Patent Application
20100234334
The present invention relates to steroidal compounds having an improved pharmacological activity and lower side effects, to a process for their preparation and to pharmaceutical formulation containing them.
Steroid anti-inflammatory compounds are still the most effective drugs in the treatment of inflammatory diseases and conditions such as: asthma, chronic obstructive pulmonary disease (COPD), intestinal diseases such as Crohn's disease, colitis, ulcerative colitis, dermatological inflammations such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritus, conjunctivitis, autoimmune diseases such as rheumatoid arthritis, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in autoimmune disease. Moreover, steroids are used as adjunct chemotherapeutic agents in treating various malignancies, including leukemias, lymphomas, myelomas, and other malignancies of the hematopoietic system.
However Steroid anti-inflammatory compounds possess numerous unfavourable side-effects, e.g., on carbohydrate metabolism, calcium resorption, secretion of endogenous corticosteroids as well as on the physiological functions of the pituitary gland, adrenal cortex and thymus.
Thus there is an acute need for steroids with an improved therapeutic profile, and/or fewer or milder side effects in particular in the long-term treatments as required for the control of diseases.
The compounds of the present invention are derivatives of known steroids, containing a NO (nitric oxide)-releasing moiety and they are therapeutically useful in the treatment of illnesses wherein the known steroid, parent or precursor steroid, is generally applied, with increased benefit in terms of pharmacological profile and fewer or milder side effects than those of the known steroids.
Therefore the compounds of the present invention may be used, according to the activity of the parent drug, as drugs having antiinflammatory activity at peripheral level, immunodepressive activity, angiostatic/angiogenetic activity, antiarthritic activity, in the therapy of neurodegenerative diseases on an inflammatory and traumatic basis of the nervous system, in the therapy of respiratory diseases such as asthma and COPD, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in dermatological disease therapies, in autoimmune disease therapy in tumoral process therapies, in inflammatory pathologies affecting the gastrointestinal system.
In the prior art nitrooxy derivatives of steroids, which are usable also as cardiovascular agents for the coronary insufficiency or angina pectoris therapy, are described.
For example, German patent DE 2,222,491 describes the preparation of pregnane derivatives having in position 21 the —CH2—O—NO2 group. In said patent it is stated that said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.
U.S. Pat. No. 3,494,941 describes steroid derivatives from 3-hydroxy-extrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris. In the structure of said compounds a ONO2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17. According to said patent it is possible to have nitrate groups also in the positions 3 and 16 of the steroidal structure. The same drawbacks mentioned above as regards the effects on the cardiac frequency can be repeated for the compounds of this patent.
U.S. Pat. No. 3,183,252 describes derivatives of 16-nitrate-alkylpregnanes wherein the alkyl group is linked to the pregnane structure by a carbon-carbon bond. The compounds according to said patent can be used as vasodilators. The same drawbacks reported for the above prior art can be repeated.
WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors.
Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound. In said application the uses concern the compounds usable in the treatment of patients in oxidative stress. Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.
The Applicant has surprisingly and unexpectedly found a class of nitric oxide releasing compounds with a better bioavailability and/or a prolonged release of NO in comparison with the compounds known in prior art. In general the compounds of the present invention have a better drugability in comparison to the corresponding compounds of the prior art.
The present invention provides compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof.
R—(Z)a—Rx (I)
wherein R is a corticosteroid residue of formula (II):
wherein:
R1 is H, OH, —OC(O)OmRi wherein m is equal to 0 or 1, R1 is a branched or straight C1-C10 alkyl, preferably Ri is a branched or straight C1-C6 alkyl, preferred Ri is selected from methyl, ethyl, n-propyl, n-butyl;
R2 is H, —CH3, ═CH2, OH,
or R1 and R2 are taken together to form a group of formula (III)
wherein RA1 and RA2 are independently selected from H, a C1-C10 linear or branched alkyl chain, preferably (C1-C5) alkyl, more preferably —CH3, a C3-C6 cycloalkyl, preferably cyclohexyl or RA1 and RA2, taken together are a C3-C6 cycloalkyl, preferably cyclohexyl, or RA1 and RA2, taken together, are the group of formula (IV)
wherein RA3 is a C1-C10 linear or branched alkyl chain, preferably (C1-C5) alkyl;
R3 is H, Cl;
R4 is H, CH3, Cl, F, CH═O,
or R3 and R4 taken together are a double bond;
R4A is H;
R5 is H,
or R4A and R5 taken together are a double bond;
R6 is H,
or R5 and R6 taken together are a double bond;
R7 is OH, OCH2CH2Cl;
R7A is H,
or R7 and R7A taken together are a ═O;
R8 is H, Cl, Br,
or R7 and R8 taken together are the group of formula (V)
R8A is H,
or R7A and R8A taken together are a double bond;
R9 is H,
or R8 and R9 taken together are a double bond;
R10 is H, Cl, F;
R11 is H, OH,
or R10 and R11 taken together are a double bond;
R11A is H,
or R11 and R11A taken together are a ═O;
R12 is H, CH3 or ═O;
wherein R1, R2, R3, R4, R4a, R5, R6, R7, R7A, R8, R8A, R9, R10, R11 and R11A can be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
excluding the following corticosteroid residues R:
a in formula (I) is equal to 0 or 1;
Z is a group capable of binding RX and is selected from —C(O)—,
or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C1-C4 alkyl, preferably R′ is H or —CH3;
Rx is a radical selected from the following meanings:
(a1) —HN—CH(R1)—C(O)-(T-Y—ONO2)
(a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2)
(a3) —HN—CH(R1a-T″-Y′—ONO2)—COOR3a
(a4) —C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a
(a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2)
(a6) —R1b—CH(COOR3a)NH-(T′Y—ONO2)
(a7) —HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2)
(a8) —C(O)—CH(R1a-T″-Y′—ONO2)—NH-(T′Y—ONO2)
(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2)
(a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2)
wherein:
R1 is selected from:
2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH2—, 3-benzothienyl-CH2—, 4-imidazolyl-CH2—, 9-anthranyl-CH2—, cyclohexyl, cyclohexyl-CH2—, cyclohexyl-(CH2)2, cyclopentyl-CH2—, (C6H5)2CH—, 4-B(OH)-2-benzyl, 4-quinolyl-CH2—, 3-quinolyl-CH2—, 2-quinolyl-CH2—, 2-quinoxalyl-CH2—, 2-furyl-CH2—, 1-naphtyl-CH2—, 2-naphtyl-CH2—, 2-pyridyl-CH2—, 3-pyridyl-CH2—, 4-pyridyl-CH2—, 2-thienyl-CH2—, 3-thienyl-CH2—, C6H4—CH═CH—CH2—, CH2═CH—CH2—, CH≡CH—CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2 (═NH)NH—(CH2)3—, P(═O)(OCH3)2, I—CH2—, preferably R1 is H, —CH3, isopropyl, benzyl;
wherein R5a is H or a linear or branched C1-C10 alkyl chain, preferably R5a is H or a linear (C1-C5) alkyl, preferably R1 is —(CH2)4—NHR″, wherein R″ is as above defined,
wherein R5a is as above defined, preferably R1 is —CH2—C(O)R″′, wherein R″′ is as above defined,
R1a is selected from:
wherein R5a is as above defined,
R4a is selected from H or —C(O)CH3 or
wherein R5a is as above defined,
R1b is selected from
—O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is —C(O)—NR′— wherein R′ is as above defined;
T″ is independently selected from —C(O)—, —C(O)—X″—, —O—CH(R′)—O—C(O)O—, wherein X″ and R′ are as above defined, with the proviso that T″ is —C(O)—, —C(O)—X″— or —C(O)—NR′—when T″ is linked to —NH—, —O—, or —S—, or
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to —C(O)—,
Y and Y′ are as below defined;
or Rx is selected from:
(b1) —HN—CH(R2)—CH2—C(O)-(T-Y—ONO2)
(b2) —C(O)—CH2—CH(R2)—NH-(T′Y—ONO2)
(b3) —HN—CH(R2a-T″-Y′—ONO2)—CH2COOR3a
(b4) —C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NHR4a
(b5) —R2b—CH(NHR4a)—CH2C(O)-(T-Y—ONO2)
(b6) —R2b—CH(CH2COOR3a)NH-(T′-Y—ONO2)
(b7) —HN—CH(R2a-T″-Y′—ONO2)—CH2—C(O)-(T-Y—ONO2)
(b8) —C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NH-(T′Y—ONO2)
(b9) —R2b—CH(NH-T′Y′—ONO2)—CH2C(O)-(T-Y—ONO2)
(b10) —R2b—CH(CH2C(O)-T-Y′—ONO2)—NH-(T′Y—ONO2)
wherein
R2 is selected from:
B1) H, —CH3, CF3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, phenyl, benzyl, 3-triptophanyl-CH2—, NH2—C(O)—CH2—, NH2—C(O)—(CH2)2—, NH2 (═NH)NH—(CH2)3—, tBuO-CH(CH3)—, benzyl-O—CH2—, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R2 is H, —CH3, isopropyl, benzyl,
B2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2-[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-OH)];
B3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably R2 is —(CH2)4—NHR″;
B4) —CH2—C(O)—R″′, —(CH2)2—C(O)—R″′, —(CH2)4—C(O)—R″′ wherein R″′ is as above defined, preferably R2 is —CH2—C(O)—R″′;
R2a is selected from:
B5) —CH2—S—, —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], preferably R2a is —CH2—O—;
B6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, preferably R2a is —(CH2)4—NH— or —CH2—NH—;
B7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—, preferably R2a is —CH2—C(O)—;
R2b is selected from
B8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, preferably R2b is —O—CH2— or [-(4-O)—(C6H4)]—CH2—;
B9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, preferably R2b is —HN—(CH2)4— or —HN—CH2—;
B10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—, preferably R2b is —C(O)—CH2—;
R3a and R4a are as above defined;
T, T″ and T″ are as above defined and Y and Y′ are as below defined;
or Rx is selected from:
(c1) —HN—(CH2)b—C(O)-(T-Y—ONO2);
(c2) —C(O)—(CH2)b—NH-(T′Y—ONO2);
wherein b is an integer from 3 to 6,
T and T″ are as above defined and Y and Y′ are as below defined;
(d1) —HN—CH(R12)—CH2—O-(T″′-Y—ONO2)
(d2) —O—CH2—CH(R12)—NH-(T′Y—ONO2)
(d3) —HN—CH(R12a-T″-Y′—ONO2)—CH2OH
(d4) —O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a
(d5) —R12b—CH(NHR4a)—CH2—O-(T″′-Y—ONO2)
(d6) —R12b—CH(CH2OH)—NH-(T′Y—ONO2)
(d7) —HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T″′-Y—ONO2)
(d8) —O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′Y—ONO2)
(d9) —R12b—CH(NH-T′Y′—ONO2)—CH2—O-(T″′-Y—ONO2)
(d10) —R12b—CH(CH2—O-T″-Y′—ONO2)—NH-(T′Y—ONO2)
wherein
T″′ is independently selected from —C(O)—, —C(O)X″— wherein X″ is —O— or —S—, or —C(O)—NR′— wherein R′ is as above defined;
T′ and T″ are as above defined,
Y and Y′ are as below defined;
R12 is selected from:
D1) H, —CH3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2) benzyl, 3-triptophanyl-CH2—, 4-imidazolyl-CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, preferably R12 is H;
D2) —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2-[(C6H3)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-OH)], preferably R12 is —CH2—OH or —CH2[(C6H4)-(4-OH)];
D3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably R12 is —(CH2)4—NHR″;
D4) —CH2—C(O)R″′, —(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is as above defined, preferably R12 is —CH2—C(O)R″′; R12a is selected from
D5) —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], —CH2-[3,5-diiodo-(C6H2)-(4-O)—], —CH2-[3-nitro-(C6H3)-4-O—], preferably R12a is CH2—O— or —CH2[(C6H4)-(4-O)—],
D6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, preferably R12a is —(CH2)4—NH— or —CH2—NH—,
D7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—, preferably R12a is —CH2—C(O)—,
R12b is selected from
D8) —O—CH2—, —O—CH(CH3)—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, preferably R12b is —O—CH2— or [-(4-O)—(C6H4)]—CH2—;
D9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, preferably R12b is —HN—(CH2)4— or —HN—CH2—;
D10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—, preferably R12b is —C(O)—CH2—;
R4a is as above defined;
or Rx is selected from:
wherein c is equal to 0 or 1, d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3, T and T″ are as above defined and Y is as below defined;
wherein e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1,
T and T″ are as above defined and Y is as below reported;
wherein R3 is H, CH3, propyl, (C6H5)2CH—, 1-naphtyl-CH2—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R3 is H, T and T″ are as above defined and Y is as below defined;
wherein R4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T″ are as above defined and Y is as below defined;
wherein R5 is H, R6 is H, or R5 and R6 when taken together are a double bond, T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T″ are as above defined and Y is as below reported;
