Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists

• US 5,693,643 A
• Filed: 08/15/1995
• Issued: 12/02/1997
• Est. Priority Date: 09/16/1991
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Gilbert, Kevin, Williams, Peter D., Veber, Daniel F., Evans, Ben E., Hobbs, Doug W.
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US08/464,808
• Time in Patent Office: 840 Days
• Field of Search: 514/253, 514/255, 514/278, 514/397, 514/409, 544/230, 544/360, 544/366, 544/372, 546/17
• US Class Current: 514/85
• CPC Class Codes: C07D 207/416 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 295/26 Sulfur atoms
• 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 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

Compounds of formula (I) wherein X is (a) or (b), R is Het as defined in the description. These compounds are oxytocin and vasopressin antagonists useful in the treatment of preterm labor, dysmenorrhea, and for the stoppage of labor preparatory to Cesarean delivery. ##STR1##

Claims

1. A compound of the formula ##STR119## or a pharmaceutically acceptable salt thereof, wherein X is ##STR120## a is a single or double bond, R is Het, wherein

Het is a substituted saturated or unsaturated heterocyclic ring wherein said substituents are independently one or more of R¹, R², R³, Alk-R¹, Alk-R², Alk-R³, --NHC(O)-Alk-R² R³, --NR⁵ -Alk-R² R³ or Alk-R² R³ ;

where Alk is C_1-10 alkyl and R¹, R² and R³ are independently selected from the group consisting of hydrogen, halogen, C_2-10 alkenyl, methylene, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkoxycarbonylamino, C_1-10 alkylamino-C_1-10 alkylaminocarbonyl, C_1-10 alkylcarbonylamino, --S--R⁴, C_1-10 alkylcarbonyloxy, C_1-10 alkylsulfonyl, C_1-10 alkylthio, amino, amino C_1-10 alkylcarbonylamino, amino C_1-10 alkylamino, carbonylamino, carbamoyl, carboxyl C_1-10 alkylamino, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylthio, di-C_1-10 alkylamino-C_1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, hydroxyl C_1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl C_1-10 alkylamino, imidazolyl C_1-10 alkylaminocarbonyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, pyrrolidinyl, sulfonyl, tetrazolyl C_1-10 alkyl-carbonylamino, tetrazolylaminocarbonyl, phosphoryl, phosphoryl C_1-10 alkylamino and thiono;

R⁴ is selected from the group consisting of imidazolyl, C_1-10 alkoxycarbonyl-C_1-10 alkyl, di-C_1-10 alkylamino-C_1-10 alkyl and C_1-5 alkyl; and

R⁵ is selected from the group consisting of hydrogen and C_1-5 alkyl.

2. The compound as claimed in claim 1, wherein

Het is a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocyclic or 7 to 10 membered heterobicyclic ring containing 1, 2 or 3 nitrogen atoms, and R¹, R² and R³ are independently selected from the group consisting of hydrogen, halogen, C_2-10 alkenyl, methylene, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkylcarbonylamino, C_1-10 alkylcarbonyloxy, C_1-10 alkylsulfonyl, --S--R⁴, amino, amino-C_1-10 alkylcarbonylamino, amino C_1-10 alkylamino, carbamoyl, carboxyl C_1-10 alkylamino, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylthio, di-C_1-10 alkylamino-C_1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, hydroxyl C_1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl C_1-10 alkylamino, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C_1-10 alkylamino and thiono.

3. The compound as claimed in claim 2, wherein said bicyclic ring is bonded to one of said heterocyclic or heterobicyclic ring'"'"'s nitrogen atoms.

4. The compound as claimed in claim 3, wherein

X is, ##STR121## and R¹, R² and R³ are independently selected from the group consisting of hydrogen, halogen, C_2-10 alkenyl, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkylcarbonylamino, C_1-10 alkylsulfonyl, --S--R⁴, amino, amino-C_1-10 alkylcarbonylamino, amino C_1-10 alkylamino, carbamoyl, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylthio, guanidinyl, hydroxyl, hydroxyl C_1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl C_1-10 alkylamino, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C_1-10 alkylamino and thiono.

5. The compound as claimed in claim 3, wherein Het is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, piperazinyl, triazaspirodecane, pyrrolo-isoxazole, pyrrolo-pyrazole and pyrrolo-pyrrole.

6. The compound as claimed in claim 1, wherein

X is ##STR122## R is Het, wherein Het is a mono, di, tri or tetra substituted saturated or unsaturated 5 or 6 membered heterocyclic ring containing 1, or 2 nitrogen atoms that is bonded to said bicyclic ring at one of said heterocyclic ring'"'"'s nitrogen atoms, wherein said substituents are independently one or more of R¹, R², R³, Alk-R¹, Alk-R², Alk-R³ or Alk-R² R³ ;

and where Alk is C_1-10 alkyl and R¹, R² and R³ are independently selected from the group consisting of hydrogen, C_2-10 alkenyl, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkoxycarbonylamino, C_1-10 alkylamino-C_1-10 alkylaminocarbonyl, C_1-10 alkylcarbonylamino, C_1-10 alkylcarbonyloxy, C_1-10 alkylsulfonyl, C_1-10 alkylthio, amino, amino-C_1-10 alkylcarbonylamino, carbonylamino, carboxyl C_1-10 alkylamino, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino C_1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl, imidazolyl C_1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperizinyl, pyrrolidinyl, sulfonyl, tetrazolyl C_1-10 alkylcarbonylamino, tetrazolylaminocarbonyl and thiono.

7. The compound as claimed in claim 6, wherein a is a single bond, and R¹, R² and R³ are independently selected from the group consisting of hydrogen, C_2-10 alkenyl, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkylcarbonylamino, C_1-10 alkylcarbonyloxy, C_1-10 alkylsulfonyl, amino, amino-C_1-10 alkylcarbonylamino, carbonylamino, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylaminocarbonyl, guanidinyl, hydroxyl, imidazolyl, imidazolyl C_1-10 alkylaminocarbonyl, indolyl, oxo, phenyl, piperidinylamino, piperazinyl, sulfonyl and thiono.

8. The compound as claimed in claim 7, wherein Het is selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl and piperazinyl.

9. The compound as claimed in claim 2, wherein

X is ##STR123## and R¹, R² and R³ are independently selected from the group consisting of hydrogen, halogen, C_2-10 alkenyl, C_1-10 alkoxycarbonyl, C_1-10 alkoxycarbonyl-C_1-10 alkylamino, C_1-10 alkylcarbonylamino, C_1-10 alkylcarbonyloxy, C_1-10 alkylsulfonyl, --S--R⁴, amino, amino-C_1-10 alkylcarbonylamino, amino C_1-10 alkylamino, carbamoyl, carboxyl, cyano, di-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylamino, di-C_1-10 alkylamino-C_1-10 alkylthio, guanidinyl, hydroxyl, hydroxyl C_1-10 alkylamino, imidazolyl, imidazolyl amino, imidazolyl C_1-10 alkylamino, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, indolyl, oxo, oxiranyl, phenyl, piperidinylamino, piperazinyl, sulfonyl, phosphoryl, phosphoryl C_1-10 alkylamino and thiono.

10. The compound as claimed in claim 9, wherein R¹, R² and R³ are independently selected from the group consisting of hydrogen, C_1-10 alkylcarbonyloxy, amino, hydroxyl, oxo, phosphoryl and oxiranyl.

11. The compound as claimed in claim 5, selected from the group consisting of ##STR124##

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in claim 1, sufficient to antagonize oxytocin from binding to its receptor site.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in claim 1 sufficient to prevent preterm labor in a mammal in need thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in claim 1, sufficient to stop labor preparatory to cesarian delivery.

15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound as claimed in claim 1, sufficient to treat dysmenorrhea.

16. A compound of the formula ##STR125## or a pharmaceutically acceptable salt thereof, wherein X is ##STR126## a and b represent a single or double bond, R is selected from the group consisting of ##STR127## R² is selected from the group consisting of -AlkR⁵ R⁶, --NH--C(O)-Alk-R⁷ R⁸, --N(R⁴)-Alk-R⁷ R⁸, amino C_1-10 alkylcarbonylamino, piperidinylamino, oxiranyl C_1-10 alkyl, imidazolylamino, C_1-10 alkoxycarbonyloxy, hydroxyl, phosphoryl, --S--R⁹, C_1-10 alkylcarbonyloxy and C_1-10 alkylcarbonylamino;

Alk is C_1-10 alkyl;

R³ is selected from the group consisting of hydrogen, hydroxyl, phosphoryl, C_1-10 alkylcarbonyloxy and C_1-10 alkoxycarbonyl;

R⁴ is selected from the group consisting of hydrogen, benzyl and C_1-10 alkyl;

R⁵ and R⁶ are independently selected from the group consisting of hydroxyl, di-C_1-10 alkylamino, piperazinyl, halogen, phosphoryl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hydroxyl C_1-10 alkylamino, cyano and --SCH₃ ;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen, hydroxyl, hydroxyl C_1-10 alkyl, C_1-10 alkylcarbonylamino, amino, phosphoryl, imidazolyl, di-C_1-10 alkylamino, guanidinyl, C_1-10 alkoxycarbonyl, carboxyl and C_1-10 alkoxycarbonylamino;

R⁹ is selected from the group consisting of di-C_1-10 alkylamino-C_1-10 alkyl, imidazolyl and C_1-10 alkoxycarbonyl-C_1-10 alkyl;

provided that R⁵ and R⁶ cannot both be hydroxyl.