BETA LACTAM INTERMEDIATE CONNECTIONS AS WELL AS PROCEDURES FOR YOUR PRODUCTION.

The available invention refers to new - lactam intermediate connections as well as to a procedure for their Herstellung.

This new Verbindungn for the production of new Antis biotika the formula H N ii, o R3 in the blanks for a phenyl, a 4-Hydroxyphenyl, a 1,4-Cyclohexadienyloder 3-Thienylgruppe stands, to R2 a primary Aminooder a Carboxygruppe represents, and stands A means R3 a hydrogen atom or a Niederalkyl, Aryloder Aralkylgruppe for the remainder of a 13-Lactamase-lnhibitors, which contains a B-Lactamring and also a Carboxygruppe, whereby A is bound over the Carboxygruppe, used werden.

The erfîndungsgemässen connections point the following formula to A-CH-X I R O) where X a split offable group represent, R3 is hydrogen Niederalkyl, aryl or Aralkyl and A represents a remainder, which is selected from the following group:

a) A remainder of the general formula Õ 0 i i o: : 'CO-- O (ri) in the R4 for hydrogen or halogen stands, for R5 hydrogen, a Aminooder ecyl amino group meant, whereby at least one of the substituents is R4 and R hydrogen, for b) a remainder of the general formula E H, /I i o b-oin the RH, for halogen stands, and c) a remainder of the general formula i I O H I " IL O OH (oEv) the procedure for the production of the new connections of the formula I is characterized by it that one a Verbinis dung of the formula TO where A is defined further above and M means a cation in a solvent by a connection of the formula Y-CH-X I R3 (v) where R3 and X defined are meant further above and Y bromine, iodine, Alkylsulfonyloxy, Arylsulfonyloxy, Chlorsulfonyloxy or Halogenalkyloxysulfonyloxy, whereby Y is more easily than X split offable, umsetzt.

Preferably one sets at a temperature from 0 to 60°C um.

M e.g. represents in particular Na+, K÷, a Ammoninm, a Trioder a Tetraalkylammoniumion, like the Tetrabutylammoniumion.

ss as preferential solvents one uses dimethylformamide, ethyl acetate, Dichlormethan, acetone and Hexamethylphosphorsäuretriamid.

The assigned parent compounds of the formula V are manufactured well-known or can in well-known procedures werden.

Most of the used connections of the formula TO or the appropriate acids are well-known. Acids and salts, in which A a remainder of the formula [...] meant and R-S stands for certain Aeylaminoreste, are new Ver4s connections. These represent penicillin dioxides, which one receives in well-known procedures kann.

The connections of the formula 1 can on would practice-borrow way to be cleaned and isolated. In some cases are present it as diastereomere mixture, which one, if desired, thus according to well-known procedures can separate, e.g. by Chromatographien.

The invention is more near described in the following examples. The preparations 1 and 2 used to refer see on the production of new parent compounds, those in some ss examples werden.

Preparation 1 6ct-Brompenicillansäure-I, 1 - dioxide:

óo of a solution of 1,90 g (12 mmol) potassium permanganate in 35 ml water and 1.36 ml (24 mmol) acetic acid was added to Kalium-6ctbrompenicillanat in 25 under agitating at a temperature from 0 to 5°C drop by drop a ice-cold solution of 1,91 g (6 mmol) ml water. After Beendi6s gung the additive (about 15 min) the mixture still min was agitated long at this low temperature. Then the cooling bath was removed and the mixture was shifted with 1,52 g (8 mmol) firm Natriumpyrosulfît, in order to reduce the über645902 schüssige oxidizing agents. The failed manganous oxides were filtered off and the filtrate (about 60 mi) was shifted with 20 g firm sodium chloride and 50 ml ethyl acetate. The pH value of the mixture was stopped by additive of 4 n hydrochloric acid under agitating to 1,5 and the organic phase was separated. The aqueous phase with valley ethyl acetate recently extracted, the united organic excerpts with satisfied aqueous sodium chlorid solution were washed, dried and in the vacuum in example 3 Chlormethyl-6a-brompenicillanat1,1 - to dioxide:

If with the procedure in accordance with example 1 instead of Penicillansäure1,1-dioxid the connection 6ct-Brompenicillansäures l, l-dioxide were used, Chlormethyl-6c became - brompenicillanat-1,1-dioxid in form of a yellowish oil erhalten.

