CN101501018B - Hydrogen sulfide derivatives of non-steroidal anti-inflammatory drugs - Google Patents

Hydrogen sulfide derivatives of non-steroidal anti-inflammatory drugs Download PDF

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CN101501018B
CN101501018B CN200780029321.2A CN200780029321A CN101501018B CN 101501018 B CN101501018 B CN 101501018B CN 200780029321 A CN200780029321 A CN 200780029321A CN 101501018 B CN101501018 B CN 101501018B
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compound
phenyl
compounds
diclofenac
cox
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CN101501018A (en
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J·L·沃雷斯
G·西里诺
V·桑塔加达
G·卡里安多
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Aetnabe Amarco
Antibe Therapeutics Inc
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Antibe Holding Co
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Abstract

The present invention relates to hydrogen sulfide derivatives of non-steroidal anti-inflam matory drugs (NSAIDs) having improved anti-inflammatory properties useful in the treatment of inflammation, pain and fever. More particularly, NSAIDs are derivatized with a hydrogen sulfide (H2S) releasing moiety to produce novel anti-inflammatory compounds having reduced side effects.

Description

The hydrogen sulfide derivatives of NSAID (non-steroidal anti-inflammatory drug)
The application submits to as the further part of the PCT/CA2006/000484 submitting on March 31st, 2006, and the latter requires the right of priority of the PCT/CA2005/000819 of submission on May 27th, 2005.60/887,188 the right of priority that the application also requires the U.S. Provisional Patent Application 60/807,639 of submitting on July 18th, 2006 and submits on January 30th, 2007.
Invention field
The derivative of NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) that the present invention relates to have the antiinflammatory property of improvement, it can be used for the treatment of inflammation, pain and fever.More specifically, NSAIDs is with hydrogen sulfide (H 2s) release portion derives, to produce the new anti-inflammatory compound with lower side effect.
Background of invention
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is widely used in treats illness various and pain, fever and inflammation-related, comprises osteoarthritis, rheumatoid arthritis gout and ankylosing spondylitis.They are also widely used in treatment acute pain and the headache relevant with surgical method (comprising dentistry method) with infringement.People extensively believe, the beneficial effect of NSAIDs is because they suppress the synthetic ability of prostaglandin(PG) by suppressing cyclooxygenase-1 (COX-1) and COX-2 (COX-2).
Yet, because NSAIDs can cause GI clinical remarkable injury, so NSAIDs formula is divided into (Wallace, the J.L.Nonsteroidalanti-inflammatory drugs and gastroenteropathy:the secondhundred years.Gastroenterology 1997 that limits life-time service; 112:1000-1016).The selective depressant of COX-2 is regarded as a progress of conventional NSAIDs, because they obviously can cause less gastrointestinal damage.But, the Cardiovascular Toxicity of these medicines has been had to more and more higher concern, may also relate to conventional NSAIDs (people such as Grosser, Biological basis forthe cardiovascular consequences of COX-2 inhibition:therapeutic challenges and opportunities.J Clin Invest.2006; 116:4-15).
As everyone knows, NSAIDs stimulates white cell to adhere to and reduces gastric mucosal blood flow, and these effects are widely regarded as the major reason (Wallace, 1997) to the pathology of the gastrointestinal damage of NSAID-induction.The induction that non-selective and COX-2-selective N SAIDs adheres to white cell also can cause the cardiovascular complication of these medicines.
Recently observe hydrogen sulfide (H 2s) performance anti-inflammatory and analgesic activity.H 2s is a kind of endogenous material, is produced, and affect a lot of functions (Wang, Two ' scompany, three ' s a crowd:can H by a lot of tissues 2s be the third endogenous gaseoustransmitter? FASEB J 2002; 16:1792-1798).It has demonstrated is a kind of vasodilator, can suppress white cell adhering on blood vessel endothelium (Wang, 2002; The people such as Fiorucci, Inhibition of hydrogen sulfide generationcontributes to gastric injury caused by anti-inflammatorynonsteroidal drugs.Gastroenterology.2005; 129:1210-1224).In addition, the people such as Fiorucci (2005) are verified, use H in rat 2s donor pretreat can reduce the severity of the gastric damage of NSAID-induction.
Astoundingly, the inventor shows in this application, when with H 2s release portion covalent attachment or and H 2when S release portion forms NSAID salt, the anti-inflammatory activity of various NSAIDs has obtained significant enhancing.In addition, these NSAID derivatives have demonstrated the side effect of reduction.Especially, the inventor shows, NSAID derivative of the present invention has one or more following additional character: the gastrointestinal damage that (1) produces is less than conventional NSAIDs; (2) promoted the healing of already present stomach ulcer; (3) systemic blood pressure causing raises significantly less than conventional NSAIDs.In addition, NSAID derivative of the present invention has reduced white cell to the adhering to of blood vessel endothelium, and this can reduce stomach and intestine and cardiovascular side effects.
Summary of the invention
In one aspect of the invention, provide the derivative of NSAIDs, described derivative comprises with NSAID covalent attachment or with NSAID and forms the H of salt 2s-release portion.Astoundingly, with alone NSAID, alone H 2s-release portion and respectively but do not use together NSAID and H 2the combination of S-release portion is compared, and compound of the present invention demonstrates the anti-inflammatory activity of enhancing in the pawl edema model of rat carrageenan-induction.In addition, NSAID derivative of the present invention makes blood plasma H 2rising appropriate, short-term that S concentration has produced.Be not associated with theory, still the blood plasma H within the scope of physiology 2the short-term of S concentration raises and can produce the anti-inflammatory activity of enhancing.
Astoundingly, compare with the non-derivative NSAID counterpart separately of compound of the present invention, compound of the present invention also demonstrates and strengthens suppressing the active ability of COX-2 (COX-2) activity and/or cyclooxygenase 1 (COX-1).The ability of this inhibition COX-2 and/or COX-1 strengthens also can make viewed anti-inflammatory activity strengthen.In addition the compound of the present invention, the inhibition of COX-1 being strengthened demonstrates thromboxane B in thrombocyte 2the remarkable inhibition producing, this can make Cardiovascular Toxicity reduce.
In addition, compound of the present invention has shown than they non--derivative less side effects of counterpart separately.For example, some compounds have been induced the remarkable less gastric damage than alone NSAID astoundingly, although these compounds have obviously suppressed the synthetic of stomach prostaglandin(PG).Although the H with these NSAIDs 2s-discharges derivative and has observed stomach security, if but to rat respectively but do not use together NSAID and H 2s-release portion, situation is just different.Be not associated with theory, compound of the present invention demonstrates and can reduce white cell to the adhering to of blood vessel endothelium, and this has just facilitated their stomach security.In addition white corpuscle adhering to reduction and can reduce the common cardiovascular side effects of life-time service NSAIDs blood vessel endothelium.
In addition, when being applied to Hypertensive Rats, what observe when only using conventional NSAIDs compares, and compound of the present invention makes the rising of systolic pressure significantly less.The tendency of elevation of blood pressure reduces to reduce cardiovascular side effect, and this side effect is common when life-time service NSAIDs.
According to the present invention, provide the compound with following general formula:
A-Y-X (formula I)
Wherein A is NSAID group, be selected from-C of Y (O) O-,-C (O) NH-,-C (O) OC (O)-,-C (O) NHCH 2c (O)-or zero, and X can (below be called H separately or when can discharge the part of hydrogen sulfide when NSAID is combined 2s-release portion), or its pharmacologically acceptable salts, wherein, when Y is zero, this NSAID derivative can be the salt of A and X.
In a preferred embodiment, the X of formula I is selected from:
Yet, should be understood that, no matter be alone or when when NSAID is combined, can use in the present invention any nontoxicity, can discharge H 2the significant part of S.
In one embodiment, compound of the present invention has following general formula:
B-C (O) O-X (formula II)
Wherein B-C (O) O-is by having the NSAID of free carboxy or the NSAID of carboxyl-replacement obtains, and X is H 2s-release portion, or its pharmacologically acceptable salts.
In one embodiment, the B-C of formula II (O) O-is selected from:
And X is hydrogen sulfide (H 2s) release portion.
In one embodiment, the X of formula II is selected from:
Yet, should be understood that, no matter be alone or when when NSAID is combined, can use in the present invention any nontoxicity, can discharge H 2the significant part of S.
The NSAIDs paying close attention in the combination of compound of the present invention comprises acetylsalicylic acid (ASA), diclofenac, Naproxen Base, indomethacin, flurbiprofen, sulindac, Ibuprofen BP/EP, Aceclofenac, acemetacin, Compd 90459, the fragrant acid of benzyl, Bromfenac, bucloxonic acid, butibufen, carprofen, celecoxib, Racemic cycloprofen, cinmetacin, clidenac, Clopirac, diflusinal, R-ETODOLAC, L-791456, fenbufen, Fenclofenac, Fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, furobufen, Furofenac (furafenac), ibufenac, indoprofen, Isoxepac, Ketoprofen, ketorolac, loxoprofen, lonazolac, Lu meter Kao former times, metiazinic acid, mefenamic acid, meclofenamic acid, meloxicam, nabumetone, piromidic acid, salsalate, miroprofen, Taisho), Oxepinac, parecoxib, Phenylbutazone, pyrroles is fragrant, piroxicam, pirozolac, protizinic acid, rofecoxib, sodium salicylate, sutoprofen, tiaprofenic acid, tolmetin, valdecoxib, zomepirac etc.
