US2007225297A1PendingUtilityA1
Deuterated hepatitis C protease inhibitors
Individually held — no corporate assignee on recordPriority: Mar 16, 2006Filed: Mar 14, 2007Published: Sep 27, 2007
Est. expiryMar 16, 2026(expired)· nominal 20-yr term from priority
Inventors:Robert B. PerniYoussef L. BennaniGregor ZlokarnikGerald J. TanouryMinzhang ChenYoung Chun JungRaymond E. ForslundFrancois Maltais
C07K 5/0202C07D 301/14C07D 209/52C07B 2200/07C07D 498/10C07C 237/04C07D 403/12C07D 403/14C07D 401/14C07C 2601/02A61P 31/14C07K 7/02C07B 2200/05C07C 231/20C07D 303/48A61P 31/12A61P 43/00A61K 31/403
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Claims
Abstract
A deuterated α-ketoamido steric specific compound of the formula wherein D denotes a deuterium atom on a steric specific carbon atom.
Claims
exact text as granted — not AI-modified1 . A deuterium-enriched α-ketoamido compound of the formula
wherein:
D denotes a deuterium atom;
R 1 is
in which
is an optionally substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R 21 moiety and to which the —C(O)—N(R 2 )—CDR 3 —C(O)—C(O)—NR 4 R 5 moiety is attached;
R 21 is Q 3 -W 3 -Q 2 -W 2 -Q 1 ; wherein
Each of W 2 and W 3 is independently a bond, —CO—, —CS—, —C(O)N(Q 4 )-, —CO 2 —, —O—, —N(Q 4 )-C(O)—N(Q 4 )-, —N(Q 4 )-C(S)—N(Q 4 )-, —OC(O)NQ 4 -, —S—, —SO—, —SO 2 —, —N(Q 4 )-, —N(Q 4 )SO 2 —, —N(Q 4 )SO 2 N(Q 4 )-, and hydrogen when any of W 2 and W 3 is the terminal group;
Each of Q 1 , Q 2 , and Q 3 is independently a bond, an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or hydrogen when any of Q 3 , Q 2 , or Q 1 is the terminal group, provided that Q 2 is not a bond when both W 3 and W 2 are present; and
Each of R 2 , R 3 , and R 4 , independently, is H or a C 1-6 alkyl; and
R 5 is H, alkyl, cycloalkyl, aryl optionally substituted with 1-4 alkyl groups, alkylaryl, aryl, amino optionally substituted with 1 or 2 alkyl groups.
2 . The compound of claim 1 , wherein R 21 is
in which
each of R 6 and R 8 is independently
a bond; or
optionally substituted (1,1- or 1,2-)cycloalkylene; or
optionally substituted (1,1- or 1,2-)heterocyclylene; or
methylene or ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group and an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent;
each of R 7 , R 9 , and R 11 is independently hydrogen or optionally substituted aliphatic group;
R 10 is an optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
L is —C(O)—, —OC(O)—, —NR 11 C(O)—, —S(O) 2 —, —NR 11 S(O) 2 —, or a bond;
n is 0 or 1.
3 . The compound of claim 2 , wherein n is 1.
4 . The compound of claim 2 , wherein R 6 is methylene substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group, and an optionally substituted aromatic group.
5 . The compound of claim 4 , wherein R 6 is methylene substituted with isobutyl.
6 . The compound of claim 2 , wherein R 7 is hydrogen.
7 . The compound of claim 2 , wherein R 8 is methylene substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group, and an optionally substituted aromatic group.
8 . The compound of claim 7 , wherein R 8 is methylene substituted with an optionally substituted cyclic group.
9 . The compound of claim 8 , wherein R 8 is methylene substituted with cyclohexyl.
10 . The compound of claim 2 , wherein R 9 is hydrogen.
11 . The compound of claim 2 , wherein L is —CO—.
12 . The compound of claim 2 , wherein R 10 is an optionally substituted aromatic group.
13 . The compound of claim 12 , wherein R 10 is selected from the group consisting of
14 . The compound of claim 12 , wherein R 10 is optionally substituted pyrazinyl.
15 . The compound of claim 14 , wherein R 10 is 2-pyrazinyl.
16 . The compound of claim 2 , wherein
is substituted monocyclic azaheterocyclyl.
17 . The compound of claim 16 , wherein
is pyrrolidinyl substituted at C-3 position with heteroaryloxy, wherein the heteroaryl is further optionally substituted with 1-4 halo groups.
18 . The compound of claim 16 , wherein
19 . The compound of claim 2 , wherein
is optionally substituted multicyclic azaheterocyclyl.
20 . The compound of claim 19 , wherein
21 . The compound of claim 20 , wherein
22 . The compound of claim 2 , wherein R 2 is hydrogen, each of R 4 and R 5 independently is hydrogen or cyclopropyl.
23 . The compound of claim 2 , wherein R 3 is propyl.
24 . The compound of claim 2 , wherein n is 0.
25 . The compound of claim 2 , wherein L is —NR 11 C(O)— and R 11 is hydrogen.
26 . The compound of claim 2 , wherein R 10 is an optionally substituted aliphatic group.
27 . The compound of claim 26 , wherein R 10 is t-butyl.
28 . The compound of claim 2 , wherein the compound is
29 . The compound of claim 19 , wherein
in which
A is —(CHX 1 ) n —;
B is —(CHX 2 ) b —;
a is 0 to 3;
b is 0 to 3, provided that a+b is 2 or 3;
each of X 1 and X 2 is independently selected from hydrogen, optionally substituted C 1-4 aliphatic, and optionally substituted aryl;
each of Y 1 and Y 2 is independently hydrogen, optionally substituted aliphatic, optionally substituted aryl, amino, or —OQ 4 ; wherein each Q 4 is independently hydrogen or an optionally substituted aliphatic;
R 22 is an optionally substituted aliphatic, an optionally substituted heteroaliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl.
30 . The compound of claim 29 , wherein R 21 is optionally substituted alkylcarbonyl.
31 . The compound of claim 30 , wherein R 21 is aminoalkylcarbonyl, haloalkylcarbonyl, arylalkylcarbonyl, arylalkylcarbonyl, cycloaliphaticalkylcarbonyl, or heterocycloaliphaticalkylcarbonyl, each of which is optionally substituted with 1-3 substituents.
32 . The compound of claim 31 , wherein R 21 is heterocycloalkyl-oxycarbonylamino-alkylcarbonyl, heteroaryl-carbonylamino-alkyl-carbonylamino-alkyl-carbonyl, bicycloaryl-sulfonylamino-alkylcarbonyl, aryl-alkoxy-carbonylamino-alkyl-carbonyl, alkyl-carbonylamino-alkyl-carbonyl, aliphatic-oxycarbonylamino-alkyl-carbonyl, cycloaliphatic-alkyl-aminocarbonylamino-alkyl-carbonyl, cycloaliphatic-alkyl-carbonylamino-alkyl-carbonyl, heteroaryl-carbonylamino-alkyl-carbonylamino-alkyl-carbonyl, alkyl-aminocarbonylamino-alkyl-carbonyl, or bicycloaryl-aminocarbonylamino-alkyl-carbonyl, each of which is optionally substituted with 1-3 substituents.
33 . The compound of claim 29 , wherein R 21 is
in which
each of R 6 and R 8 is independently
a bond; or
optionally substituted (1,1- or 1,2-)cycloalkylene; or
optionally substituted (1,1- or 1,2-)heterocyclylene; or
methylene or ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group and an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent;
each of R 7 , R 9 , and R 11 is independently hydrogen or optionally substituted aliphatic group;
R 10 is an optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
L is —C(O)—, —OC(O)—, —NR 11 C(O)—, —S(O) 2 —, —NR 11 S(O) 2 —, or a bond;
n is 0 or 1,
34 . The compound of claim 29 , wherein R 22 is an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.
35 . The compound of claim 34 , wherein R 22 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracenyl, optionally substituted naphthalene, or optionally substituted anthracene.
36 . The compound of claim 29 , wherein each of X 1 , X 2 , Y 1 , and Y 2 is hydrogen, each of a and b is 1.
37 . The compound of claim 36 , wherein R 22 is an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted cycloaliphatic, optionally substituted heterocycloaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.
38 . The compound of claim 37 , wherein R 22 is an optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracenyl, optionally substituted naphthalene, or optionally substituted anthracene.
39 . The compound of claim 38 , wherein R 21 is heterocycloalkyl-oxycarbonylamino-alkylcarbonyl, heteroaryl-carbonylamino-alkyl-carbonylamino-alkyl-carbonyl, bicycloaryl-sulfonylamino-alkylcarbonyl, aryl-alkoxy-carbonylamino-alkyl-carbonyl, alkyl-carbonylamino-alkyl-carbonyl, aliphatic-oxycarbonylamino-alkyl-carbonyl, cycloaliphatic-alkyl-aminocarbonylamino-alkyl-carbonyl, cycloaliphatic-alkyl-carbonylamino-alkyl-carbonyl, heteroaryl-carbonylamino-alkyl-carbonylamino-alkyl-carbonyl, alkyl-aminocarbonylamino-alkyl-carbonyl, or bicycloaryl-aminocarbonylamino-alkyl-carbonyl, each of which is optionally substituted with 1-3 substituents.
