Tocolytic oxytocin receptor antagonists

• US 5,464,788 A
• Filed: 03/24/1994
• Issued: 11/07/1995
• Est. Priority Date: 03/24/1994
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Gilbert, Kevin F., Rittle, Kenneth E., Bock, Mark G., Williams, Peter D., Culberson, J. Christopher, Evans, Ben E.
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US08/217,270
• Time in Patent Office: 593 Days
• Field of Search: 544/360, 544/364, 514/252, 514/253
• US Class Current: 514/253.12
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the formula X--Y--R, or the pharmaceutically acceptable salts and esters thereof, wherein X is ##STR1## Y is --SO₂ --, --(CH₂)_p -- or --CO--(CH₂)_p --; R is unsubstituted or substituted phenyl where said substitutents are one or more of R⁵, R⁶ or R⁷ ; R¹ is hydrogen, cyano, phenyl,--CONHR², --CONR² R², --(CH₂)_m --OR², --(CH₂)_p --S(O)_r --R², --(CH₂)_m --CO₂ R², --(CH₂)_m --N₃, --(CH₂)_m --NH₂ or --(CH₂)_m --NR² R² ; R² is hydrogen, C_3-8 cycloalkyl or C_1-5 alkyl; R⁵ and R⁶ are each independently selected from hydrogen, C_1-5 alkoxy, halogen or --(CH₂)_n --N(R²)--C(O)--R¹⁸ ; R⁷ is hydrogen or ##STR2## R¹¹ is selected from hydrogen, C_1-5 alkylcarbonyl, ##STR3## or substituted C_1-5 alkyl wherein said alkyl substituent is unsubstituted, mono-, di- or tri-substituted pyridyl wherein said substitutents on said pyridyl are independently selected from halogen, C_1-5 alkyl or C_1-5 alkoxyl; R¹³ is unsubstituted or substituted C_1-10 alkyl wherein the substituent is selected from --N(R²)₂, --NHR² or imidazolyl; R¹⁴ and R¹⁵ are each independently selected from C_1-5 alkyl, C_1-5 alkoxy or halogen; R¹⁶ is hydrogen or oxo; R¹⁸ is C_1-5 alkoxyl, unsubstituted or substituted C_1-5 alkyl where said substituent is Het, unsubstituted or substituted C_2-5 alkenyl where said subsituent is Het or Het; Het is benzimidazolyl, carboxymethyl-substituted benzimidazolyl or indolyl; m is an integer of from 1 to 5; p is an integer of from 1 to 3; and r is an integer of from 0 to 2. Such compounds as useful as oxytocin and vasopressin receptor antagonists.

Claims

1. A compound of the formula ##STR52## wherein Y is selected from the group consisting of --SO₂ --, --CO--(CH₂)_n -- and --(CH₂)_p --;

R¹ is selected from the group consisting of hydrogen, cyano, phenyl, --CONHR², --CONR² R², --(CH₂)_m --OR², --(CH₂)_p S(O)_r --R², --(CH₂)_m --CO₂ R², --(CH₂)_m --N₃, --(CH₂)_m --NH₂ and --(CH₂)_m --NR² R² ;

R² is selected from the group consisting of hydrogen, C_3-8 cycloalkyl and C_1-5 alkyl;

R⁵ and R⁶ are each independently selected from the group consisting of hydrogen, C_1-5 alkyl, C_1-5 alkoxy, halogen and --(CH₂)_n --N(R²)--R¹⁷ ;

R⁷ is selected from the group consisting of hydrogen and ##STR53## R¹¹ is selected from the group consisting of hydrogen, C_1-5 alkoxycarbonyl, C_1-5 alkylcarbonyl, C_1-5 alkyl, --Z--R¹³, ##STR54## and substituted C_1-5 alkyl wherein said substituent on said alkyl is unsubstituted, mono-, di- or tri-substituted pyridyl wherein said substituents on said pyridyl are independently selected from the group consisting of halogen, C_1-5 alkyl and C_1-5 alkoxyl;

R¹³ is selected from the group consisting of unsubstituted C_1-10 alkyl and substituted C_1-10 alkyl wherein said subsituent is selected from the group consisting of --N(R²)₂, --NHR² and imidazolyl;

R¹⁴ is selected from the group consisting of C_1-5 alkyl, C_1-5 alkoxy and halogen;

R¹⁵ is selected from the group consisting of hydrogen and C_1-5 alkyl;

R¹⁶ is selected from the group consisting of hydrogen and oxo;

R¹⁷ is --Z--R¹⁸ ; and

R¹⁸ is selected from the group consisting of C_1-5 alkoxyl, Het. unsubstituted or substituted C_1-5 alkyl wherein said substitutent is Het and unsubstituted or substituted C_2-5 alkenyl wherein said substituent is Het;

Het is selected from the group consisting of imidazolyl, benzimidazolyl, carboxymethyl-substituted benzimidazolyl and indolyl.

Z is --CO-- or --SO₂ --;

m is an integer of from 1 to 5;

n is an integer of from 0 to 3;

p is an integer of from 1 to 3; and

r is an integer of from 0 to 2;

provided that when R¹⁵ is hydrogen or methyl;

then R¹ is not hydrogen;

and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein

R¹ is selected from the group consisting of hydrogen, --CONHR², --(CH₂)_m --CO₂ R², --(CH₂)_m --OR², --(CH₂)_p --S(O)_r R², --(CH₂)_m --N₃, --(CH₂)_m --NH₂ and --(CH₂)_m --NR² R².

3. The compound of claim 1, of the structure ##STR55## wherein R⁵ is C_1-5 alkoxy.

4. The compound of claim 1, of the structure ##STR56##

5. The compound of claim 1, of the structure ##STR57##

6. The compound of claim 1, of the structure ##STR58##

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in claim 1.

8. A method of eliciting an oxytocin antagonizing effect in a mammal, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in claim 1.

9. A method of treating preterm labor in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in claim 1.

10. A method of stopping labor preparatory to cesarian delivery in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in claim 1.

11. A method of treating dysmenorrhea in a mammal in need thereof, comprising the step of administering to said mammal a pharmacologically effective amount of the compound as claimed in claim 1.