US2015105547A1PendingUtilityA1
Nitric oxide releasing steroids
Est. expiryFeb 5, 2027(~0.5 yrs left)· nominal 20-yr term from priority
A61P 9/14A61P 9/00A61P 9/10A61P 9/12A61P 5/44A61P 5/00A61P 27/00A61P 35/00A61P 3/10A61P 27/02A61P 29/00A61P 27/06A61P 19/02C07J 41/005A61P 1/04A61P 17/12A61P 17/06A61P 11/00A61P 1/02A61P 11/06A61P 17/04A61P 17/08A61P 17/02A61P 17/00
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Claims
Abstract
The invention relates to nitrooxyderivative of corticosteroids of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof R—(Z) a —R x (I) wherein R is the corticosteroid residue of formula (II): wherein: R 1 is OH, R 2 —CH 3 , or R 1 and R 2 are taken together to form a group of formula (III) R 3 is Cl or F; R 4 is H or F; wherein R 1 , R 2 , R 3 and R 4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β; with the proviso that: when R 1 and R 2 are the group of formula (III) then R 3 is F and R 4 is H or F; The compounds are useful in the treatment of respiratory diseases, inflammatory diseases, dermatological diseases and ocular diseases.
Claims
exact text as granted — not AI-modified1 . A compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
R—(Z) a —R x (I)
wherein R is a corticosteroid residue of formula (II):
wherein:
R 1 is OH, R 2 —CH 3 , or R 1 and R 2 are taken together to form a group of formula (III)
R 3 is CI or F;
R 4 is H or F;
wherein R 1 , R 2 , R 3 and R 4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
with the proviso that:
when R 1 and R 2 are the group of formula (III) then R 3 is F and R 4 is H or F;
when R 1 is OH and R 2 —CH 3 then R 4 is H and R 3 is CI or F;
preferred corticosteroid radicals are R of formula (II) wherein:
R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is CI in position α and R 4 is H; or
R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is F in position α and R 4 is H; or
R 1 and R 2 are taken together to form a group of formula (III)
R 3 is F and R 4 is H, R 1 , R 2 and R 3 are in position α; or
R 1 and R 2 are taken together to form a group of formula (III)
R 3 and R 4 are F, R 1 , R 2 , R 3 and R 4 are in position α;
a in formula (I) is equal to 0 or 1;
Z is a group capable of binding R x and is selected from —C(O)—, or CH(R′)—O— wherein R′ is selected from H or a straight or branched C 1 -C 4 alkyl;
R x is a radical and is selected from the the following meanings:
A)
—HN—CH(R 1 )—C(O)-(T-Y—ONO 2 ) (a1)
—C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 ) (a2)
—HN—CH(R 1a -T″-Y′—ONO 2 )—COOR 3a (a3)
—C(O)—CH(R 1a -T″-Y′—ONO 2 )—NHR 4a (a4)
—R 1b —CH(NHR 4a —C(O)-(T-Y—ONO 2 ) (a5)
—R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 ) (a6)
—HN—CH(R 1a -T″-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) (a7)
—C(O)—CH(R 1a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (a8)
—R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) (a9)
wherein:
R 1 is selected from:
A1) H, —CH 3 , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—; 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH 2 —, 3-benzothienyl-CH 2 —, 4-imidazolyl-CH 2 —, 9-anthranyl-CH 2 —, cyclohexyl, cyclohexyl-CH 2 —, cyclohexyl-(CH 2 ) 2 —, cyclopentyl-CH 2 —, (C 6 H 5 ) 2 CH—, 4-B(OH) 2 -benzyl, 4-quinolyl-CH 2 —, 3-quinolyl-CH 2 —, 2-quinolyl-CH 2 —, 2-quinoxalyl-CH 2 —, 2-furyl-CH 2 —, 1-naphtyl-CH 2 —, 2-naphtyl-CH 2 —, 2-pyridyl-CH 2 —, 3-pyridyl-CH 2 —, 4-pyridyl-CH 2 —, 2-thienyl-CH 2 —, 3-thienyl-CH 2 —, C 6 H 4 —CH═CH—CH 2 —, CH 2 ═CH—CH 2 —, CH≡CH—CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —, P(═O)(OCH 3 ) 2 , I—CH 2 —;
