N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase

• US 6,846,836 B2
• Filed: 04/18/2003
• Issued: 01/25/2005
• Est. Priority Date: 04/18/2003
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Pudzianowski, Andrew T., Hamann, Lawrence G.
• Primary Examiner(s): Henley, III, Raymond J.
• Application Number:
  US10/419,286
• Publication Number:
  US 20040209821A1
• Time in Patent Office: 648 Days
• Field of Search: 514/317
• US Class Current: 514/317
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds having the formula (I),
are useful as inhibitors of mitochondrial F₁F₀ ATP hydrolase, wherein R¹-R⁸, X, A, Z, n and m are defined herein.

Claims

1. A method of treating a mitochondrial F₁F₀ ATP hydrolase associated disorder selected from myocardial infarction;

ventricular hypertrophy;

coronary artery disease;

non-Q wave MI;

congestive heart failure;

cardiac arrhythmias;

unstable angina;

chronic stable angina;

Prinzmetal'"'"'s angina;

high blood pressure;

intermittent claudication;

peripheral occlusive arterial disease;

thrombotic or thromboembolic symptoms of thromboembolic stroke;

venous thrombosis;

arterial thrombosis;

cerebral thrombosis;

pulmonary embolism;

cerebral embolism;

thrombophilia;

disseminated intravascular coagulation;

restenosis;

atrial fibrillation;

ventricular enlargement;

atherosclerotic vascular disease;

atherosclerotic plague rupture;

atherosclerotic plague formation;

transplant atherosclerosis;

vascular remodeling atherosclerosis;

cancers having tumor cells that do not exhibit the Warburg effect;

inflammation;

systematic infection;

thromboembolic complications of surgery, artificial surfaces, interventional cardiology, immobility, medication, pregnancy and/or fetal loss; and

diabetic complications comprising retinopathy, nephropathy and neuropathy in a mammal comprising administering to the patient in need of such treatment an effective amount of at least one compound having the formula (I);

their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein;

X is selected from O or S;

A is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;

n and mare 0, 1, or 2

R¹ through R⁵ are independently selected from hydrogen, halogen, NO₂, CN, C_1-8alkyl, substituted C_1-8alkyl, C_3-8cycloalkyl, aryl, heterocyclo, heteroaryl, OR⁹, SR⁹, COR¹¹, CO₂R¹¹, CONR⁹R¹⁰ or NR⁹R¹⁰;

R⁶ and R⁷ are independently hydrogen, alkyl or substituted alkyl;

R⁸ is hydrogen;

C_1-8alkyl, substituted C_1-8alkyl, aryl, heterocyclo or heteroaryl;

Z is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, COR¹¹, CO₂R¹¹, SO₂R¹¹, S(O)R¹¹ or CONR⁹R¹⁰;

R⁹ and R¹⁰ are independently hydrogen, C_1-8alkyl, substituted C_1-8alkyl, C_3-10cycloalkyl, aryl, heterocyclo, heteroaryl, COR¹³, SO₂R¹³ or S(O)R¹³; and

R¹¹, R¹² and R¹³ are independently hydrogen, C_1-8alkyl, substituted C_1-8alkyl, C_3-10cycloalkyl, aryl, heterocyclo or heteroaryl;

wherein each occurrence of R⁹-R¹³ is chosen independently.

2. The method of claim 1 wherein n and m are both 1.

3. The method of claim 1 wherein R², R³ and R⁴ are all hydrogen.

4. The method of claim 1 wherein R⁶ and R⁷ are both hydrogen.

5. The method of claim 1 wherein R¹ and R⁵ are independently C_1-8alkyl.

6. The method of claim 5 wherein R¹ and R⁵ are both isopropyl.

7. The method of claim 1 wherein

Z is C_1-8alkyl, C_2-8alkenyl, C_1-8haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl —

COR¹¹, —

CO₂R¹¹, —

SO₂R¹¹, —

S(O)R¹¹ or —

CONR⁹R¹⁰;

R⁹ is hydrogen,

R¹⁰ is C_1-8alkyl or C_3-10cycloalkyl;

aryl or arylalkyl; and

R¹¹ is hydrogen, C_1-8alkyl, C_3-10cycloalkyl, C_3-10heterocycloalkyl, C_3-10aryl or C_3-10arylalkyl.

8. The method of claim 7 wherein Z is benzyl, —

C(O)₂H, or —

C(O)₂C₁-C₈alkyl.

9. The method of claim 1 wherein:

A is hydrogen, C_1-8alkyl, heteroaryl, aryl, or alkyl substituted with heterocyclo, aryl, OH, SH, ST¹, —

C(O)_tH, T³-NT⁵T⁶, -T⁸-C(O)_tT⁹-NT⁵T⁶ or T³-N(T²)T⁴NT⁵T⁶;

T¹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;

T² and T³ are each independently a single bond, -T⁸-S(O)_t-T⁹-, -T⁸-C(O)-T⁹-, -T¹⁸-C(S)-T⁹-, -T⁸-O-T⁹-, -T⁸-S-T⁹-, -T⁸-O—

C(O)-T⁹-, -T⁸-C(O)_tT⁹-, -T⁸-C(═

NT¹⁰)-T⁹- or -T⁸-C(O)—

C(O)-T⁹-;

T⁵, T⁶, T⁷, T⁸ and T⁹ are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, —

SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, —

OT¹¹, —

ST¹¹, —

C(O)_tH, —

C(O)_tT¹¹, —

O—

C(O)T¹¹, T⁸C(O)_tN(T¹²)T¹¹, —

SO₃H, —

S(O)_tT¹¹, S(O)_tN(T¹²)T¹¹, -T¹³-NT¹¹T¹², -T¹³-N(T¹²)-T⁴-NT¹¹T²², -T¹³-N(T¹¹)-T¹²-T¹¹ and -T¹³-N(T¹⁸)-T¹⁴-H;

or

T⁸ and T⁹ are each independently a single bond, alkylene, alkenylene or alkynylene;

T¹¹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;

T¹² is halo, cyano, nitro, OH, oxo, —

SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, —

C(O)_tH or —

SO₃H;

T¹³ and T¹⁴ are each independently a single bond, —

S(O)_t—

, —

C(O)—

, —

C(S)—

, —

O—

, —

S—

, —

O—

C(O)—

, —

C(O)_t—

, —

C(═

NT¹³)- or —

C(O)—

C(O)—

;

wherein each occurrence of T¹-T¹⁴ is chosen independently; and

t is 1 or 2.

10. The method of claim 9 wherein A is hydrogen, methyl, —

CH₂(CH₃)₂, —

(CH₂)₂(CH₃)₂, —

CH(CH₃)CH₂(CH₃), —

(CH₂)OH, hydroxyethyl, —

(CH₂)₂SCH₃, —

CH₂SH, phenyl, —

CH₂(phenyl), —

CH₂(p-hydroxyphenyl), —

CH₂(indole), —

(CH₂)C(O)NH₂, —

(CH₂)₂C(O)NH₂, —

(CH₂)₂C(O)OH, —

CH₂C(O)OH, —

(CH₂)₄NH₂, —

(CH₂)₃(═

NH)CNH₂ or —

CH₂(imidazole).

11. The method of claim 10 wherein A is —

CH(CH₃)CH₂(CH₃), phenyl, phenylalkyl or —

CH₂(2-indole).

12. The method of claim 10 wherein R⁸ is hydrogen and the configuration about the carbon marked with the * is S.

20. The method of claim 1 comprising administering to the patient in need of such treatment an effective amount of at least one compound having the formula:

i. (1S)-1-[1-Benzyl-2-(4-benzylpiperidin-1-yl)-2-oxo-ethyl]-3-(2,6-diisopropylphenyl)-urea;

(1S)-1-[1-Benzyl-2-(4-ethoxycarbonylpiperidin-1-yl)-2-oxo-ethyl]-3-(2,6-diisopropylphenyl)-urea;

(1S)-1-[1-Phenyl-2-(4-benzylpiperidin-1-yl)-2-oxo-ethyl]-3-(2,6-diisopropylphenyl)-urea;

or

(1S)-1-[1-Phenyl-2-(4-ethoxycarbonylpiperidin-1-yl)-2-oxo-ethyl]-3-(2,6-diisopropylphenyl)-urea;

or

ii. a pharmaceutically acceptable salt, prodrug or solvate thereof.

21. The method according to claims 1 or 13 wherein the F₁F₀ ATP hydrolase associated disorder is an acute coronary syndrome selected from myocardial infarction, congestive heart failure, and cardiac arrhythmias.

13. A method of treating a mitochondrial F₁F₀ ATP hydrolase associated disorder in a mammal selected from myocardial infarction;

ventricular hypertrophy;

coronary artery disease;

non-Q wave MI;

congestive heart failure;

cardiac arrhythmias;

unstable angina;

chronic stable angina;

Prinzmetal'"'"'s angina;

high blood pressure;

intermittent claudication;

peripheral occlusive arterial disease;

thrombotic or thromboembolic symptoms of thromboembolic stroke;

venous thrombosis;

arterial thrombosis;

cerebral thrombosis;

pulmonary embolism;

cerebral embolism;

thrombophilia;

disseminated intravascular coagulation;

restenosis;

atrial fibrillation;

ventricular enlargement;

atherosclerotic vascular disease;

atherosclerotic plague rupture;

atherosclerotic plague formation;

transplant atherosclerosis;

vascular remodeling atherosclerosis;

cancers having tumor cells that do not exhibit the Warburg effect;

inflammation;

systematic infection;

thromboembolic complications of surgery, artificial surfaces, interventional cardiology, immobility, medication, pregnancy and/or fetal loss; and

diabetic complications comprising retinopathy, nephropathy and neuropathy comprising administering to the patient in need of such treatment an effective amount of at least one compound having the formula (II);

their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein;

A is hydrogen, C_1-8alkyl, heteroaryl, aryl, or alkyl substituted with heterocyclo, aryl, OH, SH, ST¹, —

C(O)_tH, T³-NT⁵T⁶, -T⁸-C(O)_tT⁹-NT⁵T⁶ or T³-N(T²)T⁴NT⁵T⁶;

R¹ and R⁵ are independently C_1-8alkyl optionally substituted where valence allows;

R⁶ and R⁷ are independently hydrogen or C_1-8alkyl;

R⁸ is hydrogen, C_1-8alkyl or substituted C_1-8alkyl;

Z is hydrogen, C_1-8alkyl, C_2-8alkenyl, C_1-8haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl —

COR¹¹, —

CO₂R¹¹, —

SO₂R¹¹, —

S(O)R¹¹ or —

CONR⁹R¹⁰;

R⁹ is hydrogen,

R¹⁰ is C_1-8alkyl or C_3-10cycloalkyl;

aryl or arylalkyl;

R¹¹ is hydrogen, C_1-8alkyl, C_3-10cycloalkyl, C_3-10heterocycloalkyl, C_3-10aryl or C_3-10arylalkyl;

T¹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;

T² and T³ are each independently a single bond, -T⁸-S(O)_t-T⁹-, -T⁸-C(O)-T⁹-, -T¹⁸-C(S)-T⁹-, -T⁸-O-T⁹-, -T⁸-S-T⁹-, -T⁸-O—

C(O)-T⁹-, -T⁸-C(O)_tT⁹-, -T⁸-C(═

NT¹⁰)-T⁹- or -T⁸-C(O)—

C(O)-T⁹-;

T⁵, T⁶, T⁷, T⁸ and T⁹ are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, —

SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, —

OT¹¹, —

ST¹¹, —

C(O)_tH, —

C(O)_tT¹¹, —

O—

C(O)T¹¹, T⁸C(O)_tN(T¹²)T¹¹, —

SO₃H, —

S(O)_tT¹¹, S(O)_tN(T¹²)T¹¹, -T¹³-NT¹¹T¹², -T¹³-N(T¹²)-T⁴-NT¹¹T²², -T¹³-N(T¹¹)-T¹²-T¹¹ and -T¹³-N(T¹⁸)-T¹⁴-H;

or

T⁸ and T⁹ are each independently a single bond, alkylene, alkenylene or alkynylene;

T¹¹ is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;

T¹² is halo, cyano, nitro, OH, oxo, —

SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, —

C(O)_tH or —

SO₃H;

T¹³ and T¹⁴ are each independently a single bond, —

S(O)_t—

, —

C(O)—

, —

C(S)—

, —

O—

, —

S—

, —

O—

C(O)—

, —

C(O)_t—

, —

C(═

NT¹³)- or —

C(O)—

C(O)—

; and

t is 1 or 2.

14. The method of claim 13 wherein A is hydrogen, methyl, —

CH₂(CH₃)₂, —

(CH₂)₂(CH₃)₂, —

CH(CH₃)CH₂(CH₃), —

(CH₂)OH, hydroxyethyl, —

(CH₂)₂SCH₃, —

CH₂SH, phenyl, —

CH₂(phenyl), —

CH₂(p-hydroxyphenyl), —

CH₂(indole), —

(CH₂)C(O)NH₂, —

(CH₂)₂C(O)NH₂, —

(CH₂)₂C(O)OH, —

CH₂C(O)OH, —

(CH₂)₄NH₂, —

(CH₂)₃(═

NH)CNH₂ or —

CH₂(imidazole).

15. The method of claim 14 wherein A is —

CH(CH₃)CH₂(CH₃), phenyl, CH₂(phenyl) or —

CH₂(2-indole).

16. The method of claim 14 wherein R⁸ is hydrogen and the configuration about the carbon marked with the * is S.

17. The method of claim 13 wherein R¹ and R⁵ are both isopropyl.

18. The method of claim 13 wherein R⁶ R⁷ and R⁹ are all hydrogen.

19. The method of claim 13 wherein Z is CH₂(phenyl), —

C(O)₂H, or —

C(O)₂C₁-C₈alkyl.