CN1589784A - 5-hydroxymethyl -2-furol and its derivative analogue medical use - Google Patents
5-hydroxymethyl -2-furol and its derivative analogue medical use Download PDFInfo
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Abstract
An application of 5-hydroxymethyl-2-furaldehyde, its derivative or salt, and its like or precursor in preparing medicine is disclosed.
Description
Technical field
The present invention relates to the medical usage of 5 hydroxymethyl 2 furaldehyde and derivant thereof, analog, be specifically related to 5 hydroxymethyl 2 furaldehyde and derivant thereof, analog and their officinal salt, the purposes of prodrug in the medicine of preparation treatment TNF-α or IL-1 β associated conditions.。
Background technology
To be body cause the reaction based on defence that damage took place that inflammatory factor causes to various to inflammation, and the topical manifestations of inflammation is red, and is swollen, heat, pain and dysfunction.Comparatively obvious when these show acute body surface inflammation, how not obvious the inflammation and the chronic inflammatory disease of internal organs be then.It is local that inflammation not only shows, and often cause general reaction.Common general reaction has heating, and the leukocyte number in the blood increases and the heart, liver, and degeneration in various degree can appear in parenchymatous organs such as kidney, pathological changes such as necrosis.
By pathological classification, inflammation can be divided into alterative inflammation, serous inflammation, fibrinous inflammation, purulent inflammation, hemorrhagic inflammation, catarrhal inflammation, productive inflammation and chronic granuloma inflammation.
TNF α is a kind of monokine, is mainly produced by mononuclear cell and macrophage, and LPS is stronger stimulant.Discover that TNF α has the various biological activity: 1) kill and wound or suppress tumor cell; 2) phagocytic activity of raising neutrophilic granulocyte increases superoxide anion and produces, and participates in inflammatory reaction; 3) infection etc.According to the literature, the TNF alpha inhibitor can be used for rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, Parkinson's disease, acquired immune deficiency syndrome and dementia and syndrome, presenile dementia, depression, sepsis, Pyoderma gangrenosum, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, the treatment of various disease conditions such as obesity
(1-25)(1.Ogata H, Hibi T.et al Curr Pharm Des.2003; 9 (14): 1107-13.2.Moller DR.et al J Intern Med.2003 Jan; 253 (1): 31-40.3.Taylor PC.Et al Curr Pharm Des.2003; 9 (14): 1095-106.4.Wilkinson Net al Arch Dis Child.2003 Mar; 88 (3): 186-91.5.Nishimura F et al JPeriodontol.2003 Jan; 74 (1): 97-102.6.Weinberg JM et al Cutis.2003 Jan; 71 (1): 41-5.7.Burnham E et al Crit Care Med.2001 Mar; 29 (3): 690-1.8.Sack M.et al Pharmacol Ther.2002 Apr-May; 94 (1-2): 123-35.9.BarnesPJ.Et al Annu Rev Pharmacol Toxicol.2002; 42:81-98.10.Mageed RA etal Lupus.2002; 11 (12): 850-5.11.Tsimberidou AM et al Expert RevAnticancer Ther.2002 Jun; 2 (3): 277-86.12.Muller T.et al Curr OpinInvestig Drugs.2002 Dec; 3 (12): 1763-7.13.Calandra T et al Curr ClinTop Infect Dis.2002; 22:1-23.14.Girolomoni G et al Curr Opin InvestigDrugs.2002 Nov; 3 (11): 1590-5.15.Tutuncu Z et al Clin Exp Rheumatol.2002 Nov-Dec; 20 (6 Suppl 28): S146-51.16.Braun J et al Best Pract ResClin Rheumatol.2002 Sep; 16 (4): 631-51.17.Barnes PJ.Et al NovartisFound Symp.2001; 234:255-67; Discussion 267-72.18.Brady M, et alBaillieres Best Pract Res Clin Gastroenterol.1999 Jul; 13 (2): 265-89.19.Goldring MB.et al Expert Opin Biol Ther.2001 Sep; 1 (5): 817-29.20.Mariette X.Rev Prat.2003 Mar 1; 53 (5): 507-11.21.Sharma R et al Int JCardiol.2002 Sep; 85 (1): 161-71.22.Wang CX et al Prog Neurobiol.2002Jun; 67 (2): 161-72.23.Van Reeth K et al Vet Immunol Immunopathol.2002Sep 10; 87 (3-4): 161-8.24.Leonard BE et al Int J Dev Neurosci.2001 Jun; 19 (3): 305-12.25.Hays SJ et al Curr Pharm Des.1998 Aug; 4 (4): 335-48.).
