New heterocyclic tripeptide compounds

• US 5,098,888 A
• Filed: 06/11/1990
• Issued: 03/24/1992
• Est. Priority Date: 06/29/1989
• Status: Expired due to Fees

• Current Assignee: Adir SA
• Original Assignee: Adir SA
• Inventors: Biton, Catherine, Portevin, Bernard, Vincent, Michel, Lepagnol, Jean, Remond, Georges, Herve, Yolande
• Primary Examiner(s): LEE, LESTER
• Application Number:
  US07/536,193
• Time in Patent Office: 652 Days
• Field of Search: 530/331, 514/18, 514/19
• US Class Current: 514/9.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 453/00 Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

The invention relates to the compounds of general formula (I): ##STR1## in which: A represents, with the carbon and nitrogen atoms to which it is linked, a cycloamide group,

B represents, with the carbon and nitrogen atoms to which it is linked, a saturated polycyclic structure,

R represents a hydrogen atom, alower alkyl group or a substituted or unsubstituted 4-imidazolylmethyl group,

their diastereoisomers, enantiomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

Medicinal products.

Claims

1. A compound selected from those of the formula (I):

##STR29## in which;

A represents, with the nitrogen and carbon atoms to which it is linked;

a 2-oxo-5-pyrrolidinyl group,

a 2-oxo-6-piperidyl group,

a 2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl group,

a 2-oxo-4-thiazolidinyl group,

a 2-oxo-4-azetidinyl group,

a 1-oxo-1,2,3,4-tetrahydro-3-isoquinolyl group,

B represents, with the nitrogen and carbon atoms to which it is linked, a saturated polycyclic structure selected from 2-azabicyclo[2.2.1]heptane or 1,4-di(linear or branched lower alkyl)-2-azabicyclo[2.2.2]-octane,

R represents a hydrogen atom, a linear or branched lower alkyl group or a (4-imidazolyl)methyl group optionally substituted on one of the nitrogen atoms with a linear or branched lower alkyl radical,

the term lower indicating that the groups thus qualified contain from 1 to 6 carbon atoms, their enantiomers, diastereoisomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

2. A compound according to claim 1, such that B, with the nitrogen and carbon atoms to which it is linked, forms a 2-azabicyclo[2.2.1]heptane ring-system, their enantiomers, diastereoisomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

3. A compound according to claim 1, such that B, with the nitrogen and carbon atoms to which it is linked, forms a 1,4-dialkyl-2-azabicyclo[2.2.2]octane ring-system, their enantiomers, diastereoisomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

4. A compound according to claim 1, such that B, with the nitrogen and carbon atoms to which it is linked, forms a 1,4-dimethyl-2-azabicyclo[2.2.2]octane ring-system, their enantiomers, diastereoisomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

5. A compound according to claim 1, such that B, with the nitrogen and carbon atoms to which it is linked, forms a 4-methyl-1-isopropyl-2-azabicyclo[2.2.2]-octane ring-system, their enantiomers, diastereoisomers and epimers, as well as their addition salts with a pharmaceutically acceptable acid.

6. A compound according to claim 1, which is PyroGlu-(N.sup.τ

-Me)His-ABH-NH₂, its enantiomers, diastereoisomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, PyroGlu representing a 2-oxopyrrolidine-5-carbonyl radical, (N.sup.τ

-Me)His representing a 1-methylhistidyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

7. A compound according to claim 1, which is PyroGlu-Leu-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, PyroGlu representing a 2-oxopyrrolidine-5-carbonyl radical, Leu representing a leucyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

8. A compound according to claim 1, which is PyroGlu-(N.sup.π

-Me)His-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, PyroGlu representing a 2-oxopyrrolidine-5-carbonyl radical, (N.sup.π

-Me)His a 3-methylhistidyl radical and ABH a 2-azabicyclo[2.2.1]-heptane-3-carbonyl radical.

9. A compound according to claim 1, which is HomoPyroGlu-(N.sup.π

-Me)His-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, HomoPyroGlu representing a 2-oxopiperidine-6-carbonyl radical, (N.sup.π

-Me)His, a 3-methylhistidyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

10. A compound according to claim 1, which is HomoPyroGlu-Leu-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, HomoPyroGlu representing a 2-oxopiperidine-6-carbonyl radical, Leu representing a leucyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

11. A compound according to claim 1, which is PyroGlu-His-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, PyroGlu representing a 2-oxopyrrolidine-5-carbonyl radical, His representing a histidyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

12. A compound according to claim 1, which is HomoPyroGlu-His-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, HomoPyroGlu representing a 2-oxopiperidine-6-carbonyl radical, His a histidyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

13. A compound according to claim 1, which is HomoPyroGlu-(N.sup.τ

-Me)His-ABH-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, HomoPyroGlu representing a 2-oxopiperidine-6-carbonyl radical, (N.sup.τ

-Me)His a 1-methylhistidyl radical and ABH a 2-azabicyclo[2.2.1]heptane-3-carbonyl radical.

14. A compound according to claim 1, which is HomoPyroGlu-Leu-MIABO-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, HomoPyroGlu representing a 2-oxopiperidine-6-carbonyl radical, Leu representing a leucyl radical and MIABO a 4-methyl-1-isopropyl-2-azabicyclo[2.2.2]octane-3-carbonyl radical.

15. A compound according to claim 1, which is PyroGlu-(N.sup.π

-Me)His-dMABO-NH₂, its diastereoisomers, enantiomers and epimers, as well as its addition salts with a pharmaceutically acceptable acid, PyroGlu representing a 2-oxopyrrolidine-5-carbonyl radical, (N.sup.π

-Me)His a 1-methylhistidyl radical and dMABO a 1,4-dimethyl-2-azabicyclo[2.2.2 ]octane-3-carbonyl radical.

16. A pharmaceutical composition containing, as active principle, at least one compound according to claim 1, in combination with one or more pharmaceutically acceptable, non-toxic, inert vehicles or excipients.

17. A method for treating an animal or human living body afflicted with a condition requiring a facilitator of central cholinergic or noradrenergic neurotransmission, comprising the step of administering to the said living body an amount of a compound of claim 1 which is effective for alleviation of the said condition.