DE2050966A1 - New cephalosporin derivatives and processes for their production - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann Dr.R.Ko «nig« berger - Dipl.Phye.R. Woodcutter

8 Munich 2, Bräuhausstraße 4 / III

1361 D
95 / Si

ROUSSEL UCLAF, Paris / France

iSBSBSBS!

New cephalosporin derivatives and processes for: their manufacture

Bsss: ssB3SssssssBsass: sssB3ssassssssassSBSSJBaszssnsssB:

position

ssssaass

Addendum to patent (patent application P 19 32 505.4)

One already knows from the British patent specification 1,155-493 Cephalosporin derivatives of the general formula I

R ₁ -HN.

(D

where R ₁ denotes a substituted or unsubstituted acyl radical, Rp denotes hydrogen, a substituted or unsubstituted alkyl or aryl radical.

These compounds are particularly characterized by antibiotic Properties.

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British Patent No. 1,155,493 gives these compounds by the lactamization of the corresponding 7- (Acylamino) ^ - aminomethyl-ceph-J-em - ^ - carboxylic acid (or the Esters of this acid).

The cephalosporin derivatives of the general formula I can, on the other hand according to the main patent specification (patent application

P 19 32 505 * 4), with this process in it consists that the y ^ -lactam of the corresponding 7-amino-3-aminomethyl-ceph-3-em-4-carboxylic acid acylated at the 7-position.

The present invention relates to new cephalosporin derivatives

according to the main patent specification (patent application

P 19 32 505.4), ie the V-lactams of 6H, 7H-cis-7- (indolyl-3 ^l -acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acids in optically active form or in racemic form which correspond to the following general formula I ^1:

wherein the substituent X is an NO «- or an NHp group in the 4-, 5-, 6- or 7-position of the indole radical means.

Furthermore, if the indole radical is substituted by an amino group is, this in free form or in the form of a salt with a therapeutically acceptable inorganic or organic Acid.

The compounds of the general formula I * can likewise essentially be prepared according to the process described in the German patent specification (patent application P 19 32 505-4).

The) T-lactams of the 6H, 7H-cie-7- (indolyl-3'-acetamido) -3-eainomethyl-ceph-3-em-4-carboxylic acids of the general formula I ¹ and

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in the case where X _{denotes NH 2} , the salts thereof with an inorganic or organic therapeutically acceptable salt have interesting biological and therapeutic properties.

In particular, they have a considerable antibacterial effect.

Among these compounds, the following may be mentioned in particular:

^ Lactam of DL 6H, 7H-cis-7- (4'-nitro-indolyl-3 ^l -acetamido) -3-aminomethyl-ceph-3-em-A-carboxylic acid;

r-lactam of LL 6H, 7H-cis-7- (5'-nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid;

^ Lactam of DL 6H, 7H-cis-7 <6'-nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid;

^ "- Lactam of DL 6H, 7H-cis-7- (7 ^l -nitro-indolyl-3'-acetamido) -3-asinomethyl-ceph-3-em-4-carboxylic acid;

^ -Lactam of DL 6H, 7H-cis-7- (4'-Amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid and its hydrochloride; ^ Lactam of DL 6H, 7H-cis-7- (5'-amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid and its hydrochloride; Jf ^ -lactam of DL 6H, 7H-cis-7- (6 * -amino-indolyl-3'-acetamido) -3-amino-diethyl-ceph-3-em-4-carboxylic acid and its hydrochloride; Jf-LactamsDL and L (+) 6H, 7H-cis-7- (7'-amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acids and their hydrochlorides.

The process for the preparation of the racemic or optically active JT lactams of the 6H, 7H-cis-7- (indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acids of the general formula I ¹ and their Salts with an inorganic or organic therapeutically acceptable acid in the event that X denotes NHp, which is also an object of the present invention, consists essentially in the fact that one contains eirßCnitro-indolyl-3 ¹ ) -acetic acid or a derivative of such an acid a racemic or optically active ^ -lactam of 6H, 7H-cis-7-amino-3-aminomethylceph-3-eia-4-carboxylic acid condensed to form the If-lactam of 6H ₁ 7H-cis-7- (Kitro-indolyl -3 ^l -acetamido) -3-aminomethyl-ceph-3-em-4-

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To obtain carboxylic acid, if desired, subjecting a catalytic hydrogenation in a neutral or acidic medium and the TL & c camouflaging the eH ^ H-cis-V-CAmino-indolyl-J'-acetamido) -3-aminomethyl-ceph-5-em- 4-carboxylic acid is obtained in free form and, if desired, an inorganic or organic therapeutically acceptable acid is allowed to act on the latter compound so that the corresponding salt is obtained or, if it is in salt form, a basic agent is allowed to act on it, if desired, in order to remove the to obtain free base.

