CA1073461A - Heterocyclic compounds - Google Patents
Heterocyclic compoundsInfo
- Publication number
- CA1073461A CA1073461A CA275,531A CA275531A CA1073461A CA 1073461 A CA1073461 A CA 1073461A CA 275531 A CA275531 A CA 275531A CA 1073461 A CA1073461 A CA 1073461A
- Authority
- CA
- Canada
- Prior art keywords
- pyridin
- compound
- isothiazolo
- ethyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A class of isothiazolopyridines having an optionally substituted alkyl group attached to the nitrogen of the isothiazolo moiety, are effective in inhibiting platelet aggregation.
A class of isothiazolopyridines having an optionally substituted alkyl group attached to the nitrogen of the isothiazolo moiety, are effective in inhibiting platelet aggregation.
Description
10~34~1 This invention relates to a class of isothiazolopyridine~
which are of value in the prophylactic and therapeutic treatment of thrombotic diseases. The invention also relates to a method for the preparation of such compounds and to pharmaceutical compositions comprising them.
Arterial thrombosis develops initially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus.
The most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting.
However, although effective in venous thrombosis, where the thrombus is formed mainly of fibrin, anti-coagulant therapy has no effect on platelet aggregation and has therefore limited effectiveness in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
With the increasing recognition of the primary role of platelets in thrombosis, attention had turned to drugs which are capable of inhibiting the aggregation of platelets.
It has now been found that a class of isothiazolopyridines are effective in inhibiting platelet aggregation.
Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof:, ~ S/ (I) , , ,~ . :' , iO~3461 wherein R is an alkyl group optionally substituted with an aryl group, with a heterocyclic group, or with a group of formula (II):
~ Rl - N (II) \R2 wherein Rl and R2 are the same or different and each is hydrogen, a Cl 6alkyl or phenyl group, and Z is the residue of a fused pyridine ring which is optionally substituted with up to three groups selected from Cl 6alkyl, heterocyclyl, phenyl and substituted phenyl.
Suitable acid addition salts of the compounds of formula (I) include inorganic salts such as the sulphate, nitrate, phosphate and borate, hydrohalides such as hydrochloride, hydrobromide and hydroiodide, and or~anic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate,ascorbate, methanesulphonate and p-toluenesulphonate.
The alkyl group R may be straight or branched and may suitably have from 1 to 10 carbon atoms, especially from 1 to 6 carbon atoms. When the group R is an aryl substituted alkyl group, the aryl moiety may be for example, optionally substituted phenyl. Suitable substituents for the phenyl group include halogen, especially chlorine.
When the group R is an alkylgroup substituted with a heterocyclic ring, such a ring may be aromatic or non-aromatic mono- or polycyclic and may contain up to four heteroatmSselecteQ
from oxygen~ sulphur and nitrogen. The attachment to the alkyl group may be via a carbon or nitrogen atom which is present in the ring. Examples of such rings include pyrimidyl, -. - . .,- .,.
-: :- :
. ;:.
l~q3461
which are of value in the prophylactic and therapeutic treatment of thrombotic diseases. The invention also relates to a method for the preparation of such compounds and to pharmaceutical compositions comprising them.
Arterial thrombosis develops initially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus.
The most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting.
However, although effective in venous thrombosis, where the thrombus is formed mainly of fibrin, anti-coagulant therapy has no effect on platelet aggregation and has therefore limited effectiveness in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
With the increasing recognition of the primary role of platelets in thrombosis, attention had turned to drugs which are capable of inhibiting the aggregation of platelets.
It has now been found that a class of isothiazolopyridines are effective in inhibiting platelet aggregation.
Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof:, ~ S/ (I) , , ,~ . :' , iO~3461 wherein R is an alkyl group optionally substituted with an aryl group, with a heterocyclic group, or with a group of formula (II):
~ Rl - N (II) \R2 wherein Rl and R2 are the same or different and each is hydrogen, a Cl 6alkyl or phenyl group, and Z is the residue of a fused pyridine ring which is optionally substituted with up to three groups selected from Cl 6alkyl, heterocyclyl, phenyl and substituted phenyl.
Suitable acid addition salts of the compounds of formula (I) include inorganic salts such as the sulphate, nitrate, phosphate and borate, hydrohalides such as hydrochloride, hydrobromide and hydroiodide, and or~anic acid addition salts such as acetate, oxalate, tartrate, maleate, citrate, succinate, benzoate,ascorbate, methanesulphonate and p-toluenesulphonate.
The alkyl group R may be straight or branched and may suitably have from 1 to 10 carbon atoms, especially from 1 to 6 carbon atoms. When the group R is an aryl substituted alkyl group, the aryl moiety may be for example, optionally substituted phenyl. Suitable substituents for the phenyl group include halogen, especially chlorine.
When the group R is an alkylgroup substituted with a heterocyclic ring, such a ring may be aromatic or non-aromatic mono- or polycyclic and may contain up to four heteroatmSselecteQ
from oxygen~ sulphur and nitrogen. The attachment to the alkyl group may be via a carbon or nitrogen atom which is present in the ring. Examples of such rings include pyrimidyl, -. - . .,- .,.
-: :- :
. ;:.
l~q3461
2-, 3-, or 4-pyridyl, thiazolyl, thiazolinyl, diazolyl, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, purinyl, benzimidazolyl, benzoxazolyl, benzisothiazolonyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azabicyclo-[3.2.2.]non-yl, azabicyclo[3.3.1]non-yl, homopiperidinyl, azabicyclo[2.2.2]oct-yl.
Suitable groups for the substituents R and R2 in formula (II) include methyl, ethyl, n- and iso-propyl, n-, sec, iso-and tert-butyl. Suitably, Rl and R2 are methyl or ethyl.
The nitrogen atom in the pyridine moiety Z-may be at any one of the four possible positions. Suitably the nitrogen is present at position 7 of the nucleus. For Example, the moiety Z is unsubstituted or substituted with Cl 6 alkyl. Thus, one sub-class of compounds falling within the scope of this invention comprises compounds of formula (III) and pharmaceutically acceptable non-toxic acid addition salts thereof:
R5 ~ ~
~ ~7 ~ 12~ R (III) , .
wherein R4, R5 and R are hydrogen, Cl 6alkyl or phenyl and R is as defined above with respect to formula (I). Preferably R , R and R are all hydrogen.
A specific compound of formula (III), wherein R is a.
; Cl_6alkyl group, is:
:. : , :.:. - . ., .. : .:,: :: :~ ::: :: . . ..
- . - . . . .. . ..
: ~. : , ::: ., : :
: I . . . ~ . : . .. .. . .
:: : - -.
2-n-butylisothiazolo~5,4-b]pyridin-3-one.
A specific compound of formula (III) wherein R i3 an aryl substituted al~l group i~
2-(~-chlorobenzyl)isothiazolo[5,4-b]pyridin-3-one.
Specific compounds of formula (III) wherein R is a heterocyclyl substituted alkyl group and wherein the alkyl chain has from 2 to 6 carbon atoms include the following:
2-(2-pyrrolidin-l-ylethyl)-isothiazolo~5,4-b]pyridin-3-one, 2-(2-pyrrolidin-1-yl-ethyl)-isothiazolo[5,4-b]pyrid-in-3-one-dihydrochloride;
2-(3-morph~lin-l-ylpropyl)-isothiazolo[5,4-b]pyridin-3-one:
2-(2-pyrid -2-ylethyl)isothiazolo[5,4-b]pyridin-3-one, 2-r2-(3.-aza}~icyclo(3.2.2)non-3-yl)-ethyl]isothiazolo[5,4-b~-pyridin-3-one~
2-[2-(4-methylthiazol-Z-yl)ethyl~-5-phenylisothiazolo[5, 4-b~-pyridin~3-one, - 2-(2-pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo[5,4-b]-pyridin-3-one, 2-(2-py~rolidin-l~ylethyl)-4,5,6-trimethylisothiazolo-[5,4 b]-pyridin-3-one.
Another sub-group of compounds within the present invention is represented by formula (IVA), (IVB), and (IVC) and pharmaceutically acceptable non-toxic acid addition salts thereof:
RlO , R13 o 25R )~ ~ Rli~ ~5 (IVA) (IVB) (IVC) . ............: ..... : :- : , . ;
- . : , ; - :; :
~ ~073461 in which formulae R is as defined with respect to formula (I) above, and the groups R7 to R15 each represent hydrogen, Cl 6alkyl heterocyclyl, phenyl or substituted phenyl.
Specific compounds within formulae (IVA), (IVB), and (IVC) include:
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[4,5-b]pyridin-3-one.
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[5,4-c]pyridin-3-one.
2-(2-piperidin-1-ylethyl)-isothiazolo[5,4-c]pyr~in-3-one.
2-[2-(3-azabicyclo~3.2.2]non-3-yl3ethyl]isothLazolo[5,4-c]-pyridin-3-one.
2-(2-piperidin-1-ylethyl)isothiazolo~4,5-c]pyridin-3-one.
A further sub-class of compounds is represented by formula (V) and pharmaceutically acceptable non-toxic acid addition salts thereof: O
(V) Z ~ - A - B - R16 wherein Z is as defined with respect to formula (I) above, A and B each represent a straight or branched chain alkylene group each having from 1 to 6 carbon atoms and R16 represents a heterocyclyl group or a group of formula (II) above.
Specific compounds of formula (V) include:
2-[2-(diethylamino)ethyl]-5-phenyl-isothiazolo[5,4-b3-pyridin-3-one.
