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US 7,351,822 B2Granted
Serine protease inhibitors
AssigneeEli Lilly and Company
InventorsJohn Walter Liebeschuetz, Christopher William Murray, Stephen Clinton Young, Nicholas Paul Camp, Stuart Donald Jones, William Alexander Wylie, John Joseph Masters, Michael Robert Wiley, Scott Martin Sheehan, David Birenbaum Engel, Brian Morgan Watson, Peter Robert Guzzo, Michael John Mayer
Life of this patent
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Abstract
Compounds of formula (I) in which R2, X, Y, Cy, L and Lp(D)n have the meanings given in the specification, are inhibitors of the serine protease, Factor Xa and are useful in the treatment of cardiovascular disorders.
Claims3
A process for the preparation of serine protease inhibitor compound of formula
- wherein:
- R2 is:
- (i) phenyl optionallly being substituted in the 3 and/or 4 position by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeSO2- or R1, and optionally substituted at the 6 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido (CONH2), aminoalkyl, alkoxy or alklthio;
- (ii) naphth-2-yl optionally substiuted at the 6 or 7 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j and optionally substituted at the 3 position by amino, hxdroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio;
- (iii) isoquinolin-7yl, indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl, benzothiazol-6-yl or benzisoxazol-5-yl optionally substituted at the 3 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- (iv) benzimidazol-5-yl or benzothiazol-6-yl optionally substituted at the 2 position by amino;
- (v) thien-2-yl or thien-3-yl optionally substituted at the 4 or 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydazido, alkylthio, alkenyl, alkynyl or R1;
- (vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl, 3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-yl;
- (vii) benzothiazol-2-yl, imidazo[1,2-a]pyrimidin-2-yl or tetrahydro-imidazol[1,2-a]pyrimidin-2-yl;
- (viii) pyrazol-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (ix) pyrid-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (x) pyrid-3-yl optionally substituted at the 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (xi) benzofur-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- (xii) indol-2-yl optionally substituted on the indole nitrogen atom by alkyl and optionally substituted at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkynyl or R1j;
- (xiii) indol-6-yl substituted at the 5 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio and optionally substituted at the 3 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j:
- or
- (xiv) benzo[b]thiophen-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- with the proviso that R2 cannot be aminoisoquinolyl;
- or R2 is a group of formula (F′) or (H′)
- wherein X4 is O or S, and R13 is selected from hydrogen fluoro, chloro and methyl:
- —X—X— is —CONH—;
- R1 is hydrogen, hydroxy, alkoxy, alkyl, alkylaminoalkyl, alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;
- R1j is hydrogen, hydroxy, alkoxy, alkyl, alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;
- Y is a CH group;
- Cy is an optionally R3a substituted:
- phenyl group, or a phenyl group substituted by R3iXi;
- each R3a independently is hydrogen, hydroxyl, alkoxy, aralkyloxy, alkyl, alkylaminoalkyl, hydroxymethyl, carboxy, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, aminomethyl, CONH2, CH2CONH2, (1-6C)alkanoylamino, alkoxycarbonylamino, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, triazolyl, imidazolyl, tetrazolyl, hydrazido, alkylimidazolyl, thiazolyl, alkylthiazolyl, alkyloxazolyl, oxazolyl, alkylsulphonamido, alkylaminosulphonyl, aminosulphonyl, haloalkoxy, haloalkyl, a group of the formula —C(X3)N(R11)R12 (wherein X3 is O or S;
- and R11 and R12 are independently selected from hydrogen, methyl or ethyl or together with the nitrogen atom to which they are attached torm a pyrrolidin-1-yl, piperidin-1-yl or morpholino group), or —OCH2O— which is bonded to two adjacent ring atoms in Cy;
- Xi is a bond, O, NH or CH2;
- R3i is phenyl, pyridyl or pyrimidinyl optionally substituted by R3a;
- and
- -L-Lp(D)n is of the formula:
- in which Rr is —(CH2)c-Rc, —CHReRf, —CH2—CH2—CHReRf, or Rg in which c is 1 or 2;
- Rc is thienyl, thiazolyl(which may bear an amino substituent), isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl (which may bear an alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, (1-4C)alkoxycarbonyl, carboxy, acetylamino, chloro, fluoro, cyano, (1-3C)alkyl, trifluoromethyl, methoxy, ethoxy, nitro, hydroxy, alkylsulphonylamino, triazolyl or tetrazolyl substituent), pyrimidinyl, pyridazinyl, pyrazinyl or phenyl (which may bear a methyl, methylamino, dimethylamino, carboxy, dialkylaminosulphonyl, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, alkylaminocarbonyl, amino, amido, alkoxycarbonyl, acetylamino, chloro, fluoro, cyano, methoxy, ethoxy, nitro, hydroxy, alkylsulphonylamino, triazolyl or tetrazolyl substituent);
- each of Re and Rf independently is hydrogen or C1-3alkyl;
- or CHReRf is cyclopentyl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), cyclohexyl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 3- or 4-position), tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, pyrrolidin-3-yl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1-position), piperidin-4-yl (which may bear a hydroxy, amino, (1-3C)alkoxy, (1-3C)hydroxyalkyl, (1-3C)alkyl, carboxy, methoxycarbonyl or ethoxycarbonyl substituent at the 1-position), or indan-2-yl;
- and Rg is λ6-1,1-dioxobenzo[b]thiopen-7-yl;
- or a physiologically-tolerable salt thereof;
- which process comprises
- (a) reacting a compound of formula (10)
- H2N—Y-(Cy)-L-Lp(D)n (10)
- with a compound of formula R2-COOH, under amide bond-forming conditions;
- or
- b) when Rr is (CH2)c-Rc- reacting a compound of formula (11)
- with a compound of (12)
- OHC—(CH2)c−1-Rc (12)
- in the presence of a reducing agent;
- followed if a salt is required, by forming a physiologically acceptable salt.
45 more elements
A compound of formula (11)
- in which:
- R2 is:
- (i) phenyl optionally being substituted in the 3 and/or 4 position by halo, nitro, thiol, haloalkoxy, hydrazido, alkylhydrazido, amino, cyano, haloalkyl, alkylthio, alkenyl, alkynyl, acylamino, tri or difluoromethoxy, carboxy, acyloxy, MeSO2- or R1- and optionally substituted at the 6 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido (CONH2), aminoalkyl, alkoxy or alkylthio;
- (ii) naphth-2-yl optionally substituted at the 6 or 7 position in halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j and optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio;
- (iii) isoquinolin-7-yl, indol-5-yl, indol-6-yl, indazol-5-yl, indazol-6-yl, benzothiazol-6-yl or benzisoxazol-5-yl optionally substituted at the 3 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- (iv) benzimidazol-5-yl or benzothiazol-6-yl optionally substituted at the 2 position by amino;
- (v) thien-2-yl or thien-3-yl optionally substituted at the 4 or 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (vi) 3,4-methylenedioxyphenyl, 2,3-dihydroindol-6-yl, 3,3-dichloro-2-oxo-indol-6-yl or 1-methyl-3-aminoindazol-5-yl;
- (vii) benzothiazol-2-yl, imidazo[1,2-a]pyrimidin-2-yl or tetrahydroimidazo[1,2-a]pyrimidin-2-yl;
- (viii) pyrazol-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (ix) pyrid-2-yl optionally substituted at the 5 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (x) pyrid-3-yl optionally substituted at the 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1;
- (xi) benzofur-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- (xii) indol-2-yl optionally substituted on the indole nitrogen atom by alkyl and optionally substituted at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- (xiii) indol-6-yl substituted at the 5 position by amino, hydroxy, halo, alkyl, carboxy, alkoxycarbonyl, cyano, amido, aminoalkyl, alkoxy or alkylthio and optionally substituted at the 3 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- or
- (xiv) benzo[b]thiophen-2-yl optionally substituted at the 3 position by amino, hydroxy, halo, alkyl, carboxy, cyano, amido, aminoalkyl, alkoxy or alkylthio and at the 5 or 6 position by halo, haloalkoxy, haloalkyl, cyano, nitro, amino, hydrazido, alkylthio, alkenyl, alkynyl or R1j;
- with the proviso that R2 cannot be aminoisoquinolyl;
- or R2 is a group of formula (F′) or (H′)
- wherein is X4 is O or S, and R13 is selected from hydrogen, fluoro, chloro and methyl;
- —X—X— is —CONH—;
- R1 is hydrogen, hydroxy, alkoxy, alkyl, alkylaminoalkyl, alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;
- R1j is hydrogen, hydroxy, alkoxy, alkyl, alkanoyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkylamino, carboxyl, carboxymethyl, amido or amidomethyl;
- Y (the α-atom) is a CH group;
- Cy is an optionally R3a substituted:
- phenyl group, or a phenyl group substituted by R3iXi;
- each R3a independently is hydrogen, hydroxyl, alkoxy, aralkyloxy, alkyl, alkylaminoalkyl, hydroxymethyl, carboxy, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, aminomethyl, CONH2, CH2CONH2, (1-6C)alkanoylamino, alkoxycarbonylamino, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, triazolyl, imidazolyl, tetrazolyll, hydrazido, alkylimidazolyl, thiazolyl, alkylthiazolyl, alkyloxazolyll, oxazolyl, alkylsulphonamido, alkylaminosulphonyl, aminosulphonyl, haloalkoxy, haloalkyl, a group of the formula —C(X3)N(R11)R12 (wherein X3 is O or S;
- and R11 and R12 are independently selected from hydrogen, methyl or ethyl or together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, piperidin-1-yl or morpholino group), or —OCH2O— which is bonded to two adjacent ring atoms in Cy;
- Xi is a bond, O, NH or CH2;
- and
- R3i is phenyl, pyridyl or pyrimidinyl optionally substituted by R3a.
28 more elements
Dependencies are inferred from the claim text.