The NMR spectrum (CDCh) showed signals with 5= 1.48, (s, 3 H; 2-CH3), 1.64 (s, 3H; 2-CH3), 4.46 (s, 1 H; 3-H), 4.71 (D, J= 1.5 cycles per second, 1 H; 6-H), 5.17 (D, J= 1.5 cycles per second, I H; 5-H) and 5.80 steamed. In this way received amorphous arrears lo (ABq, J=6 cycles per second, 2H; OCH2CI) ppm. TMS as internal from ether Diisopropyläther was crystallized and supplied thereby 6 - Brompenicillansäure1, l-dioxide with Fp. 124-127°C.

By additive of 1 m Kalium-2-äthylhexanoat in 3,6 valley acetone to a solution of 0,94 g (3 mmol) 6oE-Brompenicillansäure-1, l-dioxide in 12 valley acetone under agitating became a crystalline potassium salt of this connection erhalten.

The NMR spectrum of Kalium-6oE-brompenicillanatl, l-dioxide (CD OD) showed signals with 8= 1.48 (s, 3H; 2-CH3), 1.59 (s, 3H; 2-CH3), 4.48 (s, 1 H; 3-H), 5.10 (D, J=2Hz, 1 H; 6-H) and 5.35 (D, J =2Hz, 1 H; 5-H) ppm. Tetramethylsilan became as internal standard verwendet.

Preparation 2 6oE-Chlorpenicillansäure1, I - dioxide:

When using Kalium-6a-chlorpenicillanat in place of Kalium-6oE-brompenicillanat with the procedure in accordance with production 1 6ct-Chlorpenicillansäure1 became, ldioxid from Diisopropyläther in crystallized form erhalten.

Fp. 134-137°C.

The NMR spectrum (CDC13) showed signals with 5= 1.50 (s, 3H; 2-CH3), 1.64 (s, 3H; 2-CH3), 4.46 (s, 1 H; 3-H), 4.70 (D, J-- 1,5Hz, 1 H; 6-H) and 5.18 (D, J= 1,5Hz, 1 H; 5-H) ppm.

Tetramethylsilan (TMS) became as internal standard verwendet.

A crystalline potassium salt of this connection became by additive of a äquimolaren quantity of 0,8 m Kalium-2äthylhexanoat in acetone a solution of 6ct-Chlorpenicillansäure-l, l-dioxide in acetone under agitating erhalten.

Example I Chlormethylpenicillanat1, I - dioxide:

Penicillansäure-1,1dioxid in 7,5 valley dimethylformamide 0.98 was added to a solution of 1,17 g (5 mmol) ml (7 mmol) tri ethyl amine and 2.18 valley (30 mmol) chlorine iodine methane, and the mixture was long agitated at ambient temperature 4 h. After dilution with 30 valley ethyl acetate was washed on that, dried the mixture three times with in each case 10 valley water and with valley of a gesãttigten aqueous solution by sodium chloride and evaporated in the vacuum, whereby standard verwendet.

Example 4 Chlormethyl-613-brompenicillanat:

Kalium-613-brompenicillanat instead of Penicillansäure l, l-dioxide and tri ethyl amine with the procedure by example 1 and Chlormethyl-613-brompenicillanat as viscoses oil was used gewonnen.

Example Chlormethylclavulanat:

When doing the procedure over again described in example 1 under replacement of Penicillansäure-1, l-dioxide and tri ethyl amine by Natriumclavulanat Chlormethylclavu2s lanat erhalten.

Example 6 Chlormethylpenicillanat1,1-dioxid:

Ml dimethylformamide 1.6 g until chlorine methyl sulfate were added to a suspension of 1,08 g Kaliumpenicillanat-1,1dioxid in 12, and the mixture was agitated 45 min long at ambient temperature. After diluting with 50 ml ethyl acetate was washed it with water and afterwards with aqueous Natriumbiearbonatlösung, evaporated dried 3s and in the vacuum. As arrears an oil was received, that by Chromatographieren on Silicagel was cleaned and the desired connection, which proved identical to the connection described in example 1 as, ergab.

