JPH0216727B2 - - Google Patents
Info
- Publication number
- JPH0216727B2 JPH0216727B2 JP57102393A JP10239382A JPH0216727B2 JP H0216727 B2 JPH0216727 B2 JP H0216727B2 JP 57102393 A JP57102393 A JP 57102393A JP 10239382 A JP10239382 A JP 10239382A JP H0216727 B2 JPH0216727 B2 JP H0216727B2
- Authority
- JP
- Japan
- Prior art keywords
- effect
- rheumatoid arthritis
- platonin
- compound
- therapeutic agent
- 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 - Lifetime
Links
- 239000003814 drug Substances 0.000 claims description 18
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 16
- 229940124597 therapeutic agent Drugs 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims 1
- 239000006186 oral dosage form Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 32
- 230000000694 effects Effects 0.000 description 20
- 208000009386 Experimental Arthritis Diseases 0.000 description 16
- FKFUHAJJKUCVRF-UHFFFAOYSA-N 2-[3,5-bis(3-heptyl-4-methyl-1,3-thiazol-3-ium-2-yl)penta-2,4-dienylidene]-3-heptyl-4-methyl-1,3-thiazole Chemical compound CCCCCCCN1C(C)=CSC1=CC=C(C1=[N+](C(C)=CS1)CCCCCCC)C=CC1=[N+](CCCCCCC)C(C)=CS1 FKFUHAJJKUCVRF-UHFFFAOYSA-N 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- -1 iodo ion Chemical class 0.000 description 8
- 210000004988 splenocyte Anatomy 0.000 description 7
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 6
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 6
- 239000002955 immunomodulating agent Substances 0.000 description 6
- 229940121354 immunomodulator Drugs 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 229960001614 levamisole Drugs 0.000 description 6
- 229960001639 penicillamine Drugs 0.000 description 6
- 230000003449 preventive effect Effects 0.000 description 6
- 229920006926 PFC Polymers 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000002519 immonomodulatory effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 208000031648 Body Weight Changes Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000004579 body weight change Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000003226 mitogen Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- QPJBONAWFAURGB-UHFFFAOYSA-L Lobenzarit disodium Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1NC1=CC(Cl)=CC=C1C([O-])=O QPJBONAWFAURGB-UHFFFAOYSA-L 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000035584 blastogenesis Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- OBSLLHNATPQFMJ-UHFFFAOYSA-N 2,4-Dimethylthiazole Chemical compound CC1=CSC(C)=N1 OBSLLHNATPQFMJ-UHFFFAOYSA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 230000003307 reticuloendothelial effect Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- RREURMKQENZDQR-UHFFFAOYSA-N trithiazole Chemical compound S1SC=NS1 RREURMKQENZDQR-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規な免疫調節剤、なかんづく慢性関
