FI72316B - PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVATED N2-ARYL SULPHONYL-L-ARGININAMIDER AND PHARMACEUTICAL ACCEPTABLE SALTER DAERAV - Google Patents
PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVATED N2-ARYL SULPHONYL-L-ARGININAMIDER AND PHARMACEUTICAL ACCEPTABLE SALTER DAERAV Download PDFInfo
- Publication number
- FI72316B FI72316B FI780073A FI780073A FI72316B FI 72316 B FI72316 B FI 72316B FI 780073 A FI780073 A FI 780073A FI 780073 A FI780073 A FI 780073A FI 72316 B FI72316 B FI 72316B
- Authority
- FI
- Finland
- Prior art keywords
- substituted
- arylsulfonyl
- group
- acid
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title claims description 9
- 241000277284 Salvelinus fontinalis Species 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 34
- -1 methoxy, ethoxy, hydroxy Chemical group 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 23
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- 239000001257 hydrogen Substances 0.000 claims description 15
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
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- 239000002253 acid Substances 0.000 claims description 12
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- 125000001424 substituent group Chemical group 0.000 claims description 11
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- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
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- 125000000850 2H-chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 2
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- 238000009835 boiling Methods 0.000 claims description 2
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- 238000006243 chemical reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
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- 235000014852 L-arginine Nutrition 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
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- 231100000053 low toxicity Toxicity 0.000 description 3
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- 239000000835 fiber Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- QPJSUIGXIBEQAC-UHFFFAOYSA-N n-(2,4-dichloro-5-propan-2-yloxyphenyl)acetamide Chemical compound CC(C)OC1=CC(NC(C)=O)=C(Cl)C=C1Cl QPJSUIGXIBEQAC-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004932 phenoxathinyl group Chemical group 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical class OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 239000004066 vascular targeting agent Substances 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
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- C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
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- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
7231 6 27231 6 2
Menetelmä farmaseuttisesti aktiivisten, N -aryylisulfonyyli-L-arginiini-amidien ja niiden farmaseuttisesti hyväksyttävien suolojen valmistamiseksi -Förfarande för framställning av f^rmaceutiskt aktiva N -arylsyifonyl-L-argininamider och farmaceutiskt acceptabla salter däravProcess for the preparation of pharmaceutically active N-arylsulfonyl-L-arginine amides and their pharmaceutically acceptable salts - For the preparation of pharmaceutically active N-arylsulfonyl-L-argininamides and pharmaceutically acceptable salts thereof
Esillä oleva keksintö koskee menetelmää määrättyjen uusien N -aryylisulfonyyli-L-arginiiniamidien ja niiden farmaseuttisesti hyväksyttävien suolojen valmistamiseksi, joilla yhdisteillä on erikoista arvoa johtuen niiden erinomaisista verisuonitukoksia estävistä ominaisuuksista ja alhaisesta myrkyllisyydestä.The present invention relates to a process for the preparation of certain novel N-arylsulfonyl-L-argininamides and their pharmaceutically acceptable salts, which compounds are of particular value due to their excellent anticoagulant properties and low toxicity.
Tähän asti on tehty useita yrityksiä uusien ja parempien ai- 2 neiden saamiseksi verisuonitukosten käsittelemiseksi. N -(p-tolyylisulfonyyli)-L-arginiiniesterit on todettu sellaisiksi aineiksi, joita voidaan käyttää tähän tarkoitukseen ja niiden on todettu tehokkaasti liuottavan verihyytymiä (ks. US-patenttijulkaisua n:o 3 622 615). Eräs yhdisteryhmä, joka on todettu erittäin käyttökelpoiseksi spesifisenä veri- 2 suonitukoksia estävänä aineena, on N -dansyyli-L-arginiini- esteri tai -amidi (US-patenttijulkaisu n:o 3 978 045). Li- 2 säksi tunnetaan DE-hakemusjulkaisusta 2 550 088 N -naftyyli-sulfonyyli-L-arginiiniestereitä ja -amideja, jotka ovat hyvin spesifisiä verisuonitukoksia estäviä aineita.To date, several attempts have been made to obtain new and better agents for the treatment of vascular thrombosis. N- (p-tolylsulfonyl) -L-arginine esters have been identified as substances that can be used for this purpose and have been found to be effective in dissolving blood clots (see U.S. Patent No. 3,622,615). One class of compounds that has been found to be very useful as a specific anti-thrombotic agent is N-dansyl-L-arginine ester or amide (U.S. Patent No. 3,978,045). In addition, N-naphthylsulfonyl-L-arginine esters and amides are known from DE-A-2,550,088, which are very specific anti-thrombotic agents.
2 723162,72316
Kuitenkin tarvitaan jatkuvasti erittäin spesifisiä verisuoni- tukoksia estäviä aineita, joilla on alhainen myrkyllisyys.However, there is a continuing need for highly specific anti-vascular agents with low toxicity.
22
Nyt on todettu, että tietyillä uusilla N -aryylisulfonyyli-L-arginiini-amideilla on verisuonitukoksia estävä aktiivisuus ja alhaisempi myrkyllisyys kuin em. julkaisuista US-3 978 045 ja DE-2 550 088 tunnetuilla yhdisteillä käytettäessä yhtä tehokkaita määriä kuten jäljempänä esitetystä selityksestä ilmenee.It has now been found that certain novel N-arylsulfonyl-L-arginine amides have anticoagulant activity and lower toxicity than the compounds known from the above-mentioned US-3,978,045 and DE-2,550,088 when used in equally effective amounts as will be apparent from the description below.
Esillä oleva keksintö koskee menetelmää uuden farmaseutti- 2 sesti aktiivisen N -aryylisulfonyyli-L-arginiiniamidin tai sen farmaseuttisesti hyväksyttävän suolan valmistamiseksi, jolla yhdisteellä on kaava (I): C - N - CHoCH_CH„CHC0R (I) I 2 2 2| H_N ^ H HNS0o 2 t 2The present invention relates to a process for the preparation of a novel pharmaceutically active N-arylsulfonyl-L-argininamide or a pharmaceutically acceptable salt thereof, which has the formula (I): C - N - CHoCH_CH 2 CHCO (I) I 2 2 2 | H_N ^ H HNS0o 2 t 2
Ar jossa R on (1) COOR, :r? (RC ) _ d m jossa Rg on vety tai -C^-alkyyli, kukin R^ on vety tai C^-C4-alkyyli ja m on kokonaisluku 0-2, jolloin R^ voi olla 4- tai 6-asemassa; taiAr where R is (1) COOR,: r? (RC) -D m wherein R 9 is hydrogen or -C 1-4 alkyl, each R 6 is hydrogen or C 1 -C 4 alkyl and m is an integer from 0 to 2, wherein R 6 may be in the 4- or 6-position; or
(2) COOH(2) COOH
Ό tai 7231 6 3Ό or 7231 6 3
(3) COOH(3) COOH
-N 0 tai-N 0 or
(4) COOH(4) COOH
-Nio ja Ar on fenyyliryhmä, joka on substituoitu vähintään yhdellä substituentilla, jona on amino, -Cg-alkyyliamino, hydroksialkyyli, C^-C^g-fenyylialkyyli tai -C^-hydroksi-alkoksi; tax-N 10 and Ar is a phenyl group substituted with at least one substituent selected from amino, -C 1-6 alkylamino, hydroxyalkyl, C 1-6 C 1-6 phenylalkyl or -C 1-6 hydroxyalkoxy; tax
Ar on fenyyliryhmä, joka on substituoitu vähintään yhdellä substituentilla, jona on hydroksi, C1-C,-alkyyli tai C..-C -alkoksi, ja vähintään yhdellä substituentilla, jona on C2-Cg-alkyylikarbonyyli tai fenyyli; taiAr is a phenyl group substituted with at least one substituent selected from hydroxy, C 1 -C 4 alkyl or C 1 -C 6 alkoxy, and at least one substituent selected from C 2 -C 8 alkylcarbonyl or phenyl; or
Ar on dibentsotienyyli-, 9,9-dioksodibentsotienyyli-, fenoksati'inyyli-, kinolyyli-, ftalatsinyyli-, fenatsinyyli-tai akridinyyliryhmä, joista kukin on substituoimaton tai substituoitu yhdellä tai useammalla hydroksi-, C^-C^-alkoksi-tai C^-C^-alkyyliryhmällä; taiAr is a dibenzothienyl, 9,9-dioxodibenzothienyl, phenoxathinyl, quinolyl, phthalazinyl, phenazinyl or acridinyl group, each of which is unsubstituted or substituted by one or more hydroxy, C 1 -C 4 alkoxy or C ^ -C ^ alkyl group; or
Ar on Cg-C^g-sykloalkyylifenyyli-, fluorenyyli-, tioksantenyyli-tai 2H-kromenyyliryhmä, joista kukin on substituoimaton tai substituoitu yhdellä tai useammalla -Cg-alkyyli-, C^-Cg-alkoksi- tai oksoryhmällä; taiAr is a C 8 -C 6 cycloalkylphenyl, fluorenyl, thioxanthenyl or 2H-chromenyl group, each of which is unsubstituted or substituted by one or more C 1 -C 6 alkyl, C 1 -C 6 alkoxy or oxo groups; or
Ar on fenyyliryhmä, joka on substituoitu vähintään yhdellä substituentilla, jona on C1-C4~haloalkoksi- tai C2-C7~ alkoksialkoksiryhmä ja mahdollisesti substituoitu fenyyli-ryhmä on substituoitu edelleen vähintään yhdellä substituentilla, jona on metyyli, etyyli, metoksi, etoksi, hydroksi tai halogeeni.Ar is a phenyl group substituted with at least one substituent which is a C1-C4 haloalkoxy or C2-C7 alkoxyalkoxy group and an optionally substituted phenyl group is further substituted with at least one substituent selected from methyl, ethyl, methoxy, ethoxy, hydroxy or halogen.
