DK156659B - Analogifremgangsmaade til fremstilling af heterocycliske amider af 4-hydroxy-2h-1-benzothiopyran-3-carboxylsyre-1,1-dioxid - Google Patents
Analogifremgangsmaade til fremstilling af heterocycliske amider af 4-hydroxy-2h-1-benzothiopyran-3-carboxylsyre-1,1-dioxid Download PDFInfo
- Publication number
- DK156659B DK156659B DK201673AA DK201673A DK156659B DK 156659 B DK156659 B DK 156659B DK 201673A A DK201673A A DK 201673AA DK 201673 A DK201673 A DK 201673A DK 156659 B DK156659 B DK 156659B
- Authority
- DK
- Denmark
- Prior art keywords
- hydroxy
- dioxide
- benzothiopyran
- pyridyl
- carboxamide
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 3
- GRGDQCHPFKZXSA-UHFFFAOYSA-N 4-hydroxy-1,1-dioxo-2h-thiochromene-3-carboxylic acid Chemical compound C1=CC=C2S(=O)(=O)CC(C(=O)O)=C(O)C2=C1 GRGDQCHPFKZXSA-UHFFFAOYSA-N 0.000 title description 2
- 150000001408 amides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 27
- -1 4-hydroxy-N- - (2-pyridyl) -2H-1-benzothiopyran-2-carboxamide-1,1-dioxide Chemical compound 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000002808 molecular sieve Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 235000010418 carrageenan Nutrition 0.000 description 6
- 229920001525 carrageenan Polymers 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- ATHKQEYJMAROJY-UHFFFAOYSA-N 4-hydroxy-1,1-dioxo-N-pyridin-2-yl-2H-thiochromene-3-carboxamide Chemical compound OC1=C(CS(C2=C1C=CC=C2)(=O)=O)C(=O)NC2=NC=CC=C2 ATHKQEYJMAROJY-UHFFFAOYSA-N 0.000 description 2
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JZUVOLFDJCQFGA-UHFFFAOYSA-N methyl 4-hydroxy-1,1-dioxo-2h-thiochromene-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)CC(C(=O)OC)=C(O)C2=C1 JZUVOLFDJCQFGA-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- FKPXGNGUVSHWQQ-UHFFFAOYSA-N 5-methyl-1,2-oxazol-3-amine Chemical compound CC1=CC(N)=NO1 FKPXGNGUVSHWQQ-UHFFFAOYSA-N 0.000 description 1
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 1
- QUXLCYFNVNNRBE-UHFFFAOYSA-N 6-methylpyridin-2-amine Chemical compound CC1=CC=CC(N)=N1 QUXLCYFNVNNRBE-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 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 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 156659 B
Den foreliggende opfindelse angâr en analogifrem-gangsmàde til fremstilling af hidtil ukendte heterocycliske amider af 4-hydroxy-2H-l-benzothiopyran-3-carboxylsyre-l,l--dioxid med f0lgende strukturformel OH i? 1
X CNHRX
R2~t i io °* ^ hvori R1 betyder en eventuelt med C^-4 alkyl, halogen eller nitro substitueret pyridyl-, thiazolyl- eller isoxazolylgrup-pe, og R2 betyder hydrogen, C^_4 alkyl, C^„4 alkoxy eller halogen, eller salte deraf.
15 Fra beskrivelsen til dansk patentansegning nr. 3544/72 (patent nr. 132629) kendes antiinflammatorisk virksomme 4--hydroxy-2H-l-benzothiopyran-3-carboxamid-l,1-dioxider med den almene formel OH ,? 20 i. CNHR1 J j O* \) 25 hvor R1 betyder phenyl, der eventuelt kan indeholde én eller to substituenter valgt blandt alkyl, alkoxy, ace- tyl, halogen og trifluormethyl, og R2 betyder alkyl med 1-7 carbonatomer, phenyl, phenylalkyl med 1-7 carbonatomer i alkylgruppen, alkoxy med 1-7 carbonatomer, halogen, cyano, 30 nitro eller trifluormethyl.
