التفاصيل البيبلوغرافية
| العنوان: |
PROTEASE INHIBITORS |
| Document Number: |
20120136002 |
| تاريخ النشر: |
May 31, 2012 |
| Appl. No: |
13/321078 |
| Application Filed: |
May 18, 2010 |
| مستخلص: |
A compound of formula (I) wherein R1 to R15, P1, P2, A, B and Q are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as matriptase inhibitors and are useful in the treatment of matriptase dependent conditions, particularly cancer. |
| Inventors: |
Goswami, Rajeev (Uttaranchal, IN); Vuppala, Anil Kumar (Andhra Pradesh, IN); Veludandi, Ramesh (Andhra Pradesh, IN); Sistla, Ramesh (Karnataka, IN); Ghadiyaram, Chakshusmathi (Karnataka, IN); Ramachandra, Muralidhara (Bangalore, IN) |
| Claim: |
1. A compound of formula (I) [chemical expression included] wherein P1 and P2 areindependently a bond or C1-3 alkyl; A is CH or N; B is CH or N; R1 is hydrogen, amino, —NH—SO2— ZR9R13, —NR4—CO—ZR9R13, —CO—NR7R8, —CO—O—ZR9R13, —CO—NR4RX—ZR9R13, or a group of formula [chemical expression included] wherein the ring portion in formula (II) is a 5-12 membered saturated, partially saturated, or aromatic ring, which may be monocyclic or bicyclic, and which contains 0, 1, 2, or 3 further heteroatoms selected from N, O, S, or combinations thereof; R3 is —C(NR17)NH2 when A is CH, R3 is —C(NR17)NH2 or amino C1-7 alkyl; R10, R14, and R15 are independently hydrogen, halogen, hydroxy, C1-7 alkyl, halogen C1-7 alkyl, or —C(NR17)NH2; Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously hydrogen; R4 is hydrogen or C1-7 alkyl; Z is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R9 and R13 areindependentlyhydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxycarbonyl, RANH2, or —CORBNH2; RA, RB, and Rx areindependentlya bond or C1-7 alkyl; R7 and R8 areindependentlyhydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or when A is CH, R7 and R8, independently, are hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl or C1-7 alkyl, with a proviso that R7 and R8 are not simultaneously hydrogen; R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-4 alkyl, C1-7 alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR17)NH2, or a group of formula (III) [chemical expression included] y=0-2; RD is a bond or C1-7 alkyl; G is CH or N; R11 is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl, halogen C1-7 alkoxy, —C(NR17)NH2, —NHCORGNH2, RJNHCOORU, or —CONR19R20; RG is C1-7 alkyl; RJ is a bond or C1-7 alkyl; RU is hydrogen or C1-7 alkyl; R12 and R16 areindependentlyhydrogen, halogen or C1-7 alkyl; or R12 and R16 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated, or aromatic ring, which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof, wherein said ring is substituted or unsubstituted; R17 is hydrogen, —OH, C1-7 alkoxy, —O(CO)OR18, or —(CO)OR18, R18 is C1-7 alkyl; R19 and R20 areindependentlyhydrogen, C1-7 alkyl, or C1-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof. |
| Claim: |
2. The compound according to claim 1, wherein A is CH and B is CH. |
| Claim: |
3. The compound according to claim 1, wherein R3 is —C(NR17)NH2 and R10, R14, and R15 are hydrogen. |
| Claim: |
4. The compound according to claim 1, wherein R2 is a group of formula (III), wherein G is CH, y is 0-1, R11 is —C(NR17)NH2 or amino C1-7 alkyl, and R12 and R16 are hydrogen. |
| Claim: |
5. The compound according to claim 1, wherein P1 and P2 are bonds. |
| Claim: |
6. The compound according to claim 1, wherein P1 is a bond and P2 is —CH2—. |
| Claim: |
7. The compound according to claim 1, wherein R1 is a group of formula (II). |
| Claim: |
8. The compound according to claim 7, wherein the ring portion of formula (II) is a 6 or 10 membered saturated, partially saturated, or aromatic ring. |
| Claim: |
9. The compound according to claim 8, wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro-quinolinyl, or 3,4-dihydro-1H-quinolinyl. |
| Claim: |
10. The compound according to claim 1, wherein R1 is —NR4—CO—ZR9R13, or —CO—NR4—RX—ZR13. |
| Claim: |
11. The compound according to claim 10, wherein Z is a 6 or 10 membered saturated, partially saturated, or aromatic ring. |
| Claim: |
12. The compound according to claim 11, wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl, or quinolinyl. |
| Claim: |
13. The compound according to claim 12, wherein Z is cyclohexyl or piperidinyl, R4 is hydrogen, RX is a bond, R9 is RANH2, and R13 is hydrogen. |
| Claim: |
14. A pharmaceutical composition comprising a compound of formula (I) [chemical expression included] wherein P1 and P2 are independently a bond or C1-3 alkyl; A is CH or N; B is CH or N; R1 is hydrogen, amino, —NH—SO2—ZR9R13, —NR4—CO—ZR9R13, —CO—NR7R8, —CO—O—ZR9R13, —CO—NR4—RX—ZR9R13, or a group of formula [chemical expression included] wherein the ring portion in formula (II) is a 5-12 membered saturated, partially saturated, or aromatic ring, which may be monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R3 is —C(NR17)NH2 or when A is CH, R3 is —C(NR17)NH2 or amino C1-7 alkyl; R10, R14, and R15 are inde endentl hydrogen, halogen, hydroxy, C1-7 alkyl, halogen C1-7 alkyl, or —C(NR17)NH2; Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously hydrogen; R4 is hydrogen or C1-7 alkyl; Z is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R9 and R13 are independently hydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxycarbonyl, RANH2, or —CORBNH2; RA, RB, and RX are independently a bond or C1-7 alkyl; R7 and R8 are independently hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or C1-7 alkyl, with a proviso that R7 and R8 are not simultaneously hydrogen; R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR17)NH2, or a group of formula (III) [chemical expression included] y=0-2; RD is a bond or C1-7 alkyl; G is CH or N; R11 is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl, halogen C1-7 alkoxy, —C(NR17)NH2, —NHCORGNH2, RJNHCOORU, or —CONR19R20; RG is C1-7 alkyl; RJ is a bond or C1-7 alkyl; RU is hydrogen or C1-7 alkyl; R12 and R16 are independently hydrogen, halogen or C1-7 alkyl; or R12 and R16 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated, or aromatic ring, which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof, wherein said ring is substituted or unsubstituted; R17 is hydrogen, —OH, C1-7 alkoxy, —O(CO)OR18, or —(CO)OR18; R16 is C1-7 alkyl; R19 and R20 are independently hydrogen, C1-7 alkyl, or C1-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof together with a pharmaceutically acceptable carrier. |
| Claim: |
15. A method for the treatment of a matriptase dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) [chemical expression included] wherein P1 and P2 are independently a bond or C1-3 alkyl; A is CH or N; B is CH or N; R1 is hydrogen, amino, —NH—SO2—ZR9R13, —NR4—CO—ZR9R13—CO—NR7R8, —CO—O—ZR9R13, —CO—NR4—RX—ZR9R13, or a of formula [chemical expression included] wherein the ring portion in formula (II) is a 5-12 membered saturated, partially saturated, or aromatic ring, which may be monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R3 is —C(NR17)NH2 or when A is CH, R3 is —C(NR17)NH2 or amino C1-7 alkyl; R10, R14, and R15 are independently hydrogen, halogen, hydroxy, C1-7 alkyl, halogen C1-7 alkyl, or —C(NR17)NH2; Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously hydrogen; R4 is hydrogen or C1-7 alkyl; Z is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R9 and R13 are independently hydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxycarbonyl, RANH2, or —CORBNH2; RA, RB, and RX independently ndependently a bond or C1-7 alkyl; R7 and R8 are independently hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or C1-7 alkyl, with a proviso that R7 and R8 are not simultaneously hydrogen; R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR17)NH2, or a group of formula (III) [chemical expression included] y=0-2; RD is a bond or C1-7 alkyl; G is CH or N; R11 is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl, halogen C1-7 alkoxy, —C(NR17)NH2, —NHCORGNH2, RJNHCOORU, or —CONR19R20; RG is C1-7 alkyl; RJ is a bond or C1J alkyl; RU is hydrogen or C1-7 alkyl; R12 and R16 are independently hydrogen, halogen or C1-7 alkyl; or R12 and R16 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated, or aromatic ring, which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof, wherein said ring is substituted or unsubstituted; R17 is hydrogen, —OH, C1-7 alkoxy, —O(CO)OR18, or —(CO)OR18; R18 is C1-7 alkyl; R19 and R20 are independently hydrogen, C1-7 alkyl, or C1-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof. |
| Claim: |
16. A method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) [chemical expression included] wherein P1 and P2 are independently a bond or C1-3 alkyl; A is CH or N; B is CH or N; R1 is hydrogen, amino, —NH—SO2—ZR9R13, —NR4—CO—ZR9R13, —CO—NR7R8, —CO—O—ZR9R13, —CO—NR4RX—ZR9R13, or a group of formula [chemical expression included] wherein the ring portion in formula (II) is a 5-12 membered saturated, partially saturated, or aromatic ring, which may be monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R3 is —C(NR17)NH2 or when A is CH, R3 is —C(NR17)NH2 or amino C1-7 alkyl; R10, R14, and R15 are independently hydrogen, halogen, hydroxy, C1-7 alkyl, halogen C1-7 alkyl, or —C(NR17)NH2; Q is hydrogen or halogen, with a proviso that R1 and Q are not simultaneously hydrogen; R4 is hydrogen or C1-7 alkyl; Z is a 5-12 membered saturated, partially saturated, or aromatic ring, wherein said ring is monocyclic or bicyclic, and which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof; R9 and R13 are independently hydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxycarbonyl, RANH2, or —CORBNH2i RA, RB, and RX are independently a bond or C1-7 alkyl; R7 and R8 are independently hydrogen, amino C1-7 alkyl, carboxy C1-7 alkyl, or C1-7 alkyl, with a proviso that R7 and R8 are not simultaneously hydrogen; R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, C1-7 alkoxycarbonyl C1-7 alkyl, C1-7 alkylamino, carboxy C1-7 alkylamino, RDC(NR17)NH2, or a group of formula (III) [chemical expression included] y=0-2; RD is a bond or C1-7 alkyl; G is CH or N; R11 is hydrogen, halogen, amino, carboxy, amino C1-7 alkyl, C1-7 alkoxycarbonyl, halogen C1-7 alkoxy, —C(NR17)NH2, —NHCORGNH2, RJNHCOORU or —CONR19R20; RG is C1-7 alkyl; RJ is a bond or C1-7 alkyl; RU is hydrogen or C1-7 alkyl; R12 and R16 are independently hydrogen, halogen or C1-7 alkyl; or R12 and R16 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated, or aromatic ring, which contains 0, 1, 2, or 3 heteroatoms selected from N, O, S, or combinations thereof, wherein said ring is substituted or unsubstituted; R17 is hydrogen, —OH, C1-7 alkoxy, —O(CO)OR18, or —(CO)OR18; R18 is C1-7 alkyl; R19 and R20 are independently hydrogen, C1-7 alkyl, or C1-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof. |
| Current U.S. Class: |
51425/313 |
| Current International Class: |
61; 07; 61; 61; 07; 07; 61; 07; 07; 61; 07; 61; 07; 61; 07; 61; 07; 61; 07; 07; 61; 61; 07; 61; 61; 07 |
| رقم الانضمام: |
edspap.20120136002 |
| قاعدة البيانات: |
USPTO Patent Applications |