Bicyclic pyrrole derivatives as MCP-1 inhibitors

• US 6,479,527 B1
• Filed: 07/26/2000
• Issued: 11/12/2002
• Est. Priority Date: 02/17/1998
• Status: Expired due to Fees

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Inventors: Barker, Andrew J., Kettle, Jason G., Faull, Alan W
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US09/626,378
• Time in Patent Office: 839 Days
• Field of Search: 548/453, 548/303.1, 548/153, 548/252, 514/412, 514/414, 514/393, 514/367, 514/382
• US Class Current: 514/367
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

A pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt, ester or amide thereof, which is an inhibitor of monocyte chemoattractant protein-1 and wherein A and B together form an optionally substituted 5-member aromatic ring which includes at least one heteroatom; R¹ is an optionally substituted aryl or heteroaryl ring; R² is selected from a range of organic groups including carboxy, and R³ is hydrogen, or a range of organic groups; in combination with a pharmaceutically acceptable carrier. Certain compounds of formula (I) are novel and these form a further aspect of the invention.

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt, ester or amide thereof, which is an inhibitor of monocyte chemoattractant protein-1 and wherein

A and B together form an optionally substituted 5 membered aromatic ring which includes at least one heteroatom;

X is CH₂ or SO₂;

R¹ is an optionally substituted aryl or heteroaryl ring;

R² is carboxy, cyano, —

C(O)CH₂OH, —

CONHR⁴, —

SO₂NHR⁵, tetrazol-5-yl, SO₃H, or a group of formula (VI);

 

where R⁴ is selected from the group consisting of hydrogen, alkyl, aryl, cyano, hydroxy, —

SO₂R⁹ where R⁹ is alkyl, aryl, heteroaryl, or haloalkyl, and a group-(CHR¹⁰)_r—

COOH where r is an integer of 1-3 and each R¹⁰ group is independently hydrogen and alkyl;

R⁵ is alkyl, optionally substituted aryl or optionally substituted heteroaryl or a group COR⁶ where R⁶ is hydrogen, alkyl, aryl, heteroaryl or haloalkyl;

R⁷ and R⁸ are independently hydrogen and alkyl; and

R³ is hydrogen or a functional group selected from the group consisting of halo, cyano, nitro, oxo, C(O)_nR¹¹, OR¹¹, S(O)_mR¹¹, NR¹²R^12′

, C(O)NR¹²R^12′

, OC(O)NR¹²R^12′

, —

CH═

NOR¹¹, —

NR¹²C(O)_nR¹¹, —

NR¹¹CONR¹²R^12′

, —

N═

CR¹²R^12′

, S(O)_mNR¹²R^12′

and —

NR¹²S(O)_mR¹¹ where R¹¹, R¹² and R^12′

are independently hydrogen or optionally substituted hydrocarbyl, or R¹² and R^12′

together form an optionally substituted ring which optionally contains further heteroatoms, n is an integer of 1 or 2, m is 0 or an integer of 1-3, and wherein optional substituents for hydrocarbyl groups R¹¹, R¹² and R^12′

are selected from the group consisting of halo, perhaloalkyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, and oximino, and aryloxy where the aryl group may be substituted by halo, nitro, or hydroxy;

or R³ is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy or optionally substituted cycloalkyl;

subject to the following provisos;

a) that where A—

B forms a group of sub-formula (i) or (iv);

 

where R¹³, R¹⁴ and R¹⁵ are independently hydrogen and a substituent group selected from functional groups as defined in respect to R³, R¹ is other than phenyl, amino phenyl or nitrophenyl; and

b) that where A—

B forms a group of sub-formula (iii);

 

where R¹³ is hydrogen, R¹⁴ is not CHO;

c) that where A—

B a group of sub-formula (v);

where R¹³ and R¹⁴ are as defined above in a), and X is SO₂, R¹ is other than unsubstituted phenyl.

2. A compound according to claim 1 wherein A and B together with the carbon atoms to which they are attached form a 5 membered heteroaryl ring of any one of the sub-formulae:

where R¹³, R¹⁴ and R¹⁵ are independently hydrogen, a functional group as defined in claim 1 with respect to R³, or an optionally substituted hydrocarbyl group selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and cycloalkynyl.

3. A compound according to claim 1 where R¹ is a halo-substituted phenyl or pyridyl group.

4. A compound according to claim 1 wherein in the compound of formula (I), R² is carboxy;

or a pharmaceutically acceptable salt or ester thereof.

5. A compound according to claim 1 wherein R³ is hydrogen, C_1-4alkyl or trifluoromethyl.

6. A compound of formula (IA) or (IB) as claimed in claim 1:

or a pharmaceutically acceptable salt, ester or amide thereof, where R¹ is an optionally substituted aryl or heteroaryl ring, R²⁶ is hydrogen or C_1-4 alkyl, and in formula (IA)

(i) R²⁴ is sulphur and R²⁵ is CH;

or

(ii) R²⁴ is sulphur and R²⁵ is nitrogen;

or

(iii) R²⁴ is oxygen and R²⁵ is CH;

or

(iv) R²⁴ is NCH₃ and R²⁵ is CH;

and in formula (IB)

(i) R^24′

is CH and R^25′

is sulphur;

or

(ii) R^24′

is CH and R^25′

is oxygen;

or

(iii) R^24′

is nitrogen and R^25′

is sulphur.

9. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

15. A method of preparing a compound of formula (I) as defined in claim 1, which method comprises reacting a compound of formula (VII):

where A, B and R³ are as defined in relation to formula (I) and R²⁷ is either hydrogen or a group R² as defined in claim 1 in relation to formula (I);

with compound of formula (VIII);

16. A method according to claim 15, further comprising at least one of the following steps a) and b):

a) converting the group R²⁷ into a group selected from the group consisting of carboxy, cyano, —

C(O)CH₂OH, —

CONHR⁴, —

SO₂NHR⁵, tetrazol-5-yl, SO₃H, and a group of formula (VI);

 

where R⁴ is selected from the group consisting of hydrogen, alkyl, aryl, cyano, hydroxy, —

SO₂R⁹ where R⁹ is alkyl, aryl, heteroaryl, haloalkyl, and a group-(CHR¹⁰)_r—

COOH where r is an integer of 1-3 and each R¹⁰ group is independently hydrogen and alkyl;

R⁵ is alkyl, optionally substituted aryl or optionally substituted heteroaryl or a group COR⁶ where R⁶ is hydrogen, alkyl, aryl, heteroaryl or haloalkyl;

R⁷ and R⁸ are independently hydrogen and alkyl;

b) adding substituents to the A—

B ring or converting substituents into different substituent groups in the A—

B ring.

17. A method according to claim 16, wherein said steps a) and b) are conducted subsequent to reacting the compound of formula (VII) with the compound of formula (VIII).

7. A pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt, ester or amide thereof, which is an inhibitor of monocyte chemoattractant protein-1 and wherein

A and B together form a ring of structure (i);

 

where R¹⁴ and R¹⁵ are independently hydrogen or a functional group selected from the group consisting from halo, cyano, nitro, oxo, C(O)_nR¹¹, OR¹¹, S(O)_mR¹¹, NR¹²R^12′

, C(O)NR¹²R^12′

, OC(O)NR¹²R^12′

, —

CH═

NOR¹¹, —

NR¹²C(O)_nR¹¹, —

NR¹¹CONR¹²R^12′

, —

N═

CR¹²R^12′

, S(O)_mNR¹²R^12′

and —

NR¹²S(O)_mR¹¹ where R¹¹, R¹² and R^12′

are independently hydrogen or optionally substituted hydrocarbyl, or R¹² and R^12′

together form an optionally substituted ring which optionally contains further heteroatoms, n is an integer of 1 or 2, m is 0 or an integer of 1-3, and wherein optional substituents for hydrocarbyl groups R¹¹, R¹² and R^12′

are selected from the group consisting from halo, perhaloalkyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, oximino, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryloxy group, where the aryl group may be substituted by halo, nitro, or hydroxy;

X is CH₂ or SO₂;

R¹ is a halo-substituted phenyl or pyridyl group;

R² is carboxy, cyano, —

C(O)CH₂OH, —

CONHR⁴, —

SO₂NHR⁵, tetrazol-5-yl, SO₃H, or a group of formula (VI);

 

where R⁴ is selected from the group consisting from hydrogen, alkyl, aryl, cyano, hydroxy, and —

SO₂R⁹ where R⁹ is alkyl, aryl, heteroaryl, or haloalkyl or R⁴ is a group-(CHR¹⁰)_r—

COOH where r is an integer of 1-3 and each R¹⁰ group is independently hydrogen and alkyl;

R⁵ is alkyl, optionally substituted aryl or optionally substituted heteroaryl or a group COR⁶ where R⁶ is hydrogen, alkyl, aryl, heteroaryl or haloalkyl;

R⁷ and R⁸ are independently hydrogen and alkyl; and

R³ is hydrogen, or a functional group selected from the group consisting of halo, cyano, nitro, oxo, C(O)_nR¹¹, OR¹¹, S(O)_mR¹¹, NR¹²R^12′

, C(O)NR¹²R^12′

, OC(O)NR¹²R^12′

, —

CH═

NOR¹¹, —

NR¹²C(O)_nR¹¹, —

NR¹¹CONR¹²R^12′

, —

N═

CR¹²R^12′

, S(O)_mNR¹²R^12′

and —

NR¹²S(O)_mR¹¹ where R¹¹, R¹² and R^12′

are independently hydrogen or optionally substituted hydrocarbyl, or R¹² and R^12′

together form an optionally substituted ring which optionally contains further heteroatoms, n is an integer of 1 or 2, m is 0 or an integer of 1-3, and wherein optional substituents for hydrocarbyl groups R¹¹, R¹² and R^12′

are selected from the group consisting of halo, perhaloalkyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, oximino, and aryloxy where the aryl group may be substituted by halo, nitro, or hydroxy;

or R³ is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy or optionally substituted cycloalkyl;

in combination with a pharmaceutically acceptable carrier.