節リウマチ治療剤に関する。
近年、免疫調整剤としてレバミゾール、Ｄ−ペ
ニシラミン、CCA〔Ｎ−（２−カルボキシフエニ
ル）−４−クロロアンスラニル酸二ナトリウム〕
など種々の化合物が開発されているが、生体に対
する毒性が強いなど、充分満足しうるものは少な
いのが現状である。
本発明者はこの様な事情に鑑み鋭意研究した結
果、一般式（）：
（式中、Ｒは炭素原子数１〜15個のアルキル基
（ただしｎ−ヘプチル基は除く）、Ｉ
はヨードイ
オンを示す）で表わされるトリチアゾールペンタ
メチンシアニン系化合物が毒性や副作用のない免
疫調節剤、なかんづく慢性関節リウマチ治療剤と
して有効なことを見出し、本発明を完成した。
すなわち本発明は、前記一般式（）で表わさ
れるトリチアゾールペンタメチンシアニン系化合
物を有効成分として含有する慢性関節リウマチ治
療剤に関する。
一般式（）で表わされる化合物のうちＲがｎ
−ヘプチル基である化合物はプラトニンと称され
る公知化合物であり、このものの薬理作用として
抗菌作用、創傷治癒促進作用、網内系造血臓器や
内分泌腺賦活作用、抗体産生増強作用などが知ら
れている。
しかしながら、この化合物が毒性や副作用がほ
とんどなく、とくに経口投与で優れた免疫調節作
用を示すということについては従来知られておら
ず、本発明者により初めて見出されたものであ
る。
すなわち、プラトニンは免疫機能が何らかの原
因で低下しているばあいには活性化作用を、また
免疫機能が亢進している時には抑制作用を示し、
正常のばあいはまつたく作用しないという典型的
な免疫調節作用を有している。一方従来の免疫調
節剤の通弊である顆粒球減少などの細胞毒性や嘔
吐、悪心、発熱、皮疹、筋無力症などの副作用を
有せずむしろ細胞の正常機能を維持する作用を併
せもつているというより一層理想的な免疫調節剤
であるので、長期にわたる薬剤の連続投与が可能
になり、とくに慢性関節リウマチ、腎炎などの自
己免疫疾患に対してきわめて有効であることが見
出された。
さらに他の免疫調節剤のばあいの千分の１から
１万分の１という驚くべき微量の投与量で、しか
もとくに経口投与で優れた薬理効果を発揮するこ
とが明らかになり、前述のごとく毒性、副作用が
ほとんどないことと併せて、他の免疫調節剤に比
べて非常に使いやすい薬剤であることが見出され
た。一般に慢性関節リウマチ疾患のばあいは通院
が困難であるので、他の疾患のばあいよりも一層
経口投与が好ましい。
したがつて、プラトニンを有効成分とする免疫
調節剤は免疫疾患全般の予防および治療剤とし
て、とくに慢性関節リウマチの治療剤としてきわ
めて大きく貢献するものである。
本発明者はプラトニンのチアゾール環のチツ素
原子に結合しているアルキル基を種々変えて研究
を重ねた結果、前記一般式（）で表わされる化
合物がプラトニンと同等の免疫調節作用を有し、
とくに慢性関節リウマチの治療剤として有用であ
ることを見出したのである。
前記一般式において、Ｒとしては、たとえばメ
チル、エチル、ｎ−プロピル、イソプロピル、ｎ
−ブチル、イソブチル、sec−ブチル、tert−ブ
チル、ｎ−ペンチル、イソペンチル、sec−ペン
チル、ネオペンチル、tert−ペンチル、ｎ−ヘキ
シル、イソヘキシル、sec−ヘキシル、ネオヘキ
シル、tert−ヘキシル、５−メチルヘキシル、オ
クチル、ノニル、デシル、ウンデシル、ドデシ
ル、トリデシル、テトラデシルまたはペンタデシ
ルなどのｎ−ヘプチルを除く炭素原子数１〜15個
のアルキル基があげられる。
中でもＲがヘキシル基およびオクチル基である
化合物がとくに好ましい。
本発明の慢性関節リウマチ治療剤は成人投与量
（有効成分換算値、以下同様）として１回10〜
500μｇ程度のごく微量で充分にその効果を発揮
する。とくに50〜100μｇ／１〜２日の投与量が
好ましい。
本発明の慢性関節リウマチ治療剤は経口投与で
充分に活性を示し、たとえば錠剤、カプセル剤、
散剤、顆粒剤、液剤などとして使用できる。また
点鼻剤、座剤などとしても使用できる。本発明の
慢性関節リウマチ治療剤を製剤するにあたつては
とくに制限はなく、通常用いられるキヤリヤーを
用い常法にしたがつて行なえばよい。
本発明に用いる化合物（）はつぎのようにし
て製造することができる。
モノクロルアセトンとチオアセトアミドから
２，４−ジメチルチアゾール（bp146〜147℃）
を合成し、これとアルキルアイオダイドとを油浴
中170℃に加熱反応させると３−アルキル−２，
４−ジメチルチアゾリウムアイオダイドがえられ
る。これにオルト蟻酸エチルと無水酢酸とを加
え、油浴中140〜145℃に加熱反応させ、えられた
粗生成物をエタノールで再結晶すると、目的とす
る４，4′−ジメチル−３，3′−ジアルキル−８−
〔２（４−メチル）−３−アルキルチアゾール〕−
２，2′−ジカルボシアニン・ジアイオダイドがえ
られる。
かくしてえられた化合物（）の一部の融点を
第１表に示す。
The present invention relates to a novel immunomodulator, particularly a therapeutic agent for rheumatoid arthritis. In recent years, levamisole, D-penicillamine, and CCA [disodium N-(2-carboxyphenyl)-4-chloroanthranilate] have been used as immunomodulators.
