GB1561153A - Process for the preparation of thiochroman derivatives - Google Patents

Process for the preparation of thiochroman derivatives Download PDF

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Publication number
GB1561153A
GB1561153A GB35029/76A GB3502976A GB1561153A GB 1561153 A GB1561153 A GB 1561153A GB 35029/76 A GB35029/76 A GB 35029/76A GB 3502976 A GB3502976 A GB 3502976A GB 1561153 A GB1561153 A GB 1561153A
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Prior art keywords
process according
thiochroman
hydroxythiochroman
general formula
reaction
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GB35029/76A
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Science Union et Cie
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Science Union et Cie
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Priority to GB35029/76A priority Critical patent/GB1561153A/en
Priority to YU1767/77A priority patent/YU40169B/en
Priority to MX775969U priority patent/MX5095E/en
Priority to AR168797A priority patent/AR215142A1/en
Priority to PH20127A priority patent/PH16402A/en
Priority to ES461758A priority patent/ES461758A1/en
Priority to OA56259A priority patent/OA05744A/en
Priority to NLAANVRAGE7709229,A priority patent/NL190521C/en
Priority to CA285,198A priority patent/CA1103683A/en
Priority to JP9963177A priority patent/JPS5325571A/en
Priority to SU772514702A priority patent/SU880251A3/en
Priority to CH1033677A priority patent/CH623818A5/en
Priority to HU77SI1588A priority patent/HU178104B/en
Publication of GB1561153A publication Critical patent/GB1561153A/en
Priority to HK86/84A priority patent/HK8684A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

A side chain -OCH2CHOHCH2NHR2 is fixed to a hydroxythiochroman of formula: <IMAGE> by a 2-stage synthesis, a) reaction with a glycerol halohydrin in basic medium and b) reaction of the 2,3-dihydroxypropoxythiochroman thus formed with an amine R2NH2 in the presence of an aminotriphenylphosphonium halide. The compounds (I) thus obtained and their salts are known as beta -blocking agents and used, especially, in the treatment of disorders of the cardiac rhythm. Compared with the prior process starting from the same compounds (II) and ending in the same compounds (I), the new process requires shorter reaction times and a reduced quantity of the amine R2NH2, which makes possible a selective amination of the primary alcohol functional group.