Preferred compound is those of following formula:
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl Aspirin ester (I),
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester,
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (III),
[1-(the chloro-benzoyl of 4-)-5-methoxyl group-2-Methyl-1H-indole-3-yl]-acetic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (IV),
2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (V),
2-acetoxyl group-phenylformic acid 4-(5-oxo-5H-[1,2] dithiole-3-yl)-phenylester (VI),
[2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-(5-oxo-5H-[1,2] dithiole-3-yl)-phenylester (VII),
[2-(the fluoro-phenyl amino of the chloro-6-of 2-)-5-methyl-phenyl]-acetic acid 4-(5-oxo-5H-[1,2] dithiole-3-yl)-phenylester (VIII),
[1-(the chloro-benzoyl of 4-)-5-methoxyl group-2-Methyl-1H-indole-3-yl]-acetic acid 4-(5-oxo-5H-[1,2] dithiole-3-yl) phenylester (IX),
2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-(5-oxo-5H-[1,2] dithiole-3-yl)-phenylester (X),
2-acetoxyl group-phenylformic acid 4-(5-oxyimino-5H-[1,2] dithiole-3-yl)-phenylester (XI),
[2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-(5-oxyimino-5H-[1,2] dithiole-3-yl)-phenylester (XII),
[2-(the fluoro-phenyl amino of the chloro-6-of 2-)-5-methyl-phenyl]-acetic acid 4-(5-oxyimino-5H-[1,2] dithiole-3-yl)-phenylester (XIII),
[1-(the fluoro-benzoyl of 4-)-5-methoxyl group-2-Methyl-1H-indole-3-yl]-acetic acid 4-(5-oxyimino-5H-[1,2] dithiole-3-yl) phenylester (XIV),
2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-(5-oxyimino-5H-[1,2] dithiole-3-yl)-phenylester (XV),
2-acetoxyl group-phenylformic acid 4-thiocarbamyl-phenylester (XVI),
[2-(the fluoro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-thiocarbamyl-phenylester (XVII),
[2-(the fluoro-phenyl amino of the chloro-6-of 2-)-5-methyl-phenyl]-acetic acid 4-thiocarbamyl-phenylester (XVIII),
[1-(the chloro-benzoyl of 4-)-5-methoxyl group-2-Methyl-1H-indole-3-yl]-acetic acid 4-thiocarbamyl-phenylester (XIX),
2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-thiocarbamyl-phenylester (XX),
4-isothiocyano phenyl Aspirin ester (XXI),
4-isothiocyano phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (XXII),
4-isothiocyano phenyl 2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (XXIII),
4-(isothiocyano)-phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (XXXIV),
4-isothiocyano phenyl 2-(2-methoxyl group naphthyl-6-yl) propionic ester (XXV),
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(4-isobutyl phenenyl) propionic ester (XXVI),
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(3-benzoylphenyl) propionic ester (XXVII),
4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(the fluoro-4-xenyl of 2-) propionic ester (XXVIII),
4-thiocarbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester (XXIX),
4-thiocarbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (XXX),
4-thiocarbamyl phenyl 2-(the fluoro-4-xenyl of 2-) propionic ester (XXXI),
4-isothiocyano phenyl 2-(4-isobutyl phenenyl) propionic ester (XXXII),
4-(isothiocyano)-phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (XXXIII), and
4-(isothiocyano)-phenyl 2-(the fluoro-4-xenyl of 2-) propionic ester (XXXIV).
According to methods known in the art, prepare above-mentioned precursor NSAIDs (A).Referring to, The Merck Index for example, 13 thedition (2001), Merck & Co., WhitehouseStation, N.J., by reference to being incorporated herein.When available, can use corresponding isomer, comprise optically active isomer.
The pharmacologically acceptable salts of compound of the present invention, for example, with alkali and alkaline earth metal ions, avirulent amine and amino acid whose salt are also parts of the present invention.The preferably salt of compound of the present invention is the salt with arginine and agmatine.Also comprise the acceptable acid salt of pharmacy.
In a preferred embodiment, use H 2s-release portion 4-hydroxyl thiobenzamide (being called TBZ herein) derives NSAIDs of the present invention.With 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (ADT-OH) derivative is compared, and TBZ derivative demonstrates better total anti-inflammatory activity and lower side effect consistently.Astoundingly, compare with ADT-OH derivative, TBZ derivative has produced significantly more H 2s, this strengthens anti-inflammatory activity, and side effect reduces.
In addition, compare with ADT-OH derivative, TBZ derivative has kept suppressing the ability of COX-1/COX-2 more consistently.In fact, in fact a lot of TBZ derivatives have shown the enhancing that COX-1 is suppressed or COX-2 is suppressed, or both have concurrently.In addition, with ADT-OH equivalent, compound V (Naproxen Base-ADT-OH) compares, compounds X X (Naproxen Base-TBZ derivative) is significantly better in inhibition thromboxane B2 is synthetic, with ADT-OH equivalent, compound IV (indomethacin-ADT-OH derivative) is compared, and compounds X IX (indomethacin-TBZ derivative) is significantly better in inhibition thromboxane B2 is synthetic.The enhancing that thromboxane B2 is suppressed can be facilitated the cardiovascular safety of derivative of the present invention.
Can as described in following two schemes, prepare compound of the present invention:
Scheme 1
With synthesizing as an example of 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (Compound I I), scheme 1 is as follows.
First will have the NSAID (or NSAID of carboxyl substituted) of free carboxy, for example diclofenac (1), is dissolved in dimethyl formamide, and adds hydroxybenzotriazole (HOBt) and 1,3-dicyclohexylcarbodiimide (DCC).Be applicable to for example forming compound of the present invention, 4-(5-sulfo--5H-1,2-dithiole-3-yl) (2-(2 for phenyl 2-, 6-dichlorophenyl amino) phenyl) under the condition of acetic ester (3), in this mixture, add hydrogen sulfide-release portion, 5-p-hydroxybenzene-1 for example, 2-dithiole-3-thioketones (ADT-OH) (2).Should be understood that, in this scheme, can use other hydrogen sulfide release portions, for example 4-hydroxy phenyl lsothiocyanates (being called HPI herein).
Scheme 2
With synthesizing as an example of [2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-thiocarbamyl-phenylester (compounds X VII), scheme 2 is as follows.In this scheme, after hydrogen sulfide release portion and NSAID covalent attachment, use Lawesson reagent to add sulfenyl on this release portion.
First will have the NSAID (or NSAID of carboxyl substituted) of free carboxy, for example diclofenac (1), is dissolved in dimethyl formamide, and adds hydroxybenzotriazole (HOBt) and 1,3-dicyclohexylcarbodiimide (DCC).At the precursor that be applicable to form the compound of the present invention that lacks a sulphur (for example; (2-(2 for 4-carbamyl phenyl 2-; 6-dichlorophenyl amino), under condition phenyl) acetic ester (2)), in this mixture, add hydrogen sulfide to discharge for example 4-hydroxybenzamide of precursor.Add the suitable compound that can add a sulfenyl, for example Lawesson reagent forms compound of the present invention (for example, [2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-thiocarbamyl-phenylester (3).
One other aspect, the invention provides compound of the present invention and, the pharmaceutical composition of the acceptable vehicle of pharmacy or carrier, especially for the compound of the present invention of the inflammation in treatment GI road.
Compound of the present invention can be for, but be not limited to, and treats inflammation in patient, and be used for the treatment of the disease of other and inflammation-related, for example, in treatment pain and headache as anodyne, or in treatment fever as febrifugee.For example, compound of the present invention can be used for the treatment of sacroiliitis, includes but not limited to rheumatoid arthritis, arthritis vertebralis, urarthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.These compounds of the present invention can be used for the treatment of asthma, bronchitis, menstrual cramps, tendonitis, bursitis, the illness relevant with skin be psoriasis, eczema, burn and dermatitis for example, and postoperative inflammation comprises by the eye surgery inflammation that for example cataract surgery and dioptric surgery cause.Compound of the present invention also can be used for the treatment of gastrointestinal disorder, and for example inflammatory bowel, Ke Laoen disease, gastritis, irritable bowel syndrome and ulcerative colitis, for example, for prevention or treatment cancer, colorectal carcinoma.Compound of the present invention can be used for the treatment of the inflammation in some diseases, described disease be for example vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin, sclerosis, rheumatic fever, type i diabetes, comprise myasthenia gravis Neuromuscular node disease, comprise swelling that white matter disease, sarcoidosis, nephrotic syndrome, behcet's syndrome, polymyositis, oulitis, ephritis, allergy, the damage of multiple sclerosis occur afterwards, myocardial ischemia etc.This compound also can be used for the treatment of eye disease, for example the acute injury of the retinitis, retinopathy, uveitis, eye photophobia and ocular tissue.This compound also can be used for the treatment of pneumonia, for example those relevant with virus infection and cystic fibrosis.This compound also can be used for the treatment of some central nervous system disease, for example cortex dementia alzheimer's disease for example.Compound of the present invention can be used as anti-inflammatory agent, for for example treatment of arthritis, and has significantly less additional benefits of side effect.These compounds can be used for the treatment of rhinallergosis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and the nervus centralis that caused by apoplexy, ischemic and wound damages.This compound also can be used for the treatment of pain, but is not limited to the pain that postoperative pain, toothache, myalgia and cancer cause.Except the treatment for the mankind, these compounds can be used for the treatment of Mammals, comprise horse, dog, cat, rat, mouse, sheep, pig etc.
According to concrete illness or the morbid state that will treat, patient can with any suitable treatment effectively and safe dose use compound of the present invention, it is confirmable that this is that those skilled in the art are easy to.Expectation, these compounds, with the dosage range of every day approximately 1 to about 2000mg, are used with single or fractionated dose, although can change according to the patient's that will treat body weight and situation and selected particular route of administration if desired.Should be understood that, the specific NSAID that is used to form compound of the present invention can affect dosage.Yet the dosage level of expecting is most that approximately 0.1 to about 100mg/kg, preferred approximately 5 arrive 90mg/kg, more preferably from about 5 to 50mg/kg scope.Yet according to the people's that will treat body weight and situation, they are replied the individuality of described medicine, and the type of selected pharmaceutical preparation and carry out described in time and the interval of using, can change.In some cases, the dosage level lower than the lower limit of above-mentioned scope can be more suitable, and in other situations, can use larger dosage and not cause any harmful side effect, condition is first described heavy dose to be divided into several low doses of using in whole day.