40 . The compound of claim 29 , wherein
41 . The compound of claim 40 , wherein the compound is of the structure:
42 . The compound of claim 1 , wherein the deuterium enrichment is at least 50% in the compound.
43 . The compound of claim 42 , wherein the deuterium enrichment is at least 80%.
44 . The compound of claim 43 , wherein the deuterium enrichment is at least 90%.
45 . The compound of claim 44 , wherein the deuterium enrichment is at least 99%.
46 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
47 . A method for increasing the concentration of the active isomer of a pharmaceutical agent in vivo, comprising administering to a patient in need thereof a deuterated isomer of the pharmaceutical agent in an amount sufficient to confer the pharmaceutical effect.
48 . The method of claim 47 , wherein the deuterated isomer of the pharmaceutical agent is a compound of claim 1 .
49 . A method for enhancing the bioavailability of a compound, comprising replacing a hydrogen atom that is bonded to a steric carbon atom in the compound with a deuterium atom.
50 . The method of claim 49 , wherein the deuterated compound thus obtained is a compound of claim 1 .
51 . A method for inhibiting HCV protease, comprising contacting HCV protease with a compound of claim 1 .
52 . A method for treating a patient suffering from HCV infection or a condition mediated by HCV protease, comprising administering to the patient a pharmaceutically effective amount of a compound of claim 1 .
53 . A process for preparing an optically enriched compound of Formula 1
wherein:
the carbon atoms alpha and beta to the carboxy group are stereocenters;
R 1 is independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic;
R′ 1 is deuterium such that the deuterium enrichment is at least 50%;
R′ 2 is —NHR 2 or —OE;
R 2 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and
E is C 1-6 alkyl or benzyl; comprising the steps of:
a) forming a salt of a compound of Formula 1, and b) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.
54 . The process of claim 53 , wherein R 1 is C 1-6 alkyl, and R′ 2 is —NHR 2 wherein R 2 is a C 1-6 alkyl or C 1-6 cycloalkyl.
55 . The process of claim 54 , wherein R 1 is propyl and R 2 is cyclopropyl.
56 . The process of claim 53 , further comprising aminating a compound of Formula ii
with an aminating reagent to provide a compound of Formula iii
57 . The process of claim 56 , wherein the aminating reagent is an azide salt and the intermediate azido compound is reduced by hydrogenation.
58 . The process of claim 56 , further comprising oxidizing an unsaturated compound of Formula i
wherein R′ 2 is —NHR 2 or —OE, wherein E is C 1-5 alkyl or optionally substituted benzyl, with an oxidizing reagent to provide a compound of Formula ii.
59 . The process of claim 58 , wherein the oxidizing reagent comprises t-butyl hydroperoxide.
60 . The process of claim 59 , wherein the oxidizing reagent further a chiral reagent.
61 . The process of claim 58 , wherein the oxidizing reagent is a mixture of samarium (III) isopropoxide, triphenyl arsine oxide, S-(−)1,1′-bi-2-naphthol and 4 Å molecular sieves.
62 . The process of claim 58 , wherein the oxidizing reagent comprises urea-hydrogen peroxide in the presence of trifluoroacetic anhydride.
63 . The process of claim 62 , wherein R′ 2 is —OE.
64 . The process of claim 62 , wherein R′ 2 is —NHR 2 .
65 . The process of claim 58 , further comprising hydrolyzing the compound of Formula ii to give an acid and then converting the acid to an amide compound of Formula ii wherein R′ 2 is —NHR 2 .
66 . The process of claim 58 , further comprising oxidizing a compound of Formula iv
to give the compound of Formula ii.
67 . The process of 66 , wherein the oxidation is conducted by using manganese dioxide.
68 . The process of 66 , further comprising reducing a compound of Formula v
to give the compound of Formula iv.
69 . The process of 68 , wherein the compound is reduced with Red-A 1 ® and then quenched with deuterium oxide.
70 . A process for preparing a compound of Formula 1
wherein:
R 1 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic;
R′ 1 is deuterium,
R 2 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and
the compound of Formula 1 has an enantiomeric excess of greater than 55%, comprising the steps of:
a) oxidation of an unsaturated compound of Formula i
to provide a compound of formula ii
b) reacting a compound of Formula ii with an aminating reagent to provide a compound of Formula iii
c) forming a salt of a compound of Formula iii with an optically active organic acid;
d) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.
71 . The process of claim 70 , wherein the compound of Formula 1 is (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanamide.
72 . The process of claim 71 , wherein the organic acid is L-tartaric acid or deoxycholic acid.Join the waitlist — get patent alerts
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