2-[3-(dimethylamino)propyl]-isothiazolo[4,5-b]pyridin-3-one 2-[6-(dimethylamino)hexyl]-isothiazolo[5,4-b]pyridin-3-one.
A still further sub-class of compounds within the scope of this invention is represented by formula (VI) and pharmaceutically acceptable non-toxic acid addition salts thereof:
`"` 10~73461 .
X' R17 (VI) S
wherein Z is as defined with respect to formula (I) above, R17 is hydrogen or a Cl 3 alkyl group, and R18 is a heterocyclic ring attached via a carbon atom in the ring.
One example of a compound of formula (VI) is :
2-(1-methylpyrrolidin-2-ylmethyl)-isothiazolo[5,4-b]-pyrid-3-one.
A particularly preferred group of compounds according to the invention and to which the claims are directed are those of formula (I) O
(I) z ~ N - R
wherein R is a Cl 4 alkyl group or Cl 4 alkyl group substituted with phenyl or chlorine substituted phenyl, or a group of formula (II) R
N ~R2 wherein Rl and R2 are the same and are Cl 4 alkyl, or a group -N ~ wherein -N ~ is an aromatic or non-aromatic mono-or polycyclic heterocyclic containing A
.. ,.. - .. -. -. ~. - ... .. ` .. ... -... ;. ... . .. .
`` 1073461 5 to 9 atoms in the rin~s and one of these atoms may be another heteroatom selected from oxygen, sul~ur and nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from Cl 6 alkyl, heterocyclyl and phenyl.
The compounds of this invention may be prepared by cyclising a compound of formula (VII):
o (VII) z ll NH - R
~ E - ~H
wherein R and Z are as defined above with respect to formula ~I).
The reagents for such a cyclisation are generally com-pounds which halogenate the sulphur atom in structure (VII) and allow subsequent dehydrohalogenation. A preferred reagent is iodine in the presence of a base such as sodium bicarbonate or an-hydrous potassium carbonate but other possibilities include chlorine, bromine, phosphorus pentachloride and thionyl chloride. The reac-tion may be performed in a solvent which does not react with the intermediate or reagents employed. For example in the case of the reagent iodine/sodium bicarbonate, a lower alkanol, especially - 20 ethanol may be used as a solvent but for more reactive halogenating -agents such as phosphorus pentachloride a more inert solvent is employed, such as halogenated hydrocarbon, a higher ether or di-methylformamide. The reaction is conveniently carried out at ambient temperature.
~ -7a-. , :: :
`' lOq346`1 The intermediate compounds of formula (VII) may be conveniently prepared by the route shown in Scheme 1:
-7b-A
- . . , .. .. ,~ .. ; . . . .. . . . .. .. .. ... . . .
. .. . ,., .. .`. . ; .. . .- . ` ~.. , . ~ . . . ~
. . . , . ..... ~ . . . . . .
SCHEME I
~~ C02H ~ c_C~
SH C~S/
mercuric acetate ~VII) ~ R.~H2 ~ 11 S
C_s/
wherein R and Z are as defined above with respect to formula (I).
The intermediate (VII) may conveniently be prepared and cyclised n situ to produce the corresponding compound of formula (I) Furthermore, some of the above trithiones and dithiones in Scheme I are novel intermediat~s and also form part of this invention.
A second method for the pre~aration of compounds of this invent~.on comprises treating ~ comnoun~ of formula (VIII) ~.~ith base: -C _Co2R3 (VIII) Z C _S/ NH R
. - , . . ~ . . : . -::: :: ::: . . - . ; .
. . ......... ,, ::, , , .;: . .:
.. :. . ::-` 1073461 wherein R and Z are as defined above with respect to formula (I) and R is an alkyl group, preferably lower alkyl group.
Suitable bases for the reaction include alkali metal alXoxides, alkali metal hydroxides, and tetramethylammonioum hydroxide in lower alcohols.
The compounds of formula (I) may also be prepared by reacting a compound of formula (IX):
f C~.X' Z If (IX) ~~ ~S.Y
- wherein X and Y are the same or different and each represents chlorine, or bromine, and wherein-R and Z are-a~ defined above with respect to formula (I), with an amine of formula R.~H2.
Suitable solvents include carbon tetrachloride and other halogenated hydrocarbons.
A fourth method for the preparation of compounds of formula (I) comprises treating a dimer of formula (X):
- (X~
0~N~.R~ R~NH.CO~
C S ~~ - S ~'J
_ 9 _ . . . - ., . ~ - . ~ .,~ ,. . .
.~ ' :'' . . .' . .:.' ' '' ::
~ . ~. :-. ~, :.
10'73461 wherein R and Z are as defined above with re4pect to formula (I), with either chlorine or a base.
Suitable bases include lOYo sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temDerature or elevated temperature. If chlorine is employed in this reaction it may be bubbled into a solution of compounl (X) in an inert solvent such as carbon tetrachloride.
Compounds of this invention wherein R represents an alkyl group substituted with either a n.itrogen - containing a heterocyclic ring attached via the ring nitrogen, or with a group of formula tII), may be prepared by reacting a compound of formula (XI):
.
Z ~ AlX - U
(XI) ~ S
wherein Z is as defined with respect to formula ~I) above, Alk represents a straight or branched alkylene chain and U
represents a readily displaceable group, with a compound of formula (XIIA) or (XIIB):
~ R
NH Q ~H
~ --R2 (XIIA) (XIIB) 107 ~ 6~
wherein Rl and R2 are as defined with re~erence to formula ~I) and Q is the residue of a heterocyclic ring.
Suitably the group U is a halogen atom, for example chlorine or bromine, a substituted sulphonyloxy group, for example p-toluenesulphonyloxy or methanesulphonyloxy.
The reaction may suitably be carried out in a hydrocarbon solvent such as toluene at an elevated temperature for example 100 - 120.
The invention also provide~ a pharmaceutical composition which comprises a compound of formula (I) a~ defined above together with at least one pharmaceutically acceptable carrier.
As is common practice, such compositions will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thrombus formation.
The compositions may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventiona1 excipients such as binding agents, for example, syrup, acacia gelatin sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers for example, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica;
disintegrants, for example potato starch or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be : :~: : : : :. .
'' :: : : : '. - ' . ::
: : .. . :- , .-:: - . ,, . ~ :
- , , ~. . : ., .: : ' ' ' .- .' , ' ~ -`` 1073461 coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan, monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, propylene glycol, or ethyl alcohol, preservatives, for example methyl or propyl ~-hydroxybenzoate or sorbic acid, and if desired conventional - 15 flavouring or colouring agents. The compound may also if desired be incorporated in a foodstuff, for example in the form of a biscuit.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depe~ding on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid before use.
' ~ , ~' - ,'',- ' , .' '.': -' ''' ' ` ' .
:~ .-: :,:. .
: '' ~ - .. ': ''' :
10~ ~ 61 Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99~ by weight, preferably from 10-60% by weight, of the active material, depending on the method of admin~tration. Where the compositions comprise dosage units, each unit will preferably contain from l-SOOmg. of the active ingredient. The dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range of O.01 to 30 mg/kg/day depending on the route and frequency of administration. The preferred - dose is lO to 500 mg. orally, l to 3 times a day for an adult human.
The compositions of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis in geriatric patients to prevent transient cerebral ischemic attacks;
and long term prophylaxis following myocardial lnfarcts and strokes.
The compounds of formula (I) may also have application in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs " , . . .~ . . . . . .
-: .,. , .::, . . - .. ~ : ., , :
. ... . , ~ - .. ...~: , . . .
- ' ~ . ` .:., .: '' ' ;: .,. ' . , :
107346~
e.g. the heart, and kidneys, which have been removed from a cadaver and prior to transplant.
Accordingly, t~s invention also provides a proces~
for inhibiting platelet aggregation in vitro comprising the S addition of a compound of the formula (I) or a pharmacologically acceptable acid addition salt of such a compound to whole blood or platelet-rich concentrate.
The dQsage for such an addition is preferably from 0.01 to 50 micrograms/ml of whole blood.
The invention also provides a composition comprising whole blood and a compound of formula (I) above or a pharmacologically acceptable acid addition salt of such a compound having a basic nitrogen atom in the molecule.
The following Examples illustrate the preparation of some of the compounds of this invention.
~ . .
, : -_ 14 _ !, , '' ,'.' . . ': . ~ ' .
Example 1 2-(2-Pvrrolidin-l-vl-ethyl)isothiazolo~5,4-bl~yridin-3-one (a) 1,2-Dithiolor5,4-blpyridin-3-thione 2-Mercaptonicotinic acid (17.65g., O.llmole) and phosphorus pentasulphide (lSg., 0.06 mole) in pyridine (150ml) were heated under reflux for 2 hours. The reaction mixture was then cooled, diluted with water and the product filtered off.
Recrystallisation from ethanol yielded 1,2-dithiolo[5,4-b]-pyridi~-3 ~hione (7.89g; 37%), red ned~les m.p. 185-6.
