that PARP plays a role and the acute illness that causes, such as pancreatitis and relevant liver and injury of lung (Mota etc., Br.J.Pharmacol., 2007,151 (7): 998-1005).
A plurality of small molecules PARP inhibitor have been used for illustrating the function that poly-ADP-ribosylation is repaired at DNA, in the cell of processing through alkylating agent, PARP is suppressed to cause that DNA splitting of chain and necrocytosis significantly increase (Durcacz etc., Nature., 283:593-596 (1980); Berger, N.A., Radiation Research, 101,4-14 (1985)).
In a word, the PARP inhibitor is verified effective in a lot of disease models, and these diseases comprise supersensitivity encephalitis, sacroiliitis, cancer (comprising mammary cancer, cervical cancer, colorectal carcinoma, lymphoma, melanoma etc.), multiple sclerosis, organ transplantation, Parkinson's disease, inflammation of the central nervous system, interstitial pulmonary fibrosis, (eyes, intestines, kidney and skeletal muscle etc.) ischemia-reperfusion, virus infection, septic shock, apoplexy and other traumatic nerve injury and uveitis.Particularly in tumor model, the PARP inhibitor all has been proved to be able to increase apoptosis, the growth of restriction tumour, minimizing metastases, the effect of enhancing radiation and chemotherapy of cancer cell, and then in the clinical middle prolongation cancer patient survival time.Therefore, development PARP inhibitor has the needs of reality.
Summary of the invention
The objective of the invention is to seek and have the inhibiting new compound of potent PARP.The discovery that the inventor is unexpected has the 4-(substituted benzyl)-1 (2H) of formula I structure-2，3-benzodiazine ketones derivant and has the potent PARP restraining effect and/or have good interior medicine dynamics behavior.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides the 4-shown in formula I (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug,
Wherein, R
1Be selected from and replace or unsubstituted C
1-7Alkyl replaces or unsubstituted C
3-7Cyclic hydrocarbon radical; R
2, R
3, R
4, R
5Be independently selected from respectively hydrogen, replacement or unsubstituted C
1-7Alkyl replaces or unsubstituted C
3-7Cyclic hydrocarbon radical; R
6For-C (O) R
7, R
7Be selected from and replace or unsubstituted C
1-7Alkyl, replacement or unsubstituted C
5-20Aryl or heteroaryl replace or unsubstituted C
3-7Cyclic hydrocarbon radical,
4-described according to first aspect present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, wherein said C
1-7Alkyl can be C
1-7Alkyl, C
2-7Thiazolinyl, C
2-7Alkynyl; Described C
3-7Cyclic hydrocarbon radical can be C
3-7Cycloalkyl, C
3-7Cycloalkenyl group, C
3-7Cycloalkynyl radical.
4-described according to first aspect present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, wherein said C
1-7Alkyl can be selected from but be not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, C
5Branched-chain alkyl, hexyl, C
6Branched-chain alkyl, heptyl, suberyl, C
7Branched-chain alkyl, vinyl, propenyl, allyl group, butenyl, pentenyl, hexenyl, heptenyl, ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base; Described C
3-7Cyclic hydrocarbon radical can be selected from but be not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopropenyl radical, cyclobutene base; Described C
5-20Aryl or heteroaryl can be selected from but be not limited to pyridyl, pyrryl, phenyl, furyl, thienyl, pyrimidyl, quinolyl.
4-described according to first aspect present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, wherein said C
1-7Alkyl, C
3-7Cyclic hydrocarbon radical, C
5-20The substituting group of aryl or heteroaryl can be selected from but be not limited to halogen, hydroxyl, alkoxyl group, amino, amide group, alkylamino, and described halogen is selected from fluorine, chlorine or bromine.
4-described according to first aspect present invention (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug; wherein said pharmacy acceptable salt is selected from hydrochloride, vitriol, mesylate, tosylate, fumarate, maleate and malate, perhaps the solvate of these salt hydrate for example.
4-described according to first aspect present invention (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug; in one embodiment, described R
1Be selected from methyl, ethyl; R
2, R
3, R
4, R
5Be hydrogen independently respectively; R
7Be selected from methyl, trifluoromethyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
4-(substituted benzyl)-1 (2H) shown in formula I described according to first aspect present invention-2，3-benzodiazine ketones derivant is selected from following compound:
1-(cyclopropane carbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclopropane carbonyl)-3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-ethanoyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-propionyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(isopropyl acyl group)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(ring fourth formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(ring penta formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclohexylcarbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(trifluoroacetyl group)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclopropane carbonyl)-3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine.
Second aspect present invention provides the preparation method of the described 4-of first aspect present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, and it comprises the steps:
A) by 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) phenylformic acid synthetic intermediate III;
B) intermediate III under suitable acid exists, removes the Boc protecting group and generates intermediate compound IV;
C) intermediate compound IV and suitable acyl chlorides, acid anhydrides, active amide or active ester or react to get target compounds of formula I with corresponding carboxylic acid compound in suitable coupling system;
Wherein, R be selected from-Cl or
R
1, R
2, R
3, R
4, R
5And R
6Each group has defined implication in the arbitrary embodiment of first aspect present invention.
Preparation method described according to second aspect present invention; wherein step a) in 2-fluoro-5-(4-oxo-3; 4-dihydro-phthalazines-1-ylmethyl) after activated dose of activation of benzoic carboxyl; piperazine with single N-Boc protection reacts to get intermediate III again; wherein said activator can be selected from oxalyl chloride, sulfur oxychloride or N-hydroxy-succinamide; in one embodiment, described promoting agent is oxalyl chloride.
Preparation method described according to second aspect present invention, wherein step b) described in suitable acid can be selected from trifluoroacetic acid, hydrochloric acid, p-methyl benzenesulfonic acid or sulfuric acid, in one embodiment, described suitable acid is trifluoroacetic acid.
Preparation method described according to second aspect present invention, wherein step c) described in suitable acyl chlorides, acid anhydrides, active amide or active ester be R
6Suitable acyl chlorides, acid anhydrides, active amide or active ester.
