WO2009078040A2 - Composés induisant la reperfusion dans les tissus ischémiques - Google Patents

Composés induisant la reperfusion dans les tissus ischémiques Download PDF

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Publication number
WO2009078040A2
WO2009078040A2 PCT/IN2008/000836 IN2008000836W WO2009078040A2 WO 2009078040 A2 WO2009078040 A2 WO 2009078040A2 IN 2008000836 W IN2008000836 W IN 2008000836W WO 2009078040 A2 WO2009078040 A2 WO 2009078040A2
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WIPO (PCT)
Prior art keywords
ischaemic
compounds
tissue
diabetic
tissues
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Ceased
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PCT/IN2008/000836
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English (en)
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WO2009078040A3 (fr
Inventor
Debatosh Datta
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Individual
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Individual
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Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine

Definitions

  • the present invention relates to novel diamino C ⁇ - Cu compounds having a straight chain with two terminal amino groups and a -COOH group, wherein the number of carbon atoms in the said side chain (R-group) varies between seven and eleven, said compounds being capable of effecting formation of new blood vessels in ischaemic tissues. More particularly this invention pertains to preparation and effective utilization of compound having a straight chain structure with number of carbon atoms in the varying between 7 and 11, additionally having a plurality of amino groups on the carbon atoms at two extremities and carrying a carboxyl group on ⁇ -carbon atom beside an amino group, said amino groups being capable of forming electrostatic and/ or hydrogen bonds under condition of ischaemia following administration of said compounds resulting in controlled angiogenesis.
  • Ischaemic tissues are the organs or parts of human body which on occasions or under special circumstances get no or less supply of blood, either temporarily or permanently, due to spasm, obstruction or narrowing of blood vessels. Such incidence of deprivation of blood supply could be due to formation of blood clots or thrombi obstructing the blood vessel, or else the reason could be metabolic. Either way, the process of obstruction is gradual, spanning over years, though the symptoms of obstructions are discernible and results could be devastating, leading even to mortality.
  • the most common instance of ischaemic tissue leading to severe discomfort or/ and death is ischaemic cardiac tissue or myocardium.
  • the process of obstruction of the coronary vessel(s) is more often metabolic in nature, known as "atherosclerosis", where a particular type of lipids get deposited on the interior walls of coronary vessels restricting or constricting the effective diameter over the years.
  • the affected part of myocardium gets progressively decreasing amounts of requisite gases and nutrients.
  • the narrowing process crosses a critical limit, the affected portion of myocardium dies in an acute circumstance known as 'myocardial infarction'.
  • a similar instance affecting increasing number of people is cerebral stroke where cerebral/ neural tissues get affected due to lack of blood supply to the affected region.
  • the conditions may sound or appear to be different or divergent from each other, they do have a common denominator, namely, ischaemia or lack of blood supply to the tissues of the affected part.
  • a common answer to both types of afflictions narrated above appears to be the process of revascularization, where either the available vessels are recanalized by removal of plaque formed therein, bypassed or grafted (replaced).
  • a more prudent and safe mode of treatment would be development of collateral vessels supplying the ischaemic tissues.
  • the present invention deals with low- molecular weight, straight chain compounds with 7-11 membered carbon chain (R-Group) having amino groups at two terminal carbon atoms and a COOH group, having the capacity to form charged centres on N-atoms, which in turn bond with the charges residing on the receptor protein and angiogenic factor and/ or growth factor.
  • R-Group 7-11 membered carbon chain
  • angiogenic factors referred to above are known to be liberated in excess by the endothelial cells in the ischaemic tissue. These factors (AFs) have their receptors (a kind of protein) in the endothelial cell membrane. Establishment of a bridge by the protonated compound moiety brings about an activation of capillary with consequent angiogenesis through endothelial cell division and migration.
  • Preparation of the individual compounds may be done by following the scheme of reactions shown in the drawing accompanying this specification, which has been illustrated for the first representative member of the novel compounds of this invention, namely, 1,7-diamino-heptanoic acid.
  • Adequate selection of the reaction component before arriving at intermediate nitrile compound (6) will result in higher homologues of diamino alkanoic acids with 8, 9, 10 or 11 number of carbon atoms in the chain.
  • the experiments have been conducted with the C7 compound as a representative member of the compounds with 7-11 carbon atoms in the carbon chain, each with a carboxyl group on the ⁇ -carbon atom and 2 terminal amino groups.
  • RP receptor protein
  • AF/ GF angiogenic factor/ growth factor
  • the native representative compound as in (10) of Fig. I gets activated by a process of protonation because of excess proton build-up in ischaemic tissues which triggers the change in conformation of the compound (e.g. diaminoheptanoic acid moiety) , and enabling it to fit snugly between RP and AF/ GF.
  • RP - ligand
  • AF/ GF ligand
  • the main object of this invention is to bring about angiogenesis in ischaemic tissues by employing a novel low molecular weight compound like 1,7- diamino-hexa- 1 -noic acid, a representative member selected from C 7 -Cn alkanoic acids having two terminal amino groups and a terminal -COOH group on ⁇ -carbon atom, pharmaceutically acceptable salts and/ or derivatives thereof which are capable of bringing about formation of new blood vessels in ischaemic tissues.
  • a novel low molecular weight compound like 1,7- diamino-hexa- 1 -noic acid, a representative member selected from C 7 -Cn alkanoic acids having two terminal amino groups and a terminal -COOH group on ⁇ -carbon atom, pharmaceutically acceptable salts and/ or derivatives thereof which are capable of bringing about formation of new blood vessels in ischaemic tissues.
  • Such compound gets protonated and consequently activated in the ischaemic (e.g.
  • a further object of this is to provide novel C 7 -Cn alkanoic acids, having a straight chain with two terminal amino groups and a carboxyl group on the ⁇ -carbon atom.
  • a still further object of this invention is to provide a process for preparing the aforesaid novel compound(s) and their pharmaceutically acceptable salts and/or derivatives thereof, which may be in laevo, in dextro, active laevo, active dextro or oligomeric forms.
  • Another object of this invention is to provide a process for preparing the aforesaid novel compounds each with two terminal amino groups.
  • novel diamino alkanoic acids having a straight chain with two terminal amino groups and a -COOH group as described earlier, wherein the number of carbon atoms in the R- group in the side chain varies between 7 and 11, the said compounds being capable of effecting formation of new blood vessels (capillary) in ischaemic tissues, and/ or pharmaceutically acceptable salts and/ or derivatives thereof.
  • the present invention also relates to a process for preparing the aforementioned novel diamino alkanoic acids, and pharmaceutically acceptable salts and /or derivatives thereof, characterized in that the said preparation is carried out in accordance with the sequence of reactions shown in the accompanying drawing wherein the undernoted abbreviations have been used:
  • Doxorubicin treatment increased SGPT to 62 IU/dL, SGOT to 81 IU/dL and ALP to 45 KA units in 1,7-diamino alkanoic acid compound.
  • Compound of this invention at doses between 0.1 mg/kg body weight and 30 mg/kg body weight showed no significant toxicity.
  • Example - 2 i Screening of different cells
  • Human lung epithelial cells (A549 which are highly metastatic and elaborates excess levels of angiogenic factor(s)) were grown on coverslip in DMEM/F-12 (1: 1) or RPMI 1640 media supplemented with 10% FBS, insulin (0.1 units/ ml), L-glutamine (2 mM), sodium pyruvate (100 ⁇ g/ml), nonessential amino acids (100 ⁇ M), penicillin (100 units/ml) and streptomycin (100 ⁇ g/ ⁇ l). Cells were incubated at 37 0 C in a humidified atmosphere of 5% CO2.
  • the pH of the medium was maintained at 6.2 for the binding assay of VEGF to its receptor in the presence of compound.
  • the cells were pre-treated with media alone or with 25 ⁇ g/ml compound for 30 min.
  • the cells were then incubated with 10 ng/ml human VEGF for further 30 min at 37 0 C in a humidified atmosphere of 5% CO2.
  • the cells were fixed and stained with anti-VEGF antibody coupled with Alexaflour 488. The cells were visualized in Zeiss-confocal microscope.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention porte sur une nouvelle classe d'acides diamino alcanoïques possédant une chaîne linéaire de sept à onze atomes de carbone avec deux groupes amine terminaux et un groupe -COOH (attaché à un atome de carbone alpha), qui sont capables d'entraîner la formation contrôlée de nouveaux vaisseaux sanguins, et sur des sels pharmaceutiquement acceptables et/ou dérivés de ces derniers. Les composés précités peuvent se présenter sous la forme laevo, dextro, laevo activée, dextro activée ou oligomère. L'invention se rapporte également à un procédé de préparation de la nouvelle classe de composés précitée, qui est illustrée dans la figure annexe.
PCT/IN2008/000836 2007-12-17 2008-12-16 Composés induisant la reperfusion dans les tissus ischémiques Ceased WO2009078040A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1690/KOL/2007 2007-12-17
IN1690KO2007 2007-12-17

Publications (2)

Publication Number Publication Date
WO2009078040A2 true WO2009078040A2 (fr) 2009-06-25
WO2009078040A3 WO2009078040A3 (fr) 2010-11-25

Family

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PCT/IN2008/000836 Ceased WO2009078040A2 (fr) 2007-12-17 2008-12-16 Composés induisant la reperfusion dans les tissus ischémiques

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WO (1) WO2009078040A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10717703B2 (en) 2017-08-21 2020-07-21 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705892A (en) * 1985-05-22 1987-11-10 Merck & Co., Inc. Process for preparing alpha,omega-diamino acids
WO2002094256A1 (fr) * 2001-05-23 2002-11-28 Debatosh Datta Lysine et/ou analogues et/ou polymeres de ces derniers destines a promouvoir la cicatrisation et l'angiogenese

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10717703B2 (en) 2017-08-21 2020-07-21 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
US11505522B2 (en) 2017-08-21 2022-11-22 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5- diamino-5-oxopentanoate
US11912644B2 (en) 2017-08-21 2024-02-27 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
US12435028B2 (en) 2017-08-21 2025-10-07 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate

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