wherein c is as above defined, d is equal to 0 or 1, T and T″ are as above defined and Y is as below reported;
wherein R7 is H, R8 is H, or R7 and R8 when taken together are a double bond, c is as above defined, T and T″ are as above defined and Y is as below reported;
wherein T and T″ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T″ are as above defined and Y is as below reported;
wherein R9 and R10 are H, CH3, R11 is CH3 or 4-piperidinyl with the proviso that R9 and R10 are H when R11 is 4-piperidinyl and R9 and R10 are CH3 when R11 is CH3, T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
with the proviso that in the formula (I):
a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when Rx is:
wherein
n0 is an integer from 0 to 20, preferably n0 is 0 or 1;
n1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
wherein
n0 is an integer from 0 to 20, preferably n0 is 0 or 1;
n1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 and U are as above defined;
n2 is an integer from 0 to 2, preferably n2 is 1;
R13 is H or CH3, preferably R13 is CH3;
Y1 is —CH2—CH2— or —CH═CH—(CH2)n2′—, wherein n2′ is 0 or 1, preferably Y1 is —CH═CH—(CH2)n2′— and n2′ is 0;
T1=—O—C(O)— or —C(O)O—, preferably Ti is —C(O)O—;
n1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
more preferably n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′— and n2′ is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;
wherein:
n2 is an integer from 0 to 2, preferably n2 is 1;
R13 is H or CH3, preferably R13 is CH3;
Y1 is —CH2—CH2— or —(CH2)n2′—CH═CH—, wherein n2′ is 0 or 1, preferably Y1 is —(CH2)n2′—CH═CH— and n2′ is 0;
n1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
more preferably n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′— and n2′ is 0, T1 is —OC(O)— and U is a linear C1-C10 alkylene;
wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 is an integer from 1 to 6, preferably n3 is 1;
when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group;
wherein:
n4 is an integer from 0 to 10, preferably n4 is 0 or 1;
n5 is an integer from 1 to 10, preferably n5 is 1;
R14, R15, R16, R17 are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R14, R15, R16 and R17 are H;
wherein the —ONO2 group is linked to
wherein n5 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur,
and is selected from the group consisting of:
The term “C1-C10 alkyl” as used herein refers to branched or straight alkyl groups including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
The term “cycloalkylene” as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C1-C10)-alkyl, preferably CH3.
The term “heterocyclic” as used herein refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like.
Preferred compounds of formula (I) are those wherein R is the residue of the corticosteroid selected from the group consisting of alclometasone, alclomethasone-17-propionate, betamethasone-17-benzoate, betamethasone-17-butyrate, betamethasone-17-propionate, betamethasone-17-valerate, clocortolone, cloprednol, corticosterone, cortisone, desonide, dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, diflorasone, diflorasone-17-acetate, difluocortolone, fludrocortisone, flucloronide, fluocortin, fluocortolone, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, halomethasone, halomethasone-17-propionate, halopredone, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisolone-17-ethylcarbonate, prednisone, prednival, prednylidene, triamcinolone, triamcinolone 16-acetate, 3-(2-chloroethoxy)-9-fluoro-11β,16α,17,21-tetrahydroxy-20-oxopregna-3,5-diene-6-carboxaldehyde; 5-pregnene-3β,21-diol-20-one; (11β,16α)-16,17-[cyclopentylidenebis(oxy)]-11,21-dihydroxy-9-fluoro-pregna-1,4-diene-3,20-dione; 6,16α-dimethyl-11β,17α,21-trihydroxy-2′-phenyl[3,2-c]pyrazolo-4,6-pregnadien-20-one; (11β,16β-11,21-dihydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; (11β,16β-11,21-dihydroxy-9-fluoro-2′-methyl-5/H-pregna-1,4-dieno[17,16-d]oxazole-3,2,0-dione; (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,2,0-dione; [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethoxy-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; (6a,11β)-6,9-difluoro-11,21-dihydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione; (11β,16β-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of respiratory diseases, in particular asthma and COPD, are those wherein R is the residue of the corticosteroid selected from the group consisting of dexamethasone, dexamethasone-17-acetete, dexamethasone-17-propionate, prednisolone, prednisone, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of ocular diseases, in particular ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, are those wherein R is the residue of the corticosteroid selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate; (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of inflammatory diseases are those wherein R is the residue of the corticosteroid selected from the group consisting of betamethasone 17-benzoate, betamethasone 17-butyrate, betamethasone 17-propionate, betamethasone 17-valerate, cloprednol, corticosterone, cortisone, dexamethasone, fludrocortisone, flucloronide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, prednival, prednylidene, triamcinolone, 5-pregnene-3β,21-diol-20-one, 6,16α-dimethyl-11β,17α,21-trihydroxy-2′-phenyl[3,2-c]pyrazolo-4,6-pregnadien-20-one; (11β,16β)-11,21-dihydroxy-2′-methyl-5/H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; (11β,16β)-11,21-dihydroxy-9-fluoro-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; 3-(2-chloroethoxy)-9-fluoro-11β,16α,17,21-tetrahydroxy-20-oxopregna-3,5-diene-6-carboxaldehyde.
Preferred compounds of formula (I) for the treatment of dermatological diseases, in particular corticosteroid-responsive dermatosis, atopic dermatitis, inflammation, eczema, erythema, papulation, scaling, erosion, oozing, crusting, pruritis, psoriasis, epidermalysis bullosa, erythema, hidradenitis suppurative, warts, diaper rash, jock itch, ruber lichen planus, are those wherein R is the residue of the corticosteroid selected from the group consisting of alclometasone, betamethasone-17-butyrate, betamethasone-17-propionate, betamethasone-17-benzoate, betamethasone-17-valerate, clocortolone, desonide, desoximethasone, dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, diflorasone, diflorasone-17-acetate, difluocortolone, flumethasone, flucloronide, fluocortolone, flurandrenolide, halomethasone, halomethasone-17-propionate, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, methylprednisolone, prednisolone-17-ethylcarbonate, triamcinolone, alclomethasone 17-propionate, (11β,16α)-16,17-[cyclopentylidenebis(oxy)]-11,21-dihydroxy-9-fluoro-pregna-1,4-diene-3,20-dione; (6α,11β)-6,9-difluoro-11,21-dihydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione; (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione; fluprednidene, halopredone.
One embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, preferably R′ is CH3;
RX is selected from the following meanings
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″—, —O— or —S—, or —C(O)—NR′, wherein X″ and R′ are as above defined;
T″ is independently selected from —C(O)—, —O—CH(R′)—O—C(O)—, —C(O)—X″—, wherein X″ is —O— or —S—, —NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), c), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, preferably R′ is CH3;
RX is
or RX is
(a4) wherein R1a of the group A5) is selected from —CH2—O—, CH(CH3)O— or —CH2[(C6H4)-(4-O)—], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;
or RX is selected from
(a5), (a6), (a9) or (a10) wherein
R1b of the group A10) is selected from —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—;
or RX is
(a8) wherein
R1a of the group A5) is selected from —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;
or RX is
(b2) wherein
R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl;
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2,
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′—, wherein n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
RX is selected from
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
RX is
or RX is
(a5), (a6), (a9) or (a10) wherein
R1b of the group A8) is selected from —O—CH(CH3)—, —O—CH2—, [(4-O)—(C6H4)]—CH2—, or
R1b of the group A9) is selected from —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—;
or RX is
or RX is
or RX is selected from
or RX is selected from
or RX is selected from
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2,
b) wherein n1 is 0 or n1 is 1
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′, wherein n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O—;
RX is selected from
(d5), (d6), (d9) or (d10) wherein R12b is selected from D10);
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2,
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein
n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
RX is
(d1) wherein
R12 is selected from D1);
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2,
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein n2′ is 0 and T1 is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 and R2 are taken together to form a group of formula (III) wherein RA1 is CH3 and RA2 is H, and R1 and R2 are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OC(O)OmRi wherein m is 0 and Ri is —CH2CH3 and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
and wherein
a=0 or a=1 and Z is —CH(R′)O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, preferably R′ is CH3;
RX is selected from
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″—, wherein X″ is —O— or —S—, or —C(O)—NR′—, wherein R′ is defined above;
T″ is independently selected from —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from a), b), d), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 and R2 are taken together to form a group of formula (III) wherein RA1 is CH3 and RA2 is H, and R1 and R2 are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OC(O)OmRi wherein m is O and Ri is —CH2CH3 and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
and wherein
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, preferably R′ is CH3;
RX is
or RX is
or RX is selected from
or RX is
or RX is
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2,
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 and R2 are taken together to form a group of formula (III) wherein RA1 is CH3 and RA2 is H, and R1 and R2 are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OC(O)OmRi wherein m is 0 and Ri is —CH2CH3 and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
and wherein
a=1 and Z is —C(O)—;
RX is selected from
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), d), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 and R2 are taken together to form a group of formula (III) wherein RA1 is CH3 and RA2 is H, and R1 and R2 are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OC(O)OmRi wherein m is 0 and Ri is —CH2CH3 and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
and wherein
a=1 and Z is —C(O)—;
RX is
or RX is
or RX is selected from
or RX is
or RX is
or RX is selected from
or RX is selected from
or RX is selected from
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R4 is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 and R2 are taken together to form a group of formula (III) wherein RA1 is CH3 and RA2 is H, and R1 and R2 are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OC(O)OmRi wherein m is 0 and Ri is —CH2CH3 and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position β;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is CH3 and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
or wherein R is the corticosteroid residue of formula (II) wherein
R1 is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R2 is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;
R5 and R6 form a double bond;
R8 and R9 form a double bond;
R10 is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R11 is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;
and wherein
a=0 or a=1 and Z is —CH(R′)—O—
RX is selected from
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2;
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, preferably R′ is CH3;
RX is
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2;
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein n2′ is 0 and Ti is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione;
a=1 and Z is —C(O)—;
RX is
T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C1-C10 alkylene or a C1-C10 alkylene substituted with —ONO2;
b) wherein n1 is 0 or n1 is 1;
e) wherein n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2) n2′—, wherein n2′ is 0 and T1 is —C(O) and n1 is 0 or 1, U is a C1-C10 alkylene optionally substituted with a —ONO2 group;
f) wherein T2 is —O, R13 is H and n3 is 1.