Preparation method described according to second aspect present invention, wherein step c) described in suitable coupling system can be selected from coupling reagent and suitable alkali, in organic solvent, 0 ℃ of temperature range internal reaction to organic solvent boiling point used.
Wherein, described coupling reagent can be selected from 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate and hydroxybenzotriazole, or (dimethylaminopropyl) ethyl-carbodiimide hydrochloride and hydroxybenzotriazole; Described suitable alkali can be selected from diisopropyl ethyl amine; Described organic solvent can be selected from DMF or methylene dichloride.
Third aspect present invention relates to a kind of pharmaceutical composition; it comprises the described 4-of the arbitrary embodiment of first aspect present invention (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, and optional one or more pharmaceutically acceptable carrier and/or vehicle.Randomly, said composition can also comprise one or more active substances.Preferred active substance is chemotherapeutics.Preferred chemotherapeutics is Temozolomide etc.
Fourth aspect present invention relates to the described 4-of the arbitrary embodiment of first aspect present invention (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or the prodrug purposes in the preparation medicine, described medicine is used for the treatment of and/or prevents disease or the illness relevant to PARP (PARP-1 and/or PARP-2) of Mammals (comprising the people).
Fourth aspect present invention also relates to the described 4-of the arbitrary embodiment of first aspect present invention (substituted benzyl)-1 (2H)-2,3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug are for the preparation of the purposes in the disease relevant to PARP that treats and/or prevents Mammals (comprising the mankind) or illness medicine, wherein, the described disease relevant to PARP or illness comprise vascular disease; Septic shock; Ischemia injury; Reperfusion injury; Neurotoxicity; Hemorrhagic shock; Inflammatory diseases; Multiple sclerosis; The secondary effect of diabetes; Cytotoxic acute treatment after operation on vessels of heart and supersensitivity encephalitis; Sacroiliitis; Tumour or cancer (comprising mammary cancer, cervical cancer, colorectal carcinoma, lymphoma, melanoma etc.); Organ transplantation; Parkinson's disease; Inflammation of the central nervous system; Interstitial pulmonary fibrosis; (eyes, intestines, kidney and skeletal muscle etc.) ischemia-reperfusion; Virus infection, septic shock; Apoplexy and other traumatic nerve injury and uveitis or the disease that can alleviate by suppressing PARP.Described tumour or cancer comprise the cancer of noumenal tumour such as bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung (especially nonsmall-cell lung cancer), neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva etc., and non-noumenal tumour such as leukemia, multiple myeloma or lymphoma etc.
fifth aspect present invention also relates to the described 4-of the arbitrary embodiment of first aspect present invention (substituted benzyl)-1 (2H)-2, 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug for the preparation of in the treatment mammalian cancer as auxiliary or for the preparation of the purposes in the medicine that makes tumour cell become responsive to ionizing rays or chemotherapeutics, wherein said cancer or cancer cells can be to lack homologous recombination (homologous recombinational, HR) dependent DNA double-strand break (double-strand break, DSB) repair path or its contain one or more abilities by HR DNA plerosis DSB and relatively lower or forfeiture with normal cell.Wherein said cancer or cancer cells can be also to lack BRCA1 or BRCA2 in addition.It is pointed out that above-mentioned indication individuality is heterozygote heterozygosis or BRCA1 and/or BRCA2 sudden change with regard to the sudden change of the gene of coding HR dependent DNA DSB repair path component.
The feature that arbitrary embodiment of either side of the present invention or this aspect has is equally applicable to arbitrary embodiment of other side or this other side, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.
Below the invention will be further described.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In formula I compound of the present invention:
Term " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.
The term that adopts in the present invention " alkyl " has general sense well known in the art, they are hydrocarbyl groups of straight or branched, that replace or unsubstituted, can be also saturated undersaturated, so term " alkyl " comprise subclass as described below: alkyl, thiazolinyl, alkynyl.Such as but not limited to methyl, ethyl, propyl group, trifluoromethyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, allyl group, propenyl, proyl etc.
The term that adopts in the present invention " cyclic hydrocarbon radical " has general sense well known in the art, they are that replace or unsubstituted, can be also saturated undersaturated, so term " cyclic hydrocarbon radical " comprise subclass as described below: cycloalkyl, cycloalkenyl group, cycloalkynyl radical.Such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
The term that adopts in the present invention " aryl " and " heteroaryl " and have general sense well known in the art refer to the aromatic structure of ring-type on traditional sense, namely have the ring texture of delocalizedπelectron track.Aryl can only contain carbon atom, perhaps can contain carbon atom and one or more heteroatoms that includes but not limited to nitrogen, oxygen and sulphur atom, and aryl preferably has 5 or 6 annular atomses.Aromatic ring can contain one or more substituting groups in any suitable position on ring.These substituting groups are selected from halogen, haloalkyl, nitro, hydroxyl, sulfydryl, ether, thioether, amino, C
1-7Alkyl, C
1-7Assorted alkyl and aryl.
When mentioning " alkyl ", " cyclic hydrocarbon radical ", " aryl " and " heteroaryl ", prefix (C for example
1-7, C
3-7, C
5-20) scope of expression carbon atom number or annular atoms number.Term " C used herein for example
1-7Alkyl " refer to have the alkyl of 1-7 carbon atom.Notice that prefix may change according to other restrictions, for example for unsaturated alkyl, its prefix must be 2 at least, and in addition for five yuan or hexa-atomic heteroaryl, its prefix also can be less than 5.
Relevant especially to the present invention is following tautomer pair:
Attention: in term " isomer " particularly including the compound that has one or more isotropic substances and replace.For example, H can be any isotope form, comprises
1H,
2H (D) and
3H (T); C can be any isotope form, comprises
12C,
13C and
14C; O can be any isotope form, comprises
16O and
18O; Etc..In term " isomer " also particularly including the mixture of R, S isomer.
