GB2069485A - Rifamycin derivatives - Google Patents
Rifamycin derivatives Download PDFInfo
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- GB2069485A GB2069485A GB8100554A GB8100554A GB2069485A GB 2069485 A GB2069485 A GB 2069485A GB 8100554 A GB8100554 A GB 8100554A GB 8100554 A GB8100554 A GB 8100554A GB 2069485 A GB2069485 A GB 2069485A
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- amino
- rifamycin
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- deoxy
- imidazolyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Rifamycin derivatives of the formula I:- <IMAGE> and certain oxidation products thereof, wherein Y = H or COCH3 R1 = linear or branched (C1-C7)alkyl or (C3-C4) alkenyl, R2 = linear or branched (C1-C7)alkyl, (C3-C4)alkenyl, (C2-C4)chloroalkyl, (C3-C7)cycloalkyl, cycloalkylalkyl (C3-C6 in the ring), phenyl, bornyl, (C7-C8)aralkyl, or (C7-C8)aralkyl monohalo-substituted in the aryl group. or NR1R2 = a (C5-C8) cyclic moiety, unsubstituted or mono-or di-substituted by CH3; 4-alkyl-1-piperazinyl, morpholino or 1,2,3,4- tetrahydroisoquinolinyl, have antibacterial properties and are obtained by reacting a 3-amino-4-deoxo-4-imino rifamycin S with a chloroformiminium chloride.
Description
SPECIFICATION
Rifamycin derivatives
DESCRIPTION
The invention relates to S and SV rifamycin derivatives, to methods for their preparation and to pharmaceutical compositions containing them.
The invention provides rifamycin compounds having the general formula I
wherein Y represents a hydrogen atom or an acetyl group, and either R1 represents a linear or branched alkyl group having from 1 to 7 carbon atoms or an alkenyl group having 3 or 4 carbon atoms, and R2 represents a linear or branched alkyl group having from 1 to 7 carbon atoms, a chloroalkyl group having from 2 to 4 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms in the ring, a cycloalkylalkyl group having from 3 to 6 carbon atoms in the ring, a phenyl or bornyl group, an unsubstituted aralkyl group having 7 or 8 carbon atoms, or an aralkyl group having 7 or 8 carbon atoms and substituted by one halogen atom in the aryl group, or R1 and R2 together with the nitrogen atom to which they are bonded represent an unsubstituted cyclic moiety having from 5 to 8 carbon atoms, a cyclic moiety having from 5 to 8 carbon atoms substituted by one or two methyl group(s), a 4-alkyl-i -piperazinyl group or a morpholino or 1 ,2,3,4-tetrahydroisoquinolinyl group.
The invention also provides compounds of the general formula II
wherein Y, R1 and R2 are as above defined. These compounds of the general formula II are oxidation products of the compounds of the general formula I.
The rifamycin compounds according to the invention have antibacterial activity against Grampositive and Gram-negative bacteria and against Mycobacterium Tuberculosis. The compounds of the general formula I are yellow-orange solids, while those of the general formula II are green solids. They are generally soluble in most organic solvents, such as chlorinated solvents, alcohols and esters and are partially soluble in aromatic hydrocarbons. The compounds of the general formula I are generally soluble in aqueous solutions at a pH of between 7 and 8, whereas the compounds of the general formula II are substantially insoluble in water.
The compounds of the general formula I may be prepared by a process comprising reacting a 3amino-4-deoxo-4-imino-rifamycin S of the general formula Ill
wherein Y represents a hydrogen atom or an acetyl group in the presence of a tertiary amine, suitably triethylamine, and of an aprotic solvent (such as tetrahydrofuran, dioxan, dichloromethane, benzene or toluene) with a chloroformiminium chloride of the general formula IV
wherein R1 and R2 are as above defined. Their oxidation to compounds of the general formula II may be effected in an inert organic solvent using potassium ferricyanide, potassium persulphate, manganese dioxide or nitrous acid. These processes are within the scope of the invention.
