EP0487623A1 - 5-amino-1,2,3,4-tetrahydroakridinderivate und ihre anwendung als arzneimittel - Google Patents

5-amino-1,2,3,4-tetrahydroakridinderivate und ihre anwendung als arzneimittel

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Publication number
EP0487623A1
EP0487623A1 EP90913286A EP90913286A EP0487623A1 EP 0487623 A1 EP0487623 A1 EP 0487623A1 EP 90913286 A EP90913286 A EP 90913286A EP 90913286 A EP90913286 A EP 90913286A EP 0487623 A1 EP0487623 A1 EP 0487623A1
Authority
EP
European Patent Office
Prior art keywords
group
tha
alpha
compounds according
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90913286A
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English (en)
French (fr)
Inventor
Dat Xuong Nguyen
Jean Robert Rapin
Jacques Pueyo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SYNTHESES ET RECHERCHES
Original Assignee
SYNTHESES ET RECHERCHES
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Publication date
Application filed by SYNTHESES ET RECHERCHES filed Critical SYNTHESES ET RECHERCHES
Publication of EP0487623A1 publication Critical patent/EP0487623A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems 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 carbon atoms of the ring system
    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to derivatives of 5-amino 1,2,3,4-tetrahydroacridine and the applications of these substances as medicaments.
  • THA The THA molecule, as well as methods for obtaining this molecule, are already described in the literature. We find in particular the reference of this product in the Merck index n ° 89 07, 10th edition (July 1983), under the name Tacrine. Depending on the nomenclature adopted for writing the chemical formula, THA can also be called 9-amino 1,2,3,4-tetrahydroacridine.
  • THA treatment had very significant drawbacks due in particular to the toxicity of certain impurities present in the available THA preparations.
  • N-substituted derivatives of THA are known, in particular the salts of THA para-chlorophenoxyacetate and THA para-bromophenoxyacetate which are used in the treatment of pathological conditions directly or indirectly produced by cerebral anoxia (Special Drug Patent FR-M-3.860).
  • the object of the present invention is to provide derivatives of THA having on the one hand a low toxicity and on the other hand an increased biological activity and specificity compared with unsubstituted THA, in particular with regard to its activity virulicide.
  • the subject of the invention is therefore chemical compounds derived from 5-amino 1,2,3,4-tetrahydroacridine (THA) corresponding to the general formula: in which :
  • R represents - a glycosyl group optionally substituted by a purine base
  • a thio-carbamyl group in which case said group is common to two molecules of THA which are linked to it by the group -NH in position 5, an optionally substituted adamantyl group,
  • the compound in which case the compound is present in the form of a complex comprising at least one THA molecule associated with at least one molecule chosen from alpha-adamantane, alpha-amino adamantane and a nucleoside such as l adenosine, guanosine or inosine.
  • THA THA
  • alpha-adamantane alpha-amino adamantane
  • a nucleoside such as l adenosine, guanosine or inosine.
  • the compounds for which R is different from H 2 Z can also be in the form of pharmaceutically acceptable salts.
  • R represents a glycosyl group
  • said group can be an ascorbyl group.
  • HAT ascorbate is water-soluble, which allows its intramuscular (i.m.), intravenous (i.v.) or subcutaneous (s.c.) injection or its infusion.
  • R represents a substituted glycosyl group
  • said group can be an in ⁇ sinyl, adenosine or guanidosinyl group, optionally substituted.
  • R represents a thio-carba yl group
  • said compound can be a di (tetrahydro 1,2,3,4-acrydinyl-5) thio urea.
  • R represents an adamantanyl group
  • said group can be an alpha-adamantanyl or alpha-amino-adamantanyl group.
  • R represents an H 2 Z group
  • said compound may be in the form of a THA pamoate salt.
  • THA molecules having a known pharmacological activity for example virulicide, so as to potentiate the effects of THA or to facilitate its application as a medicament, in particular the practical methods of its administration.
  • These compounds can be obtained by preparation methods known to those skilled in the art, in particular by simultaneous dissolution of THA and of another reagent in a solvent or by simultaneous spraying of THA and of another reagent in a mortar .
  • the invention also relates to medicaments containing at least one of these compounds or a para-chlorophenoxyacetate salt of HAT, in particular medicaments for the treatment of degenerative or atrophic diseases, such as AIDS, senile dementias of the Alsheimer type, multiple sclerosis or Du chesne myopathy.
  • degenerative or atrophic diseases such as AIDS, senile dementias of the Alsheimer type, multiple sclerosis or Du chesne myopathy.