In its preferred embodiments, the inventive Procedure can be further characterized by the following points:

- the functional derivative of nitroindole acetic acid is that anhydride formed in situ from nitroindole acetic acid in the presence of a dialkyl or dicycloalkylcarbodiimide, such as e.g., dicyclohexylcarbodiimide or a nitroindole acetic acid halide or an anhydride of this acid or a mixed anhydride;

- the one used to reduce the nitro derivative to the amino derivative Catalyst is a platinum family metal such as palladium;

- the catalyst is on an inert carrier, such as activated carbon, an alkaline earth metal sulfate, an alkaline earth metal carbonate, Aluminum oxide, magnesium oxide or talc deposited;

- the catalytic hydrogenation is carried out in an acidic medium and in particular by adding hydrochloric acid and es In this case the hydrochloride of ^ -lactam of a 6H, 7H-cis-7- (amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid is formed;

- the catalytic hydrogenation is carried out in a neutral medium and in this case the f -lactam of a 6H, 7H-

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cis-7- (Amino-indolyl-3'-acetamido) -J-aminomethyl-ceph-J-em - ^ - carboxylic acid;

- the conversion of the salt of the Y ^ lactam of 6H, 7H-cis-7- (amino-indolyl-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid in the y ^ lactam is made alkaline with the help of an organic Base, such as a trialkylamine or carried out with the aid of an alkali carbonate or an alkaline earth carbonate;

- 7- (Amino-indolyl) -y "-lactam can be combined with an inorganic or organic, therapeutically acceptable acid can be converted into its salt, e.g. with the hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, boric acid, formic acid, acetic acid, benzoic acid, the Salicylic acid, p-toluenesulfonic acid, anthranilic acid, the Phenylacetic acid, nalidixic acid, fusidic acid and the Colimycin methanesulfonic acid.

The ^ -lactams of the 6H, 7H-cis-7- (indolyl-3 ^l -acet8jnido) -3-aminomethyl-ceph-3-em-4-carboxylic acids of the general formula I ¹ and in the case where X denotes NHp, the salts of which with an inorganic or organic therapeutically acceptable acid can be administered by the buccal, transcutaneous or rectal route when used therapeutically, or by local route by topical application to the skin and mucous membranes. They can also be in the form of injectable solutions or suspensions, ^ form of tablets, coated tablets, capsules, syrups, suppositories or ointments. These pharmaceutical use forms are prepared according to conventional methods.

The useful dosage of these compounds ranges between 0.5 "and 5 g daily for adults depending on the Route of administration.

These compounds can be used to treat staphylomycosis, Streptomycosis, such as staph and blood poisoning Streptococci, malignant facial staphylomycosis, skin staphylomycosis, Pyoderma, septic and purulent wounds Gangrene, acute primitive or post-flu staphyroid

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lomycosis, bronchopneumonia and pulmonary ducts are used will.

The following examples further illustrate the present invention, but without restricting them. The starting material used can either be the Y ^ -lactam of 6H, 7H-cis-7-amino-3-aminomethyl-ceph-3-em-4-carboxylic acid be in racemic or in a Beiner optically active forms, their preparation in the

German patent specification (patent application P 19 32 504.3)

is described.

example 1

f-lactam der DL 6H _< 7H-cis-7- (4'-nitro-indolyl-3 ^t -acetamido) -3- aminomethyl-ceph-3-em-carboxylic acid.

