CS274344B1 - Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation - Google Patents
Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation Download PDFInfo
- Publication number
- CS274344B1 CS274344B1 CS479389A CS479389A CS274344B1 CS 274344 B1 CS274344 B1 CS 274344B1 CS 479389 A CS479389 A CS 479389A CS 479389 A CS479389 A CS 479389A CS 274344 B1 CS274344 B1 CS 274344B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- propionic acid
- preparation
- propylthio
- phenyl
- substance
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims abstract description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title 1
- 235000019260 propionic acid Nutrition 0.000 title 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 title 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 8
- HLWUKJUOPQJDOL-UHFFFAOYSA-N 2-(4-sulfanylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(S)C=C1 HLWUKJUOPQJDOL-UHFFFAOYSA-N 0.000 claims abstract description 4
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 4
- ROMJDXPPIZDMLO-UHFFFAOYSA-N 2-(4-propan-2-ylsulfanylphenyl)propanoic acid Chemical compound CC(C)SC1=CC=C(C(C)C(O)=O)C=C1 ROMJDXPPIZDMLO-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000009835 boiling Methods 0.000 claims abstract 2
- 230000000202 analgesic effect Effects 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 abstract description 5
- 229960001680 ibuprofen Drugs 0.000 abstract description 5
- 241000699670 Mus sp. Species 0.000 abstract description 3
- 231100000420 gastrotoxicity Toxicity 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 230000001741 anti-phlogistic effect Effects 0.000 abstract 2
- 230000007059 acute toxicity Effects 0.000 abstract 1
- 231100000403 acute toxicity Toxicity 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 238000001050 pharmacotherapy Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- -1 4- (2-propylthio) phenyl Chemical group 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Vynález se vzorce I týká způsobu přípravy kyseliny 2-(4-(2-propylthio)fenyl)propionová Co^fThe invention of the formula I a process for preparing 2- (4- (2-propylthio) phenyl) propionic Co ^ f
Kyselina vzorce I podle vynálezu se vyznačuje protízánětlivou účinností v několika modelech zánětu a dále účinností analgetickou.The acid of formula I according to the invention has anti-inflammatory activity in several models of inflammation and analgesic activity.
Literatura (Adams S. S. et al., □.Pharm. Sci. 56, 1686 (1967); Arch, Int. Pharmacodyn. Ther. 178, 115 (1969) uvádí látku podobné struktury II,The literature (Adams S.S. et al., Pharm. Sci. 56, 1686 (1967); Arch. Int. Pharmacodyn. Ther. 178, 115 (1969) discloses a compound of similar structure II,
COO}} ch3 (IIb která je známá pod geherickým označením ibuprofen. Také ibuprofen má protizánětlivou a analgetickou účinnost a doznal ve farmakotherapeutické praxi velkého rozšini a těší se značné oblibě u pacientů trpících bolestmi kloubů na basi arthritických onemocnění.COO}} ch 3 (II b), known under the geo-brand ibuprofen. Also ibuprofen has anti-inflammatory and analgesic efficacy and has been widely used in pharmacotherapeutic practice and enjoys great popularity in patients suffering from arthritic joint pain.
Látka vzorce I byla s ibuprofenem srovnána v řadě testů na hlodavcích a byla shledána rovnocennou, pokud Jde o protizánětlivý účinek 8 výhodnější z hlediska toxicity a analgetické účinnosti, jak je to doloženo následujícími výsledky:The compound of formula I has been compared with ibuprofen in a number of rodent tests and has been found to be equivalent to an anti-inflammatory effect 8 in terms of toxicity and analgesic efficacy, as evidenced by the following results:
(a) Akutní orální toxicita u myši, LD5Q v mg/kg: I, 2 240; II, 1 350.(a) Acute oral toxicity in mice, LD 50 in mg / kg: 1,240; II, 1350.