A2) —CH 2 —SH, —CH 2 —OH, —CH(CH 3 )—OH, —CH 2 [(C 6 H 4 )-(4-OH)], —CH 2 -[(C 6 H 2 )-(3,5-diiodo)-(4-OH)], —CH 2 -[(C 6 H 3 )-(3-nitro)-(4-OH)];
A3) —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, —C(O)CH 3 or
wherein R 5a is H or a linear or branched C 1 -C 10 alkyl chain, preferably R 5a is H or a linear (C 1 -C 5 ) alkyl, wherein R″ is as above defined;
A4) —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is —OR 5a or
wherein R 5a is as above defined, wherein R′″ is as above defined;
R 1a is selected from,
A5) —CH 2 —S—, —CH 2 —O—, —CH(CH 3 )—O—, —CH 2 [(C 6 H 4 )-(4-O)], —CH 2 -[(3,5-diiodo)-(C 6 H 2 )-(4-O)], —CH 2 -[(3-nitro)-(C 6 H 3 )-(4-O)—];
A6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—;
A7) —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
R 3a is selected from H, —R 5a or
wherein R 5a is as above defined;
R 4a is selected from H or —C(O)CH 3 or
wherein R 5a is as above defined;
R 1b is selected from
A8) —S—CH 2 —, —O—CH(CH 3 )—, —O—CH 2 —, [-(4-O)—(C 6 H 4 )]—CH 2 —, [-(4-O)-(3,5-diiodo)-(C 6 H 2 )]—CH 2 —, [-(4-O)-(3-nitro)-(C 6 H 3 )]—CH 2 —;
A9) —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;
A10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —;
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 T′ is C(O)—NR′— wherein R′ is as above defined;
T″ is independently selected from C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, O—CH(R′)—O—C(O)—, 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;
B)
—HN—CH(R 2 )—CH 2 C(O)-(T-Y—ONO 2 ) (b1)
—C(O)—CH 2 —CH(R 2 )—NH-(T-Y—ONO 2 ) (b2)
—HN—CH(R 2a -T″-Y—ONO 2 )—CH 2 COOR 3a (b3)
—C(O)—CH 2 —CH(R 2a -T″-Y—ONO 2 )—NHR 4a (b4)
—R 2b —CH(NHR 4a —CH 2 C(O)-(T-Y—ONO 2 ) (b5)
—R 2b —CH(CH 2 COOR 3a )NH-(T′-Y—ONO 2 ) (b6)
—HN—CH(R 2a -T″-Y′—ONO 2 )—CH 2 —C(O)-(T-Y—ONO 2 ) (b7)
—C(O)—CH 2 —CH(R 2a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (b8)
—R 2b —CH(NH-T′-Y′—ONO 2 )—CH 2 C(O)-(T-Y—ONO 2 ) (b9)
—R 2b —CH(CH 2 C(O)-T-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (b10)
wherein
R 2 is selected from
B1) H, —CH 3 , CF 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, 3-triptophanyl-CH 2 —, NH 2 —C(O)—CH 2 —, NH 2 —C(O)—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —, tBuO—CH(CH 3 )—, benzyl-O—CH 2 —, 4-terbutoxy-benzyl, 4-phenylbenzyl;
B2) —CH 2 —SH, —CH 2 —OH, —CH(CH 3 )—OH, —CH 2 [(C 6 H 4 )-(4-O)—], —CH 2 -[(C 6 H 2 )-(3,5-diiodo)-(4-OH)], —CH 2 -[(C 6 H 3 )-(3-nitro)-(4-OH)];
B3) —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is as above defined;
B4) —CH 2 —C(O)—R′″, —(CH 2 ) 2 —C(O)—R′″, —(CH 2 ) 4 —C(O)—R′″ wherein R′″ is as above defined;
R 2a is selected from
B5) —CH 2 —S—, —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 [(C 6 H 4 )-(4-O)], —CH 2 -[(3,5-diiodo)-(C 6 H 2 )-(4-O)], —CH 2 -[(3-nitro)-(C 6 H 3 )-(4-O)—];
B6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—;
B7) —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O);
R 2b is selected from
B8) —S—CH 2 —, —O—CH(CH 3 )—, —O—CH 2 —, [-(4-O)—(C 6 H 4 )]—CH 2 —, [-(4-O)-(3,5-diiodo)-(C 6 H 2 )]—CH 2 —, [-(4-O)-(3-nitro)-(C 6 H 3 )]—CH 2 —;
B9) —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;
B10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —;
R 3a and R 4a are as above defined;
T, T′ and T″ are as above defined and Y and Y′ are as below defined;
C)
—HN(CH 2 ) b —C(O)-(T-Y—ONO 2 ); (c1)
—C(O)(CH 2 ) b —NH-(T′-Y—ONO 2 ); (c2)
wherein b is an integer from 3 to 6,
T and T′ are as above defined;
D)
—HN—CH(R 12 )—CH 2 —O-(T′″-Y—ONO 2 ) (d1)
—O—CH 2 —CH(R 12 )—NH-(T′-Y—ONO 2 ) (d2)
—HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 OH (d3)
—O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NHR 4a (d4)
—R 12b —CH(NHR 4a )—CH 2 —O-(T′″-Y—ONO 2 ) (d5)
—R 12b —CH(CH 2 OH)—NH-(T′-Y—ONO 2 ) (d6)
—HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 —O-(T′″-Y—ONO 2 ) (d7)
—O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (d8)
—R 12b —CH(NH-T′-Y′—ONO 2 )—CH 2 —O-(T′″-Y—ONO 2 ) (d9)
—R 12b —CH(CH 2 —O-T′″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (d10)
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;
R 12 is selected from:
D1) H, —CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, 3-triptophanyl-CH 2 —, 4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —;
D2) —CH 2 —OH, —CH(CH 3 )—OH, CH 2 [(C 6 H 4 )-(4-OH)], CH 2 -[(C 6 H 3 )-(3,5-diiodo)-(4-OH)], —CH 2 -[(C 6 H 3 )-(3-nitro)-(4-ON;
D3) —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is as above defined, preferably R u is —(CH 2 ) 4 —NHR″;
D4) —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is as above defined;
R 12a is selected from
D5) —CH 2 —O—, —CH(CH 3 )—O— or CH 2 [(C 6 H 4 )-(4-O)], —CH 2 -[3,5-diiodo-(C 6 H 2 )-(4-O)], —CH 2 -[3-nitro-(C 6 H 3 )-4-O-];
D6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—;
D7) —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
R 12b is selected from
D8) —O—CH 2 —, —O—CH(CH 3 )—, [-(4-O)—(C 6 H 4 )]—CH 2 —, [-(4-O)-(3,5-diiodo)-(C 6 H 2 )]—CH 2 , [-(4-O)-(3-nitro)-(C 6 H 3 )]—CH 2 —;
D9) —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;
D10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —;
R 4a is as above defined;
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;
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;
wherein R 3 is H, CH 3 , propyl, (C 6 H 5 ) 2 CH—, 1-naphtyl-CH 2 —, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, T and T′ are as above defined;
wherein R 4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined;
wherein R 5 is H, R 6 is H, or R 5 and R 6 when taken together are a double bond, T and T′ are as above defined;
wherein T and T′ are as above defined;
wherein T and T′ are as above defined;
wherein c is as above defined, d is equal to 0 or 1, T and T′ are as above defined;
wherein R 7 is H, R 8 is H, or R 7 and R 8 when taken together are a double bond, c is as above defined, T and T′ are as above defined;
wherein T and T′ are as above defined;
wherein T and T′ are as above defined and;
wherein T and T′ are as above defined;
wherein T and T′ are as above defined;
wherein T and T′ are as above defined;
wherein R 9 and R 19 are H, CH 3 , R 11 is CH 3 or 4-piperidinyl with the proviso that R 9 and R 19 are H when R 11 is 4-piperidinyl and R 9 and R 19 are CH 3 when R 11 is CH 3 , T and T′ are as above defined;
wherein T and T′ are as above defined;
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 R x is:
(a2), (a4) or (a8);
(a5), (a6), (a9) or (a10) and R 1b is selected from the group A10);
(b2), (b4) or (b8);
(b5), (b6), (b9) or (b10) and R 2b is selected from the group B10);
(c2);
(d5), (d6), (d9) or (d10) and R 12b is selected from the group D10);
(e2), (f1), (g2), (h1), (i1) (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);
a is 1 and Z is —C(O)—, when R x is:
(a1), (a3) or (a7);
(a5), (a6), (a9) or (a10) and R 1b is selected from the groups A8) and A9);
(b1), (b3) or (b7);
(b5), (b6), (b9) or (b10) and R 2b is selected from the groups B8) or B9);
(c1);
(d1), (d2), (d3), (d4), (d7) or (d8);
(d5), (d6), (d9) or (d10) and R 2b is selected from the groups D8) or D9);
(e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1).
