US 8,283,344 B2Granted

Method of treating inherited severe neutropenia

AssigneesMerck & Co., Inc., University of Washington

InventorsDavid C. Dale, Paul E. Finke, Richard A. Mumford, Andranik Andrew Aprikyan

Life of this patent

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Abstract

The invention is directed to a method of treating severe neutropenia, and in particular, cyclic neutropenia (CN) or severe congenital neutropenia (SCN), in a patient in need of such treatment comprising: administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Claims9

Dependent claims

A method of treating cyclic or severe congenital neutropenia, in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof wherein
R1 is C1-6 alkyl or C1-6 alkoxy-C1-6alkyl;
M is
(1) hydrogen,
(2) C1-6alkyl,
(3) hydroxy C1-6alkyl,
(4) halo C1-6alkyl,
(5) C2-6alkenyl, or
(6) C1-6alkoxy-C1-6alkyl;
Ra and Rb are each individually
(1) hydrogen,
(2) C1-6alkyl,
(3) halo,
(4) carboxy,
(5) C1-6alkoxy,
(6) phenyl,
(7) C1-6alkylcarbonyl,
(8) di-(C1-6alkyl)amino;
(9) hydroxy;
R2 and R3 are each independently
(1) hydrogen,
(2) C1-6alkyl,
(3) halo,
(4) carboxy,
(5) C1-6alkoxy,
(6) phenyl,
(7) C1-6alkylcarbonyl,
(8) aminoC2-3alkyloxy carbonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(9) aminoC2-3alkylamino carbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(10) hydroxy,
(11) aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(12) hydroxymethyl,
(13) aminocarbonyloxy C1-3alkyloxy wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(14) cyano,
(15) morpholinocarbonylphenyl,
(16) amino wherein the amino is optionally mono or di-substituted with C1-6alkyl, with the proviso that R2 and R3 may be joined together to form a methylenedioxy group or a furan ring,
(17) morpholinocarbonyl;
R4 is
(a) Q-C(O)—Y—N(R7)(R8), or
(b) Q-C(O)—ORx, where Rx is carboxyC-16alkyl, benzyloxycarbonylC1-3 alkyl, or t-butoxycarbonylC1-3 alkyl,
wherein
Q is a covalent bond or —C(R5)(R6)—
wherein R5 and R6 are each individually C1-3 alkyl or hydrogen,
Y is
or a covalent bond;
R12 is hydrogen or C1-3alkyl;
R7 and R8 are each individually
(a) hydrogen,
(b) C1-6alkyl,
(c) C1-6alkyloxy C2-3alkyl,
(d) hydroxy C2-6alkyl,
(e) polyhydroxyC2-6alkyl,
(f) carboxamido C1-6alkyl,
(g) polyacyloxyC2-6alkyl
(h) C1-6alkanoyl,
(i) substituted phenyl or phenyl C1-6alkyl, wherein the substitutent is X1 as defined immediately below,
(j) C2-6alkenyl,
(k) C6-10cycloalkenyl,
(l) heteroaryl C1-6alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,
(m) carboxy C1-6alkyl,
(n) carbo C1-6alkoxy C1-3alkyl,
(o) phenylsulfonyl,
(p) C1-6alkylsulfonyl,
(q) benzyloxy,
(r) morpholinyl C1-3alkylsulfonyl,
(s) tetrahydropyranyl,
(t) aminoC1-3alkylsulfonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(u) aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(v) aminocarbonyloxyC2-6alkyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(w) azabicyclo of 7 to 12 atoms,
(x) di C1-3alkylamino C2-6alkyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(y) bicycloalkyl of 7 to 12 atoms,
(z) C3-10cycloalkyl optionally substituted with C1-6alkyl,
(aa) pyrazolidinyl,
(bb) substituted piperidinyl or pyrrolidinyl wherein the substitutent is hydrogen, C1-3 alkyl, hydroxyC1-3 alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(dd) pyrimidinyl,
(ee) N-cyano-N′-phenylamidino,
(ff) phosphonoC1-6alkyl, or
(gg) α-C1-3alkyl benzyl or mono or di-substituted benzyl or mono or di-substituted pyridylmethyl, wherein the substitutents are X1 and X2,
wherein
X1 is
(1) hydrogen,
(2) halo,
(3) C1-6alkyl,
(4) halo-C1-6alkyl,
(5) C2-6alkenyl,
(6) hydroxy-C1-6alkyl,
(7) C1-6alkylcarbonyl,
(8) C1-6alkylcarbonylamino;
(9) CN,
(10) CF3,
(11) CH3O,
(12) amino wherein the amino is optionally mono or di-substituted with C1-6 alkyl;
(13) carboxy, or
(14) phenylsulfonylaminocarbonyl;
X2 is hydrogen, halo or C1-6alkyl;
n is 1, 2, 3, 4 or 5;
R9 is selected from hydrogen, C1-4-alkyl, and C1-3alkoxyC1-3alkyl;
or phenyl, phenyl C1-3alkyl, pyridyl, and pyridyl C1-3alkyl;
R10 and R11 are each independently selected from hydrogen, C1-4alkyl, and C1-3 alkoxyC1-3alkyl, or aryl as defined above, or are together oxo;
or
wherein R7 and R8 are joined together to form mono or di-substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as
(1) piperidinyl or homopiperidinyl,
(2) piperazinyl,
(3) morpholinyl, thiomorpholinyl or
1,1-dioxo-4-thiomorpholinyl,
(4) pyrroylidinyl,
(5) pyrryl,
(6) imidazolyl,
(7) triazolyl,
(8) saturated azabicyclo of 7 to 12 atoms,
(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated,
(10) tetrazolyl,
(11) pyrazolidinyl,
(12) dihydrodimethozyisoquinolyl,
(13) azetidinyl, or
(14) diazabicyclo ring of 7-12 atoms,
wherein the substituents are each selected from the group consisting of hydrogen and C1-3alkyl, benzyloxycarbonyl, carboxy, phenyl C1-3alkyl amino carbonyl, pyrrolidinylmethyl, hydroxy C1-3 alkyl, C1-6 alkyloxy, C1-4-alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl, and oxo;
or
—N(R7)R8 may be an amino acid residue including natural amino acids such as lysine;
or R8 and R9 are joined together to form a mono or di-substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R8 and R9 are attached;
said rings to include piperazinyl and homopiperazinyl;
or R9 and R10 are joined together to
form a mono or di-substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R9 is attached;
or
wherein R9 and R12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6;
or 7 atoms, said ring having one hetero atom which is the nitrogen to which R9 is attached;
or wherein R10 and R12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms;
or
wherein R8 and R11 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R8 is attached;
and the substituents are independently selected from Hydrogen and C1-3alkyl, thereby treating cyclic or severe congenital neutropenia in a patient in need of such treatment.