7231 67231 6
Ryhmän R kaavassa (1) ryhmä Rg on esimerkiksi vety, metyyli, etyyli, propyyli, butyyli tai tert-butyyli ja kukin R^ on erikseen esimerkiksi vety, metyyli, etyyli, propyyli, iso-propyyli tai butyyli.In the formula (1) of the group R, the group R 8 is, for example, hydrogen, methyl, ethyl, propyl, butyl or tert-butyl, and each R 1 is separately, for example, hydrogen, methyl, ethyl, propyl, iso-propyl or butyl.
Tyypillisiä kaavan I mukaisia yhdisteitä ovat mm. seuraavat: 1-/N -(kinoliini-8-sulfonyyli)-L-arginyyli7-4-metyyli-2-pipe-ridiinikarboksyylihappo, 1-/N -(3-metyylikinoliini-8-sulfonyyli)-L-arginyyli/-4-metyyli-2-piperidiinikarboksyylihappo, 1- /N -(3-etyylikinoliini-8-sulfonyyli)-L-arginyyli7~4-metyyli- 2- piperidiinikarboksyylihappo, _ o 1-/N -(4-metoksi-3-sykloheksyylibentseeni-1-sulfonyyli)-L-arginyyli7~4-metyyli-2-piperidiinikarboksyylihappo, ja näiden yhdisteiden farmaseuttisesti hyväksyttävät suolat.Typical compounds of formula I include e.g. the following: 1- [N- (quinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, 1- [N- (3-methylquinoline-8-sulfonyl) -L-arginyl] -4 -methyl-2-piperidinecarboxylic acid, 1- [N- (3-ethylquinoline-8-sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid, 1- [N- (4-methoxy-3-cyclohexylbenzene) 1-sulfonyl) -L-arginyl--4-methyl-2-piperidinecarboxylic acid, and pharmaceutically acceptable salts of these compounds.
Kaavan (I) mukaisia yhdisteitä voidaan valmistaa siten, että G G 2 a) N -substituentti poistetaan N -substituoidusta N -aryyli- sulfonyyli-L-arginiiniamidista, jolla on kaava:Compounds of formula (I) may be prepared by removing the G G 2 a) N substituent from an N-substituted N-arylsulphonyl-L-argininamide of formula:
HNHN
X.X.
C - N - CH,CH,CH.,CHCOR (XX) ^ I 2 2 2| HN R" HNS0o I I 2 R' Ar jossa R ja Ar on määritelty edellä, R' ja R" ovat vety tai guanidinoryhmän suojaryhmä, ja ainakin toinen ryhmistä R' ja R" on guanidinoryhmän suojaryhmä, happohydrolysoimalla tai hydraamalla ja haluttaessa hydrolysoidaan näin saatu reaktiotuote, tai 2 b) N -aryylisulfonyyli-L-arginyylihalogenidi, jolla on kaavaC - N - CH, CH, CH., CHCOR (XX) ^ I 2 2 2 | HN R "HNSO II II R 'Ar wherein R and Ar are as defined above, R' and R" are hydrogen or a guanidino group protecting group, and at least one of R 'and R "is a guanidino group protecting group, by acid hydrolysis or hydrogenation and, if desired, hydrolysis of the reaction product thus obtained. , or 2 b) N-arylsulfonyl-L-arginyl halide of formula
MJMJ
XX
C - N - CH.CH.CH.CHCOX (XXII)C - N - CH.CH.CH.CHCOX (XXII)
/ I 2 2 2I/ I 2 2 2I
H„N H HNSO-, 2 I 2H „N H HNSO-, 2 I 2
ArAr
IIII
7231 6 jossa Ar on määritelty edellä ja X on halogeeni, saatetaan reagoimaan aminohappojohdannaisen kanssa, jolla on kaava RH (IV) jossa R on määritelty edellä, ja haluttaessa hydrolysoidaan saatu reaktiotuote, ja haluttaessa saatu kaavan I mukainen yhdiste muutetaan farmaseuttisesti hyväksyttäväksi suolaksi.7231 6 wherein Ar is as defined above and X is halogen is reacted with an amino acid derivative of formula RH (IV) wherein R is as defined above and, if desired, hydrolyzing the resulting reaction product, and if desired, converting the resulting compound of formula I into a pharmaceutically acceptable salt.
Menetelmässä a) happohydrolyysi toteutetaan yleensä saatta-G 2 maila N -substituoitu N -aryylisulfonyyli-L-arginiiniamidi (XX) ja happoylimäärä, esim. fluorivety-, kloorivety-, bromi-vety- tai trifluorietikkahappo kosketuksiin keskenään ilman liuotinta tai liuottimessa, kuten eetterissä (tetrahydrofu-raani, dioksaani), alkoholissa (metanoli, etanoli) tai etik-kahapossa lämpötilassa välillä -10 ja 100°C, edullisesti 10-60°C, ja vielä edullisemmin huoneen lämpötilassa 30 minuutin ja 24 tunnin välisen ajan. Tuotteet erotetaan haihduttamalla liuotin ja ylimääräinen happo tai hankaamalla sopivan liuottimen kanssa, jota seuraa suodattaminen ja kuivaaminen.In process a) the acid hydrolysis is generally carried out by contacting G-2 N-substituted N -arylsulfonyl-L-argininamide (XX) and an excess of acid, e.g. hydrofluoric, hydrochloric, hydrobromic or trifluoroacetic acid, without solvent or in a solvent such as ether. (tetrahydrofuran, dioxane), alcohol (methanol, ethanol) or acetic acid at a temperature between -10 and 100 ° C, preferably 10-60 ° C, and even more preferably at room temperature for 30 minutes to 24 hours. The products are separated by evaporation of the solvent and excess acid or by trituration with a suitable solvent, followed by filtration and drying.
Johtuen ylimääräisen hapon käytöstä ovat tuotteet yleensä 2 N -aryylisulfonyyli-L-arginiiniamidien (I) happoadditio-suoloja, jotka voidaan muuttaa helposti neutraloimalla vapaaksi amidiksi.Due to the use of excess acid, the products are generally acid addition salts of 2 N -arylsulfonyl-L-argininamides (I) which can be readily converted to the free amide by neutralization.
Nitroryhmän ja oksikarbonyyliryhmän, esim. bentsyylioksi-karbonyyliryhmän ja p-nitrobentsyylioksikarbonyyliryhmän , poistaminen toteutetaan helposti hydraamalla.Removal of the nitro group and the oxycarbonyl group, e.g., the benzyloxycarbonyl group and the p-nitrobenzyloxycarbonyl group, is easily accomplished by hydrogenation.
Samanaikaisesti muutetaan bentsyyliesteriryhmä, joka voi sisältyä R-ryhmään, karboksyyliryhmäksi hydrauksella .At the same time, the benzyl ester group which may be included in the R group is converted into a carboxyl group by hydrogenation.
Hydraus toteutetaan inertissä reaktioliuottimessa, esim. metanolissa, etanolissa, tetrahydrofuraanissa tai dioksaa- 7231 6 nissa, vedyllä aktivoidun katalyytin, esim. Raney-nikkelin, palladiumin tai platinan, läsnäollessa vetykehässä lämpötilassa, joka on 0°C ja liuottimen kiehumispisteen välillä ja edullisesti 10-80°C, 2-120 tunnin kuluessa.The hydrogenation is carried out in an inert reaction solvent, e.g. methanol, ethanol, tetrahydrofuran or dioxane, in the presence of a hydrogen-activated catalyst, e.g. Raney nickel, palladium or platinum, in a hydrogen atmosphere at a temperature between 0 ° C and the boiling point of the solvent, and preferably 10 ° C. 80 ° C, within 2-120 hours.
Vedyn paine ei ole kriittinen ja ilmakehän paine on riittävä. 2 N -aryylisulfonyyli-L-arginiiniamidit (I) erotetaan suodattamalla katalyytti, jota seuraa liuottimen haihduttaminen.Hydrogen pressure is not critical and atmospheric pressure is sufficient. The 2 N-arylsulfonyl-L-argininamides (I) are separated by filtration of the catalyst, followed by evaporation of the solvent.
2 N -aryylisulfonyyli-L-arginiiniamidit (I) voidaan puhdistaa trituoimalla tai kiteyttämällä uudelleen sopivasta liuotti-mesta, kuten dietyylieetteri-tetrahydrofuraanista, dietyyli-eetteri-metanolista ja vesi-metanolista, tai suorittamalla kromatografinen käsittely piioksidigeelin avulla.The 2 N-arylsulfonyl-L-argininamides (I) can be purified by trituration or recrystallization from a suitable solvent such as diethyl ether-tetrahydrofuran, diethyl ether-methanol and water-methanol, or by chromatography on silica gel.
G 2 Lähtöaineena käytetyt N -substituoidut N -aryylisulfonyyli-L-arginiiniamidit (XX) voidaan valmistaa seuraavasti: HN.G 2 The starting N-substituted N-arylsulfonyl-L-argininamides (XX) can be prepared as follows: HN.
