CN104402883B - 4,4-difluoro diamantane carboxamides derivatives, pharmaceutical composition and its production and use - Google Patents
4,4-difluoro diamantane carboxamides derivatives, pharmaceutical composition and its production and use Download PDFInfo
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- CN104402883B CN104402883B CN201410577726.1A CN201410577726A CN104402883B CN 104402883 B CN104402883 B CN 104402883B CN 201410577726 A CN201410577726 A CN 201410577726A CN 104402883 B CN104402883 B CN 104402883B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
The present invention for first conductor with Maraviroc (Malawi's promise), replaces 4,4-difiuorocyclohexyl formyl radical with 4,4-difluoro diamantane formyl radical, thus obtains 4,4-difluoro diamantane carboxamides derivatives of class structure as Suo Shi (I).Preliminary Pharmacological Activity Screening shows, this compound can be used as CCR5 antagonist, for the preparation of disease (HIV, the asthma for the treatment of CCR5 mediation, rheumatoid arthritis, autoimmune disorder and chronic obstructive pulmonary disease (COPD) etc.) medicine.
Description
Technical field
The present invention relates to compou nd synthesis field, relate generally to 4,4-difluoro diamantane carboxamides derivatives and preparation method thereof and its medicinal use, this compounds can be used as CCR5 antagonist and is particularly useful for anti-AIDS drug.
Background technology
Acquired immune deficiency syndrome (AIDS) (also known as acquired immune deficiency syndrome (AIDS), AIDS) is the T cell immunodeficiency that human immunodeficiency virus (HIV) causes is one group of main syndromes.According to World Health Organization's statistical information display, about there are 4,000 ten thousand AIDS patients in the current whole world, account for 1/150 of world population sum, and this numeral is also with speed increase (LuoM.etal, the JChromatogrBAnalytTechnolBiomedLifeSci2011 of every day 1.6 ten thousand; 879 (28): 2971-7).Therefore anti-AIDS drug is researched and developed extremely urgent.
At present, the chemical drugs of existing more than 20 kind of AntiHIV1 RT activity is ratified by FDA.According to the difference of drug effect in viral targets, roughly medicine can be divided into reverse transcriptase inhibitors, proteinase inhibitor, fusion inhibitor, integrase inhibitor and other types etc.Current each state is all at the new drug stepping up Development of New Generation AntiHIV1 RT activity for above four kinds of target drugs, and AntiHIV1 RT activity vaccine etc.In fusion inhibitor, 2007, the medicine Malawi of new generation promise (Maraviroc) of Pfizer's development is such medicine of the first oral administration mode administration, also be uniquely a kind of be approved for AIDS treatment chemokine receptor 5 accessory receptor inhibitor, it can suppress the combination of CCR5 and chemokine and gpl20 by a kind of allosterism, the N-terminal of gp41 is made not insert cytolemma, and then stop the fusion (Garcia-PerezJ of viral after birth and host cell membrane, etal., JBiolChem2011; 286 (38): 33409-21; ThieleS, etal, JBiolChem.2011; 286 (43): 37543-54; BernardLC-PJ, etal., DrugDiscovTodayTechnol2013; 10 (2): e219-314.).Especially 2013, as (the TanQ.etal..Science2013 of successfully resolved first of the three-dimensional crystalline structure of HIV-1 co-receptor CCR5; 341 (6152): 1387-90) exploitation of anti-AIDS drug of new generation, is more contributed to.This crystalline structure proves, Malawi's promise, can by the stable configuration of CCR5 in a kind of inactive state as a kind of inverse agonist.Therefore drug molecule is the object being reached opposing virus infection by a kind of indirect mechanism, by changing the conformation of CCR5, it is made to be in the non-sensitive state of a kind of HIV virus, thus the combination of blocking virus and CCR5, make virus to infect human body cell, thus reach the effect for the treatment of acquired immune deficiency syndrome (AIDS).
Although at present because market shifted onto by some medicines, acquired immune deficiency syndrome (AIDS) obtains control to a certain degree, but the drug resistance problems of HIV virus, the cost issues of the toxicity of inverase and untoward reaction and long-term prescription, pharmaceutical industry is forced to continue to seek safer, more effective inverase.CCR5 antagonist is except can be used for AntiHIV1 RT activity, also can be used for the treatment of following disease: asthma and local disorders are (as locality dermatitis, local anaphylaxis), rheumatoid arthritis, arteriosclerosis, psoriasis, meat-like knurl disease and other fibrotic disease, autoimmune disorder (as multiple sclerosis, inflammatory enteritis), also may be used for the treatment (LongYaqiuetal., WO2009052708) of COPD.
