Azetidine, pyrrolidine and piperidine derivatives as 5HT1 receptor agonists

• US 6,025,374 A
• Filed: 05/28/1997
• Issued: 02/15/2000
• Est. Priority Date: 12/06/1994
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Inventors: Matassa, Victor Giulio, Henry, Caroline, Castro Pineiro, Jose Luis, Street, Leslie Joseph, Sternfeld, Francine, Reeve, Austin John
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): MURRAY, JOSEPH H
• Application Number:
  US08/849,700
• Time in Patent Office: 993 Days
• Field of Search: 514/326, 514/331, 514/376, 514/415, 514/414, 546/208, 548/221, 548/468, 548/491
• US Class Current: 514/326
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT₁ -like receptors, being potent agonists of the human 5-HT_1Dα receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT_1Dα receptor subtype relative to the 5-HT_1Dβ subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT_1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT_1D receptor agonists.

Claims

1. A compound of formula I, or a salt or prodrug thereof:

##STR21## wherein Z represents hydrogen, halogen, cyano, nitro, trifluoromethyl, --OR⁵, --OCOR⁵, --OCONR⁵ R⁶, --OCH₂ CN, --OCH₂ CONR⁵ R⁶, --SR⁵, --SOR⁵, --SO₂ R⁵, --SO₂ NR⁵ R⁶, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵ CO₂ R⁶, --NR⁵ SO₂ R⁶, --COR⁵, --CO₂ R⁵, --CONR⁵ R⁶, or a group of formula (a), (b), (c) or (d);

##STR22## in which the asterisk * denotes a chiral centre;

X represents oxygen, sulphur, --NH-- or methylene;

Y represents oxygen or sulphur;

E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally substituted in any position by a hydroxy group;

U represents nitrogen or C--R² ;

V represents oxygen, sulphur or N--R³ ;

R², R³ and R⁴ independently represent hydrogen or C_1-6 alkyl;

R⁵ and R⁶ independently represent hydrogen, C_1-6 alkyl, trifluoromethyl, phenyl, methylphenyl, or an optionally substituted aryl(C_1-6)alkyl or heteroaryl(C_1-6)alkyl group;

or R⁵ and R⁶, when linked through a nitrogen atom, together represent the residue of an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or piperazine ring;

M represents the residue of an azetidine, pyrrolidine or piperidine ring;

R represents a group of formula --W--R¹ ;

W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

R¹ represents --OR^x, --SR^x or --NR^x R^y ;

R^x and R^y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R^x and R^y together represent a C_2-6 alkylene group; and

R^a represents hydrogen, hydroxy, hydrocarbon or a heterocyclic group.

2. A compound as claimed in claim 1 wherein Z represents --SO₂ NR⁵ R⁶ in which R⁵ and R⁶ are as defined in claim 1.

3. A compound as claimed in claim 1 wherein Z represents a group of formula (b) as defined in claim 1.

4. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof:

##STR23## wherein m is zero, 1, 2 or 3;

n is 2, 3 or 4;

p is zero, 1 or 2;

R⁵ and R⁶ are as defined in claim 1;

W¹ represents oxygen, sulphur or N--R¹² ; and

R¹¹ and R¹² independently represent hydrogen, C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted.

5. A compound as claimed in claim 1 represented by formula IIB, and salts and prodrugs thereof:

##STR24## wherein the asterisk * denotes a chiral centre;

R⁴ and Y are as defined in claim 1; and

m is zero, 1, 2or 3;

n is 2, 3 or 4;

p is zero, 1 or 2;

R⁵ and R⁶ are as defined in claim 1;

W¹ represents oxygen, sulphur or N--R¹² ; and

R¹¹ represents hydrogen, C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted.

6. A compound as claimed in claim 1 represented by formula IIC, and salts and prodrugs thereof:

##STR25## wherein the asterisk * denotes a chiral centre;

R⁴ and Y are as defined in claim 1; and

m is zero, 1, 2 or3;

n is 2, 3 or 4;

p is zero, 1 or 2;

R⁵ and R⁶ are as defined in claim 1;

W¹ represents oxygen, sulphur or N--R¹² ; and

R¹¹ represents hydrogen, C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted.

10. A pharmaceutical composition comprising a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier.

11. A process for the preparation of a compound as claimed in claim 1, which comprises;

(A) reacting a compound of formula III;

##STR26## wherein Z and E are as defined in claim 1;

with a compound of formula IV, or a carbonyl-protected form thereof;

##STR27## wherein R², Q, M, R and R^a are as defined in claim 1;

followed, where required, by N-alkylation by standard methods to introduce the moiety R³ ;

or

(B) reacting a compound of formula VII;

##STR28## wherein M, R and R^a are as defined in claim 1;

with a compound of formula VIII;

##STR29## wherein Z, E, Q, U and V are as defined in claim 1, and L² represents a suitable leaving group;

or

(C) cyclising a compound of formula X;

##STR30## wherein Z, E, Q, M, R and R^a are as defined in claim 1, and D¹ represents a readily displaceable group;

followed, where required, by N-alkylation by standard methods to introduce the moiety R³ ;

or

(D) cyclising a compound of formula XIII;

##STR31## wherein Z, E, Q, R², M, R and R^a are as defined in claim 1, and V¹ represents oxygen or sulphur; and

(E) subsequently, where required, converting a compound of formula I initially obtained into a further compound of formula I by conventional methods.

12. A method for the treatment of clinical conditions for which a subtype-selective agonist of 5-HT_1D receptors is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound as claimed in claim 1.

7. A compound selected from:

(3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(N-methyl)-aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-(N-benzyl)aminomethyl-1-[2-(5-(aminosulphonylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

and salts and prodrugs thereof.

8. A compound selected from:

(3S)-3-(N-benzyl)aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(R)-α

-(hydroxymethyl)benzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(S)-α

-methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

4-[N-(R)-α

-(hydroxymethyl)benzyl]amino-(S)-1-[3-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)propyl]piperidine;

and salts and prodrugs thereof.

9. A compound selected from:

(3S)-3-(N-benzyl-N-methyl)aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3R)-3-[N-(S)-α

-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3R)-3-[N-(S)-α

-methylbenzyl-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(4-fluorobenzyl)-N-methyl]aminomethyl-(S)-1-[2-(5-(3-methyl-2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine;

and salts and prodrugs thereof.