LV12403B - Cytotoxicaly derivatives of penicillanic acid - Google Patents

Abstract

The present invention pertains to the pharmacologically active substances, particularly to cytotoxically agents for chemotherapy for cancer. The said compounds contain modifying penicillin sulfoxide esters or penicillin sulfone esters having specifically selected substituents in the position 6 and in the 2-beta-methylgroup. According results of experiments the invented substances have cytotoxically quality in vitro on cell-lines HT 1080, MG-22A and B 16: by using law-concentration of said substances there is observable death of 50 % cells. There is observed direct correlation between cytotoxically activity of studied compounds and their ability to induce biosynthesis of NO in cells. Compounds having expressed cytotoxically activities have considerably extent the mentioned ability to induce biosynthesis.

Description

CITOTOKSISKIE PENICILĀNSKĀBES ATVASINĀJUMICYTOTOXIC PENICYLANIC ACID DERIVATIVES

Izgudrojums attiecas uz jaunām farmakoloģiski aktīvām vielām, konkrēti uz citotoksiskiem preparātiem vēža ķīmioterapijai, kas satur penicilānskābes sulfoksīdus vai sulfonus ar speciāli izvēlētiem aizvietotājiem penāma ciklā 2. un 6. stāvoklī.. Ir zināms, ka šāda tipa savienojumi tiek lietoti kā starpprodukti β-laktamāzes inhibitoru sintēzē [1-3]. Taču šajā ķīmisko savienojumu klasē nav atrastas vielas ar citotoksisku aktivitāti.The present invention relates to novel pharmacologically active substances, in particular to cytotoxic preparations for cancer chemotherapy containing penicillanic acid sulfoxides or sulfones with specially selected substituents in the penam cycle at positions 2 and 6. in synthesis [1-3]. However, no substances with cytotoxic activity have been found in this class of chemical compounds.

Izgudrojuma mērķis ir jaunu savienojumu sintēze, kuri, pateicoties pastiprinātai slāpekļa oksīda biosintēzei ļaundabīgo audzēju šūnās, raksturojas ar augstu citotoksisko aktivitāti. Tas ir jauns pretvēža darbības mehānisms, kas atšķir piedāvātos penicilīna sulfoksīdus un sulfonus no jau zināmiem pretvēža preparātiem, kuru darbības mehānisms ir saistīts ar aikilējošām, antimetaboiiskajām, imunostimulējošām vai hormonālām īpašībām [4],The object of the invention is the synthesis of novel compounds which are characterized by high cytotoxic activity due to enhanced nitric oxide biosynthesis in malignant cells. It is a novel anticancer mechanism that distinguishes penicillin sulfoxides and sulfones from known anticancer agents which have an alkylating, antimetabolic, immunostimulatory or hormonal action [4],

Šo mērķi izdevās sasniegt, lietojot kā citotoksiskas vielas jau zināmus, kā arī jaunus poliaizvietota penicilīna sulfoksīda un suifona esterus, kuri iegūti pēc shēmas 1 un ietver sekojošas reakcijas:This objective was achieved by using already known cytotoxic agents, as well as the novel poly-substituted penicillin sulfoxide and sifone esters obtained according to Scheme 1, which include the following reactions:

• 3. stāvoklī neaizvietotu kā ari aizvietotu 2-[4-(heterilditio)-2-okso-azetidinil-l]-2-(zzopropenil)-acetātu 1 ciklizāciju 2P-monometilaizvietotos penicilanātos;• cyclization of the unsubstituted and substituted 2- [4- (heterildithio) -2-oxo-azetidinyl-1] -2- (zzopropenyl) -acetates at the 3-position to 2P-monomethyl-substituted penicillates;

• 6-oksopenicilānskābes esteru 5 kondensāciju ar fosforilīdiem 6;• condensation of 6-oxo-penicillanic acid esters 5 with phosphorylides 6;

• 2P-monometilaizvietotu penicilanātu un 6-alkilidēnpenicilanātu oksidēšanu ar KMnO₄ vai• oxidation of 2P-monomethyl substituted penicillanates and 6-alkylidene penicillanates with KMnO ₄ or

3-hlorbenzopārskābi (3-HBPS) līdz sulfoksīdam vai sulfonam 2-4, 7.3-Chlorobenzoic acid (3-HBPS) to sulfoxide or sulfone 2-4, 7.

Patentējamo savienojumu citotoksiskā aktivitāte in vitro tika testēta uz četrām šūnu līnijām: MG-22A (peļu hepatoma), HT-1080 (cilvēka fibrosarkoma), Neiro 2A (peļu neiroblastoma) un B 16 (peļu melanoma). Iegūtie rezultāti atspoguļoti 1. un 2. tabulās Citotoksiskais efekts tika izvērtēts, aprēķinot testējamā savienojuma ietekmē bojā gājušo šūnu daudzumu imunoloģiskajās platītēs ar divu kolorimetrisko metožu palīdzību:The cytotoxic activity of the patented compounds was tested in vitro on four cell lines: MG-22A (murine hepatoma), HT-1080 (human fibrosarcoma), Neiro 2A (murine neuroblastoma) and B16 (murine melanoma). The results obtained are shown in Tables 1 and 2 The cytotoxic effect was evaluated by calculating the number of cells killed by the test compound in the immunological plates using two colorimetric methods:

• krāsojot tās ar kristālviolēto CV ( krāsvielu absorbē dzīvo šūnu membrānas), • krāsojot tās ar 3-(4,5-dimetiltiazol-2-il )-2,5-difeniltetrazolijbromīdu MTT (krāsvielu absorbē dzīvo šūnu mitohondriālie enzīmi).• staining with crystal violet CV (dye is absorbed by living cell membranes) • staining with 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide MTT (dye absorbed by living cell mitochondrial enzymes).