(b) 1,2-Dithiolor5,4-bl~Yridin-3-one To a stirred suspension of mercuric acetate (17.0g., 0.053 mole) in glacial acetic acid (200 ml), a solution of 1,2-dithiolo[5,4-bj-pyridin-3-thione (5g, 0.025mole) in chloroform (lOOml) was a~ded and the mixture stirred at room temRerature, for 3 days. Celite (ca,25g.) was added to the mixture, filtered and the filtrate evaporated. The residue was treated with dichloromethane (ca.
lOOml) the solid filtered off and the filtrate evaporated. This latter process was repeated several times. The product was then taken up in dichloromethane (20ml) and filtered through a short column of silica-gel made up in dichloromethane. The column was washed with sufficient dichloromethane to reco~7er all the product and the combined filtrates evaporated. Recrystallisation of the residue from ethanol yielded 1,2-dithiolo~5,4-b]pyridin-3-one (3.21g., 70%), pale yellow needles, m.p. 96-97 .
(c) N-(2-Pyrrolidin-l-yl-eth~It2-merca~tonicotinamide.
1~2-Dithiolo~5~4-b]pyridin-3-one(~l~sg; ~OO9~Qle~ 2-amino-ethyl)-pyrrolidine ~l.lg., 0.01 mole) and ethanol (30ml) were - :,- . ,. .:: .
iO7 ~ 6~
heated under reflux for 1.5 hours. The mixture was filtered hot and the filtrate evaporated to dryness. The oily residue was triturated with dichloromethane and the resulting tan ~olid recrystallised from ethanol to yield the product (0.75g., 34%) tan prisms, m.p. 202-205.
(d) 2-(2-PYrrolidin-l-Yl-ethvl)isothiazolor5,4-blpyridin-3-one A stirred suspension of N-(2-pyrrolidin-1-yl-ethyl)-2-mercapton~cotinamide (13g. 0.05 mole) and sodium bicarbonate (8.7g., 0.105 mole) in ethanol (130ml) was treated portionwise with iodine (12.35g., 0.049 mole) over 2.5 hours, and then stirred at room temperature for a further 8 hour~. The mixture was then filtered and the filtrate evaporated to dryness.
The solids from the filter and the residue from the filtrate were suspended in water (200ml) and extracted thoroughly~with chloroform (3 x 60 ml) and dried (anhyd. MgS04). Evaporation of the dried solution yielded 8.8g of crude product which was crystallised from diisopropyl ether (including charcoal treatment) yielding pure 2~2-pyrrolidin-1-yl-ethyl)isothiazolo[5,4-b]pyridin-
Suitable groups for the substituents R and R2 in formula (II) include methyl, ethyl, n- and iso-propyl, n-, sec, iso-and tert-butyl. Suitably, Rl and R2 are methyl or ethyl.
The nitrogen atom in the pyridine moiety Z-may be at any one of the four possible positions. Suitably the nitrogen is present at position 7 of the nucleus. For Example, the moiety Z is unsubstituted or substituted with Cl 6 alkyl. Thus, one sub-class of compounds falling within the scope of this invention comprises compounds of formula (III) and pharmaceutically acceptable non-toxic acid addition salts thereof:
R5 ~ ~
~ ~7 ~ 12~ R (III) , .
wherein R4, R5 and R are hydrogen, Cl 6alkyl or phenyl and R is as defined above with respect to formula (I). Preferably R , R and R are all hydrogen.
A specific compound of formula (III), wherein R is a.
; Cl_6alkyl group, is:
:. : , :.:. - . ., .. : .:,: :: :~ ::: :: . . ..
- . - . . . .. . ..
: ~. : , ::: ., : :
: I . . . ~ . : . .. .. . .
:: : - -.
2-n-butylisothiazolo~5,4-b]pyridin-3-one.
A specific compound of formula (III) wherein R i3 an aryl substituted al~l group i~
2-(~-chlorobenzyl)isothiazolo[5,4-b]pyridin-3-one.
Specific compounds of formula (III) wherein R is a heterocyclyl substituted alkyl group and wherein the alkyl chain has from 2 to 6 carbon atoms include the following:
2-(2-pyrrolidin-l-ylethyl)-isothiazolo~5,4-b]pyridin-3-one, 2-(2-pyrrolidin-1-yl-ethyl)-isothiazolo[5,4-b]pyrid-in-3-one-dihydrochloride;
2-(3-morph~lin-l-ylpropyl)-isothiazolo[5,4-b]pyridin-3-one:
2-(2-pyrid -2-ylethyl)isothiazolo[5,4-b]pyridin-3-one, 2-r2-(3.-aza}~icyclo(3.2.2)non-3-yl)-ethyl]isothiazolo[5,4-b~-pyridin-3-one~
2-[2-(4-methylthiazol-Z-yl)ethyl~-5-phenylisothiazolo[5, 4-b~-pyridin~3-one, - 2-(2-pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo[5,4-b]-pyridin-3-one, 2-(2-py~rolidin-l~ylethyl)-4,5,6-trimethylisothiazolo-[5,4 b]-pyridin-3-one.
Another sub-group of compounds within the present invention is represented by formula (IVA), (IVB), and (IVC) and pharmaceutically acceptable non-toxic acid addition salts thereof:
RlO , R13 o 25R )~ ~ Rli~ ~5 (IVA) (IVB) (IVC) . ............: ..... : :- : , . ;
- . : , ; - :; :
~ ~073461 in which formulae R is as defined with respect to formula (I) above, and the groups R7 to R15 each represent hydrogen, Cl 6alkyl heterocyclyl, phenyl or substituted phenyl.
Specific compounds within formulae (IVA), (IVB), and (IVC) include:
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[4,5-b]pyridin-3-one.
2-(2-pyrrolidin-1-ylethyl)-isothiazolo[5,4-c]pyridin-3-one.
2-(2-piperidin-1-ylethyl)-isothiazolo[5,4-c]pyr~in-3-one.
2-[2-(3-azabicyclo~3.2.2]non-3-yl3ethyl]isothLazolo[5,4-c]-pyridin-3-one.
2-(2-piperidin-1-ylethyl)isothiazolo~4,5-c]pyridin-3-one.
A further sub-class of compounds is represented by formula (V) and pharmaceutically acceptable non-toxic acid addition salts thereof: O
(V) Z ~ - A - B - R16 wherein Z is as defined with respect to formula (I) above, A and B each represent a straight or branched chain alkylene group each having from 1 to 6 carbon atoms and R16 represents a heterocyclyl group or a group of formula (II) above.
Specific compounds of formula (V) include:
2-[2-(diethylamino)ethyl]-5-phenyl-isothiazolo[5,4-b3-pyridin-3-one.
2-[3-(dimethylamino)propyl]-isothiazolo[4,5-b]pyridin-3-one 2-[6-(dimethylamino)hexyl]-isothiazolo[5,4-b]pyridin-3-one.
A still further sub-class of compounds within the scope of this invention is represented by formula (VI) and pharmaceutically acceptable non-toxic acid addition salts thereof:
`"` 10~73461 .
X' R17 (VI) S
wherein Z is as defined with respect to formula (I) above, R17 is hydrogen or a Cl 3 alkyl group, and R18 is a heterocyclic ring attached via a carbon atom in the ring.
One example of a compound of formula (VI) is :
2-(1-methylpyrrolidin-2-ylmethyl)-isothiazolo[5,4-b]-pyrid-3-one.
A particularly preferred group of compounds according to the invention and to which the claims are directed are those of formula (I) O
(I) z ~ N - R
wherein R is a Cl 4 alkyl group or Cl 4 alkyl group substituted with phenyl or chlorine substituted phenyl, or a group of formula (II) R
N ~R2 wherein Rl and R2 are the same and are Cl 4 alkyl, or a group -N ~ wherein -N ~ is an aromatic or non-aromatic mono-or polycyclic heterocyclic containing A
.. ,.. - .. -. -. ~. - ... .. ` .. ... -... ;. ... . .. .
`` 1073461 5 to 9 atoms in the rin~s and one of these atoms may be another heteroatom selected from oxygen, sul~ur and nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from Cl 6 alkyl, heterocyclyl and phenyl.
The compounds of this invention may be prepared by cyclising a compound of formula (VII):
o (VII) z ll NH - R
~ E - ~H
wherein R and Z are as defined above with respect to formula ~I).
The reagents for such a cyclisation are generally com-pounds which halogenate the sulphur atom in structure (VII) and allow subsequent dehydrohalogenation. A preferred reagent is iodine in the presence of a base such as sodium bicarbonate or an-hydrous potassium carbonate but other possibilities include chlorine, bromine, phosphorus pentachloride and thionyl chloride. The reac-tion may be performed in a solvent which does not react with the intermediate or reagents employed. For example in the case of the reagent iodine/sodium bicarbonate, a lower alkanol, especially - 20 ethanol may be used as a solvent but for more reactive halogenating -agents such as phosphorus pentachloride a more inert solvent is employed, such as halogenated hydrocarbon, a higher ether or di-methylformamide. The reaction is conveniently carried out at ambient temperature.
~ -7a-. , :: :
`' lOq346`1 The intermediate compounds of formula (VII) may be conveniently prepared by the route shown in Scheme 1:
-7b-A
- . . , .. .. ,~ .. ; . . . .. . . . .. .. .. ... . . .
. .. . ,., .. .`. . ; .. . .- . ` ~.. , . ~ . . . ~
. . . , . ..... ~ . . . . . .
SCHEME I
~~ C02H ~ c_C~
SH C~S/
mercuric acetate ~VII) ~ R.~H2 ~ 11 S
C_s/
wherein R and Z are as defined above with respect to formula (I).
The intermediate (VII) may conveniently be prepared and cyclised n situ to produce the corresponding compound of formula (I) Furthermore, some of the above trithiones and dithiones in Scheme I are novel intermediat~s and also form part of this invention.
