BENZAMIDE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS

• US 20090029991A1
• Filed: 09/16/2008
• Published: 01/29/2009
• Est. Priority Date: 04/05/2002
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Stokes, Elaine Sophie Elizabeth, Waring, Michael James, Roberts, Craig Anthony
• Application Number:
  US12/211,510
• Publication Number:
  US 20090029991A1
• Time in Patent Office: Days
• US Class Current: 514/234.200
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 237/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/26 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 251/18 with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 277/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/54 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention concerns a compound of the formula (I)

wherein Ring A is heterocyclyl; m is 0-4 and each R¹ is a group such as hydroxy, halo, trifluoromethyl and cyano; R² is halo and n is 0-2; and each R⁴ is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R³ is amino or hydroxy;
or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof,
processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by histone deacetylase.

Claims

1. A compound of the formula (I):

2. A compound of the formula (I) according to claim 1 wherein:

R¹ is a substituent on carbon and is selected from halo, amino, C_1-6alkyl, C_1-6alkoxy, N—

(C_1-6alkyl)amino, aryl, aryloxy, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl, or a group (B-E-);

wherein R¹, including group (B-E-), may be optionally substituted on carbon by one or more W; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by J;

W is hydroxy, mercapto, C_1-6alkyl, C_1-6alkoxy, N,N—

(C_1-6alkyl)₂-amino or a group (B′

-E′

-);

wherein W, including group (B′

-E′

-), may be optionally substituted on carbon by one or more Y;

Y and Z are independently selected from halo, nitro, cyano, hydroxy, C_1-6alkoxy, N,N—

(C_1-6alkyl)₂-amino or C_1-6alkanoylamino;

G, J and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_1-8alkanoyl, aryl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by hydrogen or C_1-6alkyl;

Q is cyano, hydroxy, C_1-6alkoxy, C_1-6alkanoyloxy, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, aryl, aryloxy or a group (B″

-E″

-);

wherein Q, including group (B″

-E″

-), may be optionally substituted on carbon by one or more Z;

B, B′ and

B″

are independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_3-8cycloalkylC_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl, phenyl or phenylC_1-6alkyl;

wherein B, B′ and

B″

may be optionally substituted on carbon by one or more D; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)C(O)O—

, —

OC(O)N(R^a)—

, —

C(O)N(R^a)—

, —

S(O)_r—

, —

SO₂N(R^a)—

, —

N(R^a)SO₂—

;

wherein R^a and R^b are independently selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2;

D and F are independently selected from halo, C_1-6alkoxy or N,N—

(C_1-6alkyl)₂-amino.

3. A compound of the formula (I) according to claim 1 wherein m is 1.

4. A compound of the formula (I) according to claim 1 wherein R² is fluoro and n is 0 or 1.

5. A compound of the formula (I) according to claim 1 wherein R³ is amino.

6. A compound of the formula (I) according to claim 1 wherein p is 0.

7. A compound of formula (I) according to claim 1 wherein:

Ring A is piperidinyl, wherein nitrogen within the piperidinyl ring can be optionally substituted by K;

R¹ is a substituent on carbon and is selected from halo, amino, C_1-6alkyl, C_1-6alkoxy, N—

(C_1-6alkyl)amino, aryl, aryloxy, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl, or a group (B-E-);

wherein R¹, including group (B-E-), may be optionally substituted on carbon by one or more W; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by J;

W is hydroxy, mercapto, C_1-6alkyl, C_1-6alkoxy, N,N—

(C_1-6alkyl)₂-amino or a group (B′

-E′

-);

wherein W, including group (B′

-E′

-), may be optionally substituted on carbon by one or more Y;

Y and Z are independently selected from halo, nitro, cyano, hydroxy, C_1-6alkoxy, N,N—

(C_1-6alkyl)₂-amino or C_1-6alkanoylamino;

G, J and K are independently selected from C_1-8alkyl, C_2-8alkenyl, C_1-8alkanoyl, aryl, arylC_1-6alkyl or (heterocyclic group)C_1-6alkyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by hydrogen or C_1-6alkyl;

