Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor
Reexamination Certificate
1999-07-30
2001-09-18
Tran, Hien (Department: 1764)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
C422S131000, C422S134000, C422S135000, C422S138000, C422S110000
Reexamination Certificate
active
06290915
ABSTRACT:
PRIOR FOREIGN APPLICATIONS
This application is a 35 USC §371 filing of PCT/GB98/03761, filed Dec. 15, 1998, and claims priority from GB patent application number 9726482.4, filed Dec. 15, 1997.
1. Field of the Invention
The present invention relates to a method and apparatus for chemical synthesis. In particular, but not exclusively, the invention relates to a method of and apparatus for combinatorial chemistry for the synthesis of potential drug candidate molecules.
2. BACKGROUND OF THE INVENTION
The process of drug discovery has historically adopted the following development pathway. First, specific molecular targets f or drug intervention are defined through in-depth molecular and cellular studies. Once the target is defined, an assay system is developed to monitor biological or kinetic activity of potential drug molecules. Small libraries of chemicals are then synthesised and assayed to select those few that have apparent activity. The biological properties of those selected molecules are then studied on actual cells that are targeted for drug intervention. Those that seem to have favourable biological properties on natural cells then move on to chemical optimisation to improve their potency and selectivity. Their improved biological activity is reconfirmed and, those few that seem to be promising are then moved forward into pre-clinical animal studies to evaluate biological activity in vivo.
Combinatorial chemistry represents a novel approach for the synthesis of large collections of compounds for screening. This approach began in the laboratories of peptide chemists for the generation of peptide libraries. Due to the poor oral absorption and metabolic instability of peptides, non-peptide mimetic compounds (usually molecular weight of less than 500) have been developed. In combinatorial chemistry experiments, diverse chemical libraries can be produced by selecting sets of reactants, or building blocks, and reacting the sets with each other in all possible combinations thereby generating hundreds of thousands of individual small molecules. Libraries may consist of molecules free in solution, linked to solid particles or beads, or even arrayed on surfaces of modified microorganisms. Through the intelligent selection of building blocks, these libraries can be designed either as exploratory libraries, or as targeted libraries that are focused on certain structural hypotheses.
Combinatorial libraries are created in the laboratory by one of two methods, namely split synthesis or parallel synthesis.
In split synthesis, compounds are assembled on the surfaces of microparticles or beads. In each step, beads from previous steps are partitioned into several groups and a new building block is added. The different groups of beads are then recombined and separated once again to form new groups. The next building block is added, and the process continues until the desired combinatorial library has been assembled containing a random selection of molecules. Libraries resulting from split synthesis are characterised by the phrase “one bead, one compound.” Each bead in the library holds multiple copies of a single library member.
Combinatorial libraries can also be made by parallel synthesis, in which different compounds are synthesised in separate vessels (without remixing), often in an automated fashion. Unlike split synthesis, which requires a solid support, parallel synthesis can be done either on a solid support or in solution.
Planning and performing combinatorial experiments in the laboratory is a complex and time-consuming process and thus automation is desirable. Instrumentation systems to help speed combinatorial chemistry experiments are believed to be in development at a number of biotechnology and pharmaceutical companies.
WO94/05394 suggests adoption of reusable spatially addressable solid phase plates on which all the synthesis reactions such as deprotection, cleaving and washing, can take place. U.S. Pat. No. 5,324,483, U.S. Pat. No. 5,593,642, U.S. Pat. No. 5,565,173, U.S. Pat. No. 5,582,801, U.S. Pat. No. 5,567,391 and WO94/08711 disclose the use of reservoir blocks having a plurality of wells for multiple simultaneous synthesis. WO93/12427 discloses the automation of the cleaving, deprotecting and purification processes for solid phase polypeptides. Most of the above processes have been semi-automated with robotic attachments which perform various steps required in synthesis reactions including reagent delivery, changing of reaction/collection vessels, incubation and agitation of reaction mixture, cleavage of synthesised compound from solid support in a range of environments e.g. under pressure or in a vacuum.
U.S. Pat. No. 5,503,805 and WO95/12608 disclose the development of a device for solid phase split and mix chemical synthesis in a closed system. The synthesis is carried out between a parent and daughter reaction vessels. The reagents are transported around the system by flow tubes and valves for example back and forth between the parent and daughter vessels.
The synthesis of organic compounds poses many problems in automated instrumentation including developing a device which will accommodate the wide range of manipulations required for organic synthesis. The synthesis of organic compounds often requires varied conditions such as heating, cooling, agitation, an inert atmosphere etc. Also such synthesis requires chemical compatibility between the materials used in the apparatus for synthesis and the solvents and reactants. Therefore the instruments must be constructed of materials which are resistant to organic synthesis conditions and procedures.
SUMMARY OF THE INVENTION
The present invention seeks to provide an apparatus for preparing chemicals in an efficient manner.
According to a first aspect of the present invention there is provided a chemical synthesis apparatus, comprising a plurality of reagent inputs, an input for solid supports and an input for solvents, each input being connectable to a main fluid pathway via a respective switchable valve, the apparatus further including a reaction chamber fluidly connectable to the main fluid pathway by a respective switchable valve downstream of the inputs and the reaction chamber further including an outlet downstream of a barrier arranged to prevent passage of the solid supports but allow passage of unbound molecules. The invention thus provides an apparatus which provides automated production of chemicals without the need for robotic arms for switching trays or the like, as all the manipulations take place in the fluid pathway. It is particularly advantageous for the flow through the reaction chamber to be one way as this allows much greater control of the reaction taking place within the chamber. Versatility is maintained by all of the inputs being connectable to the reaction chamber.
Preferably, the reaction chamber is one of a plurality of reaction chambers, where each reaction chamber is fluidly connectable to the main fluid pathway by a respective switchable valve downstream of the inputs and each reaction chamber further includes an outlet downstream of a barrier arranged to prevent passage of said solid supports but allow passage of unbound molecules. In this way more than one reaction may be undertaken at a time.
It is advantageous if the, some or each of the reaction chambers is removable form the apparatus. Thus physically different reaction chambers, for example with different volumes or internal coatings, can be used in the apparatus depending on the desired reaction.
It is also advantageous if the, some or each reaction chamber includes means for stirring or agitating the contents of the chamber and/or includes temperature control means arranged to control the temperature in the reaction chamber.
In a preferred embodiment of the invention, the output of the, some or each reaction chamber is connectable to detector means. The present invention allows combined synthesis and screening. All the known methods as described above can only be used to carry out synthesis. The device from U.S. Pat. No. 5,565,17
French Martin Thomas
Palmer Derek Adeyemi
Heslin Rothenberg Farley & & Mesiti P.C.
Kalibrant Limited
Tran Hien
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