Description

(54) PROCESS FOR THE PREPARATION OF THIOCHROMAN DERIVATIVES (71) We, SCIENCE UNION ET CIE, SOCIETE FRANCAISE DE RECHERCHE MEDICALE, a French Societe en nom collectif, of 14, rue du Val d'Or, 92150 Suresnes, France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a process for the preparation of thiochroman derivatives.
The present invention provides a process for the preparation of thiochroman derivatives of the general formula
in which A is a hydrogen atom or a halogen atom, R1 is a hydrogen atom or a linear or branched alkyl radical having from 1 to 5 carbon atoms, and R2 is an alkyl radical having from 1 to 7 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, which may be substituted by one or more alkyl, heterocyclic or alkyl-substituted heterocyclic radicals, said alkyl radicals having from 1 to 7 carbon atoms.
Some of these compounds have been described in our British Patent No.
1,308,191, which also describes a process which comprises reacting 1-chloro-2,3epoxypropane with a hydroxythiochroman of the general formula
in which A and R, have the meanings given above, and condensing the resulting (2,3-epoxypropoxy)-thiochroman of the general formula
with a primary amine of the general formula R3NH2 IV' in which R3 is an alkyl radical having from 1 to 5 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms.
The present invention is based on the observation that the very significant excess of the amine of general formula IV' used in the former process may be avoided, that the time required for each step of the above process may be very considerably reduced, and that optically-active compounds of the general formula I can be prepared from optically-active amino compounds, whereas the former process required the further step of resolution.
The present invention therefore provides a process for preparing a compound of the general formula I which comprises reacting a hydroxythiochroman of the general formula
in which R, and A have the meanings given above, with a l-halo-2,3dihydroxypropane in a basic medium to produce a (2,3-dihydroxypropoxy)thiochroman of the general formula
and selectively converting this glycol into an amino alcohol of the general formula I by reaction with an amine of the general formula R2NH2 IV in which R2 has the meanings given above, in the presence of an aminophosphonium halide of the formula
in which each of R'1 and R'2 is an alkyl radical having from 1 to 7 carbon atoms or a phenyl radical, and X is a halogen atom, preferably an iodine atom.
Another advantage of the process of the present invention is that use of a limited amount of the amine of the general formula IV allows selective amination of the primary alcohol function while the secondary alcohol function is unattacked.
The amine of the general formula IV is an alkylamine or a cycloalkylamine, the hydrocarbon chain of which may bear one or more substituents, for example an alkyl radical having from 1 to 7 carbon atoms or a heterocyclic radical such as a pyrrolidinyl or pyridyl radical.
Using an amine in an optically-active form results in the production of a compound of the general formula I in an optically-active form. As optically active amines, there may be used for example sec.butylamine, (N-ethylpyrrolidinyl-2) methyl amine, 2-methylcyclopropylamine, 3,3-dimethyl-2-aminobutane and 2amino-3-methylhexane.
In accordance with the preferred features of the present invention: (1) the reaction between the hydroxythiochroman of formula II and the l-halo2,3-dihydroxypropane is carried out in the presence of a strong base such as an alkali metal hydroxide, for example potassium or sodium hydroxide, sodamide or sodium hydride; (2) the reaction is carried out in a polar aprotic solvent, for example dimethyl formamide, dimethylacetamide or dimethyl sulfoxide; (3) the reaction is carried out at a temperature of from 50 to 150cm, more preferably from 75 to 1250C; (4) the phosphonium halide is preferably a N-methyl-N-phenylaminotriphenylphosphonium halide, more preferably N-methyl-N-phenylaminotriphenylphosphonium iodide; (5) the condensation is carried out in an inert solvent, more preferably in a strongly polar solvent. Suitable solvents are aromatic hydrocarbons such as benzene and toluene, and polar solvents such as dimethyl formamide, dimethyl sulfoxide and hexamethylphosphoramide.
The thiochroman derivatives of the general formula I may be salified by adding a mineral or organic acid, preferably a physiologically tolerable mineral or organic acid.