Beispíel 7 Chlomaethyl-6ct-chlorpenicillanat-l, l-dioxide:

If with the procedure of example 1 6a-Chlorpenicillansäure-l turns, l-dioxide instead of Penicillansäure-1,1-dioxid ver4s became, Chlormethyl-6oE-chlorpenicillanat-1 became, ldioxid as viscous oil erhalten.

The NMR spectrum (CDC13) showed signals with 5 = 1.48 (s, 3H; 2-CH3), 1.64 (s, 3H; 2-CH3), 4.47 (s, 1 H; 3-H), 4.68 (D, J= 1,5Hz, IH; 6-H), 5.17 (D, J l, 5Hz, 1H; 5-H) and 5.81 the desired connection in form of a yellowish oil, the 50 (ABq, J=6 cycles per second, 2H; OCH2C1) ppm. TMS became as internal from ether petroleum ether crystallized, stayed. Fp.

94-96°C.

The NMR spectrum (CDCb) showed signals with 5= 1.47 (s, 3H; 2-CH3), 1.66 (s, 3H; 2-CH3), 3.53 (D, J=3Hz, 2H; 6ct-H and 613-H), 4.46 (s, 1 H; 3-H), 4.68 (t, J =3Hz, 1 H; 5-H) and 5.85 (ABq, J=6Hz, 2H; OCH2C1) ppm. TMS became as internal standard verwendet.

Example 2 1-Chloräthylpenicillanat-l, l-dioxide:

With application of the procedure, however using 1-Color-l-jodäthan instead of chlorine iodine methane and increase of the response time to 16 h, described in example 1, raw 1-Chloräthylpenicillanat-1,1-dioxid in form of a yellow oil was received, that by Trockensäulenchromatographieren on Silieagel (ethyl acetate petroleum ether, 7: 3) to be cleaned konnte.

Standard verwendet.

Example 8 ss Jodmethylpenicillanat l, l-dioxide:

To a solution of 5,6 g (20 mmol) Chlormethylpenicillanat-1,1-dioxid in 45 valley acetone were added to 9 g sodium iodide, and the mixture was agitated at ambient temperature 16 h, 1.15 g failed Natriumchloñd were filtered off, the solvent was removed in the vacuum and in this way received arrears with ethyl acetate ether (1: 1) treated. 6 g unsolvable sodium iodide were abííltrieft, and the filtrate became under decreased pressure eingedampft.

The oil remaining as arrears became by Säulenchromatographieren on Silicagel (ethyl acetate n-hexane, 4: 6) cleaned and in the case of it the title connection resulted in the form of colorless crystals made of ether. Fp. 101-102°C.

2,645,902 example 9 Chlormethyl penicillanat l, l-dioxide:

An e mixture of 2,7 g (10 mmol) Kalium1,1-dioxopenicillanat, 6.0 g (60 mmol) potassium hydrogencarbonate and 0.34 g (1 mmol) Tetrabutylammoniumhydrogensulfat in s ml water and 15 ml Dichlormethan was shifted with 1,5 valley chlorine methyl chlorine sulfate. The mixture was agitated 1 h long with 30°C and filtered then, on which the organic layer was separated and dried over Natrinmsulfat. After diluting with 25 ml Propanol-2 the l0 solution in the vacuum was restricted on a volume of approximately 10 ml and 1 h long at a temperature of 5°C was left untouched. Then the formed crystals were filtered off, washed with cold Propanol-2 and dried in the vacuum, whereby the title connection in the form of colorless crystals is with Fp. 94-96°C receive wurde.

Example 1-Chloräthyl-penicillanat-l, l-dioxide:

Potassium l, l-dioxoz0 penicillanat, 25.5 g (0.15 mol) silver nitrate and 7.5 g Silberoxid in 750 ml acetonitrile 42 was added to a mixture of 40,7 g (0.15 mol) ml l-chlorine-l-jodäthan. After agitating more ûber one period of 48 h at ambient temperature the Silbersalze were abfîltriert, and the filtrate was evaporated in the vacuum to dry ones. The 2s arrears was solved in 200 ml ethyl acetate and the solution was washed, filtered, dried to aqueous sodium chlorid solution and in the vacuum with more satisfy, eingeengt.

Chromatographieren of the arrears on Silicagel (hexane ethyl acetate, 3: 2) resulted in the title connection in form of a crystalline mixture of the two Diastereomeren with Fp.

130-132°C.

Example I I 1 - Jodäthyl-penicillanat-1,1 - dioxide:

A solution of 30 g (about 0.1 mol) 1-Chloräthyl-l, ldioxopenicillanat in 100 mi acetone was shifted with 30 g (0.2 mol) sodium iodide and the mixture at the temperature of the environment 3 was long agitated days. Then a wäss5,59 (2d, J=4Hz, 2H became; 5-H and 6-H) and 5.77 (ABq, J=5Hz, 2H; OCH2 CI) ppm. TMS became as internal standard verwendet.

Example 13 Jodmethyl-6 [3-brompenicillanat:

A solution of 0,82 g (2.5 mmol) Chlormethyl-6 [3-brompenicillanat in 5 ml acetone was shifted with 0,75 g (5.0 mmol) firm sodium iodide, and after protection against influence of light the mixture 24 h was agitated long with Ranmtemperatur. Failed sodium chloride was filtered off and washed twice with 1 ml acetone each, and the filtrate was evaporated solved in the vacuum, whereby oily arrears became to receive, that in 20 ml ethyl acetate again wurde.

The received solution was washed to a Säulenchromatographie on Silicagel with ever 10 ml water, over magnesium sulfate dried and after restricting under decreased pressure on a volume of approximately 5 ml using petroleum ether ethyl acetate (9: 1) as Elntionsmittel unterworfen.

Parliamentary groups, which, as by Dünnschichtchromatographie was determined, which pure Titelverbindnng contained, became combined and in the vacuum evaporated. 6 [3-Brompenicillanat in form of a weakly yellowish oil became erhalten.

The NMR spectrum showed signals with 8= 1.55 (s, 3H; 2-CH3), 1.69 (s, 3H; 2-CH3), 4.50 (s, 1 H; 3-H), 5.34 and 5.57 (2d, J=4Hz, 2H; 5-H and 6-H) and 5.97 (ABq, J=5Hz, 2H; OCH2J) ppm. TMS became as internal standard verwendet.

Example 14 Chlormethyl l, l-dioxo-6D-dimethoxybenzamido) - penicillana:

1,8 ml (18 mmol) chlorine methyl chlorine sulfate became in the process of 20 min with Raumtemperatnr of a mixture of 6,2 g (15 mmol) 1,1-Dioxo-6 [3 (2,6-dimethoxybenzamido) - penicillansäure (Methicillinsulfon), 8.7 g (87 mmol) potassium hydrogencarbonate and 0.51 g (1.5 mmol) Tetrabutylammoniumhydrogensulfat in 15 valley water and 15 ml Diehlormethan zugesetzt.

rige solution added by Natriumthiosulfat and the acetone 40 after agitating over further 15 min was removed the organic in the vacuum. The solitary oil was separated solved in ethyl phase, dried and in the vacuum evaporated acetate and the solution washed with water, and resulted in an oil, from 96%igem ethanol crystallized dried and in the Vakum evaporated. The oil remaining as arrears was chromatographiert on Silicagel (Texan ethyl acetate, 3: 1) and a crystalline mixture, Is (Fp resulted in. 134-136°C) the diastereomeren l-Jodäthyl-and l-Chloräthylester, those in accordance with the results of an micro-analytic iodine regulation 40% of the iodine connection enthielt.

Example 12 so Chlormethyl-61 - brompenicillanat:

A solution of 0,96 g (3 mmol) Kalium-6 - brompenicillanat and 1.80 g (18 mmol) Kaliumbicarbonat in 9 ml water and 9 valley ethyl acetate were added 0.10 g (0.3 mmol) to Tetrabutylammoniumhydrogensulfat and afterwards 0.45 ml ss (4.5 mmol) Chlormethylehlorsulfonat, and the mixture became at ambient temperature 1.5 h long gerührt.

Then the organic phase was separated and the wässfige phase recently with 9 was extracted ml ethyl acetate. The united organic excerpts were washed, dried twice with 5 each ml water and restricted under decreased pressure on a volume of approximately 5 ml. The received concentrate became a drying column chromatography on Silicagel (petroleum ether ethyl acetate, 9: 1) subjected and pure Chlormethyl-6 [3-brompenicillanat in form of a 6s nearly colorless Öls.<br resulted in/> The NMR spectrum (CDCh) showed signals with 8= 1.54 (s, 3H; 2-CH3), 1.70 (s, 3H; 2-CH3), 4.54 (s, 1 H; 3-H), 5.35 and colorless crystals with Fp. 142-143°C (Zers.) supplied. By twice recrystallizing from acetone water an analytically pure sample with Fp became. 154-155°C (Zers.) receive. [CC: + 195°C (c= 1, CHCh).