Various compounds have been developed, but currently there are few that are fully satisfactory due to their strong toxicity to living organisms. As a result of intensive research in view of these circumstances, the inventor has developed the general formula (): (In the formula, R is an alkyl group having 1 to 15 carbon atoms (excluding n-heptyl group), and I is an iodo ion). The present invention was completed based on the discovery that the present invention is effective as a regulating agent, particularly as a therapeutic agent for chronic rheumatoid arthritis. That is, the present invention relates to a therapeutic agent for rheumatoid arthritis containing a trithiazole pentamethine cyanine compound represented by the general formula () as an active ingredient. In the compound represented by the general formula (), R is n
- The compound with a heptyl group is a known compound called platonin, and its pharmacological effects include antibacterial activity, wound healing promotion activity, activation of reticuloendothelial hematopoietic organs and endocrine glands, and enhancement of antibody production. There is. However, it has not been previously known that this compound has almost no toxicity or side effects and exhibits excellent immunomodulatory effects, especially when administered orally, and this was discovered for the first time by the present inventor. In other words, platonin has an activating effect when the immune function is decreased for some reason, and a suppressive effect when the immune function is enhanced.
It has a typical immunomodulatory effect, which does not work at all under normal conditions. On the other hand, it does not have the side effects of conventional immunomodulators, such as cytotoxicity such as granulocytopenia, vomiting, nausea, fever, skin rash, and myasthenia, but rather has the effect of maintaining normal cell function. Since it is an ideal immunomodulatory agent, it has become possible to administer the drug continuously over a long period of time, and it has been found to be particularly effective against autoimmune diseases such as rheumatoid arthritis and nephritis. Furthermore, it has been revealed that it exhibits excellent pharmacological effects, especially when administered orally, at a surprisingly small dose of 1/1000 to 1/10,000 of that of other immunomodulators. In addition to having almost no side effects, it was found to be an extremely easy-to-use drug compared to other immunomodulators. In general, it is difficult for patients with rheumatoid arthritis to go to the hospital, so oral administration is more preferable than in cases of other diseases. Therefore, immunomodulators containing platonin as an active ingredient will make an extremely important contribution as preventive and therapeutic agents for immune diseases in general, and particularly as therapeutic agents for rheumatoid arthritis. As a result of repeated research with various changes in the alkyl group bonded to the nitrogen atom of the thiazole ring of Platonin, the present inventor found that the compound represented by the general formula () has an immunomodulatory effect equivalent to that of Platonin,
They found that it is particularly useful as a therapeutic agent for rheumatoid arthritis. In the above general formula, R is, for example, methyl, ethyl, n-propyl, isopropyl, n
-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, sec-hexyl, neohexyl, tert-hexyl, 5-methylhexyl, Examples include alkyl groups having 1 to 15 carbon atoms, excluding n-heptyl, such as octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl. Among these, compounds in which R is a hexyl group or an octyl group are particularly preferred. The therapeutic agent for rheumatoid arthritis of the present invention is administered in an adult dose (active ingredient equivalent, hereinafter the same) from 10 to
A very small amount of about 500μg is enough to exert its effect. In particular, a dosage of 50 to 100 μg/1 to 2 days is preferred. The therapeutic agent for rheumatoid arthritis of the present invention exhibits sufficient activity when administered orally, such as tablets, capsules,
It can be used as powder, granules, liquid, etc. It can also be used as nasal drops and suppositories. There are no particular restrictions on the preparation of the therapeutic agent for rheumatoid arthritis of the present invention, and the preparation may be carried out in a conventional manner using a commonly used carrier. The compound () used in the present invention can be produced as follows. 2,4-dimethylthiazole (bp146-147℃) from monochloroacetone and thioacetamide
3-alkyl-2,
4-dimethylthiazolium iodide is obtained. Ethyl orthoformate and acetic anhydride are added to this, the reaction is heated to 140-145°C in an oil bath, and the resulting crude product is recrystallized from ethanol to obtain the desired 4,4'-dimethyl-3,3 '-Dialkyl-8-
[2(4-methyl)-3-alkylthiazole]-
2,2'-dicarbocyanine diiodide is obtained. Table 1 shows the melting points of some of the compounds thus obtained.