I forhold til disse kendte forbindelser har de ved fremgangsmâden ifolge opfindelsen fremstillede forbindelser en uventet bedre antiinflammatorisk virkning.
Nâr de indgives oralt eller intraperitonealt til 35 forsogsdyr, som f.eks. rotter, med en dosis pâ 10-200 mg/kg, reducerer de f.eks. den hævelse i poten, som i forvejen er 2
DK 156659 B
fremkaldt ved injektion af et irritationsmiddel, soin f.eks. carrageenin.
Disse forbindelser anvendes under betingelser, hvor de blede væv er betændt, som f.eks. ved rheumatoid arthritis 5 hos pattedyr. Der anbefales en dosis pâ 10-200 mg/kg opdelt i flere daglige doser, oralt eller ved injektion. Dette doseringsomrâde kan varieres afhængigt af vægt, aider, k0n og arten af det pattedyr, der behandles.
For at kunne anvende disse forbindelser formuleres 10 de med farmaceutiske fortyndingsmidler, sâsom lactose, og blandes til doseringsformer, sâsom tabletter. Subsidiaert kan de formuleres med et sterilt grundlag, som f.eks. vand til injektion, og blandes til suspensioner, der er egnede til parentéral indgift. Da forbindelserne er sure, kan de 15 omdannes til métal- eller aminsalte. Disse salte fâs pâ gængs mâde, f.eks. ved at behandle forbindelsen med alkali, som f.eks. natrium- eller kaliumhydroxid, og derpà udvinde saltene. Pyridylforbindelserne er amfotere. De kan sâledes ogsâ danne syreadditionssalte.
20 If0lge den foreliggende opfindelse fremstilles for- bindelseme med formlen I ved, at en /3-ketoester med folgende strukturformel OH 0 ,r ·* 25 p f'
R--| . T II
<f**o hvori R3 betyder aralkyl med 1-6 carbonatomer i alkyldelen 30 eller phenyl, og R2 har den ovenfor angivne betydning, om-sættes med en forbindelse med formlen R1NH2, hvor R1 har den ovenfor angivne betydning, under tilbagesvaling i et indifferent oplesningsmiddel, sâsom xylen, i nærværelse af en molekylsi, og eventuelt omdannes en dannet forbindelse 35 til et sait deraf. Molekylsien tjener til at fjerne alko-holen, der dannes under reaktionen.
3
DK 156659 B
Udgangsforbindelsen II fremstilles soin beskrevet i W.J. Still et al., J.O.C.. 33, 2730 (1968).
Fremgangsmâden ifdlge opfindelsen beskrives nærmere ved hjælp af f0lgende eksempler.
5
Heterocvclïske amider af 4-hYdroxv-2H-l-benzothioovran-3--carboxvlsvre-1,1-dioxid. Almen fremoangsmade.
En blanding af 8,1 g (0,032 mol) methy1-4-hydroxy--2H-l-benzothiopyran-3-carboxylat-l,1-dioxid, 0,05 mol af 10 en passende heterocyclisk amin og 250 ml xylen tilbagesvales i 16 timer i et Soxhlet-apparat, i hvis r0r der er anbragt 20 g af en Linde type 4A molekylsi. Blandingen afk0les til stuetemperatur, og det fremkomne krystallinske udfældnings-produkt opsamles og omkrystalliseres.
15
Eksempel 1
0H S
20 [il sJ*
No 25 4-Hvdroxv-N-(2-Pvridvl)-2H-l-benzothiopyran-3-carboxamid--1.1-dioxid.
En blanding af 9,4 g (0,04 mol) methyl-4-hydroxy-2H--l-benzothiopyran-3-carboxylat-l,1-dioxid, 5,2 g (0,06 mol) 2-aminopyridin og 250 ml xylen tilbagesvales i 16 timer i 30 et Soxhlet-apparat, i hvis r0r der er anbragt 20 g af en Linde type 4A molekylsi. Blandingen afk0les til stuetemperatur, og det fremkomne krystallinske udfældningsprodukt (vægt 8,6 g, smp. 236-238*0 sdnderdeling) opsamles. Det omkrystalliseres fra eddikesyre til dannelse af 6,4 g stof med smp.
