N, N-disubstituted amides that inhibit the binding of integrins to their receptors

• US 6,194,448 B1
• Filed: 10/14/1999
• Issued: 02/27/2001
• Est. Priority Date: 04/16/1998
• Status: Expired due to Term

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Texas Biotechnology Corporation (Pfizer Inc.)
• Inventors: Scott, Ian L., Lin, Shuqun, Raju, Bore G., Kassir, Jamal M., Kogan, Timothy P., Grabbe, Vanessa O., Market, Robert V., Biediger, Ronald J., Holland, George W., Wu, Chengde
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/417,857
• Time in Patent Office: 502 Days
• Field of Search: 549/60, 549/59, 549/76, 549/441, 514/438, 514/444, 514/466, 514/255, 514/321, 514/338, 514/365, 548/204, 544/377, 546/197, 546/283.7
• US Class Current: 514/438
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 317/60 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 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 333/24 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

A method for the inhibition of the binding of α₄β₁ integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which α₄β₁ is involved.

Claims

1. A compound of the structure

wherein

A is selected from the group consisting of —

O—

, —

S—

, and —

NR⁶—

;

E is selected from the group consisting of —

CH₂—

, —

O—

, —

S—

, and —

NR⁷—

;

each J is independently selected from the group consisting of —

O—

, —

S— and

—

NR⁸—

;

T is selected from the group consisting of —

C(O)— and

—

(CH₂)_b—

wherein b is an integer of from 0 to 3;

s and t are each independently integers of zero to three;

L is selected from the group consisting of —

O—

, —

NR⁹—

, —

S—

, and —

(CH₂)_n—

wherein n is an integer of 0 or 1;

M is selected from the group consisting of —

C(R¹⁰)(R¹¹)— and

—

(CH₂)_u—

wherein u is an integer of from 0 to 3;

X is selected from the group consisting of —

CO₂B, —

PO₃H₂, —

SO₃H, —

OPO₃H₂, —

C(O)NHC(O)R¹², —

C(O)NHSO₂R¹³, oxazolyl, tetrazolyl and hydrogen;

B, R¹, R², R³, 0R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, —

CF₃, nitro, amino, cyano, —

N(C₁-C₃ alkyl)—

C(O)(C₁-C₃ alkyl), —

C₁-C₃ alkylamino, alkenylamino, alkynylamino, di(C₁-C₃ alkyl)amino, —

C(O)O—

(C₁-C₃ alkyl), —

C(O)NH—

(C₁-C₃ alkyl), —

CH═

NOH, —

PO₃H₂, —

OPO₃H₂, —

C(O)N(C₁-C₃ alkyl)₂, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and —

C(O)NH(benzyl);

wherein B, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with at least one electron donating or electron withdrawing group;

and wherein R³ and R⁴ taken together may form a first ring;

R⁵ and R⁹ taken together may form a second ring;

R¹⁰ and R¹¹ taken together may form a third ring;

R¹ and R² taken together may form a fourth ring;

and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals, amides and pro-drugs thereof.

3. A compound of claim 1 wherein

M is — C(R¹⁰)(R¹¹)—

;

X is —

CO₂B;

A is —

NR⁶—

;

E is —

NR⁷—

;

each J is —

O—

;

s and t are each 1;

R¹ and R² are independently selected from the group consisting of hydrogen, aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl and alkyl;

R³ and R⁴ are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, aryl, alkylaryl, arylalkyl, heterocyclyl and alkyl;

R⁵ is selected from the group consisting of aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl and alkyl; and

,

R⁶ and R⁷ are independently selected from the group consisting of hydrogen and lower alkyl.

4. A compound of claim 1 of the structure

wherein X is selected from the group consisting of —

CO₂B, —

PO₃H₂, —

SO₃H, —

OPO₃H₂, —

C(O)NHC(O)R¹², —

C(O)NHSO₂R¹³, oxazolyl, tetrazolyl and hydrogen;

s and t are each independently integers of zero to three; and

B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R₁₀, R¹¹, R¹² and R¹³ are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, —

CF₃, nitro, amino, cyano, —

N(C₁-C₃ alkyl)—

C(O)(C₁-C₃ alkyl), —

C₁-C₃ alkylamino, alkenylamino, alkynylamino, di(C₁-C₃ alkyl)amino, —

C(O)O—

(C₁-C₃ alkyl), —

C(O)NH—

(C₁-C₃ alkyl), —

CH═

NOH, —

PO₃H₂, —

OPO₃H₂, —

C(O)N(C₁-C₃ alkyl)₂, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and —

C(O)NH(benzyl);

wherein B, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with at least one electron donating or electron withdrawing group.

5. A compound of claim 4 wherein

R¹ is selected from the group consisting of methyl, 2-thienylmethyl, 5-methylfuranylmethyl, and butyl;

R² is selected from the group consisting of 2-thienylmethyl, 3-methoxybenzyl, N-(cyclopropylmethyl)aminobenzyl, benzyl, and 5-methylfuranylmethyl; and

,

R⁵ is selected from the group consisting of 1,3-benzodioxol-5-yl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 2,3-dihydro-1-benzofuran-5-yl, phenyl, 4-flurophenyl, 4-methoxyphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4,5-trimethoxyphenyl and 3-chlorophenyl.

6. A compound of claim 4 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals, amides and pro-drugs thereof.

11. A compound of claim 4 wherein R¹ and R² taken together form a ring, and said ring is of the structure

wherein

Y, at each occurrence is independently selected from the group consisting of —

O—

, —

C(O)—

, —

C(R¹⁵)_r—

, —

S—

, —

N(R¹⁶)—

, —

SO₂N(R¹⁷)—

, —

C(O)N(R¹⁸)—

, —

NR¹⁹C(O)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O— and

—

NR²⁰SO₂—

;

R¹⁴, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, —

CF₃, nitro, amino, cyano, —

N(C₁-C₃ alkyl)—

C(O)(C₁-C₃ alkyl), —

C₁-C₃ alkylamino, alkenylamino, alkynylamino, di(C₁-C₃ alkyl)amino, —

C(O)O—

(C₁-C₃ alkyl), —

C(O)NH—

(C₁-C₃ alkyl), —

CH═

NOH, —

PO₃H₂, —

OPO₃H₂, —

C(O)N(C₁-C₃ alkyl)₂, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, hioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and —

C(O)NH(benzyl);

wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ are unsubstituted or substituted with at least one electron donating or electron withdrawing group;

y is an integer of two to eight;

z is an integer of zero to sixteen; and

r is an integer of zero to two.

12. A compound of claim 11 wherein said ring is selected from the group consisting of 4-(2-thienylmethyl)piperazino, 4-(3-thienylmethyl)piperazino, 4-(2-methoxyphenyl)piperazino, 4-(2-thienylcarbonyl)piperazino, 4-(2-thienylsulfonyl)piperazino, 4-phenyl-4-cyano-piperidino and 4-((benzyloxy)carbonyl)piperazino.

13. A compound of claim 11 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals, amides and pro-drugs thereof.

14. A compound of claim 4 wherein R² is methyl and t is zero.

15. A compound of claim 3 selected from the group consisting of:

(3S)-3-(4-(3S)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-4-morpholino-4-oxobutanoic acid, (3R)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-2,2-dimethylpropanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({(1S)-1-[(diallylamino)carbonyl]pentyl}amino)carbonyl]amino}propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({(1S)-1-[(diisobutylamino)carbonyl]pentyl}amino)carbonyl]amino}propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[bis(3-methoxybenzyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1S)-1-((bis(2-thienylmethyl)amino)carbonyl)pentyl)amino)carbonyl)(methyl)amino)propanoic acid, (3S)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-3-(2-thienyl)propanoic acid, (3S)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-3-(3-methoxyphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[4-(2-thienylsulfonyl)piperazino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising:

a compound of claim 1

in a pharmaceutically acceptable carrier.

17. A method for selectively inhibiting α

₄β

₁ integrin binding in a mammal comprising administering to said mammal a therapeutic amount of a compound of claim 1.

7. A compound of the structure

wherein

s is zero or one;

R¹ and R² are each independently selected from the group consisting of alkyl, 2-thienyl, methoxyphenyl and phenyl; and

R⁵ is selected from the group consisting of 1,3-benzodioxol-5-yl, dimethoxyphenyl, 2,3-dihydro-1-benzofuran-5-yl, fluorophenyl, and methoxyphenyl;

and pharmaceutically acceptable salts thereof.

8. A compound of claim 7 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals, amides and pro-drugs thereof.

9. A compound selected from the group consisting of:

(3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1-[methyl(2-thienylmethyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1-[methyl(3-methoxybenzyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, (3S)-3-(3,5-dimethoxyphenyl)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, (3S)-3-(2,3-dihydro-1-carbonyl}amino)propanoic acid, (3S)-3-(4-fluorophenyl)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, (3S)-3-(4-methoxyphenyl)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[butyl(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1S)-1-((bis(2-thienylmethyl)amino)carbonyl)pentyl)amino) carbonyl)amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[(1,3-thiazol-2-ylmethyl)(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)propanoic acid and pharmaceutically acceptable salts thereof.

10. A compound of claim 9 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals, amides and pro-drugs thereof.