【表】
つぎに本発明の慢性関節リウマチ治療剤を実施
例をあげて説明する。
実施例 １
〔薬理試験〕
(1) アジユバント関節炎抑制作用
７〜８週令のSD系ラツト（150ｇ前後）を１
群５匹で用い、ミコバクテリウム・ブチリクム
（mycobacterium butyricum）を流動パラフイ
ンに12mg／mlの濃度で懸濁したものをラツト一
匹あたり0.05mlの割合で右後肢足蹠の皮内に注
射し、アジユバント関節炎（AA）を誘起し
た。アジユバント注射後30日目まで両後足容積
を水銀圧排法により測定し、AAの評価とし
た。
(a) 予防効果
化合物No.１および４ならびにプラトニンを
供試化合物として用い、それらのAA予防効
果を検討するために、アジユバント投与と同
時に本剤の投与を開始し、１日１回経口投与
で30日目まで行なつた。結果を第１図に示
す。同様にして供試化合物にかえてＤ−ペニ
シラミンおよびレバミゾールを投与した結果
を第２図に示す。
その結果、化合物（）はプラトニンと同
じく0.05μｇ／匹という低用量でAAを抑制す
るが、Ｄ−ペニシラミンおよびレバミゾール
では1.5mg／匹の用量においてもAAを抑制し
ないことがわかつた。
(b) 治療効果
化合物No.１、No.４ならびにプラトニンを供
試化合物として用い、それらのAA治療効果
を検討するために、アジユバント投与後14日
目より本剤の投与を開始し、１日１回経口投
与で40日目まで行なつた。結果を第３図に示
す。
その結果、化合物（）は0.05μｇ／匹と
いうプラトニンと同程度の低用量でAAを抑
制するが、1μｇ／匹以上の用量の化合物
（）では抑制効果は見られず、至適用量が
存在することがわかつた。
(2) 体重変化
前記(1)(a)のアジユバント関節炎抑制作用の予
防効果の試験期間中において１日目、10日目、
20日目および30日目に各ラツトの体重を測定し
た。結果を第４図および第５図に示す。その結
果、Ｄ−ペニシラミンおよびレバミゾール投与
では対照に比べてラツトの体重変化に差が認め
られなかつたが、化合物（）0.05μｇ／匹投
与ではプラトニンと同様に足部の腫脹の減少に
もかかわらず、対照に比べてラツトの体重変化
に明らかな増加が認められ、併せて全身的に著
しい病状の改善が見られた。
(3) マウス脾細胞を用いたPFC応答に及ぼす作
用Balb／ｃマウス脾細胞を用いて抗SRBC
PFC応答に及ぼす作用を検討した。供試化合
物としては、化合物No.１〜４およびプラトニン
を用いた。
Balb／ｃマウスの脾細胞１×107個をSRBC
および供試化合物と共に10％牛胎児血清を含む
RPMI−1640培地にてCO2インキユベーター
（37℃）中で４日間Marbrook法により培養し、
出現するdirect PFC数をJerneの方法
（Science、140巻、405頁、1963年）で測定し
た。結果を第６図に示す。
第６図から明らかなように、化合物（）の
抗SRBC PFC応答に及ぼす作用は、プラトニ
ンのそれと同様に低濃度においては活性化、高
濃度においては抑制作用と二相性の作用が認め
られた。
(4) マウス脾細胞を用いた幼若化反応に及ぼす作
用
Balb／ｃマウス脾細胞を用いてマイトゲン
（mitogen：LPS）刺激によるリンパ球幼若化
反応に及ぼす前記(3)で用いた供試化合物の作用
を検討した。
Balb／ｃマウスの脾細胞１×105個をマイト
ゲンおよび供試化合物と共に10％牛胎児血清を
含むRPMI−1640培地にて、マイクロカルチヤ
ープレートを用いてCO2インキユベーター中で
48時間培養した。その後、0.5μCiの 3H−チミ
ジン（ 3H−TdR）を添加し、さらに18時間培
養後セルハーベスター（ラボマツシユ）にて細
胞を採取し、細胞内に取り込まれた 3H−TdR
の放射活性を測定した。結果を第７図に示す。
第７図から明らかなように、Ｂ細胞マイトゲ
ンであるLPS20μｇ／mlにより刺激したばあ
い、化合物（）はプラトニンと同様に著明な
抑制作用が認められた。
(5) 急性毒性
ddY系雄性マウス（５〜６週令）（体重25〜
30ｇ）を１群８匹で用い、５％アラビアゴム液
に懸濁させたプラトニンおよび化合物No.１〜４
の化合物（）を腹腔内投与、静脈内投与およ
び胃ゾンデで経口投与し、７日間観察して死亡
数を調べ、フアン・デル・ヴアエルデン法によ
りLD50値を求めた。結果を第２表に示す。[Table] Next, the therapeutic agent for rheumatoid arthritis of the present invention will be explained with reference to Examples. Example 1 [Pharmacological test] (1) Adjuvant arthritis suppressive effect 7-8 week old SD rats (approximately 150 g)
A suspension of Mycobacterium butyricum in liquid paraffin at a concentration of 12 mg/ml was injected intradermally into the right hind foot pad at a rate of 0.05 ml per rat. Adjuvant arthritis (AA) was induced. The volume of both hind paws was measured by the mercury exclusion method until 30 days after the adjuvant injection, and AA was evaluated. (a) Preventive effect Compounds No. 1 and 4 and platonin were used as test compounds, and in order to examine their AA preventive effects, administration of this drug was started at the same time as adjuvant administration, and oral administration was performed once