Claims
- 1. A hydroxyethylene compound of the formula
- 2. A compound according to claim 1where R1 is:
(V) —(CH2)0-3—(R1-aryl), or (VI) —(CH2)n1—(R1-heteroaryl) where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, or (B) —SO2—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, (VI) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl) where RC is:
(I) —C1-C8 alkyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl, (IV) —(CH2)0-3—OH, (V) —(CRC-xRC-y)0-4RC-aryl, (VII) —(CH2)0-4—RC-heteroaryl, (VIII) —(CH2)0-4—RC-heterocycle, (VI) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, or (E) —OCF3.
- 3. A compound according to claim 2where R1 is:
(V) —CH2—(R1-aryl), or (VI) —CH2—(R1-heteroaryl); where R2 is —H; where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, where RC is:
(III) —(CH2)0-3-(C3-C7) cycloalkyl, (V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (VIII) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 4. A compound according to claim 3 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 5. A compound according to claim 1 where R1 is
—CH2—(R1-aryl) where R1-aryl is phenyl.
- 6. A compound according to claim 1 where R1 is
—CH2—(R1-aryl) where R1-aryl is phenyl substituted with two —F.
- 7. A compound according to claim 6 where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 8. A compound according to claim 1 where R2 is:
(1) —H, (II) C1-C6 alkyl, or (III) —(CH2)0-4—R2-1 where R2-1 is R1-aryl.
- 9. A compound according to claim 1 where R2 is:
(II) C1-C6 alkyl, or (III) benzyl.
- 10. A compound according to claim 1 where RN is:
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one —CO—NRN-2RN-3 where the substitution on phenyl is 1,3-.
- 11. A compound according to claim 10 where RN-2 and RN-3 are the same and are C3 alkyl.
- 12. A compound according to claim 1 where RN is:
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one —CO—NRN-2RN-3 where the substitution on the phenyl is 1,3,5-.
- 13. A compound according to claim 12 where RN-2 and RN-3 are the same and are C3 alkyl.
- 14. A compound according to claim 1 where RN is RN-1—XN— where XN is —CO—, where RN-1 is RN-heteroaryl where RN-heteroaryl is substituted with one —CO—NRN-2RN-3.
- 15. A compound according to claim 14 where RN-2 and RN-3 are the same and are —C3 alkyl.
- 16. A compound according to claim 1 where RN is:
A-XN— where XN is —CO—, where A is:
(C) C10H7—CH(OH)—, or (D) t-butoxy.
- 17. A compound according to claim 1 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, (E) —OCF3, or (XVIII) —H.
- 18. A compound according to claim 17 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl where RC-aryl is phenyl.
- 19. A compound according to claim 18 where phenyl substituted in the 3-position or 3,5-positions.
- 20. A compound according to claim 17 where RC is:
(VI) —CH2—RC-heteroaryl,
- 21. A compound according to claim 17 where RC is:
(VII) —CH2—RC-heterocycle.
- 22. A compound according to claim 17 where RC is:
(X) -cyclohexyl ring fused to a phenyl ring.
- 23. A compound according to claim 1 where RC is:
(I) —(C1-C10)alkyl-K1-3 where each K is:
(1) H, (11) carboxyl, (16) amino unsubstituted or substituted with C1-C6 alkyl; or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[—K]1-3, where J is:
(A) a 5 to 7 atom monocyclic aryl group, or (B) a 5 to 10 atom multicyclic cycloalkyl group, and each K is:
(1) H, (3) C1-C3 alkoxy, or (11) carboxyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three:
(B) —CO—OH, (C) —CO—O—(C1-C4 alkyl), or (E) C1-C6 alkoxy, (IV) —(CH2)2-6—OH, (V) —(CH2)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, or (XVIII) —(C2-C8) alkynyl.
- 24. A compound according to claim 23 where RC is:
(I) —(C1-C10)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C1-C6 alkyl, (II) a benzyl or phenylpropyl group substituted with a carboxyl group, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups, (V) —(CH2)0-4-phenyl substituted or unsubstituted with F, (VI) —(CH2)0-4-heteroaryl, or (VII) selected from —(CH2)0-4-morpholinyl and —(CH2)0-4-tetrahydrofuryl.