Eksperimenta rezultāti rāda, ka savienojumu 2-4 citotoksiskais efekts (TD 50) attiecībā uz HT 1080, MG-22A šūnu līnijām ir novērojams pie vielu koncentrācijas 12-100 pg/ml (sk. 1. tabulā). 6-Alkilidēnpenicitīniem 7a-d šī iedarbība ir izteiktākā: HT 1080, MG-22A un B 16 50% šūnu bojā eja ir novērojama pie citotoksisko vielu koncentrācijas (TD ₅₀ ) 1-12 pg/ml (sk. 2. tabulā). Attiecībā uz Neiro 2A šūnu līniju citotoksiskais efekts ir novērots tikai savienojumam 7d.The results of the experiment show that the cytotoxic effect (TD 50) of compounds 2-4 on HT 1080, MG-22A cell lines is observed at concentrations of 12-100 pg / ml (see Table 1). For 6-alkylidene penicins 7a-d this effect is most pronounced: 50% cell death of HT 1080, MG-22A and B 16 is observed at cytotoxic concentrations (TD ₅₀ ) of 1-12 pg / ml (see Table 2). For the Neiro 2A cell line, cytotoxic effects were observed only for compound 7d.

Ir zināms, ka slāpekļa oksīda molekulām, kuras veidojas organisma šūnās, ir izteikta citotoksiskā iedarbība [5]. Spēja intensificēt NO biosintēzi ir raksturīga visiem patentējamajiem penicilīna atvasinājumam (sk. 1. un 2. tabulās) un to raksturo ar TGioo, kuru aprēķina pēc sekojošas formulas:Nitric oxide molecules, which are formed in cells of the body, are known to have pronounced cytotoxic effects [5]. The ability to intensify NO biosynthesis is characteristic of all patentable penicillin derivatives (see Tables 1 and 2) and is characterized by TGioo, which is calculated by the following formula:

TGioo = G_ex· 100/ C (ηΜ·10’7200μ1) kur: TGioo - savienojuma īpatnējā spēja ģenerēt NO biosintēzi, kas ir ekstrapolēta uz 100% dzīvo šūnu skaitu;TGioo = G _ex · 100 / C (ηΜ · 10'7200μ1) where: TGioo is the specific capacity of the compound to generate NO biosynthesis, which is extrapolated to 100% of living cells;

Gex - NO koncentrācija (nM) bioloģiskajā vidē, noteikta 200 μΐ (platītes iedobuma tilpums) pēc inkubācijas ar testēto vielu (10 vai 100 pg/ml);Gex - NO concentration (nM) in biological medium, determined at 200 μΐ (plate-well volume) after incubation with test substance (10 or 100 pg / ml);

C - izdzīvojušo šūnu daudzums procentos pēc inkubācijas ar testējamo vielu (izmantojot iekrāsošanu ar CV).C = percentage of surviving cells after incubation with test substance (using CV staining).

Shēma 1Scheme 1

a-ca-c

a) R=H, R¹=CHPh₂ a) R = H, R ¹ = CHPh ₂

b) R=CI, R¹=CHPh₂ b) R = Cl, R ¹ = CHPh ₂

c) R=CI, R¹=/-Buc) R = Cl, R ¹ = / - Bu

1. ClCH₂COOH, CH₃COOAg1. ClCH ₂ COOH, CH ₃ COOAg

a-ca-c

a) R=H, Hal=Cla) R = H, Hal = Cl

b) R=CI, Hai=Clb) R = Cl, Hal = Cl

c) R=CI, Hal=Brc) R = Cl, Hal = Br

COOR!COOR!

a, ba, b

a) R¹=CHPh₂ a) R ¹ = CHPh ₂

b) R¹=i-C₄H_g b) R ¹ = _i C ₄ H _g

1. R²CH=PPh₃ 1. R ² CH = PPh ₃

2. 3-HBPS2. 3-HBPS

COOR a-dCOOR a-d

a) R¹=CHPh₂, R²=/-BuOCO, n=1a) R ¹ = CHPh ₂ , R ² = / - BuOCO, n = 1

b) R¹=CHPh₂, R²=/-BuOCO, n=2b) R ¹ = CHPh ₂ , R ² = / - BuOCO, n = 2

c) R¹=/-Bu, IT=/-BuOCO, n=2 ·c) R ¹ = / - Bu, IT = / - BuOCO, n = 2 ·

d) R¹=/-Bu, R²=Ph, n=2d) R ¹ = / - Bu, R ² = Ph, n = 2

Tabula 1. Penicilānskabju esteru citotoksiska iedarbība, un to ietekme uz vēža šūnu spēju ģenerēt NO in vitroTable 1. Cytotoxic effects of Penicillan Scab Esters and their Effect on Cancer Cell Ability to Generate NO in vitro

Savie- nojumi Savie canopy Šūnu līnijas Cell lines HT-1080 HT-1080 MG-22A MG-22A td₅₀ (CV)³ td ₅₀ (CV) ³ TDso (MTT)^b TDso (MTT) ^b TG_1OO ^C TG _1oo ^C td₅₀ (CV)td ₅₀ (CV) td₅₀ (MTT)td ₅₀ (MTT) TGioo TGioo 2a 2a 50 50 50 50 850 850 50 50 50 50 243 243 2b 2b 100 100 >100 > 100 61 61 >100 > 100 >100 > 100 41 41 3a 3a 100 100 53 fifty three 800 800 60 60 90 90 142 142 3b 3b 13 13th 46 46 1100 1100 40 40 42 42 467 467 3c 3c 9 9th 42 42 800 800 45 45 34 34 797 797 4 4 29 29th 12 12th 900 900 45 45 28 28th 950 950