The compounds of the general formula Ill are disclosed in British Patent Specification No.
1 534075. The compounds of the general formula IV are described in British Patent Specification No.
1293590. The rifamycin compounds according to the invention may be admixed with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition within the scope of the invention. Whether alone or in such a composition, they may be formulated for administration in conventional unit dosage forms.
It should be noted that in the Examples the C atoms in the PMR spectra are numbered according to IUPAC rules. The invention is illustrated by the following Examples.
EXAMPLE 1 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'-N-piperidyl)]-rifamycin SV.
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 100 ml of dichloromethane, 7 ml of triethylamine were added and the solution was cooled to 40C C.
A solution of 8 g of chloropiperidylformiminium chloride in 50 ml of dichloromethane was added dropwise and the temperature was kept at -400C for 60 minutes. The solution was gently warmed to room temperature, washed with dilute acetic acid and then with water. After drying on anhydrous sodium sulphate the solution was concentrated to 30 my. 10 ml of petroleum ether were added and and the solution was allowed to crystallize. 0.6 g of an orange compound of the general formula I, wherein
Y = COCH3 and NR1R2= piperidyl, were obtained.
PMR (CDCl3): -0.35 6 [d, CH3-C(22)j; 0.43 a [d,CH3-C(20)J; 0.88 6 [d,CH3-C(1 6)]; 1.04 6 [d,CH3-C( 18)]; 1.82 6 [s,CH3-C(2)J; 2.00 6 [s,CH3-CO0-C(21 )i; 2.11 h [s, CH3-C(12)J;2.19 [s,CH9-C(4)];
4.6-5.4 b [m, C(21 )H and C(24)H]; 6.0--6.6 di [m, C(1 3)H, C(1 4)H, C(1 5)H and C(25)H]; 8.90 (5 [s, N(3')H]; 13.07 6 [s, C(5)0H and C(6)OHi.
MS: 804 (M+) EXAMPLE 2 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-2'morpholino-rifamycin SV.
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 1 00 ml of tetrahydrofuran. 10 ml triethylemine were added, the temperature was lowered to 0 C and 8 g of chloromorpholinoformiminium chloride were added portionwise.
After stirring for 60 minutes at 0 C and 120 minutes at ambient temperature the solution was added dropwise to 600 ml of water containing 1 5 ml of acetic acid. The precipitate obtained was filtered off, washed with water and then dissolved in 500 ml of diethyl ether. The organic solution was extracted with a phosphate buffer solution at pH 7.5. The aqueous phase was then acidified to pH 6 with acetic acid and extracted with dichloromethane. After washing with water and drying on anhydrous sodium sulphate, the dichloromethane solution was concentrated to 10 ml and 30 ml of petroleum ether were then added. 0.45 g of a crude product was obtained and then purified by column chromatography on silica gel eluting with 96:4 chloroform:methanol. Yield 0.400 g of a compound of the general formula I wherein Y=COCH3 and NR1R2=morpholino.
PMR (CDCI3):
-0.49 a [d, CH3-C(22)]; 0.38 a [d,CH3-C(20)]; 0.87 S [d,CH3C(16)]; 1.01 a [d,CH3-C(18)]; 1.80 b n[s,CH3-C(2)]; 2.00 a [s,CH3-CO0-C(21)]; 2.10 a [s,CH3C(12)]; 2.22 a [s,CH3-C(4)];
4.6--5.4 6 [m, C(21)H and C(24)H]; 6.0--6.6 S [m, C(131H, C(14)H, C(15)H and C(25)H]; 8.57 S [bs,N(3')H]; 12.27 and 13.60 S [bs, C(5)OH and C(6)0H]
MS: 806 (M+)
EXAMPLE 3 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'(hexahydro-1-H-azepin-1-yl)]rifamycin SV
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 100 ml tetrehydrofuran, 8.5 ml of triethylamine were added and the temperature was lowered to OOC. 7 g of chlorohexahydroazepinylformiminium chloride were added portionwise and the solution was stirred for 120 minutes at room temperature. 300 ml of dichloromethane were added, the organic solution was washed with dilute acetic acid and then with water, and finally was dried on anhydrous sodium sulphate.The solvent was evaporated off and the crude product was purified by column chromatography on silica gel, eluting with 99:1 chloroform:methanol. Yield: 0.75 g of a compound of the general formula I wherein
Y=COCH3 and NR1 R2=hexahydroazepinyl.
PMR (CDCl3): -0.24 S [d,CH3-C(22)]; 0.43 S [d,CH3-C(20)]; 0.85 S [d,CH3-C(1 6)]; 1.03 S [d,CH3-C(1 8)]; 1.83 S [s,CH3-C(2)]; 1.99 S [s,CH3-COO-C(21)]; 2.13 S [s,CH3-C(12)];2.20a [s,CH3-C(4)];
4.82 S [bd, C(21)H]; 5.35 S [dd,C(24)H]; 6.0-6.5 S [m,C(13)H,C(14)H, C(15)H,C(25)H];
8.43 S [s, N(3')H]; 11.70 and 12.97 S [bs,C(5)0H and C(6)OH].
MS: 818 (M+).
EXAMPLE 4 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-2'-N-dimethylaminorifamycin SV
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 40 ml of dichloromethane, 8 ml of triethylamine were added and the temperature was lowered to 0 C.5.5 g chlorodimethylformiminium chloride were added portionwise and the solution was stirred for 30 minutes at ambient temperature.
100 ml of dichloromethane were added, the organic solution was washed with dilute acetic acid and then with water, and finally was dried over anhydrous sodium sulphate. After filtration, 100 ml of petroleum ether were added, the precipitate was filtered off and the solvent was evaporated. The crude product thus obtained was purified by column chromatography on silica gel eluting with chloroform:methanol 95.5.Yield: 1.0 g of a compound of the general formula I wherein Y=COCH3 and R1=R2=CH PMR (CDCl3): -0.35 S [d,CH3-C(22)]; 0.39 S [d,CH3-C(20)]; 0.86 S [d,CH3-C(16)]; 1.03 S [d,CH3-C(18)];
1.80 S [s,CH3-C(2)]; 1.97 S [s,CH3-C0O-C(21)]; 2.08 b [s,CH3-(12)] 2.19 S [s,CH3-C(4)]; 3.04 S [s,CH3-0j; 3.21 S [s,N(CH3)2]; 4.6-5.5 S [m,C(21)H and C(24)H]; 6.0-6.7 S [m,C(1 3)H,C(1 4)H,C(1 5)H,C(25)H]; 8.53 S [bs,N(3')H]; 12.00 and 13.23 S [bs,C(5)OH and C(6)0H].
MS: 764 (M+)
EXAMPLE 5 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'-(N-pyrrolidinyl)] rifamycin SV
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 40 ml of tetrahydrofuran. 10 ml triethylamine and 7.5 g of chloropyrrolidinylformiminium chloride were added portionwise, the temperature was allowed to rise up to 400C and the solution was stirred for 30 minutes. 100 ml of chloroform were added, the solution was washed with dilute acetic acid and then with water: the organic phase was dried on anhydrous sodium sulphate and then concentrated to 30 mi.
10 ml petroleum ether were added, the solution was allowed to crystallize for 3 hours at 0 C.3.5 g of an orange compound of the general formula I, wherein Y=COCH3 and NR1R2=pirrolidyl, were obtained.
PMR (CDCl3): -0.28 S [d,CH3-C(22)]; 0.40 S [d,CH3-C(20)]; 0.85 b [d,CH3-C(16)]; 1.03 S [CH3-C(1 8)]; 1.79 S [s,CH3-C(2)J; 1.95 S [s,CH3-C0O-C(21)]; 2.06 S [s,CH3-C(12)];2.17 S [s,CH3-C(4)]; 3.03 S [s,CH30-C(23)]; 3.56 S [m, 2 CH2-N]; 4.7-5.5 S [m,C(21)H and C(24)H];; 5.9-6.6 S [m, C(1 3)H,C(1 4)H,C(1 5)H and C(25)H];
12.0 and 13.29 S [s,C(5)OH and C(6)OH].
MS: 790 (m+).
EXAMPLE 6 3-a mino-4-deoxy-4-amino-3,4-im idazolyl-(3' H)-[2'-N-(4-methyl-piperazinyl)] rifa mycin SV
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 40 ml of tetrahydrofuran.10 ml triethylamine and then 9.5 g of 4-methyl-chloropiperazinylformiminium chloride were added portionwise at +50C. After 30 minutes the reaction mixture was diluted with 200 ml chloroform, the solution was washed with dilute acetic acid and then with water: the organic phase was dried on an hydros sodium sulphate and then evaporated to dryness. The crude residue was dissolved in 300 ml of ethyl acetate and the solution was washed with a 2% aqueous solution of sodium bicarbonate. The aqueous phase was washed with diethyl ether acidified with acetic acid to pH 3.5 and then extracted with chloroform.The organic phase was washed with water, dried on anhydrous sodium sulphate and evaporated to dryness. The residue was crystallized from acetone-petroleum ether. 2.2 g of a red compound of the general formula I, wherein Y=COCH3 and NR1R2=4-methyl-piperazinyl, were obtained.
PMR (CDCI): from -0.5 S to -0.25 S [bd,CH3-C(22)]; 0.41 S [d,CH3-C(20)]; 0.86 a [d,CH3-C(16)]; 1.02 S [d,CH3-C(18)j; 1.78 [s,CH3-C(2)j; 2.00 S [s,CH3-C0O-C(2 1)]; 2.08 a [s,CH3-C(12)J; 2.21 a [s,CH3-C(4)j;
2.56 a [s,2CH2 N-CH3J; 3.03 S [s, CH3O-C (23)j; 3.61 S [bs,2CH2ssN-CH3];; 4.7-5.5 S [m, C(21 )H and C(24)H]; 6.1-6.6 S [m, C(1 3)H,C(1 4)H,C(1 5)H and C(25)H];
11.71 and 12.50 S [bs, C(5)OH and C(6)0H].
MS: 819 (M+).
EXAMPLE 7 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-2'-N-diisopropylamino-rifamycin SV
8 g of 3-amino-4-deoxo-4-imino-rifamycin S were dissolved in 40 ml of tetrahydrofuran. 1 0 ml of triethylamine and then 7 g of chlorodiisopropylformiminium chloride were added portionwise at OOC.
After 20 minutes stirring the reaction mixture was diluted with 100 ml dichloromethane, washed with dilute acetic acid and then with water: the organic phase was dried on anhydrous sodium sulphate and then concentrated to 50 ml. 30 ml of petroleum ether were added and the solution was allowed to crystallize at +5 C.2.7 g of a red compound of the general formula I, wherein Y=COCH3 and
were obtained.
PMR (CDCl3): -0.28 S [d, CH3-C(22)]; 0.47 S [d,CH3-C(20)]; 0.81 S [d,CH3-C(16)]; 1.02 S [d,CH3-C(18)];
1.78 a [s,CH3-C(2)j; 1.97 S [s,CH3-COO-C(21)]; 2.12 S [s,CH3-C(12)]; 2.15 a [s,CH3-C(4)]; 3.05 S [s,CH3-O-C(23)]; 4.7-5.4 S [m, C(21 )H and C(24)H]; 6.0-6.4 S [m,C(13)H,C(14)H,C(15)H and C(25)H];
12.17 and 13.57 S [s, C(5)0H and C(6)OH] MS: 820 (M+)
The activity in vitro of the rifamycin compounds obtained as described in Examples 1 and 2 have been tested against some Gram-positive and Gram-negative microorganisms and against
Mycobacterium Tuberculosis (serial dilution method). The results are set out in the following Table, wherein the figures are the values of the minimal inhibiting concentration (MIC) given in mcg/ml.
TABLE
Microorganisms Example 1 Example 2 Staphylococcus aureus 209 P 0.0025 0.0045 Streptococcus faecalis 0.15 0.3 Staphylococcus aureus 209 P > 200 > 200 (Rifampicin resistant) Escherichia coli B 10 10 Klebsiella pneumoniae 10 20 Escherichia coli Gin. 5 10 Escherichia coli Cl (Rifampicin resistant) 200 > 200 Pseudomonas aeruginosa 5 10 Salmonella abortivoequina 2.5 10 Mycobacterium tuberculosos H37Rv 0.005 0.005
Claims (13)
1. A rifamycin derivative having the general formula I as herein defined, or an oxidation product of such a rifamycin derivative, the oxidation product having the general formula II as herein defined.
2. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2' (N-piperidyl)] rifamycin SV.
3. m ino-4-deoxy-4-ami no-3,4-imidazolyl-(3 'H)-2'-morpholinorifa mycin SV.
4. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'-(hexahydro-1 H-azepin- 1 -yl)jrifamycin SV.
5. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-2'-N-dimethylaminorifamycin SV.
6. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'-(N-pyrrolidinyl)]rifamycin SV.
7. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-[2'-N-(4-methyl-piperazinyl)]rifamycin SV.
8. 3-amino-4-deoxy-4-amino-3,4-imidazolyl-(3'H)-2'-N-diisopropylamino-rifamycin SV.
9. A process for the preparation of a rifamycin derivative having the general formula I as herein defined, the process comprising reacting a 3-amino-4-deoxy-4-iminorifamycin S of the general formula
Ill as herein defined with a chloroformiminium chloride of the general formula IV as herein defined in the presence of a tertiary amine and of an aprotic solvent.
10. A process according to claim 9 in which the tertiary amine is triethylamine.
11. A process according to claim 9 or claim 10 in which the aprotic solvent is tetrahydrofuran, dioxan, dichloromethane, benzene or toluene.
1 2. A process for the preparation of a rifamycin derivative of the general formula I as herein defined, the process being substantially as described herein with reference to any of the Examples.
13. A process for the preparation of a rifamycin derivative of the general formula II as herein defined, the process comprising oxidising. in an inert organic solvent, a rifamycin derivative of the general formula I as herein defined with potassium ferricyanide, potassium persulphate, manganese dioxide or nitrous acid.
1 4. A pharmaceutical composition comprising a rifamycin derivative according to any of claims 1 to 8 in admixture with a pharmaceutically acceptable carrier or diluent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8100554A GB2069485B (en) | 1980-02-13 | 1981-01-09 | Rifamycin derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8004848 | 1980-02-13 | ||
| GB8100554A GB2069485B (en) | 1980-02-13 | 1981-01-09 | Rifamycin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2069485A true GB2069485A (en) | 1981-08-26 |
| GB2069485B GB2069485B (en) | 1983-11-23 |
Family
ID=26274478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8100554A Expired GB2069485B (en) | 1980-02-13 | 1981-01-09 | Rifamycin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2069485B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0049683A2 (en) * | 1980-09-25 | 1982-04-14 | Ciba-Geigy Ag | Imidazo-rifamycines, process for their preparation, pharmaceutical preparations containing them and their use |
-
1981
- 1981-01-09 GB GB8100554A patent/GB2069485B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0049683A2 (en) * | 1980-09-25 | 1982-04-14 | Ciba-Geigy Ag | Imidazo-rifamycines, process for their preparation, pharmaceutical preparations containing them and their use |
| EP0049683A3 (en) * | 1980-09-25 | 1982-09-01 | Ciba-Geigy Ag | Imidazo-rifamycines, process for their preparation, pharmaceutical preparations containing them and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2069485B (en) | 1983-11-23 |
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| Date | Code | Title | Description |
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| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |