Phosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin

• US 6,384,261 B1
• Filed: 09/03/1998
• Issued: 05/07/2002
• Est. Priority Date: 03/26/1996
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Chan, Ming Fai, Verner, Erik Joel
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US09/146,679
• Time in Patent Office: 1,342 Days
• Field of Search: 558/199, 558/200, 558/201, 564/12, 514/137, 562/809, 206/569
• US Class Current: 558/199
• 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 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 37/06 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 9/247 of aromatic amines (N-C aromatic linkage)
• CPC Class Codes: C07F 9/650905 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/653 Five-membered rings

Abstract

Phosphoramidates and phosphinic amides and related compounds are provided. Also provided are methods that use the compounds for modulating the activity of the endothelin family of peptides are provided. In particular, compounds having formula:

in which A, B, R¹ and R² are as described are provided. Also provided are methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these compounds or prodrugs thereof. Methods for elucidating the physiological and pathophysiological roles of endothelin, as well as isolating endothelin receptors are also provided.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt or ester thereof,

wherein;

Ar¹ is an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among pseudohalide, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring.

2. A compound of claim 1, wherein Ar¹ is selected from naphthyl, phenyl, and biphenyl.

3. A compound of claim 1, wherein:

Ar¹ is a 5 to 6 membered aryl group.

4. A compound of claim 1, wherein Ar¹ is unsubstituted or is substituted with one or more substituents selected from among NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl portions contain from about 4 to about 16 members in the ring.

5. The compounds of claim 1, wherein Ar¹ is selected from:

wherein;

each group is unsubstituted or substituted with one or more substituents R; and

each R, which may be the same or different, is independently selected from NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl and heteroaryl portions contain from about 4 to about 16 members.

6. A compound of claim 5, wherein each R is selected from among H, halide, pseudohalide, alkyl, alkoxy, alkenyl or alkynyl.

9. A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of formula I:

or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable carrier, wherein;

Ar¹ is alkyl, or an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring.

15. The pharmaceutical composition of claim 9 that is formulated for single dosage administration, and comprises an effective amount of one or more of the compounds or pharmaceutically acceptable salts thereof, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

7. A compound of formula I:

or a pharmaceutically acceptable salt or ester thereof,

wherein;

Ar¹ is an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A has the formula Ar²—

X_p and and B has the formula Ar³—

Y_o, wherein;

o and p are independently 0 or 1;

Ar² and Ar³ are each independently selected from aryl and heteroaryl groups;

X and Y are each independently selected from among O, N, NR ³, S or (CH₂)_n in which n is 0 to 10;

R¹³ is hydrogen or a group containing up to about 30 carbon atoms selected from alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁴ and S(O)_nR¹⁴ in which n is 0-2;

R¹⁴ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and

R¹³ and R¹⁴ are unsubstituted or are substituted with one or more substituents each selected independently from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocyclyl, alkoxyalkyl, haloalkyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.

8. A compound of claim 7, wherein Ar² and Ar³ are each independently selected from among phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrrolyl, pyrazinyl, thienyl and furyl.

10. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject in need thereof an effective amount of one or more compounds of formula I:

or pharmaceutically acceptable salts thereof,

wherein;

Ar¹ is alkyl, or an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring; and

wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

11. The method of claim 10, wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylactic shock and hemorrhagic shock.

12. The method of claim 10, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

17. The method of claim 10, wherein the disease is glaucoma.

13. A method for inhibiting the binding of an endothelin peptide to endothelin_A (ET_A) or endothelin_B (ET_B) receptors, comprising contacting the receptors an endothelin peptide and with one or more compounds of formula I:

or pharmaceutically acceptable salts thereof, wherein;

Ar¹ is alkyl or an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring; and

wherein;

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

14. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of formula I:

or pharmaceutically acceptable salts thereof, wherein;

Ar₁ is alkyl, or an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring.

16. An article of manufacture, comprising packaging material and a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein;

Ar¹ is alkyl, or an aryl group containing one ring up to three fused rings and from 3 up to about 21 members in the ring(s); and

A and B are independently selected from among halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, thioalkoxy, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, heteroaryloxy, heteroarylamino, heteroarylthio, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, amido and ureido, in which the alkyl, alkenyl and alkenyl portions contain from 1 up to about 14 carbon atoms, and are either straight or branched chains or cyclic, and in which the aryl and heteroaryl portions contain from 4 to 16 members in the ring, contained within the packaging material, wherein the compound or salt thereof is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC₅₀ of less than about 10 μ

M; and

the packaging material includes a label that indicates that the compound or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.