Y and Y′ are bivalent radicals each independently selected from the following meanings:
a)
straight or branched C 1 -C 20 alkylene;
straight or branched C 1 -C 20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO 2 or T 2 , wherein T 2 is —OC(O)(C 1 -C 10 alkyl)-ONO 2 or —O(C 1 -C 10 alkyl)-ONO 2 ;
cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C 1 -C 10 alkyl chains;
wherein
n 0 is an integer from 0 to 20;
n 1 is 0 or 1;
U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group;
wherein
n 0 is an integer from 0 to 20;
n 1 is 0 or 1;
U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;
n 1 and U are as above defined;
n 2 is an integer from 0 to 2;
R 13 is H or CH 3 ;
Y 1 is CH 2 —CH 2 — or —CH═CH—(CH 2 ) n 2′ —, wherein n 2′ is 0 or 1;
T 1 =—O—C(O)— or C(O)O—;
U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, preferably n 2 is 1;
R 13 is H or CH 3 , preferably R 13 is CH 3 ;
Y 1 is —CH 2 —CH 2 — or (CH 2 ) n 2′ —CH═CH—, wherein n 2′ is 0 or 1;
(T 1 )′=—O—C(O)—;
n 1 is 0 or 1;
U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group;
when Y and Y′ are selected from b), c), d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″-Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 -CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH— and n 3 is an integer from 1 to 6;
wherein:
n 4 is an integer from 0 to 10;
n 5 is an integer from 1 to 10;
R 14 , R 15 , R 16 , R 17 are the same or different, and are H or straight or branched C 1 -C 4 alkyl;
wherein the —ONO 2 group is linked to
wherein n 5 is as defined above;
Y 2 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:
2 . A compound of formula (I) according to claim 1 wherein R, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;
a is 0 and
R x is selected from:
—C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 ) (a2)
wherein
R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—;
R 1 of the group A2) is selected from —CH 2 —OH, —CH(CH 3 )OH— or —CH 2 [(C 6 H 4 )-(4-OH)], or
R 1 of the group A3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or —C(O)CH 3 ;
R 1 of the group A4) is selected from —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—;
or R x is
—C(O)—CH(R 1a -T″-Y′—ONO 2 )—NHR 4a (a4)
wherein R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )O— or —CH 2 [(C 6 H 4 )-(4-O)—], or
R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or
R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
R 4a is H or —C(O)CH 3 ;
T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6);
T″ is —O—, —S—, —NR′— or O—CH(R′)—O—C(O)— wherein R′ is H or CH 3 , when R 1a is selected from the group A7);
or R x is selected from
—R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) (a5)
—R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 ) (a6)
—R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or (a9)
—R 1b —CH(C(O)-T-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (a10)
wherein
R 1b of the group A10) is selected from —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —;
R 3a is H or a (C 1 -C 5 ) alkyl;
R 4a is H or —C(O)CH 3 ;
T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH 3 ;
T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
or R x is
—C(O)—CH(R 1a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (a8)
wherein
R 1a of the group A5) is selected from CH 2 —O—, —CH(CH 3 )—O— or CH 2 [(C 6 H 4 )-(4-O)], or
R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or
R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6)-;
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH 3 , when R 1a is selected from the group A7);
T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
or R x is
—C(O)—CH 2 —CH(R 2 )—NH-(T′-Y—ONO 2 ) (b2)
wherein
R 2 of the group B1) is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—;
Y and Y′ are each independently selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
n 2 is 1, R 13 is CH 3 , Y 1 is CH═CH—(CH 2 ) n 2′ and n 7 is 0, T 1 is C(O)O— and U is a linear C 1 -C 10 alkylene;
wherein:
n 2 is 1, R 13 is CH 3 ;
Y 1 is (CH 2 ) n 2′ —CH═CH— and n 2′ is 0;
(T 1 )′=—O—C(O)—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″-Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 —CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH—, n 3 is 1 or 2.