Compound of the present invention can be used with the form of any pharmaceutical preparation, and its character will depend on the approach of using.Can pass through ordinary method, with compatible, the acceptable vehicle of pharmacy or carrier, prepare these pharmaceutical compositions.The example of these compositions comprises capsule, tablet, transdermal patch, lozenge, lozenge, sprays, syrup, pulvis, granule, gelifying agent, elixir, suppository etc., for the preparation of interim solution, the preparation of injectable preparation, rectum, nose, eye, vagina.Preferred route of administration is oral and rectum approach.
For oral, comprise various vehicle for example Microcrystalline Cellulose, Trisodium Citrate, calcium carbonate, Si Liaodengji dicalcium phosphate feed grade and glycine tablet can with various disintegrating agents for example starch (preferably corn, potato and tapioca (flour)), Lalgine and some composition silicate, and particle binders for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic can together with use.In addition, for example Magnesium Stearate, Sulfuric acid,monododecyl ester, sodium salt and talcum can be for film-making objects for lubricant.Also can use the solids composition of similar type, for example in gelatine capsule as weighting agent; At preferred material aspect this, comprise lactose or toffee, and high molecular weight polyethylene glycol.When the oral aqueous suspension of needs and/or elixir, can be by activeconstituents and sweetener or seasonings, coloring material, if and the emulsifying agent and/or the suspending agent that need, and with thinner for example water, ethanol, propylene glycol, glycerine with and various combinatorial association.
Formulation can be designed for discharging immediately, controlling release, extend release, delayed release or directed delayed release.The definition of these terms is well known by persons skilled in the art.In addition, the composition of polymeric blends is, the releasing properties that many particulate compositions of the substrate composition of dressing, many particulate compositions, dressing, the composition based on ion exchange resin, the composition based on infiltration or Biodegradable polymeric composition can affect formulation.Do not wish to be associated with theory, it is believed that by good diffusion, dissolving, etch, ion-exchange, infiltration or its combination and can affect release.
For parenteral, use, can use the solution of active compound in sesame or peanut oil or in aqueous propylene glycol solution.If desired, aqueous solution should be (preferably pH is greater than 8) suitably cushioned, and first liquid diluent has isotonicity.Aqueous solution is suitable for intravenous object.By well known to a person skilled in the art that standard pharmaceutical technology is easy to realize the preparation of all these solution under aseptic condition.
The following examples further describe, and make those of ordinary skill in the art can implement and use the present invention.Yet, will be appreciated that, these embodiments are for explaining object of the present invention, and should not be construed as restriction by the defined scope of the present invention of claim.
Accompanying drawing explanation
What accompanying drawing 1 showed is to use carrier, diclofenac and two kinds of ramification of diclofenac of the present invention, the gastric damage score in the rat of Compound I I and compounds X VII treatment.
What accompanying drawing 2 showed is with carrier, diclofenac, the stomach PGE that the rat of Compound I I and compounds X VII treatment produces 2(PGE 2) amount.
What accompanying drawing 3 showed is to use carrier, Naproxen Base and two kinds of Naproxen derivatives of the present invention, the gastric damage score in the rat of compound V and compounds X X treatment.
Accompanying drawing 4 shows is thromboxane B in the blood of accompanying drawing 3 rats 2synthetic amount.
What accompanying drawing 5 showed is with carrier, the total length of the rat Small Intestine ulcer of diclofenac and Compound I I treatment.
What accompanying drawing 6 showed is to use carrier, diclofenac and Compound I I treatment front and rear, the per-cent of hematocrit in rat.
Accompanying drawing 7 shows is when with carrier, diclofenac, and when Compound I I and compounds X VII treatment, what by rat bag method, in the subcutaneous pocket of rat, produce oozes out PGE 2amount.
That accompanying drawing 8 shows is whole blood thromboxane B in the rat of accompanying drawing 7 2(TXB 2) amount.
What accompanying drawing 9 showed is with carrier, in the rat of diclofenac and Compound I I treatment, corpus unguis is amassed to the inhibition increasing.
What accompanying drawing 10 showed is with carrier, in the rat of diclofenac and compounds X VII treatment, corpus unguis is amassed to the inhibition increasing.
Accompanying drawing 11 shows is when with carrier, Naproxen Base, and when compound V and compounds X X treatment, what by rat bag method, in the subcutaneous pocket of rat, produce oozes out PGE 2amount.
What accompanying drawing 12 showed is synthetic (ng/ml) (external) of the thromboxane being caused by human blood as the function of indomethacin, compound IV and compounds X IX concentration.
Accompanying drawing 13 shows is with carrier, diclofenac, and compounds X VII, Naproxen Base and compounds X X treat every day, after totally 1 week, the surface-area of stomach ulcer in rat, unit is mm 2.
What accompanying drawing 14 showed is to use carrier, diclofenac, Compound I I, the rising of systolic blood pressure (mm Hg) in the rat of Naproxen Base and compounds X X treatment.
What accompanying drawing 15 showed is the amount of the hydrogen sulfide of blood plasma when the Compound I I with 50 μ mol/kg p.o. treats rat.
What accompanying drawing 16 showed is when cultivating at damping fluid with in liver homogenate, the amount of the hydrogen sulfide that Compound I I and compounds X VII produce.
Embodiment
the preparation of compound
Carry out tlc having on Macherey-Nagel silica gel 50 plates of fluorescent indicator, with UV light (254nm), make this plate visual.Kieselgel 60 is for column chromatography.All synthetic agents are all purchased from Aldrich-Sigma Chemical Company, and can use without purifying.Solvent be analytical reagent level or there is higher purity, and use during as providing.Buchi R-114 Rotary Evaporators is for removing desolventizing under vacuum.Pass through proton 1h-NMR and 13identify to C-NMR spectroscopy structure.Spectrum is recorded on Varian Mercuryplus 400 instruments.Chemical shift refers to respect to the Me as internal standard substance 4si.The mass spectrum of the product of synthesized is measured on Applied Biosystem API 2000 mass spectrographs.Fusing point is measured on Buchi B-540 equipment.By RP-HPLC, determine the purity of final compound.By post and Rheodyne model 7725 syringes, Waters 600HPLC system, be set to 215 or the adjustable absorption photometric detector of Waters 486 of 235nm be connected with Waters 746 chart recorders.The compound of synthesized has provided gratifying ultimate analysis; It only represents analytical results by the symbol of element, result theoretical value ± 0.4% in.
Embodiment 1
[2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (Compound I I) synthetic
Scheme 1
5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; Synthesizing ADT-OH)
Methyl allylphenol (31g, 0.21mol) and Sulfur (44.8g, 1.40mol) are heated 8 hours in DMF (250ml); After removing desolventizing, residue is almost dissolved in toluene completely.Attempt, with 2N aqueous sodium hydroxide solution extracting toluene liquid, obtaining orange solids precipitation (8.5g; M.p. over 300 ℃).This product is dissolved in boiling water, after adding hydrochloric acid, obtains orange precipitation 2 (6.2g, yield 13%)
m.p.188-189℃。
1H?NMR(DMSO-d 6)δ6.86(d，2H)，7.68(s，1H)，7.75(d，2H)，10.51(s，-OH)；MS(ESI)，m/z?225(M -)。
[2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (3) synthetic
At 0 ℃, stir under 1 hour, to 1 (diclofenac, 890mg, 3.0mmol), in the solution of the DMF of 50mL, add hydroxybenzotriazole (445mg, 3.3mmol) and DCC (680mg, 3.3mmol).In reaction mixture, add 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; 678mg, 3mmol), at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate, is dissolved in the oiliness residue obtaining like this in ethyl acetate; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 3 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9/1) wash-out, from wherein having obtained [2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (3) (1.1g, 74% yield).
1H?NMR(DMSO-d 6)：δ4.12(s，2H)，6.21(d，1H)，6.87(t，1H)，7.14(t，1H)，7.19(d，1H)，7.22(t，1H)，7.34(d，2H)，7.54(d，2H)，7.80(s，1H)，7.97(d，2H)；
13C?NMR(DMSO-d 6)：δ37.4，116.1，121.0，122.3，123.5，123.7，127.0，128.7，129.3，129.8，132.0，132.2，136.4，137.7，143.8，154.2，170.3，173.3，213.2.
MS(EI)，m/e?504(M +)；
m.p.：83-86℃。
Embodiment 2
Synthesizing of [2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-thiocarbamyl-phenylester (compounds X VII)
Scheme 2
4-carbamyl phenyl 2-[2-(2,6-dichlorophenyl amino)-phenyl] acetic ester (5) synthetic
At 0 ℃, stir under 1 hour, to 1 (diclofenac, 890mg, 3.0mmol), in the solution of the DMF of 50mL, add hydroxybenzotriazole (445mg, 3.3mmol) and DCC (680mg, 3.3mmol).In reaction mixture, add 4-hydroxybenzamide (4,616mg, 4.5mmol), at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate, is dissolved in the oiliness residue obtaining like this in chloroform; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 5 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9/1) wash-out, from wherein having obtained 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (5) (212mg, 17% yield).Synthesizing of [2-(the chloro-phenyl amino of 2,6-bis-)-phenyl]-acetic acid 4-thiocarbamyl-phenylester (6)
4-carbamyl phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (5,480mg, 1.14mmol) and Lawesson reagent (460mg, 1.14mmol) are dissolved in the dry-out benzene of 20ml.Reacting by heating to 50 ℃, and stir 6 hours.Removal of solvent under reduced pressure; By silicagel column (methylene chloride/methanol 9.5/0.5) purification of crude residue, so that pure compound 6 (446mg, 91% yield) to be provided.