IL-1 β is a kind of cytokine that is produced by mononuclear phagocyte, dendritic cell, fibroblast etc.It can stimulate propagation and differentiation, the hemopoietic of T cell and B cell and participate in inflammatory reaction.According to the literature, the IL-1 beta inhibitor can be used for the treatment of various disease conditions such as rheumatoid arthritis, septicemia, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, presenile dementia, osteoarthritis, bacterial infection, multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, respiratory virus infection, asthma, depression, scleroderma
(26～45)(26.Taylor PC.et al Curr Pharm Des.2003; 9 (14): 1095-106.27.Dellinger RP et al Clin Infect Dis.2003 May 15; 36 (10): 1259-65.28.Takashiba S et al J Periodontol.2003 Jan; 74 (1): 103-10.29.Diwan A, et al Curr Mol Med.2003 Mar; 3 (2): 161-82.30.Lundberg IE, etal Rheum Dis Clin North Am.2002 Nov; 28 (4): 799-822.31.Makhija R, etal J Hepatobiliary Pancreat Surg.2002; 9 (4): 401-10.32.Chung KF.Et alEur Respir J Suppl.2001 Dec; 34:50s-59s.33.Hallegua DS, et al AnnRheum Dis.2002 Nov; 61 (11): 960-7.34.Goldring MB.Et al Expert OpinBiol Ther.2001 Sep; 1 (5): 817-29.35.Mrak RE, Griffin WS.Et alNeurobiol Aging.2001 Nov-Dec; 22 (6): 903-8.36.Brady M, et alBaillieres Best Pract Res Clin Gastroenterol.1999 Jul; 13 (2): 265-89.37.Van der Meer JW, et al Ann N Y Acad Sci.1998 Sep 29; 856:243-51.38.Rameshwar P et al Acta Haematol.2003; 109 (1): 1-10.39.de Kozak Y et alInt Rev Immunol.2002 Mar-Jun; 21 (2-3): 231-53.40.Wang CX et al ProgNeurobiol.2002 Jun; 67 (2): 161-72.41.Van Reeth K et al Vet ImmunolImmunopathol.2002 Sep 10; 87 (3-4): 161-8.42.Stirling RG et al Br MedBull.2000; 56 (4): 1037-53.43.Leonard BE et al Int J Dev Neurosci.2001Jun; 19 (3): 305-12.44.Allan SM et al Ann N Y Acad Sci.2000; 917:84-93.45.Cafagna D et al Minerva Med.1998 May; 89 (5): 153-61.).
5 hydroxymethyl 2 furaldehyde (5-HMF) in sucrose production, beer fermentation and all kinds of production that contains confectionery and medicine and storage process with the form of the thermal degradation product of sugar and extensively exist.It also is present in simultaneously in the plant such as Fructus Corni (Xu Lizhen etc., Fructus Corni The Chemical Constituents Chinese herbal medicine 1995,26 (2) 62～65).
Chinese patent ZL 97107191.8 " medical usage of 5 hydroxymethyl 2 furaldehyde " closes discovery and separation the decoct, has identified 5-HMF from Chinese medicine ancient prescription SHENGMAI SAN first, and proves that by the test of pesticide effectiveness it has function of resisting myocardial ischemia, is better than the ginsenoside.Do not see that the bibliographical information 5 hydroxymethyl 2 furaldehyde can suppress the expression of TNF α and IL-1 β.
Derivant, the analog of the also unexposed 2-methyl of existing document-3-methyl furoate, acetic acid bran ester, 5-methyl-2-furfural, 2-acetyl group-5-methylfuran, 5-ethyl-2-furfural, 5-amino-2-furan-methyl formate, 5-ethyl-5 hydroxymethyl 2 furaldehyde such as 2-thiophene aldehyde has the activity that suppresses TNF α and IL-1 β expression.
Summary of the invention
Purpose of the present invention aims to provide compound or pharmaceutically acceptable salt thereof, prodrug and their officinal salt of general formula (I), a kind of new pharmaceutical applications of prodrug.
One aspect of the present invention relates to compound or pharmaceutically acceptable salt thereof, the purposes of prodrug in the medicine of preparation treatment TNF α associated conditions of following general formula (I):
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
Especially, the present invention relates to 5 hydroxymethyl 2 furaldehyde and derivant thereof, analog comprises 2-methyl-3-methyl furoate
, acetic acid bran ester
, 5-methyl-2-furfural
, 2-acetyl group-5-methylfuran
, 5-ethyl-2-furfural
, 5-amino-2-furan-methyl formate
With 5-ethyl-2-thiophene aldehyde
Purposes in the medicine of preparation treatment TNF α associated conditions and IL-1 β associated conditions.
Described " TNF α associated conditions " includes but not limited to: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, Parkinson's disease, presenile dementia, depression, acquired immune deficiency syndrome and dementia and syndrome, sepsis, Pyoderma gangrenosum, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection or obesity.
Described " IL-1 β associated conditions " includes but not limited to: rheumatoid arthritis, septicemia, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, presenile dementia, osteoarthritis, bacterial infection, multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, respiratory virus infection, asthma, depression or scleroderma.
Another aspect of the present invention relates to compound or pharmaceutically acceptable salt thereof, the purposes of prodrug in the medicine of preparation treatment inflammatory disease of following general formula (I):
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
Especially; the present invention relates to 5 hydroxymethyl 2 furaldehyde and derivant thereof; analog comprises 2-methyl-3-methyl furoate; acetic acid bran ester; 5-methyl-2-furfural; 2-acetyl group-5-methylfuran; 5-ethyl-2-furfural; 5-amino-2-furan-methyl formate and the 5-ethyl-2-thiophene aldehyde purposes in the medicine of preparation treatment inflammatory disease; described inflammatory disease is selected from down one or more in the group disease, and these diseases include but not limited to: rheumatoid arthritis; juvenile rheumatoid arthritis; osteoarthritis; SpA; inflammatory bowel; heart failure; diabetes; systemic lupus erythematosus (sle); scleroderma; sarcoidosis; dermatomyositis; psoriasis; multiple myeloma; myelodysplastic syndrome; acute marrow type leukemia; Parkinson's disease; presenile dementia; depression; acquired immune deficiency syndrome and dementia and syndrome; sepsis; Pyoderma gangrenosum; septicemia; septic shock; behcets disease; graft versus host disease; uveitis; Wegener ' s granuloma; the Xiu Gelianshi xerosis; chronic obstructive pulmonary disease; asthma; acute pancreatitis; periodontal disease; cachexia; cancer; central nervous system injury; respiratory virus infection; bacterial infection or obesity.
Another aspect of the present invention has provided the separation and/or the preparation method of above-claimed cpd.
The details of various aspects of the present invention will be able to detailed description in chapters and sections subsequently.By hereinafter and the description of claim, other characteristics of the present invention, purpose and advantage will be more obvious.
Appearance part of the present invention is based on so unexpected discovery: the compound or pharmaceutically acceptable salt thereof of following general formula (I), prodrug can significantly suppress the expression of TNF α and IL-1 β:
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
Particularly; 5 hydroxymethyl 2 furaldehyde and derivant thereof, analog comprise that 5 hydroxymethyl 2 furaldehyde, 2-methyl-3-methyl furoate, acetic acid bran ester, 5-methyl-2-furfural, 2-acetyl group-5-methylfuran, 5-ethyl-2-furfural, 5-amino-2-furan-methyl formate and 5-ethyl-2-thiophene aldehyde etc. can significantly suppress the expression of TNF α and IL-1 β.Therefore, 5 hydroxymethyl 2 furaldehyde and derivant thereof, analog or its officinal salt, prodrug etc. can be used for preparing the medicine of treatment TNF α and IL-1 β associated conditions.Above-claimed cpd can make by synthesis material and the method that commercial sources obtains or use is conventional.
The officinal salt of chemical compound of the present invention comprises various inorganic or acylate example hydrochloric acid salt, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates; (TRIS is tromethane) with N-methyl-glucamine for various inorganic or organic alkali salts such as sodium hydroxide, Tris.
The prodrug of chemical compound of the present invention comprises that the carboxylate that contains this chemical compound (can be by the conventional method C of this area
1-4Pure and strong contraction get), the hydroxy ester that contains this chemical compound (can be by the conventional method C of this area
1-4Carboxylic acid, C
3-6Dicarboxylic acids or its anhydride, as maleic anhydride, fumaric acid anhydride etc. are concentrated to be made), the enamine that contains this chemical compound (can be by the conventional method C of this area
1-4Aldehydes or ketones concentrate make) or contain the acetal of this chemical compound or ketal (can concentrate with chloromethyl methyl ether or chloromethyl ether by the conventional method of this area and make) etc. (Albert S.Kearney AdvancedDrug Reviews.19 (1996): 229-234)..