In addition, fluorine atom plays a part very important in anti-infectives.Have a lot of anti-infectives at present as Malawi's promise, Flucloxacillin class medicine etc. are all containing fluorine atom.Due to the uniqueness of fluorine atom, introduce in organic drug molecule and can bring theatrical change to molecular activity and pharmacological properties thereof, especially in the security of exploitation tool, there is obvious advantage alternative medicine molecule aspect.Thus attracted increasing medicine scholar and drugmaker add Drugs Containing Fluorine research and development ranks (Krik, K.L, J.FluorineChem., 2006,127,992, KlausM ü ller, ChristophFaeh,
diederich, Sceience, 2007,317,1881, O ' Hagan, D., Chem.Soc.Rev., 2008,37,308; Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V .Chem.Soc.Rev., 2008,37,320; Kirk, K.L., Org.ProcessRes.Dev., 2008,12,305; Isanbor, C.; O ' Hagan, D., J.FluorineChem., 2006,127,992).
In sum, develop the fluorine-containing CCR5 antagonist with novel structure will play and important effect in AntiHIV1 RT activity and other relative disease.
Summary of the invention
The present inventor conducts in-depth research the compound with CCR5 antagonistic activity, designs and has synthesized 4,4-difluoro diamantane carboxamides derivatives shown in formula (I).Test result shows that this 4,4-difluoro diamantane carboxamides derivatives is potent CCR5 antagonist, can be used as the entry inhibitor of HIV virus, and can develop into anti-AIDS drug, complete the present invention on this basis.
Therefore first object of the present invention is to provide shown in formula (I) 4 with antagonizing CCR 5 activity of a class formation novelty, 4-difluoro diamantane carboxamides derivatives and pharmaceutically useful salt thereof, described 4,4-difluoro diamantane benzamide types have the structural formula shown in derivative formula (I):
Shown in formula of the present invention (I) 4,4-difluoro diamantane benzamide compound pharmacy acceptable salt, according to the method for pharmaceutically conventional salt formation, is 4 shown in formula (I), 4-difluoro diamantane carboxamides derivatives and hydrochloric acid, tartrate, Citric Acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid, the salt that sulfuric acid or methylsulfonic acid are formed.
Second object of the present invention is to provide has 4,4-difluoro diamantane carboxamides derivatives of above-mentioned formula (I) and the preparation method of pharmaceutically useful salt thereof, comprises the steps:
(1) compound shown in formula (II) is at-78 DEG C-25 DEG C, under fluorination reagent effect, carries out compound shown in fluoridation production (III);
(2) compound shown in formula (III) is hydrolyzed compound shown in production (IV) under alkali effect;
(3) compound shown in formula (IV) generates acyl chlorides under thionyl chloride effect, direct and the shown compound of formula (V) without separation, 4,4-difluoro diamantane carboxamides derivatives shown in amidation production (I) under alkali effect;
Concrete reaction scheme is as follows:
In a preferred embodiment of the invention, described pharmaceutically useful salt is 4,4-difluoro diamantane carboxamides derivatives and hydrochloric acid shown in described formula (I), tartrate, Citric Acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid, the salt that sulfuric acid or methylsulfonic acid are formed.
In a preferred embodiment of the invention, fluorine reagent in described step (1) is selected from DAST (diethylin sulfur trifluoride), BAST (Deoxofluor, [two (2-methoxy ethyl) amine] sulfur trifluoride), SF
4(sulfur tetrafluoride), PhSF
3, FLUOLEAD (the 4-tertiary butyl-2,6-3,5-dimethylphenyl sulfur trifluoride), XtalFluor-E (diethylin sulfur trifluoride fluoroborate) or XtalFluor-M (MorpholinodifluorosulfiniumTetrafluoroborate, morpholinyl sulfur trifluoride fluoroborate).
In a preferred embodiment of the invention, the alkali in described step (2) is selected from sodium hydroxide, potassium hydroxide, the one in lithium hydroxide.
3rd object of the present invention is to provide 4,4-difluoro diamantane carboxamides derivatives shown in formula (I) and pharmaceutically useful salt thereof as CCR5 antagonist, the application in the medicine of the disease for the treatment of CCR5 mediation.