- 25. A compound according to claim 24 where RC is:
(I) C5H10—K or C7H14—K where K is carboxyl or carboxyl methyl ester, (II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or (III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.
- 26. A compound according to claim 1where R1 is:
(I) C1-C5 alkyl, (II) —(CH2)1-2—S—CH3, (IV) C1-C5 alkenyl, (V) —(CH2)0-3—(R1-aryl) where R1-aryl is as defined above, and (VI) —(CH2)0-3—(R1-heteroaryl) where R1-heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C1-C3 alkyl, —F, —Cl, —Br, —I, or —CF3; where R2 is:
(I) —H (II) C1-C6 alkyl, or (III) —(CH2)0-3—R2-1 where R2-1 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl is a 5 or 6-membered aryl group and R1-heteroaryl is as defined above; where RN is: (II) A-XN— where XN is —CO—,
wherein A is
(A) -T-E-(Q)m′,
(1) where -T is 81 where
(a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) the values of x and y vary independently on each carbon when m is 2 and 3, and (d) R′″ varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl; (2) -E is
(a) C1-C5 alkyl, but only if m′ does not equal 0, (b) methylthioxy(C2-C4)alkyl, (c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone, (i) phenyl(C1-C8)alkyloxyphenyl, or (j) C1-C6 alkoxy; (3) -Q is
(a) C1-C3 alkyl, (b) C1-C3 alkoxy, (c) C1-C3 alkylthioxy, (d) C1-C6 alkylacylamino, (e) C1-C6 alkylacyloxy, (f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties), (g) C1-C6 alkylamino (h) phenylamino, (i) carbamyl (including C1-C6 alkyl and phenyl amides and esters), (j) carboxyl (including C1-C6 alkyl and phenyl esters), (k) carboxy(C2-C5)alkoxy, (l) carboxy(C2-C5)alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′is 0, 1, 2 or 3; (B) -E(Q)m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3; (C) -T-E wherein -E and -Q are as defined as above; or (D) -E wherein -E is as defined as above; where RC is:
(I) —(C1-C10)alkyl-K1-3 (E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[(—(CH2)0-3—K]1-3 where K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxylmethyl ester; J is:
(A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atom monocyclic heterocyclic group, (D) a 8 to 12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group; and where B is O or NH.
- 27. A compound according to claim 1 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH3—(CH2)n—COOH where n is 0 thru 4, HOOC—(CH2)n—COOH where n is as defined above, HOOC—CH═CH—COOH and φ-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.
- 28. A compound according to claim 1 which is:
N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide, 6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid, 5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid, 4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid, 3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid, 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S) hydroxyhexanoylamino]-octanoic acid, 8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester, N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide, 4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbanoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(5)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbanoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide.
- 29. A compound according to claim 1 which is:
- 30. A compound of the formula
- 31. A compound according to claim 30 where where R1 is —CH2-phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 32. A compound according to claim 30 where PROTECTING GROUP is t-butoxycarbonyl.
- 33. A compound according to claim 30 where PROTECTING GROUP is benzyloxycarbonyl.
- 34. A compound according to claim 30 which is:
(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester, (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl ester, (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butyl ester, (L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamic acid benzyl ester, (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid benzyl ester, or (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid benzyl ester.
- 35. An epoxide compound of the formula
- 36. An epoxide compound of formula (VI) according to claim 35 where R1 is:
(B) —(CH2)n1—(R1-heteroaryl).
- 37. An epoxide compound of formula (VI) according to claim 36 where n1 is 1.
- 38. An epoxide compound of formula (VI) according to claim 35 where R1 is:
(C) —(CH2)n1—(R1-heterocycle).
- 39. An epoxide compound of formula (VI) according to claim 38 where n1 is 1.
- 40. An epoxide compound of formula (VI) according to claim 35 where phenyl is substituted in the 3- and 5-positions giving 3,5-difluorophenyl.
- 41. An epoxide compound of formula (VI) according to claim 35 where PROTECTING GROUP is t-butoxycarbonyl.
- 42. An epoxide compound of formula (VI) according to claim 35 where PROTECTING GROUP is benzyloxycarbonyl.
