Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin

• US 5,804,585 A
• Filed: 04/15/1996
• Issued: 09/08/1998
• Est. Priority Date: 04/15/1996
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Texas Biotechnology Corporation (Pfizer Inc.)
• Inventors: Verner, Erik Joel
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/632,586
• Time in Patent Office: 876 Days
• Field of Search: 546/114, 546/116, 546/113, 544/238, 548/245, 548/240, 514/301, 514/302, 514/300, 514/380
• US Class Current: 514/301
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/4743 condensed with ring systems having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

Methods, compositions, and compounds for modulating the activity of an endothelin peptide are provided. The methods use compositions that contain compounds that include those of the formula: ##STR1## where X is selected from groups that include O, S, and NH; Y is selected from O⁺ and N, and R¹ and R² are each selected independently from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H, except that R² is not halide. R³, R⁴ and R⁵ are selected from among groups that include hydrogen, halide, alkoxy, alkyl, haloalkyl; and R⁷ is selected from groups that include (CH₂)_r R¹⁸, in which r is 0 to 6 and R¹⁸ is selected from groups that include aryl, particularly pyrmidinyl and phenyl. The methods are effected by contacting endothelin receptors with one or more of the compounds or with compositions containing one or more of the compounds prior to, simultaneously with, or subsequent to contacting the receptors with an endothelin peptide.

Claims

1. A sulfonamide compound of formula (I) ##STR10## wherein:

Ar¹, which contains from 1 to 30 carbon atoms, is selected from the group consisting of optionally substituted alkyl groups, aryl groups and heteroaryl groups;

wherein the aryl and heteroaryl groups include single rings, fused bicyclic or tricyclic rings; and

the alkyl groups are straight or branched chains or straight or branched chains that include cyclic portions; and

Ar² is a group of formula;

##STR11## Y is N or O⁺ ;

X is S, O, or NR¹¹ in which R¹¹, which is hydrogen or contains up to about 30 carbon atoms, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ and S(O)_n R¹⁵ in which n is 0-2; and

R¹⁵, which is selected independently from R¹¹, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

R³, R⁴ and R⁵ are selected from (i), (ii), (iii) or (iv);

(i) R³, R⁴ and R⁵ are each selected independently from among H, NHOH, NH₂, NO₂, N₃, halide, pseudohalide, alkyl, alkenyl, alkynyl, alkenyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl, amido, where the alkyl, alkenyl, alkynl portions are straight or branched chains of from about 1 up to about 10 carbons, and the aryl portions contain from 3 up to about 10 carbons;

or, alternatively,

(ii) two of R³, R⁴ and R⁵ form 1,3-butadienyl, 4-dimethylamino-1,3 butadiene, 1-chloro-1,3-butadiene, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups or form alkylenedioxy; and

the other of R³, R⁴ and R⁵ is as defined in (i)

(iii) two of R³, R⁴ and R⁵ are independently selected from alkyl, alkoxy, halide aminoalkyl, dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10, preferably 1 to 6 carbons, and are straight or branched chains and the other is H;

or

(iv) any two of R³, R⁴ and R⁵, which are each selected as in (i), form fused carbocyclic or heterocyclic rings and the other is selected as in (i); and

R⁷ is hydrogen or contains up to about 50 carbon atoms, generally up to about 30, more generally 20 or fewer, and is selected hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, CO₂ R¹⁸, SH, S(O)_n, (CH₂)_r, (CH₂)_r R¹⁸, S(O)_n R¹⁸ in which n is 0-2, and r is 0 to 6, HNOH, NR¹⁸ R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹ NCOR¹⁸ and CONR¹⁹ R¹⁸, in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_n R²⁰ in which n is 0-2; and

R¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and

any of the groups set forth for R⁷ is unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂ R²¹, SH, S(O)_n R²¹ in which n is 0-2, NHOH, NR²² R²¹, NO₂, N₃, OR²¹, R²² NCOR²¹ and CONR²² R²¹ ;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)_n R²³ in which n is 0-2; and

R²¹ and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl.

2. A compound of claim 1 in which Ar¹ is an alkyl group or is a 5- or 6-membered substituted or unsubstituted aromatic or heteroaromatic ring.

3. A compound of claim 2, wherein is Ar¹ is isoxazolyl, pyridazinyl, pyrimidinyl, phenyl or benzyl.

4. A compound of claim 1, wherein Ar¹ is selected from alkyl, ##STR12## and R is selected from H, NH₂, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, are unsubstituted or substituted with any of the preceding groups, and straight or branched chains of from about 1 up to about 14 carbons.

5. A compound of claim 1 in which Ar¹ is an isoxazolyl.

6. A compound of claim 5 that has the formula II:

##STR13## in which Y is N;

X is S, O, NR¹¹ in which R¹¹, which is hydrogen or contains up to about 30 carbon atoms, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ and S(O)_n R¹⁵ in which n is 0-2; and

R¹⁵, which is selected independently from R¹¹, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

R¹ and R² are either (i), (ii) or (iii) as follows;

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, 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 portions contain from about 4 to about 16 carbons, except that R² is not halide or pseudohalide;

or,

(ii) R¹ and R² together form --(CH₂)_n, where n is 3 to 6;

or,

(iii) R¹ and R² together form 1,3-butadienyl.

7. A compound of claim 6, wherein R¹ is lower alkyl or halide;

R² is loweralkyl, halo loweralkyl, or hydrogen, and R¹¹ is hydrogen or aryl.

8. A compound of claim 5 that has the formula IV:

##STR14##

9. A compound of claim 5 that has the formula III:

##STR15##

10. A compound of claim 8, wherein:

R⁷ is R¹⁸, C(O)R¹⁸, CO₂ R¹⁸, (CH₂)_r R¹⁸, (CH₂)_r COR¹⁸ (CH₂)_r CO(CH₂)_s R¹⁸, NR¹⁸ R¹⁹, OR¹⁸, R¹⁹ NCOR¹⁸ or CONR¹⁹ R¹⁸ ; and

s and r are each independently selected from is 0 to 6.

11. A compound of claim 10, wherein either or both of R¹⁸ or R¹⁹ is aryl or heteroaryl.

12. A compound of claim 9, wherein:

R⁷ is R¹⁸, C(O)R¹⁸, CO₂ R¹⁸, (CH₂)_r R¹⁸, (CH₂)_r COR¹⁸ (CH₂)_r CO(CH₂)_s R¹⁸, NR¹⁸ R¹⁹, OR¹⁸, R¹⁹ NCOR¹⁸ or CONR¹⁹ R¹⁸ ; and

s and r are each independently selected from is 0 to 6.

13. A compound of claim 12, wherein either or both of R¹⁸ or R¹⁹ is aryl or heteroaryl.

14. A compound of claim 11, wherein either or both of R¹⁸ or R¹⁹ is phenyl:

##STR16## that is unsubstituted or substituted at positions 2-6 with R³², R³³, R³⁴, R³⁵ and R³⁶, respectively, which are each independently selected from (i), (ii) or (iii) as follows;

(i) R³², R³³, R³⁴, R³⁵, and R³⁶ are each independently selected from among H, NHR³⁸, CONR³⁸, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R³⁸ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

or

(ii) at least two of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R³², R³³, R³⁴, R³⁵ and R³⁶ are selected as in (i);

or

(iii) at least two of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of the others of R³³, R³⁴, R³⁵, and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the other of R³², R³³, R³⁴, R³⁵ and R³⁶ is selected as in (i).

15. A compound of claim 13, wherein R⁷ is phenyl:

##STR17## that is unsubstituted or substituted at positions 2-6 with R³², R³³, R³⁴, R³⁵ and R³⁶, respectively, which are each independently selected from (i), (ii) or (iii) as follows;

(i) R³², R³³, R³⁴, R³⁵, and R³⁶ are each independently selected from among H, NHR³⁸, CONR³⁸, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, aminocarbonyl, carboxy, carboxyalkyl, carboxyalkenyl, and formyl, where R³⁸ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

or

(ii) at least two of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the others of R³², R³³, R³⁴, R³⁵ and R³⁶ are selected as in (i);

or

(iii) at least two of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and at least two of the others of R³³, R³⁴, R³⁵, and R³⁶ are substituting adjacent carbons on the ring and together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo(lower)alkyl, and the other of R³², R³³, R³⁴, R³⁵ and R³⁶ is selected as in (i).

16. A compound of claim 15, wherein least one of R³², R³³, R³⁴, R³⁵ and R³⁶ is H and the others are selected from among (i), (ii) or (iii) as follows:

(i) alkoxy, halo, alkylcarbonyl, formyl, and alkyl, in which the alkyl portions or groups contain from 1 to 3 carbons, provided that at least one of R³², R³³, R³⁴, R³⁵, and R³⁶ is H;

(ii) at least two of R³², R³³, R³⁴, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons and together form alkylenedioxy and the one of the others of R³², R³³, R³⁴, R³⁵ and R³⁶ are selected as set forth in (i);

or

(iii) at least two of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons and together form alkylenedioxy, and at least two of the others of R³², R³³, R³⁴, R³⁵ and R³⁶ are substituting adjacent carbons and together form alkylenedioxy, and the other of R³², R³³, R³⁴, R³⁵ and R³⁶ is H.

17. A compound of claim 12, wherein:

R¹⁸ or R¹⁹ is pyrimidinyl.

18. A compound of claim 13, wherein R⁷ is (CH₂)_r R¹⁸, R¹⁸ is phenyl and at least two of R³², R³³, R³⁴, R³⁵, and R³⁶ are on adjacent carbons and form alkylenedioxy, one or two of R³², R³³, R³⁴, R³⁵, and R³⁶ are lower alkyl, lower alkoxy, methoxy, or methyl, and the others of R³², R³³, R³⁴, R³⁵, and R³⁶ are hydrogen.

19. A compound of claim 5, wherein Y is N, and X is S or O.

20. A compound of claim 1 that is selected from the group consisting of N-(4-chloro-3-methyl-5-isoxazolyi)-2-ethylthieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-5-methyl-3-isoxazolyi)-2-ethylthieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (3,4-methylenedioxy)benzoyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (3,4-methylenedioxy)benzyl)!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (4,5-methylenedioxy)-2-methylbenzyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (2,4-dimethyl)benzyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-5-methyl-3-isoxazolyl)-2- (4,5-methylenedioxy)-2-methylbenzyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- 2-(2-hydroxyethyl)-4,5-(methylenedioxy)benzyl!thieno 2,3-b!-pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- 1-naphthalene-methyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- (2,6-dimethoxy)benzyl!thieno 2,3-b!pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2- 3-(3,4 methylenedioxyphenyl)propionyl!thieno 2,3-b!pyridine-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(4,5-methylenedioxy)-2- (hydroxyethyl)benzyl!}thieno 2,3-b!pyridine-3-sulfonamide.

21. The compound of claim 1 that has formula:

##STR18## wherein Ar² has the structure;

##STR19##

22. A method for the treatment of endothelin-mediated diseases, comprising administering an effective amount of one or more compounds of claim 1 or pharmaceutically acceptable salts of the compounds of claim 1, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

23. The method of claim 21, 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, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

24. The method of claim 21, wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, pulmonary hypertension, erythropoietin-mediated vasoconstriction endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

25. 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 claim 1 or salts of the compounds of claim 1, wherein:

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

26. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more compounds of claim 1 or salts of the compounds of claim 1.

27. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of one or more compounds of claim 1 or pharmaceutically acceptable salts of the compounds of claim 1, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

28. An article of manufacture, comprising packaging material and a compound of claim 1 or pharmaceutically acceptable salt of a compound of claim 1 contained within the packaging material, wherein the compound or salt therof 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.