C - N - CH_CH_CH_CHCOOH (II) -> / I 22 2! H2N h NH2 il 7 7231 6 HN\ +RH (IV) C - N - CH„CH_CH„CHCOOH (III) I 2 2 2, -> HN ' 1C - N - CH_CH_CH_CHCOOH (II) -> / I 22 2! H2N h NH2 il 7 7231 6 HN \ + RH (IV) C - N - CH „CH_CH„ CHCOOH (III) I 2 2 2, -> HN '1
I R" HNI R "HN
I II I
R' R’" HN ^ - N - CH^CH^CH^CHCOR (V) ^ I 2 2 2. -> HN 1 1R 'R' "HN ^ - N - CH ^ CH ^ CH ^ CHCOR (V) ^ I 2 2 2. -> HN 1 1
I R" HNI R "HN
I II I
R' R"'R 'R "'
HNHN
.C - N - CH_CH-CH9CHC0R (XIX) ArSO?X(VII).C - N - CH_CH-CH9CHCO0 (XIX) ArSO? X (VII)
I II I
I R” NH9I R ”NH9
R* ZR * Z
HNHN
- N - CH_CHnCH~CHCOR (XX) / I 222.- N - CH_CHnCH ~ CHCOR (XX) / I 222.
HN 1 1 I R" HNS02 R' 1HN 1 1 I R "HNS02 R '1
ArAr
Edellä esitetyissä kaavoissa R, Ar, X, R' ja R" on määritelty edellä. Ryhmien R' ja R" ollessa guanidinoryhmän suojaryhmiä, ne ovat edullisesti nitro, tosyyli, trityyli tai oksikarbo-nyyli. R"1 on α-aminoryhmän suojaryhmä, kuten bentsyyli-oksikarbonyyli tai tert-butoksikarbonyyli.In the above formulas, R, Ar, X, R 'and R "are as defined above. When the groups R' and R" are guanidino protecting groups, they are preferably nitro, tosyl, trityl or oxycarbonyl. R "1 is a protecting group for an α-amino group such as benzyloxycarbonyl or tert-butoxycarbonyl.
Edellä esitetyssä kaaviossa L-arginiiniamidit (XX) voidaan valmistaa suojaamalla L-arginiinin (II) guanidino- ja a-ami- noryhmät nitraamalla, asetyloimalla, formyloimalla, ftaloyloi- malla, trifluoriasetyloimalla, p-metoksibentsyylikarbonyloi- malla, bentsoyloimalla, bentsyylioksikarbonyloimalla, tert- butoksikarbonyloimalla tai trityloimalla, ja kondensoimalla G 2 sitten muodostunut N -substituoitu N -substituoitu L-arginiini 7231 6 (III) vastaavan aminohappojohdannaisen (IV) kanssa käyttäen sellaista tavanomaista menetelmää kuin happokloridimenetelmää, atsidimenetelmää, sekoitettua anhydridimenetelmää, aktivoitua esterimenetelmää tai karbodi-imidimenetelmää, ja poistamalla tämän jälkeen selektiivisesti ainoastaan N -substituoidun 2 2 N -substituoidun L-arginiiniamidin (V) N -substituentti hyd- raamalla tai happohydrolyysillä ja kondensoimalla sitten tä- ten saatu N -substituoitu L-arginiiniamidi (XIX) aryylisul- fonyylihalogenidin (VII) kanssa, edullisesti kloridin kanssa, emäksen ollessa liuottimena. Aminohappojohdannaiset (IV),In the above scheme, L-arginine amides (XX) can be prepared by protecting the guanidino and α-amino groups of L-arginine (II) by nitration, acetylation, formylation, phthaloylation, trifluoroacetylation, p-methoxybenzylcarbonylation, benzoylation, benzoylation, by butoxycarbonylation or tritylation, and condensation of the G 2 then formed N-substituted N-substituted L-arginine 7231 6 (III) with the corresponding amino acid derivative (IV) using a conventional method such as acid chloride method, azide method and carbide method, mixed anhydride method, mixed anhydride method, then selectively removing only the N-substituent of the N-substituted 2 N-substituted L-argininamide (V) by hydrogenation or acid hydrolysis and then condensing the N-substituted L-argininamide (XIX) thus obtained with the arylsulfonyl halide (VII) , preferably with chloride, base ol as a solvent. Amino acid derivatives (IV),
GG
jotka ovat lähtöaineita valmistettaessa N-substituoituja N -substituoituja L-arginiiniamideja (V), voidaan esittää seuraavilla kaavoilla:which are starting materials for the preparation of N-substituted N-substituted L-argininamides (V) can be represented by the following formulas:
COOR, COOHCOOR, COOH
) \ / ^ H-N ) (X) H-N^_O (XII) (R.) b m) \ (^ H-N) (X) H-N ^ -O (XII) (R.) b m
COOHCOOH
COOH j H-N^) (XI) Η"θθ <XIII)COOH j H-N ^) (XI) Η "θθ <XIII)
Edellä mainituissa kaavoissa , R^ ja m on määritelty edellä.In the above formulas, R 1 and m are as defined above.
Aminohappojohdannaisista ovat aminohappo-tert-butyyliesteri-johdannaiset edullisimpia, koska ne voidaan helposti muuttaa muiksi esterijohdannaisiksi happohydrolyysillä vastaavan alkoholin läsnäollessa käyttäen epäorgaanista happoa (HC1, ^SO^ jne.) tai käyttäen orgaanista happoa (tolueenisulfoni-happoa, trifluorietikkahappoa jne.). Sen menetelmän mukaisesti, jota käytetään valmistettaessa 2-piperidiinikarboksyyli-happo-johdannaisia (X), kuvataan menetelmää seuraavan kaavion avulla: 11 7231 6 (^<vmJäa2£^ O-'V.-'08-» 1 » H Cl (XIV) (XV) (XVI)Of the amino acid derivatives, amino acid tert-butyl ester derivatives are most preferred because they can be easily converted to other ester derivatives by acid hydrolysis in the presence of the corresponding alcohol using an inorganic acid (HCl, SO 2, etc.) or using an organic acid (toluenesulfonic acid, trifluoroacetic acid, etc.). According to the process used for the preparation of 2-piperidinecarboxylic acid derivatives (X), the process is described by the following scheme: 11 7231 6 (^ <vmJäa2 £ ^ O-'V .- '08- »1» H Cl (XIV) (XV) (XVI)
^ N^CN (H+) ^N^CO,H^ N ^ CN (H +) ^ N ^ CO, H
' , 2', 2
H HH H
(XVII) (XVIII)(XVII) (XVIII)
Edellä esitetyn kaavion ensimmäisen reaktion mukaisesti saatetaan sopivasti substituoitu piperidiini (XIV) kosketuksiin natriumhypokloriitin vesiliuoksen kanssa lämpötilassa välillä -5 ja 0°C. Saatu tuote (XV) erotetaan uuttamalla liuottimena, esim. dietyylieetterillä, ja käsitellään sitten kaliumhydr-oksidilla alempi alkanoliliuottimessa, jolloin saadaan 1,2-de- 10 7231 6 hydropiperidiiniä (XVI). Syanogenoimisaineiden, esim. syaani-vedyn tai natriumsyanidin, vaikutuksesta muutetaan 1,2-dehyd- ' ropiperidiinit (XVI) vastaaviksi 2-syanoanalogeiksi (XVII). Hydrolysoitaessa 2-syanopiperidiinejä (XVII) 2-piperidiini-karboksyylihappojen (XVIII) valmistamiseksi suoritetaan tämä käsittelemällä 2-syanopiperidiinejä (XVII) epäorgaanisella hapolla, kuten kloorivetyhapolla tai rikkihapolla.According to the first reaction of the above scheme, the appropriately substituted piperidine (XIV) is contacted with an aqueous solution of sodium hypochlorite at a temperature between -5 and 0 ° C. The product (XV) obtained is isolated by extraction as a solvent, e.g. diethyl ether, and then treated with potassium hydroxide in a lower alkanol solvent to give 1,2-de-7231 6 hydropiperidine (XVI). Under the influence of cyanogenating agents, e.g. hydrogen cyanide or sodium cyanide, 1,2-dehydropropidines (XVI) are converted into the corresponding 2-cyano analogues (XVII). In the hydrolysis of 2-cyanopiperidines (XVII) to give 2-piperidinecarboxylic acids (XVIII), this is done by treating 2-cyanopiperidines (XVII) with an inorganic acid such as hydrochloric acid or sulfuric acid.
Aryylisulfonyylihalogenidit (VII), jotka ovat lähtöaineita 2 valmistettaessa N -aryylisulfonyyli-L-arginiiniamideja (I), voidaan valmistaa halogenoimalla vastaavia aryylisulfoni-happoja tai niiden suoloja, esim. natriumsuoloja, tavanomaisilla menetelmillä, jotka ovat alan asiantuntijalle hyvin tunnettuja. .The arylsulfonyl halides (VII) which are the starting materials 2 for the preparation of N-arylsulfonyl-L-argininamides (I) can be prepared by halogenation of the corresponding arylsulfonic acids or their salts, e.g. sodium salts, by conventional methods well known to those skilled in the art. .
Käytännössä toteutetaan halogenoiminen ilman liuotinta tai sopivassa liuottimessa, esim. halogenoidussa hiilivedyssä ’In practice, the halogenation is carried out without solvent or in a suitable solvent, eg halogenated hydrocarbon ’
tai DMF:ssä, halogenoimisaineen, esim. fosforioksikloridin, Jor in DMF, a halogenating agent, e.g. phosphorus oxychloride, J
tionyylikloridin, fosforitrikloridin, fosforitribromidin ! tai fosforipentakloridin läsnäollessa lämpötilassa välillä j -10 ja 200°C 5 minuutin ja 5 tunnin välisen ajan kuluessa.thionyl chloride, phosphorus trichloride, phosphorus tribromide! or in the presence of phosphorus pentachloride at a temperature between -10 and 200 ° C for a period of 5 minutes to 5 hours.