- 43. An epoxide compound of formula (VI) according to claim 35 which is
(1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butyl ester, or (1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid benzyl ester.
- 44. A compound of formula
- 45. A compound according to claim 44 where where R1 is —CH2-phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 46. A compound according to claim 44 where PROTECTING GROUP is 1-butoxycarbonyl.
- 47. A compound according to claim 44 where PROTECTING GROUP is benzyloxycarbonyl.
- 48. A compound according to claim 44 where R2 is —H.
- 49. A compound according to claim 44 where R2 is C1-C6 alkyl.
- 50. A compound according to claim 44 which is:
(1S,2S, 4R)-[1-(3,5-Difluorobenzyl)-4-((3aS, 8aR)-2,2-dimethyl-8,8α-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid tert-butyl ester, [2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamic acid tert-butyl ester, (1S,2S, 4R)-[1-(3,5-Difluorobenzyl)-4-((3aS, 8aR)-2,2-dimethyl-8,8α-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid benzyl ester, or [2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamic acid benzyl ester.
- 51. A compound of formula
- 52. A compound according to claim 51 where where R1 is —CH2-phenyl, where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 53. A compound according to claim 51 where PROTECTING GROUP is t-butoxycarbonyl.
- 54. A compound according to claim 51 where PROTECTING GROUP is benzyloxycarbonyl.
- 55. A compound according to claim 51 where R2 is —H.
- 56. A compound according to claim 51 where R2 is C1-C6 alkyl.
- 57. A compound according to claim 51 which is 5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-one.
- 58. A compound of formula
- 59. A compound according to claim 58 where R1 is:
(I) C1-C6 alkyl (V) —(CH2)0-1—(R1-aryl), or (VI) —(CH2)n1—(R1-heteroaryl).
- 60. A compound according to claim 59 where R1 is
—(CH2)—(R1-aryl) where R1-aryl is phenyl.
- 61. A compound according to claim 60 where phenyl is substituted with one, two or three —F, —Cl, —Br and —I.
- 62. A compound according to claim 61 where phenyl is substituted with two —F.
- 63. A compound according to claim 62 where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 64. A compound according to claim 58 where R2 is —H.
- 65. A compound according to claim 58 where R2 is C1-C6 alkyl.
- 66. A compound according to claim 58 where R2 is —(CH2)—R1-aryl where R1-aryl is phenyl.
- 67. A compound according to claim 58 where PROTECTING GROUP is t-butoxycarbonyl.
- 68. A compound according to claim 58 where PROTECTING GROUP is benzyloxycarbonyl.
- 69. A compound according to claim 58 where RN is:
(I) RN-1—XN— where XN is:
(A) —O—, or (B) —SO2—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, (V) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl).
- 70. A compound according to claim 69 where RN is:
(I) RN-1—XN— where XN is
(A) —CO—, where RN-1 is:
(A) RN-aryl, and (B) —RN-heteroaryl.
- 71. A compound according to claim 70 where RN is:
(a) RN-1XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one —CO—NRN-2RN-3 where the substitution on phenyl is 1,3- and where RN-2 and RN-3 are the same and are C3 alkyl (b) RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one —CO—NRN-2RN-3 where the substitution on the phenyl is 1,3,5- and where RN-2 and RN-3 are the same and are C3 alkyl.
- 72. A compound according to claim 58 which is N-{2-(3,5-Difluorophenyl)-(1S, 2S, 4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-yl)]ethyl}-N′,N′-dipropylisophthalamide.
- 73. A method of treating or preventing a disease or condition selected from Alzheimer's disease, mild cognitive impairment, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease or central or preipheral amyloid diseases in a patient who is in need of such treatment which comprises administration to said patient a therapeutically effective amount of a hydroxyethylene compound of the formula
- 74. A method of treatment according to claim 73 where the disease is Alzheimer's disease.
- 75. A method of treatment according to claim 73 where the disease is Down's syndrome.
- 76. A method of treatment according to claim 73 where the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
- 77. A method of treatment according to claim 73 where the disease is cerebral amyloid angiopathy,
- 78. A method of treatment according to claim 73 where the disease is degenerative dementias.
- 79. A method of treatment according to claim 73 where the disease is dementia associated with Parkinson's disease.
- 80. A method of treatment according to claim 73 where the method is treating a disease or condition that already exists.
- 81. A method of treatment according to claim 73 where the method is preventing a disease or condition from developing.
- 82. A method of treatment according to claim 73 where the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day; for depo administration and implants is from about 0.5 mg/day to about 50 mg/day; for topical administration is from about 0.5 mg/day to about 200 mg/day; for rectal administration is from about 0.5 mg to about 500 mg.
- 83. A method of treatment according to claim 73 where the therapeutically effective amount is for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.
- 84. A method of treatment according to claim 73 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.
- 85. A method of treatment according to 73where R1 is:
(V) —(CH2)0-3—(R1-aryl), or (VI) —(CH2)n1—R1-heteroaryl) where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, or (B) —SO2—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, (VI) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl) where RC is:
(I) —C1-C8 alkyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl, (IV) —(CH2)0-3—OH, (V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (VIII) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, or (E) —OCF3.
- 86. A method of treatment according to claim 85where R1 is:
(V) —CH2—(R1-aryl), or (VI) —CH2—(R1-heteroaryl); where R2 is —H; where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, where RC is:
(III) —(CH2)0-3—(C3-C7) cycloalkyl, (V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (VIII) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 87. A method of treatment according to claim 86 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 88. A method of treatment according to claim 73 where R1 is:
—CH2—(R1-aryl) where R1-aryl is phenyl.
- 89. A method of treatment according to claim 88 where R1 is:
—CH2—(R1-aryl) where R1-aryl is phenyl substituted with two —F.
- 90. A method of treatment according to claim 89 where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 91. A method of treatment according to claim 73 where R2 is:
(I) —H, (II) C1-C6 alkyl, or (III) —(CH2)0-4—R2-1 where R2-1 is R1-aryl.
- 92. A method of treatment according to claim 73 where R2 is:
(I) C1-C6 alkyl, or (III) benzyl.
- 93. A method of treatment according to claim 73 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one —CO—NRN-2RN-3 where the substitution on phenyl is 1,3-.
- 94. A method of treatment according to claim 73 where RN-2 and RN-3 are the same and are C3 alkyl.
- 95. A method of treatment according to claim 73 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one —CO—NRN-2RN-3 where the substitution on the phenyl is 1,3,5-.
- 96. A method of treatment according to claim 95 where RN-2 and RN-3 are the same and are C3 alkyl.
- 97. A method of treatment according to claim 73 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-heteroaryl where RN-heteroaryl is substituted with one —CO—NRN-2RN-3.
- 98. A method of treatment according to claim 73 where RN-2 and RN-3 are the same and are —C3 alkyl.
- 99. A method of treatment according to claim 73 where RN is:
A-XN— where XN is —CO—, where A is:
(C) C10H7—CH(OH)—, or (D) t-butoxy.
- 100. A method of treatment according to claim 73 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, (E) —OCF3, or (XVIII) —H.
- 101. A method of treatment according to claim 100 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl where RC-aryl is phenyl.
- 102. A method of treatment according to claim 101 where phenyl substituted in the 3-position or 3,5-positions.
- 103. A method of treatment according to claim 100 where RC is:
(VI) —CH2—RC-heteroaryl,
- 104. A method of treatment according to claim 100 where RC is:
(VII) —CH2—RC-heterocycle.
- 105. A method of treatment according to claim 100 where RC is:
(X) -cyclohexyl ring fused to a phenyl ring.
- 106. A method of treatment according to claim 73 where RC is:
(I) —(C1-C10)alkyl-K1-3 where each K is:
(1) H, (11) carboxyl, (16) amino unsubstituted or substituted with C1-C6 alkyl; or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[—K]1-3, where J is:
(A) a 5 to 7 atom monocyclic aryl group, or (B) a 5 to 10 atom multicyclic cycloalkyl group, and each K is:
(1) H, (3) C1-C3 alkoxy, or (11) carboxyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three:
(B) —CO—OH, (C) —CO—O—(C1-C4 alkyl), or (E) C1-C6 alkoxy, (IV) —(CH2)2-6—OH, (V) —(CH2)0-4—RC-aryl, (VI) —(CH2)0-4RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, or (XVIII) —(C2-C8) alkynyl.
- 107. A method of treatment according to claim 73 where RC is:
(I) —(C1-C10)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C1-C6 alkyl, (II) a benzyl or phenylpropyl group substituted with a carboxyl group, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups, (V) —(CH2)0-4-phenyl substituted or unsubstituted with F, (VI) —(CH2)0-4-heteroaryl, or (VII) selected from —(CH2)0-4-morpholinyl and —(CH2)0-4-tetrahydrofuryl.
- 108. A method of treatment according to claim 73 where RC is:
(I) C5H10—K or C7H14—K where K is carboxyl or carboxyl methyl ester, (II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or (III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.
- 109. A method of treatment according to claim 73where R1 is:
(1) C1-C5 alkyl, (II) —(CH2)1-2—S—CH3, (IV) C1-C5 alkenyl, (V) —(CH2)0-3—(R1-aryl) where R1-aryl is as defined above, and (VI) —(CH2)0-3—(R1-heteroaryl) where R1-heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C1-C3 alkyl, —F, —Cl, —Br, —I, or —CF3; where R2 is:
(I) —H, (II) C1-C6 alkyl, or (III) —(CH2)0-3—R2-1 where R2-1 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl is a 5 or 6-membered aryl group and R1-heteroaryl is as defined above; where RN is: (II) A-XN— where XN is —CO—,
wherein A is
(A) -T-E-(Q)m′,
(1) where -T is 90 where
(a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) the values of x and y vary independently on each carbon when m is 2 and 3, and (d) R′″ varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl; (2) -E is
(a) C1-C5 alkyl, but only if m′ does not equal 0, (b) methylthioxy(C2-C4)alkyl, (c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone, (i) phenyl(C1-C8)alkyloxyphenyl, or (j) C1-C6 alkoxy; (3) -Q is
(a) C1-C3 alkyl, (b) C1-C3 alkoxy, (c) C1-C3 alkylthioxy, (d) C1-C6 alkylacylamino, (e) C1-C6 alkylacyloxy, (f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties), (g) C1-C6 alkylamino (h) phenylamino, (i) carbamyl (including C1-C6 alkyl and phenyl amides and esters), (j) carboxyl (including C1-C6 alkyl and phenyl esters), (k) carboxy(C2-C5)alkoxy, (l) carboxy(C2-C5)alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′is 0, 1, 2 or 3; (B) -E(Q)m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3; (C) -T-E wherein -E and -Q are as defined as above; or (D) -E wherein -E is as defined as above; where RC is:
(I) —(C1-C10)alkyl-K1-3 (E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon, (F) each K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[(—(CH2)0-3—K]1-3 where K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester; J is:
(A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atom monocyclic heterocyclic group, (D) a 8 to 12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group; and where B is O or NH.
- 110. A method of treatment according to claim 73 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH3—(CH2)n—COOH where n is 0 thru 4, HOOC—(CH2)n—COOH where n is as defined above, HOOC—CH═CH—COOH and φ-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.
- 111. A method of treatment according to claim 73 wherein said compound is:
N-[(1S, 25, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide, 6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid, 5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid, 4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid, 3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid, 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid, 8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester, N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)4—(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide, 4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(5)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.
- 112. A method of treatment according to claim 73 wherein said compound is:
- 113. A pharmaceutical composition which comprises a compound of formula
- 114. The pharmaceutical composition of claim 113where R1 is:
(V) —(CH2)0-3—(R1-aryl), or (VI) —(CH2)n1—(R1-heteroaryl) where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, or (B) —SO2—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, (VI) —CO—CH(—(CH2)0-2—O—RN-10)—(CH2)0-2—RN-aryl/RN-heteroaryl) where RC is:
(I) —C1-C8 alkyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl, (IV) —(CH2)0-3—OH, (V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (VIII) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, or (E) —OCF3.
- 115. The pharmaceutical composition of claim 113where R1 is:
(V) —CH2—(R1-aryl), or (VI) —CH2—(R1-heteroaryl); where R2 is —H; where RN is:
(I) RN-1—XN— where XN is:
(A) —CO—, where RN-1 is:
(A) RN-aryl, or (B) —RN-heteroaryl, where RC is:
(III) —(CH2)0-3—(C3-C7) cycloalkyl, (V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (VIII) —C(RC-1)(RC-2)—CO—NH—RC-3, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 116. The pharmaceutical composition of claim 113 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
- 117. The pharmaceutical composition of claim 113 where R1 is:
—CH2—(R1-aryl) where R1-aryl is phenyl.
- 118. The pharmaceutical composition of claim 113 where R1 is:
—CH2—(R1-aryl) where R1-aryl is phenyl substituted with two —F.
- 119. The pharmaceutical composition of claim 113 where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
- 120. The pharmaceutical composition of claim 113 where R2 is:
(I) —H, (II) C1-C6 alkyl, or (III) —(CH2)0-4—R2-1 where R2-1 is R1-aryl.
- 121. The pharmaceutical composition of claim 113 where R2 is:
(II) C1-C6 alkyl, or (III) benzyl.
- 122. The pharmaceutical composition of claim 113 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one —CO—NRN-2RN-3 where the substitution on phenyl is 1,3-.
- 123. The pharmaceutical composition of claim 113 where RN-2 and RN-3 are the same and are C3 alkyl.
- 124. The pharmaceutical composition of claim 113 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one —CO—NRN-2RN-3 where the substitution on the phenyl is 1,3,5-.
- 125. The pharmaceutical composition of claim 113 where RN-2 and RN-3 are the same and are C3 alkyl.
- 126. The pharmaceutical composition of claim 113 where RN is
RN-1—XN— where XN is —CO—, where RN-1 is RN-heteroaryl where RN-heteroaryl is substituted with one —CO—NRN-2RN-3.
- 127. The pharmaceutical composition of claim 113 where RN-2 and RN-3 are the same and are —C3 alkyl.
- 128. The pharmaceutical composition of claim 113 where RN is:
A-XN— where XN is —CO—, where A is:
(C) C10H7—CH(OH)—, or (D) t-butoxy.
- 129. The pharmaceutical composition of claim 113 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl, (B) —CF3, (C) —F, Cl, —Br or —I, (D) C1-C3 alkoxy, (E) —OCF3, or (XVIII) —H.
- 130. The pharmaceutical composition of claim 113 where RC is:
(V) —(CRC-xRC-y)0-4—RC-aryl where RC-aryl is phenyl.
- 131. The pharmaceutical composition of claim 113 where phenyl substituted in the 3-position or 3,5-positions.
- 132. The pharmaceutical composition of claim 113 where RC is:
(VI) —CH2—RC-heteroaryl,
- 133. The pharmaceutical composition of claim 113 where RC is:
(VII) —CH2—RC-heterocycle.
- 134. The pharmaceutical composition of claim 113 where RC is:
(X) -cyclohexyl ring fused to a phenyl ring.
- 135. The pharmaceutical composition of claim 113 where RC is:
(I) —(C1-C10)alkyl-K1-3 where each K is:
(1) H, (11) carboxyl, (16) amino unsubstituted or substituted with C1-C6 alkyl; or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[—K]1-3, where J is:
(A) a 5 to 7 atom monocyclic aryl group, or (B) a 5 to 10 atom multicyclic cycloalkyl group, and each K is:
(1) H, (3) C1-C3 alkoxy, or (11) carboxyl, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three:
(B) —CO—OH, (C) —CO—O—(C1-C4 alkyl), or (E) C1-C6 alkoxy, (IV) —(CH2)2-6—OH, (V) —(CH2)0-4—RC-aryl, (VI) —(CH2)0-4—RC-heteroaryl, (VII) —(CH2)0-4—RC-heterocycle, or (XVIII) —(C2-C8) alkynyl.
- 136. The pharmaceutical composition of claim 113 where RC is:
(I) —(C1-C10)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C1-C6 alkyl, (II) a benzyl or phenylpropyl group substituted with a carboxyl group, (III) —(CH2)0-3—(C3-C7) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups, (V) —(CH2)0-4-phenyl substituted or unsubstituted with F, (VI) —(CH2)0-4-heteroaryl, or (VII) selected from —(CH2)0-4-morpholinyl and —(CH2)0-4-tetrahydrofuryl.
- 137. The pharmaceutical composition of claim 113 where Rc is:
(I) C5H10—K or C7H14—K where K is carboxyl or carboxyl methyl ester, (II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or (III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.
- 138. The pharmaceutical composition of claim 113where R1 is:
(I) C1-C5 alkyl, (II) —(CH2)1-2—S—CH3, (IV) C1-C5 alkenyl, (V) —(CH2)0-3—(R1-aryl) where R1-aryl is as defined above, and (VI) —(CH2)0-3—(R1-heteroaryl) where R1 heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C1-C3 alkyl, —F, —Cl, —Br, —I, or —CF3; where R2 is:
(I) —H (II) C1-C6 alkyl, or (III) —(CH2)0-3—R2-1 where R2-1 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl is a 5 or 6-membered aryl group and R1-heteroaryl is as defined above; where RN is: (II) A-XN— where XN is —CO—,
wherein A is
(A) -T-E-(Q)m′,
(1) where -T is 94 where
(a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) the values of x and y vary independently on each carbon when m is 2 and 3, and (d) R′″ varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl; (2) -E is
(a) C1-C5 alkyl, but only if m′ does not equal 0, (b) methylthioxy(C2-C4)alkyl, (c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone, (i) phenyl(C1-C8)alkyloxyphenyl, or (j) C1-C6 alkoxy; (3) -Q is
(a) C1-C3 alkyl, (b) C1-C3 alkoxy, (c) C1-C3 alkylthioxy, (d) C1-C6 alkylacylamino, (e) C1-C6 alkylacyloxy, (f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties), (g) C1-C6 alkylamino (h) phenylamino, (i) carbamyl (including C1-C6 alkyl and phenyl amides and esters), (j) carboxyl (including C1-C6 alkyl and phenyl esters), (k) carboxy(C2-C5)alkoxy, (l) carboxy(C2-C5)alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′ is 0, 1, 2 or 3; (B) -E(Q)m″ wherein E and -Q are as defined as above and m″ is 0, 1, 2, or 3; (C) -T-E wherein -E and -Q are as defined as above; or (D) -E wherein -E is as defined as above; where RC is:
(I) —(C1-C10)alkyl-K1-3 (E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon, (F) each K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester; (II) —(CH2)0-3-J-[(—(CH2)0-3—K]1-3 where K is:
(2) C1-C3 alkyl, (3) C1-C3 alkoxy, (4) C1-C3 alkylthioxy, (5) C1-C6 alkylacylamino, (6) C1-C6 alkylacyloxy, (7) amido, (8) C1-C6 alkylamino (9) phenylamino, (10) carbamyl, (11) carboxyl, (12) carboxy(C2-C5)alkoxy, (13) carboxy(C2-C5)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted or substituted with C1-C6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester; J is:
(A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atom monocyclic heterocyclic group, (D) a 8 to 12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group; and where B is O or NH.
- 139. The pharmaceutical composition of claim 113 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH3—(CH2), —COOH where n is 0 thru 4, HOOC—(CH2)n—COOH where n is as defined above, HOOC—CH═CH—COOH and φ-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.
- 140. The pharmaceutical composition of claim 113 wherein said compound is:
N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide, 6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid, 5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S-hydroxyhexanoylamino]-pentanoic acid, 4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid, 3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid, 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid, 8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester, N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide, 4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(2-Diethylamino-ethylcarbamoyl) 1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.
- 141. The pharmaceutical composition of claim 113 wherein said compound is:
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of invention under 35 U.S.C. §119(e) from U.S. provisional application No. 60/191,528, filed Mar. 23, 2000.
Provisional Applications (1)
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Number |
Date |
Country |
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60191528 |
Mar 2000 |
US |
Continuations (1)
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Number |
Date |
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| Parent |
09815960 |
Mar 2001 |
US |
| Child |
10847819 |
May 2004 |
US |
Patent Application
20040214846