Unless otherwise specified, the appellation of specific compound is comprised all such isomeric forms, comprise its (wholly or in part) racemic mixture and other mixtures.Preparation (for example asymmetric synthesis) is known in the art with the method for separating (for example fractional crystallization and chromatography) this class isomeric forms, and method or the currently known methods of perhaps adjusting in a known way this paper easily obtain.
At the 4-(substituted benzyl)-1 (2H)-2 shown in preparation formula I of the present invention, in the method for 3-naphthyridine ketones derivant, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by document known method, or can buy by business.In above reaction scheme, intermediate used, starting material, reagent, reaction conditions etc. all can knowledge existing according to those skilled in the art can be made appropriate change.Perhaps, the 4-(substituted benzyl)-1 (2H) shown in other formula I of also can the present invention synthetic according to the second aspect present invention method specifically not enumerating of those skilled in the art-2，3-benzodiazine ketones derivant.
4-shown in formula I of the present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant can be used in combination with the other medicines activeconstituents, as long as it does not produce other detrimental actions, for example anaphylaxis.
4-shown in formula I of the present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant active compound can use as cancer therapy drug separately, perhaps can unite use with one or more other antitumor drugs.Combination therapy realizes by each being treated component while, order or separating administration.
Term used herein " composition " means to comprise the product of respectively specifying composition of specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.
Unless otherwise specified, the appellation of specific compound also comprised its ion, salt, solvate and protected form.
May be suitable or need to prepare, purifying and/or process the salt of corresponding active compound, for example pharmacy acceptable salt.Pharmacy is existing discussion of the people such as example Berge of acceptable salt still, " pharmacy acceptable salt ", J.Pharm.Sci., 66,1-19 (1977).
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacy acceptable salt.Term " pharmacy acceptable salt " refers to be suitable for contacting with zootic tissue and excessive toxicity, stimulation, anaphylaxis etc. not occurring with the mankind in reliable medical judgment scope, and with rational effect/risk than the salt that matches.Pharmacy acceptable salt is well known in the art.Described salt can be by making the compounds of this invention the free alkali functionality and suitable organic acid reaction, in final separation and the preparation of purge process situ or the preparation separately of the compounds of this invention.representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, alkaline nitrogen-containing group can be quaternized with following material: the muriate of elementary alkyl halide such as methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; The muriate of long-chain halogenide such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide such as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to form pharmaceutically acceptable acid salt comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid such as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt can contain carboxylic moiety and suitable alkali reaction by what make the compounds of this invention, final separation and the preparation of purge process situ at the compounds of this invention, described alkali is oxyhydroxide, carbonate and the supercarbonate of pharmaceutically acceptable metallic cation for example, perhaps ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacy acceptable salt also includes but not limited to based on the positively charged ion of basic metal or alkaline-earth metal such as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other representative organic amines that can be used for forming base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
4-shown in formula I of the present invention (substituted benzyl)-1 (2H)-2,3-naphthyridine ketones derivant also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, 4-shown in formula I of the present invention (substituted benzyl)-1 (2H)-2,3-naphthyridine ketones derivant and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges in vivo described activeconstituents after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of pharmaceutically acceptable solvent such as water, ethanol etc.
The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required result for the treatment of requires.
When being used for above-mentioned treat and/or prevent or when other treatment and/or prevention, a kind of the compounds of this invention that treats and/or prevents significant quantity can be used with pure form, perhaps uses with pharmaceutically acceptable ester or prodrug forms (in the situation that having these forms).Perhaps, described compound can be accepted the pharmaceutical composition administration of vehicle to contain this purpose compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect of any therapeutic treatment and/or prevention/risk than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to many factors, and described factor comprises the severity of the obstacle for the treatment of and this obstacle; The activity of the particular compound that adopts; The concrete composition that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment time length; The medicine that is used in combination with the particular compound that adopts or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required result for the treatment of requires.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example between 0.01～100mg/kg body weight/day, for example between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.
The pharmaceutical carrier that uses those skilled in the art to be familiar with can be prepared into the pharmaceutical composition of the compounds of this invention that contains effective dosage.Therefore the present invention also provides the pharmaceutical composition that comprises with one or more nontoxic drug acceptable carriers the compounds of this invention formulated together.That described pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, for the parenteral injection or for rectal administration.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, add injection water to use immediately before injection).in described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, corn normally, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), and if necessary, also contain disintegrating agent, as starch, agar, Lalgine or its salt, sodium alginate normally, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., the matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention can by in oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The composition that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, can reach the prolongation absorption of injectable drug form.
Also can contain suspension agent except the active ingredient beyond the region of objective existence in suspensoid, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol, polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or the intramuscularly medicine.This can be by realizing with the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Perhaps, the delay of the medicament forms of parenteral admin absorb by with this medicine dissolution in or be suspended in oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-PGA.Can according to the character of medicine with ratio with the concrete polymkeric substance that adopts of polymkeric substance, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class and polyanhydrides.Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering or sterilize by the disinfectant that mixes the aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can be with oral methods or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and the enteron aisle external application preparation has injection and suppository etc.These preparations prepare according to method appreciated by those skilled in the art.The auxiliary material of conventional use in order to make tablet, capsule, Drug coating auxiliary material used, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, the solvent that liquid dosage form is used such as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).Contain and also have other auxiliary material in the preparation of the compounds of this invention, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains the 4-shown in formula I of the present invention (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant in tablet, capsule, Drug coating, injection and suppository is that the compound amount that exists in unit dosage form is calculated.The 4-shown in formula I of the present invention (substituted benzyl)-1 (2H) in unit dosage form-general content of 2，3-benzodiazine ketones derivant is 1～5000mg, and preferred unit dosage form contains 10～500mg, and preferred unit dosage form contains 20～300mg.Specifically, the present invention's solid dosage for oral administration that can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least a inertia and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.In the situation that capsule, tablet and pill also can comprise buffer reagent in described formulation.