Q is cyano, hydroxy, C_1-6alkoxy, C_1-6alkanoyloxy, C_1-6alkoxycarbonyl, C_1-6alkoxycarbonylamino, aryl, aryloxy or a group (B″

-E″

-);

wherein Q, including group (B″

-E″

-), may be optionally substituted on carbon by one or more Z;

B, B′ and

B″

are independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, C_3-8cycloalkylC_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic group, (heterocyclic group)C_1-6alkyl, phenyl or phenylC_1-6alkyl;

wherein B, B′ and

B″

may be optionally substituted on carbon by one or more D; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)O—

, —

OC(O)—

, —

C(O)—

, —

N(R^a)C(O)—

, —

N(R^a)C(O)N(R^a)—

, —

N(R^a)C(O)O—

, —

OC(O)N(R^a)—

, —

C(O)N(R^a)—

, —

S(O)_r—

, —

SO₂N(R^a)—

, —

N(R^a)SO₂—

;

wherein R^a and R^b are independently selected from hydrogen or C_1-6alkyl optionally substituted by one or more F and r is 0-2;

D and F are independently selected from halo, C_1-6alkoxy or N,N—

(C_1-6alkyl)₂-amino;

m is 0, 1, 2, 3 or 4;

wherein the values of R¹ may be the same or different;

R² is fluoro or chloro;

n is 0, 1 or 2, wherein the values of R² may be the same or different;

R³ is amino or hydroxy;

R⁴ is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl;

p is 0, 1 or 2, wherein the values of R⁴ may be the same or different;

or a pharmaceutically acceptable salt thereof.

8. A compound of formula (I) according to claim 1 wherein:

Ring A piperidinyl, wherein nitrogen within the piperidinyl ring can be optionally substituted by K;

R¹ is a substituent on carbon and is selected from fluoro, chloro, amino, methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl, naphthylethyl, piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 2-(thiomethyl)-pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1,2,5-thiadiazol-3-ylethyl, piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-E-);

wherein R¹, including group (B-E-), may be optionally substituted on carbon by one or more W; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by J;

W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino, N,N-(dibutyl)amino, or a group (B′

-E′

-);

wherein W, including group (B′

-E′

-), may be optionally substituted on carbon by one or more Y;

Y and Z are independently selected from fluoro, chloro, bromo, nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino or methylcarbonylamino;

G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl, 3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl;

wherein G, J and K may be optionally substituted on carbon by one or more Q; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by hydrogen or methyl;

Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl, t-butoxycarbonylamino, phenyl or a group (B″

-E″

-);

wherein Q, including group (B″

-E″

-), may be optionally substituted on carbon by one or more Z;

B, B′ and

B″

are independently selected from methyl, ethyl, propyl, cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl, 3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl;

wherein B, B′ and

B″

may be optionally substituted on carbon by one or more D; and

wherein if said heterocyclic group contains an —

NH—

moiety that nitrogen may be optionally substituted by a group selected from G;

E, E′ and

E″

are independently selected from —

N(R^a)—

, —

O—

, —

C(O)—

, —

NHC(O)—

, —

N(R^a)C(O)O—

;

wherein R^a is hydrogen or methyl optionally substituted by one or more F;

D and F are independently selected from fluoro, methoxy or ethoxy;

m is 0, 1, or 2;

wherein the values of R¹ may be the same or different;

R² is fluoro;

n is 0 or 1;

R³ is amino;

R⁴ is halo;

p is 0, 1 or 2, wherein the values of R⁴ may be the same or different;

or a pharmaceutically acceptable salt thereof.

9. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, which process comprises of:

(a) the reaction of a compound of the formula (II)

10. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.

11. A method of treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1.

12. A compound of formula (I) according to claim 1 wherein m is 0, 1 or 2;

wherein the values of R¹ are the same or different, n is 0;

R³ is amino and p is 0.