1H?NMR(CDC?l 3)：δ4.07(s，2H)，6.59(d，1H)，6.67(s，1H)，6.98(t，1H)，7.14(t，1H)，7.19(d，1H)，7.28(t，1H)，7.33(d，2H)，7.63(s，1H)，7.97(d，2H)；
13C?NMR(DMSO-d 6)：δ38.8，118.8，121.8，122.6，123.7，124.4，128.7，129.1，129.6，131.2，137.2，137.8，142.9，153.5，170.5，193.2，201.7
MS(EI)，m/e?431(M +)；
m.p.：170-172℃。
Embodiment 3
[2-(2-chloro-6-fluorophenyl amino)-phenyl]-acetic acid 4-(5-sulfo--5H-[1,2] dithiole-3-yl)-phenylester (compound III) synthetic
Scheme 1
Synthesizing of 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (3)
At 0 ℃, stir under 1 hour, (Lu meter Kao former times, 600mg, 2.03mmol), in the solution of the dimethyl formamide of 40mL, adds hydroxybenzotriazole (301mg, 2.23mmol) and DCC (459mg, 2.23mmol) to 1.In this reaction mixture, add 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; 504mg, 2.23mmol), and at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 3 is carried on the open post of silica gel and uses CH 2cl 2wash-out, from wherein having obtained 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (3) (299mg, 37% yield).
1H?NMR(DMSO)：δ2.32(s，3H)，4.02(s，2H)，6.41(s，1H)，6.71(d，1H)，6，93(t，1H)，6，95(d，2H)，7.14(d，1H)，7.19(d，2H)，7.39(s，1H)，7.66(d，2H)；
13C?NMR(DMSO)：δ20.8，38.7，115.2，119.2，122.5，123.2，124.0，126.1，127.2，129.3，130.3，131.7，132.2，133.6，136.4，140.3，153.7，154.4，156.8，170.3，171.6，215.7
MS(EI)，m/e?503(M +)；
m.p.：131-133℃。
Embodiment 4
Synthesizing of 4-thiocarbamyl phenyl 2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (compounds X VIII)
Scheme 2
Synthesizing of 4-carbamyl phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (5)
At 0 ℃, stir under 1 hour, (Lu meter Kao former times, 223mg, 0.75mmol), in the solution of the dimethyl formamide of 15mL, adds hydroxybenzotriazole (111mg, 0.825mmol) and DCC (170mg, 0.825mmol) to 1.In this reaction mixture, add 4-hydroxybenzamide (4,154mg, 1.125mmol), and at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in chloroform; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 5 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9/1) wash-out, from wherein having obtained 4-carbamyl phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (5) (111mg, 35% yield).
Synthesizing of 4-thiocarbamyl phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (6)
By 4-carbamyl phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester, 5 (110mg, 0.27mmol) and Lawesson reagent (109mg, 0.27mmol) are dissolved in the dry-out benzene of 15ml.Reacting by heating to 60 ℃, and stir 3 hours.Removal of solvent under reduced pressure; By silicagel column (methylene chloride/methanol 9.5: 0.5) purification of crude residue, so that pure compound 6 (59mg, 51% yield) to be provided.
1H?NMR(CDCl 3)：δ2.32(s，3H)，4.01(s，2H)，6.46(s，1H)，6.70(d，1H)，6.92(t，1H)，7.01(d，2H)，7.11(d，2H)，7.19(d，1H)，7.62(s，NH)，7.84(d，2H)；
13C?NMR(DMSO-d? 6)：δ20.8，30.7，115.1，119.2，122.0，122.3，124.1，124.9，126.1，128.2，129.2，132.3，134.8，138.6，140.9，153.7，154.6，156.2，170.4，201.7
MS(EI)，m/e?429(M +)；
m.p.：120-122℃。
Embodiment 5
Synthesizing of 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl Aspirin ester (Compound I)
Scheme 1
Synthesizing of 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl Aspirin ester (3)
At 0 ℃, stir under 1 hour, to 1 (acetylsalicylic acid, 416mg, 2.31mmol), in the solution of the dimethyl formamide of 40mL, add hydroxybenzotriazole (343mg, 2.54mmol) and DCC (523mg, 2.54mmol).In this reaction mixture, add 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; 574mg, 2.54mmol), and at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product is carried on the open post of silica gel and uses ether/sherwood oil (1/1) wash-out, from wherein having obtained 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl Aspirin ester (3) (354mg, 40% yield).
1H?NMR(DMSO-d 6)：δ2.32(s，3H)，7.20(d，1H)，7.33(d，2H)，7.40(s，1H)，7.41(t，1H)，7.67(t，1H)，7.73(d，2H)，8.21(d，1H)
13C?NMR(DMSO-d 6)：δ21.3，122.1，123.4，124.4，126.6，128.6，129.7，132.4，135.4，136.4，151.6，153.7，162.6，169.8，171.9，215.7
MS(EI)，m/e?389(M +)；
m.p.：120-122℃。
Embodiment 6
Synthesizing of 2-acetoxyl group-phenylformic acid 4-thiocarbamyl-phenylester (compounds X VI)
Scheme 2
Synthesizing of 4-carbamyl phenyl Aspirin ester (5)
At 0 ℃, stir under 1 hour, to 1 (acetylsalicylic acid, 500mg, 2.77mmol), in the solution of the dimethyl formamide of 15mL, add hydroxybenzotriazole (412mg, 3.05mmol) and DCC (628mg, 3.05mmol).In this reaction mixture, add 4-hydroxybenzamide (4,418mg, 3.05mmol), and at 0 ℃, stir 1 hour, at room temperature stir 3 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in chloroform; With salt water washing organic layer, at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 5 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9/1) wash-out, from wherein having obtained 4-carbamyl phenyl Aspirin ester (5) (410mg, 47% yield).
Synthesizing of 4-thiocarbamyl phenyl-2-(2-(the chloro-6-fluorophenyl of 2-is amino)-5-aminomethyl phenyl) acetic ester (6)
By 4-carbamyl phenyl Aspirin ester, 5 (410mg, 1.37mmol) and Lawesson reagent (554mg, 1.37mmol) are dissolved in the dry-out benzene of 35ml.Reacting by heating to 60 ℃, and stir 3 hours.Removal of solvent under reduced pressure; By silicagel column (methylene chloride/methanol 9.5/0.5) purification of crude residue, so that the pure compound 6 of 470mg to be provided.By preparative RP-HPLC, carry out the resulting compound of purifying, described preparative RP-HPLC is undertaken by two kinds of solvent systemss: A: 100% acetonitrile in 0.1%TFA, B: the 100%H in 0.1%TFA 2o (linear gradient in 35 minutes be 10%A to 60%A, at 254nm place, carry out UV detection, flow velocity 30mL/ minute), obtained pure compound 6 (324mg, 71% yield).
1H?NMR(CDCl 3)：δ2.30(s，3H)，7.17(d，1H)，7.21(d，2H)，7.40(t，1H)，7.66(t，1H)，7.94(d，2H)，8.2(d，1H)。
13C?NMR(DMSO-d 6)：δ21.2，121.9，122.4，124.3，126.4，128.7，132.4，135.1，137.3，151.5，153.7，162.7，169.8，201.8
MS(EI)，m/e 316(M +)；
m.p.：154-156℃。
Embodiment 7
[1-(the chloro-benzoyl of 4-)-5-methoxyl group-2-methyl isophthalic acid-H-indol-3-yl]-acetic acid 4-(5-sulfo--5-H-[1,2] dithiole-3-yl)-phenylester (compound IV) synthetic
Scheme 1
4-[4-(5-sulfo--5H-1,2-dithiole-3-yl)]-phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (3) synthetic
At 0 ℃, stir under 1 hour, to 1 (indomethacin, 720mg, 2.01mmol), in the solution of the dimethyl formamide of 30mL, add hydroxybenzotriazole (301mg, 2.21mmol) and DCC (456mg, 2.21mmol).In this reaction mixture, add 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; 500mg, 2.21mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product is carried on the open post of silica gel and uses methylene chloride/methanol (98/2) wash-out; from wherein having obtained 4-[4-(5-sulfo--5H-1; 2-dithiole-3-yl)]-phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (3) (257mg, 23% yield).
1H?NMR(CDCl 3)：δ2.47(s，3H)，3.84(s，3H，OCH 3)，3.93(s，2H)，6.70(d，1H)，6.88(d，1H)，7.04(s，1H)，7.21(d，2H)，7.37(s，1H)7.48(d，2H)，7.65(d，2H)，7.67(d，2H)
13C?NMR(DMSO-d 6)：δ13.6，30.8，56.0，101.5，111.6，111.9，115.3，122.9，128.4，129.4，129.6，130.6，131.1，131.4，133.9，136.3，136.6，139.7，153.8，156.4，167.5，168.9，170.4，215.7
MS(EI)，m/e?567(M +)；
m.p.：90-92℃。
Embodiment 8
Synthesizing of [1-(the chloro-benzoyl of 4-)-5-methoxyl group-2-methyl isophthalic acid-H-indol-3-yl]-acetic acid 4-thiocarbamyl-phenylester (compounds X IX)
Scheme 2
4-carbamyl phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (5) synthetic
At 0 ℃, stir under 1 hour, to 1 (indomethacin, 3g, 8.38mmol), in the solution of the dimethyl formamide of 60mL, add hydroxybenzotriazole (1.25g, 9.22mmol) and DCC (1.9g, 9.22mmol).In this reaction mixture, add 4-hydroxybenzamide (4,1.72g, 12.6mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 5 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9.5/0.5) wash-out, from wherein having obtained 4-carbamyl phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (5) (479mg, 12% yield).
4-thiocarbamyl phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester (6) synthetic
By 4-carbamyl phenyl-2-[1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-indol-3-yl]-acetic ester, 5 (340mg, 0.71mmol) and Lawesson reagent (287mg, 0.71mmol) are dissolved in the dry-out benzene of 15ml.Reacting by heating to 60 ℃, and stir 4 hours.Removal of solvent under reduced pressure; By silicagel column (methylene chloride/methanol 9.5: 0.5) purification of crude residue, so that the pure compound 6 of 178mg to be provided.By preparative RP-HPLC, carry out the resulting compound of purifying, described preparative RP-HPLC is undertaken by two kinds of solvent systemss: A: 100% acetonitrile in 0.1%TFA, B: the 100%H in 0.1%TFA 2o (linear gradient in 30 minutes be 10%A to 80%A, at 254nm place, carry out UV detection, flow velocity 30mL/ minute), obtained pure compound 6 (56mg, 16% yield).