Preferred specific embodiments of the present invention are the selected compounds reported below:
As stated above, the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines.
The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.
The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I).
Another object of the present invention provides the use of the compounds of formula (I) above reported in the treatment of inflammatory diseases and conditions such as asthma, chronic obstructive pulmonary disease (COPD), intestinal diseases such as Crohn's disease, colitis, ulcerative colitis, dermatological inflammations such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritus, conjunctivitis, autoimmune diseases such as rheumatoid arthritis, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in autoimmune disease.
The compounds object of the present invention are formulated in the corresponding pharmaceutical compositions, also with belated release, for parenteral, oral and topic use, such as for example sublingual, inhalatory, suppository, transdermal, enema, according to the well known techniques in the art, together with the usual excipients; see for example the publication “Remington's Pharmaceutical Sciences” 15th Ed.
The amount on a molar basis of the active principle in said compositions is generally the same, or lower than that of the corresponding precursor drug.
The daily administrable doses are those of the precursor drugs, or optionally lower. The precursor daily doses can be found in the publications of the field, such for example in the “Physician's Desk reference”.
1) The compound of general formula (I) as above defined wherein a is equal to 0, the radical RX is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), can be obtained:
1-i) by reacting a compound of (IIa)
wherein R1, R2, R3, R4, are as above defined, with a compound of formula (Ia)
W—X1 (Ia)
wherein W is —OH, C1-10—Ra wherein Ra is pentafluorophenyl, 4-nitrophenyl or —(N-succimidyl), X1 is as below defined, to obtain the compound of formula (IIa′)
wherein R1, R2, R3, R4, are as above defined and X1 is as below defined,
X1 is a radical having the following meaning:
wherein R5a is as defined above;
A4′) —CH2—C(O)R″″′, —(CH2)2—C(O)R″″′, —(CH2)4—C(O)R″″′ wherein R″″′ is P2, —OR5a or
wherein R5a is as above defined;
B3′) —CH2—NHR″″, —(CH2)2—NHR″″, —(CH2)3—NHR″″, —(CH2)4—NHR″″, wherein R″″ is as above defined;
B4′)—CH2—C(O)—R″″′, —(CH2)2—C(O)—R″″′, —(CH2)4—C(O)—R″″′ wherein R″″′ is as above defined;
wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, b, c, d, e and f are as above defined;
wherein P1 is a hydroxyl or thiol protecting group such as silyl ethers, such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P2 is a carboxylic protecting group such as tert-butyl ester and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P3 is a amino protecting group such as Boc, Fmoc or those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980,
T, T′, T″, Y and Y′ are as above defined,
Q is independently —ONO2 or Z2 wherein Z2 is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group, and
1-ii) when Q is Z2, by converting the compound obtained in the step 1-i) into nitro derivative by reaction with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C1-C10 alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate and
1-iii) optionally deprotecting the compounds obtained in step 1-i) or 1-ii) as described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, 2nd edition. Fluoride ion is the preferred method for removing silyl ether protecting group. Trifluoroacetic acid or anhydrous inorganic acid are the preferred method for removing Boc protecting group, anhydrous organic or inorganic acid is the preferred method for removing trityl protecting group. Organic base such as piperidine is the preferred method for removing Fmoc protecting group. Aqueous or anhydrous organic or inorganic acid is the preferred method for removing t-butyl ester protecting group.
1-i1) The reaction of a compound of formula (Ia) wherein W=—OH and X1 is as above defined, with a compound of formula (IIa) may be carried out in presence of a condensing agent as dicyclohexylcarbodiimide (DCC), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) N,N′-carbonyldiimidazole (CDI), in the presence or not of a base as for example as N,N-dimethylamino pyridine (DMAP).
The reaction is carried out in an inert organic dry solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from −20° C. to 50° C. The reaction is completed within a time range from 30 minutes to 36 hours.
1-i2) The reaction of a compound of formula (Ia) wherein W=—O—Ra wherein Ra and X1 are as above defined, with a compound of formula (IIa) may be carried out in presence of a catalyst, such as N,N-dimethylamino pyridine (DMAP) or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3.
The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from −20° C. to 40° C. The reaction is completed within a time range from 30 minutes to 36 hours.
1-i3) The reaction of a compound of formula (Ia) wherein W═—Cl, and X1 is are as above defined, with a compound of formula (IIa) may be carried out in presence of an organic base such as N,N-dimethylamino pyridine (DMAP), triethylamine, pyridine.
The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from −20° C. to 40° C. The reaction is completed within a time range from 30 minutes to 36 hours.
The compounds of formula (IIa) are commercially available.
1a) The compounds of formula (Ia) wherein W is —OH, T″ and T″ are C(O), and X1 is the radical selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ is selected from B1), B2′), B3′), B4′) and Y, Y′ and R4a′ are as above defined, can be obtained
1a-i) by reacting a compound of formula (IIIa)
P2—X2 (IIIa)
wherein P2 is as above defined, X2 is a radical having the following meaning
wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, b, c, d, e and f are as above defined;
with a compound of formula (IVa)
W1—(O)C-y-Q (IVa)
wherein W1 is OH or O—Ra and Ra and Q are as above defined, y is the radical Y when X2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X2 is selected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and
1a-ii) when Q is Z2, by converting the compound obtained in the step 1a-i) into nitro derivative by reaction with a nitrate source as above described and
1a-iii) optionally deprotecting the compounds obtained in step 1a-i) or 1a-ii) as above described.
The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVa) wherein W1 is OH, y, Q are as above defined, may be carried out as described in 1-i1) or in presence of other known condensing reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).
The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVa) wherein W1 is O—Ra, y, Q are as above defined, may be carried as described in 1-i2).
The compounds of formula (IIIa) are commercially available or can be obtained as known in the literature.
The compounds of formula (IVa) wherein W1 is OH, y and Q are as above defined, can be obtained from the corresponding alcohols of formula HOOC-y-OH (IVb) by reaction with nitric acid and acetic anhydride in a temperature range from −50° C. to 0° C. or from the corresponding derivatives of formula HOOC-y-Z2 (IVc) wherein Z2 is as above defined, by reaction with a nitrate source as above described. Alternatively the reaction with AgNO3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between about 100-180° C. for time range about 1-60 min.
The compounds of formula (IVb) are commercially available.
The compounds of formula (IVc) are commercially available or can be obtained as known in the literature.
The compounds of formula (IVa) wherein W1 is O—Ra, y, Q are as above defined, can be obtained from the corresponding acids of formula (IVa) wherein W1 is OH as known in the literature.
The compounds of formula (Ia) wherein W═Cl or O—Ra, X1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ is selected from B1), B2′), B3′), B4′), and wherein Y, Y′ and Q are as above defined and T′ and T″ are C(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in the literature.
1b) The compounds of formula (Ia) wherein W is —OH, X1 is the radical selected from (a2′), (a4′), (b2′), (b4′) (c2′), (e2′), (f1l′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ is selected from B1), B2′), B3′), B4′), Y and Y′ are as above defined, T′ and T″ are C(O)—X″, wherein X″ is —O— or —S— can be obtained
1b-i) by reacting a compound of formula (IIIa)
P2-X2 (IIIa)
wherein P2 and X2 are as defined above, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, X″ and Q are as above defined, y is the radical Y when X2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X2 is selected from (a4′) or (b4′), wherein Y and Y′ are as above defined, and
1b-ii) when Q is Z2, by converting the compound obtained in the step 1b-i) into nitro derivative by reaction with a nitrate source as above described and
1b-iii) optionally deprotecting the compounds obtained in step 1b-i) or 1b-ii) as above described.
The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y and Q are as above defined, may be carried out as described in 1-i2)
The compounds of formula (IVd) wherein Ra, X″, y, Q are as above defined, can be obtained from the compounds of formula HX″-y-Q (IVe) wherein X″, y, Q are as above defined, as known in literature.
The compound of formula (IVe) are commercially available or are known in literature.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ is selected from B1), B2′), B3′), B4′), Y, Y′ and Q are as above defined, T″ and T″ are C(O)—X″ wherein X″ is O or S, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in the literature.
1c) The compounds of formula (Ia) wherein W is —OH and X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Q is as above defined, T′ and T″ are C(O), Y and Y′ are the same and are as above defined, can be obtained
1c-i) by reacting a compound of formula (IIIb),
P2-X3 (IIIb)
wherein P2 is as above defined, X3 is the radical of formula
W1—(O)C-y-Q (IVa)
wherein W1 and Q are as above defined, wherein y is the radical Y or Y′, wherein Y and Y′ are as above defined, and
1c-ii) when Q is Z2, by converting the compound obtained in the step 1c-i) into nitro derivative by reaction with a nitrate source as above described and
1c-iii) optionally deprotecting the compounds obtained in step 1c-i) or 1c-ii) as above described.
