1. A compound of formula (VI):
wherein R2 is a straight or branched alkyl group containing 1\u20134 carbon atoms\u2014and R1 is a methyl or an ethyl group.
2. A compound of the general formula (VI):
wherein R1 stands for ethyl group and R2 stands for methyl group.
3. A compound of formula (V):
wherein R2 is a straight or branched alkyl group containing 1\u20134 carbon atoms\u2014and R1 is a methyl or an ethyl group.
4. A compound of formula (V):
wherein R1 stands for ethyl group and R2 stands for methyl group.
5. A compound of formula (IV):
wherein R2 is a straight or branched alkyl group containing 1\u20134 carbon atoms\u2014and R1 is a methyl or an ethyl group.
6. A compound of the general formula (IV):
wherein R1 stands for ethyl group and R2 stands for methyl group.
7. A process for the preparation of the compound of formula (I):
and salts thereof, which comprises:
(A) reacting a compound of formula (VII):
wherein R2 is a straight or branched alkyl group containing 1\u20134 carbon atoms, with a compound of formula (VIII):
(R1)3Si\u2014X\u2003\u2003(VIII)
wherein R1 is a methyl or an ethyl group, X is a chlorine, bromine or iodine atom,
CF3SO2\u2014O-group, azido-, cyano-, or
group or acetamido or acetyloxy, to obtain a compound of formula (VI):
wherein the meaning of R1 and R2 are as defined above;
(B) oxidizing the compound of Formula (VI) into the aldehyde of the formula (V):
wherein the meaning of R1 and R2 are as defined above;
(C) reacting the aldehyde of formula (V), with or without isolation, with a phosphonate of formula (IX)
wherein R3 is a straight or branched alkyl group containing 1\u20134 carbon atoms to obtain the compound of formula (IV):
wherein the meaning of R1 and R2 are as defined above;
(D) deprotecting the compound of formula (IV) by splitting off the protecting group at the position 11 to obtain the compound of formula (III):
wherein the meaning of R2is as defined above;
(E) reducing the compound of formula (III) to obtain the compound of formula (II):
wherein the meaning of R2 is as defined above;
(F) hydrolyzing the compound of formula (II) to obtain an acid of the formula (I); and either:
(G) (i) isolating the acid of the compound of formula (I);
(ii) reacting the isolated acid of the compound of formula (I) with a base to form a salt of the compound of formula (I); and
(ii) isolating the salt of the compound of formula (I); or
(H) (i) reacting the acid of the compound of formula (I) with a base to form a salt of the compound of formula (I); and
(ii) isolating the salt of the compound of formula (I) thus obtained.
8. The process according to claim 7, wherein in the compound of formula (VIII), R1 is ethyl and X is chlorine, bromine or iodine atom, cyano-, azido-, CF3SO2\u2014O\u2014 or
9. The process according to claim 1, wherein the compound of formula (VI) is oxidized into a compound of formula (V) by using a mixture of dimethyl sulfoxide, oxalyl chloride and triethylamine.
10. The process according to claim 1, wherein an aldehyde of formula (V) and a phosphonate of formula (IX) are reacted in a Wittig-HornerEmmon’s reaction.
11. The process according to claim 1, wherein the protecting group of the hydroxyl group at position 11 of the compound of formula (IV) is split off in the acidic medium.
12. The process according to claim 1, wherein the reduction of a compound of formula (III) is carried out with diisobutylaluminium-2,6-di-tert.butyl-4-methylphenoxide.
13. The process according to claim 1, wherein the compound of formula (II) is hydrolized in basic medium.
14. The process according to claim 1, wherein the acid of formula (I) is transformed into its sodium salt and that salt is isolated.
15. The process of claim 7, wherein the salt is a sodium salt of a compound of formula (I).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound having the formula (Ia.1):
or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein
R1 is selected from the group consisting of \u2014C(O)NR1aR1b, \u2014C(O)R1a, \u2014CH(\u2550NOH), \u2014N(R1b)C(O)R1a, \u2014SO2NR1aR1b, \u2014SO2R1a, \u2014C(O)N(R1a)OR1b, \u2014(C1\u2013C4)alkylene \u2014N(R1b)C(O)R1a, and \u2014(C1\u2013C4)alkylene-C(O)NR1aR1b; wherein R1a and R1b are selected from hydrogen, (C1\u2013C6)alkyl, (C2\u2013C4)alkenyl, (C2\u2013C6)heteroalkyl, hydroxy(C1\u2013C4)alkyl, fluoro(C1\u2013C4)alkyl, cyano(C1\u2013C4)alkyl, cyclo(C3\u2013C8)alkyl, mono- or di-hydroxycyclo(C3\u2013C8)alkyl;
R2 is selected from the group consisting of \u2014NR2aR2b and \u2014OH; wherein R2a and R2b are selected from hydrogen, (C1\u2013C6)alkyl, (C2\u2013C4)alkenyl, (C2\u2013C6)heteroalkyl, mono- or di-hydroxy(C1\u2013C4)alkyl, fluoro(C1\u2013C4)alkyl, cyano(C1\u2013C4)alkyl, cyclo(C3\u2013C8)alkyl, mono- or di-hydroxycyclo(C3\u2013C8)alkyl, aryl, aryl(C1\u2013C4)alkyl, \u2014C(O)\u2014(C1\u2013C4)alkyl, \u2014C(O)\u2014(C1\u2013C4)alkoxy, C(O)-fluoro(C1\u2013C4)alkyl;
L is a single bond,
Q is selected from the group consisting of furyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, benzofuryl, tetrahydrobenzofuryl, isobenzofuryl, benzthiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzisoxazolyl and benzothienyl, wherein each of the moieties is optionally further substituted;
X1, X2 and X3 are independently selected from the group consisting of \u2550C\u2014and \u2014CH\u2014;
Y1 and Y3 are independently selected from the group consisting of \u2550C(R5a)\u2014, \u2014C(R5)(R6)\u2014;
Y2 is \u2014S(O)m;
Y4 is \u2550N\u2014or \u2014N(R5)\u2014;
Z1 and Z2 are CH or \u2550C\u2014;
each R5 and R6 is independently selected from the group consisting of hydrogen, (C1\u2013C6)alkyl, cyclo(C3\u2013C8)alkyl, aryl, aryl(C1\u2013C4)alkyl, hetero(C1\u2013C6)alkyl, and arylhetero(C1\u2013C4)alkyl;
each R5a is independently selected from the group consisting of hydrogen, halogen, (C1\u2013C6)alkyl, cyclo(C3\u2013C8)alkyl, aryl, aryl(C1\u2013C4)alkyl, hetero(C1\u2013C6)alkyl, and arylhetero(C1\u2013C4)alkyl; and
the subscript m is 0.
2. The compound of claim 1, wherein R1 is selected from the group consisting Of \u2014C(O)NR1aR1b, \u2014SO2NR1aR1b, \u2014SO2R1a, and \u2014C(O)R1a.
3. The compound of claim 1, having the formula (III):
4. The compound of claim 1, having the formula (V):
5. The compound of claim 1, having the formula (VI):
wherein each R5a is independently from the group consisting of hydrogen, halogen, (C1\u2013C6)alkyl, cyclo(C3\u2013C8)alkyl, aryl, aryl(C1\u2013C4)alkyl, hetero(C1\u2013C6)alkyl, and arylhetero(C1\u2013C4)alkyl.
6. The compound of claim 5, wherein R2 is \u2014NHR2b.
7. The compound of claim 5, wherein R1 is selected from the group consisting of \u2014C(O)NHR1a, \u2014SO2NHR1a, and \u2014C(O)CH3 and R2 is \u2014NHR2b.
8. The compound of claim 5, wherein R1 is selected from the group consisting Of \u2014C(O)NHR1a, \u2014SO2NHR1a, \u2014SO2R1a and \u2014C(O)CH3, R2 is \u2014NHR2b and each R5a is hydrogen.
9. The compound of claim 8, wherein the compound is:
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and a compound of claim 1.
11. A compound of claim 1, wherein the compound is selected from: