WO2009083724A1

WO2009083724A1 - Processes for the preparation of thalidomide

Info

Publication number: WO2009083724A1
Application number: PCT/GB2008/004290
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Rajendra Narayanrao Kankan; Manohar Surve; Dilip Birari
Original assignee: Cipla Limited; Curtis, Philip, Anthony
Priority date: 2007-12-27
Filing date: 2008-12-24
Publication date: 2009-07-09

Abstract

The present invention provides a process for the preparation of thalidomide (I) comprising: i) reacting a compound of formula (II), where one of R represents -OH or -NH2 and the other of R represents -NH2 or -OH, respectively, with a phthaloylating agent in the presence of a base and a a non-polar organic solvent to obtain a phthaloyl derivative where R have the same meanings as above; and ii) dehydrating the phthaloyl derivative using a dehydrating agent selected from an acid anhydride, an acid halide, an ion exchange resin or a molecular sleve to obtain thalidomide (I).

Description

PROCESSES FOR THE PREPARATION OF THALIDOMIDE

Technical Field of the Invention

The present invention relates to simple and novel processes for the preparation of 2-(2,6- dioxo-3-piperdinyl)-1 H-isoindole-1 ,3-(2H)-dione or its pharmaceutically acceptable salts.

Background of the Invention

2-(2,6-dioxo-3-piperdinyI)-1 H-isoindole-1 ,3-(2H)-dione is commonly known as thalidomide. Thalidomide is represented by the following formula (I).

Thalidomide was first disclosed in 1957 for use as an antiemetic in pregnant women. Even today thalidomide is of great importance because of its use in various types of diseases such as cancer, leprosy, rheumatoid arthritis, AIDS and Crohn's disease. Thalidomide is also used as immunomodulator.

GB768821 discloses a process for the preparation of thalidomide which involves reacting N-phthalyl glutamic acid or N-phthalyl glutamic acid anhydride with urea or thiourea or dry gaseous ammonia in the presence or absence of solvent. The reaction is carried out at higher temperature, for example 170 - 180⁰C. The yield of the reaction is about 60-70%. However, the processes disclosed in GB768821 involve violent evolution of carbon dioxide or carbon disulphide and ammonia which is dangerous, difficult to manage and also not environment friendly.

EP1004581 B discloses a process for the preparation of thalidomide in which N- phthaloylglutamine or N-phthaloylisoglutamine is cyclised with N.N'-carbonyldiimidazole by heating them in anhydrous tetrahydrofuran and in the presence of an inorganic base such as sodium carbonate or sodium bicarbonate.

US20060211728 discloses a process for the preparation of thalidomide (example 1) which involves reaction of t-butoxycarbamate with carbodiimide in tetrahydrofuran (THF) to give an imide. This imide is then deprotected with trifluoroacetic acid in methylene dichloride (MDC) at room temperature to yield aminoglutarimide which on reaction with phthalic anhydride in refluxing THF in the presence of triethylamine gives thalidomide.

US20050272934 discloses a process for the preparation of thalidomide which involves reaction of glutamine with a phthaloylating agent to give N-phthaloylglutamine, which is converted to thalidomide by addition of a condensing agent like carbonyl diimidazole or thionyl chloride in the presence of polar aprotic solvent. However, carbonyl diimidazole is very costly and thionyl chloride is corrosive, so the process disclosed in US20050272934 is unsuitable for industrial scale-up. Furthermore, polar aprotic solvents as used in the process generally have a high boiling point and are difficult to remove completely from the final product at an industrial level. Still further, in the case of the use of pyridine as a solvent, the reaction mass is acidified with hydrochloric acid which is industrially not preferable. Yet further, pyridine is hazardous, hence not preferred industrially.

US20070173647 discloses the preparation of dicarboxylic imides by reaction of acid anhydride with urea in a high boiling solvent, specifically thalidomide is obtained by reaction of phthaloyl glutamic acid anhydride with urea in high boiling solvent.

Some of the reactions used in the prior art involve evolution of gases leading to foaming of the reaction mass which is dangerous and difficult to manage. Other reactions use costly reagents like carbonyl diimidazole or corrosive reagents like thionyl chloride. Some reactions are carried out at high temperatures which are not easy to achieve at industrial level and not environment friendly. Further, the use of urea or thiourea leads to an impure product due to thermal decomposition. It has now surprisingly been found that thalidomide may be prepared by a simple reaction which avoids use of urea/thiourea and costly and/or corrosive reagents. The reaction is carried out at a moderate temperature which is environmentally friendly.

Summary of the Invention

It is an object of the present invention to provide a simple process for the preparation of thalidomide which may be carried out in one pot and which may involve no isolation of intermediates formed during the process.

According to a first aspect of the present invention, there is provided a process for the preparation of thalidomide (I) comprising: i) reacting a compound of formula (II), where one of R represents -OH or -NH₂ and the other of R represents -NH₂ or -OH, respectively,

(ID with a phthaloylating agent in the presence of a base and a non-polar organic solvent to obtain a phthaloyl derivative where R have the same meanings as above,

Phthaloyl Derivative and ii) dehydrating the phthaloyl derivative using a dehydrating agent selected from an acid anhydride, an acid halide, an ion exchange resin or a molecular sieve, to obtain thalidomide (I).

(D

The compound (II) may be glutamine H2NCH(CO2H)CH2CH₂C(O)NH2 or isoglutamine (H₂NCH(CONH₂)CH₂CH₂CO₂H).

Advantageously, steps (i) and (ii) are carried out without isolation of any of the intermediates formed in the process. Alternatively or in addition, the process is carried out in one pot. In an embodiment, the solvent from step (i) is distilled out partially before the addition of dehydrating agent.

Preferably, steps (i) and (ii) are carried out simultaneously, i.e. the compound of formula (II) is reacted with the phthaloylating agent in the presence of the base, non-polar organic solvent and dehydrating agent to obtain thalidomide.

In an embodiment, the phthaloylating agent is selected from the group consisting of phthalic acid, derivatives of phthalic acid (such as phthalic anhydride, N- carbethoxyphthalimide and phthaloyl chloride) and esters of phthalic acid (such as ethyl phthalate and dimethyl phthalate). Preferably, the phthaloylating agent is phthalic anhydride or N-carbethoxyphthalimide. In an embodiment, the phthaloylating agent is phthalic anhydride. In another embodiment, the phthaloylating agent is N- carbethoxyphthalimide. In an embodiment, the base is an organic base, preferably an alkyl amine, more preferably a tertiary alkyl amines Most preferably, the base is selected from triethyl amine, trimethyl amine and dϋsopropyl ethyl amine. Preferably, the base is triethyiamine.

In an embodiment, the non-polar organic solvent is an aromatic hydrocarbon or a non- polar aprotic organic solvent. The solvent is preferably non-basic. The use of a base and a non-basic solvent according to the present invention, rather than the use of a basic solvent, is advantageous as it avoids the need for neutralization of the reaction mass. In US20050272934, particularly in Examples 1 , 2, 3 and 9, basic solvents are used in the coupling step and this requires subsequent acidification with HCl. Such acidification is not required in the present process. This lends the process of the present invention further advantages as fewer steps typically result in a higher-yield product. Typically, the solvent is selected from toluene, xylene, n-heptane, diethyl benzene, chlorobenzene, bromobenzene, iodobenzene, mesitylene, diphenyl ether and nitrobenzene. Preferably, the solvent is toluene.

In an embodiment, step (i) is carried out with azeotropic removal of the water formed during the coupling. In other words, water is produced during the coupling step and this water is removed azeotropically as the reaction progresses.

In an embodiment, the dehydrating agent is selected from a dehydrating agent that is not N,N-carbonyldiimdazole nor thionyl chloride. Preferably, the dehydrating agent is an acid anhydride, an acid halide, an ion exchange resin or a molecular sieve. The acid anhydride or acid chloride may have the formula X-C(O)-Y, wherein X is Ci to Ce alkyl and Y is Cl, Br or OAc. Suitably, X is methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, pentyl or hexyl. Y may be Cl. Preferably, Y is OAc and X is methyl. Alternatively, Y is Cl and X is methyl.

More preferably, the dehydrating agent is an acid anhydride or an acid halide. The acid anhydride may be acetic anhydride, trifluoroacetic anhydride or isobutyric anhydride. The acid halide may be acetyl chloride, acetyl bromide or propionyl chloride. Preferably, the dehydrating agent is acetic anhydride or acetyl chloride.

Most preferably, the non-polar organic solvent is toluene and the dehydrating agent is acetic anhydride.

The dehydration may be carried out in the presence or absence of a solvent. Typically, the dehydration is carried out in the presence of a solvent. The dehydration is suitably carried out in a polar aprotic solvent selected from N,N-dimethyl formamide, N-methyl pyrrolidone, dioxane, dimethyl acetamide, sulfolane, dimethyl sulphoxide or hexamethyl phosphoramide.