11. A composition according to any one of claims 7 or 8 wherein R² is carboxy;

or a pharmaceutically acceptable salt or ester thereof.

12. A composition according to any one of claims 7 or 8 wherein R³ is hydrogen, C_1-4alkyl or trifluoromethyl.

13. A composition according to any one of claims 7, 8 or 9, wherein R⁵ is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl group.

14. A composition according to any one of claims 7, 8 or 9, wherein R⁷ and R⁸ are independently selected from hydrogen or C_1-4 alkyl.

8. A pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt, ester or amide thereof, which is an inhibitor of monocyte chemoattractant protein-1 and wherein

A and B together with the carbon atoms to which they are attached form a 5 membered heteroaryl ring of any one of the sub-formulae (ii) to (xvii);

 

where R¹³, R¹⁴ and R¹⁵ are independently hydrogen or a functional group selected from the group consisting of halo, cyano, nitro, oxo, C(O)_nR¹¹, OR¹¹, S(O)_mR¹¹, NR¹²R^12′

, C(O)NR¹²R^12′

, OC(O)NR¹²R^12′

, —

CH═

NOR¹¹, —

NR¹²C(O)_nR¹¹, —

NR¹¹CONR¹²R^12′

, —

N═

CR¹²R^12′

, S(O)_mNR¹²R^12′

and —

NR¹²S(O)_mR¹¹ where R¹¹, R¹² and R^12′

are independently hydrogen or optionally substituted hydrocarbyl, or R¹² and R^12′

together form an optionally substituted ring which optionally contains further heteroatoms, n is an integer of 1 or 2, m is 0 or an integer of 1-3, and wherein optional substituents for hydrocarbyl groups R¹¹, R¹² and R^12′

are selected from the group consisting of halo, perhaloalkyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, oximino an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl and aryloxy group where the aryl group may be substituted by halo, nitro, or hydroxy;

X is CH₂ or SO₂;

R¹ is an optionally substituted aryl or heteroaryl ring;

R² is carboxy, cyano, —

C(O)CH₂OH, —

CONHR⁴, —

SO₂NHR⁵, tetrazol-5-yl, SO₃H, or a group of formula (VI);

 

where R⁴ is selected from the group consisting of hydrogen, alkyl, aryl, cyano, hydroxy, —

SO₂R⁹ where R⁹ is alkyl, aryl, heteroaryl, or haloalkyl, and a group-(CHR¹⁰)_r—

COOH where r is an integer of 1-3 and each R¹⁰ group is independently hydrogen or alkyl;

R⁵ is alkyl, optionally substituted aryl, or optionally substituted heteroaryl or a group COR⁶ where R⁶ is hydrogen, alkyl, aryl, heteroaryl or haloalkyl;

R⁷ and R⁸ are independently selected from hydrogen and alkyl; and

R³ is hydrogen, or a functional group selected from the group consisting of halo, cyano, nitro, oxo, C(O)_nR¹¹, OR¹¹, S(O)_mR¹¹, NR¹²R^12′

, C(O)NR¹²R^12′

, OC(O)NR¹²R^12′

, —

CH═

NOR¹¹, —

NR¹²C(O)_nR¹¹, —

NR¹¹CONR¹²R^12′

, —

N═

CR¹²R^12′

, S(O)_mNR¹²R^12′

and —

NR¹²S(O)_mR¹¹ where R¹¹, R¹² and R^12′

are independently hydrogen or optionally substituted hydrocarbyl, or R¹² and R^12′

together form an optionally substituted ring which optionally contains further heteroatoms, n is an integer of 1 or 2, m is 0 or an integer of 1-3, and wherein optional substituents for hydrocarbyl groups R¹¹, R¹² and R^12′

are selected from the group consisting of halo, perhaloalkyl, mercapto, hydroxy, alkoxy, oxo, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, cyano, nitro, amino, mono- or di-alkyl amino, alkylamido, oximino, and aryloxy group where the aryl group may be substituted by halo, nitro, or hydroxy;

or R³ is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy or optionally substituted cycloalkyl;

in combination with a pharmaceutically acceptable carrier.

10. A composition according to claim 8 where R¹ is a halo-substituted phenyl or pyridyl group.