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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel processes for the preparation of a compound of formula I 1 which compound is related to dihydrofolate reductase inhibitors
• the compound of formula I has valuable antibiotic properties.
• the compound can be used in the control or prevention of infectious diseases in mammals, both humans and non-humans. In particular, it exhibits pronounced antibacterial activity, even against multiresistant Gram-positive strains and against opportunistic pathogens such as e.g. Pneumocystis carinii.
• the compound can also be administered in combination with known substances of antibacterial activity and exhibits synergistic effects with some of them.
• Typical combination partners are e.g. sulfonamides or other inhibitors of enzymes, which are involved in folic acid biosynthesis such as, for example, pteridine derivatives.
• the present invention provides a process for preparing the compound of the formula I from the intermediate of formula 6.
• the intermediate of formula 3 is synthesized in 3 steps from a readily available starting material 1 (Scheme 1).
• the diamino pyrimidine substituent of 1 is selectively protected according to R.J. Griffin et al., J.Chem.Soc. Perkin Trans I, 1811 (1992) leading to compound of formula 2, which in turn is formylated to a compound of formula 3 (Scheme 1).
• Scheme 1 :
• the compound of formula I is basic in nature and can be, if desired, transformed with an acid into pharmaceutically acceptable salts.
• Suitable acids are, e.g. hydrochloric acid, maleic acid, succinic acid, L(+)-lactic acid, DL-lactic acid, glycolic acid, i-hydroxy-naphthalene-2-carboxylic acid, tartaric acid, citric acid, methane sulfonic acid. Most preferred are carboxylic acids.
• the central intermediate of formula 6 to prepare the compound of formula I may be prepared following the reaction sequences depicted in Schemes 1 to 3.
• the protection A1 of trimethoprim 1 can be done by heating compound of formula 1 with acid anhydrides, e.g. acetic anhydride, isobutyric acid anhydride or pivaloyl acid anhydride in an inert, high boiling solvent like toluene, p-xylene or in plain acid anhydride up to about 120 0 C to 160 0 C.
• the formulation B1 of the protected trimethoprim 2 can be achieved in an inert solvent, e.g.
• dichloromethane dichloroethane, preferably dichloromethane with dichloromethyl-methyl ether and a Lewis acid, e.g. tin tetrachloride at 0 0 C to -30 0 C, preferably at -10 0 C.
• compound of formula 3 can also be synthesized via protection A2 of compound 4 with acid anhydrides, e.g. acetic anhydride, methyl-propionic acid anhydride or pivaloyl acid anhydride in an inert, high boiling solvent like toluene, p- xylene or in plain acid anhydride, preferably methyl-propionic acid anhydride up to about 120 0 C to 160 0 C.
• acid anhydrides e.g. acetic anhydride, methyl-propionic acid anhydride or pivaloyl acid anhydride in an inert, high boiling solvent like toluene, p- xylene or in plain acid anhydride,
• Carbonylation B2 of compound of formula 5 can be effected in an inert atmosphere and solvent, e.g. tetrahydrofuran, with palladium tetrakis as catalyst, carbon monoxide and tri-butyl tin-hydride at 60 0 C to 80 0 C.
• the selective demethylation A3 can be done in an inert solvent, e.g. dichloromethane, acetonitrile, in combination with a Lewis acid like aluminium trichloride, boron trichloride, boron tribromide, manganese dichloride, manganese diiodide, preferably aluminium trichloride and a nucleophile, e.g. sodium iodide, dimethyl sulfide, diethyl sulfide, tetrahydrothiophene, preferably sodium iodide at room temperature up to 40 0 C.
• solvent e.g. tetrahydro
• the convergent synthesis strategy of compound of formula I deserves an additional intermediate of formulae 10 or 12.
• the starting material of formula 7 is acetylated (A4) with acetyl chloride and a Lewis acid like aluminium trichloride or tin tetra-chloride at ambient temperature to the intermediate of formula 8.
• Compound of formula 8 can be converted by protecting first (B4) the nitrogen with a sulfonyl chloride, e.g. benzyl- or p-toluene-sulfonyl chloride with a base like triethylamine, pyridine in an inert solvent at room temperature to the compound of formula 9 followed by bromination (C4) with e.g.
• bromine, N-bromosuccinimid, copper (II) bromide preferably bromine of the acetyl group in dioxane to compound of formula 10, or bromination first with e.g. bromine, N- bromosuccinimid, preferably bromine of 8 (B5) in an inert solvent like dioxane at room temperature to compound of formula 11 and subsequent protection (C5) with di-te/f-butyl dicarbonate and a pyridine base, e.g. 2,6-dimethyl-pyridine with 4- dimethylamino-pyridine as catalyst to compound of formula 12 at ambient temperature.
• a pyridine base e.g. 2,6-dimethyl-pyridine with 4- dimethylamino-pyridine as catalyst to compound of formula 12 at ambient temperature.
• tetrahydrofuran methyl alcohol, preferably tetrahydrofuran and water with a strong base like sodium or potassium hydroxide, preferably sodium hydroxide at 40 0 C to 80 0 C preferably at 50 0 C to the compound of formula 14.
• Reduction A10 of the keto function of compound of formula 14 can be done with a reducing agent, e.g. sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium acetoxyborohydride, preferably sodium cyanoborohydride, sodium borohydride or zinc borohydride in an organic solvent like methanol, isopropanol, tetrahydrofuran, dimethoxyethane or a mixture thereof, preferably isopropanol or tetrahydrofuran at temperature in the range of -20 0 C up to 70 0 C depending on the reducing agent leading to the target compound I.
• a reducing agent e.g. sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium acetoxyborohydride, preferably sodium cyanoborohydride, sodium borohydride or zinc borohydride in an organic solvent like methanol, isopropanol, tetrahydrofuran, dimethoxy
• the compounds of formulae 2, 3, 5, 6, 8 to 17 are novel and are also objects of the invention. They can be prepared according to the reaction sequences elucidated in Schemes 1 to 8. The preparation of compounds outlined in Schemes 1 to 8 are, moreover, described in more detail in the examples.
• the compound of formula I or their pharmaceutically acceptable salts have valuable antibacterial properties. These compounds are active against a large number of pathogenic microorganisms such as e.g. S. aureus, P. carinii etc. by virtue of their activity in inhibiting bacterial dihydrofolate reductase (DHFR).
• DHFR bacterial dihydrofolate reductase
• Examples 1 to 11 describe the preparation of compound 6, while examples 12 to 16 describe the preparation of the compound of formulae 10 and 12, and examples 17 to 32 describe the condensation of the compound of formula 6 with those of formulae 10 or 12 to the end product of formula I.
• Compound of formula 4 can be prepared e.g. according to M. Calas et al., Eur.J.Med.Chem.Chim.Ther., 17 (6), 497 (1982).
• Compound 7 can be prepared in analogy to e.g. W.B. Wright et al., J. Med.Chem., 11(6), 1164 (1968). All other reagents and solvents are readily commercially available, for example from Fluka or equivalent commercial suppliers. The temperatures are given in degrees Celsius.
• Solvent A 10 mM Formic acid (Formic acid 377 ⁇ l) was added to HPLC grade water (1 L, Millipore filtered)
• Solvent B Acetonitrile HPLC grade (Biosolve Ltd)
• Wavelength 210 nm to 400 nm.
• HPLC Apparatus Type Finnigan StartSystem SCN 1000, Finnigan Photodiode array detector(PDA) UV6000LP
• a solution of trimethoprim (5 g, 17.24 mmol) in pivalic anhydride (8.74 ml_, 43.10 mmol, 2.5 eq.) was heated during 2 h at 150 0 C under argon. Hot AcOEt was added, and the organic layers were washed with aqueous NaHCO 3 10%, water and brine. The org. layers were then dried over MgSO 4 , filtered and evaporated.
• trimethoprim 50 g, 172.4 mmol
• isobutyric anhydride 100 g, 105 ml_, 632 mmol, 3.6 eq.
• the warm solution was poured into 1 L of cyclohexane from where it slowly crystallized.
• a solution of trimethoprim (50 g, 172.4 mmol) in isobutyric anhydride (62 g, 65.5 ml_, 392 mmol, 2.3 eq.) was heated during 2 h at 150 0 C under Ar and stirred with a mechanical stirrer.
• the reaction mixture is poured into a solution of 300 mL 1 N K 3 PO 4 and 200 mL 1M Na/K-tartrate while cooling with an ice bath.
• the mixture pH was adjusted with 4N NaOH solution to 7-8) was then stirred for 15 minutes until complete hydrolysis, and then extracted with DCM (300 mL) together with AcOEt (500 mL).
• the organic layer was washed with 0.1 N HCI solution (2x200 mL) and brine (2x300 mL), dried over MgSO 4 , filtered and evaporated.
• the slurry was stirred at -15 0 C for two hours, at -10 0 C for one hour and 30 minutes at -5 0 C. Then 40 mL DCM was added at -5 0 C and the separated crystals at the top of the solvent layer were removed with vigorous stirring for 15 minutes. The thin slurry was transferred into a well-stirred mixture of 35 g Na 2 CO 3 (with one crystal water) dissolved in 100 mL water and 35 mL DCM at 10 0 C. The mixture was stirred for 15 minutes at RT and then transferred back to the reaction vessel to finish the workup continuing the stirring at RT.
• Sodium iodide (616 mg, 4.11 mmol) was added, and after 30 minutes, 0.5 mL of acetonitrile was added. The reaction was checked by LCMS 1 and 0.5 mL acetonitrile was added to complete the reaction. The reaction mixture was then poured into 1 N K 3 PO 4 /DCM biphasic solution. The two phases were separated. The aqueous layers were extracted twice with AcOEt and the organic layers were washed with water and brine, then dried on MgSO 4 , filtered and evaporated.
• the mixture was cooled to RT, diluted with 75 mL DCM and quenched by adding the reaction mixture to 30 mL ice-water, then 2.5 mL of concentrated HCI was slowly added, which helped to dissolve the yellow precipitate.
• the organic layer was separated and the aqueous layer extracted once more with DCM (75 mL).
• the combined organic layers were washed with brine (50 mL), twice with sodium bicarbonate solution made from 50 mL saturated sodium bi-carbonate (NaHCO 3 ) + 150 mL water (2x100 mL), 0.1 N HCI solution (50 mL) and again brine (1x50 mL).
• the resulting yellowish solution was dried over MgSO 4 and concentrated.
• step A4 This example illustrates the preparation of 3-Acetyl-5-chloro-1H-indole-2- carboxylic acid dimethylamide 8 (step A4).
• Aluminium trichloride 36 g, 270 mmol was added slowly to a suspension of 7 (30 g, 135mmol) in DCM (675 mL) at 0 0 C under Ar.
• the reaction mixture was stirred for 30 minutes and acetyl chloride (9.6 mL, 135 mmol) was added dropwise at 0 0 C.
• the gold yellow reaction mixture was stirred for an additional 1 hour, until the reaction was completed (verification by LC-MS).
• the reaction mixture is then poured on ice (250 mL).
• the pH was adjusted to pH 4.5 by addition of 4 N NaOH solution (80 mL).
• the phases were separated and the aqueous layer was extracted with DCM (2 x 200 mL). All collected organic layers were then washed with water and brine, then dried over MgSO 4 , filtered and evaporated.
• the compound 8 was obtained as a beige solid and used for the next reaction step without further purification.
• This example illustrates the preparation of 3-(2-Bromo-acetyl)-5-chloro-1-(toluene- 4-sulfonyl)-1H-indole-2-carboxylicacid-dimethyl-amide 10 (step C4).
• Example 15 This example illustrates the preparation of 3-(2-Bromo-acetyl)-5-chloro-1H-indole- 2-carboxylic acid dimethylamide 11 (step B5).
• This example illustrates the preparation of 3-(2-Bromo-acetyl)-5-chloro-2- dimethylcarbamoyl-indole-1-carboxylic acid te/f-butyl ester 12 (step C5).
• This example illustrates the preparation of 5-Chloro-3-[4-(2,4-diamino-pyrimidin-5- yl-methyl)-6,7-dimethoxy-benzofuran-2-carbonyl]-1/-/-indole-2-carboxylic acid dimethyl-amide, mesylate salt 14 (step B6).
• the mixture was cooled to RT and the pH was lowered to approximately 6.5 by adding aqueous HCI solution (75 mL, 300 mmol, 4 M). NaHCO3 saturated solution (700 mL) was added carefully, a minor formation of CO 2 was observed.
• the mixture was extracted with ethyl acetate/isopropanol 85/15 (2x1600 mL). The organic layers were washed with water/brine 90/10 (2x200 mL) and brine (1x200 mL), filtered through a plug of Celite, combined and evaporated to dryness. The resulting yellow foam was kept at high vacuum and RT for 16 hours.
• Example 26 This example illustrates the preparation of 5-Chloro-3- [4-(2,4-diamino-pyrimidin-5- yl-methyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1/-/-indole-2-carboxylic acid dimethyl-amide I (step A10).
• the mesylate salt 14 (4.88 g, 6.932 mmol) was dissolved in water (50 ml_). AcOEt (50 ml_) was added, and then the mixture was quenched with NaHCO 3 10 % (50 ml_) and stirred vigorously. The organic layers were separated and the aqueous layers were extracted with AcOEt (50 mL). The combined organic layers were washed with water (100 mL), brine (50 mL) and dried over MgSO 4 , filtered and evaporated to dryness. iPrOH (30 mL) was added to the yellowish compound, then NaBH 4 (352 mg, 9.317 mmol) was added and the mixture heated at 50 0 C during 3 h.
• Example 27 This example illustrates the preparation of 5-Chloro-3- [4-(2,4-diamino-pyrimidin-5- yl-methyl)-6,7-dimethoxy-benzofuran-2-yImethyl] ⁇ 1/-/-indole-2-carboxylic acid dimethyl-amide I (step A10).
• This example illustrates the preparation of 5-Chloro-3- [4-(2,4-diamino-pyrimidin-5- yl-methyO- ⁇ J-dimethoxy-benzofuran ⁇ -ylmethyll-IH-indole ⁇ -carboxylic acid dimethyl-amide I (step A10).
• the mesylate salt 14 (6% isopropanol) (20.0 g, 29.8 mmol) was suspended in tetrahydrofuran (THF) (200 mL) at RT.
• This slurry was cooled with an ethanol bath equipped with a Cryocool (-25 ° C, 1 h), then Zn(BH 4 ) 2 (1 ,5 mol eq, 1.5 M solution in THF, 30 mL) was slowly added dropwise (some H 2 evolution) in 3 portions (3 x 10 mL every 15 minutes). After additional 15 minutes of stirring the slurry was warmed to 0 0 C. HCI solution was added continuously (1 eq, 4 M solution in dioxane, 7.45 mL, 124 ⁇ L/min) over a 1 h period. The solution was stirred for additional 15 minutes at 0 0 C and then allowed to warm up to 20 0 C during a period of 2 h.
• This example illustrates the preparation of 5-Chloro-3- ⁇ [4-(2,4-diamino-pyrimidin-5- ylmethyO-ej-dimethoxy-benzofuran ⁇ -yll-hydroxy-methylJ-IH-indole ⁇ -carboxylic acid dimethylamide 14A (step B10).
• the mesylate salt of the compound 14 (100 mg, 0.155 mmol) was dissolved in a mixture of iPrOH/MeOH (2/0.5 mL). The reaction mixture was cooled to -20 °C, before addition of sodium borohydride (17.6 mg, 0.466 mmol).
• This example illustrates the preparation of 5-Chloro ⁇ 3-[4-(2,4-diamino-pyrimidin-5- yl-methyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1 H-indole-2-carboxylic acid dimethyl-amide I (step C10).
• the secondary alcohol 14A (50 mg, 90.9 ⁇ mol) was dissolved in THF (2 mL). The reaction mixture was cooled to -20 0 C, before addition of sodium borohydride (10.3 mg, 0.273 mmol). After 5 minutes stirring at -20 0 C, BF 3 -OEt 2 (34 ⁇ L, 50 %) was added slowly. After each drop of BF 3 OEt 2 , the color of the mixture was turning to violet, then the violet color disappeared again. After complete addition of BF 3 OEt 2 , the violet color was persistent during 3 minutes before returning to a pale yellow solution. The reaction was complete after 5 minutes and then NaOH 0.1 N (10 mL) was added. The mixture was extracted 2 times with EtOAc (15 mL each). The organic layers were washed with brine (50 mL), dried over MgSO 4 , filtered and evaporated to dryness to give the final compound I having the same LCMS signals given in Example 26.
• Example 20 This example illustrates the preparation of 5-Chloro-3-[4-(2,4-diamino-pyrimidin-5- yl-methyO- ⁇ J-dimethoxy-benzofuran ⁇ -ylmethyll-IH-indole ⁇ -carboxylic acid dimethyl-amide 1 (step A11).
• Example 21 illustrates the preparation of 5-Chloro-3-[4-(2,4-diamino-pyrimidin-5- yl-methyl)-6,7-dimethoxy-benzofuran-2-ylmethyl]-1H-indole-2-carboxylic acid dimethyl-amide I (step A12).

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