Pseudopeptides used as medicaments

• US 4,297,346 A
• Filed: 12/07/1979
• Issued: 10/27/1981
• Est. Priority Date: 12/10/1976
• Status: Expired due to Term

• Current Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Inventors: Morier, Elisabeth, Rips, Richard
• Primary Examiner(s): Phillips, Delbert R.
• Assistant Examiner(s): Hazel, Blondel
• Application Number:
  US06/101,555
• Time in Patent Office: 690 Days
• Field of Search: 260/112.5 R, 260/112 S, 260/112 TR, 260/112 LH, 424/177
• US Class Current: 514/17.6
• 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: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/28 2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07K 5/06165 and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06173 and Glp-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Abstract

The invention relates to therapeutic agents referred to as `pseudopeptides` being formed from at least one peptide radical connected by a peptide bond to a therapeutically active molecule or derivative of a therapeutically active molecule. The therapeutic agents of the invention may be in the form of derivatives such as salts, esters and amides. The basis of action of the agents of the invention is the ability of the agents of the invention to cross bodily biological barriers because of the basically peptide structure of the agents. The invention also includes the preparation of the agents of the invention.

Claims

1. Pseudopeptide formed by at least one peptide radical originated from a neuropeptide by removal of one of more of the terminal sequences, connected by a peptide bond to a molecule or to a derivative of a therapeutically active molecule acting on the central nervous system, said neuropeptide being selected from the group consisting of endorphine and neuropeptides having from 2 to 11 amino acid sequences and said therapeutically active molecular being selected from the group consisting of amphetamine (Amph), 4-nitro-amphetamine (Amph-NO₂), 4-amino-amphetamine (Amph-NH₂), 4-chloroamphetamine (Amph-Cl), N-phthaloyl-4-amino-amphetamine, 3,4-dibenzoxyphenyl ethylamine, phenyl ethylamine (PEA), dopamine, 5-(3-aminopropyliden dibenzo-(a,d)-cycloheptadi-1,4-ene (PDD), 1,3-dihydroxy-7-amino 5-phenyl-1H-benzodiazepine-(1,4)-one-(2) (BD), 20-(3-aminopropyl) 3-phenothiazine (PP), 1,5-dimethyl-2-phenyl-4-amino-3-pyrazolone (AP), 4-ethoxyaniline (PT), 4-phenyl-4-ethoxycarbonyl piperidine (NP), tryptamine (Try-NH₂) and 4-amino-barbituric acid (AB).

2. A pseudopeptide formed by at least one peptidic radical selected from the group consisting of pGlu-His originated from TRH, Pro-Leu originated from MIF, and Try-Gly-Gly originated from encephaline, said peptidic radical being connected by a ##STR12## bond to a therapeutically active molecule acting on the central nervous system selected from the group consisting of amphetamine (Amph), 4-nitro-amphetamine (Amph-NO₂), 4-amino-amphetamine (Amph-NH₂), 4-chloroamphetamine (Amph-Cl), N-phthaloyl-4-amino-amphetamine, 3,4-dibenzoxyphenyl ethylamine, phenyl ethylamine (PEA), dopamine, 5-(3-aminopropyliden dibenzo-(a,d)-cycloheptadi-1,4-ene (PPD), 1,3-dihydroxy-7-amino 5-phenyl-1H-benzodiazepine-(1,4)-one-(2) (BD), 20-(3-aminopropyl) 3-phenothiazine (PP), 1,5-dimethyl-2-phenyl-4-amino-3-pyrazolone (AP), 4-ethoxyaniline (PT), 4-phenyl-4-ethoxycarbonyl piperidine (NP), tryptamine (Try-NH₂) and 4-aminobarbituric acid (AB).

3. A pseudopeptide formed by a peptidic radical connected by a peptide bond to a central nervous system acting molecule, said pseudopeptide having central nervous system activity and being selected from the group consisting of pGlu-His-Amph, pGlu His-PEA and pGlu-His-DA.

4. A pseudopeptide formed by a peptidic radical connected by a peptide bond to a central nervous system acting molecule, said pseudopeptide having central nervous system activity and being selected from the group consisting of pGlu-His-Tyr-NH₂, pGlu-His-PP, pGlu-His-BD and pGlu-His-PDD.

5. A pseudopeptide formed by a peptidic radical connected by a peptide bond to a central nervous system acting molecule, said pseudopeptide having central nervous system activity and being selected from the group consisting of Pro-Leu-Amph, Pro-Leu-PEA, Pro-Leu-BD, Pro-Leu-PDD and Pro-Leu-PP.

6. Pseudopeptide of a formula of the group consisting of:

pGlu-His-Amph

pGlu-His-PEA

pGlu-His-Amph-Cl

pGlu-His-PEA-di-BzO

pGlu-His-DA

pGlu-His-Amph-NO₂

pGlu-His-Amph-NH₂

pGlu-His-pNH-Amph-N-Pht

pGlu-His-pNH-Amph

Cbz-Pro-Leu-Amph

Cbz-Pro-Leu-Amph-Cl

Cbz-Pro-Leu-PEA

Cbz-Pro-Leu-Amph-NO₂

Cbz-Pro-Leu-PEA-di-BzO

Pro-Leu-Amph

Pro-Leu-Amph-Cl

Pro-Leu-PEA

Pro-Leu-Amph-NO₂

Pro-Leu-Amph-NH₂

Pro-Leu-DA

pGlu-His-PDD.HCl

pGlu-His-BD.HCl

pGlu-His-PP.Hcl

Cbz-Pro-Leu-PDD

Cbz-Pro-Leu-BD

Cbz-Pro-Leu-PP

Pro-Leu-BD

Pro-Leu-PDD

pGlu-His-PT

pGlu-His-AP

Cbz-Pro-Leu-AP

Cbz-Pro-Leu-PT

Cbz-Pro-Leu-NP

Pro-Leu-AP

Pro-Leu-PT

Pro-Leu-NP

N-Cbz-(Bzo)-Tyr-Gly-Gly-PT

N-Cbz-(Bzo)-Tyr-Gly-Gly-AP

Tyr-Gly-Gly-PT

Tyr-Gly-Gly-AP

pGlu-His-Try-NH₂

pGlu-His-AB

Cbz-Pro-Leu-Try-NH₂

Cbz-Pro-Leu-AB

Pro-Leu-Try-NH₂

Pro-Leu-AB.

7. As a novel medicament for asthenia, an effective amount of a pseudopeptide of the class consisting of pGlu-His-Amph and Pro-Leu-Amph together with a pharmaceutically acceptable carrier therefor.

8. As a novel medicament for sympathomimetric action, an effective amount of a pseudopeptide of the class consisting of pGlu-His-PEA and Pro-Leu-PEA together with a pharmaceutically acceptable carrier therefor.

9. As a novel medicament for the treatment of Parkinson'"'"'s disease, an effective amount of a pseudopeptide of the class consisting of pGlu-His-DA and Pro-Leu-DA together with a pharmaceutically acceptable carrier therefor.

10. As a novel medicament for depletion of serotonin, an effective amount of a pseudopeptide of the class consisting of pGlu-His-Amph-NO₂, pGlu-His-Amph-Cl, Pro-Leu-Amph NO₂ and Pro-Leu-Amph-Cl together with a pharmaceutically acceptable carrier therefor.

11. As a novel medicament for increase of serotonin, an effective amount of a pseudopeptide of the class consisting of pGlu-His-Amph-NH₂ and Pro-Leu-Amph-NH₂ together with a pharmaceutically acceptable carrier therefor.

12. As a novel medicament for antidepressive action, an effective amount of a pseudopeptide of the class consisting of pGlu-His-PPD.HCl, and Pro-Leu-PDD, together with a pharmaceutically acceptable carrier therefor.

13. As a novel medicament for tranquilizing effect, an effective amount of a pseudopeptide of the class consisting of pGlu-His-BD.HCl, pGlu-His-PP.HCl, Pro-Leu-BD and Pro-Leu-PP together with a pharmaceutically acceptable carrier therefor.

14. As a novel medicament for anti-epilepsy activity, an effective amount of a pseudopeptide of the class consisting of pGlu-His-AB and Pro-Leu-AB together with a pharmaceutically acceptable carrier therefor.

15. As a novel medicament for analgesic activity, an effective amount of a pseudopeptide of the class consisting of pGlu-His-PT, Pro-Leu-PT and Pro-Leu-NP together with a pharmaceutically acceptable carrier therefor.