Reaktion päättymisen jälkeen kaadetaan reaktiotuote jää- · veteen ja uutetaan sitten liottimella, kuten eetterillä, j bentseenillä, etyyliasetaatilla, kloroformilla yms.After completion of the reaction, the reaction product is poured into ice water and then extracted with a solvent such as ether, benzene, ethyl acetate, chloroform and the like.
Aryylisulfonyylihalogenidi voidaan puhdistaa kiteyttämällä uudelleen jostain sopivasta liuottimesta, kuten heksaanista, bentseenistä yms.The arylsulfonyl halide can be purified by recrystallization from a suitable solvent such as hexane, benzene and the like.
22
Menetelmässä b) N -aryylisulfonyyli-L-arginiiniamidi (I) 2 valmistetaan kondensoimalla N -aryylisulfonyyli-L-arginyyli-halogenidi (XXII), edullisesti kloridi, vähintään ekvimolaa-risen määrän kanssa aminohappojohdannaista (IV).In process b) N-arylsulfonyl-L-argininamide (I) 2 is prepared by condensing N-arylsulfonyl-L-arginyl halide (XXII), preferably chloride, with at least an equimolar amount of the amino acid derivative (IV).
* i* i
Kondensaatioreaktio voidaan toteuttaa käyttämättä lisättyä liuotinta emäksen läsnäollessa. Tyydyttäviä tuloksia saadaan kuitenkin käytettäessä liuotinta, kuten emäksisiä liuottimia ti 11 7231 6 (dimetyyliformamidia, dimetyyliasetamidia jne.)» tai halo-genoituja liuottimia (kloroformia, dikloorimetaania jne.).The condensation reaction can be carried out without using an added solvent in the presence of a base. However, satisfactory results are obtained when using a solvent such as basic solvents ti 11 7231 6 (dimethylformamide, dimethylacetamide, etc.) »or halogenated solvents (chloroform, dichloromethane, etc.).
Käytetyn liuottimen määrä ei ole kriittinen ja se voi vaih- 2 della välillä noin 5-100-kertaisesti käytetyn N -aryylisulfo-nyyli-L-arginyylihalogenidin (XXII) painoon verrattuna.The amount of solvent used is not critical and can vary from about 5 to 100 times the weight of N-arylsulfonyl-L-arginyl halide (XXII) used.
Edullisimmat kondensaatioreaktion lämpötilat ovat alueella välillä -10 ja 80°C ja edullisesti 20-50°C. Reaktioaika ei ole kriittinen, mutta vaihtelee käytetystä aminohappojohdannaisesta (IV) riippuen. Yleensä 5 minuutin ja 10 tunnin välinen aika on sopiva.The most preferred condensation reaction temperatures are in the range of -10 to 80 ° C, and preferably 20 to 50 ° C. The reaction time is not critical, but varies depending on the amino acid derivative (IV) used. Generally, a time between 5 minutes and 10 hours is appropriate.
22
Saatu N -aryylisulfonyyli-L-arginiiniamidi voidaan erottaa ja puhdistaa edellä kuvatulla tavalla.The resulting N-arylsulfonyl-L-argininamide can be isolated and purified as described above.
2 Lähtöaineena käytetty N -aryylisulfonyyli-L-arginyylihaloge-nidi (XXII) voidaan valmistaa seuraavasti: HNX f - N - CH2CH2CH2CHCOOH (VII) +ArSQ2X ^ H2N NH2 ”2 The starting N-arylsulfonyl-L-arginyl halide (XXII) can be prepared as follows: HNX f - N - CH2CH2CH2CHCOOH (VII) + ArSQ2X ^ H2N NH2 ”
HN. HHN. B
X IX I
C - N - CH2CH2CH2CHCOOH (XXD _> H2N hLo, I 2C - N - CH2CH2CH2CHCOOH (XXD _> H2N hLo, I 2
Ar HN% f - N_ - CH2CH2CH2CHCOX (XXII) h~n ti* λ 2 HNS0o I 2Ar HN% f - N_ - CH2CH2CH2CHCOX (XXII) h ~ n ti * λ 2 HNS0o I 2
ArAr
Edellä esitetyissä kaavoissa R, Ar ja X on määritelty edellä.In the above formulas, R, Ar and X are as defined above.
12 7231 6 212 7231 6 2
Edellä esitetyssä kaaviossa N -aryylisulfonyyli-L-arginiini (XXI) voidaan valmistaa kondensoima11a L-arginiini (II) oleellisesti ekvimolaarisen määrän kanssa aryylisulfonyylihaloge-nidia (VII) käyttäen samanlaista menetelmää, joka on kuvattu kondensoitaessa L-arginiiniamidi aryylisulfonyylihalidin kanssa.In the above scheme, N-arylsulfonyl-L-arginine (XXI) can be prepared by condensing 11a L-arginine (II) with a substantially equimolar amount of arylsulfonyl halide (VII) using a method similar to that described for condensing L-argininamide with arylsulfonyl halide.
2 N -aryylisulfonyyli-L-arginyylihalogenidi (XXII) voidaan 2 valmistaa saattamalla N -aryylisulfonyyli-L-arginiini (XXI) reagoimaan ainakin ekvimolaarisen määrän kanssa halogenoimis-ainetta, kuten tionyylikloridia, fosforioksikloridia, fosfori-trikloridia, fosforipentakloridia tai fosforitribromidia. Halogenoiminen voidaan toteuttaa käyttäen liuotinta tai ilman tätä.2 N-Arylsulfonyl-L-arginyl halide (XXII) can be prepared by reacting N-arylsulfonyl-L-arginine (XXI) with at least an equimolar amount of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus trichloride or phosphorus pentacid chloride. The halogenation can be carried out with or without a solvent.
Edullisimpia liuottimia ovat klooratut hiilivedyt, kuten kloroformi ja dikloorimetaani, metaani ja eetterit, kuten tetrahydro-furaani ja dioksaani.The most preferred solvents are chlorinated hydrocarbons such as chloroform and dichloromethane, methane and ethers such as tetrahydrofuran and dioxane.
Käytetyn liuottimen määrä ei ole kriittinen ja voi vaihdella 2 noin 5-100-kertaisesti N -aryylisulfonyyli-L-arginiinin (XXI) painoon verrattuna.The amount of solvent used is not critical and can vary from about 5 to 100 times the weight of N-arylsulfonyl-L-arginine (XXI).
Edullisin reaktiolämpötila on arvosta -10°C aina huoneen lämpötilaan. Reaktioaika ei ole kriittinen, mutta vaihtelee riippuen halogenoimisaineesta ja reaktiolämpötilasta. Yleensä aika, joka on välillä 15 minuuttia ja 5 tuntia, on sopiva.The most preferred reaction temperature is from -10 ° C to room temperature. The reaction time is not critical, but varies depending on the halogenating agent and the reaction temperature. Generally, a time of between 15 minutes and 5 hours is appropriate.
2 Tältä alalta on hyvin tunnettua, että sellainen N -aryyli- sulfonyyli-L-arginiiniamidin (I) esterijohdannainen, jossa 2It is well known in the art that an ester derivative of N-arylsulfonyl-L-argininamide (I) in which 2
Rg on alkyyli voidaan valmistaa sellaisesta N -aryylisulfo-nyyli-L-arginiiniamidin johdannaisesta, jossa Rg on vety, tavanomaisilla esteröimismenetelmillä, jotka ovat alan asiantuntijalle hyvin tunnettuja. On myös hyvin tunnettua tältä alalta, että karboksyylihappojohdannainen voidaan valmistaa esterijohdannaisesta tavanomaisen hydrolyysi- tai asidolyy-simenetelmän avulla. Ne olosuhteet, joiden vallitessa este-röiminen, hydrolyysi tai hapolla hajottaminen voidaan toteuttaa, ovat asiantuntijalle tunnettuja.Rg is alkyl can be prepared from a N-arylsulfonyl-L-argininamide derivative wherein Rg is hydrogen by conventional esterification methods well known to those skilled in the art. It is also well known in the art that a carboxylic acid derivative can be prepared from an ester derivative by a conventional hydrolysis or acidolysis method. The conditions under which blocking, hydrolysis or acid decomposition can be carried out are known to the person skilled in the art.
tl 2 13 7231 6tl 2 13 7231 6
Keksinnön mukainen N -aryylisulfonyyli-L-arginiiniamidi (I) muodostaa happoadditiosuolan erilaisten epäorgaanisten ja 2 orgaanisten happojen kanssa. Muutamat N -aryylisulfonyyli-L-arginiiniamidit, jotka sisältävät vapaan karboksyyliryhmän muodostavat suoloja erilaisten epäorgaanisten ja orgaanisten emästen kanssa.The N-arylsulfonyl-L-argininamide (I) of the invention forms an acid addition salt with various inorganic and 2 organic acids. A few N-arylsulfonyl-L-argininamides containing a free carboxyl group form salts with various inorganic and organic bases.
Edellä kuvatut reaktiotuotteet voidaan erottaa vapaassa muodossa tai suolojen muodossa. Lisäksi tuote voidaan saada farmaseuttisesti hyväksyttävien happoadditiosuolojen muodossa saattamalla jokin vapaa emäs reagoimaan hapon, kuten kloo-rivetyhapon, bromivetyhapon, jodivetyhapon, typpihapon, rikkihapon, fosforihapon, etikkahapon, sitruunahapon, maleiini-hapon, meripihkahapon, maitohapon, viinihapon, glukonihapon, bentsoehapon, metaanisulfonihapon, etaanisulfonihapon, bent-seenisulfonihapon, p-tolueenisulfonihapon yms. kanssa. Samalla tavoin voidaan tuote saada farmaseuttisesti hyväksyttävän suolan muodossa saattamalla jokin vapaa karboksyylihappo reagoimaan emäksen, kuten natriumhydroksidin, kaliumhydroksidin, ammoniumhydroksidin, trietyyliamiinin, prokaiinin, dibentsyy-liamiinin, 1-efenamiinin, N,N'-dibentsyylietyleenidiamiinin, N-etyylipiperidiinin yms. kanssa.The reaction products described above can be isolated in free form or in the form of salts. In addition, the product can be obtained in the form of pharmaceutically acceptable acid addition salts by reacting a free base with an acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, succinic acid, succinic acid, lactic acid, succinic acid, with ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Similarly, the product can be obtained in the form of a pharmaceutically acceptable salt by reacting a free carboxylic acid with a base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine, procaine, dibenzylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, N-N-dibenzylethylenediamine.