129 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/673,588Filed 5 Sep 2008 · us provisional application
Priority: 10 Sep 2007
Published: US 2011/0059960 A110 Mar 2011
Granted: 9 Oct 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

A61K 31/4965
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed pyrazines
A61K 31/36
Having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel: compounds containing methylenedioxyphenyl groups, e.g. sesamin
A61P 35/02
Antineoplastic agents: specific for leukemia
A61K
Medicines and medical preparations

Family

Application60/993,253Us provisional application · filed 10 Sep 2007
US 2011/0059960 A1Pre-grant publication · published 10 Mar 2011
US 8,283,344 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of treating cyclic or severe congenital neutropenia, in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof wherein
R1 is C1-6 alkyl or C1-6 alkoxy-C1-6alkyl;
M is
(1) hydrogen,
(2) C1-6alkyl,
(3) hydroxy C1-6alkyl,
(4) halo C1-6alkyl,
(5) C2-6alkenyl, or
(6) C1-6alkoxy-C1-6alkyl;
Ra and Rb are each individually
(1) hydrogen,
(2) C1-6alkyl,
(3) halo,
(4) carboxy,
(5) C1-6alkoxy,
(6) phenyl,
(7) C1-6alkylcarbonyl,
(8) di-(C1-6alkyl)amino;
(9) hydroxy;
R2 and R3 are each independently
(1) hydrogen,
(2) C1-6alkyl,
(3) halo,
(4) carboxy,
(5) C1-6alkoxy,
(6) phenyl,
(7) C1-6alkylcarbonyl,
(8) aminoC2-3alkyloxy carbonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(9) aminoC2-3alkylamino carbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(10) hydroxy,
(11) aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(12) hydroxymethyl,
(13) aminocarbonyloxy C1-3alkyloxy wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(14) cyano,
(15) morpholinocarbonylphenyl,
(16) amino wherein the amino is optionally mono or di-substituted with C1-6alkyl, with the proviso that R2 and R3 may be joined together to form a methylenedioxy group or a furan ring,
(17) morpholinocarbonyl;
R4 is
(a) Q-C(O)—Y—N(R7)(R8), or
(b) Q-C(O)—ORx, where Rx is carboxyC-16alkyl, benzyloxycarbonylC1-3 alkyl, or t-butoxycarbonylC1-3 alkyl,
wherein
Q is a covalent bond or —C(R5)(R6)—
wherein R5 and R6 are each individually C1-3 alkyl or hydrogen,
Y is
or a covalent bond;
R12 is hydrogen or C1-3alkyl;
R7 and R8 are each individually
(a) hydrogen,
(b) C1-6alkyl,
(c) C1-6alkyloxy C2-3alkyl,
(d) hydroxy C2-6alkyl,
(e) polyhydroxyC2-6alkyl,
(f) carboxamido C1-6alkyl,
(g) polyacyloxyC2-6alkyl
(h) C1-6alkanoyl,
(i) substituted phenyl or phenyl C1-6alkyl, wherein the substitutent is X1 as defined immediately below,
(j) C2-6alkenyl,
(k) C6-10cycloalkenyl,
(l) heteroaryl C1-6alkyl wherein the hetero aryl includes pyridinyl, imidazolyl, triazolyl, benzylimidazolyl, and furyl,
(m) carboxy C1-6alkyl,
(n) carbo C1-6alkoxy C1-3alkyl,
(o) phenylsulfonyl,
(p) C1-6alkylsulfonyl,
(q) benzyloxy,
(r) morpholinyl C1-3alkylsulfonyl,
(s) tetrahydropyranyl,
(t) aminoC1-3alkylsulfonyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(u) aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(v) aminocarbonyloxyC2-6alkyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(w) azabicyclo of 7 to 12 atoms,
(x) di C1-3alkylamino C2-6alkyl wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(y) bicycloalkyl of 7 to 12 atoms,
(z) C3-10cycloalkyl optionally substituted with C1-6alkyl,
(aa) pyrazolidinyl,
(bb) substituted piperidinyl or pyrrolidinyl wherein the substitutent is hydrogen, C1-3 alkyl, hydroxyC1-3 alkylbenzyl, carboxamido or amino wherein the amino is optionally mono or di-substituted with C1-6 alkyl,
(cc) substituted pyrrolidinyl wherein the substitutent is carboxamido or amino wherein the amino is optionally mono or di-substituted with C1-6alkyl,
(dd) pyrimidinyl,
(ee) N-cyano-N′-phenylamidino,
(ff) phosphonoC1-6alkyl, or
(gg) α-C1-3alkyl benzyl or mono or di-substituted benzyl or mono or di-substituted pyridylmethyl, wherein the substitutents are X1 and X2,
wherein
X1 is
(1) hydrogen,
(2) halo,
(3) C1-6alkyl,
(4) halo-C1-6alkyl,
(5) C2-6alkenyl,
(6) hydroxy-C1-6alkyl,
(7) C1-6alkylcarbonyl,
(8) C1-6alkylcarbonylamino;
(9) CN,
(10) CF3,
(11) CH3O,
(12) amino wherein the amino is optionally mono or di-substituted with C1-6 alkyl;
(13) carboxy, or
(14) phenylsulfonylaminocarbonyl;
X2 is hydrogen, halo or C1-6alkyl;
n is 1, 2, 3, 4 or 5;
R9 is selected from hydrogen, C1-4-alkyl, and C1-3alkoxyC1-3alkyl;
or phenyl, phenyl C1-3alkyl, pyridyl, and pyridyl C1-3alkyl;
R10 and R11 are each independently selected from hydrogen, C1-4alkyl, and C1-3 alkoxyC1-3alkyl, or aryl as defined above, or are together oxo;
or
wherein R7 and R8 are joined together to form mono or di-substituted ring of 4, 5, 6, or 7 atoms or 7 to 12 atoms such as
(1) piperidinyl or homopiperidinyl,
(2) piperazinyl,
(3) morpholinyl, thiomorpholinyl or
1,1-dioxo-4-thiomorpholinyl,
(4) pyrroylidinyl,
(5) pyrryl,
(6) imidazolyl,
(7) triazolyl,
(8) saturated azabicyclo of 7 to 12 atoms,
(9) azaspiro having 3 to 9 carbon atoms, said ring being saturated,
(10) tetrazolyl,
(11) pyrazolidinyl,
(12) dihydrodimethozyisoquinolyl,
(13) azetidinyl, or
(14) diazabicyclo ring of 7-12 atoms,
wherein the substituents are each selected from the group consisting of hydrogen and C1-3alkyl, benzyloxycarbonyl, carboxy, phenyl C1-3alkyl amino carbonyl, pyrrolidinylmethyl, hydroxy C1-3 alkyl, C1-6 alkyloxy, C1-4-alkyloxy carbonyl, aminocarbonyl wherein the amino is optionally mono or di-substituted with C1-6 alkyl, and oxo;
or
—N(R7)R8 may be an amino acid residue including natural amino acids such as lysine;
or R8 and R9 are joined together to form a mono or di-substituted saturated monocyclic ring of 6 to 7 atoms and having two hetero atoms which are the nitrogens to which R8 and R9 are attached;
said rings to include piperazinyl and homopiperazinyl;
or R9 and R10 are joined together to
form a mono or di-substituted monocyclic saturated ring of 5 to 7 atoms and having one hetero atom which is the nitrogen to which R9 is attached;
or
wherein R9 and R12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6;
or 7 atoms, said ring having one hetero atom which is the nitrogen to which R9 is attached;
or wherein R10 and R12 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 carbon atoms;
or
wherein R8 and R11 are joined together to form a mono or di-substituted saturated monocyclic ring of 5, 6, or 7 atoms, said ring having one hetero atom which is the nitrogen to which R8 is attached;
and the substituents are independently selected from Hydrogen and C1-3alkyl, thereby treating cyclic or severe congenital neutropenia in a patient in need of such treatment.

129 more elements

Facts

Application

12/673,588Filed 5 Sep 2008 · us provisional application

Priority

10 Sep 2007

Published

US 2011/0059960 A110 Mar 2011

Granted

9 Oct 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

A61K 31/4965
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed pyrazines
A61K 31/36
Having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel: compounds containing methylenedioxyphenyl groups, e.g. sesamin
A61P 35/02
Antineoplastic agents: specific for leukemia
A61K
Medicines and medical preparations