A second method for the pre~aration of compounds of this invent~.on comprises treating ~ comnoun~ of formula (VIII) ~.~ith base: -C _Co2R3 (VIII) Z C _S/ NH R
. - , . . ~ . . : . -::: :: ::: . . - . ; .
. . ......... ,, ::, , , .;: . .:
.. :. . ::-` 1073461 wherein R and Z are as defined above with respect to formula (I) and R is an alkyl group, preferably lower alkyl group.
Suitable bases for the reaction include alkali metal alXoxides, alkali metal hydroxides, and tetramethylammonioum hydroxide in lower alcohols.
The compounds of formula (I) may also be prepared by reacting a compound of formula (IX):
f C~.X' Z If (IX) ~~ ~S.Y
- wherein X and Y are the same or different and each represents chlorine, or bromine, and wherein-R and Z are-a~ defined above with respect to formula (I), with an amine of formula R.~H2.
Suitable solvents include carbon tetrachloride and other halogenated hydrocarbons.
A fourth method for the preparation of compounds of formula (I) comprises treating a dimer of formula (X):
- (X~
0~N~.R~ R~NH.CO~
C S ~~ - S ~'J
_ 9 _ . . . - ., . ~ - . ~ .,~ ,. . .
.~ ' :'' . . .' . .:.' ' '' ::
~ . ~. :-. ~, :.
10'73461 wherein R and Z are as defined above with re4pect to formula (I), with either chlorine or a base.
Suitable bases include lOYo sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temDerature or elevated temperature. If chlorine is employed in this reaction it may be bubbled into a solution of compounl (X) in an inert solvent such as carbon tetrachloride.
Compounds of this invention wherein R represents an alkyl group substituted with either a n.itrogen - containing a heterocyclic ring attached via the ring nitrogen, or with a group of formula tII), may be prepared by reacting a compound of formula (XI):
.
Z ~ AlX - U
(XI) ~ S
wherein Z is as defined with respect to formula ~I) above, Alk represents a straight or branched alkylene chain and U
represents a readily displaceable group, with a compound of formula (XIIA) or (XIIB):
~ R
NH Q ~H
~ --R2 (XIIA) (XIIB) 107 ~ 6~
wherein Rl and R2 are as defined with re~erence to formula ~I) and Q is the residue of a heterocyclic ring.
Suitably the group U is a halogen atom, for example chlorine or bromine, a substituted sulphonyloxy group, for example p-toluenesulphonyloxy or methanesulphonyloxy.
The reaction may suitably be carried out in a hydrocarbon solvent such as toluene at an elevated temperature for example 100 - 120.
The invention also provide~ a pharmaceutical composition which comprises a compound of formula (I) a~ defined above together with at least one pharmaceutically acceptable carrier.
As is common practice, such compositions will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thrombus formation.
The compositions may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventiona1 excipients such as binding agents, for example, syrup, acacia gelatin sorbitol, tragacanth, or polyvinyl-pyrollidone; fillers for example, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica;
disintegrants, for example potato starch or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be : :~: : : : :. .
'' :: : : : '. - ' . ::
: : .. . :- , .-:: - . ,, . ~ :
- , , ~. . : ., .: : ' ' ' .- .' , ' ~ -`` 1073461 coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan, monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, propylene glycol, or ethyl alcohol, preservatives, for example methyl or propyl ~-hydroxybenzoate or sorbic acid, and if desired conventional - 15 flavouring or colouring agents. The compound may also if desired be incorporated in a foodstuff, for example in the form of a biscuit.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depe~ding on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid before use.
' ~ , ~' - ,'',- ' , .' '.': -' ''' ' ` ' .
:~ .-: :,:. .
: '' ~ - .. ': ''' :
10~ ~ 61 Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99~ by weight, preferably from 10-60% by weight, of the active material, depending on the method of admin~tration. Where the compositions comprise dosage units, each unit will preferably contain from l-SOOmg. of the active ingredient. The dosage employed for adult treatment will of course depend on the dose-response characteristics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range of O.01 to 30 mg/kg/day depending on the route and frequency of administration. The preferred - dose is lO to 500 mg. orally, l to 3 times a day for an adult human.
The compositions of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis in geriatric patients to prevent transient cerebral ischemic attacks;
and long term prophylaxis following myocardial lnfarcts and strokes.
The compounds of formula (I) may also have application in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs " , . . .~ . . . . . .
-: .,. , .::, . . - .. ~ : ., , :
. ... . , ~ - .. ...~: , . . .
- ' ~ . ` .:., .: '' ' ;: .,. ' . , :
107346~
e.g. the heart, and kidneys, which have been removed from a cadaver and prior to transplant.
Accordingly, t~s invention also provides a proces~
for inhibiting platelet aggregation in vitro comprising the S addition of a compound of the formula (I) or a pharmacologically acceptable acid addition salt of such a compound to whole blood or platelet-rich concentrate.
The dQsage for such an addition is preferably from 0.01 to 50 micrograms/ml of whole blood.
The invention also provides a composition comprising whole blood and a compound of formula (I) above or a pharmacologically acceptable acid addition salt of such a compound having a basic nitrogen atom in the molecule.
The following Examples illustrate the preparation of some of the compounds of this invention.
~ . .
, : -_ 14 _ !, , '' ,'.' . . ': . ~ ' .
Example 1 2-(2-Pvrrolidin-l-vl-ethyl)isothiazolo~5,4-bl~yridin-3-one (a) 1,2-Dithiolor5,4-blpyridin-3-thione 2-Mercaptonicotinic acid (17.65g., O.llmole) and phosphorus pentasulphide (lSg., 0.06 mole) in pyridine (150ml) were heated under reflux for 2 hours. The reaction mixture was then cooled, diluted with water and the product filtered off.
Recrystallisation from ethanol yielded 1,2-dithiolo[5,4-b]-pyridi~-3 ~hione (7.89g; 37%), red ned~les m.p. 185-6.
(b) 1,2-Dithiolor5,4-bl~Yridin-3-one To a stirred suspension of mercuric acetate (17.0g., 0.053 mole) in glacial acetic acid (200 ml), a solution of 1,2-dithiolo[5,4-bj-pyridin-3-thione (5g, 0.025mole) in chloroform (lOOml) was a~ded and the mixture stirred at room temRerature, for 3 days. Celite (ca,25g.) was added to the mixture, filtered and the filtrate evaporated. The residue was treated with dichloromethane (ca.
lOOml) the solid filtered off and the filtrate evaporated. This latter process was repeated several times. The product was then taken up in dichloromethane (20ml) and filtered through a short column of silica-gel made up in dichloromethane. The column was washed with sufficient dichloromethane to reco~7er all the product and the combined filtrates evaporated. Recrystallisation of the residue from ethanol yielded 1,2-dithiolo~5,4-b]pyridin-3-one (3.21g., 70%), pale yellow needles, m.p. 96-97 .
(c) N-(2-Pyrrolidin-l-yl-eth~It2-merca~tonicotinamide.
1~2-Dithiolo~5~4-b]pyridin-3-one(~l~sg; ~OO9~Qle~ 2-amino-ethyl)-pyrrolidine ~l.lg., 0.01 mole) and ethanol (30ml) were - :,- . ,. .:: .
iO7 ~ 6~
heated under reflux for 1.5 hours. The mixture was filtered hot and the filtrate evaporated to dryness. The oily residue was triturated with dichloromethane and the resulting tan ~olid recrystallised from ethanol to yield the product (0.75g., 34%) tan prisms, m.p. 202-205.
(d) 2-(2-PYrrolidin-l-Yl-ethvl)isothiazolor5,4-blpyridin-3-one A stirred suspension of N-(2-pyrrolidin-1-yl-ethyl)-2-mercapton~cotinamide (13g. 0.05 mole) and sodium bicarbonate (8.7g., 0.105 mole) in ethanol (130ml) was treated portionwise with iodine (12.35g., 0.049 mole) over 2.5 hours, and then stirred at room temperature for a further 8 hour~. The mixture was then filtered and the filtrate evaporated to dryness.
The solids from the filter and the residue from the filtrate were suspended in water (200ml) and extracted thoroughly~with chloroform (3 x 60 ml) and dried (anhyd. MgS04). Evaporation of the dried solution yielded 8.8g of crude product which was crystallised from diisopropyl ether (including charcoal treatment) yielding pure 2~2-pyrrolidin-1-yl-ethyl)isothiazolo[5,4-b]pyridin-
-3-one (4~7g, 37%) as tan needles, m.p. 67-69.
-- .
, _ _ . . . - ~ - - . .
. , . -. . ~, . . - . --, .
:. . :: ,. ..
Exam~les 2-6 From 1,2-dithiolo[5,4-b]pyridin-3-one, the intermediate ' prepared in Example l(b), the following compound~ were prepared by the method of Example l(c) and l(d) respectively:
Example No.
2. (a) N-(3-Morphol-l-ylpropyl)-2-mercaptonicotinamide, m.p. 139-140.
(b) 2-(3-Morpholin-l-ylpropyl)-isothiazolo[5,4-b]-pyridin-3-one hydrochloride, m.p. 258-259C.
3. (a) N-P-chlorobenzyl-2-mercaptonicotinamide m.p. 216-219C.
(b) 2-(~-Chlorobenzyl)isothiazolo[5,4-b]-pyridin-3-one, m.p. 160-162&.
-- .
, _ _ . . . - ~ - - . .
. , . -. . ~, . . - . --, .
:. . :: ,. ..
Exam~les 2-6 From 1,2-dithiolo[5,4-b]pyridin-3-one, the intermediate ' prepared in Example l(b), the following compound~ were prepared by the method of Example l(c) and l(d) respectively:
Example No.
2. (a) N-(3-Morphol-l-ylpropyl)-2-mercaptonicotinamide, m.p. 139-140.
(b) 2-(3-Morpholin-l-ylpropyl)-isothiazolo[5,4-b]-pyridin-3-one hydrochloride, m.p. 258-259C.
3. (a) N-P-chlorobenzyl-2-mercaptonicotinamide m.p. 216-219C.
(b) 2-(~-Chlorobenzyl)isothiazolo[5,4-b]-pyridin-3-one, m.p. 160-162&.
4. (a) N-n-Butyl-2-mercaptonicotinamide, m.p. 129-131& .
(b) 2-n-Butylisothiazolo~5,4-b]-pyridin-3-one, m.p. 62-64C.
(b) 2-n-Butylisothiazolo~5,4-b]-pyridin-3-one, m.p. 62-64C.
- 5. (a) N-(2-Pyrid-2-ylethyl)-2-mercaptonicotinamide, m.p. 188-190C.
(b) 2-(2-Pyrid-2-ylethyl)isothiazolo[5,4-b]-pyridin-3-one, m.p. 85-86C.
(b) 2-(2-Pyrid-2-ylethyl)isothiazolo[5,4-b]-pyridin-3-one, m.p. 85-86C.
6. (a) N-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]-2-mercaptonicotinamide hydrochloride, m.p.
237-240C.
(b) 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo~5.4-b]pyridin-3-one, m.p. 133-135C.
Exam~le 7 (a) 1,2-Dithiolor5,4-cl~Yridin-3-thione, m.p. 155-156&
was prepared by the method of Example l(aj.
(b) 1,2-Dithiolor5.4-cl~vridin-3-one, m.p. 142-142.5 C
was prepared from the above thione by the method of Example l(b).
(c) 2-(2-piperidin-1-Ylethvl)isothiazolor5,4-cl~yridin-3-one A solution of N-(2-piperidin-1-yl)ethylamine (1.4g, O.Ollmole) in ethanol (SOml) was treated with 1,2-dithiolo[5,4-c~-pyridin-3-one (1.69g; O.Olmole) and heated under re'lux until solution was complete (ca. 15 minutes). The reaction mixture was cooled to 25 and anhydrous potassium carbonate (2g, 0.014mole3 was added. The resulting suspension was stirred and treated dropwise with a solution of iodine (2.54g, O.Olmole) in methanDl (lSml) over 1 hour and then allowed to stand at room temperature over night. The reaction mixture was evaporated to dryness under reduced pressure and the residue suspended in water and ex~racted with dichloromethane (3x50ml). The organic extract was washed with a solution of sodium thiosulphate (50ml - 10%), saturated brine (50ml) and dried over ~nhydrous MgS04. Removal of the drying agent and solvent yielded a gummy solid which after chromatography on silica-gel, eluting with l~/o MeOH/CH2C12 and recrystallisation from ~H2C12/di-isopropylether yielded pure 2-(2-piperidin-1-ylethyl)-isothiazolo[5,4-c]pyridin-3-one, 0.78g, m.p. 101-103C, yield 29%.
-::- : -: , .
107346~ .
Examples 8-9 From 1,2-dithiolo[5,4-c]pyridin-3-one (Example 7(b), the following compounds were prepared by the method of Example 7(c):
Example ~o.
8. 2-(2-Pyrrolidin-l-ylethyl)isothiazolo~5;4-c]- -pyridin-3-one, m.p~ 75-77C.
9. 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]isothia~olo-; ~5,4-c]pyridin-3-one, m.p. 117-119C.
Example 10.
(a) 1,2-Dithiolor4,5-blpYridin-3-thione, m.p. 174-176 C
was prepared by the method of Example l(a).
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p. 133-135C
was prepared from the above thione by the method of Example l(b).
(c) 2-(2-Pvrrolidin-l-vlethvl)isothiazolor4,5-blpyridin-3-one, m.p. 93-95C was prepared from 1,2-dithiolot4,5-b]-pyridin-3-one and 2-pyrrolidin-1-ylethylamine by the method of Example 7(c).
~- Example 11.
2-(3-DimethYlaminoproPYl)isothiazolor4~5-blpyridin-3-one~
m.p. 59-60 C was prepared from 1,2-dithiolo-[4,5-b]pyridin-3-one, (Example lO(b))and 3-dimethylaminopropylamine by the method of Example 7(c).
Example 12. ~)S-C
A ( a) 1,2-Dithiolor1,5 bl~Yridin-3-thione. m.p.206-208 was prepared by the method of Example l(a) C
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p.157-160 was prepared from the above thione by the method of Example l(b).
(c) 2-~2-Pi~eridin-l-vlethYl)iSothiaZolOr4~5 pyridin-3-one, m.p. 96-98 C. was prepared from 1,2-dithiolo[4,5-c]pyridin-3-one and 2-piperidin-1-ylethyl-
237-240C.
(b) 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo~5.4-b]pyridin-3-one, m.p. 133-135C.
Exam~le 7 (a) 1,2-Dithiolor5,4-cl~Yridin-3-thione, m.p. 155-156&
was prepared by the method of Example l(aj.
(b) 1,2-Dithiolor5.4-cl~vridin-3-one, m.p. 142-142.5 C
was prepared from the above thione by the method of Example l(b).
(c) 2-(2-piperidin-1-Ylethvl)isothiazolor5,4-cl~yridin-3-one A solution of N-(2-piperidin-1-yl)ethylamine (1.4g, O.Ollmole) in ethanol (SOml) was treated with 1,2-dithiolo[5,4-c~-pyridin-3-one (1.69g; O.Olmole) and heated under re'lux until solution was complete (ca. 15 minutes). The reaction mixture was cooled to 25 and anhydrous potassium carbonate (2g, 0.014mole3 was added. The resulting suspension was stirred and treated dropwise with a solution of iodine (2.54g, O.Olmole) in methanDl (lSml) over 1 hour and then allowed to stand at room temperature over night. The reaction mixture was evaporated to dryness under reduced pressure and the residue suspended in water and ex~racted with dichloromethane (3x50ml). The organic extract was washed with a solution of sodium thiosulphate (50ml - 10%), saturated brine (50ml) and dried over ~nhydrous MgS04. Removal of the drying agent and solvent yielded a gummy solid which after chromatography on silica-gel, eluting with l~/o MeOH/CH2C12 and recrystallisation from ~H2C12/di-isopropylether yielded pure 2-(2-piperidin-1-ylethyl)-isothiazolo[5,4-c]pyridin-3-one, 0.78g, m.p. 101-103C, yield 29%.
-::- : -: , .
107346~ .
Examples 8-9 From 1,2-dithiolo[5,4-c]pyridin-3-one (Example 7(b), the following compounds were prepared by the method of Example 7(c):
Example ~o.
8. 2-(2-Pyrrolidin-l-ylethyl)isothiazolo~5;4-c]- -pyridin-3-one, m.p~ 75-77C.
9. 2-[2-(3-Azabicyclo(3.2.2)non-3-yl)ethyl]isothia~olo-; ~5,4-c]pyridin-3-one, m.p. 117-119C.
Example 10.
(a) 1,2-Dithiolor4,5-blpYridin-3-thione, m.p. 174-176 C
was prepared by the method of Example l(a).
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p. 133-135C
was prepared from the above thione by the method of Example l(b).
(c) 2-(2-Pvrrolidin-l-vlethvl)isothiazolor4,5-blpyridin-3-one, m.p. 93-95C was prepared from 1,2-dithiolot4,5-b]-pyridin-3-one and 2-pyrrolidin-1-ylethylamine by the method of Example 7(c).
~- Example 11.
2-(3-DimethYlaminoproPYl)isothiazolor4~5-blpyridin-3-one~
m.p. 59-60 C was prepared from 1,2-dithiolo-[4,5-b]pyridin-3-one, (Example lO(b))and 3-dimethylaminopropylamine by the method of Example 7(c).
Example 12. ~)S-C
A ( a) 1,2-Dithiolor1,5 bl~Yridin-3-thione. m.p.206-208 was prepared by the method of Example l(a) C
(b) 1,2-Dithiolor4,5-blPvridin-3-one, m.p.157-160 was prepared from the above thione by the method of Example l(b).
(c) 2-~2-Pi~eridin-l-vlethYl)iSothiaZolOr4~5 pyridin-3-one, m.p. 96-98 C. was prepared from 1,2-dithiolo[4,5-c]pyridin-3-one and 2-piperidin-1-ylethyl-
7(c~
amine by the method of Example ~.
Example 13.
(a) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-thione, m.p.l35 was prepared by the method of Example l(a) (b) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-one, m.p.l49-150.5, was prepared from the above thione by the method of Example l(b).
(c) 2-(2-DiethYlaminoethvl)-5-Phenylisothiazolor5~4-bl-pYridin-3-one, m.p. 85-87 was prepared from 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one and 2-diethylaminoethylamine by the method of Example 7(c).