Samalla tavoin käsiteltäessä suoloja emäksellä tai hapolla aikaansaadaan vapaan amidin regeneroiminen. 1Similarly, treatment of salts with a base or acid provides for regeneration of the free amide. 1
Kuten edellä mainittiin, on keksinnön mukaisille N -aryyli-sulfonyyli-L-arginiiniamideille ja niiden suoloille tunnusomaista niiden erittäin spesifinen estovaikutus imettäväisissä verisuonitukosten suhteen samoin kuin niiden oleellinen myrkyttömyys, ja tämän johdosta nämä yhdisteet ovat käyttökelpoisia diagnostisina reagensseina määrättäessä verisuonitukoksia veressä ja/tai verisuonitukosten estämiseksi .As mentioned above, the N-arylsulfonyl-L-argininamides of the invention and their salts are characterized by their highly specific inhibitory effect on vascular thrombosis in mammals as well as their substantial non-toxicity, and are therefore useful as diagnostic reagents in the determination of vascular occlusion or .
7231 6 147231 6 14
Keksinnön mukaiset yhdisteet o\ t myös käyttökelpoisia estettäessä verihiutaleiden aggregoituminen.The compounds of the invention are also useful in inhibiting platelet aggregation.
22
Keksinnön mukaisen N -aryylisulfonyyli-L-arginiiniamidin verisuoni-tukoksia hajottavaa aktiivisuutta verrattiin tunnetun verisuonitu- n koksia vastustavan aineen N -(p-tolyylisulfonyyli)-L-arginiinime-tyyliesterin vaikutukseen määräämällä fibrinogeenin koaguloitumisaika. Fibrinogeenin koaguloimusaikamittaukset suoritettiin seuraavasti: 0,8 ml:n suuruinen osa fibrinogeeniliuosta, joka oli valmistettu liuottamalla 150 mg naudan fibrinogeeniä (Cohn-fraktio I), jota valmistaa Armour Inc., 40 ml:an boraatti-suolapuskuria (pH 7,4) sekoitettiin 0,1 ml:n kanssa boraattisuolapuskuria, pH 7,4 (vertailu), tai samassa puskurissa olevan näyteliuoksen kanssa, ja 0,1 ml trom-biiniliuosta (5 yksikköä/ml), jota valmistaa Mochida Pharmaceutical Co., Ltd., lisättiin näihin liuoksiin jääkylvyllä.The vasoconstrictive activity of the N-arylsulfonyl-L-argininamide of the invention was compared to the effect of the known anti-coke agent N - (p-tolylsulfonyl) -L-arginine methyl ester by determining the coagulation time of fibrinogen. Fibrinogen coagulation time measurements were performed as follows: A 0.8 ml aliquot of fibrinogen solution prepared by dissolving 150 mg of bovine fibrinogen (Cohn fraction I) manufactured by Armor Inc. in 40 ml of borate-salt buffer (pH 7.4) was mixed. With 0.1 ml of borate salt buffer, pH 7.4 (comparison), or with a sample solution in the same buffer, and 0.1 ml of thrombin solution (5 units / ml) manufactured by Mochida Pharmaceutical Co., Ltd. was added. to these solutions in an ice bath.
Välittömästi sekoittamisen jälkeen johdettiin reaktioseos jääkyl-vyltä sellaiseen kylpyyn, jota pidettiin lämpötilassa 25°C. Koa-guloimisajaksi otettiin se aika, joka kului siirrosta 25°C lämpötilan omaavaan kylpyyn siihen hetkeen, jolloin ensimmäiset fibriini-säikeet ilmaantuivat. Niissä tapauksissa, joissa lääkenäytteitä ei lisätty, oli koaguloitumisaika 50-55 sek. Koetulokset on esitetty taulukossa 1. Termi "väkevyys, joka vaaditaan pidentämään koagu-loimisaika kaksinkertaiseksi", on sen aktiivisen aineosan väkevyys, joka tarvitaan pidentämään normaali koaguloitumisaika, 50-55 sekuntia, 100-110 sekunniksi.Immediately after stirring, the reaction mixture was passed from an ice bath to a bath maintained at 25 ° C. The coagulation time was taken to be the time from the transfer to the 25 ° C bath to the time the first fibrin fibers appeared. In those cases where drug samples were not added, the coagulation time was 50-55 sec. The experimental results are shown in Table 1. The term "concentration required to double the coagulation time" is the concentration of the active ingredient required to increase the normal coagulation time, from 50 to 55 seconds, to 100 to 110 seconds.
Väkevyys, joka tarvittiin pidentämään koaguloitumisaika kaksinkertaiseksi käytettäessä tunnettua verisuonitukoksia estävää ainetta N1-(p-tolyylisulfonyyli)-L-arginiinimetyyliesteriä, oli llOO^um. Inhibiittorit on esitetty taulukossa 1 esittämällä R ja Ar kaavassa (I) ja addiitioryhmä.The concentration required to double the coagulation time using the known anticoagulant N1- (p-tolylsulfonyl) -L-arginine methyl ester was 1100. The inhibitors are shown in Table 1 by showing R and Ar in formula (I) and the addition group.
yy
Annettaessa liuosta, joka sisälsi keksinnön mukaista N -aryyli-sulfonyyli-L-arginiiniamidia intravenööttisesti eläimille, säilyi voimakas verisuonitukoksia estävä aktiivisuus kiertävässä veressä 1-3 tuntia. Keksinnön mukaisten verisuonitukoksia estävien yhdisteiden puoliintumisaika kiertävässä veressä oli suunnilleen 60 min. Koe-eläinten (rotat, kaniinit, koirat ja simpanssit) fysiologiset 4* 15 7231 6 tilat voitiin hyvin ylläpitää. Fibrinogeenin kokeellinen hajottaminen eläimissä, joka aikaansaatiin infusoimalla trombiinia, voitiin valvoa tyydyttävästi antamalla samanaikaisesti keksinnön mukaisia yhdisteitä.When a solution containing the N-arylsulfonyl-L-argininamide of the invention was administered intravenously to animals, strong anticoagulant activity was maintained in the circulating blood for 1 to 3 hours. The circulating half-life of the anti-thrombotic compounds of the invention was approximately 60 minutes. The physiological 4 * 15 7231 6 physiological conditions of the experimental animals (rats, rabbits, dogs and chimpanzees) could be well maintained. Experimental degradation of fibrinogen in animals by infusion of thrombin could be satisfactorily controlled by co-administration of the compounds of the invention.
Akuuttiset myrkyllisyysarvot (LD^q) määrättynä antamalla laskimon sisäisesti kaavan (I) mukaisia yhdisteitä hiirille (uros-hiiri 20 g) ovat noin 150-600 mg/kg ruumiin painoa.The acute toxicity values (LD ^ q) determined by intravenous administration of the compounds of formula (I) to mice (male-mouse 20 g) are about 150-600 mg / kg body weight.
Keksinnön mukaisten yhdisteiden tyypilliset LD^^-arvot on esitetty seuraavassa taulukossa.Typical LD 2 values for the compounds of the invention are shown in the following table.
YhdisteCompound
HNHN
XX
C - NH - (CH~)CHCORC - NH - (CH ~) CHCOR
/ 2 3i H2N HNS02Ar LD50 (mg/kg)/ 2 3i H2N HNS02Ar LD50 (mg / kg)
Ar RWith R
CH3 /—\ I - N V- CH_ 270 \ / 3 'CH3 / - \ I - N V- CH_ 270 \ / 3 '
1 COOH1 COOH
Cl J ‘ ">_V CH3 300Cl J '"> _V CH3 300
I COOHI COOH
Vastaavasti saatiin seuraavat LD^Q-arvot annettaessa hiirille laskimonsisäisesti US-patenttijulkaisusta 3 978 045 tun-2 nettuja N -dansyyli-L-arginiinijohdannaisia.Similarly, the following LD50 values were obtained when N-dansyl-L-arginine derivatives disclosed in U.S. Patent No. 3,978,045 were administered intravenously to mice.
16 7231 616 7231 6
Yhdiste HN.Compound HN.
VV
C - NH - (CH0)oCHC0RC - NH - (CHO) oCHCO
/ 2 3I/ 2 3I
h2n hnso2 /v/^lh2n hnso2 / v / ^ l
{JLJ{JLJ
n(ch3) 2n (ch3) 2
Yhdiste R LD5Q(mg/kg) 2 N -dansyyli-L-arginiinin -0(CH2)3CH3 60 n-butyyliesteri 4-metyyli-1-(N2-dansyyli- _ ^ VCH 8 L-arginyyli)piperidiini V_/ ^ 4-etyyli-1- (N^-dansyyli) - . Ν^Λ-ΟΗ,α!, 8 L-arginyyli)piperidiini \—f 2- (N2-dansyyli-L-arginyyli) - _ 0 isoindoliiniCompound R LD50 (mg / kg) 2 N-dansyl-L-arginine-O (CH2) 3CH3 60 n-butyl ester 4-methyl-1- (N2-dansyl-N-VCH8 L-arginyl) piperidine -ethyl-1- (N, N-dansyl) -. Ν (Λ-ΟΗ, α, 8 L-arginyl) piperidine (2 - (N2-dansyl-L-arginyl) -0-isoindoline)
Vastaavat LD^^-arvot annettaessa yllämainittuja yhdisteitä suun kautta ovat >6000, 1310, 1375 ja 1360 mg/kg, kuten on esitetty US-patenttijulkaisun 3 978 045 palstan 13 riveillä 36-44.The corresponding LD50 values for oral administration of the above compounds are> 6000, 1310, 1375 and 1360 mg / kg, as shown in U.S. Pat. No. 3,978,045, column 13, lines 36-44.
