CN107400124A - A kind of nicotinamide compound, synthetic route and its application in Claritin is prepared - Google Patents

A kind of nicotinamide compound, synthetic route and its application in Claritin is prepared Download PDF

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CN107400124A
CN107400124A CN201710829031.1A CN201710829031A CN107400124A CN 107400124 A CN107400124 A CN 107400124A CN 201710829031 A CN201710829031 A CN 201710829031A CN 107400124 A CN107400124 A CN 107400124A
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刘双伟
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of nicotinamide compound formula（Ⅰ）, synthetic route and its application in Claritin is prepared,, wherein, R1Selected from H, F or Cl, R2Selected from H or Cl, R3Selected from H or Cl.Formula of the present invention（Ⅰ）For the histamine receptor antagonists of brand-new framework types, belong to first public, be the stronger histamine receptor antagonists of a kind of activity, toxic side effect is low, can be used for the further investigation and exploitation of antihistamine drug, antianaphylaxis disease medicament, asthmatic medicament.

Description

A kind of nicotinamide compound, synthetic route and its in Claritin is prepared Using
Technical field
The present invention relates to a kind of nicotinamide compound formula（Ⅰ）, synthetic route and its in Claritin is prepared should With.
Background technology
H1Expression of receptor is in many cell types, including endothelial cell, most of smooth muscle cells, cardiac muscle, maincenter god Through system（CNS）Neuron and lymphocyte.H1Receptors signal transduction causes smooth muscle contraction（Including bronchoconstriction）, blood vessel The vasopermeability of diastole and enhancing, allergy and the anaphylactoid feature of other i.e. hair property.In central nervous system, H1Acceptor Activation is relevant with egersis.Its activation is also relevant with the itch in skin and mucosal tissue and nociception.For many years, H1Acceptor is short of money The antiallergy and anti-inflammatory activity of anti-agent have been used for the lesion for treating acute and chronic allergic condition and the mediation of other histamine, such as send out Itch and nettle rash.
Ratify the common H used at present1Receptor antagonist pharmaceuticals include：Systemic agents, such as diphenhydramine, cetirizine （Zyrtec）, Fei Suofennading（Allegra）, Loratadine（Claritin）And Desloratadine（Clarinex）, Yi Jiju Portion's medicament, such as olopatadine（Patanol、Pataday、Patanase）, Ketotifen, azelastine（Optivar, Astelin） And epinastine（Elestat）.Traditional purposes has included：Anaphylactia and reaction（Such as asthma, rhinitis and other chronic resistances Plug property tuberculosis）, illness in eye（Such as allergic conjunctivitis）, allergic dermatitis and different pathogeny itch.
The content of the invention
The present invention relates to a kind of nicotinamide compound formula（Ⅰ）, synthetic route and its in Claritin is prepared should With,
Wherein, R1Selected from H, F or Cl, R2Selected from H or Cl, R3Selected from H or Cl.
Further, formula（Ⅰ）The compound of expression, its salt or its solvated compounds.
Further, formula（Ⅰ）Synthetic route be
。
Further, described Formula（Ⅰ）Application in antihistamine drug is prepared.
Further, described Formula（Ⅰ）Application in antianaphylaxis disease medicament is prepared.
Further, described Formula（Ⅰ）Application in anti-asthmatic medicament is prepared.
Further, the anaphylactia is itch, nettle rash, allergic rhinitis, allergic dermatitis or anaphylaxis Conjunctivitis.
Further, a kind of composition, including the Formula described in claim 1（Ⅰ）It is and medically acceptable auxiliary Material.
Beneficial effect：
1. nicotinamide compound formula of the present invention（Ⅰ）For the histamine receptor antagonists of brand-new framework types, belong to first Secondary disclosure, it is the stronger histamine receptor antagonists of a kind of activity, can be used for antihistamine drug, antianaphylaxis disease medicament gos deep into Research and development.
2. experiment proves nicotinamide compound formula of the present invention（Ⅰ）Contestable with body H1Acceptor with reference to and Blocking histamine and H1The effect of acceptor, biological effect is played so as to suppress histamine, plays antianaphylactic effect.Anti-histamine activity Screening experiment shows that such compound has stronger anti-histamine activity, MTS methods compared with positive control Desloratadine Detect influence of the compounds of this invention to RAW264.7 cell-proliferation activities and show that toxic side effect is low.