35 236-238°C (s0nderdeling).
4
DK 156659 B
Analyse for C15H12N2O4S:
C H N S
Beregnet: 56,95 3,82 8,86 10,14
Fundet: 56,70 3,77 8,73 10,39 5
Eksemoel 2 ONa » λ—\ 10 f\\ \ Xk=v/ ' ^ «A»
Natriumsalt af 4-hvdroxv-N-f2-pyridvl)-2H-l-benzothiopvran-15 -3-carboxamid-l.1-dioxid.
Til en oplesning af 0,64 g (0,016 mol) natriumhydroxid i 30 ml methanol sættes (ait sammen pâ én gang i form af pulver) 2,53 g (0,008 mol) - 4-hydroxy-N-(2-pyridyl)-2H-1--benzothiopyran-3-carboxamid-l,1-dioxid, og blandingen om-20 reres ved stuetemperatur i én time. Det fremkomne udfæld-ningsprodukt (2,6 g, smp. 243°C, senderdeling) omkrystal-liseres ved oplesning i 150 ml éthanol og koncentrering til et volumen pâ 90 ml. Det fremkomne produkt terres i vakuum ved 65"C i 3 dage til dannelse af 2,0 g natriumsalt. Smp.
25 243-246°C, senderdeling (farves merkt ved 220”C).
Analyse for CisHn^C^SNa·1/2H20: C H N S Na
Beregnet: 51,86 3,48 8,07 9,23 6,62
Fundet: 51,83 3,49 7,97 9,21 6,49 5
Eksempel 3
DK 156659 B
f S /—\ cm-Jy \-ch, or o 4-Hydroxv-N-(5-methyl-2-pyridvl) -2H-l-benzothiopvran-3-carb-10 oxamid-1.1-dioxid.
Ovenstâende produkt fàs ved som amin at anvende 2--amino-5-methyl-pyridin. Det omkrystalliseres fra eddikesyre. Udbytte: 6,5 g, smp. 228°C, sdnderdeling.
Analyse for C^H^^C^S:
15 C H N S
Beregnet: 58,17 4,27 8,48 9,71
Fundet: 58,12 4,41 8,35 9,89
Eksempel 4 20 OH » CE, O·* 25 <A> 4-Hydroxv-N- ( 4-methvl-2-pvridvlï -2H-l-benzothiopvran-3-carb-oxamid-1,1-dioxid.
Ovenstâende produkt fâs ved som amin at anvende 2-30 amino-4-methylpyridin. Det omkrystalliseres fra eddikesyre. Udbytte: 8,0 g, smp. 236-238°C, senderdeling.
Analyse for C15H14N204S:
C H N S
Beregnet: 58,17 4,27 8,48 9,71 35 Fundet: 58,20 4,31 8,32 9,61
Eksemoel 5
DK 156659 B
6 \ OH n ^d>\ 4-Hvdroxv-N-(5-chlor-2-Pvridvl)-2H-l-benzothiopvran-3-carb-10 oxamid-1.1-dioxid.
Ovenstâende produkt fâs ved som amin at anvende 2--amino-5-methylpyridin. Det omkrystallisérés fra eddikesyre. üdbytte: 7,3 g, smp. 196-198°C, S0nderdeling (flyder hen ved 160eC).
15 Analyse for CjjgHijCl^C^S:
C H Cl N S
Beregnet: 51,36 3,16 10,11 7,99 9,14
Fundet: 51,12 3,07 10,04 8,06 9,00 20 Eksempel 6 0H 0 Y [ | <A> 4-Hydroxv-N-f5-nitro-2-PvridvH-2H-l-benzothiopvran-3-carb-oxamid-1.1-dioxid.
30 Ovenstâende produkt fâs ved som amin at anvende 2- -amino-5-nitropyridin. Det omkrystallisérés fra eddikesyre. üdbytte: 4,5 g, smp. 237-239“C, s0nderdeling.
Analyse for C15H11N3O6S:
C H N S
35 Beregnet: 49,86 3,07 11,63 8,87
Fundet: 50,08 3,17 11,56 8,92
Eksemoel 7 7
DK 156659 B
°H cm_\ 5 l </ o 4-Hvdroxv-N- (6-methvl-2-pvridvl^ -2H-l-benzothioovran-3-carb-10 oxamid-1,1-dioxid.
Ovenstâende produkt fâs ved som amin at anvende 2--amino-6-methylpyridin. Det omkrystalliseres fra 75 ml ed-dikesyre. Udbytte: 8,0 g (88%), smp. 226,5-228eC, spnder-deling.
15 Analyse for CigH^^C^S:
C H N S
Beregnet: 58,17 4,27 8,48 9,71
Fundet: 57,97 4,31 8,29 9,91 20 Eksempel 8 OH n ^ JL .CNH—r' %
\\ I
| n_Il
25 ^ /A. >L
<f % 4-Hvdroxv-N-(2-thiazolvlï-2H-l-benzothiopvran-3-carboxamid--1.1-dioxid.
30 Ovenstâende produkt fâs ved som amin at anvende 2- -aminothiazol. Det omkrystalliseres fra 1900 ml eddikesyre. Udbytte: 4,5 g, smp. 274-277°C, sonderdeling.
Analyse for C13H10N2O4S:
C H N S
35 Beregnet: 48,44 3,13 8,69 19,89
Fundet: 48,27 3,13 8,69 19,70
Eksempel 9
DK 156659B
8
OH S
· 1 XNH—.-- 5 m Tl 3 4-Hvdroxv-N-f 5-methyl-3-isoxazolvl^-2H-l-benzothiopvran-3-10 -carboxamid-1.1-dioxid.
Ovenstâende produkt fâs ved soin amin at anvende 3--amino-5-methylisoxazol. Det omkrystalliseres fra 700 ml eddikesyre. Udbytte: 7,8 g, smp. 244-247°C, sonderdeling.
Analyse for Ci4Hi2N2°4S:
15 C H N S
Beregnet: 52,50 3,78 8,75 10,01
Fundet: 52,45 3,80 8,53 10,18
DK 156659 B
9 î o g O CM *î ^ o in
- bû I O CM
ο α) o 1
u-1 +J \ oo CM
Q V W) t" Λ 00
P ° s r*' iS
<J 5-1 — t—I ^
O O
Q
OT P.
PÔ
O
fc M
§ \ en en en O
q bû ~ ~ ~
§ 5 ° " S
O Q
Οι ω w a
H
H
M Q ►J 03 ω h m h <3 Pô H ω u § n $ z 5 § s à ° 'ω o en cm vo H OS ^ a ω ^ w w . p b | g g g a
g o P"° O /u=° ,* P- O
w . v i S <\/—1 ta °*r( k o*0~° o'v)-0 oX_>-§ 0>(V0 \_j/ \_y o en °\ m ,-ι en σ> μ oo rH -cf <r à cj\ · · σ> ο ο ο £5 rH Η ι-ί 10
DK 156659 B
jj r—! td > o - ω ο a> M m jj \ q jj ω a o e <S u ^
ü O
Q
CO p<
PS
O
Qu bû g Λί m ο o vo ω \ cm - -
JJ o bû O O
cd q S 'Ο 10 ^ ^
M W ^ V
JJ EH
MO Q
O Ph W
<h ta g v-^ h M g “
W H
« ω <d ps h ω u £> Q ^ o
g bû r-J CO ‘O £M
Μ Μ o 00 Γ' • o \ co - - _r
g f- bû .-I in CM H
h Q S N
g ω w » o o U w" § 0 d £3 Ό jj Μ 1 l /
3 S £ £ M
g ν·° p,o u=o g=o " Vy§ VA_§ °»4 s v(«
/=\ °* w~ °Λ=< 0<ν7~S
S H £1 g g «tf <f · ο θ' θ' ο g rH h 11
DK 156659B
μ
- bO o a) Λ! in μ \ q μ bO
ι-l O S
<; μ 'χ' O o © OT (¾ PÔ
O
ta M
^ I \ m O O O o_ a § s ri O « g g 03 H ^ m CM min μ H „
U O Q
O P4 W
m ta g
^ H H
W O fJ * ta h « ta <ti Pô h ta u P o
g ω° <1· <r 2 S
pH ^ CM h~ θ' iH i-l I O λ ** ** ”
gjl^bOCM <5 J