3 . A compound of formula (I) according to claim 1 wherein R, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ,
A is 1 and Z is C(O)—,
R x is
—HN—CH(R 1 )—C(O)-(T-Y—ONO 2 ) (a1)
wherein
R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from F, —Cl, —I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—;
or
R 1 of A2) is selected from CH 2 —OH, —CH(CH 3 )—OH— or —CH 2 [(C 6 H 4 )-(4-OH)], or
R 1 of the group A3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or C(O)CH 3 ,
R 1 of the group A4) is —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;
T is —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl;
Y is as below defined;
or R x is
—HN—CH(R 1a -T′″-Y′—ONO 2 )—COOR 3a (a3)
wherein
R 1a of the group A5) is selected from CH 2 —O—, —CH(CH 3 )O— or CH 2 [(C 6 H 4 )O p -], or
R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or
R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
R 3a is H or a (C 1 -C 5 ) alkyl;
T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6);
T″ is —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, when R 1a is selected from the group A7);
Y′ is as below defined;
or R x is
—R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) (a5)
—R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 ) (a6)
—R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or (a9)
—R 1b —CH(C(O)-T-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (a10)
wherein
R 1b of the group A8) is selected from —O—CH(CH 3 )—, —O—CH 2 —, [-4-O)—(C 6 H 4 )]—CH 2 —, or
R 1b of the group A9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;
R 3a is H or a (C 1 -C 5 ) alkyl;
R 4a is H or C(O)CH 3 ;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl;
T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
Y and Y′ are as below defined;
or R x is
—HN—CH(R 1a -T″-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) (a7)
wherein
R 1a of the group A5) is selected from CH 2 —O—, —CH(CH 3 )—O— or CH 2 [(C 6 H 4 )-(4-O)—], or
R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or
R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, when R 1a is selected from A7);
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl;
Y and Y′ are as below defined;
or R x is
—HN—CH(R 2 )—CH 2 C(O)-(T-Y—ONO 2 ) (b1)
wherein
R 2 of the group B1) is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
R 2 of the group B2) is selected from CH 2 —OH, —CH(CH 3 )—OH— or CH 2 [(C 6 H 4 )(4-OH)], or
R 2 of the group B3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or C(O)CH 3 ,
R 2 of the group B4) is —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a
wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl;
Y is as below defined;
or R x is selected from
—HN—CH(R 12 )—CH 2 —O-(T′″-Y—ONO 2 ) (d1)
—O—CH 2 —CH(R 12 )—NH-(T′-Y—ONO 2 ) (d2)
wherein
R 12 of the group D1) is selected from H, CH 3 , isobutyl, isopropyl, benzyl, or
R 12 of the group D2) is selected from CH 2 —OH, —CH(CH 3 )OH— or CH 2 [)C 6 H 4 )-(4-OH)], or
R 12 of the group D3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″ wherein R″ is H, or
R 12 of the group D4) is —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a
wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;
T′ and T′″ are each independently selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
Y is as below defined;
or R x is selected from
—HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 OH (d3)
—O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NHR 4a (d4)
—HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 —O-(T′″-Y—ONO 2 ) or (d7)
—O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (d8)
wherein
R 12a of the group D5) is selected from CH 2 —O—, —CH(CH 3 )—O— or CH 2 [(C 6 H 4 )-(4-O)—], or
R 12a of the group D6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or
R 12a of the group D7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;
R 4a is H or —C(O)CH 3 ;
T″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl;
T′″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—;
Y and Y′ are as below defined;
or R x is selected from
—R 12b —CH(NHR 4a )—CH 2 —O-(T′″-Y—ONO 2 ) (d5)
—R 12b —CH(CH 2 OH)—NH-(T′-Y—ONO 2 ) (d6)
—R 12b —CH(NH-T′-Y′—ONO 2 )—CH 2 —O-(T′″-Y—ONO 2 ) or (d9)
—R 12b —CH(CH 2 —O-T′″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 ) (d10)
wherein
R 12b of the group D8) is selected from —O—CH(CH 3 )—, —O—CH 2 —, [—O p (C 6 H 4 )]—CH 2 —, or
R 12b of the group D9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;
R 4a is H or —C(O)—CH 3 ,
T′ and T′″ are each independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—;
Y and Y′ are each independently selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or C(O)O—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
n 2 is 1, R 13 is CH 3 , Y 1 is CH═CH—(CH 2 ) n 2′ - and n 7 is 0, T 1 is C(O)O— and U is a linear C 1 -C 10 alkylene;
wherein:
n 2 is 1, R 13 is CH 3 ;
Y 1 is (CH 2 ) n 2′ —CH═CH— and n 2′ is 0;
(T 1 )′=—O—C(O)—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 —CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH—, n 3 is 1 or 2.
