التفاصيل البيبلوغرافية
| العنوان: |
QUINOLINES |
| Document Number: |
20120136018 |
| تاريخ النشر: |
May 31, 2012 |
| Appl. No: |
13/359933 |
| Application Filed: |
January 27, 2012 |
| مستخلص: |
The present invention relates to 2-aminoquinolines of formula I [chemical expression included] wherein R1, R2 and R3 are as defined in the specification, as 5-HT5A receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use for the treatment of CNS disorders. |
| Inventors: |
Kolczewski, Sabine (Loerrach, DE); Riemer, Claus (Freiburg, DE); Steward, Lucinda (Basel, CH); Wichmann, Juergen (Steinen, DE); Woltering, Thomas (Freiburg, DE) |
| Claim: |
1. A compound of formula I [chemical expression included] wherein R1 is —NRa—Ar1, —NRbCH2—Ar1, —CH2NRb—Ar1, —NRcC(O)—Ar1, —OCH2—Ar1, —CH2O—Ar1, —CH2CH2—Ar1, —CH═CH—Ar1, —NHC(O)NH—Ar1, —NHSO2NH—Ar1, —NRcC(O)O—Ar1, —C(O)NRcCH2—Ar1, —CH2NRbCH2—Ar1, —NHC(═N—Ar1)—Ar1, —NRbCH2CH2CH2—Ar1, or —NRbCH2CH2O—Ar1, R2 is —Ar2, —CHRd—Ar2, or —CH2CH2O—Ar2, R3 is hydrogen, phenyl, or pyridinyl, optionally substituted with one or more C1-4-alkyl, halo, or C1-4-alkoxy, —NReRf, wherein Re and Rf are each independently hydrogen, or —(CH2)m—ORg, wherein m is from 2 to 6, Ar1 and Ar2 are each independently aryl or heteroaryl, each optionally substituted by one or more B, B is C1-7-alkoxy, C1-7-haloalkoxy, hydroxy, halo, C1-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano, —S(O)2—C1-7-alkyl, —NRiRii, —NRiiiS(O)2Riv, —NRiiiC(O)Riv, —C(O)NRiiiRiv, —S(O)2—NRiiiRiv, —CH2—O—Rv, —(OCH2CH2)n—ORv, wherein n is from 1 to 3, —CH2—(OCH2CH2)n—ORv, wherein n is from 1 to 3, —C(O)Rv, cyano, nitro, allyl, C3-7-cycloalkyl, 5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula —CH2CH2CH2—, —CH2CH2CH2CH2—, —OCH2CH2O—, —OCH(Rvii)CH(Rviii)—, Ra, Rb, Rc, Rd, and Rg are each independently hydrogen or C1-7-alkyl; Ri, Rii, Riii, Riv, and Rv are each independently hydrogen, C1-7-alkyl or —(CH2)n—C3-7-cycloalkyl, wherein n is from 0 to 3; Rvi, Rvii, and Rviii are each independently hydrogen, C1-4-alkyl or halogen; or a pharmaceutically acceptable salt thereof. |
| Claim: |
2. The compound of claim 1, wherein R1 is —NRa—Ar1, —NRbCH2—Ar1, —CH2O—Ar1, —CH2CH2—Ar1, —CH═CH—Ar1, —NHC(O)NH—Ar1, —NHSO2NH—Ar1, or —NRcC(O)O—Ar1. |
| Claim: |
3. The compound of claim 2, wherein R1 is —NH—Ar1, —NHCH2—Ar1, —CH2O—Ar1, —CH2CH2—Ar1, —CH═CH—Ar1, —NHSO2NH—Ar1, or —NRcC(O)O—Ar1. |
| Claim: |
4. The compound of claim 1, wherein Ar1 and Ar2 are each independently phenyl, naphthyl, aromatic 5- or 6-membered monocyclic heteroaryl or aromatic 9- or 10-membered bicyclic heteroaryl, wherein the aromatic 5- or 6-membered monocyclic heteroaryl or aromatic 9- or 10-membered bicyclic heteroaryl each contain one, two, three or four heteroatoms selected from N, O and S, the remaining ring atoms being C, and wherein each Ar1 and Ar2 is optionally and independently substituted by one or more B. |
| Claim: |
5. The compound of claim 4, wherein Ar1 and Ar2 are each independently selected from the group selected from the group consisting of phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxyzolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl, or pteridinyl, each optionally substituted with one or more B. |
| Claim: |
6. The compound of claim 4, wherein Ar1 and Ar2 are each independently selected from the group selected from the group consisting of phenyl, tetrazolyl, [1,3,4]-oxadiazolyl, [1,2,4]-oxadiazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl, pyridinyl, pyrimidinyl or benzoxazolyl, each optionally substituted with one of more B. |
| Claim: |
7. The compound of claim 1, wherein R2 is —CH2—Ar2 or —CH2CH2O—Ar2. |
| Claim: |
8. The compound of claim 1, wherein R3 is hydrogen. |
| Claim: |
9. The compound of claim 1 wherein B is selected from the group consisting of C1-7-alkoxy, C1-7-haloalkoxy, halo, C1-7-alkyl, optionally substituted with one or more halo, or hydroxy, —CH2—O—Rv, —(OCH2CH2)n—ORv, wherein n is from 1 to 3, —CH2—(OCH2CH2)n—ORv, wherein n is from 1 to 3, C3-7-cycloalkyl, 5- to 7-membered monocyclic heterocycloalkyl, preferably piperidinyl, and two residues B in ortho-position to each other forming a —O—C(Rvi)2—O— bridge; wherein Rv is as defined above, preferably Rv is methyl; and wherein Rvi is as defined above, preferably Rvi is hydrogen. |
| Claim: |
10. The compound of claim 9, wherein B is selected from the group consisting of C1-7-alkoxy, C1-7-haloalkoxy, halo, C1-7-alkyl, optionally substituted with one or more halo, or hydroxy, —CH2—O—Rv, —(OCH2CH2)n—ORv, wherein n is from 1 to 3, —CH2—(OCH2CH2)n—ORv, wherein n is from 1 to 3, C3-7-cycloalkyl, and piperidinyl; wherein Rv is as defined above, preferably Rv is methyl. |
| Claim: |
11. The compound of claim 9, wherein B is selected from the group consisting of C1-7-alkoxy, halo, C1-7-alkyl, optionally substituted with one or more halo, and two residues B in ortho-position to each other forming a —O—C(Rvi)2—O— bridge, wherein Rvi is as defined above, and preferably is hydrogen. |
| Claim: |
12. The compound of claim 1, selected from the group consisting of N2-(2-phenoxy-ethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-phenoxy-ethyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-4-phenyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N2,N6-bis-(2-methoxy-benzyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(2-trifluoromethoxy-benzyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, and N2,N6-bis-(2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine. |
| Claim: |
13. The compound of claim 1, selected from the group consisting of N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-(2-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-(3-methoxy-benzyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-4-o-tolyl-quinoline-2,6-diamine, N-2-(2-methoxy-benzyl)-4-(3-methoxy-phenyl)-N-6-pyridin-3-ylmethyl-quinoline-2,6-diamine, 4-(2,5-difluoro-phenyl)-N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N-6-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-quinoline-2,6-diamine, N-2-(4-fluoro-2-methoxy-benzyl)-4-phenyl-N-6-&-pyridin-4-ylmethyl-quinoline-2,6-diamine, and N-6-2-benzyl-N-2-(4-fluoro-2-methoxy-benzyl)-4-o-tolyl-quinoline-2,6-diamine. |
| Claim: |
14. The compound of claim 1, selected from the group consisting of N6-benzyl-N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N6-benzyl-N2-(2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-(5-methyl-furan-2-ylmethyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N6-benzyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,4,6-triamine, N2-(3-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, N6-benzyl-N2-(5-fluoro-2-methoxy-benzyl)-quinoline-2,4,6-triamine, N2-(5-fluoro-2-methoxy-benzyl)-N6-pyridin-3-ylmethyl-quinoline-2,4,6-triamine, N2-benzo[1,3]dioxol-4-ylmethyl-N6-pyridin-3-ylmethyl-quinoline-2,6-diamine, 1-[2-(2-methoxy-benzylamino)-quinolin-6-yl]-3-(4-methoxy-phenyl)-urea, and N-(4-fluorophenyl)-N′-{2-[(2-methoxybenzyl)amino]quinolin-6-yl}sulfamide. |
| Claim: |
15. The compound of claim 1, selected from the group consisting of N6-(2-ethyl-2H-tetrazol-5-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(5-methyl-isoxazol-3-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-methyl-pyrimidin-2-yl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-pyridin-2-yl-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(4-trifluoromethyl-pyrimidin-2-yl)-quinoline-2,6-diamine, N6-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-N2-(2-methoxy-benzyl)-quinoline-2,6-diamine, N2-(2-methoxy-benzyl)-N6-(6-trifluoromethyl-pyridin-2-yl)-quinoline-2,6-diamine, 2-{3-[2-(2-methoxy-benzylamino)-quinolin-6-ylamino]-phenyl}-ethanol, and N2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl)-N6-(6-methyl-pyridin-2-yl)-quinoline-2,6-diamine. |
| Claim: |
16. The compound of claim 1, wherein R1 is —NRa—Ar1, —NRbCH2—Ar1, —CH2O—Ar1, —CH2CH2—Ar1, —CH═CH—Ar1, —NHC(O)NH—Ar1, —NHSO2NH—Ar1, or —NRcC(O)O—Ar1. R2 is —Ar2, —CH2—Ar2, or —CH2CH2O—Ar2, R3 is hydrogen, or phenyl or pyridinyl, optionally substituted with one or more C1-4-alkyl, halo, or C1-4-alkoxy, Ar1 and Ar2 are each independently phenyl, naphthyl, aromatic 5- or 6-membered monocyclic heteroaryl or aromatic 9- or 10-membered bicyclic heteroaryl, wherein each heteroaryl contains one, two, three or four heteroatoms selected from N, O and S, the remaining ring atoms being C, each Ar1 and Ar2 is optionally and independently substituted by one or more B, B is C1-7-alkoxy, C1-7-haloalkoxy, hydroxy, halo, C1-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano, —S(O)2—C1-7-alkyl, —NRiRii, —NRiiiS(O)2Riv, —NRiiiC(O)Riv, —C(O)NRiiiRiv, —S(O)2—NRiiiRiv, —CH2—O—Rv, —(OCH2CH2)n—ORv, wherein n is from 1 to 3, —CH2—(OCH2CH2)n—ORv, wherein n is from 1 to 3, —C(O)Rv, cyano, nitro, allyl, C3-7-cycloalkyl, 5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula —CH2CH2CH2—, —CH2CH2CH2CH2—, —OCH2CH2O—, —OCH(Rvii)CH(Rviii)—, Ra, Rb, Rc, and Rg are each independently hydrogen or C1-7-alkyl; Ri, Rii, Riii, Riv, and Rv are each independently hydrogen, C1-7-alkyl or —(CH2)n—C3-7-cycloalkyl, wherein n is from 0 to 3; Rvi, Rvii, and Rviii are each independently hydrogen, C1-4-alkyl or halogen; or a pharmaceutically acceptable salt thereof. |
| Claim: |
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I [chemical expression included] wherein R1 is —NRa—Ar1, —NRbCH2—Ar1, —CH2NRb—Ar1, —NRcC(O)—Ar1, —OCH2—Ar1, —CH2O—Ar1, —CH2CH2—Ar1, —CH═CH—Ar1, —NHC(O)NH—Ar1, —NHSO2NH—Ar1, —NRcC(O)O—Ar1, —C(O)NRcCH2—Ar1, —CH2NRbCH2—Ar1, —NHC(═N—Ar1)—Ar1, —NRbCH2CH2CH2—Ar1, or —NRbCH2CH2O—Ar1, R2 is —Ar2, —CHRd—Ar2, or —CH2CH2O—Ar2, R3 is hydrogen, phenyl, or pyridinyl, optionally substituted with one or more C1-4-alkyl, halo, or C1-4-alkoxy, —NReRf, wherein Re and Rf are each independently hydrogen, or —(CH2)m—ORg, wherein m is from 2 to 6, Ar1 and Ar2 are each independently aryl or heteroaryl, each optionally substituted by one or more B, B is C1-7-alkoxy, C1-7-haloalkoxy, hydroxy, halo, C1-7-alkyl, optionally substituted with one or more halo, hydroxy, or cyano, —S(O)2—C1-7-alkyl, —NRiRii, —NRiiiS(O)2Riv, —NRiiiC(O)Riv, —C(O)NRiiiRiv, —S(O)2—NRiiiRiv, —CH2—O—Rv, —(OCH2CH2)n—ORv, wherein n is from 1 to 3, —CH2—(OCH2CH2)n—ORv, wherein n is from 1 to 3, —C(O)Rv, cyano, nitro, allyl, C3-7-cycloalkyl, 5- to 7-membered monocyclic heterocycloalkyl, or two residues B in ortho-position to each other form a 3- to 4-membered bridge of the formula —CH2CH2CH2—, —CH2CH2CH2CH2—, —OCH2CH2O—, —OCH(Rvi)CH(Rvi)—, Ra, Rb, Rc, Rd, and Rg are each independently hydrogen or C1-7-alkyl; Ri, Rii, Riii, Riv, and Rv are each independently hydrogen, C1-7-alkyl or —(CH2)n—C3-7-cycloalkyl, wherein n is from 0 to 3; Rvi, Rvii, and Rviii are each independently hydrogen, C1-4-alkyl or halogen; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. |
| Current U.S. Class: |
514/275 |
| Current International Class: |
61; 07; 07; 07; 07; 07; 07; 07; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 07 |
| رقم الانضمام: |
edspap.20120136018 |
| قاعدة البيانات: |
USPTO Patent Applications |