(b) Gastrotoxicita u krys (Robert A., Nezamis □. E., Proč-Soc.Exp. Biol. Med. 99, 443 (1958)), uvedeny orálni dávky v mg/kg a hodnoty ulcerogenního indexul(b) Gastrotoxicity in rats (Robert A., Nezamis E.E., Proc-Soc.Exp. Biol. Med. 99, 443 (1958)) reported oral doses in mg / kg and ulcerogenic index values
I, 50, 97,5; 100, 270; 200, 300I, 50, 97.5; 100, 270; 200, 300
II, 50, 208; 100, 233; 200, 300 (c) Protizánětlivá aktivita u krys při použiti karragaeninového modelového zánětu; jsou uvedena procenta inhibice zánětu při použiti dávky 100 mg/kg p. o. :II, 50, 208; 100, 233; 200, 300 (c) Anti-inflammatory activity in rats using a carragaenine model inflammation; the percent inhibition of inflammation at 100 mg / kg p.o. is given:
I 58 (statisticky významné)I 58 (statistically significant)
II, 55 (statisticky významné) (d) Protizánětlivá aktivita u krys při použiti kaolinového modelového záoětu;II, 55 (statistically significant) (d) Anti-inflammatory activity in rats using kaolin model inflammation;
Jsou uvedena procenta inhibice zánětu při použiti dávky 100 mg/kg p. o. :The percent inhibition of inflammation at a dose of 100 mg / kg p.o. is given:
I, 40 (statisticky významné)I, 40 (statistically significant)
II, 40 (statisticky významné) (e) Protizánětlivá aktivita u krys při použiti adjuvantniho otoku zadni končetiny jako modelu zánětu; jsou uvedena procenta inhibice zánětu při použití dávkyII, 40 (statistically significant) (e) Anti-inflammatory activity in rats using adjuvant hindlimb swelling as an inflammatory model; the percent inhibition of inflammation at the dose is indicated
100 mg/kg p. o. :100 mg / kg p.o.
I, 35 (statisticky významné)I, 35 (statistically significant)
CS 274 344 BlCS 274 344 Bl
II, 55 (statisticky významné) (f) Analgetická účinnost u myší v testu intraperitoneálnlho drážděni, ED50 v m9/'<9 P. o. ·II, 55 (statistically significant) (f) Analgesic efficacy in mice in the intraperitoneal irritation test, ED 50 at m 9 / < 9 P. o ·
I, 82; II, 170.I, 82; II, 170.
(g) Analgetická účinnost u krys v testu zánětlivé hyperelgesie (algesimetr) vyjádřená v procentech inhibice bolesti po podání dávek 150 mg/kg p. o. :(g) Analgesic efficacy in rats in an inflammatory hyperelgesia test (algesimeter), expressed as a percentage of pain inhibition after 150 mg / kg p.o.
I, 37; II, 45 (obě hodnoty statisticky významné) (h) Analgetická účinnost u krys v testu tlakové analgesie po podáni orálních dávek 200 mg/kg p. o. : účinnost je vyjádřena v procentech zvýšeni prahu bolesti oproti neléčené kontrolní skupině v intervalech 1 h a 3 h po podání:I, 37; II, 45 (both statistically significant) (h) Analgesic efficacy in rats in a pressure analgesia test after oral dosing of 200 mg / kg po: efficacy is expressed as a percentage of increase in pain threshold versus untreated control group at 1 h and 3 h after administration :
I, 129 %, 87 %; II, 100 %, 81 %I, 129%, 87%; II, 100%, 81%
Látke vzorce I podle vynálezu má tedy určité výhody ve srovnání s ibuprofenem (II). Látka vzorce I je po chemické stránce nová, tj. nikdy nebyla popsána jako charakterizovaná substance. Nelze ji však chránit látkově, protože byla zahrnuta do obecného vzorce v předmětu GB patentu č. 1 012 480. Vztahuji se na ni tedy i možnosti přípravy v citovaném patentu uvedené pro látky analogické.Thus, the compound of formula I of the invention has certain advantages over ibuprofen (II). The compound of formula I is new in chemical terms, ie it has never been described as a characterized substance. However, it cannot be protected by substance because it has been included in the general formula in GB patent No. 1 012 480. Therefore, it also extends to the preparation possibilities given in the cited patent for analogous substances.