A mixture of 40 ecm of nitromethane, 1.3 g of 4-nitro-indolyl-3-acetic acid (obtained according to J. Org. Chem. J51, 70 (1966)), 0.422 g of Γ-lactam from DL 6H is stirred for one night , 7H-cis-7-amino-3-aminomethyl'Ceph-3-em-4-carboxylic acid, 0.64 g of dicyclohexylcarbodiimide and 3 drops of pyridine; it is suctioned off, the precipitate is taken up in its aqueous sodium bicarbonate solution, suctioned off again, the precipitate is made into a paste with dimethylformamide; the solvent is evaporated off in vacuo, the residue is taken up in alcohol, cooled, filtered off with suction, washed with ether and dried; 0.733 g of the Y ^ -lactam of DL 6H, 7H-cis-7- (4 ¹ -nitro-indolyl-3 ¹ -acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid is obtained in the form of yellow Crystals which are soluble in dimethylformamide and insoluble in alcohol and water and whose melting point is above 250 ^° C. (yield: 88%).

Analysis: C ₁₈ H ₁₅ OcN ₅ S «413.42

calc .: 0 96 52.29 H % 3.66 N% 16.94- B% 7.76 found: 52.1 3.8 16.9 7.6

IR spectrum

Presence of bands at 1776, 1690, 1657 and 1537 * ¹

Presence of -NO ₂ at 1507 and 1309 cm " ¹ .

As far as is known, this connection is not in the literature wrote.

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The ^ -lactam of DL 6H, 7H-cis-7- (5'nitro-indolyl-3'-acetamido) ^ - aminomethyl-cephr ^ -em - ^ - carboxylic acid is obtained in an analogous manner by condensation of (5-nitro-indolyl-3) -acetic acid with the y ^ -lactam of DL eH ^ H-cis ^ -amino-J-aminomethyl-ceph ^ -em-4 ~ carboxylic acid.

As well as "known, this connection is not described in the literature.

Example 2 Hydrochloride of the f ^ -lactam of DL 6H, 7H-cis-7- ( ⁱ > - ^> -amino-indolyl-

J> ^t -acetamido) -3-aminomethyl-ceph-3-one ^/ t-carboxylic acid.

1.) Preparation of the catalyst

170 mg of activated charcoal, 1.4 ecm of a 2% aqueous solution are mixed Palladium chloride solution and 1.5 ecm of water, leads one Hydrogen flow through and stir until complete activation the palladium activated carbon catalyst; it is suctioned off and washed with water until the washing water is neutral.

2.) reduction

Mix 1.5 ecm of dimethylformamide, 170 mg of J ^ -lactam of DL 6H, 7H-C1S-7- (4-'Ni ^ tro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em- 4-carboxylic acid (obtained according to Example 1), 0.49 ecm in hydrochloric acid and the activated carbon palladium catalyst, which was prepared as above; the mixture is placed in a hydrogen atmosphere and stirred; After the uptake of 29.7 ecm of hydrogen in the course of one hour and 30 minutes, the hydrogenation is terminated and the precipitate is filtered off with suction and the filter is rinsed with an aqueous solution of 50% strength ethanol containing a drop of hydrochloric acid. The filtrate is distilled in vacuo; the residue is taken up in ethanol, filtered off with suction, the precipitate is washed with ethanol, then with ether and dried; 123 mg of the hydrochloride of the X- lactam of DL GH ^ H-cis ^ -C ^ Amino-iMolyl ^ '- acetamido) ^ - aminomethyl-ceph-3-em-4 ~ carboxylic acid in the form of a colorless solid product which soluble in water, insoluble in alcohol and having a melting point above 250 ^° C. (yield: 70%).

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_ 8th _
Analysis: C ₁₈ H ₁₈ O ₅ N ₅ SCl - 419.90

calc .: C 96 56.38 Έ. % 4.47 Ν% 18.27 Β% 8.36 found: 56.2 4.5 16 7.6

IR spectrum

-1
Presence of C = O at 1775 cm

Complex absorption at 1678 and 1645 cm presence of aromatics.

As far as is known, this connection is not described in the literature.

The hydrochloride of the T-lactam of DL 6H, 7H-cis-7- (5 ^l -amino-indolyl-3'-acetamido) -3-ajöinomethylceph-3-em-4-carboxylic acid is obtained in an analogous manner, starting from the corresponding nitro derivative.

As far as is known, this compound is not described in the literature.

