GB2174094A - Imidazo [1,5-a] pyridine derivatives - Google Patents
Imidazo [1,5-a] pyridine derivatives Download PDFInfo
- Publication number
- GB2174094A GB2174094A GB08609765A GB8609765A GB2174094A GB 2174094 A GB2174094 A GB 2174094A GB 08609765 A GB08609765 A GB 08609765A GB 8609765 A GB8609765 A GB 8609765A GB 2174094 A GB2174094 A GB 2174094A
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- compound
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- halogen
- pharmaceutically acceptable
- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to pharmaceutical compositions comprising mainly novel compounds of formula: <IMAGE> or pharmaceutically acceptable acid addition salt thereof wherein the dotted lines represent optional bonds; R<1> represents hydrogen, lower alkyl, lower alkoxy or halogen; A represents a direct bond or a saturated or unsaturated acyclic hydrocarbon chain having 1 to 5 carbon atoms and R represents an aryl or C5-C7 cycloalkyl radical each optionally substituted by one or more substituents independently selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl, or nitro and the term 'lower' means a group contains 1 to 6 carbon atoms; and a pharmaceutically acceptable carrier. Compounds of formula I possess thromboxane synthetase inhibitory properties and can be used in the treatment of cardiovascular disorders.
Description
SPECIFICATION lrnidazofl,5-a]pyridine derivatives
This invention relates to pharmaceutical compositions comprising heterocyclic compounds, more particularly to compositions comprising imidazo[l ,5-alpyridine derivatives, to novel compounds contained in these compositions, and their preparation.
In a first aspect this invention provides a pharmaceutical composition comprising a compound of formula
or a pharmaceutically acceptable acid addition salt thereof wherein the dotted lines represent optional bonds; R1 represents hydrogen, lower alkyl, lower alkoxy or halogen, A represents a direct bond or a saturated or unsaturated acyclic hydrocarbon chain having 1 to 5 carbon atoms and R represents an optionally substituted aryl or C5;uC7 cycloalkyl radical in which the substituents are independently selected from one or more of the following: halogen, lower aikyl, lower alkoxy, trifluoromethyl or nitro; and a pharmaceutically acceptable carrier.
By the term 'lower' as used herein to quaiify a group is meant a group containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Examples of lower alkyl groups for R1 are methyl, ethyl, n-propyl and n-butyl. Lower alkoxy groups for R include methoxy, ethoxy and n-propoxy. R1, when halogen, can be chlorine or bromine.
Examples of -A- are saturated alkylene chains of formula -(CH2)n wherein n is 1 to 5. Preferably n is 1.
When unsaturated A may be alkylene or alkynylene chains such as -CH=CH-, -CH2-CH=CH- or -CH=CH-CH2-.
Other examples of A include -CH(CH3)-, -CH2CH(CH3)-.
By the term aryl is meant a carbocyclic radical possessing aromatic character preferably having 6 to 10 carbon atoms such as phenyl and naphthyl.
Examples of R are phenyl, or phenyl substituted one or more groups selected from halogen (e.g.
2-chlorophenyl 2,6-dichlorophenyl), lower alkyl (e.g. 2-methylphenyl, 2,6-dimethylphenyl), lower alkoxy (e.g.
2-methoxyphenyl, 2,6-dimethoxyphenyl), nitro (e.g. 2-nitrophenyl or 2,4-dinitrophenyl) or combinations of such substituents (e.g. 2-methoxy-6-methylphenyl).
Examples of cycloalkyl groups for R include cyclohexyl and cycloheptyl.
When both lines represent bonds the compounds are imidazo[l,5-a]pyridines and when both dotted lines are absent the compounds are 5,6,7,8-tetrahydroimidazo[l ,5-a]-pyridines.
Preferred compounds of formula I have the radical -A-R in the 5-position.
Particularly preferred compositions comprise a compound of formula I having the formula
wherein R2 is hydrogen or methyl, R3 and R4 independently represent hydrogen, lower alkyl, lower alkoxy or halogen and m is an integer from 1 to 4.
In a second aspect this invention provides novel compounds having the general formula las shown hereinabove or salts thereof in which formula the dotted lines, R1 A and R are as defined above providing that R cannot represent monohalophenyl.
The compounds of formula I possess pharmaceutical activity, in particular they are thromboxane synthetase inhibitors. Accordingly they are useful in the treatment or prevention of diseases responsive to the inhibition of thromboxane synthetase especially cardiovascular disorders such as thrombosis, atherosclerosis, cerebral ischaemic attacks; and angina pectoris.