DE-hakemusjulkaisun 2 550 088 sivulla 31 on esitetty, että LD^Q-arvot määritettynä antamalla hiirille (uroshiiri 20 g) suun kautta N2-naftyylisulfonyyli-L-arginiinijohdannaisia ovat noin 1000-10 000 mg/kg ruumiin painoa. On huomattava, että nämä LD^Q-arvot on saatu antamalla yhdisteitä suun kautta, joten ne eivät ole suoraan vertailukelpoisia niihin LDj-Q-arvoihin, jotka on saatu antamalla keksinnön mukaisia 17 7231 6 yhdisteitä laskimonsisäisesti hiirille. On yleisesti omaksuttu, että suun kautta annetun yhdisteen LD^^-arvo on paljon suurempi kuin jos samaa yhdistettä annetaan laskimonsisäisesti. Yleensä laskimonsisäisesti annetun yhdisteen LD^^-arvo eroaa suun kautta antamalla saadusta LD,...-arvosta kertoimella 100. Tämä merkitsee sitä, että DE-hakemusjulkaisussa 2 550 088 esitetyt, suun kautta antamalla saadut LD^-arvot 1000-10 000 rag/kg vastaavat laskimonsisäisellä annostuksella likimain LD^-Q-arvoja 10-100 mg/kg.On page 31 of DE-A-2 550 088 it is shown that the LD 2 values determined by oral administration to mice (male mouse 20 g) of N 2 -naphthylsulfonyl-L-arginine derivatives are about 1000-10,000 mg / kg body weight. It should be noted that these LD50 values have been obtained by oral administration of the compounds, so that they are not directly comparable to the LD50 values obtained by intravenous administration of the compounds of the invention to 17,731 6 mice. It is generally accepted that the LD50 value of an orally administered compound is much higher than if the same compound is administered intravenously. In general, the LD50 value of an intravenously administered compound differs from the LD50 value obtained by oral administration by a factor of 100. This means that the LD50 values obtained by oral administration in DE-A-2,550,088 are 1000-10,000 rag. / kg for intravenous dosing correspond to approximately LD 1 -Q values of 10-100 mg / kg.
Edellä esitetystä ilmenee selvästi, että keksinnön mukaisilla 2 uusilla N -aryylisulfonyyli-L-arginiiniamideilla on olennaisesti alhaisempi myrkyllisyys kuin US-patenttijulkaisusta 3 978 045 ja DE-hakemusjulkaisusta 2 550 088 tunnetuilla yhdisteillä.It is clear from the above that the 2 novel N-arylsulfonyl-L-argininamides according to the invention have substantially lower toxicity than the compounds known from U.S. Pat. No. 3,978,045 and DE Application No. 2,550,088.
On ilmeistä, että typpeä sisältävän renkaan, kuten piperi-diinin, 2-asemaan sitoutunut karboksyylihapporyhmä keksinnön mukaisissa yhdisteissä myötävaikuttaa yllättävän alhaiseen myrkyllisyyteen.It is apparent that the carboxylic acid group attached to the 2-position of a nitrogen-containing ring, such as piperidine, in the compounds of the invention contributes to a surprisingly low toxicity.
Keksinnön mukaisia terapeuttisia aineita voidaan annostella imettäväisille, ihmiset mukaanlukien, pelkästään sellaisinaan tai yhdessä farmaseuttisesti sopivien kantaja-aineiden kanssa, joiden määrä määrätään riippuen yhdisteen liukoisuudesta ja kemiallisesta luonteesta, annostustavasta ja tavanomaisesta farmaseuttisesta käytännöstä.Therapeutic agents of the invention may be administered to mammals, including humans, alone or in combination with pharmaceutically acceptable carriers, the amount of which will be determined depending on the solubility and chemical nature of the compound, the mode of administration, and conventional pharmaceutical practice.
Näitä yhdisteitä voidaan injektoida esim. parenteraalisesti, so. lihakseen intravenööttisesti tai subkutaanisesti. Parente-raalista annostelua käytettäessä voidaan yhdisteitä käyttää steriilien liuosten muodossa, jotka sisältävät muita liukenevia aineita, esim. riittävästi suolaa tai glukoosia, liuoksen tekemiseksi isotoniseksi. Yhdisteet voidaan annostella oraalisesti tablettien, kapselien tai rakeiden muodossa, jotka sisältävät sopivia lisäaineita, kuten tärkkelystä, laktoosia, sokeria yms. Yhdisteet voidaan annostella myös sublinguaali-sesti rakeiden tai juoksevassa muodossa, jolloin kukin aktii- 18 7231 6 vinen aineosa on sekoitettu sokerin ja maissisiirapin kanssa sekä maku- ja väriaineiden kanssa ja dehydrattu sitten riittävästi seoksen tekemiseksi sopivaksi puristusta varten kiinteään muotoon. Yhdisteet voidaan annostella myös oraalisesti sellaisten liuosten muodossa, jotka voivat sisältää väri- ja makuaineita. Lääkäri määrää näiden terapeuttisten aineiden sen annoksen, joka on sopivin ihmisille, ja nämä annokset voivat vaihdella riippuen annostustavasta ja käytetystä yhdisteestä. Lisäksi annostus voi vaihdella riippuen käsiteltävästä potilaasta.These compounds can be injected e.g. parenterally, i. intramuscularly or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other soluble substances, e.g., enough salt or glucose, to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules or granules containing suitable excipients such as starch, lactose, sugar and the like. The compounds may also be administered sublingually in granular or liquid form, each active ingredient being mixed with sugar and corn syrup. with flavors and colorants and then sufficiently dehydrated to make the mixture suitable for compression into a solid form. The compounds may also be administered orally in the form of solutions which may contain coloring and flavoring agents. The physician will determine the dosage of these therapeutic agents which will be most suitable for humans, and these dosages may be varied depending upon the mode of administration and the compound employed. In addition, the dosage may be varied depending upon the host treated.
Kun seosta annostellaan oraalisesti, niin suurempi aktiivisen aineen määrä tarvitaan saman vaikutuksen aikaansaamiseksi mikä aikaansaadaan pienempää parenteraalista annosta käytettäessä.When the mixture is administered orally, a larger amount of active substance is required to achieve the same effect as with a lower parenteral dose.
Terapeuttinen annos on yleensä 10-50 mg/kg aktiivista aineosaa parenteraalisesti ja 10-500 mg/kg oraalisesti vuorokaudessa .The therapeutic dose is generally 10 to 50 mg / kg of active ingredient parenterally and 10 to 500 mg / kg orally per day.
Seuraavassa keksintöä kuvataan lähemmin suoritusesimerkkien avulla.In the following, the invention will be described in more detail by means of exemplary embodiments.
Esimerkki 1 _G 2 (A) Etyyli-1-/N -nitro-N -(3-sykloheksyyli-4-metoksifenyyli-sulfonyyli)-L-arginyyli7-4-metyyli-2-piperidiinikarb-oksylaatti.Example 1G2 (A) Ethyl 1- [N-nitro-N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.
Hyvin sekoitettuun liuokseen, jossa oli 2,05 g etyyli-1-(N -nitro-L-arginyyli)-4-metyyli-2-piperidiinikarboksylaatti-hydrokloridia ja 1,26 g NaHCO^ 10 ml:ssa vettä ja 40 ml:ssa dioksaania, lisättiin annoksittain 2,2 g 3-sykloheksyyli-4-metoksibentseenisulfonyylikloridia samalla kun lämpötila pidettiin arvossa 0°C. Reaktioseosta sekoitettiin yön yli huoneen lämpötilassa. Tämän jakson päätyttyä reaktioseos haihdutettiin kuiviin. Jäännös liuotettiin 50 ml:aan etyyliasetaattia ja etyyliasetaattiliuos pestiin peräkkäin 10 %:sella sitruunahapolla, kyllästetyllä NaClrlla, kyllästetyllä tl 19 7231 6To a well-stirred solution of 2.05 g of ethyl 1- (N-nitro-L-arginyl) -4-methyl-2-piperidinecarboxylate hydrochloride and 1.26 g of NaHCO 3 in 10 ml of water and 40 ml of dioxane, 2.2 g of 3-cyclohexyl-4-methoxybenzenesulfonyl chloride were added portionwise while maintaining the temperature at 0 ° C. The reaction mixture was stirred overnight at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was dissolved in 50 ml of ethyl acetate and the ethyl acetate solution was washed successively with 10% citric acid, saturated NaCl, saturated tl 19 7231 6
NaHCO.j:lla ja kyllästetyllä NaCl-liuoksella. Etyyliasetaatti- liuos haihdutettiin ja jäännöstä käsiteltiin kromatografi- sesti piioksidigeelillä, joka oli pakattu kloroformiin, ja eluoitiin kloroformilla, joka sisälsi 3 % metanolia. Pääfrak- tio haihdutettiin kuiviin, jolloin saatiin 2,6 g etyyli-1-— G 2 /N -nitro-N -(3-sykloheksyyli-4-metoksibentseenisulfonyyli)-L-arginyyli7-4-metyyli-2-piperidiinikärboksylaattia.NaHCO 3 and saturated NaCl solution. The ethyl acetate solution was evaporated and the residue was chromatographed on silica gel packed in chloroform and eluted with chloroform containing 3% methanol. The main fraction was evaporated to dryness to give 2.6 g of ethyl 1- [G 2 / N-nitro-N- (3-cyclohexyl-4-methoxybenzenesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.