  • the present invention also relates to a pharmaceutical composition containing an effective amount of at least one of the compounds or of a para-chlorophenoxy acetate THA salt previously described, in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. .
  • compositions are particularly intended for the treatment of degenerative or atrophic diseases ques, in particular of the Alzheimer type, multiple sclerosis, Duchesne's myopathy as well as AIDS.
  • this composition is presented for oral, parenteral or intravenous administration.
  • the invention further relates to a method of treating degenerative or atrophic diseases, in particular senile dementias of the Alzheimer type, multiple sclerosis, Duchesne's myopathy and AIDS by administration of at least one of the compounds. previously described or of a para-chloro-phenoxyacetate salt of THA.
  • routes of administration of such compounds are those customary for these types of treatment, in particular by oral, parenteral or intravenous route.
  • Figures 1 and 20 respectively representing the nuclear magnetic resonance (NMR) spectra of the HBA ascorbate and of the final compound of Example 11.
  • Figures 2, 4, 7, 9, 10, 11, 13, 15 , 17 and 19 representing the infrared spectra (IR) of the compounds described in examples 1, 2, 4, 5, 6, 7, 8, 9, 10 and 11.
  • Figures 3, 5, 6, 8, 12, 14 , 16 and 18 represent the Ultraviolet (UV) spectra obtained on a BECKMANN-D64 spectrophotometer of the compounds described in examples 1, 2, 3, 4, 7, 8, 9, 10.
  • Example 1 - Preparation and characterization of ascorbate THA ascorbate can be represented by the structural formula (I):
  • the two solutions are then mixed and a final pH of between 5 and 7 is obtained.
  • Two characteristic effects are observed, on the one hand an exothermic effect, the mixture of the two solutions giving off heat, and on the other hand a bathochro effect, the two constituents being colorless and the final product being yellow or yellowish.
  • the excess solvent is removed in a water bath under vacuum until dry.
  • a light yellow microcrystalline powder is then obtained, soluble in water, in alcohols and in glycols, and having a melting point in capillary tube of 174 ° C.
  • the elementary analysis of the product obtained is as follows:
  • THA parachlorophenoxyacetate (C ? 1 H ? 1 N, 0 ⁇ Cl) THA parachlorphenoxy acetate can be represented by the structural formula (II)
  • the infrared spectrum of the final compound is shown in Figure 4 and the UV spectrum in Figure 5, highlighting 4 characteristic peaks at 282 nm, 252 nm, 248 nm and 206 nm.
  • Example 3 Preparation and characterization of _.__ diftétra- hydro 1,2,3,4 acridinyl-5) thio-urea
  • the di (te rahydro-l, 2,3,4 acridinyl-5) thio urea can be represented by the structural formula (III)
  • THA base 4 g is added in cold in 50 m of absolute ethanol, in a 150 ml container fitted with a cooler, with magnetic stirring, and which can be heated in a water bath.
  • the solution is slightly warm to dissolve all the HAT. It is cooled and 5 ml of carbon sulfide are introduced.
  • the product obtained is in the form of a yellow microcrystalline powder having a melting point of 268 ° C.
  • the centesimal analysis of the product is as follows:
  • THA pamoate f ⁇ M HN, 0 ⁇ THA pamoate can be represented by the following developed formula (IV):
  • the product obtained is in the form of fine colorless crystals soluble in alcohols and glycol and having a melting point of 256 ° C.
  • the centesimal analysis gives the following results: Carbon% 73.70 Hydrogen% 5.15 Nitrogen% 4.77
  • the infrared spectrum of the compound is shown in Figure 7 and its UV spectrum in Figure 8, highlighting 5 characteristic peaks at 209 nm, 238 np, 289 nm, 302 nm and 318 nm.
  • N alpha-adamantanyl THA (C, .H 7R N?)
  • N alpha-adamantanyl THA has the following structural formula:
  • THA base 1 g is THA base is dissolved separately in 25 ml of absolute ethyl alcohol.
  • the two solutions previously obtained are mixed with magnetic stirring; a change in pH and an exothermic reaction are observed.
  • the reaction is allowed to proceed for 30 min with stirring and then the excess alcohol is removed in a water bath under vacuum until dry.
  • a product is obtained with a yield of approximately 95% in the form of a colorless microcrystalline powder, insoluble in water, soluble in alcohols, glycols and in acetone and having a melting point of 108 ° C.
  • N alpha-amino adamantanyl THA can be represented by the following structural formula:
  • THA hydrochloride 1.18 g are introduced into a mortar with a capacity of 100 ml, which are finely pulverized, and then 0.94 g of alpha-amino adamantane hydrochloride is introduced in small portions. After mixing these two powders, spraying is continued for another 15 minutes in the cold.
  • the product obtained is in the form of fine colorless crystals soluble in alcohols, glycols and in water and having a melting point of 250 ° C.
  • the centesimal analysis gives the following results:
  • the N (isatinyl-5) THA can be represented by the following structural formula:
  • Adenosinyl THA (C.. H 7 N 7 0_) Adenosinyl THA can be represented by the following structural formula:
