Development of Methods of Synthesising Active Pharmaceutical Substances and Study of Pharmacological Profile

On 2 December 2013, JSC Olainfarm entered into an agreement with the State Education Development Agency No. 2013/0030/2DP/2.1.1.1.0/13/APIA/VIAA/001 on the implementation of the European Regional Development Fund project “Development of methods of synthesising active pharmaceutical substances and study of pharmacological profile”. The overall aim of the project is to develop a new product for the treatment of neurodegenerative peripheral and central nervous system conditions.

In order to develop a new neurodegenerative drug substances, innovative approaches will be employed, which will be made possible, owing thanks to a successful synergy between the well-known scientific expertise of the Latvian Institute of Organic Synthesis and the competence of JSC Olainfarm in the development of innovative pharmaceutical products.

It is expected to complete the project by 31 August 2015.

The total project costs are 570,030.90 EUR. Of these costs, 442,642.61 EUR are the total eligible project costs, whereas the financing amount of European Regional Development Fund is 287,717.49 EUR.

 

Project chronology:

  • On 1 April 2014, amendments No. 1/2014/2DP/212 took effect, which introduced changes in the scientific staff involved in the project, and project costs were converted to the euro currency as well.

 

On 3 March 2014, the 1st contract research report was received from the Latvian Institute of Organic Synthesis. Achievements of the project in the 1st report period:

Chemistry:

  1. Substance A (the structure is confidential) — the study covered the generation of an intermediate product in an oxidation reaction in base, using air oxygen or Oxon as the oxidant. The study also looked at the intermediate product reaction with organomagnesium in zinc chloride.
  2. Substance B (the structure is confidential) — the first synthesis stages have been developed. A total of 70 catalytic hydrogenation experiments have been performed.
  3. Substance C (the structure is confidential) — 30 crystallisation experiments have been performed with chiral acids to obtain optically pure isomers.

Pharmacology:

  1. Research of anti-inflammatory activity of preparation D (the structure is confidential) has been performed. The effect of preparation F (the structure is confidential) on the post-stroke rehabilitation period was studied.

 

On 30 June 2014, the 2nd contract research report was received from the Latvian Institute of Organic Synthesis. Achievements of the project in the 2nd report period:

Chemistry:

  1. Substance A (the structure is confidential) — hyperesterification reaction conditions have been developed. Crystallisation to obtain a diastereomerically pure product was tested.
  2. Substance B (the structure is confidential) — the process of synthesis has been optimised, transfer hydrogenation reaction has been studied, at least 200 hydrogenation experiments have been carried out.
  3. Substance C (the structure is confidential) — studies have been performed regarding the synthesis of the critical raw material from malic acid in a 3-stage synthesis.

Pharmacology:

  1. Research of the analgesic and anti-inflammatory activity of the preparation D (the structure is confidential) was performed in comparison with the preparation E (the structure is confidential).
  • On 25 July 2014, the Progress Report and a payment request was submitted at the State Education Development Agency.
  • On 30 July 2014, an announcement was disseminated through mass media “Olainfarm in co-operation with the Latvian Institute of Organic Synthesis are developing a technology for the production of new active pharmaceutical substances and optically active compounds”; afterwards, this project was reported on by the news agency LETA, BNS, portals medicine.lv, farmacija-mic.lv, reitingi.lv, as well as the radio SWH medicine news.
  • On 5 September 2014, 65 % of the European Union co-financing payment to JSC Olainfarm was performed in the amount of 94,823.80 EUR, as per eligible costs approved by the State Education Development Agency in the amount of 145,882.78 EUR for the report period from 02.01.2014 until 30.06.2014.

 

On 30 September 2014, the 3rd contract research report was received from the Latvian Institute of Organic Synthesis. Achievements of the project in the 3rd report period:

Chemistry:

  1. Substance A (the structure is confidential) — the conditions of the Grignard reagent’s nucleophilic addition reaction were studied, in an attempt to minimise the formation of the reduced by-product. The hyperesterification reaction is further optimised. Diastereomeric purity of the obtained product was improved by optimising the crystallisation conditions.
  2. Substance B (the structure is confidential) — the conditions that would allow reducing the formation of undesirable alkalising reagent disintegration by-products were studied. The cyclical intermediate product structure was established.
  3. Substance C (the structure is confidential) — studies were performed to obtain intermediate products of racemic and enantiomerically pure amines.

Pharmacology:

  1. Study of anti-inflammatory activity of the preparation D (the structure is confidential) continued with the carrageenan triggered foot oedema test.

 

On 15 December 2014, the 4th contract research report was received from the Latvian Institute of Organic Synthesis. Achievements of the project in the 4th report period:

Chemistry:

  1. Substance A (the structure is confidential) — optimised keto ester reaction with Grignard reagent in various additives. A method of purification of the intermediate product using hydrolysis of esters and acid/base extraction in water environment was developed. Esterification reaction conditions were studied, using CDI as the splicing reagent.
  2. Substance B (the structure is confidential) — amine alkylation reaction conditions have been optimised. Work has been done with the technology of purification of the synthesised product by means of crystallisation of various salts.
  3. Substance C (the structure is confidential) — studies were performed to obtain enantiomerically pure hydroxymethyl intermediate products.

Pharmacology:

  1. A study of the analgesic activity of the preparation G (the structure is confidential) in the partial ligation model of sciatic nerve.
  • On 29 January 2015, the Second Progress Report and a payment request was submitted at the State Education Development Agency.

 

On 31 March 2015, the 5th contract research report was received from the Latvian Institute of Organic Synthesis. Achievements of the project in the 5th report period:

Chemistry:

  1.  Substance A (the structure is confidential) — scaling of the Grignard reaction and acid discharge obtained after hydrolysis was performed in laboratory conditions in 70 g loads. Diastereomerically pure critical intermediate product was isolated and its structure was proven. Analytical methods of control of admixtures and diastereomeric purity were developed. Optimisation of the last stage of synthesis — quaternisation — was performed.
  2. Substance C (the structure is confidential) — conditions of obtaining the critical methylamino intermediate product were optimised and both enantiomers of this compound were isolated in salt form. Crystallisation conditions and analytical methods for the control of enantiomeric purity were developed.
  3. Substance B (the structure is confidential) — the synthesis of the critical intermediate product — dehydro-B — and isolation in salt form have been optimised. The stoichiometric composition of the isolated salt has been studied. Hydrogenation conditions have been optimised — scaling experiments of the hydrogenation reaction have also been performed, and the structure of the main by-products of the reaction has been elucidated. Development of analytical methods for the final control and the admixture control of reactions has been performed.

Pharmacology:

  1. A study of the anti-neuropathic pain activity of the preparation G (the structure is confidential) in a long-term administration model has been performed. Bioavailability of the preparation has been studied.

On 27 May 2015, the Third Progress Report and a payment request was submitted at the State Education Development Agency.

  • On 31 July 2015, the contract study with the Latvian Institute of Organic Synthesis was concluded and the final report on the study results was submitted.
  • The project was finalised on 31 August 2015.
  • On 9 September 2015, the Fourth and Final Progress Report and a payment request was submitted at the State Education Development Agency.
  • On September 28, 2015 was approved and paid support funding. The total public funding received 287 717.49 EUR (ERDF).

Knowledge and intellectual property rights gained during the project will allow JSC Olainfarm to develop new drugs to expand the company’s product portfolio, to increase competitiveness and exportability. In the future, it will contribute positively to the economies of Latvia and the European Union.

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SigitaDevelopment of Methods of Synthesising Active Pharmaceutical Substances and Study of Pharmacological Profile