Example 14. phcnylIso~zolo 2-r2-(4-MethYlthiazol-2-yl)ethY11-5 ohonylioothia~olo ridin-3-one, m.p. 115-116 was prepared from 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one (Example 13(b)) -i`
and 2-(4-methylthiazol-2-yl)ethylamine by the method of Example 7(c).
.
- 20 _ . . .
10~3~46 Exam~les 15-16 Following the procedure of Examples l(a) - l(d) respectively, the following compounds were prepared:
Exam~le ~o~
15. (a) 4,5,6-Trimethyl-1,2-dithiolo~5,4-b]pyridin-3-thione, m.p. 155-157C.
(b) 4,5,6-Trimethyl-1,2-dithiolo[5,4-b]pyridin-3-one, m.p. 182-184C.
(c) ~-(2-Pyrrolidin-l-ylethyl)-2-mercapto-4,5,6-trimethyl nicotinamide, m.p. 158-160C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one,di~ydrochloride monohydrate, m.p. 198-203 C (dec).
16. (a) 4,6-9imethyl-1,2-dithiolo~5,4-b]pyridin-3-thione, m.p. 140-141C.
(b) 4,6-Dimethyl-1,2-dithiolo~5,4-b]pyridin-3-one, m.p. 168-169C.
(c) N-(2-Pyrrolidin-l-ylethyl)-4,6-dimethyl-2-mercapto-nicotinamide, m.p. 181-183 C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo-[5,4-b~-pyridin-3-one dihydrochloride, m.p. 193-- 196C.
:: . - .: . . :
BIOLOGICAL DATA
~he compounds of Examples 1-16 above were treated for their ability to inhibit platelet aggregation in vitro as follows:-Human blood (20ml) is drawn into a plastic syringe and immediately anti-coagulated by mixing with 0.1 volumes of 3.8% (w/v) trisodium citrate dihydrate. Platelet-rich-plasma (PRP) is prepared by centrifuging the anti-coagulated blood at 180g., for 12 min., at room temperature. Collagen (ex bovine achilles tendon) is suspended in 0.9% (w/v) saline, using a commercially available mixer emulsifier. PRP was mixed with O.l volumes saline ( control) or compound dissolved in saline and incubated at 37 for 3 min., before the addition of collagen. Water-insoluble compounds were added to PRP
dissolved in 0.005 volumes dimethylformamide, the solvent being - included in controls when appropriate. The final concentration of each compound was 100~M.
; Platelet aggregation in response to collagen was measured photometrically (Born, G.V.R., 1962, ~ature, 94, 927) in a - 20 Bryston aggregOmQter coupled to a Vitatron linear pen recorder.
The activity of each compound was expressed as percentage inhibition of the aggregation response to a dose of collagen producing a just-maximal change in light transmission in control PRP.
, - -, . ~ ,,.. - , ~...... . .
:: . , . ::, . . ~
.
- -. . -' , 10~3461 Results Table I lists % inhibition of platelet aggregation in response to collagen by~lOO~M solutions of several compounds of this invention.
TABLE I
Compound of % Inhibition Exam~le ~o.
. 4 100 : 7 100 ~ 8 . 85 .
' .
. 14 100 .. . ....
,,
amine by the method of Example ~.
Example 13.
(a) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-thione, m.p.l35 was prepared by the method of Example l(a) (b) 5-Phenyl-1,2-dithiolor5,4-bl~Yridin-3-one, m.p.l49-150.5, was prepared from the above thione by the method of Example l(b).
(c) 2-(2-DiethYlaminoethvl)-5-Phenylisothiazolor5~4-bl-pYridin-3-one, m.p. 85-87 was prepared from 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one and 2-diethylaminoethylamine by the method of Example 7(c).
Example 14. phcnylIso~zolo 2-r2-(4-MethYlthiazol-2-yl)ethY11-5 ohonylioothia~olo ridin-3-one, m.p. 115-116 was prepared from 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one (Example 13(b)) -i`
and 2-(4-methylthiazol-2-yl)ethylamine by the method of Example 7(c).
.
- 20 _ . . .
10~3~46 Exam~les 15-16 Following the procedure of Examples l(a) - l(d) respectively, the following compounds were prepared:
Exam~le ~o~
15. (a) 4,5,6-Trimethyl-1,2-dithiolo~5,4-b]pyridin-3-thione, m.p. 155-157C.
(b) 4,5,6-Trimethyl-1,2-dithiolo[5,4-b]pyridin-3-one, m.p. 182-184C.
(c) ~-(2-Pyrrolidin-l-ylethyl)-2-mercapto-4,5,6-trimethyl nicotinamide, m.p. 158-160C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one,di~ydrochloride monohydrate, m.p. 198-203 C (dec).
16. (a) 4,6-9imethyl-1,2-dithiolo~5,4-b]pyridin-3-thione, m.p. 140-141C.
(b) 4,6-Dimethyl-1,2-dithiolo~5,4-b]pyridin-3-one, m.p. 168-169C.
(c) N-(2-Pyrrolidin-l-ylethyl)-4,6-dimethyl-2-mercapto-nicotinamide, m.p. 181-183 C.
(d) 2-(2-Pyrrolidin-l-ylethyl)-4,6-dimethylisothiazolo-[5,4-b~-pyridin-3-one dihydrochloride, m.p. 193-- 196C.
:: . - .: . . :
BIOLOGICAL DATA
~he compounds of Examples 1-16 above were treated for their ability to inhibit platelet aggregation in vitro as follows:-Human blood (20ml) is drawn into a plastic syringe and immediately anti-coagulated by mixing with 0.1 volumes of 3.8% (w/v) trisodium citrate dihydrate. Platelet-rich-plasma (PRP) is prepared by centrifuging the anti-coagulated blood at 180g., for 12 min., at room temperature. Collagen (ex bovine achilles tendon) is suspended in 0.9% (w/v) saline, using a commercially available mixer emulsifier. PRP was mixed with O.l volumes saline ( control) or compound dissolved in saline and incubated at 37 for 3 min., before the addition of collagen. Water-insoluble compounds were added to PRP
dissolved in 0.005 volumes dimethylformamide, the solvent being - included in controls when appropriate. The final concentration of each compound was 100~M.
; Platelet aggregation in response to collagen was measured photometrically (Born, G.V.R., 1962, ~ature, 94, 927) in a - 20 Bryston aggregOmQter coupled to a Vitatron linear pen recorder.
The activity of each compound was expressed as percentage inhibition of the aggregation response to a dose of collagen producing a just-maximal change in light transmission in control PRP.
, - -, . ~ ,,.. - , ~...... . .
:: . , . ::, . . ~
.
- -. . -' , 10~3461 Results Table I lists % inhibition of platelet aggregation in response to collagen by~lOO~M solutions of several compounds of this invention.
TABLE I
Compound of % Inhibition Exam~le ~o.
. 4 100 : 7 100 ~ 8 . 85 .
' .
. 14 100 .. . ....
,,
Claims (35)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of an isothiazolopyridine of formula (I):
(I) or a pharmaceutically acceptable non-toxic acid addition salt thereof, wherein R is a C1-4 alkyl group or C1-4 alkyl group sub-stituted with phenyl or chlorine substituted phenyl, a group of formula (II):
(II) wherein R1 and R2 are the same and are C1-4 alkyl, or a group wherein is an aromatic or non-aromatic mono- or polycyclic heterocyclic containing 5 to 9 atoms in the rings and one of these atoms may be another heteroatom selected from oxygen, sulfur and nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from C1-6 alkyl, heterocyclyl and phenyl, which process comprises:
(a) cyclising a compound of formula (VII):
(VII) wherein R and Z are as defined above; or (b) treating a compound of formula (VIII):
(VIII) wherein R and Z are as defined above; and R is an alkyl group with a base; or (c) reacting a compound of formula (IX):
(IX) wherein Z is as defined above and X and Y are the same or different and each represents chlorine or bromine; with amine of formula R.NH2; or (d) treating a dimer of formula (X):
(X) wherein R and Z are as defined above; with either chlorine or a base; or (e) when R represents an alkyl group substituted either with a nitrogen-containing ring attached via the ring nitrogen; or with a group of formula (II) as defined, reacting a compound of formula (XI) (XI) wherein Z is as defined for formula (I), Alk represents a straight or branched alkylene chain and U represents a readily displaceable group; with a compound of formula (XIIA) or (XIIB) wherein R1 and R2 are as defined for formula (I) and Q is the resi-due of the heterocyclic ring defined as for formula (I);
and recovering the compound of formula (I) and where required converting it to a pharmaceutically acceptable salt thereof.
(I) or a pharmaceutically acceptable non-toxic acid addition salt thereof, wherein R is a C1-4 alkyl group or C1-4 alkyl group sub-stituted with phenyl or chlorine substituted phenyl, a group of formula (II):
(II) wherein R1 and R2 are the same and are C1-4 alkyl, or a group wherein is an aromatic or non-aromatic mono- or polycyclic heterocyclic containing 5 to 9 atoms in the rings and one of these atoms may be another heteroatom selected from oxygen, sulfur and nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from C1-6 alkyl, heterocyclyl and phenyl, which process comprises:
(a) cyclising a compound of formula (VII):
(VII) wherein R and Z are as defined above; or (b) treating a compound of formula (VIII):
(VIII) wherein R and Z are as defined above; and R is an alkyl group with a base; or (c) reacting a compound of formula (IX):
(IX) wherein Z is as defined above and X and Y are the same or different and each represents chlorine or bromine; with amine of formula R.NH2; or (d) treating a dimer of formula (X):
(X) wherein R and Z are as defined above; with either chlorine or a base; or (e) when R represents an alkyl group substituted either with a nitrogen-containing ring attached via the ring nitrogen; or with a group of formula (II) as defined, reacting a compound of formula (XI) (XI) wherein Z is as defined for formula (I), Alk represents a straight or branched alkylene chain and U represents a readily displaceable group; with a compound of formula (XIIA) or (XIIB) wherein R1 and R2 are as defined for formula (I) and Q is the resi-due of the heterocyclic ring defined as for formula (I);
and recovering the compound of formula (I) and where required converting it to a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1 (a) wherein the compound of formula VII is prepared by reacting a compound of formula with a compound of formula R.NH2 wherein Z and R are as already defined and cyclizing the compound of formula VII in situ by treating the reaction mixture with iodine, chlorine, bromine, phosphorus pentachloride or thionyl chloride.