³ vielu koncentrācija (pg/ml), kura izsauc 50% šūnu bojā eju, nosakot to ar CV krāsošanas metodi ^b vielu koncentrācija (pg/ml), kura izsauc 50% šūnu bojā eju, nosakot to ar MTT krāsošanas metodi ^c savienojuma īpatnējā spēja ģenerēt NOConcentration of ³ substances (pg / ml) causing 50% cell death as determined by CV staining ^b Concentration (pg / ml) causing 50% cell death as determined by MTT staining ^c specificity generate NO

Eksperimentālā dalaExperimental part

Peniciiīni 2 - 4 un 7 iegūti pēc sekojošām metodēm;Penicillins 2-4 and 7 were obtained by the following methods;

Piemērs 1Example 1

Benzhidril-2P-benzotiazolilsulfonilmetil-2a-metilpenām-3a-karboksilāta sulfons (2a) Benzhidril-2-[4-(2-benzotiazolilditio)-2-okso-azetidinil-l]-2-(zzo-propenil)-acetāta (340 mg, 0,51 mM) šķīdumam 14 ml dihiormetānā nitrometānā (1:1) pieliek BF₃-Et₂O (0,05 ml). Reakcijas maisījumu iztur 24 stundas istabas temperatūrā un šķīdinātājus ietvaicē pie pazemināta spiediena. Atlikumu (0,17 g) šķīdina etiķskābē (3,5 ml), pieliek ūdeni (1,0 ml) un KMnO₄ (600 mg, 3,8 mM). Suspensiju maisa 2 stundas istabas temperatūrā, atdzesē ledus ūdens vannā un KMnO₄ pārākumu reducē ar ūdeņraža peroksīdu, atšķaida ar ūdeni (30 ml) un ekstraģē ar dihlormetānu (30 ml). Organisko fāzi mazgā ar piesātinātu NaHCO₃ šķīdumu, žāvē ar Na₂SO₄. Dihlormetānu atdestilē pie pazemināta spiediena, atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas (eluents: benzols acetons, 4:1). Iegūst 100 mg (54%) benzhidril-23-benzotiazolilsulfonilmetil-2a-metilpenām-3a-karboksilāta sulfonu, k.t. 170-171°C. Pamatvielas saturs: 93% (pēc AEŠH).Benzhydryl-2P-benzothiazolylsulfonylmethyl-2a-methylpenamine-3a-carboxylate sulfone (2a) Benzhydryl-2- [4- (2-benzothiazolylthiothio) -2-oxo-azetidinyl-1] -2- (zzo-propenyl) -acetate (340) mg, 0.51 mM) was added BF ₃ -Et ₂ O (0.05 mL) in 14 mL of dichloromethane in nitromethane (1: 1). The reaction mixture is allowed to stand for 24 hours at room temperature and the solvents are evaporated under reduced pressure. The residue (0.17 g) is dissolved in acetic acid (3.5 mL), water (1.0 mL) and KMnO ₄ (600 mg, 3.8 mM) are added. Suspension stirred for 2 hours at room temperature, cool in an ice water bath and _KMnO4 superiority reduced using hydrogen peroxide diluted with water (30 ml) and extracted with dichloromethane (30 ml). The organic phase is washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ . Dichloromethane is distilled off under reduced pressure, and the residue is chromatographed on a Merck Kieselgel (0.063-0.230 mm) column (eluent: benzene-acetone, 4: 1). 100 mg (54%) of benzhydryl-23-benzothiazolylsulfonylmethyl-2a-methylpenamine-3a-carboxylate sulfone are obtained, m.p. 170-171 ° C. Assay Content: 93% (by HPLC).

PMR (CDC1₃), δ: 1,52 (3H, s, CH₃); 3,48 (2H, m, 6-H); 3,90, 4,15 (2H, AB-q, >14, CH₂SO₂); 4,59 (IH, d, d, >2, >4, 5-H); 5,28 (IH, s, 3-H); 6,85 (IH, CHPh₂); 7,15-7,44 (10H, m, 2C6H₅); 7,48-8,28 (4H, m, CeH,).PMR (CDCl ₃ ), δ: 1.52 (3H, s, CH ₃ ); 3.48 (2H, m, 6-H); 3.90, 4.15 (2H, AB-q, > 14, CH ₂ SO ₂ ); 4.59 (1H, d, d,>2,> 4, 5-H); 5.28 (1H, s, 3-H); 6.85 (1H, CHPh ₂ ); 7.15 to 7.44 (10H, m, 2C6H _5); 7.48-8.28 (4 H, m, Ce H).

Atr. % : C 56,55; H 4,14; N 4,64. C₂₈H₂₄N₂O₇S₃. Apr. %: C 56,36; H 4,05; N 4,68.Discover %: C, 56.55; H, 4.14; N, 4.64. C ₂₈ H ₂₄ N ₂ O ₇ S ₃ . Apr. %: C, 56.36; H, 4.05; N, 4.68.