H Q B -¾ ^ Μ g ta ta o m tu , p ^ p î
u J m J
I n I o=S I W
μ 0=p | O = U W
" °>\TV§ °yys °v~V§ os J=° ° }\ ° )\ oX3~° '“V '“Λ Ο U ο Ο u po 0 W = O c •rl m <t· μ . oj- oo m vo ·μ μ σ\ CM i-H 10 P*
Hr · · »03 S O H CM O < J3 1-) i—I «“· H -
DK 156659B
12
TABEL II
Antiinflammatorisk virkning i det carrageenin-inducerede rottepote0demfors0g med forbindelser kendt fra dansk patent-ans0gning nr. 3544/72 (patent nr. 132.629) 5 oh q 10 “
W9.153 RX=H R2=H W10.040 R1=0-CH3 R2=H
W9.474 R1=p-CH3 R2=H W10.041 Rx=2,3-dimethyl R2=H
W9.482 R^O-Cl R2=H W10.893 RX=H R2=CH3 15 W9.486 Rx=0-F3C R2=H W10.946 RX=H R2=cl CIRPE Φ W Forbindelse -
Dosis % 20 (mg/kg) Inhibering W9.153 10 -22* 25 -43* 50 -48* 25 100 -58* W9.474 6,25 -19 25.0 -34* 100.0 -50* 30 W9.482 6,25 -33* 25.0 -40* 100.0 -48* 35 W9.486 6,25 -19 25.0 -47* 100.0 -40* W10.040 100 -40* 40 W10.041 100 -30* W10.893 100 -46* 45 W10.946 6,25 -31* 12,5 -42* 25.0 -54* 100.0 -52* 50 Wl.989 50 -38* (Acetylsalicylsyre) 200 -63* 400 -57* Θ Carrageenin-induceret rottepote0dem 55 * Signifikant forskellig fra kontroller (p<50,05) 13
DK 156659 B
TABEL III
Antiinflammatorisk virkning i det carrageenin-inducerede rottepote0demfors0g med forbindelser fremstillet ved frem-gangsmâden if0lge opfindelsen 5 v f ? 10 * R1 R2
W10.110 5-methyl-2-pyridyl H
W9.985 2-pyridyl H
W10.435 - 6-methyl-2-pyridyl H
15 W10.499 4-methyl-2-pyridyl H
W10.535 5-chlor-2-pyridyl H
W10.900 2-pyridyl CH3 W10.945 2-pyridyl Cl 20 -- CIRPE® W Forbindelse -;-
Dosis % (mg/kg) Inhibering 25-- W10.110 6,25 22,0* 12,5 46,0* 25 57,6* 30 W10.100 0,37 21,5* 1,11 11,1 3,33 25,4* 9,99 46,4* 35 29,97 59,4* W10.110 12,5 47,2* 25 51,4* 50 64,1* 40 100 47,2* W9.985 0,37 21,1* 1,11 43,6* 45 3,33 40,8* 10 47,8* 30 50,7* W9.985 25 48,9* 50 50 50,4* 100 55,3* 14
DK 156659 B
TABEL III (fortsat)
Antiinflammatorisk virkning i det carrageenin-inducerede rottepoteddemforsdg med forbindelser fremstillet ved frem-gangsmàden if0lge opfindelsen 5 CIRPE© W Forbindelse -
Dosis % 10 (mg/kg) Inhibering W10.435 0,37 14,2 1,11 24,1* 3,33 31,9* 15 10 45,4* W10.435 6,25 33,3* 12.5 60,5* 20 W10.435 25 45,9* 50 52,0* W10.435 100 50,0* 25 W10.499 100 33,6 100 42,1 W10.499 25 27,1 50 40,7 30 100 42,7 W10.499 1,56 4,8 6.25 ---- 25 9,5 35-- W10.535 100 48,8 100 51,7 6.25 27,2 12.5 59,7 40 25,0 49,1 50.0 47,9 100,0 46,7 W10.535 1,1 9,4 45 3,33 13,0 10.0 11,5 W10.535 0,39 6,8 1,56 4,5 50 6,25 19,3 W10.535 3,12 4,4 6.25 31,0 12.5 23,9
DK 156659 B
15 tabel III (fortsat)
Antiinflammatorisk virkning i det carrageenin-inducerede rottepote0demfors0g med forbindelser fremstillet ved frem-gangsmâden if0lge opfindelsen 5 CIRPE® W Forbindelse -
Dosis % 10 (mg/kg) Inhibering W10.900 100 45,1 100 41,7 15 W10.900 25 29,8 50 25,4 W10.900 6,25 20,3 25.0 45,8 20 100 66,9 W10.900 0,39 5,8 1.56 30,6 6.25 49,6 25-- W10.945 100 37,7 100 57,0 W10.945 50 52,1 30 W10.945 25 27,6 W10.945 6,25 23,0 12,5 38,0 35 W10.945 1,56 23,1 6.25 37,2 25.0 72,7 40 W10.945 0,39 ---- 1.56 20,0 6.25 25,9 W10.945 25,0 33,0 45 --
Claims (9)
1. Analogifremgangsmâde til fremstilling af 4-hydroxy- -2H-l-benzothiopyran-l, l-dioxid-3-carboxylsyreamider med den almene formel 5 n OH 0 I "1 CNHR R2__| I &S%' 10 hvori R1 betyder en eventuelt med C1-4 alkyl, halogen eller nitro substitueret pyridyl-, thiazolyl- eller isoxazolyl-gruppe, og R2 betyder hydrogen, C^-4 alkyl, C1-4 alkoxy eller halogen, eller salte deraf, kendetegnet 15 ved, at en forbindelse med den almene formel OH 0 ^ X .COR3 2 R--| II 20 (f^O hvori R3 betyder aralkyl med 1-6 carbonatomer i alkyldelen eller phenyl, og R2 har den ovenfor angivne betydning, om-sættes med en forbindelse med formlen R1NH2, hvor R1 har 25 den ovenfor angivne betydning, under tilbagesvaling i et indifferent oplosningsmiddel i nærværelse af en molekylsi, og eventuelt omdannes en dannet forbindelse til et sait deraf.
2. Fremgangsmâde ifplge krav 1, kendeteg- 30 net ved, at den fremstillede forbindelse er 4-hydroxy-N- -(2-pyridyl)-2H-l-benzothiopyran-2-carboxamid-l,l-dioxid.
3. Fremgangsmâde ifolge krav 1, kendeteg net ved, at den fremstillede forbindelse er 4-hydroxy-N--(2-( 5-methyl) pyridyl) -2H-l-benzothiopyran-2-carboxamid-l, 1- 35 -dioxid.
4. Fremgangsmâde ifplge krav 1, kendeteg- DK 156659 B net ved, at den fremstillede forbindelse er 4-hydroxy-N--(2-(4-methyl)pyridyl)-2H-l-benzothiopyran-2-carboxamid--1,1-dioxid.
5. Fremgangsmâde if0lge krav 1, kendeteg-5 net ved, at den fremstillede forbindelse er 4-hydroxy-N- -(2-(5-chlor)pyridyl)-2H-l-benzothiopyran-2-carboxamid-1,1--dioxid.
6. Fremgangsmâde if0lge krav 1, kendeteg- n e t ved, at den fremstillede forbindelse er 4-hydroxy-N- 10 -(2-(5-nitro)pyridyl)-2H-l-benzothiopyran-2-carboxamid-l,1- -dioxid.
7. Fremgangsmâde ifelge krav 1, kendeteg- n e t ved, at den fremstillede forbindelse er 4-hydroxy-N--(2-(6-methyl)pyridyl)-2H-l-benzothiopyran-2-carboxamid- 15 -1,1-dioxid.