1H?NMR(CDCl 3)：δ2.45(s，3H)，3.83(s，3H，OCH 3)，3.91(s，2H)，6.70(d，1H)，6.88(d，1H)，7.04(s，1H)，7.11(d，2H)，7.47(d，2H)，7.67(d，2H)，7.88(d，2H)。
13C?NMR(DMSO-d? 6)：δ13.6，30.8，56.0，101.5，111.9，112.0，115.3，121.7，128.6，129.4，，130.8，131.2，131.4，134.0，136.8，137.1，139.7，156.2，157.9，167.6，169.8，201.8。
MS(EI)，m/e?493(M +)；
m.p.：224-226℃。
Embodiment 9
2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-(5-sulfo--5-H-[1,2] dithiole-3-yl)-phenylester (compound V) synthetic
Scheme 1
Synthesizing of 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(2-methoxynaphthalene methylene radical-6-yl) propionic ester (3)
At 0 ℃, stir under 1 hour, to 1 (Naproxen Base, 595mg, 2.58mmol), in the solution of the dimethyl formamide of 20mL, add hydroxybenzotriazole (388mg, 2.87mmol) and DCC (593mg, 2.87mmol).In this reaction mixture, add 5-p-hydroxybenzene-1,2-dithiole-3-thioketones (2; 650mg, 2.87mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product is carried on the open post of silica gel and uses methylene dichloride wash-out, from wherein having obtained 4-(5-sulfo--5H-1,2-dithiole-3-yl) phenyl 2-(2-methoxynaphthalene-6-yl) propionic ester (3) (406mg, 36% yield).
1H?NMR(DMSO-d 6)：δ1.59(d，3H)，3.86(s，3H，OCH 3)，4.24(dd，1H)，7.18(d，1H)，7.22(d，2H)，7.31(s，1H)，7.50(d，1H)，7.77(s，1H)7.85(d，1H)，7.86(s，1H)，7.87(d，1H)，7.91(d，2H)。
13C?NMR(DMSO-d 6)：δ19.1，45.2，55.9，106.5，119.6，123.5，126.6，126.9，128.0，129.2，129.4，129.5，129.6，129.9，134.2，135.6，136.5，154.2，158.1，173.2，216.2。
MS(EI)，m/e?439(M +)；
m.p.：111-113℃。
Embodiment 10
Synthesizing of 2-(6-methoxyl group-naphthalene-2-yl)-propionic acid 4-thiocarbamyl-phenylester (compounds X X)
Scheme 2
Synthesizing of 4-carbamyl phenyl 2-(2-methoxynaphthalene-6-yl) propionic ester (5)
At 0 ℃, stir under 1 hour, to 1 (Naproxen Base, 4g, 17.4mmol), in the solution of the dimethyl formamide of 80mL, add hydroxybenzotriazole (2.59g, 19.14mmol) and DCC (2.59g, 19.14mmol).In this reaction mixture, add 4-hydroxybenzamide (4,3.58g, 26.1mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 5 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9.5/0.5) wash-out, from wherein having obtained 4-carbamyl phenyl 2-(2-methoxynaphthalene-6-yl)-propionic ester (5) (1.91g, 32% yield).
Synthesizing of 4-thiocarbamyl phenyl 2-(2-methoxynaphthalene-6-yl) propionic ester (6)
By 4-carbamyl phenyl 2-(2-methoxynaphthalene-6-yl)-propionic ester, 5 (1.80g, 4.34mmol) and Lawesson reagent (1.75g, 4.34mmol) are dissolved in the dry-out benzene of 130ml.Reacting by heating to 60 ℃, and stir 4 hours.Removal of solvent under reduced pressure; By silicagel column (methylene chloride/methanol 9.75: 0.25) purification of crude residue, so that the pure compound 6 of 2.9g to be provided.By silica gel, open the resulting compound of column purification and use CH 2cl 2/ MeOH (9.5/0.5) wash-out, obtains compound 6 (970mg, 61% yield).
1h NMR (DMSO-d 6): δ 1.59 (d, 3H), 3.86 (s, 3H, OCH 3), 4.24 (dd, 1H), 7.06 (d, 2H), 7.18 (d, 1H), 7.31 (s, 1H), 7.50 (d, 1H), 7.84 (s, 1H) 7.85 (d, 1H), 7.86 (s, 1H), 7.89 (d, 2H), 9.47 and 9.84 (s, 2H, NH 2).
13C?NMR(DMSO-d 6)：δ19.1，45.2，55.9，106.5，119.6，121.6，126.6，126.9，128.0，129.4，129.9，134.2，135.6，137.8，153.4，158.1，173.3，199.7.
MS(EI)，m/e?366(M +)；
m.p.：196-198℃。
Embodiment 11
Synthesizing of 4-thiocarbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester (compounds X XIX)
At 0 ℃, stir under 1 hour, to 1 (Ibuprofen BP/EP, 3.87g, 18.8mmol), in the solution of the dimethyl formamide of 80mL, add hydroxybenzotriazole (2.8g, 20.7mmol) and DCC (4.27g, 20.7mmol).In this reaction mixture, add 4-hydroxybenzamide (2,3.9g, 28mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 3 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9.5/0.5) wash-out, from wherein obtaining 4-carbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester (3) (2.48g, 40% yield).
Synthesizing of 4-thiocarbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester (4)
By 4-carbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester, 3 (2.48g, 7.62mmol) and Lawesson reagent (3.1g, 7.62mmol) are dissolved in the dry-out benzene of 130ml.Reacting by heating to 60 ℃, and stir 4 hours.Removal of solvent under reduced pressure.By silica gel, open the resulting compound of column purification and use CH 2cl 2/ MeOH (9.5/0.5) wash-out, obtains compound 4 (1.45g, 55% yield).
1h NMR (DMSO-d 6): δ 0.84 (d, 6H), 1.48 (d, 3H), 1.79-1.82 (m, 1H), 2.42 (d, 2H), 4.05 (dd, 1H), 7.05 (d, 2H), 7.15 (d, 2H), 7.28 (d, 2H) 7.88 (d, 2H), 9.49 and 9.87 (s, 2H, NH 2).
13C?NMR(DMSO-d 6)：δ19.2，22.9，30.3，44.9，121.6，127.9，129.5，130.0，137.8，138.0，140.8，153.3，173.3，199.6.
MS(EI)，m/e?341(M +)；
m.p：121-123℃。
Embodiment 12
Synthesizing of 4-thiocarbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (compounds X XX)
Synthesizing of 4-carbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (3).
At 0 ℃, stir under 1 hour, to 1 (Ketoprofen, 3g, 11.8mmol), in the solution of the dimethyl formamide of 80mL, add hydroxybenzotriazole (1.76g, 13mmol) and DCC (2.68g, 13mmol).In this reaction mixture, add 4-hydroxybenzamide (2,2.43g, 17.7mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 3 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9.5/0.5) wash-out, from wherein obtaining 4-carbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (3) (1.84g, 42% yield).
Synthesizing of 4-thiocarbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (4).
4-carbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (3) (1.84g, 4.93mmol) and Lawesson reagent (2g, 4.93mmol) are dissolved in the dry-out benzene of 100ml.Reacting by heating to 60 ℃, and stir 4 hours.Removal of solvent under reduced pressure.By silica gel, open the resulting compound of column purification and use CH 2cl 2/ MeOH (9.5/0.5) wash-out, obtains compound 4 (0.45g, 23% yield).
1h NMR (DMSO-d 6): δ 1.53 (d, 3H), 4.25 (dd, 1H), 7.08 (d, 2H), 7.54-7.73 (m, 9H), 7.90 (d, 2H), 9.51 and 9.88 (s, 2H, NH 2).
13C?NMR(DMSO-d 6)：δ19.2，44.9，121.6，129.3，129.5，129.8，130.3，132.6，133.5，137.6，137.9，138.1，141.2，153.3，154.5，156.1，163.8，172.9，199.6.
MS(EI)，m/e?390(M +)；
m.p：114-116℃。
Embodiment 13
Synthesizing of 4-thiocarbamyl phenyl 2-(3-fluorine, 4-phenyl) phenylpropionic acid ester (compounds X XXI)
Synthesizing of 4-carbamyl phenyl 2-(3-fluorine, 4-phenyl) phenylpropionic acid ester (3)
At 0 ℃, stir under 1 hour, to 1 (flurbiprofen, 2g, 8.2mmol), in the solution of the dimethyl formamide of 80mL, add hydroxybenzotriazole (1.22g, 9.02mmol) and DCC (1.86g, 9.02mmol).In this reaction mixture, add 4-hydroxybenzamide (2,1.7g, 12.2mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate; With salt solution, NaHCO 35%, citric acid 10% washing organic layer, then at anhydrous MgSO 4upper dry, filter and evaporating solvent.Thick product 3 is carried on the open post of silica gel and uses CH 2cl 2/ MeOH (9.5/0.5) wash-out, from wherein obtaining 4-carbamyl phenyl 2-(3-fluorine, 4-phenyl) phenylpropionic acid ester (3) (1.09g, 37% yield).
Synthesizing of 4-thiocarbamyl phenyl 2-(3-fluorine, 4-phenyl) phenylpropionic acid ester (4)
By 4-carbamyl phenyl 2-(3-fluorine, 4-phenyl) phenylpropionic acid ester, 3 (1.09g, 3mmol) and Lawesson reagent (1.21g, 3mmol) are dissolved in the dry-out benzene of 70ml.Reacting by heating to 60 ℃, and stir 4 hours.Removal of solvent under reduced pressure.By silica gel, open the resulting compound of column purification and use CH 2cl 2/ MeOH (9.5/0.5) wash-out, obtains pure compound 4 (0.35g, 31% yield).