The reaction of a compound of formula (IIIb) wherein P2 and X3 are as above defined, with a compound of formula (IVa) wherein W1 is OH, y and Q are as above defined, may be carried out as described in 1a-i) using a ratio (IIIb)/(IVa) 1:2.
The reaction of a compound of formula (IIIb) wherein P2 and X3 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, may be carried out as described in 1-i2) using a ratio (IIIb)/(IVa) 1:2.
The compounds of formula (IIIb) are commercially available or can be obtained as known in the literature.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6) and wherein Y, Y′ and Q are as above defined and T″ and T″ are C(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in the literature.
1d) The compounds of formula (Ia) wherein W is —OH, X1 is the radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O), can be obtained
1d-i) by reacting a compound of formula (Ib)
P2—X3′ (Ib)
wherein P2 is as above defined, X3′ is the radical of formula
W1—(O)C-y-Q (IVa)
wherein W1 and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and
1d-ii) when Q is Z2, by converting the compound obtained in the step 1d-i) into nitro derivative by reaction with a nitrate source as above described and
1d-iii) optionally deprotecting the compounds obtained in step 1d-i) or 1d-ii) as above described.
The reaction of a compound of formula (Ib) wherein P2 and X3′ are as above defined, with a compound of formula (IVa) wherein W1 is OH, y and Q are as above defined, may be carried out as described in 1a-i).
The reaction of a compound of formula (Ib) wherein P2 and X3′ are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined may be carried out as described in 1-i2).
The compounds of formula (Ib) wherein T″ is C(O), P2 and X3′ are as above defined, are obtained as described in 1a).
The compounds of formula (Ib) wherein T″ is C(O)—X″, P2 and X3′ are as above defined, are obtained as described in 1b).
The compounds of formula (Ia) wherein W is —Cl or O—Ra′, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6) and wherein Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1e) The compounds of formula (Ia) wherein W is —OH, X1 is the radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Q is as above defined, Y and Y′ are the same and are as above defined, T″ and T″ are C(O)—X″— wherein X″ is as above defined, can be obtained
1e-i) by reacting a compound of formula (IIIb)
P2-X3 (IIIb)
wherein P2 and X3 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and
1e-ii) when Q is Z2, by converting the compound obtained in the step 1e-i) into nitro derivative by reaction with a nitrate source as above described and
1e-iii) optionally deprotecting the compounds obtained in step 1e-i) or 1e-ii) as above described.
The reaction of a compound of formula (IIIb) wherein P2 and X3 are as above defined, with a compound of formula (IVd) wherein Ra, y and Q are as above defined, may be carried out as described in 1-i2) using a ratio (IIIb)/(IVd) 1:2.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6) and wherein Y and Y′, Q is as above defined and T″ and T″ are C(O)—X″— wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1f) The compounds of formula (Ia) wherein W is —OH, X1 is selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O)—X″, can be obtained
1f-i) by reacting a compound of formula (Ib)
P2—X3′ (Ib)
wherein X3′ and P2 are as above defined, with a compound of formula (IVd)
W1—O—C(O)—X″-y-Q (IVd)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
1f-ii) when Q is Z2, by converting the compound obtained in the step 1f-i) into nitro derivative by reaction with a nitrate source as above described and
1f-iii) optionally deprotecting the compounds obtained in step 1f-i) or 1f-ii) as above described.
The reaction of a compound of formula (Ib) wherein P2 and X3′ are as above defined, with a compound of formula (IVd) wherein W1 is OH, y and Q are as above defined, may be carried out as described in 1a-i).
The reaction of a compound of formula (Ib) wherein P2 and X3′ are as above defined, with a compound of formula (IVd) wherein W1 is ORa, y and Q are as above defined may be carried out as described in 1-i2).
The compounds of formula (Ib) wherein T″ is C(O), P2 and X3′ are as above defined, are obtained as described in 1a).
The compounds of formula (Ib) wherein T″ is C(O)—X″, P2 and X3′ are as above defined, are obtained as described in 1b).
The compounds of formula (Ia) wherein W is —Cl or O—Ra′, X1 is a radical selected from (a8′) or (b8′) wherein R1a is A5) or A6), R2a is B5) or B6) and wherein Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ and T″ is C(O)—X, wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1g) The compounds of formula (Ia) wherein W is —OH, X1 is a radical is selected from (a8′) or (b8′), wherein R1a is selected from A5), A6), R2a is selected from B5), B6), Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O)—NR′ wherein R′ is above defined, can be obtained
1g-i) by reacting a compound of formula (Ib)
P2—X3′ (Ib)
wherein P2 and X3′ are as above defined, with a compound of formula
Ra—O—(O)C—NR′-y-Q (IVf)
wherein Ra, R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
1g-ii) when Q is Z2, by converting the compound obtained in the step 1g-i) into nitro derivative by reaction with a nitrate source as above described and
1g-iii) optionally deprotecting the compounds obtained in step 1g-i) or 1g-ii) as above described.
The reaction of a compound of formula (Ib) wherein P2 and X3′ are as above defined, with a compound of formula (IVf) wherein Ra, R′, y, Q are as above defined, may be carried out as described in 1-i2).
The compounds of formula (Ib) wherein T″ is C(O), wherein P2 and X3′ are as above defined, are obtained as described in 1a-i), 1a-ii).
The compounds of formula (Ib) wherein T″ is C(O)—X″, wherein P2 and X3′ are as above defined, are obtained as described in 1b-i), 1b-ii).
The compounds of formula (IVf) wherein R′, y and Q are as above defined, can be obtained from the compounds of formula HR′N-y-Q (IVg) by reaction with a chloroformate as known in the literature.
The compounds of formula (IVg) wherein y is as above defined and Q is Z2 is commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO2 may be obtained from the compound of formula P3—R′N-y-ONO2 (IVh) wherein P3 is as above defined by deprotection of amino group as known in literature. The compounds of formula (IVh) wherein P3, y are as above defined may be obtained from the alcohol P3—R′N-y-OH (IVi) by reacting with tetraalkylammonium nitrate as already described for analogous compounds. The compounds of formula (IVi) are commercially available or known in literature. Alternatively the compounds of formula (IVh) wherein P3, y are as above defined may be obtained from the corresponding compounds of formula P3—R′N-y-Z2 (IVl) wherein P3, y, Z2 are as above defined, by reaction with a nitrate source as above described.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6) and wherein Y, Y′ and Q are as above defined and T′ is C(O) or C(O)—X″, T″ is C(O)—NR′—, wherein X″ and R′ are as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1h) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a is selected from B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″, T″ is X″ wherein X″ is above defined, can be obtained
1h-i) by reacting a compound of formula (Ie),
P2-X5 (Ie)
wherein P2 is defined above, X5 is the radical of formula
HX″-y-Q (IVe)
wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
1h-ii) when Q is Z2, by converting the compound obtained in the step 1h-i) into nitro derivative by reaction with a nitrate source as above described and
1h-iii) optionally deprotecting the compounds obtained in step 1h-i) or 1h-ii) as above described.
The reaction of a compound of formula (Ie) wherein P2 and X5 are as above defined, with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i1).
The compounds of formula (Ie) wherein T″ is C(O), wherein P2 and X5 are as above defined, are obtained as described in 1a-i), 1a-ii)
The compounds of formula (Ie) wherein T″ is C(O)—X″, wherein P2 and X5 are as above defined, are obtained as described in 1b-i), 1b-ii).
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a is selected from B7) and wherein Y, Y′ and Q are as above defined, T″ is C(O) or C(O)—X″, and T″ is X″ wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1i) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a is selected from B7), Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is —NR′ wherein R′ is above defined, can be obtained
1i-i) by reacting a compound of formula (Ie),
P2-X5 (Ie)
wherein is P2 and X5 are defined above, with a compound of formula (IVg)
HR′N-y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
1i-ii) when Q is Z2, by converting the compound obtained in the step 1i-i) into nitro derivative by reaction with a nitrate source such above described and
1n-iii) optionally deprotecting the compounds obtained in step 1i-i) or 1i-ii) as above described.
The reaction of a compound of formula (Ie) wherein P2 and X5 are as above defined, with a compound of formula (IVg) wherein R′, y and Q are as above defined, may be carried out as described in 1a-i).
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a is selected from B7) and wherein Y, Y′ and Q are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —NR′ wherein R′ is as above defined can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature
11) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a is selected from B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, can be obtained
1l-i) by reacting a compound of formula (Ie),
P2-X5 (Ie)
wherein is P2 and X5 are defined above, with a compound of formula (IVm)
Hal-CH(R′)—O—(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 1l-ii) when Q is Z2, by converting the compound obtained in the step 1l-i) into nitro derivative by reaction with a nitrate source such above described and
1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or 1l-ii) as above described.
The reaction of a compound of formula (Ie) wherein P5 and X5 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined may be carried out in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0° to 100° C. or in a double phase system H2O/Et2O at temperatures range between 20° to 40° C.
The compounds of formula (IVm) wherein y, Q, R′ are as above defined, Hal is an halogen atom may be obtained by reacting a compound R′—CH2—CHO, commercially available, with a compound of formula Hal-(O)C-y-Q (IVn), wherein y and Q are as above defined, Hal is a chlorine atom and ZnCl2 as known in literature.
The compounds of formula (IVn) may be obtained as known in literature.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a is selected from B7) and wherein Y, Y′, and Q are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —O—CH(R′)—O—C(O)— wherein R′ is as above defined can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1m) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a is B7), Q, Y and Y′ are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is —O—CH(R′)—O—C(O)O—, wherein R′ is as above defined, can be obtained
1m-i) by reacting a compound of formula (Ie),
P2-X5 (Ie)
wherein is P2 and X5 are defined above, with a compound of formula (IVo)
Hal-CH(R′)—O—(O)C—O-y-Q (IVo)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, Hal is an halogen atom, and
1l-ii) when Q is Z2, by converting the compound obtained in the step 1l-i) into nitro derivative by reaction with a nitrate source such above described and
1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or 1l-ii) as above described.
The reaction of a compound of formula (Ie) wherein P2 and X5 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined may be carried out as described in 1l-i).
The compounds of formula (IVo) wherein y, R′, Q are as above defined, may be obtained by reacting the compounds of formula Hal-(R′)CH—OC(O)Hal, wherein Hal is as above defined, commercially available, with a compound of formula HO-y-Q (IVe) wherein y, Q are as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0° to 65° C.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a selected from A7), R2a selected from B7) and wherein Y, Y′ and Q are as above defined, T″ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —O—CH(R′)—O—C(O)O—, may be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1n) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is X″ wherein X″ is as above defined, can be obtained
1n-i) by reacting a compound of formula (IIIc)
P2—X5′ (IIIc)
wherein P2 is defined above, X5′ is
HX″-y-Q (IVe)
wherein X″ and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
1n-ii) when Q is Z2, by converting the compound obtained in the step 1n-i) into nitro derivative by reaction with a nitrate source as above described and
1n-iii) optionally deprotecting the compounds obtained in step 1n-i) or 1n-ii) as above described.