After reaction of the dehydrating agent, the excess of dehydrating agent may be partially distilled out and the thalidomide isolated by crystallization. The crystallizing solvent may be selected from C1-C4 alcohols, ketones and esters. For example, the crystallizing solvent may be selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, isobutanol, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n- butyl acetate and mixtures thereof.

Another advantage of the process of the present invention is that the thalidomide product does not require recrystallization. This is to be contrasted with the process disclosed in US20050272934, in which the thalidomide product is isolated as a solid and then recrystallised. Again, fewer steps in the present process typically result in a higher yield product. Therefore, in an embodiment, the process of the present invention does not require recrystallization of the thalidomide product.

According to another aspect of the present invention, there is provided thalidomide prepared according to the process defined above. There is also provided a pharmaceutical composition comprising thalidomide prepared according to the process defined above together with one or more pharmaceutically acceptable excipients. Such excipients and compositions are well known to those skilled in the art. According to yet another aspect of the present invention, there is provided the use of thalidomide prepared according to the process defined above in medicine, particularly in the treatment of cancer, leprosy, rheumatoid arthritis, AIDS and Crohn's disease. There is also provided a method of treating cancer, leprosy, rheumatoid arthritis, AIDS and Crohn's disease comprising administering to a patient in need thereof a therapeutically effective amount of thalidomide prepared according to the process defined above.

Detailed Description of the Invention

In one embodiment of the present invention, thalidomide is prepared by the novel process in a single reactor which comprises reaction a compound of formula (II) with a phthaloylating agent to obtain a phthaloyl derivative of formula (II) and then converting the phthaloyl derivative to thalidomide, without isolating the intermediate phthaloyl derivative of formula (II).

Wherein, R--0H or -NH₂

In the context of the present invention, the term "without isolation" means that the product being referred to as not being isolated is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, "without isolation" may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.

The phthaloylating agent may be selected from the group consisting of phthalic acid, derivatives of phthalic acid (such as phthalic anhydride, N-carbethoxyphthalimide and phthaloyl chloride) and esters of phthalic acid (such as ethyl phthalate and dimethyl phthalate). The preferred phthaloylating agents are phthalic anhydride and N- carbethoxyphthalimide.

In another embodiment of the present invention, the reaction of the compound of formula (II) with the phthaloylating agent is carried out in a non-polar organic solvent selected from either aromatic hydrocarbons which may or may not be substituted or an aprotic organic solvent. The solvents may be selected from the group consisting of toluene, xylene, n- heptane, diethyl benzene, chlorobenzene, bromobenzene, iodobenzene, mesitylene, diphenyl ether and nitrobenzene. The preferred solvent is toluene.

In yet another embodiment of the present invention, the reaction of the compound of formula (II) with the phthaloylating agent is carried out in the presence of a base, particularly in the presence of an organic base, more particularly alkyl amines and further more particularly tertiary alkyl amines such as, but not limited to, triethyl amine, trimethyl amine, diisopropyl ethyl amine.

In another embodiment of the present invention, the conversion of the phthaloyl derivative of compound of formula (II) to thalidomide is carried out in the presence of a dehydrating agent such as an acid anhydride, an acid halide, an ion exchange resin or a molecular sieve. The acid anhydride may be acetic anhydride, trifluoroacetic anhydride or isobutyric anhydride. The acid halide may be acetyl chloride, acetyl bromide or propionyl chloride. The preferred dehydrating agents are acetic anhydride and acetyl chloride.

The thalidomide obtained may be further isolated using a suitable crystallizing solvent.

In another embodiment of the present invention, the solvent from step (i) is distilled out partially before the addition of dehydrating agent. Further, the dehydrating agent may be added with or without a suitable solvent. After reaction of the dehydrating agent, the excess of dehydrating agent may be distilled out and then a suitable crystallizing solvent may be added to the reaction mass. In an embodiment, the reaction mass is refluxed for up to 2 hours, or up to 3 hours, preferably for around half an hour. The reaction mass may then be cooled to a temperature ranging from 10⁰C to 30⁰C, preferably from 15°C to 20⁰C.

Typically, the solvent is a polar aprotic solvent which may be selected from the group consisting of N,N-dimethyl formamide (DMF), N-methyl pyrrolidone, dioxane, dimethyl acetamide, sulfolane, dimethyl sulphoxide and hexamethyl phosphoramide.

The crystallizing solvent may be selected from C-₁-C₄ alcohols, ketones and esters. For example, the crystallizing solvent may be selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, isobutanol, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, n-butyl acetate and mixtures thereof.

