N-substituted .alpha.-amino acids and derivatives thereof having pharmaceutical activity

• US 5,179,085 A
• Filed: 04/22/1991
• Issued: 01/12/1993
• Est. Priority Date: 03/15/1989
• Status: Expired due to Term

• Current Assignee: Warner-Lambert Company (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: Johnson, Graham, Bigge, Christopher F.
• Primary Examiner(s): Bond, Robert T.
• Assistant Examiner(s): WARD, EDWARD C
• Application Number:
  US07/689,726
• Time in Patent Office: 631 Days
• Field of Search: 558/170, 558/190, 514/114, 514/119
• US Class Current: 514/114
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3826 Acyclic unsaturated acids
• CPC Class Codes: C07F 9/3834 Aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/3882 Arylalkanephosphonic acids C07F9/3839 takes precedence
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4015 Esters of acyclic unsaturated acids
• CPC Class Codes: C07F 9/4021 Esters of aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/4056 Esters of arylalkanephosphonic acids C07F9/4025 takes precedence

Abstract

N-substituted α-amino acids and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful in selectively blocking the N-methyl-D-aspartate (NMDA) excitatory amino acid receptors in mammals and also are useful in treating cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus and cerebral trauma as well as for treating schizophrenia, epilepsy, neurodegenerative disorders, Alzheimer'"'"'s disease or Huntington'"'"'s disease and also additionally useful as anesthetics in surgical procedures where a finite risk of cerebrovascular damage exists.

Claims

1. A compound of Formula I ##STR55## wherein X is --CH₂ CH₂ --,

--CH═

CH--, ##STR56## wherein R⁵ and R⁶ are independently selected from hydrogen, lower alkyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, lower alkoxy, lower alkylthio, halogen, hydroxy, or trifluoromethyl, ##STR57## wherein R⁵ and R⁶ are as defined above, ##STR58## wherein n is 1 to 3, or ##STR59## wherein n is as defined above;

A and D are independently selected from --(CH₂)_m --, wherein m is 0 to 3, --CH═

CH--, or --CH═

CHCH₂ --;

R is --OPO₃ R⁷ R⁸, wherein R⁷ and R⁸ are independently selected from hydrogen, lower alkyl, lower alkenyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, or a pharmaceutically acceptable labile group, --PO₃ R⁷ R⁸, wherein R⁷ and R⁸ are as defined above, or --PO₂ R⁷ R⁸, wherein R⁷ and R⁸ are as defined above;

R¹ is hydrogen, lower alkyl, lower alkenyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, --CO--alkyl, ##STR60## R₂ is hydrogen, --CH₃, --CH₂ OH, --CH₂ --CO₂ H, --CH₂ --CONH₂, --CH₂ CH₂ --CO₂ H, --CH₂ CH₂ --CONH₂, --CH₂ SH, ##STR61## R₃ is --OR⁷, wherein R⁷ is as defined above, or --NR⁹ R¹⁰, wherein R⁹ and R¹⁰ are independently selected from hydrogen, lower alkyl, lower alkenyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, or a pharmaceutically acceptable labile group;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 in which X is

--CH₂ CH₂ --,

--CH═

CH--, or ##STR62## wherein R⁵ and R⁶ are independently selected from hydrogen, lower alkyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, lower alkoxy, lower alkylthio, halogen, hydroxy or trifluoromethyl;

R is --PO₃ R⁷ R⁸, wherein R⁷ and R⁸ are independently selected from hydrogen, lower alkyl, lower alkenyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, or a pharmaceutically acceptable labile group;

R² is hydrogen, ##STR63## R³ is --OR⁷, wherein R⁷ is as defined above.

3. A compound according to claim 2, in which X is

--CH₂ CH₂ --,

--CH═

CH--, or ##STR64## wherein R⁵ and R⁶ are independently selected from hydrogen, lower alkyl, phenyl, phenyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, phenyl lower alkyl, phenyl lower alkyl substituted by one to four substituents selected from lower alkyl of from one to six carbon atoms, lower alkoxy of from one to six carbon atoms, halogen or trifluoromethyl, lower alkoxy, lower alkylthio, halogen, hydroxy, or trifluoromethyl; and

R¹ is hydrogen.

4. A compound according to claim 3 selected from the group consisting of:

N-[[3-(phosphonomethyl)phenyl]methyl]glycine, hydrochloride;

N-[2-[3-(phosphonomethyl)phenyl]ethyl]glycine, monohydrochloride;

N-[[4-(phosphonomethyl)phenyl]methyl]glycine, monohydrochloride;

N-(4-phosphono-2-butenyl)glycine, monohydrochloride;

N-(4-phosphono-2-butenyl)-DL-alanine, monohydrochloride; and

N-(4-phosphono-3-butenyl)glycine, diammonium salt (mixture of E and Z isomers).

5. A method of treating cerebrovascular disorders responsive to the blockade of glutamic acid or aspartic acid receptors in a mammal comprising administering to a mammal in need thereof a therapeutic effective amount of a compound according to claim 1 or a pharmaceutical composition comprising said compound.

6. A pharmaceutical composition for the treatment of cerebrovascular disorders responsive to the blockade of glutamic acid or aspartic acid receptors in mammals comprising a therapeutic effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.