The solids composition of similar type uses such as lactose and high molecular weight polyethylene glycol etc. of vehicle, also can be used as the weighting material in soft capsule and hard capsule.
The solid dosage of tablet, dragee, capsule, pill and granule can prepare together with dressing and shell material such as enteric coating material and known other clothing materials of field of medicine preparations.These solid dosages can be chosen wantonly and contain opalizer, and its composition also can make it just or preferentially choose wantonly with the delayed mode release of active ingredients at certain position of enteron aisle.The example of operable embedding composition comprises polymer substance and wax class.If be fit to, active compound also can be made into the micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material except comprising inert diluent, for example wetting agent, emulsifying agent, suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by for example theobroma oil, polyoxyethylene glycol or suppository wax mix to prepare with the compounds of this invention and suitable non-irritating excipient or carrier, they are at room temperature solid, therefore but next at body temperature is liquid, can melt in rectal cavity or vaginal canal and discharges active compound.
Compound of the present invention and composition thereof are also considered for topical.Comprise powder, sprays, ointment and inhalation for the local dosage form that gives the compounds of this invention.Under aseptic condition with active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution also are considered within the scope of the present invention.
The compounds of this invention also can the liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stablizer, sanitas, vehicle etc. except containing the compounds of this invention.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.
Embodiment
Further illustrate the present invention below by concrete Preparation Example and biological experiment, but, should be appreciated that these embodiment and biological experiment are only used for the use that specifically describes more in detail, and should not be understood as for limiting in any form the present invention.
Although for to realize that many materials and working method that the object of the invention is used are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify, material used and working method are well known in the art.
In basis, unless otherwise indicated, wherein: (i) temperature with degree centigrade (℃) expression, operate under room temperature or temperature environment and carry out; (ii) organic solvent anhydrous sodium sulfate drying, the evaporation of solvent Rotary Evaporators reduction vaporization is bathed temperature not higher than 60 ℃; (iii) reaction process is followed the tracks of with thin-layer chromatography (TLC); (iv) end product have satisfied proton magnetic resonance (PMR) spectrum (
1H-NMR) and mass spectrum (MS) data; (v) wherein part of compounds to survey optically-active data solution used be methyl alcohol, temperature is 20 ℃.
The preparation of 4-(substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant intermediate
1,3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
A) 1-(uncle's fourth oxygen formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) first
Base]-the 2-fluorobenzoyl] preparation of piperazine (intermediate III)
Under room temperature, get 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) phenylformic acid 3.0g (10mmol) is suspended in the 100ml methylene dichloride, slowly adding wherein oxalyl chloride 5ml (55mmol), N, 2 of dinethylformamides keep room temperature reaction 5h, the evaporated in vacuo desolventizing, with (20ml * 3) toluene steam altogether remove residual oxalyl chloride after, then add in the reaction flask sealing of 50ml methylene dichloride standby; Separately get 2.0g (10mmol) 4-Boc-2 (S)-methylpiperazine and join 50ml methylene dichloride and 2.8ml (20mmol) triethylamine, at 0～5 ℃ of the outer temperature of maintenance reaction flask, drip wherein 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) dichloromethane solution of Benzoyl chloride, after dropwising, rise to room temperature reaction 5h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC.With 20ml distilled water, the water washing of 20ml saturated common salt, with anhydrous sodium sulfate drying, the rear evaporate to dryness that spends the night obtains faint yellow solid (intermediate III) 4.1g (productive rate 85%) with organic layer.
ES-API(m/z)：[M+Na]
+503.4。
B) 3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
With 1g (2mmol) 1-(uncle's fourth oxygen formyl radical)-3 (S)-methyl-4-[5-[(3; 4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine (intermediate III) is dissolved in the mixing solutions of 20ml methylene dichloride and 10ml trifluoroacetic acid; room temperature reaction 1h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC.The evaporate to dryness desolventizing obtains faint yellow solid (intermediate compound IV) 0.97g (productive rate 93%).
ES-API(m/z)：[M+H]
+381.2。
2,3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
A) 1-(uncle's fourth oxygen formyl radical)-3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) first
The base]-the 2-fluorobenzoyl] piperazine (intermediate III) preparation
Under room temperature, get 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) phenylformic acid 3.0g (10mmol) is suspended in the 100ml methylene dichloride, slowly adding wherein oxalyl chloride 5ml (55mmol), N, 2 of dinethylformamides keep room temperature reaction 5h, the evaporated in vacuo desolventizing, with (20ml * 3) toluene steam altogether remove residual oxalyl chloride after, then add in the reaction flask sealing of 50ml methylene dichloride standby; Separately get 2.0g (10mmol) 4-Boc-2 (R)-methylpiperazine and join 50ml methylene dichloride and 2.8ml (20mmol) triethylamine, at 0～5 ℃ of the outer temperature of maintenance reaction flask, drip wherein 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) dichloromethane solution of Benzoyl chloride, after dropwising, rise to room temperature reaction 5h, (developping agent DCM: MeOH=20: 1) detection reaction is complete for TLC.With 20ml distilled water, the water washing of 20ml saturated common salt, with anhydrous sodium sulfate drying, the rear evaporate to dryness that spends the night obtains faint yellow solid (intermediate III) 4.1g (productive rate 85%) with organic layer.
ES-API(m/z)：[M+Na]
+503.4。
B) 3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
With 1g (2mmol) 1-(uncle's fourth oxygen formyl radical)-3 (R)-methyl-4-[5-[(3; 4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine (intermediate III) is dissolved in the mixing solutions of 20ml methylene dichloride and 10ml trifluoroacetic acid; room temperature reaction 1h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC.The evaporate to dryness desolventizing obtains faint yellow solid (intermediate compound IV) 0.98g (productive rate 95%).