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Piemērs 2Example 2

Benzhidril-23-benzotiazoIilsulfonilmetil-6a-hlor-2a-metilpenām-3a-karboksilāta sulfons (2b)Benzhydryl-23-benzothiazolylsulfonylmethyl-6a-chloro-2a-methylpenamine-3a-carboxylate sulfone (2b)

Savienojumu sintezē no benzhidril-2-[4-(2-benzotiazolilditio)-3-hlor-2-okso-azetidinil-l]-2(zzo-propenil)-acetāta (500 mg, 0,96 mM) saskaņā ar 1. piemērā uzrādīto metodi, izmantojot kolonu hromatogrāfijai eluentu etilacetāts-heksāns (1:2). Iegūst 40 mg (6,6%) benzhidril-2Pbenzotiazolilsulfonilmetil-6a-hlor-2a-metilpenām-3a-karboksilāta sulfonu, k.t. 57-59°C. Pamatvielas saturs 97% (pēc AEŠH).The compound is synthesized from benzhydryl-2- [4- (2-benzothiazolyldithio) -3-chloro-2-oxo-azetidinyl-1] -2- (2-isopropyl) -acetate (500 mg, 0.96 mM) according to Example 1. Example 1 using ethyl acetate-hexane (1: 2) as the eluent for column chromatography. 40 mg (6.6%) of benzhydryl-2-benzothiazolylsulfonylmethyl-6a-chloro-2a-methylpenam-3a-carboxylate sulfone are obtained, m.p. 57-59 ° C. Content of the basic substance 97% (based on AESH).

PMR (CDC1₃), δ: 1,37 (3H, s, CH₃); 3,67, 4,13 (2H, AB-q, J=14, CH₂S ); 5,04 (IH, s, 3-H); 5,13 (IH, d J=lHz, 5-H); 5,40 (IH, d J=lHz, 6-H); 7,00 (IH, CHPh₂); 7,22-8,00 (14H, m, 2CeH5, C6H4).PMR (CDCl ₃ ), δ: 1.37 (3H, s, CH ₃ ); 3.67, 4.13 (2H, AB-q, J = 14, CH ₂ S); 5.04 (1H, s, 3-H); 5.13 (1H, d J = 1Hz, 5-H); 5.40 (1H, d J = 1Hz, 6-H); 7.00 (1H, CHPh ₂ ); 7.22-8.00 (14H, m, 2CeH5, C6H4).

Atr. % : C 53,43; H 4,03; N 4,15. C₂₈H23C1N₂O₇S₃ Apr. %: C 53,28; H 3,67; N 4,43.Discover %: C, 53.43; H, 4.03; N, 4.15. C ₂₈ H23C1N ₂ O ₇ S ₃ Apr. %: C, 53.28; H, 3.67; N, 4.43.

Benzhidril-2P-hlormetil-2a-metilpenām-3a-karboksilāta sulfons (3a) sintezēts saskaņā ar metodi [2],Benzhydryl-2P-chloromethyl-2a-methylpenam-3a-carboxylate sulfone (3a) was synthesized according to method [2],

Benzhidril--2P-hlormetil-6a-hlor-2a-metilpenām-3a-karboksilāta sulfons (3b) sintezēts saskaņā ar metodi [2].Benzhydryl-2P-chloromethyl-6a-chloro-2a-methylpenam-3a-carboxylate sulfone (3b) was synthesized according to method [2].

BenzhidriI-2P-brommetiI-6a-hlor-2ct-metilpenām-3a-karboksilāta sulfons (3c) sintezēts saskaņā ar metodi [2],Benzhydryl-2β-bromomethyl-6α-chloro-2α-methylpenamine-3α-carboxylate sulfone (3c) was synthesized according to method [2],

Piemērs 3Example 3

Benzhidril-2P-hloracetoksimetil-6-hlor-2a-metilpenām-3a-karboksi]āta sulfons (4)Benzhydryl-2P-chloroacetoxymethyl-6-chloro-2a-methylpenamine-3a-carboxylate sulfone (4)

Sudraba acetāta (0,84 g, 5 mM) suspensijai dihlormetānā (40 ml) pieliek hloretiķskābi (8,40 g, 87,5 mM) un benzhidril-2-[4-(2-benzotiazolilditio)-3-hlor-2-okso-azetidinil-l]-2(zzo-propenil)-acetātu (1,46 g, 2,5 mM) dihlormetānā (5 ml). Reakcijas maisījumu iztur 4 stundas istabas temperatūrā. Suspensiju filtrē caur silikagela kolonu. Organisko fāzi mazgā ar piesātinātu NaHCO₃ šķīdumu, žāvē ar Na₂SO4 un dihlormetānu atdestilē pie pazemināta spiediena. Atlikumam uzlej ēteri (2 ml), pēc ietvaicēšanas iegūst 820 mg (64%) kristāliska benzhidril-2P-hloracetoksimetil-2a-metilpenām-3a-karboksilāta. Pamatvielas saturs 80% (pēc AEŠH).To a suspension of silver acetate (0.84 g, 5 mM) in dichloromethane (40 mL) was added chloroacetic acid (8.40 g, 87.5 mM) and benzhydryl-2- [4- (2-benzothiazolyldithio) -3-chloro-2- oxo-azetidinyl-1] -2- (2-isopropenyl) acetate (1.46 g, 2.5 mM) in dichloromethane (5 mL). The reaction mixture is allowed to stand for 4 hours at room temperature. The suspension is filtered through a silica gel column. The organic phase is washed with a saturated solution of NaHCO ₃ , dried over Na ₂ SO 4 and distilled under reduced pressure. The residue was poured into ether (2 mL) and evaporated to give 820 mg (64%) of crystalline benzhydryl-2P-chloroacetoxymethyl-2a-methylpenam-3a-carboxylate. Content of the basic substance 80% (by HPLC).

