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

• US 6,329,387 B2
• Filed: 11/17/1999
• Issued: 12/11/2001
• Est. Priority Date: 04/15/1996
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Verner, Erik Joel
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US09/441,643
• Publication Number:
  US 20010014684A1
• Time in Patent Office: 755 Days
• Field of Search: 546/114, 514/300, 514/301, 514/302, 514/378, 514/443
• 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:

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)_rR¹⁸, in which r is 0 to 6 and R¹⁸ is selected from groups that include aryl, particularly pyrimidinyl 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 method of altering nitric oxide levels, comprising administering an effective amount of an endothelin antagonist, wherein the endothelin antagonist is a sulfonamide compound of formula (I)

wherein:

Ar¹, which contains from 1 to 30 carbon atoms, is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl and fused bicyclic or tricyclic rings, wherein the alkyl, alkenyl and alkynyl groups may be straight or branched chains, or straight or branched chains that include cyclic portions; and

Ar² is a group of formula;

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, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ and S(O)_nR¹⁵ 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, heterocyclyl, 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, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl and amido, where the alkyl, alkenyl and alkynyl 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

(ii) two of R³, R⁴ and R⁵ form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 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);

or

(iii) two of R³, R⁴ and R⁵ are independently selected from alkyl, alkoxy, halide, aminoalkyl and dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10 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 and is selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, CO₂R¹⁸, (CH_2rCOR¹⁸, (CH₂)_rCO(CH₂)_sR¹⁸, SH, (CH₂)_rR¹⁸, S(O)_nR¹⁸ in which n is 0-2, and r is 0 to 6, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²⁰ and S(O)_nR²⁰ in which n is 0-2; and

R¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and 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, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_nR²¹ in which n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)_nR²³ in which n is 0-2; and

R²¹ and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl, whereby nitric oxide levels are altered.

2. The method of claim 1, wherein Ar¹ is isoxazolyl.

3. The method of claim 2, wherein the compound has the formula II:

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)_nR¹⁵ 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.

4. The method of claim 1, wherein Y is N, and X is S or O.

5. The method of claim 1, wherein the compound is N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylthieno[2,3-b]pyridine-3-sulfonamide, N-(4-chloro-5-methyl-3-isoxazolyl)-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-methylene-dioxy)benzyl)]thieno[2,3-b]pyridine-3-sulfonamide, N-(4-chloro-3-methyl-5-isoxa-zolyl)-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-isoxa-zolyl)-2-{(4,5-methylenedioxy)-2-[2-(oxy)ethyl]benzyl}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-naphthalenemethyl]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 or N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(3,4 methylenedioxyphenyl)propionyl]thieno[2,3-b]pyridine-3-sulfonamide.