3. A compound of the formula (I) (I) wherein R is a C1-4 alkyl group or C1- 4 alkyl group substituted with phenyl or chlorine substituted phenyl, or a group of formula (II) wherein R1 and R2 are the same and are C1-4 alkyl, or a group wherein is an aromatic or non-aromatic mono- or polycyclic heterocyclic containing 5 to 9 atoms in the rings and one of these atoms may be another heteroatom selected from oxygen, sulfur and nitrogen;
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from C1-6 alkyl, heterocyclyl and phenyl; and pharmaceutically acceptable salts thereof when prepared by the process of claim 1 or 2 or an obvious chemical equivalent.
and Z is the residue of a fused pyridine ring or the residue of a fused pyridine ring substituted with up to three groups selected from C1-6 alkyl, heterocyclyl and phenyl; and pharmaceutically acceptable salts thereof when prepared by the process of claim 1 or 2 or an obvious chemical equivalent.
4. A process for the preparation of the compound 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-(2-pyrrolidin-1-yl-ethyl)-2-mercaptonicotin-amide with iodine in the presence of a base and a solvent and recovering the required compound.
5. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 4 or an obvious chemical equivalent.
6. A process for the preparation of the salt 2-(3-morpholin-1-yl propyl)-isothiazolo[5,4-b]pyridin-3-one hydrochloride which comprises reacting N-(3-morphol-1-yl propyl)-2-mercaptonicotinamide with iodine in the presence of a base and a solvent and recovering 2-(3-morpholin-1-yl propyl)-isothiazolo[5,4-b]pyridin-3-one and con-verting it to the hydrochloride salt and recovering said salt.
7. 2-(3-morpholin-1-yl propyl)-isothiazolo[5,4-b]pyridin-3-one hydrochloride when prepared by the process of claim 6 or an obvious chemical equivalent.
8. A process for the preparation of the compound 2-(p-chlorobenzyl)-isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-p-chlorobenzyl-2-mercaptonicotinamide with I2 in the presence of a base and a solvent and recovering the required compound.
9. 2-(p-chlorobenzyl)-isothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 8 or an obvious chemical equiva-lent.
10. A process for the preparation of the compound 2-n-butyl-isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-n-butyl-2-mercaptonicotinamide with I2 in the presence of a base and a solvent and recovering the required compound.
11. 2-n-butylisothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 10 or an obvious chemical equivalent.
12. A process for the preparation of the compound 2-(2-pyrid-2-ylethyl)-isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-(2-pyrid-2-ylethyl)-2-mercaptonicotinamide with iodine in the presence of a base and a solvent and recovering the required compound.
13. 2-(2-pyrid-2-ylethyl)-isothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 12 or an obvious chemical equivalent.
14. A process for the preparation of the compound 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo[5,4-b]pyridin-3-one which comprises reacting N-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]-2-mercaptonicotinamide with iodine in the presence of a base and a solvent and recovering the required compound.
15. 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]-isothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 14 or an obvious chemical equivalent.
16. A process for the preparation of the compound 2-(2-piperidin-1-yl-ethyl)-isothiazolo[5,4-c]pyridin-3-one which com-prises reacting 1,2-dithiolo[5,4-c]-pyridin-3-one with N-(2-piperidin-1-yl)ethylamine in a solvent and after addition of a base treating the reaction mixture with iodine and recovering the required compound.
17. 2-(2-piperidin-1-yl-ethyl)-isothiazolo[5,4-c]pyridin-3-one when prepared by the process of claim 16 or an obvious chemi-cal equivalent.
18. A process for the preparation of the compound 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-c]pyridin-3-one which com-prises reacting 1,2-dithiolo[5,4-c]pyridin-3-one and N-(2-pyrroli-din-1-yl)ethyl amine in a solvent and after addition of a base treating the reaction mixture with iodine and recovering the required compound.
19. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[5,4-c]pyridin-3-one when prepared by the process of claim 18 or an obvious chemical equivalent.
20. A process for the preparation of the compound 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo[5,4-c]pyridin-3-one which comprises reacting 1,2-dithiolo[5,4-c]pyridin-3-one with N-[2-(3-azabicyclo(3.2.2)non-3-yl)]ethyl amine in a solvent and after addition of a base treating the reaction mixture with iodine and recovering the required compound.
21. 2-[2-(3-azabicyclo(3.2.2)non-3-yl)ethyl]isothiazolo [5,4-c]pyridin-3-one when prepared by the process of claim 20 or an obvious chemical equivalent.
22. A process for the preparation of the compound 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[4,5-b]pyridin-3-one which com-prises reacting 1,2-dithiolo[4,5-b]pyridin-3-one with N-(2-pyrroli-din-1-yl)ethyl amine in a solvent and after addition of a base treating the reaction mixture with iodine and recovering the required compound.
23. 2-(2-pyrrolidin-1-yl ethyl)-isothiazolo[4,5-b]pyridin-3-one when prepared by the process of claim 22 or an obvious chemical equivalent.
24. A process for the preparation of the compound 2-(3-dimethylaminopropyl)-isothiazolo[4,5-b]pyridin-3-one which com-prises reacting 1,2-dithiolo-[4,5-b]pyridin-3-one with 3-dimethyl-aminopropylamine in a solvent and after addition of a base treating the reaction mixture with iodine and recovering the required com-pound.
25. 2-(3-dimethylaminopropyl)-isothiazolo[4,5-b]pyridin-3-one when prepared by the process of claim 24 or an obvious chemi-cal equivalent.
26. A process for the preparation of the compound 2-(2-piperidin-1-yl ethyl)-isothiazolo[4,5-c]pyridin-3-one which comprises reacting 1,2-dithiolo[4,5-c]pyridin-3-one with N-(2-piperidin-1-yl)ethylamine in a solvent and after addition of a base, treating the reaction mixture with iodine and recover-ing the required compound.
27. 2-(2-piperidin-1-yl ethyl)-isothiazolo[4,5-c]pyridin-3-one when prepared by the process of claim 26 or an obvious chemical equivalent.
28. A process for the preparation of the compound 2-(2-diethylaminoethyl)-5-phenylisothiazolo[5,4-b]pyridin-3-one which comprises reacting 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one with 2-diethylaminoethylamine in a solvent and after addition of a base, treating the reaction mixture with iodine and recovering the required compound.
29. 2-(2-diethylaminoethyl)-5-phenylisothiazolo[5,4-b]pyridin-3-one when prepared by the process of claim 28 or an obvious chemical equivalent.
30. A process for the preparation of the compound 2-[2-(4-methylthiazol-2-yl)ethyl]-5-phenylisothiazolo[5,4-b]pyridin-3-one which comprises reacting 5-phenyl-1,2-dithiolo[5,4-b]pyridin-3-one with 2-(4-methylthiazol-2-yl)ethylamine in a solvent and after addition of a base, treating the reaction mixture with iodine and recovering the required compound.
31. 2-[2-(4-methylthiazol-2-yl)ethyl]-5-phenylisothiazolo [5,4-b]pyridin-3-one when prepared by the process of claim 30 or an obvious chemical equivalent.
32. A process for the preparation of the salt 2-(2-pyrrolidin-1-yl ethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one dihydro-chloride monohydrate which comprises reacting N-(2-pyrrolidin-1-yl ethyl)-2-mercapto-4,5,6-trimethyl nicotinamide with iodine in the presence of a base and a solvent and recovering 2-(2-pyrrolidin-1-yl ethyl)-4,5,6-trimethyl-isothiazolo[5,4-b]pyridin-3-one and converting it to the dihydrochloride monohydrate and recovering said salt.
33. 2-(2-pyrrolidin-1-yl ethyl)-4,5,6-trimethyl-isothiazolo [5,4-b]pyridin-3-one dihydrochloride monohydrate when prepared by the process of claim 32 or an obvious chemical equivalent.
34. A process for the preparation of the salt 2-(2-pyrrolidin-1-yl ethyl)-4,6-dimethylisothiazolo[5,4-b]pyridin-3-one dihydro-chloride which comprises reacting N-(2-pyrrolidin-1-ylethyl)-4,6-dimethyl-2-mercaptonicotinamide with iodine in the presence of a base and a solvent, recovering 2-(2-pyrrolidin-1-yl ethyl)-4,6-dimethylisothiazolo[5,4-b]pyridin-3-one and converting it to the hydrochloride salt.