1h NMR (DMSO-d 6): δ 1.55 (d, 3H), 4.21 (dd, 1H), 7.32-7.55 (m, 8H), 7.90 (d, 2H), 9.51 and 9.88 (s, 2H, NH 2).
13C?NMR(DMSO-d 6)：δ19.1，44.7，115.9，116.2，121.7，124.8，128.6，129.3，129.4，129.5，131.7，135.8，137.7，142.6，153.7，158.3，163.5，173.1，199.6.
MS(EI)，m/e?380(M +)；
m.p：142-144℃。
Embodiment 14
Synthesizing of 4-(isothiocyano)-phenyl 2-(2-methoxynaphthalene-6-yl) propionic ester (compounds X XV)
At 0 ℃, stir under 1 hour, to 1 (Naproxen Base, 691mg, 3mmol), in the solution of the dimethyl formamide of 20mL, add hydroxybenzotriazole (446mg, 3.3mmol) and DCC (619mg, 3.3mmol).In this reaction mixture, add 4-hydroxy phenyl lsothiocyanates (2; 500mg, 3.3mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate, removes precipitation.Evaporating solvent, is carried on thick product on the open post of silica gel and uses methylene dichloride wash-out, from wherein obtaining 4-(isothiocyano)-phenyl 2-(2-methoxynaphthalene-6-yl) propionic ester (3) (230mg, 21% yield).
1H?NMR(DMSO-d 6)：δ1.57(d，3H)，3.86(s，3H，OCH 3)，4.20(dd，1H)，7.10(d，2H)，7.15(d，1H)，7.29(s，1H)，7.43(d，2H)，7.48(d，1H)，7.78(d，1H)7.80(s，1H)，7.83(d，1H)。
13C?NMR(DMSO-d 6)：δ19.1，45.2，55.9，106.5，119.6，123.8，126.6，126.9，128.0，128.3，129.2，129.9，134.2，134.6，135.7，150.2，158.1，173.2，215.1.
m.p.66-68℃；MS(EI)，m/e?364(M +)。
Embodiment 15
Synthesizing of 4-isothiocyano phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (compounds X XII)
4-isothiocyano phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (3)
At 0 ℃, stir under 1 hour, to 1 (diclofenac, 1717mg, 5.8mmol), in the solution of the dimethyl formamide of 60mL, add hydroxybenzotriazole (862mg, 6.38mmol) and DCC (1316mg, 6.38mmol).In this reaction mixture, add 4-hydroxy phenyl lsothiocyanates (2; 965mg, 6.38mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate, removes precipitation.Evaporating solvent, is carried on the open post of silica gel and with 9: 1 wash-outs of chloroform/normal hexane, from wherein obtaining 4-isothiocyano phenyl 2-(2-(2,6-dichlorophenyl is amino) phenyl) acetic ester (3) (580mg, 23% yield) by thick product.
1H?NMR(DMSO-d 6)：δ4.09(s，2H)，6.19(d，1H)，6.83(t，1H)，7.05(t，1H)，7.14(bs，1H，NH)，7.21(d，2H)，7，25(d，2H)，7，47-7，54(m，3H)。
13C?NMR(DMSO-d 6)：δ37.4，116.1，121.0，122.7，124.0，127.1，127.8，128.3，128.7，129.8，132.0，132.2，137.7，144.0，150.3，170.5，215.1.
m.p.132-134℃；MS(EI)，m/e?430(M +)。
Embodiment 16
Synthesizing of 4-isothiocyano phenyl Aspirin ester (compounds X XI)
4-isothiocyano phenyl Aspirin ester (3)
At 0 ℃, stir under 1 hour, to 1 (acetylsalicylic acid, 1200mg, 6.67mmol), in the solution of the dimethyl formamide of 60mL, add hydroxybenzotriazole (992mg, 7.34mmol) and DCC (1520mg, 7.34mmol), and.In this reaction mixture, add 4-hydroxy phenyl lsothiocyanates (2; 1109mg, 7.34mmol), and at 0 ℃, stir 1 hour, at room temperature stir 2 hours.After filtration, reduction vaporization filtrate is to remove desolventizing.The oiliness residue obtaining is like this dissolved in ethyl acetate, removes precipitation.Evaporating solvent, is carried on thick product on the open post of silica gel and with 6: 4 wash-outs of chloroform/normal hexane, from wherein obtaining 4-isothiocyano phenyl Aspirin ester (3) (150mg, 7% yield).
1H?NMR(CDCl 3)：δ2.31(s，3H)，7.17(d，1H)，7.19(d，2H)，7.29(d，2H)，7.38(t，1H)，7.66(t，1H，8.20(d，1H)。
13C?NMR(CDCL 3)：δ21.3，122.2，123.3，124.4，126.6，127.2，129.4，132.4，135.2，149.3，151.5，163.0，170.0，215.1.
m.p.84-86℃；MS(EI)，m/e?272(M +)。
Embodiment 17
The stomach and intestine security of compound of the present invention
With rat, evaluate two kinds of ramification of diclofenac of the present invention, the stomach and intestine security of Compound I I and compounds X VII.Especially, measure gastric damage, stomach PGE 2synthetic, small intestinal ulcer and hematocrit.
At single port, take 1% carboxymethyl cellulose (carrier; 0.2mL) or the oral following a kind of medicine that is dissolved in this carrier: diclofenac (20mg/kg), Compound I I (32mg/kg), ADT-OH (12mg/kg), diclofenac+ADT-OH, compounds X VII (27.3mg/kg), first 18 hours of the hydrogen sulfide release portion of 4-hydroxyl thiobenzamide (TBZ) (7.3mg/kg), on compounds X VII or diclofenac+TBZ, allow the male Wistar rat fasting of body weight 175-200g.The diclofenac of the dosage of Compound I I and compounds X VII and 20mg/kg dosage is equimolar.Similarly, the dosage of the dosage of ADT-OH and TBZ and Compound I I and compounds X VII is respectively equimolar.
Every group has 5 rats.Using test-compound after 3 hours, putting to death rat, " blind property ground " measures the degree (mm of unit) of gastrorrhagia infringement.The prejudicial length of institute in stomach is added, obtains " gastric damage score ".First with reference to accompanying drawing 1, in " carrier ", " Compound I I " or " compounds X VII " group, do not observe gastric damage.Compound I I and compounds X VII have caused than the remarkable less gastric damage of diclofenac.In addition, if use respectively rather than simultaneously the H of NSAID part (diclofenac) and Compound I I and compounds X VII 2s-release portion (being respectively ADT-OH and TBZ), does not observe gastric damage effect.
By subsequently, " blind property " Histological determining is confirmed in these observations.As previous detailed description (people such as Wallace, Cyclooxygenase 1 contributes to inflammatoryresponses in rats and mice:implications for gastrointestinaltoxicity.Gastroenterology 1998; 115:101-109, by reference to being incorporated herein) described in, cut out the sample (100-200) of stomach-tissue for PGE 2(PGE 2) synthetic mensuration.In brief, in the time of 30 minutes, with scissors, tissue sample is shredded, be then placed in the sodium phosphate buffer (pH 7.4) of 1mL, and be placed in the water-bath (37 ℃) 20 minutes of vibration.Then immediately by sample with 9,000g centrifugal 1 minute, immediately that supernatant liquor is freezing at-80 ℃, for the PGE being undertaken by specific ELISA subsequently 2concentration determination (people such as Wallace, 1998).
With reference to accompanying drawing 2, can find out, diclofenac (with or do not use together with ADT-OH or TBZ), Compound I I and compounds X VII significantly reduced stomach PGE 2synthetic amount, has shown the restraining effect to COX-1 and/or COX-2.Compare with carrier, alone ADT-OH and TBZ can not reduce stomach PGE 2synthetic.Therefore, as shown in Figure 1, with the rat that Compound I I or compounds X VII treat, gastric damage not occurring is not to change because these medicines suppress the synthetic ability of stomach prostaglandin(PG)s.To stomach PGE 2synthetic inhibition is almost by these medicines completely, and etc. the diclofenac of molar dose complete.
Accompanying drawing 3 has shown that two kinds of Naproxen derivatives of the present invention (compound V and XX) have caused than significantly less infringement of Naproxen Base itself.To carry out these experiments with mode almost identical shown in accompanying drawing 1.With the oral Naproxen Base of dosage difference of 60 μ mol/kg, compound V and compounds X X, after 3 hours, " blind property ground " evaluates gastric damage.In any rat with compound V or compounds X X treatment, all can't detect gastric damage.Every group comprises 5 rats.These observations can " blind property " Histological determining be confirmed by subsequently.
With identical rat, also can measure the inhibition of COX-1.(people such as Wallace, Gastroenterology 1998) as discussed previously after the exudate of collecting bag, extracts immediately the blood of 1mL, and is placed in Glass tubing, and condense 45 minutes from the postcava of each rat.Then by sample with 9,000g centrifugal 3 minutes, supernatant liquor is freezing at-80 ℃, for the thromboxane B being undertaken by specific ELISA subsequently 2concentration determination.As shown in Figure 4, compare with vehicle treatment group, Naproxen Base, compound V and compounds X X all significantly (* p < 0.05) suppressed the activity of COX-1.Aspect the degree of inhibition COX-1, use compound V than a little bit smaller with Naproxen Base or compounds X X.
NSAIDs also can cause significant small intestine infringement, relatively diclofenac and the Compound I I effect to the infringement of induction small intestine after repetitive administration.After time 0 and 12 and 24 hours, with the dosage of 50 μ mol/kg, give 5 male Wistar rat diclofenacs or the Compound I I of each group.The rat of another group is accepted carrier (1% carboxymethyl cellulose).
Hematocrit refers to the part of the blood consisting of pcv, and it is expressed as volume percent, when experiment starts to after after medicine final dose 24 hours from tail venous blood sampling liquid sample determination hematocrit.Within 24 hours after medicine final dose, put to death rat, open abdominal cavity.By knowing rat, whether do not accept the length that the investigator for the treatment of measures all hemorrhage corrosion/ulcer in small intestine.By every prejudicial length of rat being added and calculating small intestine and damage score.
As shown in Figure 5, in 24 hours, use the development that 3 times diclofenac causes producing corrosion widely and ulcer in small intestine.On the other hand, the degree of damage observing in the rat of Compound I I treatment is less than the rat > 90% with diclofenac treatment.In addition, as shown in Figure 6, diclofenac treatment causes hematocrit greatly to reduce (* p < 0.05), and this may be the result of enteric hemorrhage, and has no significant effect for hematocrit with Compound I I treatment.
Embodiment 18
Inhibition to COX-2 (COX-2) and cyclooxygenase-1 (COX-1)
With previously described model (people such as Wallace, Limited anti-inflammatoryefficacy of cyclo-oxygenase-2 inhibition incarrageenan-airpouch inflammation.Br J Pharmacol 1999; 126:1200-1204, by reference to being incorporated herein) modified version measure the inhibition of COX-2 in body.In brief, by duplicate injection gas within a couple of days, produce subcutaneous " bag ".Once produce, 1% zymosan of injection 1mL can induce inflammation in bag.This causes PGE in bag 2(PGE 2) greatly increase, it is almost completely just derived by COX-2 according to the show.At carrageenin, inject first 30 minutes, allow each group 5 Oral Administration in Rats carriers (1% carboxymethyl cellulose), diclofenac (3mg/kg), Compound I I (4.8mg/kg) or compounds X VII (4.1mg/kg).5 rat vehicle treatment of another group, but bag is accepted the injection of 0.9% Sterile Saline rather than zymosan.
From accompanying drawing 7, can find out, with diclofenac or, Compound I I or compounds X VII pretreat have significantly reduced PGE in bag 2concentration, PGE wherein 2injection zymosan is replied and produced.With respect to the group with the treatment of carrier+zymosan, * p < 0.05.These results show, all these three kinds of compounds significantly suppress COX-2.On the contrary, the activity that alone hydrogen sulfide release portion (ADT-OH and TBZ) can remarkably influenced COX-2.
By identical method as described in accompanying drawing 4, also with identical rat, measure the inhibition to COX-1.As shown in Figure 8, diclofenac, it is synthetic that Compound I I and compounds X VII have suppressed respectively to surpass the thromboxane of 80% whole blood, described syntheticly occur by COX-1.On the contrary, the activity that alone hydrogen sulfide release portion (ADT-OH and TBZ) can remarkably influenced COX-1.
Embodiment 19
The effect of NSAID derivative to COX-1 in gastric damage, body and COX-2 activity
Antiphlogistic effects (COX-2 and COX-1 suppress) and stomach security with the more a lot of compounds of above-mentioned analysis.Result is summarized in table 1.All parent NSAIDs have caused significant gastric damage.But compare H of the present invention with parent drug 2s-discharges derivative and has shown the stomach security improving.From table 1, also can find out, compare with parent drug, TBZ derivative maintains or has in fact strengthened them and suppresses the ability of COX-1 and/or COX-2.
Table 1
The effect of NSAID derivative to COX-1 in gastric damage, body and COX-2 activity
Embodiment 20
Compound of the present invention is for the effect of inflammation
With people such as previous Wallace, the carrageenin rear solid end edema model described in Gastroenterology 1998 carrys out the antiphlogistic effects of assessing compound II and compounds X VII and diclofenac.Give the male Wistar rat oral test compound of body weight 175-200g, the 1% λ carrageenin of sole of the foot flesh hemostasis 100ul after 30 minutes.Before injection carrageenin and thereafter with the interval of 1 hour, totally 5 hours, use Ugo Basile hydroplethysmometer to measure the volume of pawl.Each group that comprises 5 rats is with 1,3 or the diclofenac of 10mg/kg dosage, or with the Compound I I of the molar doses such as diclofenac of 3mg/kg or compounds X VII treatment.
As shown in Figure 9, alleviated to diclofenac dose dependency the pawl oedema of sole of the foot flesh hemostasis carrageenin induction.The Compound I I giving with the molar doses such as diclofenac with 3mg/kg has alleviated pawl oedema to a greater degree.Really, Compound I I is equivalent to the effect of the diclofenac of 10mg/kg dosage for the effect of pawl oedema.Similarly, as shown in Figure 10, the compounds X VII giving with the molar doses such as diclofenac with 3mg/kg has reduced pawl oedema dramatically, and the effect of the diclofenac of this degree and 10mg/kg dosage is suitable.
Due to Compound I I and compounds X VII, all with the degree identical with diclofenac, to suppress prostaglandin(PG) synthetic, the strong active another kind of characteristic that probably relate to this compound of new compound of the present invention in pawl edema model.Previously verified, hydrogen sulfide donor can significantly alleviate pawl oedema (people such as Zanardo, the Hydrogen sulphideis an endogenous modulator of leukocyte-mediated inflammation.FASEB J 2006 of the induction of carrageenin in rat; 20:2118-2120, by reference to being incorporated herein), therefore, be not associated with theory, likely, H in Compound I I and compounds X VII 2the release of S can explain that why stronger than the antiphlogistic effects of diclofenac it is.
Be not associated with theory, also possible that, compound of the present invention some additional activity in inflammatory model strengthens owing to the inhibition to COX-2 activity.(as shown in Figure 7) comparison carrier in rat air pocket model, Naproxen Base, the effect of compound V and compounds X X.Every group comprises 5 rats.With the dosage of 60 μ mol/kg, use Naproxen Base respectively, compound V and compounds X X.As shown in Figure 11, compare with vehicle treatment group, all these medicines have all significantly suppressed the activity (* p < 0.05, * * p < 0.01) of COX-2.But, and with Naproxen Base or compound V is viewed compares, compounds X X caused COX-2 activity more reduce significantly greatly ( Ψp < 0.05).
Be not associated with theory, also possible that, compound of the present invention some additional activity in inflammatory model strengthens owing to the inhibition to COX-1 activity.Compare carrier, indomethacin and two kinds of compound compound IV of the present invention and compounds X IX are for vitro human whole blood thromboxane B 2synthetic effect.The blood of the equal portions from Healthy People blood volunteer (0.5mL) is joined in Glass tubing, and wherein this Glass tubing only comprises a kind of in the methyl alcohol of 10uL or prepared test-compound, and making ultimate density is 0.1,0.3,1 or 3 μ M.This pipe is placed in to the water-bath (37 ℃) 45 minutes of slight vibration, and then by they are centrifugal (1,000xg) 10 minutes.Then as shown in the research of accompanying drawing 4, by specific ELISA, determine thromboxane B in each sample 2concentration.As shown in Figure 12, compare with vehicle treatment group, all these three kinds of medicines have all produced concentration-dependent inhibition to the activity of COX-1.But under the concentration of 1 and 3 μ M, the effect producing with indomethacin is compared, compounds X IX has produced significantly larger restraining effect (* p < 0.05) to the activity of COX-1.
Embodiment 21
The white cell of compound of the present invention adheres to blood vessel endothelium
In inflammatory reaction, it is a kind of early stage event that white cell is attached on blood vessel endothelium, and causes thrombosis.Hydrogen sulfide donor has demonstrated the white cell that can reduce by Asprin or proinflammatory tripeptides fMLP induction and has adhered to (people such as Zanardo, FASEB J 2006; 20:2118-2120).As people FASEB J 2006 such as Zanardo; 20:2118-2120 describes in detail, in rat, with intravital microscopy, evaluates the effect that several NSAIDs derivatives of the present invention adhere to for white cell.
In brief, under opticmicroscope, check the Postcapillary mesentery venule of the rear rat of anesthesia.After date is recorded on basis at 5 minutes, a kind of test-compound that following table 2 is listed is used with the dosage of 30 μ mol/kg by gavage, but except Naproxen Base and Naproxen derivatives (compound V and XX), they is to use with the dosage of 60 μ mol/kg.In the carrier of 1% carboxymethyl cellulose, prepare all test-compounds.The change of adhering to the white cell in the camera record venule being connected with microscope, and the white blood cell count of adhering to by evaluation record-reproduce head image in the mode of " blind property " is quantitative.Every group of male Wistar rat that comprises 5 heavy 150-175g.If white cell keeps fixing in 30 seconds or longer time, think that it is " adhering to " (result is below expressed as mean value ± SEM).When experiment finishes, open stomach, and check and whether have gastric damage under dissecting microscope.
Table 2
White cell on blood vessel endothelium adheres to
Test-compound The leukocytic quantity of adhering to (every 100 μ m length of vessel) The morbidity per-cent of gastric damage
Carrier (1%) 2.0±0.2 0
Asprin 7.1±0.4* 80
Compound I 2.5±0.3 20
Compounds X VI 2.3±0.3 0
Diclofenac 8.6±0.6* 100
Compound I I 3.0±0.5 0
Compounds X VII 2.8±0.5 20
Lu meter Kao former times 9.3±1.0* 0
Compound III 1.7±0.3 0
Compounds X VIII 2.3±0.4 0
Indomethacin 14.4±0.7* 100
Compound IV 3.6±0.7 20
Compounds X IX 3.0±0.4 0
Naproxen Base 10.2±0.4* 100
Compound V 3.5±0.7 0
Compounds X X 2.3±0.5 0
With respect to vehicle treatment group, * p < 0.05 (ANOVA and the check of Dunnett ' s multiple comparisons).
As can be seen from Table 2, compare with alone acetylsalicylic acid, aspirin derivatives of the present invention, particularly compounds X VI and Compound I have significantly reduced the leukocytic quantity that every 100 μ m length of vessel are adhered to.In addition, compare with alone acetylsalicylic acid, compounds X VI and Compound I have significantly reduced the sickness rate of gastric damage.Similarly, table 2 also shows, compares with alone diclofenac, and ramification of diclofenac of the present invention, particularly Compound I I and compounds X VII have significantly reduced the leukocytic quantity that every 100 μ m length of vessel are adhered to, and has significantly reduced the sickness rate of gastric damage.Similarly, table 2 also shows, compare with alone Naproxen Base, and Naproxen derivatives of the present invention, compound V and compounds X X have significantly reduced the leukocytic quantity that every 100 μ m length of vessel are adhered to, and have significantly reduced the sickness rate of gastric damage.