The compounds were tested for their ability to inhibit thromboxane production by the following standard test: a) Generation of thromboxanes Blood (approx. 75 ml) is obtained from an anaesthetised rabbit and centrifuged at 2009 for 10 minutes to obtain platelet rich plasma (PRP). An aliquot of PRP is incubated for 10 minutes at 37"C in the presence of vehicle or drug. Piatelet aggregation is induced by the addition of adenosine diphosphate and adrenalin. The tubes are incubated for 3 minutes, centrifuged at 10,0009 for 3 minutes and a 50 ml aliquot of the supernatanttaken for radio-immunoassayofthromboxane B2 (TxB2).
(h) Radio-immunoassayof TxB2 The total incubation volume is 150 ul containing 50 oil of 3H - TX B2 (0.00511Ci),50ml of sample or authentic TX B2 ranging from 5 to 300 pg per tube as standards and 50 oil of rabbit anti-sera to TxB2 (in a concentration which will bind 50% of3H-TxB2). After incubation for 1 hour at room temperature the tubes are further incubated for 1620 hours at 4"C. 1 ml of dextran-coated charcoal is then added to the tubes which are further incubated on ice for 10 minutes.Following the incubation the samples are centrifuged at 10,0009 for 10 minutes and 500ml of the supernatant added to 5 ml of scintillation cocktail. Measurement of the radioactivity in the supernatant quantitates the amount of [3H]-Tx B2 bound by the antibody. The concentration of unlabelled TxB2 in the sample is then determined from a linear standard curve.
In the above mentioned test a representative compound of formula I, namely 5-(2,6-dimethylbenzyl) imidazo[1,5-a]-pyridine hydrochloride, possesses an IC50 of about 9 x 10-7M for thromboxane synthetase inhibition.
This invention also provides processes for preparing novel compounds of formula I. In general both the compounds of formula I and intermediates of analogous structure may be prepared by processes which are known or are analogous to known processes involving building up the molecule from known constituent parts suitably activated and/or protected where required.
A first general process for preparing compounds of formula I where the optional bonds are present comprises cyclising a compound of formula:
wherein A, Rand R1 are as hereinbefore defined and R2 is hydrogen or lower alkyl. The cyclisation may be carried out using an acid, such as polyphosphoric acid or derivative thereof, e.g. phosphorus oxychloride or polyphosphate ester, preferably in an inert solvent such as toluene, heating if required.
A second process for peparing compounds of formula I, wherein the optional bonds are present, comprises removing the blocking group B from a compound of formula
where the dotted lines R, R1 and A are as hereinbefore defined and B is a blocking group replaceable by hydrogen. Examples of B are -SH or -S-alkyl especially where alkyl represents an alkyl group of 1 to 6 carbon atoms, e.g. methyl or ethyl. In such cases the blocking group is removed by desulphurizing, e.g. using Raney nickel.
Compounds of formula Ill wherein A is other than a direct bond may be prepared by alkylating a starting material of formula
wherein B is a blocking group such as -S-alkyl and M is hydrogen or an alkali metal such as lithium, e.g. using a compound of formula R-A-X where Xis halogen or an equivalent replaceable group such as an organic sulphonyloxy group, e.g. tosyl.
Compounds of formula Ill wherein A is a direct bond may be prepared by coupling a compound of formula
with a compound R-Y1, in which formulae B, R1 and R are as hereinbefore defined and one of Y andY1 is ZnX where Xis halogen, e.g. Cl and the other of Y andY1 is halogen (e.g. Cl, Br or I) in the presence of nickel or palladium catalysts such as (Ph3P)4Ni, (Ph3P)4Pd or 1,4-bis(diphenylphosphino)-butane palladium dichloride.
Compounds of formula Ill wherein B is -SH may be prepared bycyclising a compound of formula
wherein R1, A and R are as herein before defined using CS2 or an aryl isothiocyanate, eg a phenyl or substituted phenyl isothiocyanate, respectively via an intermediate dithiocarbamic acid or an arylthiourea, which intermediates are converted into the desired intermediate by thermolysis in a suitable solvent.
A third process for preparing compounds of formula I wherein the dotted lines are bonds comprises reacting a compound of formula (V) as hereinbefore defined with formic acid or reactive derivative thereof such as triethylorthoformate. This reaction may be carried out by heating in an inert solvent preferably at reflux.