a day. I continued until the 30th day. The results are shown in Figure 1. FIG. 2 shows the results of administering D-penicillamine and levamisole in place of the test compound in the same manner. As a result, it was found that compound (), like platonin, suppresses AA at a low dose of 0.05 μg/mouse, but D-penicillamine and levamisole do not suppress AA even at a dose of 1.5 mg/mouse. (b) Therapeutic effect Compounds No. 1, No. 4 and platonin were used as test compounds. In order to examine their AA therapeutic effects, administration of this drug was started on the 14th day after administration of the adjuvant, and 1 day after administration. A single oral administration was carried out until the 40th day. The results are shown in Figure 3. As a result, compound () suppresses AA at a low dose of 0.05 μg/mouse, which is similar to platonin, but no inhibitory effect was observed at doses of 1 μg/mouse or higher, indicating that an optimal dose exists. I found out. (2) Body weight change On day 1, day 10, during the test period for the preventive effect of the adjuvant arthritis inhibitory effect in (1)(a) above,
The weight of each rat was measured on the 20th and 30th day. The results are shown in FIGS. 4 and 5. As a result, no difference was observed in the body weight changes of rats when D-penicillamine and levamisole were administered compared to controls, but when compound () was administered at 0.05 μg/animal, similar to platonin, despite the decrease in paw swelling. A clear increase in body weight change was observed in the rats compared to controls, and a marked improvement in systemic symptoms was also observed. (3) Effect on PFC response using mouse splenocytes Anti-SRBC using Balb/c mouse splenocytes
The effect on PFC response was investigated. Compounds Nos. 1 to 4 and platonin were used as test compounds. SRBC
and 10% fetal bovine serum with test compound.
Cultured in RPMI-1640 medium in a CO 2 incubator (37°C) using the Marbrook method for 4 days,
The number of direct PFCs that appeared was measured by Jerne's method (Science, vol. 140, p. 405, 1963). The results are shown in Figure 6. As is clear from FIG. 6, the effect of compound () on the anti-SRBC PFC response was biphasic, with an activation effect at low concentrations and an inhibitory effect at high concentrations, similar to that of platonin. (4) Effect on the blastogenesis reaction using mouse splenocytes The test used in (3) above on the lymphocyte blastogenesis response induced by mitogen (LPS) stimulation using Balb/c mouse splenocytes. The effects of the compounds were investigated. 1 x 10 splenocytes of Balb/c mice were incubated with mitogen and test compound in RPMI-1640 medium containing 10% fetal bovine serum in a CO 2 incubator using a microculture plate.