Benzhidril-2P-hloracetoksimetil-2a-metilpenām-3a-karboksilāta (500 mg, 1,15 mM) šķīdumam etiķskābē (10 ml) pieliek ūdeni (1,7 ml) un KMnO4 (320 mg, 2,02 mM). Suspensiju maisa istabas temperatūrā 3 stundas, atdzesē ledus ūdens vannā, un KMnO₄ pārākumu reducē ar ūdeņraža peroksīdu. Reakcijas maisījumu atšķaida ar ūdeni un dihlormetānu. Organisko fāzi mazgā ar piesātinātiem NaHCO₃ un NaCI šķīdumiem, žāvē ar Na₂SO4. Šķīdumu ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eluents: heksāns.etilacetāts (3:1).Iegūst 232 mg (40%) benzhidril-2P-hloracetoksimetil-2a-metilpenām-3a-karboksilāta sulfonu, k.t. 57-59°C. Pamatvielas saturs 98% (pēc AEŠH).To a solution of benzhydryl-2P-chloroacetoxymethyl-2a-methylpenam-3a-carboxylate (500 mg, 1.15 mM) in acetic acid (10 mL) was added water (1.7 mL) and KMnO4 (320 mg, 2.02 mM). The suspension is stirred at room temperature for 3 hours, cooled in an ice-water bath and the excess KMnO ₄ is reduced with hydrogen peroxide. The reaction mixture was diluted with water and dichloromethane. The organic phase is washed with saturated solutions of NaHCO ₃ and NaCl, dried over Na ₂ SO 4. Evaporate the solution under reduced pressure. Chromatograph the residue on a column of Merck Kieselgel (0.063-0.230 mm), eluent: hexane: ethyl acetate (3: 1). Obtain 232 mg (40%) of benzhydryl-2P-chloroacetoxymethyl-2a-methylpenam-3a-carboxylate sulfone, m.p. 57-59 ° C. Content of basic material 98% (by HPLC).

PMR (CDC1₃), δ: 1,33 (3H, s, CH₃); 3,78, 4,00 (2H, d,d, J=12, CH₂C1); 4,71 (IH, d J=lHz, 5-H); 4,80 (IH, s, 3-H); 5,17 (IH, d J=lHz, 6-H); 6,97 (IH, CHPh₂); 7,40 (10H, m, 2C₆H₅).PMR (CDCl ₃ ), δ: 1.33 (3H, s, CH ₃ ); 3.78, 4.00 (2H, d, d, J = 12, CH ₂ Cl); 4.71 (1H, d J = 1 Hz, 5-H); 4.80 (1H, s, 3-H); 5.17 (1H, d J = 1Hz, 6-H); 6.97 (1H, CHPh ₂ ); 7.40 (10H, m, 2C ₆ H ₅ ).

Piemērs 4.Example 4.

Benzhidril-6(Z)-terc-butoksikarbonilmetiIēnpenicilanāta 1-oksīds (7a).Benzhydryl-6 (Z) -tert-butoxycarbonylmethylene penicillanate 1-oxide (7a).

Benzhidril-6(Z)-/erobutoksikarbonilmetilēnpenicilanāta [3] (500 mg, 1,04 mM) šķīdumu dihlormetānā (20 ml) atdzesē līdz O’C, pieliek 3-hlorbenzopārskābi (180 mg, 1,04 mM) un maisa 1 stundu pie 0“C un 1 stundu istabas temperatūrā. Reakcijas maisījumu mazgā ar piesātinātiem NaHCO₃ un NaCI šķīdumiem, žāvē ar Na₂SŪ4. Šķīdumu ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eluents: etilacetāts heksāns (1:1). Iegūst 250 mg (48%) benzhidril-6(Z)-/erc-butoksikarbonilmetilēnpenicilanāta sulfoksīdu, k.t. 179-181°C.A solution of benzhydryl-6 (Z) - / erobutoxycarbonylmethylene penicillanate [3] (500 mg, 1.04 mM) in dichloromethane (20 mL) was cooled to O'C, added with 3-chlorobenzoic acid (180 mg, 1.04 mM) and stirred for 1 hour. at 0 C and 1 hour at room temperature. The reaction mixture is washed with saturated solutions of NaHCO ₃ and NaCl, dried over Na ₂ SO 4. Evaporate the solution under reduced pressure. Chromatograph the residue on a Merck Kieselgel (0.063-0.230 mm) column, eluting with ethyl acetate-hexane (1: 1). 250 mg (48%) of benzhydryl-6 (Z) - tert -butoxycarbonylmethylene penicillanate sulfoxide are obtained, m.p. 179-181 ° C.

PMR (CDCb), δ: 0,98 (3H, s, 2-CH₃); 1,51 (9H, s, C4H9); 1,67 (3H, s, 2-CH₃); 4,78 (IH, s, 3-H); 5,68 (IH, d, J=2, 5-H); 6,49 (IH, d, >2, -CH=); 7,01 (IH, CHPh₂); 7,34 (10H, s, 2C₆H₅).PMR (CDCl 3), δ: 0.98 (3H, s, 2-CH ₃ ); 1.51 (9H, s, C 4 H 9); 1.67 (3H, s, 2-CH _3); 4.78 (1H, s, 3-H); 5.68 (1H, d, J = 2.5-H); 6.49 (1H, d,> 2, -CH =); 7.01 (1H, CHPh ₂ ); 7.34 (10H, s, 2 C ₆ H ₅ ).

Atr. % : C 56,55; H 4,14; N 4,64. C₂₈H₂4N₂O₇S₃ Apr. %: C 56,36; H 4,05; N 4,68.Discover %: C, 56.55; H, 4.14; N, 4.64. C ₂₈ H ₂ 4N ₂ O ₇ S ₃ Apr. %: C, 56.36; H, 4.05; N, 4.68.

BenzhidriI-6(Z)-fcrobutoksikarbonilmetiIenpenicilanāta sulfons (7b) sintezēts saskaņā ar metodi [3],Benzhydryl-6 (Z) -carbutoxycarbonylmethylene-penicillanate sulfone (7b) was synthesized according to method [3],

Piemērs 5.Example 5.