Chemical compound of the present invention can be by the conventional method preparation or the purification of this area.Particularly, 5 hydroxymethyl 2 furaldehyde of the present invention can be from plant Fructus Corni (Cornus Officinalis) be separated according to a conventional method and is obtained, and is about to Fructus Corni acid solution extracting, with extract mix, filtration; Filtrate is by polarity or nonpolar macroporous adsorption resin, again water, ethanol elution pillar successively; After eluent is purified, concentrated, collect fraction, drying makes.Confirm as 5 hydroxymethyl 2 furaldehyde (5-HMF) through ultraviolet, infrared, mass spectrum, hydrogen spectrum, carbon spectrum identification and analysis.110 ℃ of its boiling points, 31.5 ℃ of fusing points are pale brown color needle-like solid, its structural formula is:
C
6H
6O
3.Mol.Wt.：126.11
UV(λ
max，nm)：284，230，195；
IR(cm
-1，KBr)：3350，1673，1522，1399，1193，1024，777；
1H?NMR(600MHz，D
2O)δ：4.60(2H，s，H-9)，6.58(1H，d，J＝3.5Hz，H-6)，7.43(1H，d，J＝3.8Hz，H-8)，9.35(1H，s，H-4)；
13C?NMR(100MHz，D
2O)δ：58.5，113.3，129.2，154.0，163.5，182.5；
EIMS(m/z)：126(M
+)
Described " TNF-α associated conditions " includes but not limited to: rheumatoid arthritis (rheumatoidarthritis), juvenile rheumatoid arthritis (juvenile rheumatoid arthritis), osteoarthritis (osteoarthritis), SpA (spondyloarthropathies), inflammatory bowel (inflammatory bowel disease), heart failure (heart failure), diabetes (diabetesmellitus), systemic lupus erythematosus (sle) (systemic lupus erythematosus), scleroderma (scleroderma), sarcoidosis (sarcoidosis), dermatomyositis (polymyositis/dermatomyositis), psoriasis (psoriasis), multiple myeloma (multiple myeloma), myelodysplastic syndrome (myelodysplastic syndrome), acute marrow type leukemia (acute myelogenous leukemia), Parkinson's disease (Parkinson ' sdisease), acquired immune deficiency syndrome and dementia and syndrome (AIDS dementia complex), presenile dementia (Alzheimer ' s disease), depression (depression), sepsis (sepsis), Pyoderma gangrenosum (pyoderma gangrenosum), septicemia (hematosepsis), septic shock (septic shock), behcets disease (Behcet ' s syndrome), graft versus host disease (graft-versus-host disease), uveitis (uveitis), Wegener ' s granuloma (Wegener ' s granulomatosis), Xiu Gelianshi xerosis (Sjogren ' s syndrome), chronic obstructive pulmonary disease (chronic obstructive pulmonary disease), asthma (asthma), acute pancreatitis (acute pancreatitis), periodontal disease (Periodontal disease), cachexia (cachexia), cancer (cancer), central nervous system injury (central nervous systeminjury), respiratory virus infection (viral respiratory disease), fat (obesity) etc.
Described " IL-1 β associated conditions " includes but not limited to: rheumatoid arthritis (rheumatoidarthritis), septicemia (hematosepsis), periodontal disease (Periodontal disease), heart failure (heart failure), dermatomyositis (polymyositis/dermatomyositis), acute pancreatitis (acute pancreatitis), chronic obstructive pulmonary disease (chronic obstructive pulmonarydisease), presenile dementia (Alzheimer ' s disease), osteoarthritis (osteoarthritis), bacterial infection (Bacterial infections), multiple myeloma (multiple myeloma), myelodysplastic syndrome (myelodysplastic syndrome) uveitis (uveitis), central nervous system injury (central nervous system injury), respiratory virus infection (viralrespiratory disease), asthma (asthma), depression (depression), scleroderma (scleroderma) etc.
" juvenile rheumatoid arthritis " (juvenile rheumatoid arthritis) is a kind of common connective tissue disease in children's's period, with chronic arthritis is its main feature, and, comprise joint, skin, flesh, liver, spleen, lymph node with the getting involved of whole body multisystem.Young infant often has the irregular heating of persistence earlier, and its General Symptoms is more remarkable than the joint symptom; The more joint symptom that is limited to of older youngster or adult patients.The primary disease clinical manifestation differs greatly, can be divided into dissimilar, so name is numerous, as still disease (1897), the high repeatedly pattern of fever of juvenile rheumatoid disease (Wissler Franconi syndrome), chronic arthritis childhood (juvenile chronic arthritis), juvenile rheumatoid disease (juvenile rheumatoid disease) and juvenile arthritis (juvenile arthritis) etc.
" spinal column arthrosis " (spondyloarthropathies) is meant one group of multisystem diseases associated with inflammation with internal relation.Therefore the rheumatoid factor (rheumatoid factor) in its blood of class disease patient is negative, so be called " seronegative spondyloanthropathy (seronegativespondyloarthropathies) again.Primary disease can involve spinal column, periphery joint, joint surrounding structure or three and all involve, and with showing outside the various distinctive joints, as acute and chronic gastrointestinal or inflammation of genito-urinary system disease (can be infection sometimes), preocular inflammation, psoriasis skin, fingernail infringement etc.This group disease mainly comprises: ankylosing spondylitis (Ankylosing spondylitis), auspicious special syndrome (Reiter ' s syndrome), psoriasis arthropathica (Psoriatic arthropathy), inflammatory bowel characteristic of disease arthritis (Inflammatory bowel disease arthritis), undifferentiated type SpA (Undifferentiated spondyloarthropathy) etc.
" osteoarthritis " (osteoarthritis) is meant " osteoarthritis ", and it is modal a kind of in all types arthritis.Usually retrograde arthropathy takes place in meeting on the joint of middle age or old people's cervical region, back, knee and ilium, causes restriction and difficulty on the joint motion.Its degenerative process is: composition → cartilage erosion → edge, joint produces vegetation, i.e. bony spur to cartilage forfeiture sclerotin.
" inflammatory bowel " (inflammatory bowel disease) is the general designation of crohn (Crohn ' s disease) and two kinds of non-specific enteritis of ulcerative colitis (ulcerative colitis).
" chronic obstructive pulmonary disease " (chronic obstructive pulmonary disease COPD) is meant chronic bronchitis and/or the emphysema (American Thoracic Society (ATS) and the definition of respiratory system association of Chinese Medical Association) with airflow obstruction feature.Some bronchial asthma develops into the irreversibility airflow obstruction in disease process, when bronchial asthma and chronic bronchitis and (or) the overlapping existence of emphysema or when being difficult to differentiate, also can list the COPD scope in.The principal character of COPD is the chronic progressive external airflow obstruction.
Be appreciated that chemical compound of the present invention, its officinal salt or its prodrug can be used for preparing the medicine for the treatment of above-mentioned inflammatory disease.Term " inflammatory disease " is meant one group of disease that has the inflammatory reaction pathological change, includes but not limited to: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, Parkinson's disease, presenile dementia, depression, acquired immune deficiency syndrome and dementia and syndrome, sepsis, Pyoderma gangrenosum, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, bacterial infection or obesity.
Should be appreciated that, described " inflammatory disease " may be proved to be in the future have other, may not with the closely-related pathogeny of expression of TNF α and IL-1 β.But this does not influence the application at the medicine of the above-mentioned disease of preparation treatment of chemical compound of the present invention, its officinal salt or prodrug.
Chemical compound of the present invention, its officinal salt or prodrug can use separately or use with the form of pharmaceutical composition.Pharmaceutical composition comprises chemical compound of the present invention, its officinal salt or prodrug and the pharmaceutically suitable carrier as active ingredient.Preferable, pharmaceutical composition of the present invention contains the chemical compound of the present invention as active ingredient, its officinal salt or the prodrug of 0.1-99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of chemical compound of the present invention, its officinal salt or prodrug, its effective dose simultaneously, and promptly can playing pharmaceutical carrier, to make the consumption of time spent nontoxic to human body.
" pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-alpha-tocopherol cetomacrogol 1000 succinate, the surfactant that pharmaceutical preparatioies such as tween (Tweens) or other similar polymerisation mediums are used, serum albumin such as human serum albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glycerol ester admixture, water, salt, electrolyte such as sulfate protamine, phosphoric acid hydrogen two is received, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polypropylene acid esters, ethylene-polyoxyethylene-block polymer and wool grease, cyclodextrin such as α-, β-and gamma-cyclodextrin or its all can be used for promoting the drug delivery of chemical compound of the present invention, its officinal salt or prodrug through hydroxyalkyl cyclodextrin such as the derivant of chemical modification such as 2-and 3-HP-or other soluble derivatives etc.
Other pharmaceutically acceptable auxiliaries such as filler (as Lactis Anhydrous, starch, lactose beadlet and glucose), binding agent (as microcrystalline Cellulose), disintegrating agent (as crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and cross-linked pvp), lubricant (as magnesium stearate), absorption enhancer, flavouring agent, sweeting agent, diluent, excipient, wetting agent, solvent, solubilizing agent and coloring agent etc. also can add in the pharmaceutical composition of the present invention.
The chemical compound of the invention described above, its officinal salt or prodrug and pharmaceutical composition can pass through intestinal or parenteral route administration.Non-intestinal drug delivery agent comprises injection, cream, ointment, patch, spray etc.That route of administration comprises is subcutaneous, in the Intradermal, intra-arterial, intravenous, intramuscular, intraarticular, synovial fluid, in the breastbone, in the sheath, intralesional, intracranial injection or infusion.That its route of administration comprises is oral, local, rectum, per nasal, through cheek, vagina, Sublingual, Intradermal, mucosa, trachea, urethra.Chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition can also by the suction aerosol or implantation be accumulated or the administration of acupuncture mode.
The oral formulations of chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition includes but not limited to capsule, tablet, Emulsion, aqueous suspension agent, solution, microcapsule, pill, lozenge, granule or powder.The pharmaceutically suitable carrier that is usually used in tablet comprises lactose and corn starch.Usually also can add lubricants such as magnesium stearate.The pharmaceutically suitable carrier that is usually used in capsule comprises lactose and dried corn starch.When making oral aqueous suspension agent and/or Emulsion, described chemical compound or its prodrug can suspend or be dissolved in the oil phase and with emulsifying agent or suspending agent and combine.Also can add some sweeting agents and/or flavouring agent and/or toner as required.
Chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition can be made into aseptic injection, as the suspension of aseptic water or oil phase.This suspension can promptly use suitable dispersant or wetting agent (as Tween 80) and suspending agent etc. to make by the conventional method of this area.But described aseptic injection can also be at the nontoxic diluent of intestinal external administration or solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Its available support or solvent comprise mannitol, water, ringer's solution, isotonic sodium chloride etc.In addition, aseptic fixedly oil often is used as the media of solvent or suspending agent, thereby the fixedly oil of various gentlenesses (bland fixed oil) all is suitable for as synthetic monoglyceride or diglyceride etc.Fatty acid, injection as described in can be used for preparing as octadecenic acid and glyceride ester derivatives thereof is as olive oil or Oleum Ricini and polyoxyethylene radical derivative thereof etc.Described oil solution or suspension also can comprise a kind of ethanol dilution agent or dispersant or carboxymethyl cellulose or similar dispersant of long-chain, and this type of material is usually used in preparing pharmaceutical acceptable emulsion and/or suspending agent.Surfactant that some other pharmaceutical preparation is commonly used such as Tweens or Spans and/or other similar emulsifying agents or bioavailability promoter etc. all can be used for preparing this preparation.
Chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition can be made into suppository with rectally, method is that described chemical compound, its officinal salt or prodrug are mixed with the non-irritating excipient that suits, the latter is liquid under rectal temperature for solid at room temperature, thereby this suppository can melt in rectum and discharges active ingredient.This type of excipient includes but not limited to: cupu oil, Cera Flava, Polyethylene Glycol.The local administration preparation (as ointment) of chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition can directly apply to the affected part.This topical formulations contains active ingredient and pharmaceutically suitable carrier, and described pharmaceutically suitable carrier includes but not limited to mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene or the polyoxy third desaturation compound, emulsifying is cured and water.In addition, chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition also can be made into lotion or oil preparation.Its carrier that is suitable for includes but not limited to: mineral oil, sorbitol monostearate, polysorbate60, spermaceti ester, hexadecanol, 2-octadecanol, benzyl second alcohol and water.Chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition also can be made into enema etc. and carry out the rectum topical.The topical transdermal patch is also within protection scope of the present invention.But chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition be per nasal spraying or inhalation also, promptly uses benzyl ethanol or other antiseptic, absorption enhancer, fluorocarbon and/or other solubilizing agents or dispersant to make saline solution by the conventional method of this area.
Chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition also can pass through drug delivery implant.Adopt the drug delivery implant mode can reach effect lasting in the administration subject, that timing discharges chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition.In addition, drug delivery implant can also be at local organization and organ site-specific delivery of drugs (Negrin et al., Biomaterials 22 (6): 563,2001) the timing release tech also can be used for the administration of chemical compound of the present invention, its officinal salt or prodrug and pharmaceutical composition, as delayed release capsule, slow release method and the preparation technique for packing (as polymer and liposome) etc. based on the polymer technology.
Patch comprises within the scope of the present invention equally.It comprises basic unit's (as polymer, cloth, yarn and binder) and pharmaceutical composition of the present invention.One side of basic unit can be provided with a protective layer to prevent the outflow of active ingredient.Described patch also can contain a binding agent that is used for fixing, and the latter can be a kind of natural or synthetic material, can temporarily adhere on the skin when it contacts with the administration subject's skin.Binding agent can be a waterproof.
Chemical compound of the present invention, its officinal salt or the prodrug of treatment effective dose and pharmaceutical composition are between 0.001～100mg/kg/d.Any consumption within above-mentioned scope is all effective dose of the present invention, wherein than low dosage between 0.001mg/kg/d and 99.999mg/kg/d, higher dosage is between 0.002mg/kg/d and 100mg/kg/d.Described " treatment effective dose " can be used for the single drug or the drug combination treatment of relevant disease.One of skill in the art can understand, and the consumption when actual administration can be higher or lower than above-mentioned dosage range.All multifactor influences be can be subjected at " the treatment effective dose " of a certain object (as mammal-people) and concrete therapeutic scheme, age, body weight, ordinary circumstance, sex, diet, administration time, disease susceptibility, the disease process of drug activity, administration object of compound used therefor or its prodrug and the judgement etc. of accepting the doctor for medical treatment comprised.
For the ease of understanding the present invention, the spy enumerates following examples.Its effect should be understood that it is to annotation of the present invention but not to the restriction of any way of the present invention.Each above listed pertinent literature all is incorporated herein by reference with a full piece of writing.
Description of drawings
Fig. 1 is 5 hydroxymethyl 2 furaldehyde (5-HMF) stimulates PBMC cellular expression TNF α to LPS inhibition
Fig. 2 is 5 hydroxymethyl 2 furaldehyde (5-HMF) stimulates PBMC cellular expression IL1-β to LPS inhibition
The specific embodiment
The separation and the evaluation of embodiment 15 hydroxymethyl 2 furaldehyde (5-HMF)
With the Fructus Corni of 500g with little aqueous hydrochloric acid solution (5000mL) extracting of 0.36% of boiling 3 times, each 2 hours.Three times extracts are mixed, filter.Filtrate through HP-20 macroporous resin adsorption post (6.5 * 100mm), water successively then, 10% ethanol, 15% ethanol elution.15% alcoholic acid eluent is after concentrating, and through the RP-18 column purification, water is cooked eluent.After eluent concentrates, partly prepare HPLC instrument [Zorbax C18 post (9.4 * 250mm)] purification with Gilson, mobile phase is CH
3OH/H
2O (8/92), flow velocity are 8mL/ minute, and the collection retention time is 5 minutes a fraction, and drying gets chemical compound 5-methylol-2 furfural 100mg (productive rate 0.02%).
UV(λ
max，nm)：284，230，195；
IR(cm
-1，KBr)：3350，1673，1522，1399，1193，1024，777；
1H?NMR(600MHz，D
2O)δ：4.60(2H，s，H-9)，6.58(1H，d，J＝3.5Hz，H-6)，7.43(1H，d，J＝3.8Hz，H-8)，9.35(1H，s，H-4)；
13C?NMR(100MHz，D
2O)δ：58.5，113.3，129.2，154.0，163.5，182.5；
EIMS(m/z)：126(M
+)
Embodiment 25 hydroxymethyl 2 furaldehyde are expressed experiment at the vitro inhibition pro-inflammatory cytokine
Experiment material:
1. cell: peripheral blood lymphocytes
2. be subjected to the reagent thing: 5 hydroxymethyl 2 furaldehyde (5-HMF)
3. positive control: dexamethasone
4. reagent: Ficoll-Paque Plus (Amersham Bioscience); Endotoxin (LPS, lipopolysaccharide) and dexamethasone (CalBiochem.); TNFa ELISA Kit and IL-1 β ELISA Kit (brilliant U.S. bio-engineering corporation); DMSO (Sigma).
Method and result:
Fresh blood is anticoagulant with EDTA, and separating periphery blood monocytic cell is suspended in RIMP 1640 culture medium that contain 10%FBS.Adding 100 μ l density in 96 orifice plates is 1 * 10
5The new isolated cells of cell/ml, every porocyte adds up to 10
4Individual, each sample is done 3 holes.
1) in cell, add the 5 hydroxymethyl 2 furaldehyde (final concentration is respectively 3,10,30,100,300ug/ml, the application of sample amount is 10ul) of prescribed concentration and positive control (dexamethasone, 10uM).Place 37C to contain 5%CO
2Incubator in the insulation 15 minutes;
2) adding 10ul concentration is the LPS of 100ug/ml, places 37 ℃ to contain 5%CO
2Incubator in the insulation 16 hours;
3) with centrifugal 15 minutes of 1000rpm, supernatant is transferred in the new plate, measures TNFa and IL-1 β concentration; Or cold storage is avoided multigelation in-20 ℃.
TNFa expression inhibiting rate (%)=[TNFa]
LPS-[TNFa]
5-HMF/ [TNFa]
LPS* 100%
IL-1 β expression inhibiting rate (%)=[IL-1 β]
LPS-[IL-1 β]
5-HMF/ [IL-1 β]
LPS* 100%
Experimental result:
| 5 hydroxymethyl 2 furaldehyde suppresses the expression of TNF α | ||
| 5 hydroxymethyl 2 furaldehyde concentration (μ g/ml) | Emiocytosis TNF α concentration (pg/ml) | TNF alpha expression suppression ratio (%) |
| ????3 | ????124.4±15.2 | ????15.7±10.3 |
| ????10 | ????107.9±20.0 | ????26.8±13.6 |
| ????30 | ????82.9±27.9 | ????43.8±18.9 |
| ????100 | ????39.3±19.7 | ????73.4±13.4 |
| ????300 | ????0.3±6.4 | ????99.3±4.3 |
| ????LPS | ????147.5±10.0 | ????/ |
| ????10uM?DEX | ????39.5±9.0 | ????73.2±6.1 |
| 5 hydroxymethyl 2 furaldehyde suppresses the expression of IL-1 β | ||
| 5 hydroxymethyl 2 furaldehyde concentration (μ g/ml) | Emiocytosis IL-1 β concentration (pg/ml) | IL-1 β expression inhibiting rate (%) |
| ????3 | ????69.9±12.6 | ????40.2±10.8 |
| ????10 | ????62.7±10.5 | ????46.4±9.0 |
| ????30 | ????40.1±2.4 | ????65.7±2.0 |
| ????100 | ????13.0±3.7 | ????88.8±3.1 |
| ????300 | ????0±5.0 | ????100±4.3 |
| ????LPS | ????116.9±28.5 | ????/ |
| ????10uM?DEX | ????20.2±7.0 | ????82.7±6.0 |
More than experiment shows, 5 hydroxymethyl 2 furaldehyde can significantly suppress the expression of TNFa and IL-1 β in the PBMC cell that LPS stimulates.
Embodiment 3 contains the preparation of 5 hydroxymethyl 2 furaldehyde (embodiment 1) tablet
5 hydroxymethyl 2 furaldehyde 30g
Starch 3g
Starch slurry (10%) is an amount of
Citric acid 0.15g
Pulvis Talci 1.5g
5 hydroxymethyl 2 furaldehyde is added the starch uniform mixing, add 8% starch slurry and make software, granulate with 14 order nylon mesh, 70～80 ℃ of dryings are through 10～12 order iron wire sieve granulate, with usefulness 12mm punch die tabletting behind the Pulvis Talci mixing.
Embodiment 4 contains the preparation of 5 hydroxymethyl 2 furaldehyde (embodiment 1) injectable powder
5 hydroxymethyl 2 furaldehyde 20g
NaOH is an amount of
The 5 hydroxymethyl 2 furaldehyde adding distil water is dissolved, transfer PH to 7.4 with NaOH, with the filtering with microporous membrane of 0.22um, under the aseptic condition, be loaded on respectively in the 10ml cillin bottle, rotating disk, precooling (being lower than 10～20 ℃ of fusing points) is put into and is lower than-45 ℃ household freezer, go out sublimation drying after the crystallization, outlet rolls lid, gets final product.
Many aspects involved in the present invention have been done as above and have been set forth.Yet, it should be understood that under the prerequisite of spirit that does not depart from the present invention and scope, any modification of foregoing description is all allowed.Equally, similarly situation is also included within the claim.
Claims (14)
1. the compound or pharmaceutically acceptable salt thereof of following general formula (I), the purposes of prodrug in the medicine of preparation treatment TNF α associated conditions:
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
2. the purposes of claim 1, wherein said TNF α associated conditions is selected from rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, Parkinson's disease, presenile dementia, depression, acquired immune deficiency syndrome and dementia and syndrome, sepsis, Pyoderma gangrenosum, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection or obesity.
3. the compound or pharmaceutically acceptable salt thereof of following general formula (I), the purposes of prodrug in the medicine of preparation treatment IL-1 β associated conditions:
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
4. the purposes of claim 3, wherein said IL-1 β associated conditions is selected from rheumatoid arthritis, septicemia, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, presenile dementia, osteoarthritis, bacterial infection, multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, respiratory virus infection, asthma, depression or scleroderma.
5. the compound or pharmaceutically acceptable salt thereof of following general formula (I), the purposes of prodrug in the medicine of preparation treatment inflammatory disease, it is characterized in that described inflammatory disease is selected from down one or more in the group disease: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute marrow type leukemia, Parkinson's disease, presenile dementia, depression, acquired immune deficiency syndrome and dementia and syndrome, sepsis, Pyoderma gangrenosum, septicemia, septic shock, behcets disease, graft versus host disease, uveitis, Wegener ' s granuloma, the Xiu Gelianshi xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, bacterial infection or obesity:
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
6. claim 1 or 3 or 5 purposes, wherein X represents oxygen; Y represents hydrogen; Z represents methylol; A represents hydrogen; B represents key.
7. claim 1 or 3 or 5 purposes, wherein X represents oxygen; Z represents hydrogen; A represents hydrogen; The B represent methylidene.
8. claim 1 or 3 or 5 purposes, wherein X represents oxygen; The Y represent methylidene; Z represents hydrogen; A represents hydrogen; B represents inferior methoxyl group.
9. claim 1 or 3 or 5 purposes, wherein X represents oxygen; Y represents hydrogen; The Z represent methylidene; A represents hydrogen; B represents key.
10. claim 1 or 3 or 5 purposes, wherein X represents oxygen; The Y represent methylidene; The Z represent methylidene; A represents hydrogen; B represents key.
11. the purposes of claim 1 or 3 or 5, wherein X represents oxygen; Y represents hydrogen; Z represents ethyl; A represents hydrogen; B represents key.
12. the purposes of claim 1 or 3 or 5, wherein X represents oxygen; The Y representation methoxy; Z represents amino; A represents hydrogen; B represents key.
13. the purposes of claim 1 or 3 or 5, wherein X represents sulfur; Y represents hydrogen; Z represents ethyl; A represents hydrogen; B represents key.
14. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof that is selected from following general formula (I) for the treatment of effective dose, one or more and pharmaceutically suitable carrier in the prodrug:
Wherein, X represents oxygen or sulfur;
Y represents hydrogen, hydroxyl, C
1-4Alkyl or C
1-4Alkoxyl;
Z represents hydrogen, C
1-4Alkyl, C
1-4Alkoxyl, amino, C
1-4Alkylamino or hydroxyl C
1-4Alkyl;
A represents hydrogen, C
1-4Alkyl or C
1-4Alkoxyl;
B represents C
1-4Alkylidene, oxygen base C
1-4Alkylidene, C
1-4Alkylidene oxygen base or key.
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Cited By (1)
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|---|---|---|---|---|
| CN103040803A (en) * | 2013-01-25 | 2013-04-17 | 南通大学 | Application of 5-hydroxymethyl-2-furfural and derivatives thereof in preparation of pharmaceutical compositions for preventing and treating bone metabolic disorder diseases |
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2003
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|---|---|---|---|---|
| CN103040803A (en) * | 2013-01-25 | 2013-04-17 | 南通大学 | Application of 5-hydroxymethyl-2-furfural and derivatives thereof in preparation of pharmaceutical compositions for preventing and treating bone metabolic disorder diseases |
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