35. 2-(2-pyrrolidin-1-yl ethyl)-4,6-dimethylisothiazolo [5,4-b]pyridin-3-one dihydrochloride when prepared by the process of claim 34 or an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB17165/76A GB1560726A (en) | 1976-04-28 | 1976-04-28 | Isothiazolo-pyridines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1073461A true CA1073461A (en) | 1980-03-11 |
Family
ID=10090431
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA275,531A Expired CA1073461A (en) | 1976-04-28 | 1977-04-04 | Heterocyclic compounds |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS52131597A (en) |
| AT (1) | AT359063B (en) |
| AU (1) | AU2451277A (en) |
| BE (1) | BE853779A (en) |
| CA (1) | CA1073461A (en) |
| DE (1) | DE2718707A1 (en) |
| DK (1) | DK185577A (en) |
| ES (1) | ES457993A1 (en) |
| FI (1) | FI771236A (en) |
| FR (1) | FR2349591A1 (en) |
| GB (1) | GB1560726A (en) |
| HU (1) | HU174416B (en) |
| IE (1) | IE44873B1 (en) |
| IL (1) | IL51812A0 (en) |
| NL (1) | NL7704542A (en) |
| NZ (1) | NZ183755A (en) |
| SE (1) | SE7704800L (en) |
| ZA (1) | ZA771963B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005705A1 (en) * | 2011-06-30 | 2013-01-03 | Abbott Laboratories | Novel inhibitor compounds of phosphodiesterase type 10a |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU84091A1 (en) * | 1982-04-16 | 1984-03-02 | Oreal | N-CARBAMOYL DERIVATIVES OF ISOTHIAZOLO- (5,4B) PYRIDINE ONE-3, THEIR PREPARATION METHOD AND THEIR USES AS BACTERICIDAL AND FUNGICIDAL AGENTS |
| LU84491A1 (en) * | 1982-11-26 | 1984-06-13 | Oreal | ANTI-ACNE COMPOSITION CONTAINING AS AN ACTIVE COMPOUND A DERIVATIVE OF ISOTHIAZOLO- (5,4B) PYRIDINE ONE-3 |
| FR2555450B1 (en) * | 1983-11-24 | 1988-04-01 | Oreal | ANTI-ACNE COMPOSITION CONTAINING AS AN ACTIVE COMPOUND A DERIVATIVE OF ISOTHIAZOLO- (5,4B) PYRIDINE ONE-3 |
| US5734081A (en) * | 1994-08-05 | 1998-03-31 | Warner-Lambert Company | Arylthio compounds |
| US5620997A (en) * | 1995-05-31 | 1997-04-15 | Warner-Lambert Company | Isothiazolones |
| US6001863A (en) * | 1996-11-26 | 1999-12-14 | Warner-Lambert Company | Isothiazolones |
| JP4982790B2 (en) * | 2006-09-26 | 2012-07-25 | 独立行政法人産業技術総合研究所 | Method for producing isothiazolopyridin-3-one compound |
| JP4853910B2 (en) * | 2006-09-26 | 2012-01-11 | 独立行政法人産業技術総合研究所 | Method for producing isothiazolopyridin-3-one compound |
| JP4853911B2 (en) * | 2006-09-26 | 2012-01-11 | 独立行政法人産業技術総合研究所 | Method for producing isothiazolopyridin-3-one compound |
| FR2968661B1 (en) * | 2010-12-14 | 2016-01-01 | Oreal | PROCESS FOR DEPIGMENTING KERATINIC MATERIALS USING THIOPYRIDINONE COMPOUNDS |
| FR3115207B1 (en) | 2020-10-15 | 2022-10-07 | Oreal | Use of thiopyridinone compounds to prevent the formation of cutaneous blackheads |
-
1976
- 1976-04-28 GB GB17165/76A patent/GB1560726A/en not_active Expired
-
1977
- 1977-03-31 NZ NZ183755A patent/NZ183755A/en unknown
- 1977-03-31 ZA ZA00771963A patent/ZA771963B/en unknown
- 1977-04-01 IL IL51812A patent/IL51812A0/en unknown
- 1977-04-04 CA CA275,531A patent/CA1073461A/en not_active Expired
- 1977-04-19 FI FI771236A patent/FI771236A/fi not_active Application Discontinuation
- 1977-04-20 BE BE176868A patent/BE853779A/en unknown
- 1977-04-20 FR FR7711844A patent/FR2349591A1/en active Granted
- 1977-04-20 ES ES457993A patent/ES457993A1/en not_active Expired
- 1977-04-21 AU AU24512/77A patent/AU2451277A/en not_active Expired
- 1977-04-26 SE SE7704800A patent/SE7704800L/en not_active Application Discontinuation
- 1977-04-26 NL NL7704542A patent/NL7704542A/en not_active Application Discontinuation
- 1977-04-26 AT AT291977A patent/AT359063B/en not_active IP Right Cessation
- 1977-04-27 JP JP4903077A patent/JPS52131597A/en active Pending
- 1977-04-27 DK DK185577A patent/DK185577A/en not_active Application Discontinuation
- 1977-04-27 IE IE847/77A patent/IE44873B1/en unknown
- 1977-04-27 DE DE19772718707 patent/DE2718707A1/en active Pending
- 1977-04-28 HU HU77BE1295A patent/HU174416B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005705A1 (en) * | 2011-06-30 | 2013-01-03 | Abbott Laboratories | Novel inhibitor compounds of phosphodiesterase type 10a |
| US9938269B2 (en) * | 2011-06-30 | 2018-04-10 | Abbvie Inc. | Inhibitor compounds of phosphodiesterase type 10A |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ183755A (en) | 1979-03-28 |
| AU2451277A (en) | 1978-10-26 |
| ZA771963B (en) | 1978-03-29 |
| FR2349591B1 (en) | 1980-02-01 |
| GB1560726A (en) | 1980-02-06 |
| FI771236A (en) | 1977-10-29 |
| IE44873L (en) | 1977-10-28 |
| ES457993A1 (en) | 1978-07-16 |
| IL51812A0 (en) | 1977-06-30 |
| HU174416B (en) | 1980-01-28 |
| BE853779A (en) | 1977-10-20 |
| DK185577A (en) | 1977-10-29 |
| JPS52131597A (en) | 1977-11-04 |
| DE2718707A1 (en) | 1977-11-10 |
| NL7704542A (en) | 1977-11-01 |
| ATA291977A (en) | 1980-03-15 |
| IE44873B1 (en) | 1982-04-21 |
| FR2349591A1 (en) | 1977-11-25 |
| SE7704800L (en) | 1977-10-29 |
| AT359063B (en) | 1980-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1073461A (en) | Heterocyclic compounds | |
| SU1375127A3 (en) | Method of producing derivatives of 1.2-diaminocyclobutene-3.4-dion or chlorohydrates thereof | |
| US4212979A (en) | 2-Substituted benzisothiazolones | |
| CA2188918A1 (en) | Novel quinolone 5-(n-heterosubstituted amino) antimicrobials | |
| AU703634B2 (en) | Novel crystalline forms of anhydrous 7-{(1alpha,5alpha, 6alpha)-6-amino-3-azabicyclo(3.1.0)hex-3-y1}-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid, methanesulfonic acid salt. | |
| DK149024B (en) | ANALOGY PROCEDURE FOR PREPARING CRYSTALLINIC WATER SOLUBLE SALTS OF N- (2-PYRIDYL) -2-METHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE-1,1-DIOXIDE | |
| US3847921A (en) | Pharmacologically active 3-piperazinyl-carbonyloxy-2-pyridyl-isoindolin-1-ones | |
| GB1593609A (en) | Pyridine sulfonamides | |
| DK153150B (en) | ANALOGY PROCEDURE FOR PREPARING 4-OXO-1,6,7,8-TETRAHYDRO-4H-PYRIDOOE1,2AAAPYRIMIDINE DERIVATIVES | |
| JPH05504358A (en) | Substituted urea compounds and their preparation and use | |
| US3719671A (en) | 10-imidoylphenothiazines | |
| US3822269A (en) | 6-aminoalkylamino-hexahydrophenanthridines useful as antiarrhythmic agents | |
| US4187303A (en) | Thiazine derivatives | |
| US4215120A (en) | Penicillin esters and their preparation | |
| EP0000254B1 (en) | Antithrombotic 2-(gamma-(1-piperidinyl)propyl)1,2-benzisothiazol 3-one, its pharmaceutically acceptable acid addition salts, their preparation and their compositions | |
| IE46375B1 (en) | 3-imino-1,5,10,10a-tetrahydrothiazolo(3,4-b)isoquinoline derivatives | |
| US4164579A (en) | Hydroxythiazolidine-2-thiones | |
| KR860000103B1 (en) | Process for preparing 3'-substituted-5'-(2-amino-4-pyridyl)-1',2'4'-triazoles | |
| US4189480A (en) | Isoquinoline derivatives | |
| US4450109A (en) | Thiazinobenzimidazole derivatives | |
| IE45293B1 (en) | Esters of penicillin antibiotics | |
| DE2753391A1 (en) | BENZISOTHIAZOLONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL PREPARATIONS CONTAINING THESE COMPOUNDS | |
| CS198166B2 (en) | Method of producing new 1,1-disubstituted octahydroindolo/2,3-a/quinolizines | |
| KR800001069B1 (en) | Process for preparation of benz isothiazolones | |
| SE441357B (en) | 4-PYRIDINO - CYANOGUANIDE INGREDIENTS, PROCEDURES FOR PREPARING THIS AND A COMPOSITION WITH ANTI-PRESSURING EFFECT |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |