Processes for preparing heterocyclic compounds including trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof
The present invention relates to compounds and processes for preparing compounds of Formula (I), including compounds such as trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof (e.g., NXL-104).
1. A pharmaceutical composition comprising (i) a compound of the Formula (VIII):
or a pharmaceutically acceptable salt thereof; and
(ii) a compound of Formula (III) or a salt, solvate, hydrate, enantiomer, diastereomer or analog thereof;
wherein
R1, R2, R5, R6 and R7 are identical or different and are independently selected from the group consisting of hydrogen, oxygen, nitrogen, amino, carbonyl, carbamoyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, trialkylsilyl and heterocycle; wherein each of R1, R2, R5, R6 and R7 is optionally substituted by one or more halogen, oxygen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, alkylamido, carbamoyl, ureido, dimethylamino, carboxyl, alkyl, allyl, halogenated alkyl, trialkylsilyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl or a combination thereof; or
R1 and R2 together form a heterocycle; optionally substituted by one or more halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido, alkylamido, carbamoyl, ureido, dimethylamino, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkythio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl or a combination thereof; or
R5 or R6 are independently selected from the group consisting of COH, COB′, COOB′, CONH 2 , CONHB′, CONHOH, CONHSO 2 B′, CH 2 COOH, CH 2 COOB′, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 B′, CH 2 PO(OB′) 2 , CH 2 PO(OB′)(OH), CH 2 PO(B′)(OH) and CH 2 PO(OH) 2 ; wherein B′ is selected from the group consisting of alkyl containing 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, —CH 2 -alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms; wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH 2 , N O2 , alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms; or
R5 or R6 are independently OR′ or OP′; wherein
R′ is selected from the group consisting of SO 3 , SO 2 , SO 2 NHCOH, SO 2 NHCO, SO 2 NHCOO, SO 2 NHCONH and SO 2 NHCONH 2 ; and R′ is optionally substituted by hydrogen or alkyl group optionally substituted by a pyridyl or carbamoyl radical, —CH 2 — alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms, wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH 2 , NO 2 , alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms; and
P′ is selected from the group consisting of PO(OH) 2 , PO 3 , PO 2 , PO, PO(OH)(O—), PO 2 NHCOH, PO 2 NHCO, PO 2 NHCOO, PO 2 NHCONH and PO 2 NHCONH 2 ; and P′ is optionally substituted by hydrogen or alkyl group optionally substituted by a pyridyl or carbamoyl radical, —CH 2 -alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms, wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH 2 , NO 2 , alkyl containing 1 to 6 carbon 15 atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms.
2. The compound of claim 1 wherein R5 is allyl or trialkylsilyl and R6 and R7 are hydrogen.
3. The compound of claim 1 , wherein R5 is benzyloxy and R1, R2, R6 and R7 are hydrogen.
4. The compound of claim 1 , wherein R1 is a heterocycle.
5. The compound of claim 1 , wherein R7 is amide.
6. The compound of claim 1 , wherein R1 is piperidinyl, R5 is benzyloxy and R2, R6 and R 7 are hydrogen.
7. The compound of claim 1 , wherein R1, R2 and R6 are hydrogen.
8. The compound of claim 1 , wherein R5 is OSO 3 H.
9. The compound of claim 1 , wherein R1, R2 and R6 are hydrogen, R5 is OSO 3 H and R7 is carbamoyl.
10. The compound of claim 1 , wherein R1 is piperidinyl, R2 and R6 are hydrogen, R5 is OSO 3 H and R7 is carbamoyl.
11. The compound of claim 1 , wherein R5 is benzyloxy and R6 and R7 are hydrogen.
12. A compound of the formula
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising the compound of claim 12 or a salt thereof, and a pharmaceutical acceptable carrier.
14. The pharmaceutical composition of claim 12 , further comprising a compound of the Formula (VIII):
or a pharmaceutically acceptable salt thereof.