ES-API(m/z)：[M+H]
+381.2。
3,3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
A) 1-(uncle's fourth oxygen formyl radical)-3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) first
Base]-the 2-fluorobenzoyl] preparation of piperazine (intermediate III)
Under room temperature, get 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) phenylformic acid 3.0g (10mmol) is suspended in the 100ml methylene dichloride, slowly adding wherein oxalyl chloride 5ml (55mmol), N, 2 of dinethylformamides keep room temperature reaction 5h, the evaporated in vacuo desolventizing, with (20ml * 3) toluene steam altogether remove residual oxalyl chloride after, then add in the reaction flask sealing of 50ml methylene dichloride standby; Separately get 2.0g (10mmol) 4-Boc-2 (S)-ethyl piperazidine and join 50ml methylene dichloride and 2.8ml (20mmol) triethylamine, at 0～5 ℃ of the outer temperature of maintenance reaction flask, drip wherein 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) dichloromethane solution of Benzoyl chloride, after dropwising, rise to room temperature reaction 5h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC.With 20ml distilled water, the water washing of 20ml saturated common salt, with anhydrous sodium sulfate drying, the rear evaporate to dryness that spends the night obtains faint yellow solid (intermediate III) 4.1g (productive rate 85%) with organic layer.
E S-API(m/z)：[M+H]
+495.3。
B) 3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine
The preparation of piperazine trifluoroacetate (intermediate compound IV)
With 1g (2mmol) 1-(uncle's fourth oxygen formyl radical)-3 (S)-ethyl-4-[5-[(3; 4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine (intermediate III) is dissolved in the mixing solutions of 20ml methylene dichloride and 10ml trifluoroacetic acid; room temperature reaction 1h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC.The evaporate to dryness desolventizing obtains faint yellow solid (intermediate compound IV) 0.92g (productive rate 90%).
ES-API(m/z)：[M+H]
+395.2。
Embodiment 1:1-(cyclopropane carbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 1)
Compound 1
with 0.5g (0.9mmol) 3 (S)-methyl-4-[5-[(3, 4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine trifluoroacetate and 0.6ml (3.9mmol) triethylamine be dissolved in the 20ml methylene dichloride, keep dripping 0.12ml (1.3mmol) cyclopropyl formyl chloride at 0～5 ℃ of the outer temperature of bottle, rise to room temperature reaction 5h, (developping agent: methylene dichloride: methyl alcohol=20: 1) detection reaction is complete for TLC, with 15ml distilled water, the water washing of 15ml saturated common salt, with organic layer with anhydrous sodium sulfate drying, the rear evaporate to dryness that spends the night obtains faint yellow solid, column chromatography gets sterling (compound 1) 0.36g (productive rate 80%).Purity: 98.68%.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.59(s，1H)，8.27～8.25(m，1H)，8.00～7.94(m，1H)，7.92～7.86(m，1H)，7.46～7.40(br，1H)，7.40～7.32(br，1H)，7.28～7.20(m，1H)，4.41(s，2H)，4.70～4.00(m，3H)，3.60～2.60(m，4H)，2.10～1.82(m，1H)，1.40～0.70(m，4H)，0.50～0.30(br，3H)。
ES-API(m/z)：[M+H]
+449.2，[α]
D 20℃＝27.4°。
Embodiment 2:1-(cyclopropane carbonyl)-3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 2)
Compound 2
Described title compound is according to the method for embodiment (1), take 4-Boc-2 (R)-methylpiperazine and cyclopropyl formyl chloride as the raw material preparation, gets product compound 2, purity: 98.68%.
ES-API(m/z)：[M+H]
+449.3，[α]
D 20℃＝-27.5°。
Embodiment 3:1-ethanoyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) first
Base]-the 2-fluorobenzoyl] preparation of piperazine (compound 3)
Compound 3
Described title compound is according to the method for embodiment (1), and preparation, get product compound 3, purity: 99.17% take diacetyl oxide as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.61(s，1H)，8.29～8.26(m，1H)，8.00～7.95(m，1H)，7.92～7.86(m，1H)，7.86～7.82(m，1H)，7.46-7.41(m，1H)，7.40～7.33(m，1H)，7.28～7.21(m，1H)，4.34(s，2H)，4.70～3.50(m，3H)，3.50～2.58(m，4H)，2.10～1.92(m，3H)，1.20～0.90(m，3H)。
ESI-MS(m/z)：[M+H]
+423.5。
Embodiment 4:1-propionyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) first
Base]-the 2-fluorobenzoyl] preparation of piperazine (compound 4)
Compound 4
Described title compound is according to the method for embodiment (1), and preparation, get product compound 4, purity: 99.39% take propionic anhydride as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.65(s，1H)，8.31～8.29(m，1H)，8.10～7.97(m，1H)，7.95～7.89(m，1H)，7.89～7.84(m，1H)，7.49-7.43(m，1H)，7.43～7.34(m，1H)，7.31～7.23(m，1H)，4.36(s，2H)，4.76～3.60(m，3H)，3.50～2.58(m，4H)，2.51～2.21(m，2H)，1.21～0.98(m，6H)。
E S-API(m/z)：[M+H]
+437.3。
Embodiment 5:1-isopropyl acyl group-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)
Methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 5)
Compound 5
Described title compound is according to the method for embodiment (1), and preparation, get product compound 5, purity: 98.03% take isobutyric anhydride as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.60(s，1H)，8.28～8.25(m，1H)，7.99～7.94(m，1H)，7.92～7.86(m，1H)，7.86～7.82(m，1H)，7.46-7.41(m，1H)，7.40～7.33(m，1H)，7.28～7.21(m，1H)，4.30(s，2H)，4.74～3.50(m，3H)，3.30～2.57(m，4H)，1.25～1.14(m，1H)，1.10～0.85(m，9H)。