Compounds of formula I wherein the dotted lines are absent may be pepared by reducing compounds of formula I wherein the dotted lines are bonds for example by hydrogenation e.g. using a platinum on charcoal catalyst or palladium under acidic conditions.
In any of the aforementioned reactions compounds of formula I may be isolated in free base form or as acid addition salts as desired. Acid addition salts include salts with inorganic or organic acids especially salts with pharmaceutically acceptable acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, hydroiodic, sulphonic (e.g. methane- or toluene-sulphonic), acetic, maleic, citric, tartaric, fumaric, malonic and formic acid.
The invention further provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt for use as a pharmaceutical.
The invention provides a pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid.
Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient.
Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.
Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.
The following Examples illustrate the invention:
Example 1 5-(2, 6-Dimeth ylbenryl)3-eth ylthioimidazo[l, & ]p yridine To a solution of 3-ethylthioimidazo[l ,5-a]pyridine (1.789, 0.01m) in tetrahydrofuran (35ml) cooled to -780C was added a solution of n-butyllithium (1 .6m, 7ml, 0.011 m) over 5 minutes and the mixture was stirred at this temperature for 0.5 hour. A solution of 2,6-dimethylbenzyl chloride (1.79, 0.011m) in THF (1 Oml) was added.
The mixture was allowed to warm up to room temperature andthen poured into ice/water (100g). The mixture was extracted with ether (3 times) dried (MgSO4) and evaporated to give an oil. This was purified by column chromatography on silica using a 1 to 1 mixture by volume of ether and n-hexane as eluent to give the title compound which crystallised from ether (1.29) m.p. 10811 00C.
Analysis
Found: C, 72.46, H, 6.56; N,10.00% C18H20N2S requires C, 72.93, H, 6.80, N, 9.45.
Example 2 5-(2, 6-Dimethylbenzylkmidazof1, 5-alp yridine 5-(2,6-Dimethylbenzyl)-3-ethylthioimidazo[1,5-a]-pyridine (1.29) in isopropyl alcohol (75ml) with Raney
Nickel was heated under reflux for 3 hours then filtered. The solvent was removed under reduced pressure and acidified with ethanolic HC1. The title compound as the hydrochloride, hemihydrate was collected by filtration and dried (0.55g, 50%) m.p. 1981970C.
Analysis
Found: C, 68.27; H, 6.21; N, 9.68; C16H15N2.HCl.1/2H2O requires C, 68.20; H, 6.44; N, 9.94.
Example 3 5-(2,6-Dimethylbenzyl)-5,6,7,8-tetraDydroimidazof 1,5-a]-pyridine 5-(2,6-Dimethylbenzyl)imidazo[1,5-a]pyridine (from Example 2) is reduced using platinum on charcoal catalyst or palladium on carbon under acidic conditions e.g. hydrochloric acid in ethanol to give the title compound.
Example 4
Using a procedure analogous to Examples 1 and 2 involving the reaction sequence:
compounds of formula I wherein R and A have the following values are prepared:
(a) -OH2- 2,6-dichlorophenyl
(b) -CH2- 2,6-dimethoxyphenyl
(c) -(CH2)3- 2,6-dimethylphenyl
(d) -CH2- 3,4-dimethylphenyl
(e) -(CH2)2- 2,6-dimethylphenyl
(f) -CH2- cyclohexyl
(g) -(CH2)2- 3,4-dimethylphenyl
(h) -(CH2)3- 3,4-dimethylphenyl
(i) -(CH2)- 3-methyl-4-methoxyphenyl
Claims (11)
1. A pharmaceutical composition comprising a compound of formula
or a pharmaceutically acceptable acid addition salt thereof wherein the dotted lines represent optional bonds; R1 represents hydrogen, lower alkyl, lower alkoxy or halogen;
A represents a direct bond, or a saturated or unsaturated acyclic hydrocarbon chain having 1 to 5 carbon atoms and R represents an aryl or C9C7 cycloalkyl radical optionally substituted by one or more substituents independently selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro; the term 'lower' means a group contains 1 to 6 carbon atoms and a pharmaceutically acceptable carrier.
2. A compound of formula I
or an acid addition salt thereof wherein R, A and R1 are as defined in Claim 1 with the proviso that R does not represent monohalophenyl.
3. A compound or composition according to Claim 1 or Claim 2 where A represents a chain formula -(CH2)n- wherein n is 1 to 5; -CH=CH-, -CH2-CH=CH-; -CH=CH-CH2, -CH(CH3)- or -CH2CH(CH3)-.
4. A compound or composition as claimed in any one of Claims 1 to 3 wherein R represents phenyl optionally substituted by one or two substituents independently selected from lower alkyl, lower alkoxy or halogen.
5. A compound or composition as claimed in any one of Claims 1 to 4 wherein -A-R is in the 5-position.
6. A compound or composition as claimed in any one of Claims 1 to 5 wherein the compounds are imidazo[l,5-a]pyridines.
7. 5-(2,6-Dimethylbenzyl)imidazo[1 ,5-a]pyridine or a pharmaceutically acceptable salt thereof.
8. A process for preparing a compound as claimed in Claim 2 which comprises
(a) cyclising a compound of formula
wherein R, R1 and A are as defined in Claim 1 and R2 is hydrogen or lower alkyl to give a compound of formula I wherein the optional bonds are present, or (b) removing the blocking group B from a compound of formula
wherein R, A and R1 are as defined in Claim 1 and B is a blocking group replaceable by hydrogen to give a compound of formula I wherein the optional bonds are present, or
(c) reacting a compound of formula V
wherein A, R and R1 are as defined in Claim 1 with formic acid or a reactive derivative thereof to give a compound of formula I wherein the optional bonds are present, or
(d) reducing a compound of formula las defined in Claim 1 wherein the optional bonds are present to give a compound of formula I in which the bonds are absent, or
(e) converting a compound of formula I in free base form to an acid addition saltthereoforviceversa.
9. A process for preparing a compound of formula I as claimed in Claim 8 substantially as hereinbefore described with reference to Example 2.
10. A compound according to Claim 2 whenever prepared by a process as claimed in Claim 8 or Claim 9.
11. A compound as claimed in Claim 2 or Claim 7 for use as a pharmaceutical.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858510541A GB8510541D0 (en) | 1985-04-25 | 1985-04-25 | Heterocyclic compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8609765D0 GB8609765D0 (en) | 1986-05-29 |
| GB2174094A true GB2174094A (en) | 1986-10-29 |
| GB2174094B GB2174094B (en) | 1989-12-20 |
Family
ID=10578181
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858510541A Pending GB8510541D0 (en) | 1985-04-25 | 1985-04-25 | Heterocyclic compounds |
| GB8609765A Expired GB2174094B (en) | 1985-04-25 | 1986-04-22 | Imidazo(1,5-a)pyridine derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858510541A Pending GB8510541D0 (en) | 1985-04-25 | 1985-04-25 | Heterocyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB8510541D0 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4728645A (en) * | 1982-12-21 | 1988-03-01 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives and other substituted bicyclic derivatives, useful as aromatase inhibitors |
| JP2006508970A (en) * | 2002-11-18 | 2006-03-16 | ノバルティス アクチエンゲゼルシャフト | Method for treating diseases mediated by imidazo [1,5A] pyridine derivatives and aldesterone |
| WO2018054365A1 (en) | 2016-09-24 | 2018-03-29 | Beigene, Ltd. | NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES |
| US10501458B2 (en) | 2015-07-06 | 2019-12-10 | Iomet Pharma Ltd. | Substituted bicyclic fused ring compounds as indoleamine-2,3-dioxygenase inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4617307A (en) * | 1984-06-20 | 1986-10-14 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors |
-
1985
- 1985-04-25 GB GB858510541A patent/GB8510541D0/en active Pending
-
1986
- 1986-04-22 GB GB8609765A patent/GB2174094B/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4728645A (en) * | 1982-12-21 | 1988-03-01 | Ciba-Geigy Corporation | Substituted imidazo[1,5-A]pyridine derivatives and other substituted bicyclic derivatives, useful as aromatase inhibitors |
| JP2006508970A (en) * | 2002-11-18 | 2006-03-16 | ノバルティス アクチエンゲゼルシャフト | Method for treating diseases mediated by imidazo [1,5A] pyridine derivatives and aldesterone |
| US10501458B2 (en) | 2015-07-06 | 2019-12-10 | Iomet Pharma Ltd. | Substituted bicyclic fused ring compounds as indoleamine-2,3-dioxygenase inhibitors |
| WO2018054365A1 (en) | 2016-09-24 | 2018-03-29 | Beigene, Ltd. | NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2174094B (en) | 1989-12-20 |
| GB8510541D0 (en) | 1985-05-30 |
| GB8609765D0 (en) | 1986-05-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19950422 |