7erc-butil-6(Z)-terc-butoksikarboniImetilēnpeniciIanāta sulfons (7c).7ert-Butyl-6 (Z) -tert-butoxycarbonylmethylene-penicillanate sulfone (7c).

7erc-butil-6-oksopenicilanāta (1,00 g, 3,69 mM) un terobutoksikarbonilmetilēntrifenilfosforāna (1,60 g, 4,43 mM) šķīdumu dihlormetānā (30 ml) maisa istabas temperatūrā 2 stundas. Šķīdinātāju ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eluents: etilacetāts heksāns (1:1). Iegūst 250 mg (15%) terc-butil-6-terc-butoksikarbonilmetilēnpenicilanāta Z un E izomēru maisījumu.A solution of 7-tert-butyl-6-oxo-penicillanate (1.00 g, 3.69 mM) and terobutoxycarbonylmethylene triphenylphosphorane (1.60 g, 4.43 mM) in dichloromethane (30 mL) was stirred at room temperature for 2 hours. The solvent is evaporated off under reduced pressure. Chromatograph the residue on a Merck Kieselgel (0.063-0.230 mm) column, eluting with ethyl acetate-hexane (1: 1). 250 mg (15%) of a mixture of Z and E isomers of tert-butyl 6-tert-butoxycarbonylmethylene penicillate are obtained.

7erc-butil-6-terc-butoksikarbonilmetilēnpenicilanāta (200 mg, 0,54 mM) šķīdumu dihlormetānā (20 ml) atdzesē Sdz 0 “ C, pieliek 3-hlorbenzopārskābi (400 mg, 2,32 mM) un maisa 1 stundu pie 0 ’ C un 1 stundu istabas temperatūrā. Reakcijas maisījumu mazgā ar piesātinātiem NaHCO₃ un NaCI šķīdumiem, žāvē ar Na₂SC>4. Šķīdumu ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eiuents: etilacetāts heksāns (1:1). Iegūst 120 mg (57%) terc-butil-6(Z)-terc-butoksikarbonilmetilēnpeniciIanāta sulfonu, k.t. 138-140°C. Pamatvielas saturs 90% (pēc AEŠH).A solution of 7-tert-butyl-6-tert-butoxycarbonylmethylene penicillanate (200 mg, 0.54 mM) in dichloromethane (20 mL) was cooled to 0 DEG C., added with 3-chlorobenzoic acid (400 mg, 2.32 mM) and stirred for 1 hour at 0 '. C and 1 hour at room temperature. The reaction mixture is washed with saturated solutions of NaHCO ₃ and NaCl, dried with Na ₂ SC> 4. Evaporate the solution under reduced pressure. Chromatograph the residue on a Merck Kieselgel (0.063-0.230 mm) column, eluting with ethyl acetate: hexane (1: 1). 120 mg (57%) of tert-butyl-6 (Z) -tert-butoxycarbonylmethylene penicillanate sulfone are obtained, m.p. 138-140 ° C. Content 90% (by HPLC).

PMR (CDC1₃), δ: 1,28 (3H, s, CH₃); 1,44-1,66 (21H, m, CH₃, 2C4H9); 4,42 (IH, s, 3-H); 5,46 (IH, d, J=2, 5-H); 6,51 (IH, d, J=2, -CH=).PMR (CDCl ₃ ), δ: 1.28 (3H, s, CH ₃ ); 1.44-1.66 (21H, m, CH ₃ , 2C ₄ H 9); 4.42 (1H, s, 3-H); 5.46 (1H, d, J = 2.5, H); 6.51 (1H, d, J = 2, -CH =).

Piemērs 6.Example 6.

Terc-butil-6-benzilidēnpenicilanāta sulfons (7d).Tert-butyl 6-benzylidene penicillanate sulfone (7d).

7crc-butil-6-oksopenicilanāta (0,80 g, 2,95 mM) un benzilidēntrifenilfosfonijhlorida (2,60 g, 5,95 mM) šķīdumam dihlormetānā (40 ml) pieliek nātrijā hidrīdu (84 mg, 3,5 mM). Šķīdumu maisa istabas temperatūrā 2 stundas, mazgā ar atšķaidītu HCI, žāvē ar Na₂SO4. Šķīdinātāju ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eluents: etilacetāts petrolejas ēteris (1:2). Iegūst 500 mg (49%) Zerc-butil-6benzilidēnpenicilanāta Z un E izomēru maisījumu (3:1).Sodium hydride (84 mg, 3.5 mM) was added to a solution of 7c-butyl-6-oxopenicyanate (0.80 g, 2.95 mM) and benzylidene triphenylphosphonium chloride (2.60 g, 5.95 mM) in dichloromethane (40 mL). The solution is stirred at room temperature for 2 hours, washed with dilute HCl, dried with Na ₂ SO 4. The solvent is evaporated off under reduced pressure. Chromatograph the residue on a column of Merck Kieselgel (0.063-0.230 mm), eluting with ethyl acetate / petroleum ether (1: 2). 500 mg (49%) of a mixture of Z and E isomers of Zert-butyl-6-benzylidene penicillate (3: 1) are obtained.

