JPS6115079B2 - - Google Patents
Info
- Publication number
- JPS6115079B2 JPS6115079B2 JP3806677A JP3806677A JPS6115079B2 JP S6115079 B2 JPS6115079 B2 JP S6115079B2 JP 3806677 A JP3806677 A JP 3806677A JP 3806677 A JP3806677 A JP 3806677A JP S6115079 B2 JPS6115079 B2 JP S6115079B2
- Authority
- JP
- Japan
- Prior art keywords
- compound according
- general formula
- formula
- integer
- acid addition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 51
- -1 8-heptylaminoadenosine Chemical compound 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 150000003835 adenosine derivatives Chemical class 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- VNQNQOYCXACDNJ-LSCFUAHRSA-N (2r,3r,4s,5r)-2-[6-amino-8-(octylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CCCCCCCCNC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VNQNQOYCXACDNJ-LSCFUAHRSA-N 0.000 claims description 3
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FPVWKLJZYCXWQC-SDBHATRESA-N (2r,3r,4s,5r)-2-[6-amino-8-(hexylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CCCCCCNC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O FPVWKLJZYCXWQC-SDBHATRESA-N 0.000 claims description 2
- OTIPDTUHAZOPTP-IDTAVKCVSA-N (2r,3r,4s,5r)-2-[6-amino-8-(pentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CCCCCNC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OTIPDTUHAZOPTP-IDTAVKCVSA-N 0.000 claims description 2
- XOWZWLCZAPAIDQ-RVXWVPLUSA-N C(CCCCC)C=1N([C@H]2[C@H](S)[C@H](O)[C@@H](CO)O2)C=2N=CN=C(C=2N=1)N Chemical compound C(CCCCC)C=1N([C@H]2[C@H](S)[C@H](O)[C@@H](CO)O2)C=2N=CN=C(C=2N=1)N XOWZWLCZAPAIDQ-RVXWVPLUSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 10
- 230000003834 intracellular effect Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229960000278 theophylline Drugs 0.000 description 5
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 230000004660 morphological change Effects 0.000 description 4
- 229960001789 papaverine Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000001766 physiological effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229940063674 voltaren Drugs 0.000 description 3
- VJUPMOPLUQHMLE-UUOKFMHZSA-N 8-Bromoadenosine Chemical compound BrC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VJUPMOPLUQHMLE-UUOKFMHZSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VPIAKHNXCOTPAY-UHFFFAOYSA-N Heptane-1-thiol Chemical compound CCCCCCCS VPIAKHNXCOTPAY-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001687 destabilization Effects 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 2
- 238000004816 paper chromatography Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000002889 sympathetic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000012219 Autonomic Nervous System disease Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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The present invention relates to a novel adenosine derivative, a method for producing the same, and an anti-inflammatory agent containing the same as an active ingredient. Phosphodiesterase (hereinafter abbreviated as PDE) is known as an enzyme that hydrolyzes adenosine-3',5'-monophosphonate (hereinafter abbreviated as c-AMP). By the way, compounds capable of inhibiting the activity of PDE, such as theophylline and papaverine, are widely used as coronary vasodilators, platelet aggregation inhibitors, and bronchodilators. The present inventors have discovered that these conventionally known
As a result of extensive research in order to provide compounds that exhibit even more potent effects than PDE inhibitors, adenosine itself has the ability to inhibit PDE activity and increase the level of c-AMP in cultured animal cells. Surprisingly, the 8-long chain alkylthio substituted product or the 8-long chain alkylamino substituted product has the ability to competitively inhibit PDE activity in higher animals, and the theophylline, It was found that the biological activity using cultured cells derived from Chinese hamster ovary is 100 to 500 times higher than that of papaverine. The present invention has been made based on this knowledge. That is, the present invention provides the general formula (X in the formula is -NH- or -S-, and n is 4 to
The present invention provides a novel adenosine derivative represented by the formula (an integer of 19) and a physiologically acceptable acid addition salt thereof. The compound in which X is -S- in the general formula (1) has the general formula (Y in the formula is a halogen atom) 8-halogenoadenosine and the general formula CH 3 (CH 2 ) o SH ... () (n in the formula has the same meaning as above) It can be produced by reacting a linear alkyl mercaptan or an alkali metal salt thereof. The reaction between the 8-halogenoadenosine of the general formula () and the linear alkyl mercaptan of the general formula () is carried out using an alcohol such as methyl alcohol, ethyl alcohol, or propyl alcohol as a solvent in the presence of an alcoholate such as sodium methylate. It is preferable to carry out heating while boiling. In this case, the amount of the compound of the general formula () to be used is selected in the range of equimolar to 10 times the molar amount of the compound of the general formula (). The reaction time depends on the raw materials used, the solvent, the reaction temperature, etc.