I.R. (KBr): 3400, 1735, 1635, 1250 (cm‘1).I.R. (KBr): 3400, 1735, 1635, 1250 (cm-1).
_2 (B) Etyyli-1-/N -(3-sykloheksyyli-4-metoksifenyylisulfonyyli)-L-arginyyli7~4-metyyli-2-piperidiinikarboksylaattiase-taatti.(2) Ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate.
_G 2_G 2
Liuokseen, jossa oli 2,6 g etyyli-1-/N -nitro-N - (3-sykloheksyy- li-4-metoksifenyylisulfonyyli)-L-arginyyli7-4-metyyli-2-piperi-diinikarboksylaattia 40 ml:ssa etanolia, 10 ml vettä ja 20 ml etikkahappoa, lisättiin 0,5 g palladiummustaa ja tämän jälkeen seosta ravistettiin vetykehässä 15 tuntia huoneen lämpötilassa. Liuos suodatettiin katalyytin poistamiseksi ja haihdutettiin, jolloin saatiin öljymäinen tuote.To a solution of 2.6 g of ethyl 1- [N-nitro-N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate in 40 ml of ethanol, 10 ml of water and 20 ml of acetic acid, 0.5 g of palladium black were added, and then the mixture was shaken under a hydrogen atmosphere for 15 hours at room temperature. The solution was filtered to remove the catalyst and evaporated to give an oily product.
Saostettaessa uudelleen etanoli-dietyylieetteristä saatiin 2 2,4 g etyyli-1-/N -(3-sykloheksyyli-4-metoksifenyylisulfonyyli)-L-arginyyli7-4-metyyli-2-piperidiinikarboksylaattiasetaattia.Recrystallization from ethanol-diethyl ether gave 2.4 g of ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate.
_2 (C) 1-/N -(3-sykloheksyyli-4-metoksifenyylisulfonyyli)-L-arginyyli7-4-metyyli-2-piperidiinikarboksyylihappo.(2) 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid.
_2_2
Liuosta, jossa oli 2,4 g etyyli-1-/N -(3-sykloheksyyli-4-metoksifenyylisulfonyyli)-L-arginyyli/-4-metyyli-2-piperi-diinikarboksylaattiasetaattia 10 ml:ssa etanolia ja 10 ml 1-n NaOH-liuosta, sekoitettiin yli yön huoneen lämpötilassa.A solution of 2.4 g of ethyl 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate acetate in 10 ml of ethanol and 10 ml of 1-n NaOH solution, stirred overnight at room temperature.
Tämän jälkeen reaktioseos väkevöitiin ja liuotettiin 10 ml:aan vettä. Liuos neutraloitiin 2N HCl-liuoksella, jolloin saatiin valkoinen, kumimainen sakka, joka liuotettiin 150 mlraan kloroformia. Kloroformiliuos pestiin kyllästetyllä NaCl-liuoksel- 20 7231 6 la, kuivattiin vedettömällä natriumsulfaatilla ja haihdutet- -2 tiin tyhjössä, jolloin saatiin 1,52 g 1-/N - (3-sykloheksyyli-4-metoksifenyylisulfonyyli)-L-arginyyli7-4-metyyli-2-piperi-diinikarboksyylihappoa amorfisena kiinteänä aineena.The reaction mixture was then concentrated and dissolved in 10 ml of water. The solution was neutralized with 2N HCl to give a white, gummy precipitate which was dissolved in 150 mL of chloroform. The chloroform solution was washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.52 g of 1- [N- (3-cyclohexyl-4-methoxyphenylsulfonyl) -L-arginyl] -4- methyl-2-piperidinecarboxylic acid as an amorphous solid.
I.R. (KBr): 3350, 2920, 1620, 1250 cm"1.I.R. (KBr): 3350, 2920, 1620, 1250 cm -1.
Analyysi - laskettu yhdisteelle C26H41°6N5S (%): C 56,60; H 7,49; N 12,70 Todettu (%): C 56,51; H 7,53; N 12,68Analysis - Calculated for C 26 H 41 O 6 N 5 S (%): C, 56.60; H 7.49; N 12.70 Found (%): C 56.51; H 7.53; N 12.68
Esimerkki 2 Tässä esimerkissä esitetään yleinen kuvaus, kuinka kaavan I 2 mukaisia N -aryylisulfonyyli-L-arginiiniamideja voidaan valmistaa menetelmällä b.Example 2 This example provides a general description of how N-arylsulfonyl-L-argininamides of formula I 2 can be prepared by Method b.
2 (A) N -(trisubstituoitu fenyylisulfonyyli)-L-arginiini.2 (A) N- (trisubstituted phenylsulfonyl) -L-arginine.
Hyvin sekoitettuun liuokseen, jossa oli 16,7 g L-arginiinia 150 ml:ssa 10 %:sta kaliumkarbonaattiliuosta, lisättiin 26,1 g trisubstituoitua fenyylisulfonyylikloridia 150 ml:ssa bentsee-niä. Reaktioseosta sekoitettiin 60°C:ssa 5 tuntia, jolloin tuote saostui. Reaktioseoksen annettiin seistä yhden tunnin ajan huoneen lämpötilassa, minkä jälkeen sakka erotettiin suodattamalla ja pestiin peräkkäin bentseenillä ja vedellä, jolloin 2 saatiin 31,4 g (81 %) N -(trisubstituoitua fenyylisulfonyyli)-L-arginiinia.To a well-stirred solution of 16.7 g of L-arginine in 150 ml of 10% potassium carbonate solution was added 26.1 g of trisubstituted phenylsulfonyl chloride in 150 ml of benzene. The reaction mixture was stirred at 60 ° C for 5 hours at which time the product precipitated. The reaction mixture was allowed to stand for one hour at room temperature, after which the precipitate was filtered off and washed successively with benzene and water to give 31.4 g (81%) of N- (trisubstituted phenylsulfonyl) -L-arginine.
2 (B) N -(trisubstituoitu fenyylisulfonyyli)-L-arginyyli-kloridi.2 (B) N- (trisubstituted phenylsulfonyl) -L-arginyl chloride.
22
Suspensiota, jossa oli 3,93 g N -(trisubstituoitua fenyyli-sulfonyyli)-L-arginiinia 20 mltssa tionyylikloridia, sekoitettiin 2 tuntia huoneen lämpötilassa. Lisättäessä kylmää kuivaa dietyylieetteriä muodostui sakka, joka erotettiin suodattamalla ja pestiin useita kertoja kuivalla dietyylieetteril- 2 lä, jolloin saatiin N -(trisubstituoitua fenyylisulfonyyli)-L-arginyylikloridia.A suspension of 3.93 g of N- (trisubstituted phenylsulfonyl) -L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether gave a precipitate which was filtered off and washed several times with dry diethyl ether to give N- (trisubstituted phenylsulfonyl) -L-arginyl chloride.
li _2 21 7231 6 (C) Etyyli-1-^N - (trisubstituoitu fenyylisulfonyyli)-L-arginyyli7-4-metyyli-2-piperidiinikarboksylaatti.li 2 21 7231 6 (C) Ethyl 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate.
Sekoitettuun liuokseen, jossa oli 1,7 g 4-metyyli-2-piperi- diinikarboksyylihapon etyyliesteriä ja 4,0 ml trietyyliamii- nia 50 ml:ssa kloroformia ja jota jäähdytettiin jää-suola- 2 hauteella, lisättiin varovasti yllä valmistettua N -(tri- substituoitua fenyylisulfonyyli)-L-arginyylikloridia. Reak- tioseosta sekoitettiin yön yli huoneen lämpötilassa. Tämän ajanjakson lopussa lisättiin 50 ml kloroformia ja klorofor- miliuos pestiin kahdesti 25 ml:11a kyllästettyä natrium- kloridiliuosta, kuivattiin vedettömällä natriumsulfaatilla ja haihdutettiin tyhjössä, öljymäinen jäännös pestiin etyyli- -2 eetterillä, jolloin saatiin 2,1 g jauhemaista etyyli-1-/N -(trisubstituoitua fenyylisulfonyyli)-L-arginyyli/-4-metyyli- 2-piperidiinikarboksylaattia.To a stirred solution of 1.7 g of 4-methyl-2-piperidinecarboxylic acid ethyl ester and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt 2 bath, was carefully added the N - (tri - substituted phenylsulfonyl) -L-arginyl chloride. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform were added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo, the oily residue was washed with ethyl-2-ether to give 2.1 g of a powdery ethyl-1 / N- (trisubstituted phenylsulfonyl) -L-arginyl / -4-methyl-2-piperidinecarboxylate.
-2 — (D) 1-/N -(trisubstituoitu fenyylisulfonyyli)-L-arginyyli/- 4-metyyli-2-piperidiinikarboksyylihappo.2- (D) 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid.
_2_2
Liuos, jossa oli 2,0 g etyyli-1-^N -(trisubstituoitua fenyylisulf onyyli) -L-arginyyli7~4-metyyli-2-piperidiinikarboksylaat-tia 10 mlsssa metanolia ja 10 mlrssa 2N NaOH-liuosta, lämmitettiin lämpötilaan 40°C ja pidettiin tässä lämpötilassa 10 tuntia. Tämän ajanjakson lopussa reaktioseos väkevöitiin ja (r) kromatografoitiin 200 ml:11a Daiaion ^ SK 102-ioninvaihto-hartsia (200-300 mesh, H+-muoto, valmistaja Mitsubishi Chemical Industries Limited), joka oli pakattu veteen ja pesty etanoli/vedellä (1:4), eluoiden etanoli/vesi/NH^OH:11a (10:9:1). Pääfraktio haihdutettiin kuiviin ja pestiin etyyli-eetterillä, jolloin saatiin 1,2 g (69 %) 1-/N -(trisubstituoitua fenyylisulfonyyli)-L-arginyyli7_4-metyyli-2-piperidiini-karboksyylihappoa amorfisena kiinteänä aineena.A solution of 2.0 g of ethyl 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylate in 10 ml of methanol and 10 ml of 2N NaOH solution was heated to 40 ° C. and maintained at this temperature for 10 hours. At the end of this period, the reaction mixture was concentrated and (r) chromatographed on 200 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H + form, manufactured by Mitsubishi Chemical Industries Limited) packed in water and washed with ethanol / water (1 : 4), eluting with ethanol / water / NH 4 OH (10: 9: 1). The main fraction was evaporated to dryness and washed with ethyl ether to give 1.2 g (69%) of 1- [N- (trisubstituted phenylsulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid as an amorphous solid.
22
Erilaisia muita N -aryylisulfonyyli-L-arginiiniamideja tai niiden happoadditiosuoloja valmistettiin synteettisesti edellä esitetyissä esimerkeissä kuvattujen menetelmien avulla ja koetulokset on esitetty taulukossa 1.Various other N-arylsulfonyl-L-argininamides or their acid addition salts were prepared synthetically by the methods described in the above examples, and the experimental results are shown in Table 1.
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Seuraavassa taulukossa 2 esitetyt yhdisteet valmistettiin samalla tavoin. Tässä taulukossa esitetty viittaus aikaisempaan tekniikkaan (taulukon toisessa sarakkeessa) esittää sen yhdisteen valmistusmenetelmän, joka on esitetty toisessa sarakkeessa.The compounds shown in Table 2 below were prepared in a similar manner. The reference to the prior art in this table (in the second column of the table) shows the production method of the compound shown in the second column.
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te "m <n r^| Ote "m <n r ^ | O
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<Ö e W __/ ' n 2' Z<Ö e W __ / 'n 2' Z
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o u g So u g S
ro -H -H a n « λ; 2 mi «a* ij —- -e ro ”· ^ (¾ ·*τ| • <ro -H -H a n «λ; 2 mi «a * ij —- -e ro” · ^ (¾ · * τ | • <
_>3 U_> 3 U
O roro ·· 2 -------O roro ·· 2 -------
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI842539A FI74455C (en) | 1977-01-19 | 1984-06-21 | PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL ACTIVATED N2-ARYLSULFONYL-L-ARGININAMIDER OR PHARMACEUTICAL ACCEPTABLA SALTER DAERAV. |
Applications Claiming Priority (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76067277 | 1977-01-19 | ||
US76074577 | 1977-01-19 | ||
US05/760,668 US4073913A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
US76066877 | 1977-01-19 | ||
US05/760,929 US4101653A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-argininamides and the pharmaceutically acceptable salts thereof |
US76067677 | 1977-01-19 | ||
US76092977 | 1977-01-19 | ||
US05/760,672 US4093712A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
US05/760,676 US4097472A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-l-argininamides and the pharmaceutically acceptable salts thereof |
US05/760,745 US4066773A (en) | 1974-11-08 | 1977-01-19 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
US77619577 | 1977-03-10 | ||
US05/776,195 US4097591A (en) | 1974-11-08 | 1977-03-10 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
JP6650877 | 1977-06-06 | ||
JP6650877A JPS6010028B2 (en) | 1977-06-06 | 1977-06-06 | N↑2-arylsulfonyl-L-argininamides and pharmaceutically acceptable salts thereof |
US80433177 | 1977-06-07 | ||
US05/804,331 US4140681A (en) | 1974-11-08 | 1977-06-07 | N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
US80436877 | 1977-06-07 | ||
US05/804,368 US4131673A (en) | 1974-11-08 | 1977-06-07 | N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
FI780073A FI780073A (en) | 1978-07-20 |
FI72316B true FI72316B (en) | 1987-01-30 |
FI72316C FI72316C (en) | 1987-05-11 |
Family
ID=27577127
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI780073A FI72316C (en) | 1977-01-19 | 1978-01-10 | Process for the preparation of pharmaceutically active N2-arylsulfonyl-L-argininamides and pharmaceutically acceptable salts thereof. |
Country Status (17)
Country | Link |
---|---|
CA (1) | CA1131621A (en) |
CH (2) | CH648293A5 (en) |
DD (1) | DD137352A5 (en) |
DE (1) | DE2801478A1 (en) |
DK (1) | DK150521C (en) |
FI (1) | FI72316C (en) |
GB (1) | GB1596971A (en) |
GR (1) | GR60787B (en) |
IL (1) | IL53685A (en) |
IT (1) | IT1126229B (en) |
NL (1) | NL187746C (en) |
NO (1) | NO158681C (en) |
NZ (1) | NZ186198A (en) |
PH (1) | PH15913A (en) |
SE (1) | SE452624B (en) |
SU (1) | SU1181539A3 (en) |
UA (1) | UA8370A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE48623B1 (en) * | 1978-08-31 | 1985-03-20 | Mitsubishi Chem Ind | Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances |
JPS5533499A (en) * | 1978-08-31 | 1980-03-08 | Mitsubishi Chem Ind Ltd | N2-arylsulfonyl-l-arginineamide and its pharmaceutically acceptable salt |
GB9209032D0 (en) * | 1992-04-25 | 1992-06-10 | Ciba Geigy Ag | New peptide derivatives |
GB9426038D0 (en) | 1994-12-22 | 1995-02-22 | Iaf Biochem Int | Low molecular weight bicyclic thrombin inhibitors |
US6057314A (en) * | 1995-12-21 | 2000-05-02 | Biochem Pharma Inc. | Low molecular weight bicyclic thrombin inhibitors |
FR2761065B1 (en) * | 1997-03-20 | 2000-03-03 | Synthelabo | N- (ARGINYL) BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
CN111961114A (en) * | 2020-08-03 | 2020-11-20 | 扬州中宝药业股份有限公司 | Argatroban intermediate and preparation method and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3978045A (en) * | 1973-08-13 | 1976-08-31 | Mitsubishi Chemical Industries Ltd. | N2 -dansyl-L-arginine derivatives, and the pharmaceutically acceptable acid addition salts thereof |
-
1977
- 1977-12-16 CA CA293,199A patent/CA1131621A/en not_active Expired
- 1977-12-23 IL IL53685A patent/IL53685A/en unknown
- 1977-12-27 IT IT31297/77A patent/IT1126229B/en active
-
1978
- 1978-01-10 FI FI780073A patent/FI72316C/en not_active IP Right Cessation
- 1978-01-11 NZ NZ186198A patent/NZ186198A/en unknown
- 1978-01-13 DE DE19782801478 patent/DE2801478A1/en active Granted
- 1978-01-13 NL NLAANVRAGE7800448,A patent/NL187746C/en not_active IP Right Cessation
- 1978-01-13 PH PH20660A patent/PH15913A/en unknown
- 1978-01-17 SE SE7800512A patent/SE452624B/en not_active IP Right Cessation
- 1978-01-18 GB GB2063/78A patent/GB1596971A/en not_active Expired
- 1978-01-18 NO NO780191A patent/NO158681C/en unknown
- 1978-01-18 SU SU782566652A patent/SU1181539A3/en active
- 1978-01-18 CH CH4530/82A patent/CH648293A5/en not_active IP Right Cessation
- 1978-01-18 UA UA2776611A patent/UA8370A1/en unknown
- 1978-01-18 CH CH51978A patent/CH633773A5/en not_active IP Right Cessation
- 1978-01-18 DK DK026378A patent/DK150521C/en not_active IP Right Cessation
- 1978-01-18 GR GR55191A patent/GR60787B/en unknown
- 1978-01-19 DD DD78203302A patent/DD137352A5/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO780191L (en) | 1978-07-20 |
GB1596971A (en) | 1981-09-03 |
CH633773A5 (en) | 1982-12-31 |
SE7800512L (en) | 1978-07-20 |
NO158681C (en) | 1988-10-19 |
UA8370A1 (en) | 1996-03-29 |
FI72316C (en) | 1987-05-11 |
DK150521B (en) | 1987-03-16 |
GR60787B (en) | 1978-08-28 |
DD137352A5 (en) | 1979-08-29 |
NO158681B (en) | 1988-07-11 |
DK26378A (en) | 1978-07-20 |
PH15913A (en) | 1983-04-22 |
NL187746B (en) | 1991-08-01 |
IL53685A0 (en) | 1978-03-10 |
NL7800448A (en) | 1978-07-21 |
IL53685A (en) | 1985-12-31 |
FI780073A (en) | 1978-07-20 |
NL187746C (en) | 1992-01-02 |
DE2801478A1 (en) | 1978-07-20 |
DE2801478C2 (en) | 1991-01-31 |
DK150521C (en) | 1987-10-19 |
SU1181539A3 (en) | 1985-09-23 |
CA1131621A (en) | 1982-09-14 |
NZ186198A (en) | 1980-12-19 |
CH648293A5 (en) | 1985-03-15 |
IT1126229B (en) | 1986-05-14 |
SE452624B (en) | 1987-12-07 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MA | Patent expired | ||
MA | Patent expired |
Owner name: MITSUBISHI KASEI CORPORATION Owner name: OKAMOTO, SHOSUKE |