4th object of the present invention is to provide treats 4, the 4-difluoro diamantane carboxamides derivatives shown in one or more formulas (I) of significant quantity and the pharmaceutical composition of pharmaceutically useful salt thereof a kind of comprising.
Described pharmaceutical composition, it also comprises drug excipient or the carrier of preparation permission.
Described dosage form is solid or liquid preparation.
The promise of contrast Malawi (
maraviroc) and 4 shown in formula (I), 4-difluoro diamantane carboxamides derivatives, the activity of 4,4-difluoro diamantane carboxamides derivatives (IC50=2.5nM) shown in formula (I) is apparently higher than Malawi's promise (IC50=28nM).
Embodiment
The present invention is described further in conjunction with the embodiments.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Ratio and per-cent based on weight, unless stated otherwise.
Except as otherwise noted, term " room temperature " and " envrionment temperature " represent the temperature between 16 DEG C to 25 DEG C.
Embodiment 1: preparation 4,4-difluoro adamantanecarboxylic acid
0 DEG C, under stirring, fluorination reagent DAST (diethylin sulfur trifluoride, 8.3g, 38mmol, 1.6eq.) be added drop-wise to raw material (II) (5g, 24mmol, 1.0eq.) in the solution of methylene dichloride (10mL), then reaction solution rises to room temperature, continues stirring reaction 3 hours, ice-water bath, under stirring, reaction solution is slowly poured in the salt of wormwood saturated aqueous solution of 40 milliliters, and aqueous solution ethyl acetate (30mL*3) extracts, extraction liquid uses water after merging respectively, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, filtering and concentrating.Resistates column chromatography (petroleum ether-ethyl acetate) purifying obtains intermediate (III) (3.6g), yield: 55%
Intermediate (III) (25g, 109mmol, 1.0eq.) is dissolved in THF-H2O (v/v=9:1,1L), add LiOH.H2O (6.8g, 162mmol, 1.5eqp.), reaction solution room temperature for overnight, concentrate and remove THF, the rare HCl of aqueous phase is neutralized to PH=2, separate out white solid product, filter, solid petroleum ether-ethyl acetate recrystallization obtains product (IV) 22g, yield: 80%.
1HNMR(400MHz,CDCl3)δppm＝2.26(br.s,2H),2.13～2.17(m,2H),1.89～2.02(m,7H),1.69～1.74(m,2H).19FNMR(400MHz,CDCl3)δppm＝-98.54(d,1F),-101.82(d,1F)。
Embodiment 2: 4,4-difluoro diamantane carboxamides derivatives shown in preparation formula (I)
Taking acid (IV) (0.48g, 2.2mmol, 1.5eq) is dissolved in 15ml toluene, add sulfur oxychloride (1.4g, 11.7mmol, 7.8eq), reflux 2 hours, it is complete that TLC shows acid-respons, directly concentrates, add the dissolving of 5ml toluene in residue after, substrate ammonia (V) (0.55g is added drop-wise under stirring at room temperature, in the mixed solution of 1.5mmol, 1.0eq., THF (10ml) and 5.5ml saturated sodium bicarbonate aqueous solution.React about 30 minutes TLC display aimnosubstrates to react completely.Reaction solution regulates about PH=11 with 2N aqueous sodium hydroxide solution again, dichloromethane extraction, merges organic phase, drying, concentrated, thick product silica gel column chromatography separating purification, obtain 4,4-difluoro diamantane carboxamides derivatives 0.65g shown in formula (I), yield: 77%.
1HNMR(400MHz,CDCl3)δ7.37～7.33(m,2H),7.29～7.24(m,3H),6.59(br,1H),5.07～5.05(m,1H),3.47～3.42(dd,2H),2.99～2.97(m,1H),2.55～2.46(br,5H),2.28～2.10(br,4H),2.05～1.89(br,14H),1.75～1.60(m,6H),1.39(dd,6H).MS-ESI(+):cal.565,found:566(M+H)。
Embodiment 3: 4,4-difluoro diamantane carboxamides derivatives shown in formula (I) are to the antagonistic activity measuring method of Chemokine Receptors (CCR5) and result
(1). by the HEK293 cell kind of stably express CCR5/G16 in 96 orifice plates, overnight incubation.
(2). suck the training liquid of planting and having in the hole of cell, add freshly prepared dyestuff 40l/ hole, constant-temperature incubation 40 minutes in 37 DEG C of incubators.
(3). with calcium damping fluid, drug dilution to be measured is mixed.
Activation pattern:
(4). dyestuff is exhausted and discards, after washing one time with freshly prepared calcium damping fluid, change 50l calcium damping fluid.
(5). detect with FlexStationII instrument, beginning in the 15th second adds by instrument the calcium damping fluid that 25l is dissolved with medicine to be measured automatically, final reading 525nm place fluorescent value.
Antagonist mode:
(4). dyestuff is exhausted and discards, after washing one time with freshly prepared calcium damping fluid, change the calcium damping fluid that 50l is dissolved with medicine to be measured.
(5). detect with FlexStationII instrument, beginning in the 15th second adds by instrument the calcium damping fluid that 25l is dissolved with known agonist automatically, final reading 525nm place fluorescent value.
Table one: CCR5 antagonistic activity the selection result:
* Malawi's promise (Maraviroc) is positive control.
Claims (10)
1. 4,4-difluoro diamantane carboxamides derivatives shown in formula (I) and pharmaceutically useful salt thereof, described 4,4-difluoro diamantane benzamide types have the structural formula shown in derivative formula (I):
。
2. 4 shown in formula according to claim 1 (I), 4-difluoro diamantane benzamide compound pharmacy acceptable salt, it, according to the method for pharmaceutically conventional salt formation, is 4 shown in formula (I), 4-difluoro diamantane carboxamides derivatives and hydrochloric acid, tartrate, Citric Acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid, the salt that sulfuric acid or methylsulfonic acid are formed.
3. 4,4-difluoro diamantane carboxamides derivatives of formula according to claim 1 (I) and the preparation method of pharmaceutically useful salt thereof, is characterized in that, comprise the steps:
(1) compound shown in formula (II) is at-78 DEG C-25 DEG C, under fluorination reagent effect, carries out compound shown in fluoridation production (III);
(2) compound shown in formula (III) is hydrolyzed compound shown in production (IV) under alkali effect;
(3) compound shown in formula (IV) generates acyl chlorides under thionyl chloride effect, direct and the shown compound of formula (V) without separation, 4,4-difluoro diamantane carboxamides derivatives shown in amidation production (I) under alkali effect;
Concrete reaction scheme is as follows:
。
4. preparation method as claimed in claim 3, it is characterized in that, described pharmaceutically useful salt is 4,4-difluoro diamantane carboxamides derivatives and hydrochloric acid shown in described formula (I), tartrate, Citric Acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, phosphoric acid, the salt that sulfuric acid or methylsulfonic acid are formed.
5. preparation method as claimed in claim 3, it is characterized in that, the fluorine reagent in described step (1) is selected from DAST, BAST, SF
4, PhSF
3, FLUOLEAD, XtalFluor-E or XtalFluor-M.
6. preparation method as claimed in claim 3, it is characterized in that, the alkali in described step (2) is selected from sodium hydroxide, potassium hydroxide, the one in lithium hydroxide.
7. the application in the medicine of the disease of preparation treatment CCR5 mediation of 4,4-difluoro diamantane carboxamides derivatives shown in formula according to claim 1 (I) and pharmaceutically useful salt thereof.
8. a pharmaceutical composition, is characterized in that, comprises treatment one or more 4,4-difluoro diamantane carboxamides derivatives shown in formula according to claim 1 (I) of significant quantity and the pharmaceutical composition of pharmaceutically useful salt thereof.
9. pharmaceutical composition according to claim 8, is characterized in that, also comprises drug excipient or the carrier of preparation permission.
10. pharmaceutical composition according to claim 9, is characterized in that, described dosage form is solid or liquid preparation.
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| PCT/CN2015/092823 WO2016062293A1 (en) | 2014-10-24 | 2015-10-26 | 4,4-difluoro adamantane formamide derivative, pharmaceutical composition and preparation method and uses thereof |
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| CN101412692B (en) * | 2007-10-18 | 2012-10-17 | 中国科学院上海药物研究所 | 1-(3-amino propyl) piperidine-4-aminoamide compounds, and pharmaceutical composition, preparation and use thereof |
| CN101712679B (en) * | 2008-10-08 | 2013-04-10 | 中国科学院上海药物研究所 | Acylamide class compound, medicine composition, preparation method and application thereof |
| AU2010319142B2 (en) * | 2009-11-11 | 2016-02-11 | Sumitomo Dainippon Pharma Co., Ltd. | 8-azabicyclo[3.2.1]octane-8-carboxamide derivative |
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| CN104693039B (en) * | 2015-01-06 | 2016-11-16 | 中山大学 | A kind of amantadine analog derivative and its preparation method and application |
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