Usually it takes about 0.5 to 3 hours. The reaction mixture is concentrated to dryness, and the residue is dissolved in a suitable solvent such as methyl alcohol and poured into cold water, whereby the target compound precipitates out as colorless crystals. Examples of target compounds obtained in this way include 8-pentylthioadenosine, 8-hexylthioadenosine, 8-heptylthioadenosine,
Examples include 8-octylthioadenosine, 8-decylthioadenosine, 8-dodecylthioadenosine, and 8-eicosylthioadenosine. These compounds can also be obtained by reacting the compound of the general formula () with an alkali metal salt such as a sodium salt or potassium salt of the compound of the general formula () in an alcohol. Next, the compound in which X is -NH- in the general formula () is 8-halogenoadenosine of the general formula () and the compound of the general formula CH 3 (CH 2 )n NH 2 ... () (in the formula n has the same meaning as above). This reaction involves combining both with water, alcohols, dialkyl-substituted amides such as dimethylformamide,
It is advantageously carried out in a solvent such as dimethylacetamide, dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide, and heated to 50 DEG -150 DEG C. In this case, the amount of the compound of general formula () to be used is preferably selected within the range of equimolar to 20 times the molar amount of the compound of general formula (). To separate the target compound from the reaction mixture, the reaction mixture is evaporated to dryness, the residue is dissolved in a suitable solvent such as an alcohol, an alkali is added to this solution to make the pH slightly alkaline, and it is separated as crystals. Let it precipitate. Examples of compounds of general formula () obtained in this way include 8-pentylaminoadenosine,
8-hexylaminoadenosine, 8-heptylaminoadenosine, 8-nonylaminoadenosine,
Examples include 8-decylaminoadenosine, 8-dodecylaminoadenosine, and 8-eicosylaminoadenosine. A physiologically acceptable acid addition salt of the compound of the general formula () can be prepared by treating the free form of the compound obtained as described above with an acid according to a conventional method. . In some cases, 8-halogenoadenosine of general formula () used as a raw material may be used in the form of an acid addition salt, and it may be obtained by reacting this with general formula () or a compound of general formula (). You can also do it. Examples of acid addition salts obtained in this way include inorganic acid salts such as hydrochloride, hydrobromide, and phosphate, and organic acid salts such as oxalate, acetate, and lactate. I can do it. As mentioned above, the compounds of the present invention have the ability to significantly increase intracellular c-AMP levels. This c-AMP is a substance found in the cells of all higher animals, and is known as an intracellular transmitter of hormones, controlling cell proliferation, differentiation,
It is involved in fat metabolism in adipose tissue. In addition, c-AMP is related to nerve cells, especially sympathetic nerves, as an intracellular transmitter, so the physiological effects of organs and tissues under the control of sympathetic nerves are influenced by c-AMP within the nerve cells. - Strongly influenced by the level of AMP. Examples of physiological effects affected in this way include constriction of visceral and cutaneous blood vessels, dilation of coronary and skeletal muscle vessels, bronchodilation,
It can increase heart excitement. Therefore,
It is expected that diseases caused by disorders of these physiological functions can be treated by administering the compounds of the present invention, and their effects have actually been confirmed for certain diseases. That is, from the results of in vitro experiments and higher animal culture cell experiments using the compounds of the present invention, it was found that the compounds of the present invention have the ability to significantly increase intracellular c-AMP levels. Therefore, the compounds of the present invention can be highly expected to have therapeutic effects on autonomic nervous system diseases such as coronary vascular disorders, bronchial asthma, various inflammations, psoriasis, and cancer. In addition, it is also promising as an agent for promoting fat metabolism and cholesterol metabolism, and as a therapeutic agent for treating cholera infections. Furthermore, since c-AMP is known to be involved in stabilizing biological membranes such as cell membranes and intracellular granulosa, the compounds of the present invention are also useful as platelet aggregation inhibitors and anti-inflammatory agents. It is. That is, platelet aggregation is thought to be caused by the release of enzymes such as thrombokinase and the release of brostaglandin as a result of destabilization of the cell membrane and intracellular granule membrane. On the other hand, the inflammatory effect occurs due to the destabilization of the intracellular granulosa and the release of substances accumulated therein, followed by the progression of tissue infiltration accompanied by dilation of blood vessels such as the skin. The present inventors investigated the anti-inflammatory effect of the compound of the present invention using the rat footpad carrageenin method, and found that it had an effect equivalent to that of Voltaren, a known anti-inflammatory agent. When using the compound of the present invention as an anti-inflammatory agent,
It is formulated into an oral dosage form using conventional stabilizers and excipients and administered in the range of 50 to 250 mg/person per day.
Examples of stabilizers and excipients used in this case include starch, colloidal silicon dioxide, and magnesium stearate. In addition, it can also be formulated into parenteral preparations, such as injections and suppositories, if desired. The toxicity of the compound of the present invention was tested using ddY male mice, and it was confirmed that the toxicity was low in both intravenous and oral administration. Next, the present invention will be explained in more detail with reference to Examples. Example 1 1 g (3 mmol) of 8-bromadenosine and n-
4.8 ml (30 mmol) of octylamine was dissolved in 30 ml of methylcellosolve and reacted at 140°C for 2 hours. As a result, the reaction proceeded almost quantitatively and was completed. After cooling the reaction solution, it was concentrated to dryness using an evaporator. Next, the residue was dissolved in 20 ml of methyl alcohol, adjusted to weak alkalinity by adding 1N aqueous sodium hydroxide solution, and crystals were precipitated while stirring under cooling. In this way, 400 mg (yield 35%) of 8-octylaminoadenosine was obtained. This gave a single spot in paper electrophoresis and paper chromatography. Moreover, the elemental analysis values of this product were as follows. As elemental analysis value C 18 H 30 N 6 O 4
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ã¢ããã·ã³ã®ç©æ§ã第ïŒè¡šã«ç€ºãã[Table] In this example, other alkylamines were used in place of n-octylamine, and the reaction was carried out in exactly the same manner, to obtain the corresponding 8-alkylaminoadenosines. Table 1 shows the physical properties of various 8-alkylaminoadenosines thus obtained.
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ããã·ã³ã®ç©æ§ã第ïŒè¡šã«ç€ºãã[Table] Example 2 2.5 g (15 mmol) of n-heptyl mercaptan and 1 g (3 mmol) of 8-bromadenosine were added to 30 ml of anhydrous methyl alcohol containing 486 mg (9 mmol) of sodium methylate, and the mixture was heated under reflux for 1 hour. After the reaction was completed, the reaction solution was cooled and concentrated to dryness, the residue was dissolved in 20 ml of methyl alcohol, and the solution was poured into 100 ml of cold water. The precipitated crystals were collected to obtain 500 mg of 8-heptylthioadenosine (yield: 44%). This crystal gave a single spot in filter paper electrophoresis and paper chromatography. The elemental analysis values of this product were as follows. Elemental analysis value C 18 H 29 N 5 O 4 S Calculated value (%) C52.55, H7.36, N22.10, O16.84 Actual value (%) C54.01, H7.35, N21.47, O17.27 In this example, other alkyl mercaptans were used instead of n-heptyl mercaptan, and the same reaction was carried out in the same manner, and the corresponding 8-
Alkylthioadenosine was obtained. Table 2 shows the physical properties of various 8-alkylthioadenosines thus obtained.
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«çãšããŠç¬¬ïŒè¡šã«ç€ºãã[Table] Example 3 Six male rats (Wistar albino) weighing 120 to 140 g were used as a group to carry out the rat carrageenin footpad method described in Basic Course on Pharmaceutical Development, Volume 5, page 239. An anti-inflammatory test was conducted according to the following. That is, the compound of the present invention and Voltaren for comparison were suspended in physiological saline at a concentration of 0.2%, and orally administered at a dose of 100 mg/Kg 60 minutes before the start of the experiment. In addition, as a control, only physiological saline was given. Next, 0.1 ml of a 1% suspension of carrageenan was injected into the rat footpad, and the footpad volume after 1 to 4 hours was measured using a rat footpad volume meter manufactured by Ugo Basile. The results are shown in Table 3 as the edema rate.
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第15å·»ã第1408ããŒãžã«èšèŒãããæ¹æ³ã«æºãã
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æ¬é
µçŽ åå¿ç³»ã®åºè³ªãâAMPã®æ¿åºŠã¯0.5ïœïŒ
ã§ãã€ãããŸããæ¬çºæååç©ã®æ·»å æ¿åºŠã¯
0.125ïœïŒã§ãã€ãããã®çµæã第ïŒè¡šã«ç€ºãã[Table] As is clear from this table, the compound of the present invention exhibited an anti-inflammatory effect comparable to or superior to Voltaren until 1 to 2 hours after the start of the measurement. And 8
It was confirmed that those having a substituent at the position of 7 or more carbon atoms exhibited particularly excellent anti-inflammatory effects. Therefore, it can be seen that the compounds of the present invention are effective as anti-inflammatory agents. Reference Example 1 In order to investigate the inhibitory properties of the compounds of the present invention against PDE, biochemistry (Biochemistry),
The inhibitory ability of the compounds of the present invention was investigated using a method similar to that described in Volume 15, page 1408.
The concentration of C-AMP, the substrate for this enzyme reaction system, is 0.5mM.
It was hot. In addition, the concentration of the compound of the present invention is
It was 0.125mM. The results are shown in Table 4.
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ãã®çµæã第ïŒè¡šã«ç€ºãã[Table] For comparison, when theophylline was used, the degree of inhibition was 62.8%. This shows that the PDE inhibiting ability of the compounds of the present invention is much greater than that of known theophyllines. This PDE inhibiting ability is particularly remarkable when the substituent at position 8 has 6 to 10 carbon atoms. Reference Example 2 It is known that when C-AMP or its derivatives are added to cancerous cells, the intracellular C-AMP level increases and the cancerous cells transform into normal cells. This phenomenon can be used to measure intracellular C-AMP levels. That is, the compound of the present invention and commercially available drugs theophylline and papaverine as controls were added to cancerous cells (CHO-K 1 cells) at concentrations of 10 -5 M and 10 -4 M, respectively, and the morphological changes were observed. The lowest effective concentration (LC 50 ) that causes a morphological change was determined. The results are shown in Table 5.
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ãã®çµæãã第ïŒè¡šã«ç€ºãã[Table] As is clear from this table, even papaverine, which is said to have 50 times the ability to inhibit PDE than theophylline, cannot be used alone to inhibit CHO.
-Although it was not possible to cause morphological changes in K1 cells, the compounds of the present invention can cause morphological changes alone and at fairly low concentrations. In particular, those in which the 8-substituent had 5 to 10 carbon atoms showed excellent physiological activity. Reference Example 3 8-heptylthioadenosine and 8-octylaminoadenosine were administered intravenously and orally to ddY male mice, and the acute toxicity value LD 50 was determined. The results are shown in Table 6.
Claims (1)
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ç¯å²ç¬¬ïŒïŒé èšèŒã®æ¹æ³ã ïŒïŒ äžè¬åŒ ïŒåŒäžã®ïŒžã¯âNHâåã¯ââã§ãããïœã¯ïŒã
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容ãããé žä»å å¡©ãæå¹æåãšããæççå€ã[Claims] 1. General formula (X in the formula is -NH- or -S-, and n is 4 to
an integer of 19) and physiologically acceptable acid addition salts thereof. 2 X in the general formula is -NH-, and n is 5 to 10
The compound according to claim 1, which is an integer of . 3. The compound according to claim 2, which is 8-pentylaminoadenosine. 4. The compound according to claim 2, which is 8-hexylaminoadenosine. 5. The compound according to claim 2, which is 8-heptylaminoadenosine. 6. The compound according to claim 2, which is 8-octylaminoadenosine. 7. The compound according to claim 2, which is 8-nonylaminoadenosine. 8. The compound according to claim 2, which is 8-decylaminoadenosine. 9. The compound according to claim 1, wherein X in the general formula is -S- and n is an integer of 5 to 10. 10. The compound according to claim 9, which is 8-pentylthioadenosine. 11. The compound according to claim 9, which is 8-hexylthioadenosine. 12. The compound according to claim 9, which is 8-heptylthioadenosine. 13. The compound according to claim 9, which is 8-octylthioadenosine. 14. The compound according to claim 9, which is 8-nonylthioadenosine. 15. The compound according to claim 9, which is 8-decylthioadenosine. 16 General formula (Y in the formula is a halogen atom) 8-halogenoadenosine and a linear alkyl represented by the general formula CH 3 (CH 2 ) o SH (n in the formula is an integer from 4 to 19) General formula, characterized in that the mercaptan or its alkali metal is reacted, optionally converting the product into a physiologically acceptable acid addition salt. (n in the formula has the same meaning as above) A method for producing an adenosine derivative and a physiologically acceptable acid addition salt thereof. 17. The method according to claim 16, wherein the reaction is carried out in a solvent selected from alcohols and alcohols including sodium alcoholate. 18. The method according to claim 16, wherein the alkyl mercaptan or its alkali metal salt is used in an equimolar to 10 times the molar amount of 8-halogenoadenosine, and the reaction is carried out at the boiling temperature of the solvent. 19 General formula (Y in the formula is a halogen atom) 8-halogenoadenosine and a linear chain represented by the general formula CH 3 (CH 2 ) o NH 2 (n in the formula is an integer from 4 to 19) A general formula characterized by reacting with an alkylamine and optionally converting the product into a physiologically acceptable acid addition salt. (n in the formula has the same meaning as above) A method for producing an adenosine derivative and a physiologically acceptable acid addition salt thereof. 20. The method according to claim 19, wherein the reaction is carried out in a solvent selected from water, alcohols, dimethylformamide, dimethyl sulfoxide and dioxane. 21 Alkylamine is used in an equimolar to 20 times molar amount relative to 8-halogenoadenosine,
20. The method of claim 19, wherein the reaction is carried out at a temperature in the range 50-150<0>C. 22 General formula (X in the formula is -NH- or -S-, and n is 4 to
An anti-inflammatory agent containing as an active ingredient an adenosine derivative represented by (an integer of 19) or a physiologically acceptable acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3806677A JPS53124293A (en) | 1977-04-05 | 1977-04-05 | Novel adenosine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3806677A JPS53124293A (en) | 1977-04-05 | 1977-04-05 | Novel adenosine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS53124293A JPS53124293A (en) | 1978-10-30 |
| JPS6115079B2 true JPS6115079B2 (en) | 1986-04-22 |
Family
ID=12515109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3806677A Granted JPS53124293A (en) | 1977-04-05 | 1977-04-05 | Novel adenosine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS53124293A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3406533A1 (en) * | 1984-02-23 | 1985-08-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | USE OF ADENOSINE DERIVATIVES AS ANTIALLERGICA AND MEDICINAL PRODUCTS CONTAINING THEM |
-
1977
- 1977-04-05 JP JP3806677A patent/JPS53124293A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS53124293A (en) | 1978-10-30 |
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