3. experiment proves nicotinamide compound formula of the present invention（Ⅰ）Relievingd asthma in the cavy of asthma caused by histamine work With better than Desloratadine group.
4. preparation method provided by the invention has reaction condition gentle, abundant raw material is easy to get, and operates and post-processes and be simple The features such as.
Embodiment
The synthesis of the N- of embodiment 1 [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5)-niacinamide
1st, the synthesis of N- [(4- methyl piperazines base -1) methene]-(4- phenyl thiazoles base -5)-imines
4- phenyl thiazole base -5- primary amine (10 mmol) and 4- methyl piperazine base -1- formaldehyde (11 mmol) are dissolved in 40 milliliters of first In alcohol, stir 2 hours, system can not be handled further, directly carry out next step reduction reaction.1H-NMR (400 MHz, CDCl3) δ: 2.89(s, 3H), 2.25(t, 4H), 3.59(t, 4H), 7.46-7.49(m, 3H), 7.59(s, 1H), 8.22(m, 2H), 9.01(s, 1H).LC-MS(ESI, pos, ion) m/z: 287[M+1].
2nd, the synthesis of N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine
5 milliliters of glacial acetic acids will be added in the reaction solution of previous step, be cooled to 0-5 DEG C, then add 1.2 g sodium borohydrides, low temperature Lower stirring 2 hours, it is warmed to room temperature and continues to stir half an hour, 100 ml water are then added into system, stir 1 hour, filtering, obtain To 2.1 g yellow solids, as N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine, two step yields are total to 73%。1H-NMR (400 MHz, CDCl3) δ: 2.14(s, 3H), 2.32(s, 8H), 4.02(s, 1H), 4.34(s, 1H), 7.49-7.53(m, 3H), 7.84(m, 2H), 8.19(s, 1H), 9.59(s, 1H).LC-MS(ESI, pos, ion) m/z: 289[M+1].
3rd, the synthesis of N- [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5)-niacinamide
N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine (10 mmol) is dissolved in 50 ml dichloromethanes Alkane solution, adds 10 ml triethylamines thereto, and control temperature is less than 10 DEG C, nicotinoyl chlorine (12 mmol) is added dropwise into system Dichloromethane solution, recover room temperature after being added dropwise, stirring at normal temperature 10 hours, then washed with 50 ml 5% aqueous sodium carbonate Wash reaction system, organic phase anhydrous Na2SO4Dry, after solvent evaporated, obtained solid flash column chromatography separates, and obtains 3.6 G off-white colors N- [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5)-niacinamide solid, yield 91.5%.1H- NMR (400 MHz, CDCl3) δ: 2.13(s, 3H), 2.31(s, 8H), 4.68(s, 2H), 7.41-7.45(m, 4H), 7.80(m, 2H), 8.07(dt, 1H), 8.72-8.75(m, 2H), 8.95(m, 1H).13C-NMR (75 MHz, CDCl3) δ:46.06, 52.97, 54.39, 72.21, 123.72, 126.59, 128.62, 129.47, 132, 134.13, 135.73, 137.7, 144.21, 149.36, 151.49, 151.8, 170.53.LC-MS(ESI, pos, ion) m/z: 394[M+1].
The synthesis of the N- of embodiment 2 [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -2- fluorine niacinamide
N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine (10 mmol) is dissolved in 40 ml dichloromethanes Alkane solution, adds 10 ml triethylamines thereto, and control temperature is less than 10 DEG C, 2- fluorine nicotinoyl chlorine (12 is added dropwise into system Mmol dichloromethane solution), room temperature, stirring at normal temperature 10 hours, then with 50 ml 5% sodium carbonate are recovered after being added dropwise Aqueous solution washing reaction system, organic phase anhydrous Na2SO4To dry, after solvent evaporated, obtained solid flash column chromatography separates, The light yellow N- of 3.7 g [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -2- fluorine niacinamide solids are obtained, Yield 90%.1H-NMR (400 MHz, CDCl3) δ: 2.16(s, 3H), 2.32(s, 8H), 4.67(s, 2H), 7.49-7.53(m, 3H), 7.71(t, 1H), 7.84(m, 2H), 8.60-8.64(m, 2H), 8.79(s, 1H).13C-NMR (75 MHz, CDCl3) δ:46.06, 52.97, 54.39, 72.21, 116.58, 119.38, 126.59, 128.62, 129.47, 134.13, 137.7, 138.75, 144.21, 151.27, 151.8, 159.2, 164.68. LC-MS(ESI, pos, ion) m/z: 412[M+1].
The synthesis of the N- of embodiment 3 [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -2- chloro-nicotinamides
N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine (10 mmol) is dissolved in 40 ml dichloromethanes Alkane solution, adds 10 ml triethylamines thereto, and control temperature is less than 10 DEG C, 2- chloronicotinoyl chlorides (12 are added dropwise into system Mmol dichloromethane solution), room temperature, stirring at normal temperature 10 hours, then with 50 ml 5% sodium carbonate are recovered after being added dropwise Aqueous solution washing reaction system, organic phase anhydrous Na2SO4To dry, after solvent evaporated, obtained solid flash column chromatography separates, Obtain 3.9 g whites N- [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -2- chloro-nicotinamide solids, yield 91%。1H-NMR (400 MHz, CDCl3) δ: 2.14(s, 3H), 2.35(s, 8H), 4.69(s, 2H), 7.52(m, 3H), 7.84-7.88(m, 6H), 8.49(m, 1H), 8.63(m, 1H), 8.74(s, 1H).13C-NMR (75 MHz, CDCl3) δ:46.06, 52.97, 54.39, 72.21, 122.55, 126.59, 128.62, 129.47, 133.29, 134.13, 137.48, 137.7, 144.21, 150.34, 150.84, 151.8, 167.91.LC-MS(ESI, pos, ion) m/z: 428[M+1].
The synthesis of the N- of embodiment 4 [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -4- chloro-nicotinamides
N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine (10 mmol) is dissolved in 40 ml dichloromethanes Alkane solution, adds 10 ml triethylamines thereto, and control temperature is less than 10 DEG C, 4- chloronicotinoyl chlorides (12 are added dropwise into system Mmol dichloromethane solution), room temperature, stirring at normal temperature 10 hours, then with 50 ml 5% sodium carbonate are recovered after being added dropwise Aqueous solution washing reaction system, organic phase anhydrous Na2SO4To dry, after solvent evaporated, obtained solid flash column chromatography separates, 3.7 g off-white colors N- [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -4- chloro-nicotinamide solids are obtained, are produced Rate 86%.1H-NMR (400 MHz, CDCl3) δ: 2.13(s, 3H), 2.33(s, 8H), 4.70(s, 2H), 4.49- 7.53(m, 3H), 7.60(d, 1H), 7.84(m, 2h), 8.68(d, 1H), 8.79(s, 1H), 9.02(s, 1H).13C-NMR (75 MHz, CDCl3) δ:46.06, 52.97, 54.39, 72.21, 125.23, 126.59, 128.62, 129.47, 131.62, 134.13, 137.7, 143.33, 144.21, 149.56, 151.8, 152.67, 169.31.LC-MS(ESI, pos, ion) m/z: 428[M+1].
The synthesis of the N- of embodiment 5 [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -6- chloro-nicotinamides
N- [(4- methyl piperazines base -1) methyl]-(4- phenyl thiazoles base -5)-secondary amine (10 mmol) is dissolved in 40 ml dichloromethanes Alkane solution, adds 10 ml triethylamines thereto, and control temperature is less than 10 DEG C, 6- chloronicotinoyl chlorides (12 are added dropwise into system Mmol dichloromethane solution), room temperature, stirring at normal temperature 10 hours, then with 50 ml 5% sodium carbonate are recovered after being added dropwise Aqueous solution washing reaction system, organic phase anhydrous Na2SO4To dry, after solvent evaporated, obtained solid flash column chromatography separates, Obtain 4.0 g whites N- [(4- methyl piperazines base -1) methyl]-N- (4- phenyl thiazoles base -5) -6- chloro-nicotinamide solids, yield 93%。1H-NMR (400 MHz, CDCl3) δ: 2.16(s, 3H), 2.42(s, 8H), 4.71(s, 2H), 7.49- 7.55(m, 4H), 7.84(m, 2H), 8.49(d, 1H), 8.79(s, 1H), 9.01(d, 1H). 13C-NMR (75 MHz, CDCl3) δ:46.06, 52.97, 54.39, 72.21, 124.09, 126.59, 128.62, 129.47, 131.65, 134.13, 136.71, 137.7, 144.21, 149.44, 151.8, 153.14, 170.53.LC-MS (ESI, pos, ion) m/z: 428[M+1].
Test example 1：H1Receptor antagonism is tested
The active generally use guinea pig ileum shrinkage of compound antagonism H1 acceptors is tested to judge.By comparing guinea pig ileum Contracted length, calculate the IC of inhibitory activity value50Value.
Cavy one is taken, its head is hit with mallet and puts to death, split abdominal cavity immediately, find ileocecus, at from ileocecus 1cm Ileum is cut, one section of about 10cm or so ileum is taken out, is placed in the tyrode's solution culture dish for filling and being filled with air, intestines are removed along intestinal wall Mesentery, ileum is then cut into several segments（Per 1~1.5cm of segment）, draw tyrode's solution with 5mL syringes and rinse intestinal contents Totally, change standby with fresh tyrode's solution.Pay attention to not pulling intestinal segment during operation in order to avoid influenceing contractile function.Take intestinal tube to be placed in and fill platform In the culture dish of family name's liquid, at its both ends diagonal wall, threaded respectively with suture needle, and knot.Pay attention to keeping intestinal tube unobstructed, do not make it Closing.Intestinal tube one end line is lain on ventilation hook hook, is then placed in 37 DEG C of Magnus' baths.With screw clamp regulation air pump gas outlet Sebific duct, draft speed is escaped one by one with the bubble in Magnus' bath to be advisable.The other end of intestinal tube is added on pulling force transducing again Device, and Muscle tensility is adjusted to appropriateness, preload 1g.After the stable 1h of Ileum From A White, after recording one section of normal contraction curve, successively Agents are added dropwise in Magnus' bath.After adding 0.3 μ g/mL histamine 0.1mL, contact 2 minutes, and observe shrinkage amplitude, so Afterwards with tyrode's solution continuous flushing for several times, the level before baseline restorer to medication is treated, then records one section of baseline.Plus 10- then 5mol/L histamine solution, each 0.1mL is continuously plus until intestinal contraction reaches maximum.（Due to histamine work have it is certain Hysteresis quality, so to be added when adding every time at the preceding second largest value once shunk.）Then elute for several times, treat baseline restorer Originally height adds testing sample, is incubated 15min, then adds 10-5mol/L histamine solution as previously described.It should be noted that addition group The amount that the total amount of amine should be added with last time is consistent.The compound of table 1 suppresses the IC that guinea pig ileum shrinks activity50。
The compound of table 1 suppresses the IC that guinea pig ileum shrinks activity50
Compound number IC50（μM）
Desloratadine 0.072
Astemizole 0.862
KZAL1206 0.623
KZAL1209 0.796
KZAL1210 0.322
KZAL1222 0.298
KZAL1235 0.586
The compounds of this invention suppresses the IC that guinea pig ileum shrinks activity50Value is below astemizole, but above Ground chlorine thunder he It is fixed, show that the compounds of this invention suppresses guinea pig ileum and shrinks activity by force.Illustrate that compound has stronger antagonism H1The work of acceptor Property.
Test example 2：To the antiasthmatic effect of asthmatic guinea pigs caused by histamine
Cavy is taken, is placed in lucite bell jar, ultrasonic atomizatio sprays into salt histamine solution (0.8mg/mL) 40s, record cavy production The time of raw asthma, using the time twitched, fallen as incubation period, the cavy more than 180s is not selected, by the cavy selected with Machine is grouped, every group 10, Normal group, Desloratadine group (1mg/kg), testing compound group (0.1mg/kg).With 2mL/ Kg bw gastric infusions, 60min after administration, are respectively put into glass bell jar, by similarity condition spraying histamine hydrochloride during pre-selection Solution, in the incubation period that record asthma occurs, if not occurring asthma person yet more than 6min, in terms of 6min, as a result carry out at statistics Reason.Its result is as shown in table 2：
Table 2 be test compound antiasthmatic effect result (, n=10)
Compound number Incubation period before administration（s） Incubation period after administration（s）
Normal group 108.2±38.4 117.9±42.3
Desloratadine group 116.7±35.9 261.4±43.1*
KZAL1206 106.3±35.9 264.4±41.6*
KZAL1209 112.0±32.6 259.4±38.2*
KZAL1210 120.4±41.0 305.9±32.1* #
KZAL1222 109.7±29.9 301.8±28.8* #
KZAL1235 107.6±36.6 260.7±47.6*
* compared with Normal group：P<0.05, # compared with Desloratadine group：P<0.05
60min after the compounds of this invention administration, gives histamine hydrochloride solution, is hidden before finding the incubation period relatively administration that asthma occurs Phase extends, and incubation period is noticeably greater than in the case that the compounds of this invention dosage is Desloratadine group 1/10, after administration Loratadine group has KZAL1210 and KZAL1222, KZAL1206, KZAL1209 and KZAL1235 and Desloratadine group phase Than no significant difference.Illustrate that the compounds of this invention antiasthmatic effect is suitable or more excellent with Desloratadine.
Test example 3：The influence of cell proliferation activity
Influence of the MTS methods detection compound to RAW264.7 cell-proliferation activities.Cell is inoculated in 96 orifice plates, sets blank respectively Control group, compound group (10 μ g/ mL and 100 μ g/mL various concentrations), every group sets three multiple holes.Add the μ L of MTS solution 20 per hole, 1-2 hours are incubated, its light absorption value is surveyed under the conditions of wavelength 490nm using ELIASA.It was found that compound group（Two concentration）With it is right According to group absorbance without significant difference, illustrate that the compounds of this invention does not interfere with the proliferation activity of RAW264.7 cells.
Above-mentioned pharmacological testing shows that compound of the invention is respectively provided with excellent antagonizing histamine function of receptors, has excellent Antiasthmatic activity, have more plus depth research and development potentiality.

Claims (7)

  1. A kind of 1. nicotinamide compound formula（Ⅰ）
    Wherein, R1Selected from H, F or Cl, R2Selected from H or Cl, R3Selected from H or Cl.
  2. A kind of 2. nicotinamide compound formula（Ⅰ）
    Wherein, R1Selected from H, F or Cl, R2Selected from H or Cl, R3Selected from H or Cl, it is characterized in that, synthetic route is yes
    。
  3. 3. Formula as claimed in claim 1（Ⅰ）Application in antihistamine drug is prepared.
  4. 4. Formula as claimed in claim 1（Ⅰ）Application in antianaphylaxis disorder medicine is prepared.
  5. 5. Formula as claimed in claim 1（Ⅰ）Application in anti-asthmatic medicament is prepared.
  6. 6. Formula as claimed in claim 4（Ⅰ）Application, the anaphylactia be itch, nettle rash, allergia nose Scorching, allergic dermatitis or allergic conjunctivitis.
  7. 7. a kind of composition, including the Formula described in claim 1（Ⅰ）And medically acceptable auxiliary material.
CN201710829031.1A 2017-09-14 2017-09-14 A kind of nicotinamide compound, synthetic route and its application in Claritin is prepared Pending CN107400124A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021555A2 (en) * 1997-10-27 1999-05-06 Takeda Chemical Industries, Ltd. Adenosine a3 receptor antagonists
EP1205478A1 (en) * 1999-08-06 2002-05-15 Takeda Chemical Industries, Ltd. p38MAP KINASE INHIBITORS
CN1732164A (en) * 2002-10-30 2006-02-08 沃泰克斯药物股份有限公司 Compositions useful as inhibitors of ROCK and other protein kinases
WO2007087427A2 (en) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021555A2 (en) * 1997-10-27 1999-05-06 Takeda Chemical Industries, Ltd. Adenosine a3 receptor antagonists
EP1205478A1 (en) * 1999-08-06 2002-05-15 Takeda Chemical Industries, Ltd. p38MAP KINASE INHIBITORS
CN1732164A (en) * 2002-10-30 2006-02-08 沃泰克斯药物股份有限公司 Compositions useful as inhibitors of ROCK and other protein kinases
WO2007087427A2 (en) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Thiazole and thiadiazole compounds for inflammation and immune-related uses

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Application publication date: 20171128