The thiochroman derivatives of the general formula I and their physiologically tolerable salts possess valuable pharmacological and therapeutic properties, especially cardiovascular properties and may be used as blocking agents for the cardiac p-adrenergic receptors, for which purpose they may be formulated as pharmaceutical compositions in admixture or conjunction with a pharmaceutically suitable carrier. Such compositions can be in a form suitable for oral, rectal or parenteral administration.
The amination reaction of the present invention is of general use. It may be applied to any kind of glycol to produce the corresponding amino a-hydroxy derivative.
The hydroxy compounds of the general formula II used as starting materials are described in our British Patents Nos. 1,308,191 and 1,261,111.
The phosphonium halides may be obtained in the manner described in the literature (Tanigawa, Tetrahedron letters (1975) 471-472).
The following Examples illustrate the invention. The temperatures are expressed in degrees Centrigrade.
EXAMPLE I dl 8-(3-tert.butylamino-2-hydroxypropoxy)-thiochroman Step A To a three-necked flask are successively added 4 g of sodium hydroxide and 20 ml water, and after dissolution, 16.6 g of 8-hydroxythiochroman in 200 ml ethanol.
The mixture is heated to SOC for 15 minutes while stirring and then 12.1 g of 1chloro-2,3-dihydroxypropane are added dropwise. The mixture is kept at 50 for 3 hours, further portions of l-chloro-2,3-dihydroxypropane being added every hour.
The reaction medium is finally heated at SOC for 5 hours, allowed to cool to room temperature and then evaporated to dryness. The crude residue is taken up with water and rapidly stirred. The insoluble matter is filtered off, washed with water until the washings are neutral, and dried.
The residue weighs 16 g (yield=66%). It consists substantially of 8-(2,3dihydroxypropoxy)-thiochroman which melts at 115-1 20C. It is further purified by recrystallizing it from ethyl acetate. The pure compound melts at 118120 .
Step B 2.4 g of 8-(2,3-dihydroxypropoxy)-thiochroman are dissolved in 10 ml dimethylformamide and 0.24 g sodium hydride are added thereto. The mixture is heated to 80C for 30 minutes and a solution of 4.95 g of N-methyl-Nphenylaminotriphenylphosphonium iodide in dimethylformamide and a solution of 1.46 g of tert. butylamine in dimethylformamide are then added.
The reaction mixture is heated to 80 for about 2 hours and then allowed to cool to room temperature. The solvent is distilled off under reduced pressure and the residue is taken up in chloroform. The organic solution is extracted with N/10 solutions of hydrochloric acid. The acidic phases are united, rendered basic with sodium hydroxide, and extracted three times with ether. The ether solutions are washed with water, dried over magnesium sulphate, filtered and evaporated. The oily residue weighs 2.4 g. It is further purified by chromatography on silica and elution with a mixture of benzene-methanol (1:1). Evaporation of the solvent provides the desired dl 8-(3-tert. butylamino-2-hydroxypropoxy)-thiochroman in a yield of 60 ,ó. It melts at 7072 .
EXAMPLE II dextrorotatory 8-(3-sec.butylamino-2-hydroxypropxy)-thiochroman Using the procedure of Example I and starting from 8-(2,3-dihydroxypropoxy)thiochroman obtained in step A of Example I and from (+) sec.butylamine, there is obtained dextrorotatory 8-(3-sec.butylamino-2-hydroxypropoxy)-thiochroman in a yield of 55%.
It melts at 8088 [&alpha;]30578=+4.1 (C=1% methanol) 1a]3 =+11 (C=1% methanol) EXAMPLE III levorotatory 8-(3-sec.butylamino-2-hvdroxypropoxy)-thiochroman In the manner described in Example fi ana sraringfranl (-) sec.butylamine, there is obtained levorotatory 8 - (3 - sec.butylamino - 2 - hydroxypropoxy) thiochroman, in a yield of 55%.
l]35%=4.lC (C=1% methanol) [a]3 85=11 (C=1% methanol) Preparation of 8-hydroxythiochroman 300 g of polyphosphoric acid are gently warmed to 40C on a water bath and at this temperature, 30 g ,B-(o-methoxyphenylthio)-propionic acid are added over a period of 90 minutes. The whole viscous mixture is stirred for 2 hours at 40C and then poured onto crushed ice. After hydrolysis of the excess reagent, the product is isolated by filtration, dried, washed with water and dried in an oven.
21.9 g. of 8-methoxythiochroman-4-one are obtained as a yellowish powder, which is readily oxidised by atmospheric oxygen. The pure compound melts at 98 looo (yield 80%).
23.96 g of 8-methoxythiochroman-4-one are introduced into a flask with a mixture of 27.4 ml hydrazine hydrate and 112 ml ethyleneglycol. The whole is heated to reflux then allowed to cool to room temperature. 15.8 g of potassium hydroxide are added while stirring vigorously. Once the alkaline reagent has dissolved, the mixture is heated to reflux while eliminating the water produced. The temperature is progressively increased to 205210 and then maintained for 6 hours. After this time the mixture is allowed to cool to room temperature, and a further 10 ml hydrazine hydrate are added. Heating is then renewed for 6 hours.
After that, the reaction mixture is poured into cold water. The suspension is made acidic by adding hydrochloric acid and the aqueous suspension is extracted three times with chloroform. The chloroform solutions are united, washed with water then dried and evaporated to dryness. The dry residue is purified by fractional distillation. The pure compound is recovered from the main fraction distilling at 104106 /0.1 mm Hg. The yield is about 13.61 g i.e. 67%.
8-Hydroxy thiochroman is a colourless compound melting at 8688 .
From the water-glycol distillates, a further crop of thiochroman may be recovered. The distillates are extracted with chloroform, the chloroform solutions are washed with dilute hydrochloric acid and with water and then dried and evaporated to dryness. 3.11 g of 8-methoxythiochroman are recovered as a viscous liquid, BP=115118 /0.06 mm Hg nD3=1.61 10 8-Methoxythiochroman is converted into 8-hydroxythiochroman by demethylation with an acetic acid-boron trifluoride complex in methylene chloride.
A second crop of 8-hydroxythiochroman is thus obtained.
WHAT WE CLAIM IS: 1. A process for the preparation of a compound of the general formula
in which A is a hydrogen or a halogen atom, R1 is a hydrogen atom or a linear or branched alkyl radical having from 1 to 5 carbon atoms, and R2 is an alkyl radical having from 1 to 7 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, which may be substituted by one or more alkyl, heterocyclic or alkyl-substituted heterocyclic radicals, said alkyl radicals having from 1 to 7 carbon atoms, which comprises reacting a hydroxythiochroman of the general formula
in which R, and A have the meanings specified above, with a 1-halo-2,3dihydroxypropane in a basic medium to produce a (2,3-dihydroxypropoxy)thiochroman of the general formula
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (14)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    Preparation of 8-hydroxythiochroman
    300 g of polyphosphoric acid are gently warmed to 40C on a water bath and at this temperature, 30 g ,B-(o-methoxyphenylthio)-propionic acid are added over a period of 90 minutes. The whole viscous mixture is stirred for 2 hours at 40C and then poured onto crushed ice. After hydrolysis of the excess reagent, the product is isolated by filtration, dried, washed with water and dried in an oven.
    21.9 g. of 8-methoxythiochroman-4-one are obtained as a yellowish powder, which is readily oxidised by atmospheric oxygen. The pure compound melts at 98 looo (yield 80%).
    23.96 g of 8-methoxythiochroman-4-one are introduced into a flask with a mixture of 27.4 ml hydrazine hydrate and 112 ml ethyleneglycol. The whole is heated to reflux then allowed to cool to room temperature. 15.8 g of potassium hydroxide are added while stirring vigorously. Once the alkaline reagent has dissolved, the mixture is heated to reflux while eliminating the water produced. The temperature is progressively increased to 205210 and then maintained for 6 hours. After this time the mixture is allowed to cool to room temperature, and a further 10 ml hydrazine hydrate are added. Heating is then renewed for 6 hours.
    After that, the reaction mixture is poured into cold water. The suspension is made acidic by adding hydrochloric acid and the aqueous suspension is extracted three times with chloroform. The chloroform solutions are united, washed with water then dried and evaporated to dryness. The dry residue is purified by fractional distillation. The pure compound is recovered from the main fraction distilling at 104106 /0.1 mm Hg. The yield is about 13.61 g i.e. 67%.
    8-Hydroxy thiochroman is a colourless compound melting at 8688 .
    From the water-glycol distillates, a further crop of thiochroman may be recovered. The distillates are extracted with chloroform, the chloroform solutions are washed with dilute hydrochloric acid and with water and then dried and evaporated to dryness. 3.11 g of 8-methoxythiochroman are recovered as a viscous liquid, BP=115118 /0.06 mm Hg nD3=1.61 10 8-Methoxythiochroman is converted into 8-hydroxythiochroman by demethylation with an acetic acid-boron trifluoride complex in methylene chloride.
    A second crop of 8-hydroxythiochroman is thus obtained.
    WHAT WE CLAIM IS: 1. A process for the preparation of a compound of the general formula
    in which A is a hydrogen or a halogen atom, R1 is a hydrogen atom or a linear or branched alkyl radical having from 1 to 5 carbon atoms, and R2 is an alkyl radical having from 1 to 7 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, which may be substituted by one or more alkyl, heterocyclic or alkyl-substituted heterocyclic radicals, said alkyl radicals having from 1 to 7 carbon atoms, which comprises reacting a hydroxythiochroman of the general formula
    in which R, and A have the meanings specified above, with a 1-halo-2,3dihydroxypropane in a basic medium to produce a (2,3-dihydroxypropoxy)thiochroman of the general formula
    and selectively converting this glycol into an amino alcohol of the general formula I by reaction with an amine of the general formula R2NH2 in which R2 has the meanings specified above, in the presence of an aminophosphonium halide of the formula
    in which each of R', and R'2 is an alkyl radical having from 1 to 7 carbon atoms or a phenyl radical, and X is a halogen atom.
  2. 2. A process according to claim 1, in which the amine R2NH2 is in an opticallyactive form.
  3. 3. A process according to claim 1 or claim 2, in which the reaction between the hydroxythiochroman and the l-halo-2,3-dihydroxypropane is carried out in the presence of a strong base.
  4. 4. A process according to any one of claims I to 3, in which the reaction between the hydroxythiochroman and the l-halo-2,3-dihydroxypropane is carried out in a polar aprotic solvent, for example dimethyl formamide, dimethyl acetamide or dimethylsulfoxide.
  5. 5. A process according to any one of claims 1 to 4, in which the reaction between the hydroxychroman and the 1-halo-2,3-dihydroxypropane is carried out at a temperature of from 50 to 150 C.
  6. 6. A process according to any one of claims 1 to 5, in which the phosphonium halide is a N-methyl-N-phenylamino-triphenylphosphonium halide.
  7. 7. A process according to claim 6, in which the phosphonium halide is Nmethyl-N-phenylamino-triphenylphosphonium iodide.
  8. 8. A process according to any one of claims 1 to 7, in which the condensation with the phosphonium halide is carried out in an inert solvent.
  9. 9. A process according to any one of claims 1 to 8 which includes the further step of salifying the product by adding a mineral or organic acid.
  10. 10. A process according to claim 1 carried out substantially as described in any one of Examples I to III herein.
  11. 11. A compound according to claim 1 or an acid addition salt thereof whenever obtained by a process according to any one of claims 1 to 10.
  12. 12. A pharmaceutical composition comprising as active ingredient a compound according to claim 11 in admixture or conjunction with a pharmaceutically suitable carrier.
  13. 13. dextrorotatory 8-(3-sec. butylamino-2-hydroxypropoxy)-thiochroman.
  14. 14. levorotatory 8-(3-sec.butylamino-2-hydroxypropoxy)-thiochroman.
GB35029/76A 1976-08-23 1976-08-23 Process for the preparation of thiochroman derivatives Expired GB1561153A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
GB35029/76A GB1561153A (en) 1976-08-23 1976-08-23 Process for the preparation of thiochroman derivatives
YU1767/77A YU40169B (en) 1976-08-23 1977-07-15 Process for obtaining thiochromane derivatives
MX775969U MX5095E (en) 1976-08-23 1977-08-08 IMPROVED PROCEDURE FOR OBTAINING THIOCROMAN DERIVATIVES
AR168797A AR215142A1 (en) 1976-08-23 1977-08-15 PROCEDURE FOR OBTAINING DERIVATIVES OF (3-AMINO MONOSUBSTITIDO-2-HIDROXIPROPOXI) -TIOCROMANO
PH20127A PH16402A (en) 1976-08-23 1977-08-16 Process for the preparation of thiochroman derivatives
ES461758A ES461758A1 (en) 1976-08-23 1977-08-19 Process for the preparation of thiochroman derivatives
OA56259A OA05744A (en) 1976-08-23 1977-08-20 Process for obtaining thiochroman derivatives
NLAANVRAGE7709229,A NL190521C (en) 1976-08-23 1977-08-22 Process for the preparation of (3-amino-2-hydroxypropoxy) thiochroman derivatives.
CA285,198A CA1103683A (en) 1976-08-23 1977-08-22 No translation available
JP9963177A JPS5325571A (en) 1976-08-23 1977-08-22 Production of thiochmaron derivatives
SU772514702A SU880251A3 (en) 1976-08-23 1977-08-23 Method of preparing thiochromane derivatives or their salts
CH1033677A CH623818A5 (en) 1976-08-23 1977-08-23 Process for producing derivatives of thiochroman
HU77SI1588A HU178104B (en) 1976-08-23 1977-08-23 Process for producing tiochromane derivatives
HK86/84A HK8684A (en) 1976-08-23 1984-02-01 Process for the preparation of thiochroman derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB35029/76A GB1561153A (en) 1976-08-23 1976-08-23 Process for the preparation of thiochroman derivatives

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GB1561153A true GB1561153A (en) 1980-02-13

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GB35029/76A Expired GB1561153A (en) 1976-08-23 1976-08-23 Process for the preparation of thiochroman derivatives

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JP (1) JPS5325571A (en)
AR (1) AR215142A1 (en)
CA (1) CA1103683A (en)
CH (1) CH623818A5 (en)
ES (1) ES461758A1 (en)
GB (1) GB1561153A (en)
HK (1) HK8684A (en)
HU (1) HU178104B (en)
MX (1) MX5095E (en)
NL (1) NL190521C (en)
OA (1) OA05744A (en)
PH (1) PH16402A (en)
SU (1) SU880251A3 (en)
YU (1) YU40169B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2530954A1 (en) * 1982-07-29 1984-02-03 Adir PHARMACEUTICAL COMPOSITION BASED ON 8- (3-TERTBUTYLAMINO, 2-HYDROXY-PROPOXY) -THIACHROMAN
FR2588260A1 (en) * 1985-10-04 1987-04-10 Adir NOVEL THIOCHROMAN DERIVATIVE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5947574A (en) * 1982-09-08 1984-03-17 Tlv Co Ltd Multidirection ball valve
JPS63280785A (en) * 1987-05-14 1988-11-17 Mitsui Toatsu Chem Inc Structural adhesive

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1308191A (en) * 1970-04-06 1973-02-21 Science Union & Cie Thiochroman derivatives and a process for preparing them

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2530954A1 (en) * 1982-07-29 1984-02-03 Adir PHARMACEUTICAL COMPOSITION BASED ON 8- (3-TERTBUTYLAMINO, 2-HYDROXY-PROPOXY) -THIACHROMAN
FR2588260A1 (en) * 1985-10-04 1987-04-10 Adir NOVEL THIOCHROMAN DERIVATIVE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
EP0228920A1 (en) * 1985-10-04 1987-07-15 Adir Et Compagnie Thiochroman derivative, process for its preparation and pharmaceutical compositions containing it
US4703057A (en) * 1985-10-04 1987-10-27 Adir Et Compagnie Beta-blocking thiochroman derivatives, compositions and method of use therefor

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Publication number Publication date
SU880251A3 (en) 1981-11-07
CA1103683A (en) 1981-06-23
JPS5325571A (en) 1978-03-09
AR215142A1 (en) 1979-09-14
JPS623150B2 (en) 1987-01-23
CH623818A5 (en) 1981-06-30
ES461758A1 (en) 1978-05-01
HU178104B (en) 1982-03-28
YU176777A (en) 1982-06-30
PH16402A (en) 1983-09-22
OA05744A (en) 1981-05-31
YU40169B (en) 1985-08-31
NL7709229A (en) 1978-02-27
NL190521C (en) 1994-04-05
HK8684A (en) 1984-02-10
MX5095E (en) 1983-03-16
NL190521B (en) 1993-11-01

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 19950823