The reaction of a compound of formula (IIIc) wherein X5′ and P2 are as above defined, with a compound of formula (IVe) wherein X″, y, Q are as above defined may be carried out as described in 1-i1).
The compounds of formula (IIIc) wherein X5′ and P2 are as above defined, are commercially available or can be obtained as known in the literature.
The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′ and Q are as above defined, T″ is X″, wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.
1o) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained
1o-i) by reacting a compound of formula (IIIc)
P2—X5′ (IIIc)
wherein P2 and X5′ are as above defined, with a compound of formula (IVg)
HR′N-y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y′, and 1o-ii) when Q is Z2, by converting the compound obtained in the step 1o-i) into nitro derivative by reaction with a nitrate source as above described and
1o-iii) optionally deprotecting the compounds obtained in step 1o-i) or 1o-ii) as above described.
The reaction of a compound of formula (IIIc) wherein X5′ and P2 are as above defined, with a compound of formula (IVg) wherein R′, y and Q are as above defined may be carried out as described in 1a-i).
The compounds of formula (Ia) wherein W is —Cl or —ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7) and wherein Y′, Q are as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained may be obtained from the corresponding acids (Ia) wherein W═—OH as known in literature.
1p) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained
1p-i) by reacting a compound of formula (IIIc)
P2—X5′ (IIIe)
wherein P2 and X5′ are as above defined, with a compound of formula (IVm)
Hal-CH(R′)—O—(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, Hal is an halogen atom and
1p-ii) when Q is Z2, by converting the compound obtained in the step 1p-i) into nitro derivative by reaction with a nitrate source as above described and
1p-iii) optionally deprotecting the compounds obtained in step 1p-i) or 1p-ii) as above described.
The reaction of a compound of formula (IIIc) wherein P2 and X5′ are as above defined, with a compound of formula (IVm) wherein R′, y, Q, Hal are as above defined, may be carried out as described in 1l-1).
The compounds of formula (Ia) wherein W is —Cl or ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7) and wherein Y and Q are as above defined and T″ is the group —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained from the corresponding acids (Ia) wherein W═—OH as known in literature.
1q) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, can be obtained
1q-i) by reacting a compound of formula (IIIc)
P2—X5′ (IIIc)
wherein P2 and X5′ are as above defined, with a compound of formula (IVo)
Hal-CH(R′)—O(O)C—O-y-Q (IVo)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, Hal is an halogen atom and
1q-ii) when Q is Z2, by converting the compound obtained in the step 1q-i) into nitro derivative by reaction with a nitrate source as above described and
1q-iii) optionally deprotecting the compounds obtained in step 1q-i) or 1q-ii) as above described.
The reaction of a compound of formula (IIIc) wherein P2 and X5′ are as above defined, with a compound of formula (IVo) wherein R′, y, Q, Hal are as above defined, may be carried out as described in 1l-1).
The compounds of formula (Ia) wherein W is —Cl or ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7) and wherein Y, Q, are as above defined and T″ is the group —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, can be obtained may be obtained from the corresponding acids (Ia) wherein W═—OH as known in literature.
2) The compound of general formula (I) as above defined wherein a is equal to 1, the radical RX is the radical selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (hi), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 alkyl, can be obtained:
2-i) by reacting a compound of formula (IIa)
R—OH (IIa)
wherein R is as above defined with a compound of formula (If)
Hal-CH(R′)—O—X1 (If)
wherein Hal is an halogen atom, R′ and X1 are as above defined and
2-ii) when Q is Z2, by converting the compound obtained in the step 2-i) into nitro derivative by reaction with a nitrate source as above described and
2-iii) optionally deprotecting the compounds obtained in step 2-i) or 2-ii) as above described.
The reaction of a compound of formula (If) wherein X1 and R′ are as above defined, with a compound of formula (IIa) wherein R is as above defined, may be carried out as described in 1l-i).
The compounds of formula (If) are obtained by reacting a compound R′—CHO, wherein R′ is as above defined with compounds of formula (Ia)
W—X1 (Ia)
wherein W is a chlorine atom, X1 is as above defined, and ZnCl2 as known in literature.
3) The compound of general formula (I) as above defined wherein a is equal to 1, the radical RX is selected from (al), (a3), (a7), (b1), (b3), (b7), (c1), (e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t1), (u1), (v1), Z is C(O), can be obtained
3-i) by reacting a compound of formula
R—C(O)—O—Ra (IIb)
wherein R and Ra are as above defined, with a compound of formula (Ig)
H—X2 (Ig)
wherein X2 is a radical having the following meanings:
wherein R5a is as above defined;
wherein T, T″, Y and Y′ are as above defined,
3-ii) when Q is Z2, by converting the compound obtained in the step 3-i) into nitro derivative by reaction with a nitrate source such above described and
3-iii) optionally deprotecting the compounds obtained in step 3-i) or 3-ii) as above described.
The reaction of a compound of formula (IIb) wherein R and Ra are as above defined, with a compound of formula (Ig) wherein X1 is as above defined, may be carried out as described in 1-i2).
The compounds of formula R—C(O)—O—Ra (IIb) wherein R and Ra are as above defined, are obtained from the compounds R—H (IIa) by reaction with the compounds of formula Cl—C(O)—O—Ra wherein Ra is as above defined, as known in literature.
3a) The compounds of formula (Ig) wherein X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), Y and Y′ are as above defined, T and T″ are X″ wherein X″ is as above defined may be obtained
3a-i) by reacting a compound of formula (IIIe),
P3—X6 (IIIe)
wherein P3 is as above defined, X6 is a radical having the following meanings:
with a compound of formula (IVe)
HX″-y-Q (IVe)
wherein Q and X″ are as above defined y is the radical Y when X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3a-ii) when Q is Z2, by converting the compound obtained in the step 3a-i) into nitro derivative by reaction with a nitrate source as above described and
3a-iii) optionally deprotecting the compounds obtained in step 3a-i) or 3a-ii) as above described.
The reaction of a compound of formula (IIIe) wherein P3 and X6 are as above defined, with a compound of formula (IVe), wherein y, Q and X″ are as above defined, may be carried out as described in 1-i1).
The compounds of formula (IIIe) are commercially available or can be obtained as known in the literature.
3b) The compounds of formula (Ig) wherein X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —NR′ wherein R′ is as above defined may be obtained
3b-i) by reacting a compound of formula (IIIe),
P3—X6 (IIIe)
wherein P3 and X6 are as above defined, with a compound of formula
HR′N-y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y when X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3b-ii) when Q is Z2, by converting the compound obtained in the step 3b-i) into nitro derivative by reaction with a nitrate source as above described and
3b-iii) optionally deprotecting the compounds obtained in step 3b-i) or 3b-ii) as above described.
The reaction of a compound of formula (IIIe) wherein P3 and X6 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out 1a-i).
3c) The compounds of formula (Ig) wherein X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, may be obtained
3c-i) by reacting a compound of formula (IIIe)
P3-X6 (IIIe)
wherein P3, X6 are as above defined with compounds of formula (IVm)
Hal-CH(R′)—O—(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y when X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3c-ii) when Q is Z2, by converting the compound obtained in the step 3c-i) into nitro derivative by reaction with a nitrate source as above described and
3c-iii) optionally deprotecting the compounds obtained in step 3c-i) or 3c-ii) as above described.
The reaction of a compound of formula (IIIe) wherein P3 and X6 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i)
3d) The compounds of formula (Ig) wherein X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —O—CH(R′)—O—C(O)O— wherein R′ is as above defined may be obtained
3d-i) by reacting a compound of formula (IIIe)
P3-X6 (IIIe)
wherein P3 and X6 are as above defined, with compounds of formula (IVo)
Hal-CH(R′)—O—(O)C—O-y-Q (IVo)
wherein R′ and Q are as above defined, Hal is an halogen atom y is the radical Y when X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3d-ii) when Q is Z2, by converting the compound obtained in the step 3d-i) into nitro derivative by reaction with a nitrate source as above described and
3d-iii) optionally deprotecting the compounds obtained in step 3d-i) or 3d-ii) as above described.
The reaction of a compound of formula (IIIe) wherein P3 and X6 are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).
3e) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A5) or A6), R1b is selected from B5) or B6) T″ is —C(O)—, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3e-i) by reacting a compound of formula (Ih)
P3-X7 (Ih)
wherein P3 is as above defined and X7 is the radical having the following meaning
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3e-ii) when Q is Z2, by converting the compound obtained in the step 3e-i) into nitro derivative by reaction with a nitrate source as above described and
3e-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3e-ii) as above described.
The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVa) wherein y, Q, W1 are as above defined may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-i).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —X″ are obtained as described in 3a).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —NR′ are obtained as described in 3b).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
3f) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7) wherein R1a is selected from A5) or A6), R1b is selected from B5) or B6) T″ is —C(O)—X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3f-i) by reacting a compound of formula (Ih)
P3—X7 (Ih)
wherein P3 and X7 are as above defined with compounds of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3f-ii) when Q is Z2, by converting the compound obtained in the step 3f-i) into nitro derivative by reaction with a nitrate source as above described and
3f-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3f-ii) as above described.
The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVd) wherein y, Q, Ra are as above defined, may be carried out as described in 1-i2).
3g) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A5), A6), R1b is selected from B5), B6), T″ is —C(O)—NR′, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3g-i) by reacting a compound of formula (Ih)
P3—X7 (Ih)
wherein P3 and X7 are as above defined, with compounds of formula (IVf)
Ra—O—C(O)—NR′—y-Q (IVf)
wherein Ra and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3g-ii) when Q is Z2, by converting the compound obtained in the step 3g-i) into nitro derivative by reaction with a nitrate source as above described and
3g-iii) optionally deprotecting the compounds obtained in step 3g-i) or 3g-ii) as above described.
The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVf) wherein y, Q, Ra and R′ are as above defined may be carried out as described in 1-i2).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —X″ are obtained as described in 3a).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —NR′ are obtained as described in 3b).
The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
The compounds of formula (II) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
3h) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b is selected from B7), T″ is —X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3h-i) by reacting a compound of formula (Iv)
P3—X8 (Iv)
wherein P3 is as above defined and X8 is the radical having the following meaning
H—X″-y-Q (IVe)
wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3h-ii) when Q is Z2, by converting the compound obtained in the step 3h-i) into nitro derivative by reaction with a nitrate source as above described and
3h-iii) optionally deprotecting the compounds obtained in step 3h-i) or 3h-ii) as above described.
The reaction of a compound of formula (Iv) wherein P3 and X8 are as above defined, with a compound of formula (IVe) wherein y, Q, X″ are as above defined, may be carried out as described in 1-i1), 1-i2) and 1a-1).
The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —X″ are obtained as described in 3a).
The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —NR′ are obtained as described in 3b).
The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
3i) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b is selected from B7), T″ is NR′, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3i-i) by reacting a compound of formula (Iv)
P3—X8 (Iv)
wherein P3 and X8 are as above defined, with compounds of formula (IVg)
H—NR′—y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3i-ii) when Q is Z2, by converting the compound obtained in the step 3i-i) into nitro derivative by reaction with a nitrate source as above described and
3i-iii) optionally deprotecting the compounds obtained in step 3i-i) or 3i-ii) as above described.
The reaction of a compound of formula (Iv) wherein P3 and X8 are as above defined, with a compound of formula (IVg) wherein y, Q, R′ are as above defined, may be carried out as described in 1a-i).
3l) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b is selected from B7), T″ is —O—CH(R′)—O—C(O)—, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3l-i) by reacting a compound of formula (Iv)
P3—X8 (Iv)
wherein P3 and X8 are as above defined with compounds of formula (IVm)
Hal-CH(R′)—O(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, Hal is an halogen atom and
3l-ii) when Q is Z2, by converting the compound obtained in the step 3l-i) into nitro derivative by reaction with a nitrate source as above described and
3l-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3l-ii) as above described.
The reaction of a compound of formula (Iv) wherein P3 and X8 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).
3m) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b is selected from B7), T″ is —O—CH(R′)—O—C(O)O—, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3m-i) by reacting a compound of formula (Iv)
P3—X8 (Iv)
wherein P3 and X8 are as above defined with compounds of formula (IVo)
Hal-CH(R′)—O(O)C—O-y-Q (IVo)
wherein R′ and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, Hal is an halogen atom and 3m-ii) when Q is Z2, by converting the compound obtained in the step 3m-i) into nitro derivative by reaction with a nitrate source as above described and
3m-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3m-ii) as above described.
The reaction of a compound of formula (Iv) wherein P3 and X8 are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).
3n) The compounds of formula (Ig) wherein X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O) may be obtained
3n-i) by reacting a compound of formula (IIIf),
P3—X9 (IIIf)
wherein P3 is as above defined, X8 is a radical having the following meaning
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3n-ii) when Q is Z2, by converting the compound obtained in the step 3n-i) into nitro derivative by reaction with a nitrate source as above described and
3n-iii) optionally deprotecting the compounds obtained in step 3n-i) or 3n-ii) as above described.
The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i1), 1-i2), 1a-1).
The compounds of formula (IIIf) wherein P3 and X9 are as above defined, is commercially available or obtained as known in literature.
3o) The compounds of formula (Ig) wherein X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O)—X″ wherein X″ is as above defined, can be obtained
3o-i) by reacting a compound of formula (IIIf)
P3—X9 (IIIf)
wherein P3 and X9 are as above defined with compounds of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, X″, Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3o-ii) when Q is Z2, by converting the compound obtained in the step 3o-i) into nitro derivative by reaction with a nitrate source as above described and
3o-iii) optionally deprotecting the compounds obtained in step 3o-i) or 3o-ii) as above described.
The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y, Q are as above defined, may be carried out as described in l-1-2).
3p) The compounds of formula (Ig) wherein X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O)—NR′ wherein R′ is as above defined, can be obtained
3p-i) by reacting a compound of formula (IIIg),
P3—X9 (IIIf)
wherein P3 and X9 are as above defined, with compounds of formula (IVf)
Ra—O—(O)C—NR′-y-Q (IVf)
wherein Ra, R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3p-ii) when Q is Z2, by converting the compound obtained in the step 3p-i) into nitro derivative by reaction with a nitrate source as above described and
3p-iii) optionally deprotecting the compounds obtained in step 3p-i) or 3p-ii) as above described.
The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVf) wherein Ra, R′, y, Q are as above defined, may be carried out as described in 1-i2).
4) The compound of general formula (I) as above defined wherein a is equal to 1, the radical RX is selected from (d1), (d2), (d3), (d4), (d7), (d8), Z is C(O), can be obtained
4-i) by reacting a compound of formula (IIb)
R—C(O)—O—Ra (IIb)
wherein R and Ra are as above defined, with a compound of formula (Im)
H—X12 (Im)
wherein X12 is the radical RX having the following meaning
D2′) —CH2—OP1, —CH(CH3)—OP1, —CH2[(C6H4)-(4-OP1)], —CH2-[(C6H3)-(3,5-diiodo)-(4-OP1)], —CH2-[(C6H3)-3-nitro-(4-OP1)];
D3′) —CH2—NHR″″, —(CH2)2—NHR″″, —(CH2)3—NHR″″, —(CH2)4—NHR″″, wherein R″″ is as above defined;
D4′) —CH2—C(O)R″″, —(CH2)2—C(O)R″″′, —(CH2)4—C(O)R″″′, wherein R″″′ is as above defined;
wherein R12a is as above defined;
and
4-ii) when Q is Z2, by converting the compound obtained in the step 4-i) into nitro derivative by reaction with a nitrate source as above described and
4-iii) optionally deprotecting the compounds obtained in step 4-i) or 4-ii) as above described.
The reaction of a compound of formula (IIb) wherein R and Ra are as above defined, with a compound of formula (Im) wherein X12 is as above defined, may be carried out as described in 1-i2).
4a) The compound of formula (Im) wherein X12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R12′ is selected from D1), D2′), D3′) or D4′) and R12a is selected from D5) or D6), Y and Y′ are as above defined, T′ and T″ and T″′ are C(O) can be obtained
4a-i) by reacting a compound of formula (IIIi),
P4—X13 (IIIi)
wherein P4 is P3 or P1 as above defined and X13 is a radical having the following meaning
W1—(O)C-y-Q (IVa)
wherein Q and W1 are as above defined, y is the radical Y when X13 is selected from (d1′) or (d2′), y is the radical Y′ when X13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4a-ii) when Q is Z2, by converting the compound obtained in the step 4a-i) into nitro derivative by reaction with a nitrate source as above described and
4a-iii) optionally deprotecting the compounds obtained in step 4a-i) or 4a-ii) as above described.
The reaction of a compound of formula (IIIi) wherein X13 and P4 are as above defined, with a compound of formula (IVa) wherein W1, y and Q are as above defined, may be carried out as described in 1-i1) and 1-i2).
The compounds of formula (IIIi) wherein X13 and P4 are as above described, are commercially available or known in literature.
4b) The compound of formula (Im) wherein X12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R12′ is selected from D1), D2′), D3′) or D4′) and R12a is selected from D5) or D6), Y and Y′ are as above defined, T′ and T″ and T″′ are C(O)—X″, wherein X″ is as above defined, can be obtained
4b-i) by reacting a compound of formula (IIIi),
P4—X13 (IIIi)
wherein P4 and X13 are defined above, with a compound of formula (IVd)
Ra—O—(O)C—X″-y-Q (IVd)
wherein Q, Ra and X″ are as above defined, y is the radical Y when X13 is selected from (d1′) or (d2′), y is the radical Y′ when X13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4b-ii) when Q is Z2, by converting the compound obtained in the step 4b-i) into nitro derivative by reaction with a nitrate source as above described and
4b-iii) optionally deprotecting the compounds obtained in step 4b-i) or 4b-ii) as above described.
The reaction of a compound of formula (IIIi) wherein X13 and P4 are as above defined, with a compound of formula (IVd) wherein y, Q, Ra and X″ are as above defined, may be carried out as described in 1-i2).
4c) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Y′ and Y are as above defined, T′ and T″ and T″′ are C(O), can be obtained
4c-i) by reacting a compound of formula (IIIl),
P4—X14 (IIIl)
wherein P4 is P1 or P3, X14 is the radical having the following meaning
W1—(O)C-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4c-ii) when Q is Z2, by converting the compound obtained in the step 4c-i) into nitro derivative by reaction with a nitrate source as above described and
4c-iii) optionally deprotecting the compounds obtained in step 4c-i) or 4c-ii) as above described.
The reaction of a compound of formula (IIIl) wherein P4 and X14 are as above defined, with a compound of formula (IVa) wherein W1 is OH, y and Q are as above defined, may be carried out as described in 1-i1) using a ratio (IIIl)/(IVa) 1:2.
The reaction of a compound of formula (IIIl) wherein P4 and X14 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, may be carried out as described in 1-i2) using a ratio (IIIl)/(IVa) 1:2.
The compounds of formula (IIIl) wherein P4 and X14 are as above described, are commercially available or known in literature.
4d) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″, T″′ and T″ are C(O), can be obtained
4d-i) by reacting a compound of formula (In)
P4—X15 (In)
wherein P4 is defined above and X15 is the radical having the following meaning
W1—(O)C-y-Q (IVa)
wherein W1, y and Q′ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4d-ii) when Q is Z2, by converting the compound obtained in the step 4d-i) into nitro derivative by reaction with a nitrate source as above described and
4d-iii) optionally deprotecting the compounds obtained in step 4d-i) or 4d-ii) as above described.
The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is OH, y and Q are as above defined, may be carried out as described in 1-i1).
The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, may be carried out as described in 1-i2).
The compounds of formula (In) wherein P4 and X15 are as above defined, T″ and T″′ are —C(O)— can by obtained as described in 4a).
4e) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″ is C(O)—X″ wherein X″ is as above defined, T″ and T″′ are C(O), can be obtained
4e-i) by reacting a compound of formula (In)
P4—X15 (In)
wherein P4 and X15 are defined above, with a compound of formula (IVa)
W1—(O)C-y-Q (IVa)
wherein W1, y and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4e-ii) when Q is Z2, by converting the compound obtained in the step 1e-i) into nitro derivative by reaction with a nitrate source as above described and
4e-iii) optionally deprotecting the compounds obtained in step 4e-i) or 4e-ii) as above described.
The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is OH, y and Q are as above defined, can by carried out as described in 1-i1).
The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, can by carried out as described in 1-i2).
The compounds of formula (In) wherein P4 and X15 are as above defined can by obtained as described in 4b).
4f) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Y and Y′ are the same and are as above defined, T″, T″ and T″′ are C(O)—X″ wherein X″ is as above defined, can be obtained
4f-i) by reacting a compound of formula (IIIl),
P4—X14 (IIIl)
wherein P4 and X14 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4f-ii) when Q is Z2, by converting the compound obtained in the step 4f-i) into nitro derivative by reaction with a nitrate source as above described and
4f-iii) optionally deprotecting the compounds obtained in step 4f-i) or 4f-ii) as above described.
The reaction of a compound of formula (IIIl) wherein P4 and X14 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y and Q are as above defined, may be carried out as described in 1-i2) using a ratio (IIIl)/(IVd) 1:2.
4g) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″ is C(O)—X″, T′ and T′″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4g-i) by reacting a compound of formula (In)
P4—X15 (In)
wherein P4 and X15 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4g-ii) when Q is Z2, by converting the compound obtained in the step 4g-i) into nitro derivative by reaction with a nitrate source as above described and
4g-iii) optionally deprotecting the compounds obtained in step 4g-i) or 4g-ii) as above described.
The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y and Q are as above defined, may be carried out as described in 1-i2).
The compounds of formula (In) wherein T″ or T″′ are C(O), P4 and X15 are as above defined are obtained as described in 4a-i), 4a-ii).
The compounds of formula (In) wherein T″ or T″′ are C(O)—X″, wherein P4 and X15 are as above defined are obtained as described in 4b-i), 4b-ii).
4h) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″ is C(O)—NR′—, T′ and T′″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4h-i) by reacting a compound of formula (In)
P4—X15 (In)
wherein P4 and X15 are as above defined, with a compound of formula
Ra—O—(O)C—NR′—y-Q (IVf)
wherein Ra, R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4h-ii) when Q is Z2, by converting the compound obtained in the step 4h-i) into nitro derivative by reaction with a nitrate source as above described and
4h-iii) optionally deprotecting the compounds obtained in step 4h-i) or 4h-ii) as above described.
The reaction of a compound of formula (In) P4 and X15 are as above defined, with a compound of formula (IVf) wherein Ra, R′, y, Q are as above defined, may be carried out as described in 1-i2).
The compounds of formula (In) wherein T″ or T″′ are C(O), wherein P4 and X15 are as above defined, are obtained as described in 4a-i), 4a-ii).
The compounds of formula (In) wherein T″ or T″′ are C(O)—X″, wherein P4 and X15 are as above defined, are obtained as described in 4b-i), 4b-ii).
4i) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D7), Q, Y and Y′ are as above defined, T″ is X″, wherein X″ is as above defined, T″ and T″′ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4i-i) by reacting a compound of formula (Ir),
P4—X16 (Ir)
HX″-y-Q (IVe)
wherein Y′, X″ and Q are as above defined, Y is the radical Y′, wherein Y′ is as above defined, and
4i-ii) when Q is Z2, by converting the compound obtained in the step 4i-i) into nitro derivative by reaction with a nitrate source as above described and
4i-iii) optionally deprotecting the compounds obtained in step 4i-i) or 4i-ii) as above described.
The reaction of a compound of formula (Ir) wherein P4 and X16 are as above defined with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i1).
The compounds of formula (Ir) wherein T″ or T″′ are C(O), P4 and X16 are as above defined are obtained as described in 4a-i), 4a-ii).
The compounds of formula (Ir) wherein T″ or T″′ are C(O)—X″, P4 and X16 are as above defined, are obtained as described in 4b-i), 4b-ii).
4l) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D7), Q, Y and Y′ are as above defined, T″ is —NR′ wherein R′ is as above defined, T″ and T″′ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4l-i) by reacting a compound of formula (Ir),
P4—X16 (Ir)
wherein P4 and X16 are as above defined and R12a is selected from D7), with a compound of formula
HR′N-y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4l-ii) when Q is Z2, by converting the compound obtained in the step 4l-i) into nitro derivative by reaction with a nitrate source such above described and
4l-iii) optionally deprotecting the compounds obtained in step 4l-i) or 4l-ii) as above described.
The reaction of a compound of formula (Ir) P4 and X16 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1-i1).
4m) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D7), Q, Y and Y′ are as above defined, T″ is —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, T″ and T″′ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4m-i) by reacting a compound of formula (Ir),
P4—X16 (Ir)
wherein P4 and X16 are as above defined and R12a is selected from D7), with a compound of formula (IVm)
Hal-CH(R′)—O(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and
4m-ii) when Q is Z2, by converting the compound obtained in the step 4m-i) into nitro derivative by reaction with a nitrate source such above described and
4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or l1-ii) as above described.
The reaction of a compound of formula (Ir) wherein P4 and X16 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).
4n) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a is selected from D7), Q, Y and Y′ are as above defined, T″ is —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, T″ and T″′ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained
4n-i) by reacting a compound of formula (Ir),
P4—X16 (Ir)
wherein P4 and X16 are as above defined and R12a is selected from D7), with a compounds of formula (IVo)
Hal-CH(R′)—O(O)C—O-y-Q (IVo)
wherein R and Q′ are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 4n-ii) when Q is Z2, by converting the compound obtained in the step 4n-i) into nitro derivative by reaction with a nitrate source as above described and
4n-iii) optionally deprotecting the compounds obtained in step 4n-i) or 4n-ii) as above described.
The reaction of a compound of formula (Ir) wherein P4 and X16 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined, may be carried out as described in 1l-i).
4o) The compound of formula (Im) wherein X12 is (selected from d3′) or (d4′) wherein R12a is selected from D7), Y′ is as above defined, T″ is X″, wherein X″ is defined above, can be obtained
4o-i) by reacting a compound of formula (IIIm),
P4—X17 (IIIm)
wherein P4 is defined above and X17 is the radical
wherein R12a is selected from D7), wherein P1 and R4a′ are as above defined, with a compound of formula (IVe)
HX″-y-Q (IVe)
wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4o-ii) when Q is Z2, by converting the compound obtained in the step 4o-i) into nitro derivative by reaction with a nitrate source as above described and
4o-iii) optionally deprotecting the compounds obtained in step 4o-i) or 4o-ii) as above described.
The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i1).
The compounds of formula (IIIm), wherein P4 and X17 are as above defined, are commercially available or obtained as known in literature.
4p) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a is selected from D7), Y′ is as above defined, T″ is —NR′ wherein R′ is as above defined, can be obtained
4p-i) by reacting a compound of formula (IIIm),
P4—X17 (IIIm)
wherein P4 and X17 are as defined above, wherein R12a is selected from D7), with a compound of formula
HR′N-y-Q (IVg)
wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4p-ii) when Q is Z2, by converting the compound obtained in the step 4p-i) into nitro derivative by reaction with a nitrate source such above described and
4p-iii) optionally deprotecting the compounds obtained in step 4p-i) or 4p-ii) as above described.
The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1a-i).
4q) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a is selected from D7), Y′ is as above defined, T″ is —O—CH(R′)—O—C(O)— wherein R′ is as above defined, can be obtained
4q-i) by reacting a compound of formula (IIIm),
P4—X17 (IIIm)
wherein P4 and X17 are as defined above, wherein R12a is selected from D7), with a compound of formula (IVm)
Hal-CH(R′)—O(O)C-y-Q (IVm)
wherein R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and
4q-ii) when Q is Z2, by converting the compound obtained in the step 4q-i) into nitro derivative by reaction with a nitrate source such above described and
4q-iii) optionally deprotecting the compounds obtained in step 4q-i) or 4q-ii) as above described.
The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined, with a compound of formula (IVm) wherein R′, y, Q are as above defined, may be carried out as described in 1-i).
4r) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a is selected from D7), Y′ is as above defined, T″ is —O—CH(R′)—O—C(O)—O— wherein R′ is as above defined, can be obtained
4r-i) by reacting a compound of formula (IIIm),
P4—X17 (IIIm)
wherein P4 and X17 are as defined above, wherein R12a is selected from D7), with a compound of formula (IVo)
Hal-CH(R′)—O(O)C—O-y-Q (IVo)
wherein R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and
4r-ii) when Q is Z2, by converting the compound obtained in the step 4r-i) into nitro derivative by reaction with a nitrate source as above described and
4r-iii) optionally deprotecting the compounds obtained in step 4r-i) or 4r-ii) as above described.
The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined, may be carried out as described in 1l-i).
5) The compound of general formula (I) as above defined wherein a is equal to 0, RX is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b is selected from D10) can be obtained
5-i) by reacting a compound of formula (IIa)
R—H (IIa)
wherein R is as above defined, with a compound of formula (Is)
W—X18 (Is)
wherein W is as above defined, X is the radical having the following meanings
The reaction of a compound of formula (IIa) wherein R is as above defined, with a compound of formula (Is) wherein W and X is are as above defined may be carried out as described in 1).
5a) The compounds of formula (Is) wherein X18 is a radical of formula (d5′) or (d6′), wherein R12b is selected from D10), T″ and T″′ are C(O) can be obtained
5a-i) by reacting a compound of formula (IIIn),
P2—X19 (IIIn)
wherein P2 is as above defined, X19 is the radical having the following meanings
W1—C(O)-y-Q (IVa)
wherein W1, y, Q are as above defined, y is the radical Y, wherein Y is as above defined, and
5a-ii) when Q is Z2, by converting the compound obtained in the step 5a-i) into nitro derivative by reaction with a nitrate source as above described and
5a-iii) optionally deprotecting the compounds obtained in step 5a-i) or 5a-ii) as above described.
The reaction of a compound of formula (IIIn) wherein P2 and X19 are as above defined, with a compound of formula (IVa) W1, y, and Q are as above defined may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
The compounds of formula (IIIn), wherein P2 and X19 are as above defined, are commercially available or obtained as known in literature.
5b) The compounds of formula (Is) wherein X18 is a radical of formula (d5′) or (d6′), wherein R12b is selected from D10), T″ and T″′ are C(O)—X″, wherein X″ is defined above, can be obtained
5b-i) by reacting a compound of formula (IIIn),
P2—X19 (IIIn)
wherein P2 and X19 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and Q, X″ are as above defined, y is the radical Y, wherein Y is as above defined, and
5b-ii) when Q is Z2, by converting the compound obtained in the step 5b-i) into nitro derivative by reaction with a nitrate source as above described and
5b-iii) optionally deprotecting the compounds obtained in step 5b-i) or 5b-ii) as above described.
The reaction of a compound of formula (IIIn) wherein P2 and X19 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
5c) The compounds of formula (Is) wherein X18 is a radical of formula (d9′), wherein R12b is selected from D10), Y and Y′ are as defined above, T′ is C(O)— and T″′ is C(O) or C(O)—X″, wherein X″ is defined above, can be obtained
5c-i) by reacting a compound of formula (It),
P2—X20 (It)
wherein P2 is as above defined and X20 is the radical having the following meanings
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5c-ii) when Q is Z2, by converting the compound obtained in the step 5c-i) into nitro derivative by reaction with a nitrate source as above described and
5c-iii) optionally deprotecting the compounds obtained in step 5c-i) or 5c-ii) as above described.
The reaction of a compound of formula (It) wherein P2 and X20 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
5d) The compounds of formula (Is) wherein X18 is a radical of formula (d9′), wherein R12b is selected from D10), T′ is C(O)—X″ and T″′ is C(O)— or C(O)—X″, wherein X″ is defined above, can be obtained
5d-i) by reacting a compound of formula (It′),
P2—X20′ (It′)
wherein P2 and X20′ are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5d-ii) when Q is Z2, by converting the compound obtained in the step 5d-i) into nitro derivative by reaction with a nitrate source as above described and
5d-iii) optionally deprotecting the compounds obtained in step 5d-i) or 5d-ii) as above described.
The reaction of a compound of formula (It′) wherein P2 and X20′ are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
5e) The compounds of formula (Is) wherein X is the radical of formula (d10′), wherein R12b is selected from D10), Y and Y′ are as defined above, T″′ is C(O)— and T′ is C(O) or C(O)—X″, wherein X″ is defined above, can be obtained
5e-i) by reacting a compound of formula (It),
P2—X20 (It)
wherein P2 is as above defined and X20 is the radical having the following meaning
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5e-ii) when Q is Z2, by converting the compound obtained in the step 5e-i) into nitro derivative by reaction with a nitrate source as above described and
5e-iii) optionally deprotecting the compounds obtained in step 5e-i) or 5e-ii) as above described.
The reaction of a compound of formula (It) wherein P2 and X20 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
5f) The compounds of formula (Is) wherein X is the radical of formula (d10′), wherein R12b is selected from D10), T″′ is C(O)—X″ and T′ is C(O)— or C(O)—X″, wherein X″ is defined above, can be obtained
5f-i) by reacting a compound of formula (It′),
P2—X20′ (It′)
wherein P2 and X20′ are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5f-ii) when Q is Z2, by converting the compound obtained in the step 5f-i) into nitro derivative by reaction with a nitrate source as above described and
5f-iii) optionally deprotecting the compounds obtained in step 5f-i) or 5f-ii) as above described.
The reaction of a compound of formula (It′) wherein P2 and X20′ are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
6) The compounds of general formula (I) as above defined wherein a is equal to 1, RX is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b is selected from D10), Z is —CH(R′)—O—, wherein R′ is defined above, can be obtained
6-i) by reacting a compound of formula (IIa)
R—OH (IIa)
wherein R is as above defined with a compound of formula (Iu)
Hal-CH(R′)—O—X21 (Iu)
wherein Hal is an halogen atom, R′ is as above defined and X21 is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R12b is selected from D10), and
6-ii) when Q is Z2, by converting the compound obtained in the step 6-i) into nitro derivative by reaction with a nitrate source as above described and
6-iii) optionally deprotecting the compounds obtained in step 6-i) or 6-ii) as above described.
The reaction of a compound of formula (Iu) wherein Hal, X21 and R′ are as above defined, with a compound of formula (IIa) wherein R is as above defined, may be carried out as described in 1l-i).
The compounds of formula (Iu) are obtained by reacting a compound R′—CHO, wherein R′ is as above defined with compounds of formula (IIIo)
W—X22 (IIIo)
wherein W is a chlorine atom, X22 is the radical having the following meanings
The compounds of formula (IIIo), wherein W and X22 are as above defined, may be carried out as described in 5).
7) The compounds of general formula (I) as above defined wherein a is equal to 1, RX is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b is selected from D8) or D9), Z is —C(O)—, can be obtained
7-i) by reacting a compound of formula (IIb)
R—C(O)—O—Ra (IIb)
wherein R and Ra are as above defined with a compound of formula (Iv)
H—X23 (Iv)
wherein X23 is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R12b is selected from D8) or D9), and
7-ii) when Q is Z2, by converting the compound obtained in the step 7-i) into nitro derivative by reaction with a nitrate source as above described and
7-iii) optionally deprotecting the compounds obtained in step 7-i) or 7-ii) as above described.
The reaction of a compound of formula (Iv) wherein X23 and is as above defined, with a compound of formula (IIb) wherein R is as above defined, may be carried out as described in 1l-i).
8) The compound of general formula (I) as above defined wherein a is equal to 0, RX is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R1b is selected from A10) and R2b is selected from B10), can be obtained
8-i) by reacting a compound of formula (IIa)
R—H (IIa)
wherein R is as above defined, with a compound of formula (Iz)
W—X24 (Iz)
wherein W is as above defined, X24 is the radical RX having the following meanings
The reaction of a compound of formula (IIa) wherein r is as above defined, with a compound of formula (Iv) wherein W and X24 are as above defined may be carried out as described in 1).
8a) The compounds of formula (Iz) wherein X24 is a radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R1b is selected from A10) and R2b is selected from B10), T and T′ are C(O) can be obtained
8a-i) by reacting a compound of formula (IIIq),
P2—X25 (IIIq)
wherein P2 is as above defined, X25 is the radical having the following meanings
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y, wherein Y is as above defined, and
8a-ii) when Q is Z2, by converting the compound obtained in the step 8a-i) into nitro derivative by reaction with a nitrate source as above described and
8a-iii) optionally deprotecting the compounds obtained in step 8a-i) or 8a-ii) as above described.
The reaction of a compound of formula (IIIq) wherein P2 and X25 are as above defined, with a compound of formula (IVa) W1, Y, and Q are as above defined may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
The compounds of formula (IIIq), wherein P2 and X25 are as above defined, are commercially available or obtained as known in literature.
8b) The compounds of formula (Iz) wherein X24 is the radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R1b is selected from A10) and R2b is selected from B10), T and T′ are C(O)—X″, wherein X″ is defined above, can be obtained
8b-i) by reacting a compound of formula (IIIq),
P2—X25 (IIIq)
wherein P2 and X25 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra, Q and X″ are as above defined, y is the radical Y,
wherein Y is as above defined, and
8b-ii) when Q is Z2, by converting the compound obtained in the step 8b-i) into nitro derivative by reaction with a nitrate source as above described and
8b-iii) optionally deprotecting the compounds obtained in step 8b-i) or 8b-ii) as above described.
The reaction of a compound of formula (IIIq) wherein P2 and X25 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
8c) The compounds of formula (Iz) wherein X24 is the radical of formula (a9′) or (b9′) wherein R1b is selected from A10), and R2b is selected from B10) Y and Y′ are as defined above, T is C(O)— or C(O)—X″, wherein X″ is defined above and T″ is C(O) can be obtained
8c-i) by reacting a compound of formula (Iy),
P2—X26 (Iy)
wherein P2 is as above defined and X26 is the radical having the following meanings
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
8c-ii) when Q is Z2, by converting the compound obtained in the step 8c-i) into nitro derivative by reaction with a nitrate source as above described and
8c-iii) optionally deprotecting the compounds obtained in step 8c-i) or 8c-ii) as above described.
The reaction of a compound of formula (Iy) wherein P2 and X26 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
8d) The compounds of formula (Iz) wherein X24 is the radical of formula (a9′) or (b9′) wherein R1b is selected from A10), R2b is selected from B10), Y and Y′ are as defined above, T is C(O)— or C(O)—X″, wherein X″ is defined above and T″ is C(O)—X″ can be obtained
8d-i) by reacting a compound of formula (Iy),
P2—X26 (Iy)
wherein P2 and X26 are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8d-ii) when Q is Z2, by converting the compound obtained in the step 8d-i) into nitro derivative by reaction with a nitrate source as above described and
8d-iii) optionally deprotecting the compounds obtained in step 8d-i) or 8d-ii) as above described.
The reaction of a compound of formula (Iy) wherein P2 and X20 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
8e) The compounds of formula (Iz) wherein X24 is the radical of formula (a10′) or (b10′) wherein R1b is selected from A10), and R2b is selected from in B10) Y and Y′ are as defined above, T is C(O)— or C(O)—X″, wherein X″ is defined above and T′ is C(O) can be obtained
8e-i) by reacting a compound of formula (Iy′),
P2—X26′ (Iy′)
wherein P2 is as above defined and X26′ is the radical having the following meanings
W1—C(O)-y-Q (IVa)
wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8e-ii) when Q is Z2, by converting the compound obtained in the step 8e-i) into nitro derivative by reaction with a nitrate source as above described and
8e-iii) optionally deprotecting the compounds obtained in step 8e-i) or 8e-ii) as above described.
The reaction of a compound of formula (Iy′) wherein P2 and X26′ are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i1), 1-i2), 1-i3) and 1a-1).
8f) The compounds of formula (Iz) wherein X24 is the radical of formula (a10′) or (b10′) wherein R1b is selected from A10), and R2b is selected from B10), Y and Y′ are as defined above, T is C(O)— or C(O)—X″, wherein X″ is defined above and T′ is C(O)—X″ can be obtained
8f-i) by reacting a compound of formula (Iy′),
P2—X26′ (Iy′)
wherein P2 and X26′ are as above defined, with a compound of formula (IVd)
Ra—O—C(O)—X″-y-Q (IVd)
wherein Ra and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8f-ii) when Q is Z2, by converting the compound obtained in the step 8f-i) into nitro derivative by reaction with a nitrate source as above described and
8f-iii) optionally deprotecting the compounds obtained in step 8f-i) or 8f-ii) as above described.
The reaction of a compound of formula (Iy′) wherein P2 and X26′ are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i2).
9) The compounds of general formula (I) as above defined wherein a is equal to 1, RX is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R1b is selected from A8) or A9), R2b is selected from B8) or B9), Z is —C(O)—, can be obtained
9-i) by reacting a compound of formula (IIb)
R—C(O)—O—Ra (IIb)
wherein R and Ra are as above defined with a compound of formula (Ix)
H—X27 (Ix)
wherein X27 is the radical selected from (a5′), (a6′), (a9′), (a10′), (b5′), (b6′), (b9′) or (b10′), wherein R1b is selected from A8) or A9), R2b is selected from B8) or B9), and
9-ii) when Q is Z2, by converting the compound obtained in the step 9-i) into nitro derivative by reaction with a nitrate source as above described and
9-iii) optionally deprotecting the compounds obtained in step 9-i) or 9-ii) as above described.
The reaction of a compound of formula (Ix) wherein X27 and is as above defined, with a compound of formula (IIb) wherein R is as above defined, may be carried out as described in 1l-i).
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2008/050948 | 1/28/2008 | WO | 00 | 3/5/2010 |
| Number | Date | Country | |
|---|---|---|---|
| 60899376 | Feb 2007 | US | |
| 60929456 | Jun 2007 | US |