What is interesting is, the selective depressant reed rice of the COX-2 that the side effect of stomach is less is examined the derivative of former times, especially compound III and compounds X VIII have still shown that the sickness rate of gastric damage is 0, but examine former times with alone reed rice, compare, these two derivatives have all significantly reduced the leukocytic quantity that every 100 μ m length of vessel are adhered to.Therefore, by hydrogen sulfide release portion and COX-2 optionally NSAIDs covalent attachment can reduce the cardiovascular side effects of these cox 2 inhibitors.
Therefore, NSAID derivative of the present invention can adhere to the cardiovascular side effects that reduces NSAID by reducing white cell.
Embodiment 22
Compound of the present invention is for the effect of gastric ulcer healing
NSAIDs, comprise COX-2 is had optionally to those, healing (the people such as Stadler that conventionally can suppress the stomach ulcer of preexist, Diclofenac delays heliang ofgastroduodenal mucosal lesions.Double-blind, placebo-controlled endoscopic study in healthy volunteers.Digestive Diseases and Sciences 1991; 36:594-600).In order to determine two kinds of compounds of the present invention (compounds X VII and compounds X X), the effect for ulcer healing while comparing with diclofenac and Naproxen Base respectively induces after ulcer in rat stomach, with these pharmacological agenies they.As people such as Elliott, Anitric oxide-releasingnonsteroidal anti-inflammatory drug accelerates gastric ulcerhealing in rats.Gastroenterology 1995; Described in 109:524-530, by inducing stomach ulcer with acetic acid on serous coat.After starting 3 days, with carrier, diclofenac (30 μ mol/kg), compounds X VII (30 μ mol/kg), each group that Naproxen Base (60 μ mol/kg) or compounds X X (60 μ mol/kg) oral administration comprise 5 rats, every day 2 times.Treating like this after 4 days, put to death rat, excision stomach is also taken a picture.By not knowing that the people who gives which kind for the treatment of of rat comes from the area (mm of unit of the definite ulcer of plane 2).In induction stomach ulcer, (start before pharmacological agent) in the subgroup of 5 rats of putting to death after 3 days, the average area of ulcer is 24 ± 2mm 2.As shown in Figure 13, with carrier, the rat of diclofenac or Naproxen Base treatment has shown the healing that degree is similar.But the rat with compounds X VII or compounds X X treatment, has shown significantly better healing (comparing respectively * p < 0.05 with diclofenac with Naproxen Base).Compare with vehicle treatment group, hydrogen sulfide release portion (TBZ) treatment of alone these two kinds of compounds has no significant effect the healing of stomach ulcer.
Embodiment 23
Compound of the present invention is for the effect of blood pressure
NSAIDs, comprise COX-2 is shown optionally to those, can increase the weight of already present hypertension, and disturb validity (Whelton, the A.Nephrotoxicity of nonsteroidal anti-inflammatory drugs:physiologic foundations and clinical implications.Am.J.Med.1999 of some antihypertensive drug; 106 (5B): 13S-24S).While comparing with Naproxen Base with diclofenac respectively for definite two kinds of compounds of the present invention (Compound I I and compounds X X), for the effect of blood pressure, after first inducing hypertension, by intraperitoneal, give rat these medicines.As the people such as Ribeiro (Chronic inhibition of nitric oxide synthesis:A new model orarterial hypertension.Hypertension 1992; 20:298-303) institute is aforementioned, and before experiment, rat is drunk the water 7 days that is supplemented with N ω-nitro-L-arginine methyl ester (400mg/L).With halothane anesthesia rat (every group of 5-8 is only), intubate is inserted to carotid artery and measure blood pressure, blood pressure continuous recording is on chart recorder.After being measured to the stabilizing blood pressure of at least 15 minutes, by peritonaeum, inject wherein a kind of medicine (Naproxen Base, diclofenac, Compound I I or compounds X X) (diclofenac and Compound I I use with 30 μ mol/kg, and Naproxen Base and compounds X X use with 60 μ mol/kg).In injection, record afterwards the variation of 60 minutes blood pressures.Average basic blood pressure is 150 ± 6mm Hg.Accompanying drawing 14 shows that diclofenac and Naproxen Base cause contraction to be pressed with substantial rising.On the contrary, compare Compound I I and the compounds X X systolic pressure that can not raise, being changed significantly lower than respectively by the blood pressure of diclofenac and Naproxen Base induction of blood pressure with vehicle treatment group.
Embodiment 24
Blood plasma H 2the mensuration of S concentration
In order to determine the H discharging from Compound I I 2the kinetics of S, 5 rats of processing each group with the Compound I I of 50 μ mol/kgp.o. dosage, and 10,30, after 60 and 180 minutes, put to death.Then construct blood plasma H 2s concentration through time curve.As previous (Ubuka, T.Assay methods and biological roles of labile sulfur in animaltissues.J Chromatogr B Analyt Technol Biomed Life Sci.2002; 781:227-249 and Zhao W, Zhang J, Lu Y, Wang R.Thevasorelaxant effect of H 2s as a novel endogenous gaseous K (ATP) channel opener.EMBO J.2001; 20:6008-6016, by these two pieces of documents by reference to being incorporated herein) described and slightly make improvements, measure blood plasma H 2s concentration.In brief, the blood plasma of 250 μ l is joined in the NaOH0.1N of 250 μ l ice-cold in the 3-neck reactor of sealing.Allow the constant gas of nitrogen pass through this mixture through air inlet kapillary.Reactor is remained at 37 ℃, by introducing the 10% trichoroacetic acid(TCA) solution of 1ml, start H 2s extracts.The logical overcooled junctor of nitrogen gas stream in another reactor carries sulfuric acid, and bubbles in the anti-oxidant buffer reagent of sulfide (SAOB) solution of 2ml, and this solution is by 2M KOH, and 1M Whitfield's ointment and 0.22M xitix form, and pH 12.8.After 30 minutes, remove SAOB solution, with sulfide susceptibility electrode (Model 9616 S 2-/ Ag +electrode, Orion Research, Beverly, MA, USA) measure sulfide concentration, use H 2s represents (Ubuka, 2002; The people such as Khan, 1980).
For comparative compound XVII and Compound I I, and TBZ and ADT-OH (both are H of compounds X VII and Compound I I afterwards 2s release portion) the external H of induction 2s discharges, by the liver of 100-150mg separation homogenization in the ice-cooled T-PER proteins extraction device of 1ml.In the same reactor of plasma analysis, guide H 2s discharges.The analyze reaction mixture of 2ml is incorporated in reactor.To comprise 1mM Compound I I, 1mM compounds X VII, the mixture of 1mM TBZ or 1mM ADT-OH is dissolved in PEG and 100mM potassium phosphate buffer (pH=7.4).10% (w/v) liver homogenate and 2mM PLP exist or not in the presence of start to cultivate.Allow the constant gas of nitrogen pass through this mixture through air inlet kapillary.By this pipe is moved on to 37 ℃ of water-baths and starts to react from ice bath.Nitrogen gas stream in second reactor carries sulfuric acid, comprises the foregoing SAOB of 2ml in this second reactor.At 37 ℃, cultivate after 90 minutes, in this mixture, add the 50% trichoroacetic acid(TCA) solution of 1ml with stopped reaction.By H remaining in this mixture 2s cultivates 30 minutes through nitrogen gas stream at 37 ℃ again.Concentration (Ubuka, 2002 with foregoing sulfide susceptibility determination of electrode SAOB solution medium sulphide content; The people such as Khan, 1980).
As shown in Figure 15, oral administration of compound II causes blood plasma H 2s level significantly (p < 0.05) raises.After single administered compound II, observe blood plasma H in 180 minutes 2s has compared with little and constant increase.Accompanying drawing 16 has shown that in damping fluid, cultivating Compound I I or compounds X VII causes than ADT-OH or the TBZ of a great deal of discharge significantly more H respectively 2s.Similarly, when cultivating with liver homogenate, compare with ADT-OH or TBZ, from Compound I I and compounds X VII, discharged more H 2s.

Claims (13)

1. compound or its pharmacologically acceptable salts with following general formula:
B-C (O) O-X (formula II)
Wherein, B-C (O) O-is selected from the following NSAID by having free carboxy to obtain:
And X is:
2. compound, it is
Or its pharmacologically acceptable salts.
3. compound, it is
Or its pharmacologically acceptable salts.
4. compound, it is
Or its pharmacologically acceptable salts.
5. compound, it is
Or its pharmacologically acceptable salts.
6. compound, it is
Or its pharmacologically acceptable salts.
7. compound, it is
4-thiocarbamyl phenyl 2-(4-isobutyl phenenyl) propionic ester (XXIX),
Or its pharmacologically acceptable salts.
8. compound, it is
4-thiocarbamyl phenyl 2-(4-oxo phenyl)-phenylpropionic acid ester (XXX), or its pharmacologically acceptable salts.
9. compound, it is
4-thiocarbamyl phenyl 2-(the fluoro-4-xenyl of 2-) propionic ester (XXXI), or its pharmacologically acceptable salts.
10. a pharmaceutical composition, it comprises compound as required for protection in claim 1 to 9 any one and the acceptable vehicle of pharmacy or carrier.
The compound of 11. claim 1 to 9 any one in preparation to treating the purposes in the medicine of patient treatment inflammation of inflammation.
The compound of 12. claim 1 to 9 any one in preparation to treating the purposes in the medicine of patient treatment pain of pain.
Purposes in the medicine that the compound of 13. claim 1 to 9 any one is had a fever to the patient treatment of needs treatment fever in preparation.
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