Example Jodmethyl1,1 - dioxo-613 (2,6-dimethoxybenzamido) - penicillant:

3 g (20 mmol) sodium iodide became a solution of 2,31 g (5 mmol) Chlormethyl l, 1-dìoxo-613 (2,6-dimethoxybenzamido) - acetone penicillanat added in 10 ml, and the mixture became over night at ambient temperature gerührt.

The title connection in crystalline form was precipitated by additive of water, and the crystals were filtered off and dried in the vacuum. Fp. 153-156°C (Zers.).

The product was solved in a mixture of acetone and 96%igem ethanol, which acetone in the vacuum far away and which crystallize desired connection. By repetition of this procedure way the Fp konnt. to 169-170°C (Zers.) to be increased. [ct: + 197° (c= 1, CHCI3).

Example 16 Chlormethyl l, l-dioxo-6cc-chlorpenicillanat:

When using Kalium1, l-dioxo-6cc-chlorpenicillanat in place of Kalium-613-brompenicillanat with the procedure in accordance with example 12 became the title connection in form 645,902 of colorless crystals from ether Diisopropyläther erhalten.

Fp. I 11-113°C. : + 210° (c=0,5, CHCh).

Example 1 7 Jodmethyl l, l-dioxo-6ct-chlorpenicillanat:

If Chlormethyl-1,1 were used - diodo-6ct-chlorpenicillanat instead of Chlormethyl-613-brompenicillanat with the procedure in accordance with example i 3, the title connection in form of a colorless foam became gewonnen.

The NMR spectrum (CDCb) showed signals with 8= 1.49 (s, 3H; 2-CH3), 1.62 (s, 3H; 2-CH3), 4.41 (s, 1 H; 3-H), 4.66 and 5.16 (2d, J= 1.5 cycles per second, 2H; 5-H and 6-H) and 6.01 (ABq, J=5 cycles per second, 2H; OCH2J) ppm. TMS was used as internal standard, brompenicillanat is example 18 ChiormethylI, I - diodo-6e -:

Kalium1,1-dioxo-6ct-brompenicillanat instead of Kalium-615-brompenicillanat with the procedure by example 12 and the title connection was used in the form of colorless crystals from ether i) iisopropyläther erhalten.

Fp. 92-93°C. ö: + 185° (c=0,5, CHCh).

Example 19 Jodmethyl-1, I-dioxo-6ct-brompenicillan RK:

With application of the procedure using Chlormethyl1,1-dioxo-6, described in example 13 - brompenicillanat instead of Chlormethyi-613-brompenicillanat brompenicillanat with the procedure of example and the title connection in form of a colorless oil uses 12 erhalten.

The NMR spectrum (CDCh) showed signals with = 1.53 s (s, 3H; 2-CH3), 1.69 (s, 3H; 2-CH3), 4.54 (s, 1 H; 3-H), 5.24 and 5.62 (2d, J=4 cycles per second, 2H; 5-H and 6-H) and 5.80 (ABq, J=5 cycles per second, 2H; OCHzC1) ppm. TMS became as internal standard verwendet.

! o example 23 Jodmethyl-615-chlorpenicillanat:

With application of the procedure using Chlorrnethyl-613-chlorpenicillanat instead of Chlormethyl-615-brompeniciilanat, stated in example 13, the title connection in form of a weakly yellowish oil could won werden.

The NMR spectrum (CDCh) showed signals at õ= 1.52 (s, 3H; 2-CHa), 1.69 (s, 3H; 2-CHe), 4.52 (s, I H; 3-H), 5.22 and 5.58 (2d, J=4 cycles per second, 2H; 5-H and 6--H) and 5.99 (ABq, J=5 cycles per second, 2H; OCH2J) ppm. TMS became as internal standard verwendet.