Cultured for 48 hours. Then, 0.5 μCi of 3 H-thymidine ( 3 H-TdR) was added, and after further culturing for 18 hours, the cells were harvested using a cell harvester (Labo Matsushiyu) to remove 3 H-TdR taken into the cells.
The radioactivity was measured. The results are shown in FIG. As is clear from FIG. 7, when stimulated with 20 μg/ml of LPS, a B cell mitogen, compound () had a significant suppressive effect similar to that of platonin. (5) Acute toxicity ddY male mice (5-6 weeks old) (body weight 25~
Platonin and Compounds Nos. 1 to 4 were suspended in 5% gum arabic solution using 30 g of 8 animals per group.
The compound () was administered intraperitoneally, intravenously, and orally using a gastric tube, and the animals were observed for 7 days to determine the number of deaths, and the LD 50 value was determined by the van der Weerden method. The results are shown in Table 2.
【表】
第２表に示すごとく、腹腔内投与のばあいの
LD50値は23.4〜300mg／Kg体重であり、経口投
与のばあいのLD50値は1.4ｇ／Kg体重以上であ
り、前記(1)のアジユバント関節炎抑制作用にお
いて0.05μｇ／匹であることを考え合せると、
本発明の慢性関節リウマチ治療剤はきわめて安
全域の広いものであることがわかる。
化合物No.１〜４をそれぞれ有効成分として用
い、つぎのごとき各種剤型の慢性関節リウマチ治
療剤を調製した。
(1) 錠 剤
つぎの処方の錠剤を常法により調製した。
成 分 mg／錠
有効成分 0.05
乳 糖 79.95
コーンスターチ 62.50
シヨ糖脂肪酸エステル 7.50
合計150
胃溶性剤のばあいはTc−５の５重量％コー
テイングを施したのち糖衣を施した。腸溶性剤
のばあいはHP−55の10重量％コーテイングを
施したのち糖衣を施した。
(2) カプセル剤
つぎの処方のカプセル剤を常法により調製し
た。
成 分 mg／カプセル
有効成分 0.05
乳 糖 146.95
シヨ糖脂肪酸エステル 3.00
合計150
(3) 散 剤
つぎの処方の散剤を常法により調製した。
成 分 mg
有効成分 0.05
乳 糖 499.95
合計500
(4) 座 剤
つぎの２種の処方の座剤を常法により調製し
た。
座剤Ａ
成 分 mg／剤
有効成分 0.05
PEG＃1000 1440
PEG＃4000 59.95
合計1500
座剤Ｂ
成 分 mg／剤
有効成分 0.05
ウイテブゾールＨ−15 1280
ウイテブゾールＨ−85 319.95
合計1600
(5) シロツプ
つぎの処方のシロツプ（１回服用量：50μ
ｇ／５ml）を常法により調製した。
成 分 含有量／100ml
有効成分 １mg
砂 糖 60ｇ
グリセリン 10ｇ
クエン酸ナトリウム 0.1ｇ
安息香酸ナトリウム 0.3ｇ
サツカリンナトリウム 0.1ｇ
精製水 適量[Table] As shown in Table 2, for intraperitoneal administration,
The LD 50 value is 23.4 to 300 mg/Kg body weight, and the LD 50 value in the case of oral administration is 1.4 g/Kg body weight or more, considering that the adjuvant arthritis suppressive effect in (1) above is 0.05 μg/mouse. When combined,
It can be seen that the therapeutic agent for chronic rheumatoid arthritis of the present invention has an extremely wide safety margin. Using Compounds Nos. 1 to 4 as active ingredients, the following various formulations of therapeutic agents for rheumatoid arthritis were prepared. (1) Tablets Tablets with the following formulation were prepared by a conventional method. Ingredients mg/tablet Active ingredient 0.05 Lactose 79.95 Cornstarch 62.50 Sucrose fatty acid ester 7.50 Total 150 In the case of gastrosoluble agents, a 5% by weight coating of Tc-5 was applied, followed by sugar coating. In the case of enteric-coated agents, a 10% by weight coating of HP-55 was applied, followed by sugar coating. (2) Capsules Capsules with the following formulation were prepared by a conventional method. Ingredients mg/capsule Active ingredient 0.05 Lactose 146.95 Sucrose fatty acid ester 3.00 Total 150 (3) Powder A powder with the following formulation was prepared by a conventional method. Ingredients mg Active ingredient 0.05 Lactose 499.95 Total 500 (4) Suppositories Suppositories with the following two formulations were prepared using conventional methods. Suppository A Ingredient mg/active ingredient 0.05 PEG#1000 1440 PEG#4000 59.95 Total 1500 Suppository B Ingredient mg/active ingredient 0.05 Uitebuzol H-15 1280 Uitebuzol H-85 319.95 Total 1600 (5) Syrup Next Prescription syrup (1 dose: 50μ
g/5ml) was prepared by a conventional method. Ingredients Content/100ml Active ingredients 1mg Sugar 60g Glycerin 10g Sodium citrate 0.1g Sodium benzoate 0.3g Saccharin sodium 0.1g Purified water Appropriate amount
第１図はラツトにおけるアジユバント関節炎に
対する供試化合物の予防効果を示すグラフ、第２
図はラツトにおけるアジユバント関節炎に対する
Ｄ−ペニシラミンおよびレバミゾールの予防効果
を示すグラフ、第３図はラツトにおけるアジユバ
ント関節炎に対する供試化合物の治療効果を示す
グラフ、第４図は供試化合物がアジユバント関節
炎ラツトの体重に及ぼす影響を示すグラフ、第５
図はＤ−ペニシラミンおよびレバミゾールがアジ
ユバント関節炎ラツトの体重に及ぼす影響を示す
グラフ、第６図はマウス脾細胞を用いたPFC応
答に及ぼす供試化合物の作用を示すグラフ、第７
図はマウス脾細胞を用いた幼若化反応に及ぼす供
試化合物の作用を示すグラフである。
Figure 1 is a graph showing the preventive effect of the test compound on adjuvant arthritis in rats.
The figure is a graph showing the preventive effect of D-penicillamine and levamisole on adjuvant arthritis in rats. Figure 3 is a graph showing the therapeutic effect of the test compound on adjuvant arthritis in rats. Figure 4 is a graph showing the therapeutic effect of the test compound on adjuvant arthritis in rats. Graph showing the effect on body weight, 5th
Figure 6 is a graph showing the effects of D-penicillamine and levamisole on the body weight of rats with adjuvant arthritis. Figure 6 is a graph showing the effects of test compounds on PFC responses using mouse splenocytes.
The figure is a graph showing the effect of test compounds on the rejuvenation reaction using mouse splenocytes.
Claims (1)
（ただしｎ−ヘプチル基は除く）、Ｉ はヨードイ
オンを示す）で表わされるトリチアゾールペンタ
メチンシアニン系化合物を有効成分として含有す
る慢性関節リウマチ治療剤。 ２ 前記一般式（）中のＲがオクチル基である
特許請求の範囲第１項記載の慢性関節リウマチ治
療剤。 ３ 投与形態が経口剤である特許請求の範囲第１
項または第２項記載の慢性関節リウマチ治療剤。[Claims] 1 General formula (): (In the formula, R is an alkyl group having 1 to 15 carbon atoms (excluding n-heptyl group), and I is an iodo ion.) Rheumatoid arthritis treatment. 2. The therapeutic agent for rheumatoid arthritis according to claim 1, wherein R in the general formula () is an octyl group. 3 Claim 1 in which the dosage form is an oral dosage form
The therapeutic agent for chronic rheumatoid arthritis according to item 1 or 2.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10239382A JPS58219116A (en) | 1982-06-14 | 1982-06-14 | Immunological regulating agent |
| US06/404,843 US4464383A (en) | 1981-11-24 | 1982-08-03 | Immunomodulator containing trithiazole pentamethine cyanine derivative |
| DE19823234711 DE3234711A1 (en) | 1981-11-24 | 1982-09-18 | A TRITHIAZOLPENTAMETHINCYANINE DERIVATIVE CONTAINING IMMUNOMODULATOR |
| CH5540/82A CH650673A5 (en) | 1981-11-24 | 1982-09-20 | A PHARMACEUTICAL AGENT CONTAINING TRITHIAZOLPENTAMETHINCYANINE DERIVATIVE. |
| GB08227128A GB2116422B (en) | 1981-11-24 | 1982-09-23 | Immunomodulator containing trithiazole pentamethine cyanine derivative |
| BE0/209198A BE894635A (en) | 1981-11-24 | 1982-10-07 | NOVEL IMMUNOMODULATORY DRUGS CONTAINING A TRITHIAZOLE-PENTAMETHYLIDENE CYANINE DERIVATIVE |
| FR8216813A FR2516793B1 (en) | 1981-11-24 | 1982-10-07 | NOVEL IMMUNOMODULATORY DRUGS CONTAINING A TRITHIAZOLEPENTAMETHYLIDENE-CYANINE DERIVATIVE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10239382A JPS58219116A (en) | 1982-06-14 | 1982-06-14 | Immunological regulating agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58219116A JPS58219116A (en) | 1983-12-20 |
| JPH0216727B2 true JPH0216727B2 (en) | 1990-04-18 |
Family
ID=14326197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10239382A Granted JPS58219116A (en) | 1981-11-24 | 1982-06-14 | Immunological regulating agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58219116A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4580479B2 (en) * | 1998-12-21 | 2010-11-10 | 株式会社林原生物化学研究所 | Anti-HIV infection agent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1169660A (en) * | 1968-01-31 | 1969-11-05 | Eisai Co Ltd | Quarternary Compounds |
-
1982
- 1982-06-14 JP JP10239382A patent/JPS58219116A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1169660A (en) * | 1968-01-31 | 1969-11-05 | Eisai Co Ltd | Quarternary Compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58219116A (en) | 1983-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4734276A (en) | L-lysine pyruvate and l- histidine pyruvate and their use in therapy of tissue and mucosa damage | |
| EP0001727B1 (en) | New derivatives of 4-phenyl-2-(2',2',2-trichlorethoxycarboxamido)-thiazole useful as medicaments, pharmaceutical compositions containing them and process for the preparation of these compounds | |
| US3644626A (en) | Novel pyridones in compositions and methods for treating inflammation pain and fever | |
| CA1297033C (en) | Use of carboxylic acid amides for treating inflammations | |
| JPH0475205B2 (en) | ||
| JPH0216727B2 (en) | ||
| NL8105635A (en) | MEDICINAL PRODUCT WITH TRANSPLANT REPELLENT AND / OR IMMUNOLOGICAL ANTI-INFLAMMATORY EFFECTS, AND METHOD FOR INHIBITING TRANSPLANT REPELLENT AND / OR IMMUNOLOGICAL IGNITION. | |
| FR2620450A1 (en) | NOVEL SALTS OF ORGANOGERMANIC COMPOUNDS AND MEDICAMENTS CONTAINING SAME | |
| US4464383A (en) | Immunomodulator containing trithiazole pentamethine cyanine derivative | |
| JPS60158149A (en) | Antiinflammatory 1,4-naphthoquinone derivative | |
| EP0194571B1 (en) | Heterocyclic disulfides, process for their preparation and pharmaceutical preparations containing them | |
| US3852454A (en) | Treatment of rheumatoid arthritis | |
| US4447437A (en) | Pharmaceutical composition and method for treatment of peptic ulcer | |
| JP2005507869A (en) | A group of new anticancer compounds with special structure | |
| EP0623623B1 (en) | 2-aminoethanesulfonic acid/zinc complex | |
| JPS6245525A (en) | Hypolipemic agent | |
| Capasso et al. | The effects of levamisole and d-penicillamine on some inflammatory models in vivo and on PG production in vitro | |
| US3885045A (en) | Therapeutic composition containing 1-(2-hydroxy-2-indanyl)-propylamine | |
| JPS5835186A (en) | Dicarboxyaminothiazole derivative and medical composition containing it | |
| CA1270762A (en) | Pharmaceutical composition comprising a derivative of maleopiramic acid | |
| JPH04210631A (en) | Protective agent for digestive tract wall | |
| JPH0216285B2 (en) | ||
| KR920001762B1 (en) | Agent for treating hyperuricemia | |
| JPS6245843B2 (en) | ||
| JPH053474B2 (en) |