8. Fremgangsmâde if0lge krav 1, kendeteg- n e t ved, at den fremstillede forbindelse er 4-hydroxy-N--(2-thiazolyl)-2H-l-benzothiopyran-2-carboxamid-l,1-dioxid.
9. Fremgangsmâde if0lge krav 11 k e n d e t e g- 20 net ved, at den fremstillede forbindelse er 4-hydroxy-N--(3-(5-methyl)isoxazolyl)-2H-l-benzothiopyran-2-carboxamid--1,1-dioxid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24850972A | 1972-04-28 | 1972-04-28 | |
| US24850972 | 1972-04-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK156659B true DK156659B (da) | 1989-09-18 |
| DK156659C DK156659C (da) | 1990-02-05 |
Family
ID=22939461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK201673A DK156659C (da) | 1972-04-28 | 1973-04-12 | Analogifremgangsmaade til fremstilling af heterocycliske amider af 4-hydroxy-2h-1-benzothiopyran-3-carboxylsyre-1,1-dioxid |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US3769292A (da) |
| JP (1) | JPS5128633B2 (da) |
| CA (1) | CA980780A (da) |
| DE (1) | DE2316641C3 (da) |
| DK (1) | DK156659C (da) |
| FR (1) | FR2183008B1 (da) |
| GB (1) | GB1365849A (da) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3868379A (en) * | 1972-04-28 | 1975-02-25 | Warner Lambert Co | Heterocyclic amides of 4-hydroxy-2H-1-benzothiopyran-3-carboxylic acid 1,1-dioxide |
| US3835156A (en) * | 1973-03-23 | 1974-09-10 | Warner Lambert Co | Acyl derivatives of 4-hydroxy-2h-1-benzothiopyran-3-carboxamide 1,1-dioxide |
| US3878198A (en) * | 1974-04-26 | 1975-04-15 | Warner Lambert Co | {62 -Ketoacyl derivatives of 6-aminopenicillanic acid and process thereof |
| US4166126A (en) * | 1974-09-26 | 1979-08-28 | Ciba-Geigy Corporation | 1-benzothiepin-4-carboxamides |
| US4226998A (en) * | 1974-09-26 | 1980-10-07 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxamides |
| US4242266A (en) * | 1974-09-26 | 1980-12-30 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxylic acid derivatives |
| SE420725B (sv) * | 1974-09-26 | 1981-10-26 | Ciba Geigy Ag | Sett att framstella 2,3-dihydro-1-benstiepin-4-karboxylsyraamider |
| US4074048A (en) * | 1976-05-10 | 1978-02-14 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides |
| US4329357A (en) * | 1980-02-08 | 1982-05-11 | Ciba-Geigy Corporation | 1-Benzothiepin-4-carboxyamides |
| SG186430A1 (en) * | 2010-07-09 | 2013-01-30 | Active Biotech Ab | Method for manufacturing of quinoline-3-carboxamides |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK132629B (da) * | 1971-07-15 | 1976-01-12 | Warner Lambert Co | Analogifremgangsmade til fremstilling af 4-hydroxy-2h-1-benzothiopyran-3-carboxamid-1,1-dioxider |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3591584A (en) * | 1968-08-27 | 1971-07-06 | Pfizer | Benzothiazine dioxides |
-
1972
- 1972-04-28 US US00248509A patent/US3769292A/en not_active Expired - Lifetime
-
1973
- 1973-04-03 DE DE2316641A patent/DE2316641C3/de not_active Expired
- 1973-04-04 GB GB1604373A patent/GB1365849A/en not_active Expired
- 1973-04-12 DK DK201673A patent/DK156659C/da not_active IP Right Cessation
- 1973-04-24 FR FR7314821A patent/FR2183008B1/fr not_active Expired
- 1973-04-27 CA CA169,747A patent/CA980780A/en not_active Expired
- 1973-04-27 JP JP48047340A patent/JPS5128633B2/ja not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK132629B (da) * | 1971-07-15 | 1976-01-12 | Warner Lambert Co | Analogifremgangsmade til fremstilling af 4-hydroxy-2h-1-benzothiopyran-3-carboxamid-1,1-dioxider |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1365849A (en) | 1974-09-04 |
| DK156659C (da) | 1990-02-05 |
| US3769292A (en) | 1973-10-30 |
| FR2183008B1 (da) | 1976-12-31 |
| AU5376473A (en) | 1974-09-26 |
| CA980780A (en) | 1975-12-30 |
| DE2316641B2 (de) | 1980-01-17 |
| FR2183008A1 (da) | 1973-12-14 |
| DE2316641C3 (de) | 1980-09-11 |
| DE2316641A1 (de) | 1973-11-08 |
| JPS5128633B2 (da) | 1976-08-20 |
| JPS4947375A (da) | 1974-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2423351C2 (ru) | Пирид-2-оны, применимые как ингибиторы протеинкиназ семейства тес для лечения воспалительных, пролиферативных и иммунологически-опосредованных заболеваний | |
| CA2762680C (en) | Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics | |
| JP6281952B2 (ja) | Ｈｉｖ複製阻害剤 | |
| CN112513042B (zh) | 多环氨基甲酰基吡啶酮衍生物 | |
| JPH01216974A (ja) | 置換ピリジン類 | |
| CA1334972C (en) | Pyridine-2,4- and -2,5-dicarboxylic acid amides, processes for their preparation, the use thereof, and medicaments based on these compounds | |
| RU2125565C1 (ru) | Производные фенокси- или феноксиалкилпиперидина и антивирусная композиция на их основе | |
| JP2024156867A (ja) | マトリプターゼ２阻害剤及びその使用 | |
| JP2007519735A (ja) | Ｈｉｖインテグラーゼ阻害剤として有用であるｎ−ベンジル−３，４−ジヒドロキシピリジン−２−カルボキサミド及びｎ−ベンジル−２，３−ジヒドロキシピリジン−４−カルボキサミド化合物 | |
| CZ293392A3 (en) | Leucotriene biosynthesis inhibitors | |
| JP7402170B2 (ja) | Ｔｌｒ２シグナル伝達の調節剤としての化合物 | |
| DK156659B (da) | Analogifremgangsmaade til fremstilling af heterocycliske amider af 4-hydroxy-2h-1-benzothiopyran-3-carboxylsyre-1,1-dioxid | |
| PT605228E (pt) | Derivados tiazolidinadionas sua preparacao e sua utilizacao | |
| JPWO2017006953A1 (ja) | ＴｒｋＡ阻害活性を有する複素環誘導体 | |
| CN116507607A (zh) | 作为tlr信号传导调节剂的化合物和组合物 | |
| KR20060006850A (ko) | 아릴-헤테로방향족 생성물, 이를 함유하는 조성물 및 이의용도 | |
| JP6579549B2 (ja) | Ｈｉｖ複製阻害作用を有する３環性複素環誘導体 | |
| WO2001029035A1 (en) | 4-oxoquinolizine antimicrobials having 2-pyridone skeletons as the partial structure | |
| WO2021127302A1 (en) | 2-(1h-indole-3-carbonyl)-thiazole-4-carboxamide derivatives and related compounds as aryl hydrocarbon receptor (ahr) agonists for the treatment of e.g. angiogenesis implicated or inflammatory disorders | |
| DE3601143C2 (de) | Cyclische Imidderivate von 2-(4-Butylpiperazin-1-yl)-pyridinen, Verfahren zu deren Herstellung und diese Verbindungen enthaltende pharmazeutische Mittel | |
| MX2012005189A (es) | Inhibidores de ire-1-alfa. | |
| US3816446A (en) | (alpha-(3-trifluoromethylphenoxy)-4-chlorobenzyl)heterocycles | |
| IL294092A (en) | 4-phenyl-n-(phenyl)thiazol-2-amine derivatives and related compounds as aryl hydrocarbon receptor (ahr) agonists for the treatment of e.g. angiogenesis implicated or inflammatory disorders | |
| JPH0378854B2 (da) | ||
| JPS58110585A (ja) | イミダゾ（４，５−ｃ）ピリジン化合物これらの化合物を含有する医薬製剤およびそれらの製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |