US 7,001,899 B2Granted

Interleukin converting enzyme inhibitors

AssigneeThe Procter & Gamble Company

InventorsJohn August Wos, Yili Wang, Kofi Abeka Oppong, Steven Victor O'Neil, Michael Christopher Laufersweiler, David Lindsey Soper, Biswanath De, Thomas Prosser Demuth, Jr.

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Abstract

The present invention relates to novel compounds, compositions comprising said compounds, and uses thereof, said compounds having the formula: wherein each X is independently selected from: i) —C(W)2—; ii) —C(O)—; iii) —NR2—; iv) —S—; v) —S(O)—; vi) —S(O)2—; vii) two units, one from each adjacent X unit, can be taken together to form a substituted or unsubstituted double bond having the formula —CW═CW—; wherein each W is hydrogen of a unit having the formula —(L2)j—R2, the index j is 0 or 1; R is a carbocyclic or heterocyclic aryl ring; R1 is a cysteine trap; each R2 is independently a suitable substituent; and L, L1, and L2 are linking units.

Claims41

Dependent claims

A compound or its enantiomeric or diasteriomeric form or a pharmaceutically acceptable salt thereof, said compound having the formula:

wherein each W is hydrogen of a unit having the formula —(L2)j—R2, the index j is 0 or 1;
wherein R is a ring chosen from:
i) substituted or unsubstituted C3–C10 non-aromatic carbocyclic;
ii) substituted or unsubstituted C6–C10 aryl;
iii) substituted or unsubstituted C1–C10 heterocyclic;
and
iv) substituted or unsubstituted C1–C10 heteroaryl;
R1 is a cysteine trap;
each R3 is independently selected from the group consisting of:
i) hydrogen;
ii) a hydrocarbyl unit having the formula:
—[C(R3)2]p(CH═CH)qR3;
iii) —C(═Z)R3;
iv) —C(═Z)AR3;
v) —C(═Z)[C(R3)2]p(CH═CH)qR3;
vi) —C(═Z)N(R3)2;
vii) —C(═Z)NR3N(R3)2;
viii) —CN;
xix) —CF3;
x) —N(R3)2;
xi) —NR3CN;
xii) —NR3C(═Z)R3;
xiii) —NR3C(═Z)N(R3)2;
xiv) —NHN(R3)2;
xv) —NHOR3;
xvi) —NO2;
xvii) —OR3;
xviii) —OCF3;
xix) —F, —Cl, —Br, or —I;
—xx) —SO3M;
—xxi) —OSO3M;
xxii) —SO2N(R3)2;
xxiii) —SO2R3;
xxiv) —P(O)(OR3)R3;
xxv) —P(O)(OR3)2;
xxvi) and mixtures thereof;
each R3 is independently hydrogen, substituted or unsubstituted C1–C20 linear, branched, or cyclic alkyl, substituted or unsubstituted C6–C20 aryl, C1–C20 substituted or unsubstituted heterocyclic, C1–C20 substituted or unsubstituted heteroaryl;
Z is O, S, or NR3;
M is hydrogen, or a salt forming cation;
the index p is from 0 to 12;
the index q is from 0 to 12;
L, L1, and L2 are each independently a linking group having the formula:
T, T1, and T2 are each independently selected from the group consisting of:
i) —NR6—;
ii) —O—;
iii) —S(O)2—;
iv) —NR6S(O)2—;
and
v) —S(O)2NR6—;
R6 is hydrogen, substituted or unsubstituted C1–C10 linear, branched, or cyclic alkyl, C6–C10 aryl, and C7–C12 alkylenearyl;
the indices w, w1, and w2 are each independently 0 or 1;
R4a, R4b, R5a, and R5b are each independently:
i) hydrogen;
ii) C1–C4 linear, branched, and cyclic alkyl;
iii) R4a and R4b or R5a, and R5b can be taken together to form a carbonyl unit;
and
iv) two R3a or two R3b units from adjacent carbon atoms or two R4a or two R4b units from adjacent carbon atoms can be taken together to form a double bond;
the index m is from 0 to 5;
the index n is from 0 to 5.

56 more elements

A compound selected from the group consisting of:

Isoquinoline-1-carboxylic acid {1-[(2-hydroxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
Isoquinoline-1-carboxylic acid {1-[(2-ethoxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
Naphthalene-2-carboxylic acid {1-[(2-ethoxy-5-oxo-tetra-hydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
Benzothiaphene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
Benzothiaphene-2-carboxylic acid {1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl} amide;
N-{1-[(2-Hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
N-{1-[(2-Ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Fluoro-N-{1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Fluoro-N-{1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Trifluoromethyl-N-{1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Trifluoromethyl-N-{1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Methoxy-N-{1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Methoxy-N-{1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Acetyl-N-{1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Acetyl-N-{1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
3-Benzoyl-N-{1-[(2-hydroxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide;
and
3-Benzoyl-N-{1-[(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-yl-benzamide.

16 more elements

A compound selected from the group consisting of:

Isoquinoline-1-carboxylic acid {6-(benzoylamino-methyl)-1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7,-tetrahydro-1H-azepin-3-yl}-amide;
Isoquinoline-1-carboxylic acid {6-(benzoylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7,-tetrahydro-1H-azepin-3-yl}-amide;
Isoquinoline-1-carboxylic acid [(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-(methanesulfonylamino-methyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]-amide;
Isoquinoline-1-carboxylic acid {6-(benzenesulfonylamino-methyl)-1-[(2-hydroxy-5-oxo-tretrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(3-methoxy-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(2-methoxy-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methoxy-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-[(4-tert-butyl-benzylamino)-methyl]-1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahdyro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(2-methyl-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(3-methyl-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methyl-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methanesulfonyl-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(4-[1,2,3]thiadiazol-4-yl-benzylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-isopropyl-benzylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(4-pentyl-benzylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-(benzoylamino-methyl)-1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-(benzenesulfonylamino-methyl)-1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-[(2-fluoro-benzoylamino)-methyl]-1-[3-(2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-oxo-propyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-[(3-fluoro-benzoylamino)-methyl]-1-[3-(2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-oxo-propyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-[(4-fluoro-benzoylamino)-methyl]-1-[3-(2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-2-oxo-propyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(2-methoxy-benzoylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(3-methoxy-benzoylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methoxy-benzoylamino)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(4-methyoxy-benzenesulfonylamino)-methyl}-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(toluene-3-sulfonylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(toluene-2-sulfonylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-[(toluene-4-sulfonylamino)-methyl]-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-6-[(3-methyoxy-benzenesulfonylamino)-methyl}-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
Naphthalene-2-carboxylic acid {6-benzylsulfanylmethyl-1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide;
and
Naphthalene-2-carboxylic acid {1-[(2-hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-6-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepin-3-yl}-amide.

28 more elements

A pharmaceutical composition comprising:

A) an effective amount of one or more compounds, including all enantiomeric or diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:
wherein each W is hydrogen of a unit having the formula —(L2)j—R2, the index j is 0 or 1;
wherein R is a ring chosen from:
i) substituted or unsubstituted C3–C10 non-aromatic carbocyclic;
ii) substituted or unsubstituted C6–C10 aryl;
iii) substituted or unsubstituted C1–C10 heterocyclic;
and
iv) substituted or unsubstituted C1–C10 heteroaryl;
R1 is a cysteine trap;
each R2 is independently selected from the group consisting of:
i) hydrogen;
ii) a hydrocarbyl unit having the formula:
—[C(R3)2]p(CH═CH)qR3;
iii) —C(═Z)R3;
iv) —C(═Z)AR3;
v) —C(═Z)[C(R3)2]p(CH═CH)qR3;
vi) —C(═Z)N(R3)2;
vii) —C(═Z)NR3N(R3)2;
viii) —CN;
xix) —CF3;
x) —N(R3)2;
xi) —NR3CN;
xii) —NR3C(═Z)R3;
xiii) —NR3C(═Z)N(R3)2;
xiv) —NHN(R3)2;
xv) —NHOR3;
xvi) —NO2;
xvii) —OR3;
xviii) —OCF3;
xix) —F, —Cl, —Br, or —I;
xx) —SO3M;
xxi) —OSO3M;
xxii) —SO2N(R3)2;
xxiii) —SO2R3;
xxiv) —P(O)(OR3)R3;
xxv) —P(O)(OR3)2;
xxvi) and mixtures thereof;
each R3 is independently hydrogen, substituted or unsubstituted C1–C20, linear, branched, or cyclic alkyl, substituted or unsubstituted C4–C20 aryl, C1–C20 substituted or unsubstituted heterocyclic, C1–C20 substituted or unsubstituted heteroaryl;
Z is O, S, or NR3;
M is hydrogen, or a salt forming cation;
the index p is from 0 to 12;
the index q is from 0 to 12;
L, L1, and L2 are each independently a linking group having the formula:
T, T1, and T2 are each independently selected from the group consisting or
i) —NR6—;
ii) —O—;
iii) —S(O)2;
iv) —NR6S(O)2—;
and
v) —S(O)2NR6—;
R6 is hydrogen, substituted or unsubstituted C1–C10 linear, branched, or cyclic alkyl, C6–C10 aryl, and C7–C1 alkylenearyl;
the indices w, w1, and w2 are each independently 0 or 1;
R4a, R4b, R5a, and R5b are each independently;
i) hydrogen;
ii) C1–C4 linear, branched, and cyclic alkyl;
iii) R4a and R4b or R5a, and R5b can be taken together to form a carbonyl unit;
and
iv) two R3a or two R3b units from adjacent carbon atoms or two R4a or two R4b units from adjacent carbon atoms can be taken together to form a double bond;
the index m is from 0 to 5;
the index n is from 0 to 5;
and
B) the balance one or more pharmaceutically acceptable excipients.

59 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/457,720Filed 9 Jun 2003 · us provisional application
Priority: 10 Jun 2002
Published: US 2004/0009966 A115 Jan 2004
Granted: 21 Feb 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 19/10
For bone diseases, e.g. rachitism, Paget's disease: for osteoporosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…