Example 3

/ "- Lactam of DL 6H, 7H-cis-7- (6'-nitro-indolyl ^ '- acetamido) - ^ -aminomethyl-ceph-3-em-4-carboxylic acid

A mixture of 1.76 g of 6-nitro-indolyl-3'-acetic acid [described in J. Am. Chem. Soc., 22 "3 ⁸ 39 (1955)], 920 mg of dicyclohexylcarbodiimide and 10 cc of nitromethane for 30 minutes. The precipitate is isolated by suction filtration and made into a paste with dimethylformamide; 422 mg of the lactam of DL 6H, 7H-cis-7-amino-3-aminomethylceph-3-em-4-carboxylic acid are added to the organic solution obtained and the mixture is stirred for 30 minutes. A 2% aqueous sodium bicarbonate solution is then added, and the precipitate is filtered off with suction and washed with water and then dried. The residue is taken up in 2.5 cc of dimethylformamide, heated to 40 ⁰ C, methanol is added and bring it back to room temperature; the insoluble fraction is isolated by suction, rinsed with methanol and then with ether, dried and 820 mg of the ^ lactam of DL 6H, 7H-cis-7- (6 ^l -nitro-indolyl-3 ^l acetamido) -3-aminomethyl is obtained -ceph-3-em-4 * carboxylic acid in fora of

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yellow crystals, which are soluble in dimethylformamide and in water, Methanol and ether are insoluble and their melting point is above 250 ° C (yield: 98%).

Analysis:

ber .: C% 52.3 TSL% 3.7 found: 52.3 3.9

IR spectrum (Nujol)
Presence of C «0

7.8 N% 16.9 7.4 16.7-16.8

Presence of NOp at 15Ο6 and 1339 cm

As far as is known, this compound is not described in the literature.

Example 4 Hydrochloride of the V-lactam of DL 6H, 7H-cis-7- (6'-amino-indolyl-

3'-acetamido) -3-aminomethyl-ceph - ^ - em-4-carboxylic acid

By proceeding as indicated in Example 2 and by reducing the Γ-lactam of DL 6H, 7H-cis-7- (6'-nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4 -carboxylic acid the hydrochloride of the ^ lactam of DL 6H, 7H-cis-7- (6'-amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid is obtained.

This compound is in the form of a colorless solid product, which is soluble in water and insoluble in alcohol and whose melting point is above 250 ° C.

Analysis: C ₁₈ H ₁₈ O ₅ N ₅ SCl = 419.90

calc .: 0% 54.35 H% 4.7 S% 8.06

found:

54.4

4.7

8.3

As far as is known, this connection is not described in the literature.

Example 5 Γ-Lactam der DL 6H, 7H-cis-7- (7'-nitro-indolyl-3'-acetamido) -3

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aminomethyl-ceph - ^ - em - ^ - carboxylic acid

By going as in Example 3, starting from 7-nitro-to7 dolyl-3-acetic acid (obtained according CA., £ 2, 8855 f, $ 196) and the X-lactam of DL oeh ^ H ^ -amino-cis ^ -aminomethyl-eeph ^ -em-4-carboxylic acid is obtained the J ^ lactam of DL 6H, 7H-cis-7- (7'-nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3- em-4-carboxylic acid. The compound is in the form of yellow crystals which are sparingly soluble in the majority of solvents and the melting point of the crystals is above 25O ⁰ C.

Analysis: C ₁₈ H ₁₅ O ₅ N ₅ S = 413.4-0

calc .: G% 52.29 H% 3.66 N% 16.94 S% 7.76 found: 52.0 4.0 16, '5 7.8

I.B. spectrum

-1 Presence of the β-lactam at 1779 cm

Presence of (amide + ^ lactam + C = C) bands at 1703, 1689 and 1658 cm "" ¹

Presence of NOp at 1305 cm.

As far as is known, this compound is not described in the literature.

Example 6 Hydrochloride of / T-lactam of DL 6H, 7H-cis-7- (7 ^t -amino-indolyl-

3 '-acetamido) ^ -aminomethyl-ceph ^ -em ^ -carboxylic acid

The procedure is as in Example 2 and, by reducing the ^ lactam, the DL 6H, 7H-cis-7- (7'-nitro-indolyl-3 ¹ -acetamido) -3-aminomethyl-ceph-3-em-4- carboxylic acid the hydrochloride of the / ^ - lactam of DL 6H, 7H-cis-7- (7 ^l -amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid with a yield of 48 %.

The compound is in the form of slightly colored crystals which are soluble in dimethyl formamide, which are slightly soluble in chloroform, are insoluble in ether and water, and whose melting point is above 250 ⁰ C.

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Analysis: C ₁₈ H ₁₇ O ₅ N ₅ S (solvation of 0.75 moles CH ₅ OH per mole) = 407.72

calc .: C% 55.24 H% 4.95 N% 17.18 S% 7.86 found: 55.3 4.6 16.8 7.6

UV spectrum (HCl n / 10)

Max. at 219 - 220 mn K cm «844 Max. at 262 Βΐμ 1 cm _p 194 Infl . around 286 - 287 must _F 1%
^E 1 cm = 99

As far as is known, this compound is not described in the literature.

In an analogous manner, starting from the ^ lactam, the L (+) 6H, 7H-cis-7-amino-3-aminomethyl-ceph-3-em-4-carboxylic acid and the (7-Mtro-indolyl-3) - acetic acid the hydrochloride das / '- lactams of L (+) 6H, 7H-cis-7- (7'-amino-indolyl-3 ^l -s.cetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid : Melting point above 250 ⁰ C with decomposition.

Ca] | ⁰ = + 73 ° ± 2 ° (c = 1% dimethylformamide).

As far as is known, this compound is not described in the literature.

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Claims (11)

Claims BSS = SSS SSSSSSSSSSS SSSSSSSSSSSSSSS 1. ^ Lactams of the 6H, 7H-cis-7- (indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em ~ 4-carboxylic acids in racemic or optically active form of the following general formula, according to the main patent (Patent application P 19 32 505.4) CH ₂ -CO-NH-τ-j-S \ ■■> wherein the substituent X represents the radical NOp or the radical NHp in the Positions 4, 5> 6 or 7 of the indole radical "means, as well as for in the event that X denotes NHp, its salts with an inorganic or organic therapeutically acceptable acid. 2. Γ-Lactam of DL 6H, 7H-cis-7- (4 ¹ nitro-indolyl-3 ^f -acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid. 3. ^ Lactam of DL 6H, 7H-cis-7- (5'-nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid. 4. ^ Lactam of DL 6H, 7H-cis-7- (6'-nitro-indolyl-3 ^f acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid. 5. Γ-Lactam of DL 6H, 7H-cis-7- (7 ^l -nitro-indolyl-3 ^l acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid. 6. ^ Lactam of DL 6Η, 7Η-οίΒ- (4 · -Μίηο-ίηαο ^ 1-3'-βοβΐ-amido) -3-aminomethyl-ceph-3-em-4-carboxylic acid and its hydrochloride. 7. i ^ -Lactam of DL 6H, 7H-cis-7- (5'-amino-indolyl-3'-acetamido) -3-aminomethyl-ceph-3-em-4-carboxylic acid and its hydrochloride. 8.iflLactam der DL 6H, 7H-cis-7- (6'-amino-indolyl-3 ^l -acet- 1 0 9 8 1 8/7 7 ς ·> amido) ^ -aminomethyl-ceph ^ -em - ^ - carboxylic acid and its hydrochloride. 9. ^ Lactameder DL and L (+) 6H, 7H-cis-7- (7'-amino-indolyl-3'-acetamido) - ^ - aminomethyl-ceph-3-61Q - ^ - carboxylic acids and their hydrochlorides. 10. A process for the preparation of the compounds according to claim 1, characterized in that a (nitro-indolyl-3 '-) acetic acid or a functional derivative of such an acid with a ^ lactam of 6H, 7H-cis-7-amino-3 -aminomethylceph-3-em-4- carboxylic acid in racemic or optically active form condensed with formation of the ^ lactam of a 6H, 7H-cis-7- (nitro-indolyl-3'-acetamido) -3-aminomethyl-ceph-3- em-4-carboxylic acid that, if desired, is subjected to the catalytic hydrogenation in a neutral or acidic medium, so that the ^ -lactam of a 6H _i 7H-cis-7- (amino-indolyl-3'-acetamido) -3- amino-methyl-ceph-3-em-4-carboxylic acid is obtained in free form and, if desired, an inorganic or organic therapeutically acceptable acid is allowed to act on the latter compound, so that the corresponding salt; or, if it is in the form of a salt, if desired, a basic agent is allowed to act thereon in order to obtain the free base. 11. Pharmaceutical compositions, characterized in that that they contain as active ingredient at least one compound according to claim 1 and a pharmaceutical carrier therefor. 109818 /? 252