ES-API(m/z)：[M+H]
+451.3。
Embodiment 6:1-(ring fourth formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 6)
Compound 6
Described title compound is according to the method for embodiment (1), and preparation, get product compound 6, purity: 93.40% take cyclobutyl formyl acyl chlorides as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.63(s，1H)，8.30～8.26(m，1H)，8.00～7.95(m，1H)，7.92～7.86(m，1H)，7.86～7.82(m，1H)，7.47-7.41(m，1H)，7.41～7.31(m，1H)，7.29～7.21(m，1H)，4.34(s，2H)，4.78～3.50(m，3H)，3.50～2.56(m，4H)，2.24～1.68(m，7H)，1.18～0.90(m，3H)。
ES-API(m/z)：[M+H]
+463.3。
Embodiment 7:1-(ring penta formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 7)
Compound 7
Described title compound is according to the method for embodiment (1), and preparation, get product compound 7, purity: 98.40% take the cyclopentyl formyl chloride as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.61(s，1H)，8.29～8.25(m，1H)，8.00～7.94(m，1H)，7.93～7.86(m，1H)，7.86～7.81(m，1H)，7.47-7.41(m，1H)，7.41～7.31(m，1H)，7.29～7.20(m，1H)，4.34(s，2H)，4.76～3.50(m，3H)，3.30～2.58(m，4H)，1.88～1.46(m，9H)，1.20～0.90(m，3H)。
E S-API(m/z)：[M+H]
+477.3。
Embodiment 8:1-(cyclohexylcarbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 8)
Compound 8
Described title compound is according to the method for embodiment (1), and preparation, get product compound 8, purity: 96.74% take the cyclohexyl formyl chloride as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.60(s，1H)，8.29～8.25(m，1H)，8.00～7.93(m，1H)，7.93～7.86(m，1H)，7.86～7.81(m，1H)，7.47-7.39(m，1H)，7.39～7.30(m，1H)，7.28～7.20(m，1H)，4.33(s，2H)，4.75～3.50(m，3H)，3.50～2.50(m，4H)，1.74～1.54(m，6H)，1.48～1.20(m，5H)，1.20～1.00(m，3H)。
ES-API(m/z)：[M+H]
+491.3。
Embodiment 9:1-trifluoroacetyl group-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)
Methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 9)
Compound 9
Described title compound is according to the method for embodiment (1), and preparation, get product compound 9, purity: 97.85% take trifluoroacetic anhydride as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.61(s，1H)，8.30～8.25(m，1H)，8.00～7.94(m，1H)，7.93～7.87(m，1H)，7.86～7.82(m，1H)，7.48-7.42(m，1H)，7.41～7.35(m，1H)，7.30～7.22(m，1H)，4.34(s，2H)，4.86～3.85(m，3H)，3.80～2.90(m，4H)，2.10～1.90(m，3H)，1.21～0.92(m，3H)。
E S-API(m/z)：[M+H]
+477.2。
Embodiment 10:1-(cyclopropane carbonyl)-3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazines
Base) methyl]-the 2-fluorobenzoyl] preparation of piperazine (compound 10)
Compound 10
Described title compound is according to the method for embodiment (1), and preparation, get product compound 10, purity: 98.85% take 4-Boc-2 (S)-ethyl piperazidine as raw material.
1H-NMR(600MHz，DMSO-d
6，δ
ppm)：12.61(s，1H)，8.30～8.24(m，1H)，8.01～7.93(m，1H)，7.93～7.85(m，1H)，7.85～7.81(m，1H)，7.51-7.20(m，3H)，4.34(s，2H)，4.64～3.56(m，3H)，3.50～2.50(m，4H)，2.05～1.15(m，5H)，0.95～0.60(m，5H)。
ES-API(m/z)：[M+H]
+463.3。
Biological experiment
Can measure compound of the present invention to the restraining effect of Poly ADP-Ribose Polymerase (poly ADP-ribose polymerase, PARP) and in vivo to the growth-inhibiting effect of human colon cancer cell SW620 transplanted tumor in nude mice with following test.
The kinase reaction damping fluid that uses in experiment, PARP enzyme and Substrate DNA, NAD (Reduced nicotinamide-adenine dinucleotide, nicotinamide adenine dinucleotide, NAD), fluorescent marker Resazurin and Cycling enzyme, stop buffer all derive from the TREVIGEN INC. PARP of company assay kit (#4690-096-K).
A) PARP enzyme activity assay
External PARP enzyme analysis detects with the TREVIGEN INC. PARP of company assay kit (#4690-096-K), operation steps reference reagent box specification sheets.The method can be in the poly ADP ribose modification of vitro detection PARP enzyme to Substrate DNA, and when add testing compound in reaction system, namely detectable compounds is to the effect of PARP enzymeinhibition.Incubation PARP enzyme and Substrate DNA, NAD and add the compound 1-10 for preparing in embodiment 1-10 in the kinase reaction damping fluid under room temperature, after the room temperature lucifuge is hatched 30 minutes, add fluorescent marker Resazurin and Cycling enzyme, continue incubated at room 45 minutes, and added the stop buffer termination reaction.Detect fluorescence on the microplate reader of Molecular Device company, optical maser wavelength 544nm, emission wavelength 590nm calculates IC
50Value (nM), result is as shown in table 1.
The restraining effect of table 1. the compounds of this invention to the PARP enzymic activity
| Tester | IC 50(nM) |
| Compound 1 | 5 |
| Compound 2 | 55 |
| Compound 3 | 53 |
| Compound 4 | 1 |
| Compound 5 | 10 |
| Compound 6 | 1 |
| Compound 7 | 4 |
| Compound 8 | 1 |
| Compound 9 | 15 |
| Compound 10 | 50 |
Can see from above-mentioned experimental result, the compounds of this invention has stronger inhibition activity for the PARP enzymic activity.
B) the compounds of this invention cell levels and Temozolomide (TMZ) the enhanced sensitivity test of share
When share with the cytotoxic drug that acts on DNA, the PARP inhibitor can obviously increase the effect of cell toxicity medicament, the sensitization that the method detection the compounds of this invention and Temozolomide (TMZ) share.
Non-small cell lung carcinoma cell A549 (available from US mode culture collection warehousing American type culture collection) is in containing the F12 substratum of 10% foetal calf serum, 2mM glutamine and non-essential amino acid, at 37 ℃, 5%CO
2Culturing cell in cell culture incubator is used trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from Tissue Culture Flask.Cell adds 96 porocyte culture plates at 37 ℃, 5%CO with 2000/ hole (1ml substratum)
2In cell culture incubator, adherent culture is spent the night, change the fresh culture that contains different concns testing compound (compound 1-10) and Temozolomide (the Temozolomide consumption is 50mg/kg), DMSO (dimethyl sulfoxide (DMSO), Dimethyl sulfoxide, DMSO) ultimate density is 0.25%, with Tissue Culture Plate at 37 ℃, 5% CO
2Cultivated 72 hours under condition, then the trichoroacetic acid(TCA) fixed cell, dye with SRB, measures the absorbancy at 565nm place; Disposal data calculates and suppresses active and corresponding IC
50And the synergy multiple, result is as shown in table 2.Wherein, synergy multiple (chemosensitization ratio, CR)=IC
50(TMZ)/IC50 (TMZ+0.1 μ M TMZ).
Table 2. on the A549 cell, the sensitization of the compounds of this invention 0.1 μ M to Temozolomide (TMZ, 50mg/kg)
| Tester | IC 50(μM) | The synergy multiple |
| TMZ | ＞500 | - |
| TMZ+0.1 μ M compound 1 | 207.9 | ＜2.4 |
| TMZ+0.1 μ M compound 2 | 411 | ＜1.2 |
| TMZ+0.1 μ M compound 3 | 302 | ＜1.6 |
| TMZ+0.1 μ M compound 4 | 155.3 | ＜3.2 |
| TMZ+0.1 μ M compound 5 | 135.2 | ＜3.7 |
| TMZ+0.1 μ M compound 6 | 96.9 | ＜5.2 |
| TMZ+0.1 μ M compound 7 | 79.8 | ＜6.3 |
| TMZ+0.1 μ M compound 9 | 168.9 | ＜3 |
| TMZ+0.1 μ M compound 10 | 329 | ＜1.5 |
Can see from above-mentioned experimental result, the compounds of this invention has stronger biologic activity, and chemical compound lot all can significantly increase the cytotoxicity of TMZ.
C) evaluating drug effect in body
The BALB/cA nude mouse, female, age in 4-6 week, body weight 22 ± 2g, available from Beijing China Fukang biotech inc, SPF level environment is raised.
The human colon cancer cell SW620 cell (available from US mode culture collection warehousing American type culture collection) of vitro culture is inoculated in nude mice right side armpit subcutaneous, approximately inoculates 5 * 10 for every
6Individual cell is inoculated under the armpit of nude mouse right side.With vernier caliper measurement knurl footpath, after tumor growth to 100～200mm3 with the animal random packet.Compound 1-10 (being 10mg/kg), Temozolomide (50mg/kg), compound 1-10 (being 10mg/kg) share gastric infusion with Temozolomide (50mg/kg) respectively, once a day, continuous 5 days, control group was to equivalent solvent (with the solvent of Temozolomide equivalent).Five days administration phases and 45 days are recovered the observation period, measure weekly Mouse Weight and knurl footpath 2～3 times.Calculate gross tumor volume and relative tumour volume according to take off data, the calculation formula of gross tumor volume (tumor volume, TV) is: TV=1/2 * a * b2, wherein a, b represent respectively tumour major diameter and minor axis.Calculate relative tumour volume (relative tumor volume, RTV) according to the result of measuring, calculation formula is: RTV=Vt/V0.Gross tumor volume when wherein V0 is on-test, Vt are the gross tumor volume of measuring each time.The evaluation index of anti-tumor activity is relative tumor proliferation rate T/C (%), and calculation formula is as follows: T/C (%)=TRTV/CRTV * 100%, TRTV are treatment group RTV; The negative control group of CRTV (being the solvent control group) RTV, inhibition rate of tumor growth (being tumour inhibiting rate)=(1-T/C) * 100% relatively.Result is as shown in table 3.
The therapeutic action of table 3. the compounds of this invention to the SW620 Nude Mice
Annotate: D
14: referred to begin after administration the 14th day; D
50: referred to begin after administration the 50th day.
Result shows: compound 1, compound 5, compound 6, when compound 7 is alone, for the growth of SW620 and have no significant effect, when itself and cytotoxic drug Temozolomide share, can obviously strengthen the drug effect of Temozolomide, the tumour of slowing down is recovered the time of growth.Show with experimental result in the upper body, the compounds of this invention has effect of enhanced sensitivity preferably to cell toxicant based chemotherapy medical instrument.
Claims (10)
1. the 4-shown in formula I (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug,
Wherein, R
1Be selected from and replace or unsubstituted C
1-7Alkyl replaces or unsubstituted C
3-7Cyclic hydrocarbon radical; R
2, R
3, R
4, R
5Be independently selected from respectively hydrogen, replacement or unsubstituted C
1-7Alkyl replaces or unsubstituted C
3-7Cyclic hydrocarbon radical; R
6For-C (O) R
7, R
7Be selected from and replace or unsubstituted C
1-7Alkyl, replacement or unsubstituted C
5-20Aryl or heteroaryl replace or unsubstituted C
3-7Cyclic hydrocarbon radical,
Wherein said C
1-7Alkyl is C
1-7Alkyl, C
2-7Thiazolinyl, C
2-7Alkynyl; Described C
3-7Cyclic hydrocarbon radical is C
3-7Cycloalkyl, C
3-7Cycloalkenyl group, C
3-7Cycloalkynyl radical;
Randomly, described C
1-7Alkyl is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, C
5Branched-chain alkyl, hexyl, C
6Branched-chain alkyl, heptyl, suberyl, C
7Branched-chain alkyl, vinyl, propenyl, allyl group, butenyl, pentenyl, hexenyl, heptenyl, ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base;
Randomly, described C
3-7Cyclic hydrocarbon radical is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopropenyl radical, cyclobutene base;
Randomly, described C
5-20Aryl or heteroaryl are pyridyl, pyrryl, phenyl, furyl, thienyl, pyrimidyl, quinolyl;
Randomly, described C
1-7Alkyl, C
3-7Cyclic hydrocarbon radical, C
5-20The substituting group of aryl or heteroaryl is selected from halogen, hydroxyl, alkoxyl group, amino, amide group, alkylamino, and described halogen is selected from fluorine, chlorine or bromine.
2. 4-claimed in claim 1 (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug; wherein; described pharmacy acceptable salt is selected from hydrochloride, vitriol, mesylate, tosylate, fumarate, maleate and malate, perhaps the solvate of these salt.
3. 4-as claimed in claim 1 (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, wherein, R
1Be selected from and be methyl, ethyl; R
2, R
3, R
4, R
5Be hydrogen independently respectively; R
7Be selected from methyl, trifluoromethyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
4. 4-as claimed in claim 1 (substituted benzyl)-1 (2H)-2; 3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug; wherein; described 4-(substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant is selected from following compound:
1-(cyclopropane carbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclopropane carbonyl)-3 (R)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-ethanoyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-propionyl-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(isopropyl acyl group)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(ring fourth formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(ring penta formyl radical)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclohexylcarbonyl)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(trifluoroacetyl group)-3 (S)-methyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine;
1-(cyclopropane carbonyl)-3 (S)-ethyl-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-the 2-fluorobenzoyl] piperazine.
5. the preparation method of the described 4-of claim 1-4 any one (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, it comprises the following steps:
A) by 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazines-1-ylmethyl) phenylformic acid synthetic intermediate III;
B) intermediate III under suitable acid exists, removes the Boc protecting group and generates intermediate compound IV;
C) intermediate compound IV and suitable acyl chlorides, acid anhydrides, active amide or active ester or react to get target compounds of formula I with corresponding carboxylic acid compound in suitable coupling system;
Wherein, R be selected from-Cl or
R
1, R
2, R
3, R
4, R
5And R
6Described in claim 1;
Randomly, wherein step a) in 5-[(3,4-dihydro-4-oxo-1-phthalazinyl) methyl]-activated dose of activation of carboxyl of 2-fluorobenzoic acid after, piperazine with single N-Boc protection reacts to get intermediate III again, wherein said activator is selected from oxalyl chloride, sulfur oxychloride or N-hydroxy-succinamide, randomly, described promoting agent is oxalyl chloride;
Randomly, step b wherein) the suitable acid described in is selected from trifluoroacetic acid, hydrochloric acid, p-methyl benzenesulfonic acid or sulfuric acid, and randomly, described suitable acid is trifluoroacetic acid;
Randomly, suitable acyl chlorides, acid anhydrides, active amide or active ester step c wherein) are R
6Suitable acyl chlorides, acid anhydrides, active amide or active ester;
Randomly, step c wherein) the suitable coupling system described in can be selected from coupling reagent and suitable alkali, in organic solvent, and 0 ℃ of temperature range internal reaction to organic solvent boiling point used;
Randomly, described coupling reagent is selected from 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate and hydroxybenzotriazole, or (dimethylaminopropyl) ethyl-carbodiimide hydrochloride and hydroxybenzotriazole; Described suitable alkali is selected from diisopropyl ethyl amine; Described organic solvent is selected from DMF or methylene dichloride.
6. pharmaceutical composition, it comprises the described 4-of claim 1 to 4 any one (substituted benzyl)-1 (2H)-2,3-naphthyridine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug, and optional one or more pharmaceutically acceptable carrier and/or vehicle; Randomly, said composition can also comprise one or more active substances; Preferred active substance is chemotherapeutics; Preferred chemotherapeutics is Temozolomide.
7. pharmaceutical composition as claimed in claim 6, the formulation of this pharmaceutical composition is tablet, capsule, solution, enteric coated tablets, powder, ointment, dispersion agent, suspensoid, emulsion, injection, suppository, pill, granule, syrup, elixir, sprays, inhalation or liposome.
The described 4-of claim 1 to 4 any one (substituted benzyl)-1 (2H)-2，3-benzodiazine ketones derivant, isomer, its pharmacy acceptable salt, solvate, chemoproection form or prodrug for the preparation of in treating and/or preventing mammiferous disease or the illness medicine relevant to PARP, being used for the treatment of mammalian cancer as auxiliary or the purposes that is used for making tumour cell to become responsive medicine to ionizing rays or chemotherapeutics.
9. purposes as claimed in claim 8, wherein, the described disease relevant to PARP or illness comprise vascular disease; Septic shock; Ischemia injury; Reperfusion injury; Neurotoxicity; Hemorrhagic shock; Inflammatory diseases; Multiple sclerosis; The secondary effect of diabetes; Cytotoxic acute treatment after operation on vessels of heart and supersensitivity encephalitis; Sacroiliitis; Tumour or cancer; Organ transplantation; Parkinson's disease; Inflammation of the central nervous system; Interstitial pulmonary fibrosis; The ischemia-reperfusion of eyes, intestines, kidney and skeletal muscle; Virus infection; Septic shock; Apoplexy and other traumatic nerve injury and uveitis or the disease that can alleviate by suppressing PARP,
Randomly, described tumour or cancer comprise cancer, nonsmall-cell lung cancer, mammary cancer, cervical cancer, colorectal carcinoma, lymphoma, the melanomatous noumenal tumour that is selected from bile duct, bone, bladder, brain/central nervous system, breast, knot rectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, esophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva, and are selected from leukemia, multiple myeloma or lymphadenomatous non-noumenal tumour.
10. purposes as claimed in claim 8 or 9, wherein, described Mammals is the mankind.
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| CN201110427580.9A CN103172619B (en) | 2011-12-20 | 4-(substituted benzyl)-1 (2H)-phthalazone analog derivative and preparation method thereof, pharmaceutical composition and purposes |
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| CN103172619A true CN103172619A (en) | 2013-06-26 |
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