The compound of formula (II) and phthalic anhydride may be reacted at a temperature ranging from about 20°C to about 5O⁰C, preferably from about 20°C to about 30°C. After addition of the base, the temperature of reaction mass may be increased for example up to around 140°C, preferably up to a temperature ranging from about 105⁰C to about 110°C. Typically, the reaction mass is refluxed until reaction completion. After reaction completion, the temperature of the reaction mass may be lowered for example up to a temperature of about 5O⁰C. After addition of the dehydrating agent, the temperature of the reaction mass may be increased for example up to a temperature of around 140°C, preferably up to about 105°C to about 11O⁰C, typically under stirring.

The molar ratio of compound of formula (II) to phthalic anhydride may range from 1 :1 to 1 :1.5, preferably from 1 :1 to 1 :1.3.

The molar ratio of compound of formula (II) to organic base can range from 1 :1 to 1 :1.5, preferably from 1 :1 to 1 :1.3.

The molar ratio of compound of formula (II) to dehydrating agent may range from 1 :1 to 1 :5, preferably from 1 :1 to 1 :3. In an embodiment, the process of the present invention may be represented as shown below in reaction Scheme A:

SCHEME A

Wherein, R=-OH or -NH,

Phthalic anhydride (D)

Triethyl amine Toluene

Phthaloyl Derivative

Thalidomide (I) In the most preferred embodiment of the present invention, thalidomide is prepared in a single step whereby the reaction of compound of formula (II) with phthaloylating agent in the presence of a base and further conversion of phthaloyl derivative of compound of formula (II) to thalidomide using a dehydrating agent are carried out simultaneously. In other words, steps (i) and (ii) are combined. In a particularly preferred embodiment, the process may be represented by scheme B.

Another advantage of the processes of present invention is that the reactions are carried out in a single reaction vessel without isolation of the intermediate formed in the process. Thus the yield is higher and the processing time is lower.

SCHEME B

Wherein, R=-0H or -NH₇

Phthalic anhydride (H)

Toluene

Acetic anhydride

Triethyl amine

Thalidomide (I) The present invention is now further illustrated by the following examples, which do not, in any way, limit the scope of the invention.

Example 1 L-glutamine (10Og) and phthalic anhydride (14Og) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (100 ml) was added to the flask. The contents of the flask were heated gradually to 110°C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60°C and acetic anhydride (200 ml) was added thereto slowly. The resulting suspension was heated at 110⁰C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (80 g).

Example 2 L-isoglutamine (100g) and phthalic anhydride (12Og) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (120 ml) was added to the flask. The contents of the flask were heated gradually to 110⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60⁰C and acetic anhydride (200ml) was added thereto slowly. The resulting suspension was heated at 110°C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (75g).

Example 3 L-glutamine (100g) and phthalic anhydride (135g) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (135ml) was added to the flask. The contents of the flask were heated gradually to 110⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60°C and acetyl chloride (200ml) was added thereto slowly. The resulting suspension was heated at 110⁰C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (65g).

Example 4 L-isoglutamine (100g) and phthalic anhydride (14Og) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (135ml) was added to the flask. The contents of the flask were heated gradually to 110⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60⁰C and acetyl chloride (200ml) was added slowly to the reaction mass. The resulting suspension was heated at 110⁰C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50- 55⁰C to obtain thalidomide (68g).

Example 5 L-glutamine (100g) and phthalic anhydride (14Og) were suspended in xylene (1 liter) in a flask provided with a dean stark water separator followed by triethyl amine (130ml). The contents of the flask were heated gradually to 140⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60⁰C and acetic anhydride (200ml) was added thereto slowly. The resulting suspension was heated at 110⁰C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (73g).

Example 6 L-isoglutamine (100g) and phthalic anhydride (14Og) were suspended in xylene (1 liter) in a flask provided with a dean stark water separator followed by triethyl amine (100ml). The contents of the flask were heated gradually to 140°C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60°C and acetic anhydride (200ml) was added thereto slowly. The resulting suspension was heated at 110°C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (65 g).

Example 7 L-glutamine (100g) and phthalic anhydride (125g) suspended in chlorobenzene (1 liter) in a flask provided with a dean stark water separator followed by triethyl amine (135ml). The contents of the flask were heated gradually to 11O⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60⁰C and acetic anhydride (200ml) was added thereto slowly. The resulting suspension was heated to 110⁰C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (72g).

Example 8 L-isoglutamine (100g) and phthalic anhydride (14Og) suspended in chlorobenzene (1 liter) in a flask provided with a dean stark water separator followed by triethyl amine (135ml). The contents of the flask were heated gradually to 110°C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, the reaction mass was cooled to 50-60⁰C and acetyl chloride (200ml) was added thereto slowly. The resulting suspension was heated to 110°C, maintained for about three hours and cooled to 25-3O⁰C to obtain a solid. The solid was filtered and dried at 50-55⁰C to obtain thalidomide (75g).

Example 9 L-glutamine (100g) and phthalic anhydride (125g) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (100ml) was added to the flask. The contents of the flask were heated gradually to 110⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, toluene was distilled out under vacuum. Acetic anhydride (200ml) was added thereto slowly. The reaction mass was heated at 120°C and maintained for two hours. Acetic anhydride was distilled out under vacuum to obtain a residue. Denatured alcohol (200ml) was added to the residue, refluxed for about half an hour and cooled to 15-20⁰C to obtain a solid. The solid was filtered and dried under vacuum to obtain thalidomide (65g).

Example 10

L-glutamine (100g) and phthalic anhydride (135g) were suspended in toluene (1 liter) in a flask provided with a dean stark water separator. Triethyl amine (100ml) was added to the flask. The contents of the flask were heated gradually to 11O⁰C. The water generated during the course of reaction was separated azeotropically. After completion of reaction, toluene was distilled out under vacuum. Acetyl chloride (20OmI) was added slowly to the flask followed by N,N-dimethyl formamide (200ml). The temperature of the reaction mass was raised to 5O⁰C and maintained for 2 hours. Acetyl chloride was distilled out under vacuum to obtain a residue. Denatured alcohol (200ml) was added to the residue, refluxed for about half an hour and cooled to 15-20⁰C to obtain a solid. The solid was filtered and dried under vacuum to obtain thalidomide (55g).

Example 11

L-glutamine (10g) and phthalic anhydride (10g) were suspended in toluene (100ml) in a flask followed by triethyl amine (10ml) and acetic anhydride (20ml). The contents of the flask were heated gradually to 110°C, refluxed until completion of the reaction and cooled to 25-30°C to obtain a solid. The solid was filtered and dried under vacuum to obtain thalidomide (7.4g).

It will be appreciated that the invention may be modified within the scope of the appended claims.

Claims

1. A process for the preparation of thalidomide (I) comprising: (i) reacting a compound of formula (II), where one of R represents -OH or -NH2 and the other of R represents - NH2 or -OH, respectively,

(H)

with a phthaloylating agent in the presence of a base and a non-polar organic solvent to obtain a phthaloyl derivative where R have the same meanings as above,

Phthaloyl Derivative

and (ii) dehydrating the phthaloyl derivative using a dehydrating agent selected from an acid anhydride, an acid halide, an ion exchange resin or a molecular sieve, to obtain thalidomide (I).

2. A process according to claim 1 , wherein steps (i) and (ii) are carried out without isolation of any of the intermediates formed in the process.

3. A process according to claim 1 or 2, wherein the process is carried out in one pot.

4. A process according to claim 1 , 2 or 3, wherein steps (i) and (ii) are carried out simultaneously.

5. A process according to any preceding claim, wherein the non-polar organic solvent is an aromatic hydrocarbon or a non-polar aprotic organic solvent.

6. A process according to claim 5, wherein the non-polar organic solvent is selected from toluene, xylene, n-heptane, diethyl benzene, chlorobenzene, bromobenzene, iodobenzene, mesitylene, diphenyl ether and nitrobenzene.

7. A process according to any preceding claim, wherein step (i) is carried out with azeotropic removal of water.

8. A process according to any preceding claim, wherein the phthaloylating agent is selected from the group consisting of phthalic acid, derivatives of phthalic acid and esters of phthalic acid.

9. A process according to any preceding claim, wherein the base is an alkyl amine.

10. A process according to claim 9, wherein the dehydrating agent is an acid anhydride or an acid halide.

11. A process according to any preceding claim, wherein the non-polar organic solvent is toluene and the dehydrating agent is acetic anhydride.

12. A process according to any preceding claim, wherein the dehydration is carried out in the presence or absence of a solvent.

13. A process according to claim 12, wherein the dehydration is carried out in a polar aprotic solvent selected from N,N-dimethyl formamide, N-methyl pyrrolidone, dioxane, dimethyl acetamide, sulfolane, dimethyl sulphoxide or hexamethyl phosphoramide.

14. A process according to any preceding claim, wherein the thalidomide is isolated by addition to the reaction mass of a crystallization solvent selected from a C₁-C₄ alcohol, a ketone and an ester.

15. A process for the preparation of thalidomide substantially as herein described with reference to the examples.