  • the compound obtained has an infrared spectrum shown in Figure 13, and a UV spectrum shown in Figure 14 on which we will note characteristic peaks at 212.5 nm, 243.5 nm and 318.5 nm.
  • the product obtained is in the form of fine colorless crystals soluble in alcohols, glycols in water and having a melting point of 208 ° C.
  • the centesimal analysis gives the following results:
  • Inosinyl THA (C. HN * 0.) Inosinyl THA can be represented by the following developed formula:
  • the procedure is similar to that described in Examples 5 and 6, namely that one reduces to a fine powder, cold in a mortar, successively 1.18 g of THA hydrochloride and then gradually in small portions 1.35 g inosine base by extending the spray for 15 minutes.
  • the product obtained is in the form of fine colorless crystals soluble in alcohols, glycols, in water and having a melting point of 216 ° C.
  • THA alpha-ketoglutarate can be represented by the following formula:
  • the method of preparation is similar to the method of preparation of the compound of Example 2, the parachlorophenoxyacetic acid being replaced by alpha-ketoglutaric acid and the mixture of this compound with THA being progressively
  • the final compound is in the form of a microcrystalline powder or fine colorless crystals having a melting point of 122 ° C.
  • the UV spectrum shows the characteristic bands of HAT.
  • the infrared spectrum of the final compound is shown in Figure 19 and its Nuclear Magnetic Resonance spectrum is shown in Figure 20.
  • the calculated LDs are 37 mg for THA hydrochloride (total mortality at 50 mg and total survival at 20 mg / kg) and 26 mg for THA ascorbate.
  • the therapeutic dose of HAT is 100 to 200 mg per 24 hours per os, or 1.6 to 3.2 mg / kg, which corresponds to about 1/12 of the LD 50 ( ip) in mice. Keeping the same ratio, the dosage would be 1 to 2 mg / kg for HAT ascorbate per day in humans, or 70 to 140 mg per 24 h.
  • cirrhosis is caused in rats by repeated injection of carbon tetrachloride in order to study on this model the ⁇ s effects of THA in the form of hydrochloride or ascorbate.
  • All the animals then receive orally for four days, at a rate of one administration per day (between 11 a.m. and 11:30 a.m.), 1.25 mg / kg of carbon tetrachloride mixed in equal parts with d oil. 'olive.
  • the animals receive intraperitoneally after the third administration of tetrachloride (1/2 h after) and 4 times (12 h, 20 h, 8 h, 16 h): - either physiological solution [ 1 ml / kg (10 rats)] or THA hydrochloride solution (2 mg / kg / ml) corresponding to 1.57 mg of THA in base form (10 rats) or THA ascorbate (2 mg / kg / ml) corresponding to 1.06 mg of HAT (10 rats)
  • the animals are examined for the establishment of a neurological score, then sacrificed (after weighing).
  • a blood sample is taken, for the study of hepatic enzymes, on heparin, and the plasma, quickly separated after centrifugation, is stored at 0 ° C overnight.
  • Treatment with ascorbate or HAT hydrochloride does not significantly change the gross appearance of the liver.
  • Table II collates the results given with carbon tetrachloride and the various treatments. Table II: Neurological score
  • HAT causes a very significant decrease in spontaneous motor activity, the rats remain prostrate in the cage. HAT ascorbate does not have this action, no doubt due to the psychostimulatory action of ascorbate. 4 - Biological results on plasma
  • ASAT Aspartate amino transferase
  • ALAT Alanine amino transferase
  • P.OH alkaline phosphatase
  • GT Glutamine transferase
  • Table IV Result of the hepatic enzyme assessment
  • the THA ascorbate obtained from purissime THA has very low hepatotoxicity.
  • the activity on the cholinergic domain of HAT has been demonstrated in animals and in humans. HAT inhibits cholinesterase and increases the transfer of choline to the nerve endings.
  • HAT ascorbate which has a greater effect on retro-viruses. Its water-soluble dosage form allows intravenous infusions and injections in hospitals.
  • HAT ascorbate has given very good results: increase in the number of CD 4 lymphocytes of the patients in significant proportions; decrease in antigens p 24, - regression of opportunistic diseases.
  • THA ascorbate is as active as THA for the treatment of AIDS, in lower doses than base THA and it can be administered as an infusion thanks to its solubility in water, which has a big advantage.
  • the dosage is 70 to 140 mg per 24 h.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
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  • Communicable Diseases (AREA)
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  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP90913286A 1989-08-25 1990-08-24 5-amino-1,2,3,4-tetrahydroakridinderivate und ihre anwendung als arzneimittel Withdrawn EP0487623A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8911283 1989-08-25
FR8911283A FR2651230B1 (fr) 1989-08-25 1989-08-25 Derives de la 5-amino-1,2,3,4 tetrahydro-acridine et applications comme medicaments.

Publications (1)

Publication Number Publication Date
EP0487623A1 true EP0487623A1 (de) 1992-06-03

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ID=9384932

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90913286A Withdrawn EP0487623A1 (de) 1989-08-25 1990-08-24 5-amino-1,2,3,4-tetrahydroakridinderivate und ihre anwendung als arzneimittel

Country Status (5)

Country Link
EP (1) EP0487623A1 (de)
JP (1) JPH05500055A (de)
CA (1) CA2064999A1 (de)
FR (1) FR2651230B1 (de)
WO (1) WO1991002725A1 (de)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9103752D0 (sv) * 1991-12-18 1991-12-18 Astra Ab New compounds
RU2036198C1 (ru) * 1993-04-01 1995-05-27 Товарищество с ограниченной ответственностью "Полисан" N-МЕТИЛ-N-( α,D -ГЛЮКОПИРАНОЗИЛ) АММОНИЯ-2-(АКРИДОН-9-ОН-10-ИЛ)АЦЕТАТ(ЦИКЛОФЕРОН), ОБЛАДАЮЩИЙ ИНТЕРФЕРОНОГЕННОЙ, ПРОТИВОВИРУСНОЙ, В ТОМ ЧИСЛЕ АНТИВИЧ, АНТИПАРАЗИТАРНОЙ, АНТИПРОМОТОРНОЙ И РАДИОПРОТЕКТИВНОЙ АКТИВНОСТЬЮ
PL207853B1 (pl) * 2000-04-04 2011-02-28 Fundacja Rozwoju Diagnostyki I Terapii Nowe (1-adamantyloamino)pirydyny, sposób ich wytwarzania i zastosowanie medyczne
DE10132726A1 (de) 2001-07-05 2003-02-27 Gruenenthal Gmbh Verwendung von substituierten gamma-Lactonverbindungen als Arzneimittel
GB0223494D0 (en) * 2002-10-09 2002-11-13 Neuropharma Sa Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease
GB0316094D0 (en) 2003-07-09 2003-08-13 Neuropharma Sa Acetylcholinesterase dual inhibitors
WO2012154879A2 (en) * 2011-05-09 2012-11-15 Van Andel Research Institute Autophagy inhibitors
CN105330646B (zh) * 2015-12-04 2019-05-24 上海勋和医药科技有限公司 一种抗肿瘤药马来酸来那替尼的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3860M (fr) * 1962-12-21 1966-01-24 Madan Ag Acides halogénophénoxyacétiques et leurs sels.
US4816456A (en) * 1986-10-01 1989-03-28 Summers William K Administration of monoamine acridines in cholinergic neuronal deficit states
US4985430A (en) * 1987-12-03 1991-01-15 Mitsubishi Kasei Corporation 9-acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9102725A1 *

Also Published As

Publication number Publication date
FR2651230A1 (fr) 1991-03-01
WO1991002725A1 (fr) 1991-06-07
FR2651230B1 (fr) 1992-03-13
JPH05500055A (ja) 1993-01-14
CA2064999A1 (fr) 1991-02-26

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