7erc-butil-6-benzilidēnpenicilanāta (300 mg, 0,87 mM) šķīdumu dihlormetānā (20 ml) atdzesē līdz 0’C, pieliek 3-hlorbenzopārskābi (450 mg, 2,61 mM) un maisa 1 stundu pie 0‘C un 1 stundu istabas temperatūrā. Reakcijas maisījumu mazgā ar piesātinātiem NaHCO₃ un NaCI šķīdumiem, žāvē ar Na₂SO4. Šķīdumu ietvaicē pie pazemināta spiediena. Atlikumu hromatografe uz Merck Kieselgel (0,063-0,230 mm) kolonas, eluents: etilacetāts heksāns (1:2). Iegūst 100 mg (32%) terc-butil-6-benzilidēnpenicilanāta sulfona Z- un E-izomēru maisījumu (5:1). Pamatvielas saturs 98% (pēc AEŠH).A solution of 7-tert-butyl-6-benzylidene penicillanate (300 mg, 0.87 mM) in dichloromethane (20 mL) was cooled to 0'C, added with 3-chlorobenzoic acid (450 mg, 2.61 mM) and stirred for 1 hour at 0'C and 1 hour at room temperature. The reaction mixture is washed with saturated solutions of NaHCO ₃ and NaCl, dried over Na ₂ SO 4. Evaporate the solution under reduced pressure. Chromatograph the residue on a Merck Kieselgel (0.063-0.230 mm) column, eluting with ethyl acetate-hexane (1: 2). 100 mg (32%) of a mixture of Z- and E-isomers of the tert-butyl 6-benzylidene penicillanate sulfone are obtained (5: 1). Content of basic material 98% (by HPLC).

Z-izomērs. PMR (CDC1₃), δ: 1.40-1.67 (15H, m, 2CH₃, C4H9); 4,38 (IH, s, 3-H); 5,43 (IH, d, J=0,5, 5-H), 7,40 (IH, d, J=0,5, -CH=); 7.40-7.58 (3H, m, C₆H₅); 7.92-8.00 (2H, m, C₆H₅).Z-isomer. PMR (CDCl ₃ ), δ: 1.40-1.67 (15H, m, 2CH ₃ , C 4 H 9); 4.38 (1H, s, 3-H); 5.43 (1H, d, J = 0.5, 5-H), 7.40 (1H, d, J = 0.5, -CH =); 7.40-7.58 (3H, m, C ₆ H ₅ ); 7.92-8.00 (2H, m, C ₆ H ₅ ).

E-izomērs. PMR (CDC1₃), δ: 1.40-1.67 (15H, m, 2CH₃,C4H₉); 4,59 (IH, s, 3-H); 5,14 (IH, br.s, 5-H); 6,84 (IH, br.s, -CH=); 7.40-7.58 (5H, m, C₆H₅).E-isomer. PMR (CDCl ₃ ), δ: 1.40-1.67 (15H, m, 2CH ₃ , C ₄ H ₉ ); 4.59 (1H, s, 3-H); 5.14 (1H, br.s, 5-H); 6.84 (1H, br.s, -CH =); 7.40-7.58 (5H, m, C ₆ H ₅ ).

Citotoksisko efektu noteikšana in vitroDetermination of cytotoxic effects in vitro

Testējamo savienojumu šķīdumus dimetilsulfoksīdā ievadījām 96-lauciņu platīšu iedobēs kopā ar šūnām. Šūnas (3xl0⁴ šūnu/ml) kultivējām 72 stundas DMEM vidē bez indikatora un antibiotikām. Pēc ampulu atsaldēšanas šūnas pārsējām ne vairāk kā četras reizes. Kontrolšūnas bez preparāta kultivējām uz atsevišķas platītes. Citotoksisko efektu tika vērtēts pēc izdzīvojušo šūnu skaitu, ko noteica ar divām kolorimetriskām metodēm:Solutions of test compounds in dimethyl sulfoxide were injected into 96-well plates together with cells. Cells (3x10 ⁴ cells / ml) were cultured for 72 hours in DMEM medium without indicator and antibiotics. After thawing the ampoules, the cells were transfused no more than four times. Control cells without culture were cultured on a separate plate. The cytotoxic effect was evaluated by the number of surviving cells as determined by two colorimetric methods:

a) krāsojot ar kristālvioleto CV (krāsviela absorbējas uz dzīvo šūnu membrānām),a) staining with crystal violet CV (the dye is absorbed on the membranes of living cells),

b) krāsojot ar 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolijbromīdu) MTT (krāsviela absorbējas uz dzīvo šūnu mitohondriālajiem enzīmiem) [6],(b) staining with 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) MTT (the dye is absorbed by the mitochondrial enzymes of living cells) [6],

Dzīvo šūnu daudzumu kontrolpanelī pieņēmām par 100%.The amount of live cells in the control panel was assumed to be 100%.

Slāpekļa oksīda koncentrācija pētāmo vielu klātbūtnē tika noteikta ar Greisa metodi [7],The concentration of nitric oxide in the presence of test substances was determined by the Grace method [7],

Mēs patentējam:We patent:

1. Penicilānskābes atvasinājumi ar kopējo formulu:1. Penicillanic acid derivatives of the general formula:

kur: R un R‘ abi kopā vai atsevišķi ņemti ir ūdeņraža atomi, halogēns vai 'aizvietota metilēngrupa, Y ir ūdeņraža atoms, halogēni, aciloksigrupa vai 2-benzotiazoiilsulfongrupa, R² ir diarilalkil- vai alkilgrupas, n=l, 2.wherein: R and R ', taken together or individually, are hydrogen, halogen or' substituted methylene, Y is hydrogen, halogen, acyloxy or 2-benzothiazolylsulfon, R ² is diarylalkyl or alkyl, n = 1, 2.

2. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā vai atsevišķi ņemti ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no ūdeņraža un hlora; Y ir 2-benzotiazolilsulfongrupa un R² ir benzhidrilgrupa.Structural analogs of penicillin sulfone according to pl, wherein R and R ^1, taken together or separately, are substituents selected from the group consisting of hydrogen and chlorine; Y is 2-benzothiazolylsulfone and R ² is benzhydryl.

3. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā vai atsevišķi ņemti ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no ūdeņraža un hlora; Y ir hloracetoksigrupa; un R² ir benzhidrilgrupa.3. Penicillin sulfone structural analogues according to pl, wherein R and R ¹ taken together or separately are substituents selected from the group consisting of hydrogen and chlorine; Y is chloroacetoxy; and R ² is benzhydryl.

4. Penicilīna sulfoksīda vai sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no alkoksikarbonilmetilēn- vai arilmetilēngrupām un R² ir diarilalkil- vai alkilgrupas.Structural analogs of penicillin sulfoxide or sulfone according to pl, wherein R and R ¹ together are substituents selected from the group consisting of alkoxycarbonylmethylene or arylmethylene and R ² is diarylalkyl or alkyl.

5. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā ir aizvietotāji, kas izvēlēti no ferc-butoksikarbonilmetilēn- vai benzilidēngrupām un R² ir Zerc-butilgrupa.Structural analogs of penicillin sulfone according to pl, wherein R and R ¹ together are substituents selected from tert-butoxycarbonylmethylene or benzylidene and R ² is tert-butyl.

6. Penicilīna sulfoksīda vai sulfona struktūranalogu pēc p.l. pielietošana audzēju ārstēšanai.The structural analogue of penicillin sulfoxide or sulfone according to p.l. use in the treatment of tumors.

7. Penicilīna struktūranalogu pēc p.l. pielietošana audzēju ārstēšanai, kur: R un R^I= H, H un Cl, PhCH=; /-B«COOCH= ; Y= H, Cl, C1CH2COO, SO2-Het; Het = 2-benzotiazolil; R²= CHPh2, r-Bu; n=l, 2.Use of penicillin structural analogues after pl for the treatment of tumors wherein: R and R ^{1 =} H, H and Cl, PhCH =; / -B «COOCH =; Y = H, Cl, C1CH2COO, SO2-Het; Het = 2-benzothiazolyl; R ² = CHPh ² , r-Bu; n = 1, 2.

γί mγί m

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Freshliey P.J.; Culture of Animal Celis (A Manual of Basic Technique), Wiley-Liss, NewYork, 1994, 296-297.Freshliey P.J.; Culture of Animal Celis (A Manual of Basic Technique), Wiley-Liss, NewYork, 1994, 296-297.

Claims (7)

1. Penicilānskābes atvasinājumi ar kopējo formulu:1. Penicillanic acid derivatives of the general formula: kur: R un R¹ abi kopā vai atsevišķi ņemti ir ūdeņraža atomi, halogēns vai aizvietota metilēngrupa, Y ir ūdeņraža atoms, halogēni, aciloksigrupa vai 2-benzotiazolilsulfongrupa, R² ir diarilalkil- vai alkilgrupas, n=l, 2.wherein: R and R ^1, taken together or individually, are hydrogen, halogen or substituted methylene, Y is hydrogen, halogen, acyloxy or 2-benzothiazolylsulfon, R ² is diarylalkyl or alkyl, n = 1, 2. 2. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā vai atsevišķi ņemti ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no ūdeņraža un hlora; Y ir 2-benzotiazolilsulfongrupa un R² ir benzhidrilgrupa.Structural analogs of penicillin sulfone according to pl, wherein R and R ^1, taken together or separately, are substituents selected from the group consisting of hydrogen and chlorine; Y is 2-benzothiazolylsulfone and R ² is benzhydryl. 3. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā vai atsevišķi ņemti ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no ūdeņraža un hlora; Y ir hloracetoksigrapa; un R² ir benzhidrilgrupa.3. Penicillin sulfone structural analogues according to pl, wherein R and R ¹ taken together or separately are substituents selected from the group consisting of hydrogen and chlorine; Y and chloroacetoxygrapa; and R ² is benzhydryl. 4. Penicilīna sulfoksīda vai sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā ir aizvietotāji, kas izvēlēti no grupas, kas sastāv no alkoksikarbonilmetilēn- vai arilmetilēngrupām un R² ir diarilalkil- vai alkilgrupas.Structural analogs of penicillin sulfoxide or sulfone according to pl, wherein R and R ¹ together are substituents selected from the group consisting of alkoxycarbonylmethylene or arylmethylene and R ² is diarylalkyl or alkyl. 5. Penicilīna sulfona struktūranalogi pēc p.l., kas atšķiras ar to, ka R un R¹ abi kopā ir aizvietotāji, kas izvēlēti no Zerc-butoksikarbonilmetilēn- vai benzilidēngrupām un R² ir terc-butilgrupa.Structural analogs of penicillin sulfone according to p 1, characterized in that R and R ¹ together are a substituent selected from tert-butoxycarbonylmethylene or benzylidene and R ² is a tert-butyl group. 6. Penicilīna sulfoksīda vai sulfona struktūranalogu pēc p.l. pielietošana audzēju ārstēšanai.The structural analogue of penicillin sulfoxide or sulfone according to p.l. use in the treatment of tumors. 7. Penicilīna struktūranalogu pēc p.l. pielietošana audzēju ārstēšanai, kur: R un R¹⁼ H, H un Cl, PhCH=; Z-5«C00CH= ; Y= H, Cl, C1CH2COO, SO2-Het; Het = 2-benzotiazolil; R²= CHPh2, f-Bu; n=l, 2.Use of penicillin structural analogues after pl for the treatment of tumors, wherein: R and R ^{1 =} H, H and Cl, PhCH =; Z-5 «C00CH =; Y = H, Cl, C1CH2COO, SO2-Het; Het = 2-benzothiazolyl; R ² = CHPh ² , f-Bu; n = 1, 2.