Beispiel24 Chlormethyl-6 - brompenicillanat:

A. Chlormethyl-6,6-dibrompenicillanat:

When using Kalium-6,6-dibrompenicillanat instead of Kalium-613-brompeniciilanat with 12 procedures stated in example the title connection as weak the title connection in form of a colorless foam a0 yellowish oil, which crystallized from ether Diisopropyläther, to be won, to that to the crystallization not be brought konnte.

The NMR spectrum (CDCh) showed signals with 8 = 1.49 (s, 3H; 2-CH3), 1.63 (s, 3H; 2-CH3), 4.41 (s, 1 H; 3-H), 4.70 and 5.16 (2d, J= 1.5 cycles per second, 2H; 5-H and 6-H) and 6.01 (ABq, J=5 cycles per second, 2H; OCH_, J) ppm. TMS became as internal standard verwendet.

Example Chlormethyl-6lS-jodpenicillanat:

When using Kaliam-613-jodpenicillanat in place of Kalium-613-brompenicillanat with the procedure of example 12 the title connection in form of a weakly yellowish oil became erhalten.

The NMR spectrum (CDCb) showed signals with 8= 1.52 (s, 4s 3H; 2-CH3), 1.71 (s, 3H; 2-CH3), 4.55 (s, 1 H; 3-H), 5.40 and 5.63 (2d, J=3,5 cycles per second, 2H; 5-H and 6-H) and 5.78 (ABq, J=5,5 cycles per second, 2H; OCH2CI) ppm. TMS became as internal standard verwendet.

Example 2I Jodmethyl-613-jodpenicillanat:

If Chlormethyl-61 - jodpenicillanat instead of Chiormethyl615-brompenicillanat with the procedure in accordance with example 13 one used, the Titeiverbindung became as yellowish oil gewonnen.

The NMR spectrum (CDCI3) showed signals with 8= 1.53 (s, 3H; 2-CH3), 1.70 (s, 3H; 2-CH3), 4.53 (s, I H; 3-H), 5.39 and 5.61 (2d, J= 3.5 cycles per second, 2H; 5-H and 6-H) and 6.00 (ABq, J = 5.5 cycles per second, 2H; OCH q) ppm. TMS became as internal standard verwendet.

Beispiel22 Chlormethyl-61 - chlorpenicillanat:

It became Kalium-613-chlorpenieillanat instead of Kalium-615erhalten. Fp. 105-107°C. [¢qö: +206° (c=0,5, CHCI3).

The NMR spectrum (CDCh) showed signals at õ= 1.54 (s, 3H; 2-CHe), 1.66 (s, 3H; 2-CH3), 4.60 (s, 1 H; 3-H), 5.80 (ABq, J=5 cycles per second, 2H; OCH2C1) and 5.83 (s, 1 H; 5-H) ppm.

as TMS became as internal standard verwendet.

s0 B. Chlormethyl-60-brompenicillanat:

Chlormethyi-6,6dibrompeniciilanat in 40 valley dry benzene in a nitrogen was added to a solution of 1,63 g (4mmol) an atmosphere with 0°C under agitating 1.16 g (4 mmol) tri n-butyl tin hydride. After agitating at ambient temperature during one period of 18 h the mixture in the vacuum was evaporated. The oil remaining as arrears became by Trockensäulenchromatographieren on Sili: agel (petroleum ether ethyl acetate, 85:15) cleaned and pure Chlormethyl-615-brompenicillanat resulted in as weakly yellowish Öl.

The NMR spectrum of the connection was identical to that of the Verbindung.<br described in example 12/> Example Bromethyl penicillanatI, I - dioxide:

A solution of 1,0 g sodium bromide shifted in 10 ml N, N-dimethylformamide with 0,28 g (1 mmol) Chlorss methyl1, l-dioxopenicillanat and agitated the mixture at ambient temperature 20 h long. After diluting with ml ethyl acetate the mixture was washed four times, dried with ever 10 ml water and in the vacuum eingedampft.

The arrears were cleaned by Säulenchromatographieren on Silicagel and resulted in the desired connection in form of a yellowish Öls.

The NMR spectrum (CDCh) showed signals with 8= 1.49 (s, 3H; 2-CH3), 1.64 (s, 3H; 2-CH3), 3.52 (m, 2H; 6-H, 4.47 (s, I H; 3-H), 4.75 (m, 1 H; 5-H) and 5.98 (ABq, J 4.5 cycles per second, 2H; 6s OCH2Br) ppm. TMS was used as internal standard.