4 . (canceled)
5 . A compound of formula (I) according to claim 1 wherein
R, R 1 , R 2 , R 3 , and R 4 are as defined in claim 1 ;
A is 0;
R x is
—R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) or (a5)
—R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) (a9)
wherein
R 1b is C(O)—CH 2 —,
R 4a is H or C(O)CH 3 ;
T is selected from O—, —S—, —NR′— wherein R′ is as above defined,
T′ is C(O)— and
Y and Y′ are each independently selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or C(O)O—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
n 2 is 1, R 13 is CH 3 , Y 1 is CH═CH—(CH 2 ) n 2′ - and n 7 is 0, T 1 is C(O)O— and U is a linear C 1 -C 10 alkylene;
wherein:
n 2 is 1, R 13 is CH 3 ;
Y 1 is (CH 2 ) n 2′ —CH═CH— and n 2′ is 0;
T 1 )′=—O—C(O)—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″-Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 —CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH—, n 3 is 1 or 2;
6 . A compound of formula (I) according to claim 1 wherein R, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;
A is 1 and Z is C(O)—,
R x is
—R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) or (a5)
—R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) (a9)
wherein R 1b of A10) is —O—CH 2 — or [—O p —(C 6 H 4 )]—CH 2 —,
R 4a is H or C(O)CH 3 ,
T is selected from O—, —S—, —NR′— wherein R′ is as above defined,
T′ is C(O)— and
Y and Y′ are each independently selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or C(O)O—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is C(O)O— and U is a linear C 1 -C 10 alkylene;
wherein:
n 2 is 1, R 13 is CH 3 ;
Y 1 is (CH 2 ) n 2′ —CH═CH— and n 2′ is 0;
(T 1 )′=—O—C(O)—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″-Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 —CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH—, n 3 is 1 or 2.
7 . A compound of formula (I) according to claim 1 wherein R, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ;
A is 0,
R x is
—C(O)—CH 2 —CH(R 2 )—NH-(T′-Y—ONO 2 ) (b2)
wherein
R 2 is H,
T′ is C(O)—;
Y and Y′ are each independently selected from
a)
a straight or branched C 1 -C 10 alkylene,
a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
wherein:
n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or C(O)O—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
n 2 is 1, R 13 is CH 3 , Y 1 is CH═CH—(CH 2 ) n 2′ - and n 7 is 0, T 1 is C(O)O— and U is a linear C 1 -C 10 alkylene;
wherein:
n 2 is 1, R 13 is CH 3 ;
Y 1 is (CH 2 ) n 2′ —CH═CH— and n 2′ is 0;
(T 1 )′=—O—C(O)—;
n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′∝ 1 -Y′—ONO 2 ) is linked to the (CH 2 )— group;
—(CH 2 —CH 2 -T 2 ) n 3 —CH 2 —CH 2 — f)
wherein T 2 is —O— or —S—, —NH— n 3 is 1 or 2.
8 . (canceled)
9 . (canceled)
10 . A compound of formula (I) according to claim 1 for use in the treatment of ocular diseases.
11 . (canceled)
12 . A compound of formula (I) according to claim 1 for use in the treatment of respiratory diseases.
13 . (canceled)
14 . A compound of formula (I) according to claim 1 for use in the treatment of dermatological diseases.
15 . (canceled)
16 . (canceled)Join the waitlist — get patent alerts
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