Nyni bylo zjištěno, že látku vzorce I lze připravit způsobem, který neni uveden ani Jeko možnost v popisu a nárocích citovaného patentu. Tento způsob spočívá v reakci známé kyseliny 2-(4-merkaptofenyl)propionové (Fr. MS,444, Addn. 0296) vzorceIt has now been found that the compound of formula (I) may be prepared in a manner that is not mentioned in the specification and claims of the cited patent. This process consists in reacting the known 2- (4-mercaptophenyl) propionic acid (Fr. MS, 444, Addn. 0296) of the formula
III.III.
(III), s 2-brompropanem v dimethylformamidu při teplotách 50 až 80 °C za přítomnosti uhličitanu draselného a v následujíc! hydrolýze vzniklého a necharakterizovaného meziproduktu hydroxidem sodným ve vodném ethanolu. Kyselina vzorce I vzniká tímto způsobem v dobrém výtěžku a jedinou krystalizaci z petroletheru ji lze ziskat v čistém stavu. Ději identita byla zajištěna jednak analyticky, jednak pomocí spekter (IČ, NMR). De to krystalická látka tajici při 66 až 67 °C. Podrobnosti způsobu přípravy, kzerý je předmětem vynálezu, uvádi přiklad, který je znázorněn možnosti přípravy látky vzorce I podle vynálezu.(III), with 2-bromopropane in dimethylformamide at temperatures of 50-80 ° C in the presence of potassium carbonate and in the following steps: hydrolysis of the formed and uncharacterized intermediate with sodium hydroxide in aqueous ethanol. The acid of formula (I) is formed in this manner in good yield and can be obtained in a pure state by a single crystallization from petroleum ether. The identity was ensured both analytically and by spectra (IR, NMR). De to crystalline substance melting at 66-67 ° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention illustrates the preparation of the compound of formula (I) according to the invention.
Směs 25,5 g kyseliny 2-(4-merkaptofenyl)propionové, 38 g uhličitanu draselného, 34,4 g 2-brompropanu a 100 ml dimethylformamidu se míchá a zahřívá 5 hodin na 60 °C.A mixture of 25.5 g of 2- (4-mercaptophenyl) propionic acid, 38 g of potassium carbonate, 34.4 g of 2-bromopropane and 100 ml of dimethylformamide is stirred and heated at 60 ° C for 5 hours.
Po ochlazeni se směs zředi 200 ml vody, vyloučený meziprodukt se extrahuje benzenem a extrakt se zpracuje. Odpařením získaný zbytek (30,4 g) se rozpustí v 50 ml ethanolu, přidá se roztok 30 g hydroxidu sodného ve 100 ml vody a směs se voři 5,5 hodinyAfter cooling, the mixture is diluted with 200 ml of water, the precipitated intermediate is extracted with benzene and the extract is worked up. The residue obtained by evaporation (30.4 g) is dissolved in 50 ml of ethanol, a solution of 30 g of sodium hydroxide in 100 ml of water is added and the mixture is boiled for 5.5 hours.
CS 274 344 Bl pod zpětným chladičem. Ethsnol se odpaří, zbytek se rozpusti ve 400 ml vody, roztok se promyje benzenem a okyselí se kyselinou chlorovodíkovou. Vyloučený produkt se izoluje extrakci benzenem a získá se jeho odpařenímj 22 g (70 %), t, t. 56 až 63 °C. Krystalizací z petroletheru se získá čistá látka, tj, kyselina vzorce I, tající při 66 až 67 °C.CS 274 344 B1 under reflux condenser. The ethanol is evaporated, the residue is dissolved in 400 ml of water, the solution is washed with benzene and acidified with hydrochloric acid. The precipitated product is isolated by extraction with benzene and is obtained by evaporating it to 22 g (70%), mp 56-63 ° C. Crystallization from petroleum ether gave the pure product, i.e. the acid of formula I, melting at 66-67 ° C.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS479389A CS274344B1 (en) | 1989-08-14 | 1989-08-14 | Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS479389A CS274344B1 (en) | 1989-08-14 | 1989-08-14 | Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS479389A1 CS479389A1 (en) | 1990-09-12 |
| CS274344B1 true CS274344B1 (en) | 1991-04-11 |
Family
ID=5391488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS479389A CS274344B1 (en) | 1989-08-14 | 1989-08-14 | Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS274344B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2136018A1 (en) * | 1997-06-17 | 1999-11-01 | Menarini Lab | Cyclooxygenase-i selective inhibitors and the use thereof as analgesic, antiinflammatory and antiarthritic agents |
-
1989
- 1989-08-14 CS CS479389A patent/CS274344B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2136018A1 (en) * | 1997-06-17 | 1999-11-01 | Menarini Lab | Cyclooxygenase-i selective inhibitors and the use thereof as analgesic, antiinflammatory and antiarthritic agents |
Also Published As
| Publication number | Publication date |
|---|---|
| CS479389A1 (en) | 1990-09-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HU178015B (en) | Process for preparing new 5-methyl-isoxazola-4-carboxylic acid-/4-trifluoromethyl/-anilide | |
| JPH02292272A (en) | New naphthalenylalkyl-3h-1,2,3,5-oxathiadiazole 2-oxide useful as antihyperglycemia agent | |
| JPS582936B2 (en) | 5↓-Production method of aroylpyrroleacetic acid and its salts | |
| JPH024235B2 (en) | ||
| JPS5811850B2 (en) | 1-oxo-2,2-dithicane-5-indanyloxy | |
| JPS646191B2 (en) | ||
| US3766263A (en) | Substituted 2-phenoxyphenylacetic acids | |
| CA1339687E (en) | Indole derivatives, processes for their preparation, and their use as medicaments | |
| NO174848B (en) | Analogous Process for Preparing Therapeutically Active Substitutes | |
| US4272507A (en) | Phenylaminothiophenacetic acids, their synthesis, compositions and use | |
| US3394181A (en) | Phenoxy-lower-alkyl-amidoximes and phenylamino-lower-alkyl-amidoximes | |
| JPH033658B2 (en) | ||
| US4251543A (en) | 2-(p-Prenylphenyl)propionic acid | |
| CS274344B1 (en) | Method of 2-/4-(2-propylthio)phenyl/propionic acid's preparation | |
| US4473583A (en) | Compositions containing certain derivatives of 4-phenyl-4-oxobuten-2-oic acid and methods of treatment using them | |
| EP0588797B1 (en) | N- 4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl]carbonyl]amino acids useful in the therapy of osteoarticular affections | |
| US4080380A (en) | 2-Naphthyl-lower-alkylamines | |
| US4116972A (en) | Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation | |
| US4362891A (en) | Alkanoic acid derivatives | |
| DK155936B (en) | METHOD OF ANALOGY FOR THE PREPARATION OF 2-AMINO-3- (HALOGENBENZOYL) -METHYLPHENYL ACID ACID ACIDS OR ALKYL ESTERS OR METAL SALTS THEREOF | |
| JPS6044304B2 (en) | Method for producing phenylpropionic acid derivatives | |
| Cohen et al. | The interaction of p-phenolate ions with side-chain electrophiles | |
| US3845215A (en) | Phenylalkane derivatives in the treatment of inflammation | |
| US4161533A (en) | 5-Sulfamoyl-orthanilic acids and process for their preparation | |
| US4126625A (en) | Certain 5-substituted-3-methyl-2-benzofuran acetic acids |