GB2137618A - Furo-(3,4-c)-pyridine derivatives - Google Patents
Furo-(3,4-c)-pyridine derivatives Download PDFInfo
- Publication number
- GB2137618A GB2137618A GB08407082A GB8407082A GB2137618A GB 2137618 A GB2137618 A GB 2137618A GB 08407082 A GB08407082 A GB 08407082A GB 8407082 A GB8407082 A GB 8407082A GB 2137618 A GB2137618 A GB 2137618A
- Authority
- GB
- United Kingdom
- Prior art keywords
- furo
- dihydro
- pyridine
- hydroxy
- methyl
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Abstract
<IMAGE> Furo-(3,4-c)-pyridine derivatives of formula I(A1,A2=C1-5 hydrocarbon, hererocyclic, carbomonoocyclic, phenylalkenyl or phenylalkyl group, all optionally substituted) are diuretics and anti-histaminic agents and are further useful in lowering blood pressure and protecting kidneys. Their preparation and pharmaceutical competitions containing them are also claimed.
Description
SPECIFICATION
Nuro - (3,4-c) - Pyridine derivatives
The invention relates to furo - (3,4-c) - pyridine derivatives, to a process fortheir preparation and to pharmaceutical compositions containing them.
The invention provides 1,3 - dihydro - 6 - methyl - 7 hydroxy -furo - (3,4-c) - pyridine derivatives of the general formula I (and theirtherapeutically acceptable addition salts):
wherein each of A1 and A2 independently represents a straight chain saturated or unsaturated hydrocarbon group having from 1 to 5 carbon atoms, a heterocyclic group having up to 6 ring atoms, a carbomonocyclicgroup, a phenylalcyl group ora phenylalkenyl group, each ofthe groups represented byA1 and A2 being unsubstituted or being substituted by one or more chlorine orfluorine atoms, trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups in which each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in which each of the two alkyl groups and the alkoxy groups has from 1 to 5 carbon atoms or a- - or ss - alkoxy - N - pyrrolidinyl groups in which the alkoxy group has from 1 to 5 carbon atoms.
The compounds according to the invention are of interestfortheirtherapeutical activity, principally in the fields of diuresis,the lowering of blood pressure and kidney protection, and as anti-histaminic agents.
The invention further provides a process forthe preparation of 1,3 - dihydro - 6 - methyl - 7 - hydroxyfuro - (3,4 - c) - pyridine derivatives ofthe general formula las above defined, the process comprising oxidizing a secondary alcohol ofthe general formula
II
wherein A1 is as above defined, reacting the resultant ketonewith a compound of the general formula XA2 wherein X represents a bromine or iodine atom and
A2 is as above defined in the presence of magnesium in diethyl ether at the boil and treating the resultant tertiary alcohol with an acidic agent to provoke breaking ofthe isopropylidene ring and 3,4cyclisation. The starting secondary alcohol Il may be obtained as described in Patent Application 2092586.
The oxidation may be carried out by any usual technique, for example oxidation with manganese dioxide.
The process according to the invention is illustrated by the following reaction scheme:
The invention also provides pharmaceutical compositions comprising a furo - (3,4 - c) - pyridine derivative ofthe general formula las herein defined in admixture with a pharmaceutically acceptable diluent or carrier.
The invention is illustrated bythefollowing examples.
Example 1 1,3- dmydro - 3,3,6- trimethyl - 7- hydroxy- furo - (3,4 -c)-pyridine Into a 3-litre reactor fitted with stirring, warming and cooling means, previously submitted to a nitrogen circulation, were poured 3.47 g (0.143 mol) of magnesium. Slowly, under stirring, there was then added 20.3 g (0.143 mol) of methyl iodide dissolved in 400 ml of distilled diethyl ether. The mixture was refluxed for 2to 3 hours, then cooled to 10-15 C and 22.8 g (0.11 mol) of a4, 3 - o - isopropylidene pyridoxal dissolved in 600 ml of distilled diethyl ether were slowly added.The mixture was stirred for 12 hours at room temperature, and then the diethyl ether was evaporated off under reduced pressure (end of preparation of starting secondary alcohol). 450 ml of dry methylene dichloride with 30.5 g (0.142 mol) of pyridinium chlorochromate and 2.35 g (0.0285 mol) of pure and dry sodium acetate were poured all at once into the reactor and the mixture was stirred for 2 hours at room temperature, and then for some minutes, after addition of 200 ml of dry diethyl ether.
After elimination of insoluble matter, the organic phase was filtered and evaporated to dryness, leading to an oily product (end of step (ii)). This product was dissolved in 400 ml of diethyl ether and treated under stirring for 12 hours at room tempera turewitha mixture obtained byrefluxingfor2hours 400 ml of diethyl ether, 20 g (0.14 mol) of methyl iodideand3.45g (0.14 mol) of magnesium. The diethyl etherwasevaporatedoffunderreduced pressure; after cooling, there were added 0.51 of chloroform and, dropwise, under stirring, 150 ml of 2N hydrochloric acid.Stirring was maintained for 2 hours, the mixture was decanted, the precipitate washed with water, dried on an hydrous sodium sulphate, redissolved in diethyl ether, recrystallized, washed and dried (end of step (iii)). The compound thus obtained was then treated with 100 ml of concentrated hydrochloric acid at room temperature, under stirring for 12 hours. The precipitate obtained was treated twice by ethanol and recrystallized from acetone. Yield 15.9 g (67%) of a pale yellow product melting at 247 C (Tottoli), elemental analysis of which showed good correspondence with the formula
C10H13NO2HCl. The product exhibited good solubility in water at room temperature.
Example 2 1,3- dihydro -3- In -pentyl)-3,6- dimethyl - 7 - hydroxy - furo - (3,4 - c) - pyridine This compound was obtained as described in example 1 but replacing the methyl iodide by n-pentyl bromide t step (iii). Yield: 72% of a product melting at 2220C (Tottoli), elemental analysis ofwhich showed good correspondence with theformula
C14H21 NO2.HCl. The compound exhibited very good solubility in water at room temperature.
Example 3 1,3-dihydro-3-phenyl-3,6-dimethyl-7-hydroxyfuro - (3,4 - c) - pyridine
This compound was obtained as described in example 1 but replacing the methyl iodide by phenyl bromide in step (i). Yield: 69% of a cream-white product melting at245C (Tottoli), elemental analysis of which showed good correspondence with the formula C15H15NO2. The compounds was insoluble in water at room temperature.
Example 4
1,3-dihydro-3-(p-chlorophenyl)-3,6-dimethyl-7 hydroxy - furo - (3,4 - c) - pyridine
This compound was obtained as described in
example 1, but using p-chlorophenyl bromide instead of methyl iodide in step (i). Yield: 63% of a white crystalline powder melting at 228 C (Tottoli), elemental analysis of which showed good corres
pondence with the formula C15H14ClN02.HCl. The compound was insoluble in water at room temperature.
Example 6 1,3 - dihydro - 3 - (p - fluorophenyl) - 3,6- dimethyl - 7 - hydroxy- furo - (3,4-c) - pyridine
The compound was obtained as described in example 1, but using p-fluorophenyl bromide instead of methyl iodide in step (i). Yield: 71 % of a white crystalline powder melting at 238 C (Tottoli), elemental analysis ofwhich showed good correspondence with the formula C15H14FNO2. The compound was insoluble in water at room temperature, but soluble in 0.1 N HCI.
Example 6 '1,3- dihydro-3-(oc- thienyl)-3,6- dimethyl-7- hydroxy- furo - (3,4 - c) - pyridine
This compound was obtained as described in example 2, but using oethienyl chloride instead of n-pentyl bromide. Yield: 74% of a beige product melting at 198 C (Tottoli), elemental analysis of which showed good correspondence with the formula
C13H13NO2S.HCl. The compound was soluble in water.
Example 7 7,3 - dihydro - 3 - [2 - (3,4,5- trimethoxyphenyl) - ethyl] -3,6-dimethyl-7-hydroxy-furo-(3,4-c)-pyridine
This compound was obtained as described in example 1, but replacing the methyl iodide by 1 chloro - 2 - (3,4,5 -trimethoxyphenyl) ethane, in step (i). Yield: 83% of a white product melting at 219 C (Tottoli), elemental analysis of which showed good correspondence with theformula C20H25NO5HCl. The compound was soluble in water at room temperature.
Example 8 1,3- dihydro-3-ethyl-3- (n -propyl)-6-methyl- 7- hydroxy-furo-(3,4-c)-pyridine
This compound was obtained as described in example 1, but replacing the methyl iodide by n-propyl bromide in step (i) and by ethyl iodide instep (iii). Yield: 71 % of a white crystalline product melting at 212 C (Tottoli), elemental analysis of which showed good correspondence with the formula
C18H19NO2.HCl. The compound was insoluble in water at room temperature.
Example 9 1,3-dihydro-3-ethyl-3-(n-butyl) - 6- methyl - 7- hydroxy - furo - (3,4 - c) - pyridine
This compound was obtained as described in example 8, but replacing the n-propylbromide by n-butyl bromide. Yield: 67% of a white crystalline product melting at2380C (Tottoli), elemental analysis of which showed good correspondence with the formula C14H21NO2HCl. The compound was insoluble in water at room temperature.
Example 10 1,3 - dihydro - 3 - ethyl - 3 - phenyl - methyl -7- hydroxy-furo-(3,4-c)-pyridine
This compound was prepared as described in example 8, but replacing the n-propyl bromide by phenyl bromide. Yield: 66% of a white crystalline product melting at 234 C (Tottoli), elemental analysis ofwhich showed good correspondence with the formula C16H17NO2. The compound was insoluble in water at room temperature.
Example 71 1,3 - dihydro - 3 - ethyl - 3-(p - chlorophenyl) - 6 - methyl - 7- hydroxy- furo - (3,4 - c) - pyridine
This compound was obtained as described in example 8, but replacing the n-propyl bromide by p-chlorophenyl bromide. Yield: 77% of a cream whiteproductmelting at215C(Tottoli),elemental analysis of which showed good correspondence with the formula C16H16CINO2. The compound was insoluble in water at room temperature.
Example 72 1,3 - dihydro - 3 - ethyl - 3 - (m - trifluoromethyl phenyl)-6-methyl-7-hydroxy-furo-(3,4-c)pyridine
This compound was prepared as described in example 8, but replacing the n-propyl bromide by m- trifluoromethyl - phenyl bromide. Yield: 69% of a white crystalline product melting at 207-208 C (Tottoli). elemental analysis of which showed good correspondence with theformula C16H16F3NO2.The com
pound was insoluble in water at room temperature, butsolublein0.1N HCI.
Example 13 1,3-dihydro-3-ethyl-3-(α-furyl)-6-methyl-7- hydroxy- furo - (3,4-c) pyridine This compound was obtained as described in
example 8, but replacing the n-propyl bromide by oc-furyl bromide. Yield: 73% of a pink product melting
at 192 C (Tottoli) with decomposition, elemental
analysis of which showed good correspondence with
the formula C14H15NO3.HCl. The compound was
insoluble in water at room temperature.
Example 14 1,3- dihydro - 3 - vinyl - 3 - (p - methylthio - phenyl) - 6 methyl - 7 - hydroxy- furo - (3,4 - c) - pyridine
This compound was obtained as described in example 1 but replacing the methyl iodide byp methylthio - phenyl bromide in step (i) and by vinyl bromide in step (iii). Yield: 63% of a cream white crystalline product melting at 2000C (Tottoli), elemental analysis of which showed good correspondence with the formula C17H17NO2S.HCl. The compound was insoluble in waterat room temperature but soluble in dimethylsulphoxide.
Example 15 1,3-dihydro-3- propyl - 3- (p - chlorophenyl) - 6 - methyl - 7 - hydroxy - furo - (3,4 - c) - pyridine
This compound was obtained as described in example 1 but replacing the methyl iodide by p-chlorophenyl bromide in step (i) and by propyl iodide in step (iii). Yield: 61 % of a white crystalline product melting with decomposition at 188-190 C (Tottoli), elemental analysis of which showed good correspondence with the formula C17H18CI NO2. The compound was insoluble in water at room temperature but soluble in 0.1 N HCI.
Example 16
1,3 - dihydro - 3 - dimethylaminopropyl-3-p chlorophenyl-6-methyl-7-hydroxy-furo-(3,4-c)pyridine
This compond was prepared as described in example 15 but replacing the propyl iodide by dimethylamino-propyl bromide. Yield: 56% of a white crystalline product melting at 21 20C (Tottoli), elemental analysis ofwhich showed good correspondence with the formula C19H23N2O2Cl. The compound was insoluble in water at room temperature but soluble in dimethylsulphoxide.
Example 17 1,3- dihydro - 3,3 - diphenyl- 6 - methyl - 7 - hydroxyfuro - (3,4 - c) - pyridine
This compound was obtained as described in
example 1 but replacing the methyl iodide by phenyl
bromide in both steps (i) and (iii). Yield: 66% of a white crystalline powder melting at 260 C (Tottoli) with decomposition, elemental analysis of which
showed good correspondence with the formula C20H17NO2.HCl. The compound was insoluble in
water at room temperature.
Example 18 1,3- dihydro -3-phenyl-3- (p - toluyl) - 6-methyl- 7- hydroxy - furo - (3,4 - c) - pyridine
This compound was obtained as described in
example 17 but replacing, in step (i),the phenyl bromidebyp-toluyl bromide. Yield: 73% of a white
crystalline product melting at 253 C (Tottoli) with
decomposition, elemental analysis ofwhich showed
good correspondence with the formula
C21H19NO2.HCl. The compound was insoluble in
water at room temperature.
Example 19
1,3-dihydro-3-phenyl-3-(p-fluorophenyl)-6 methyl- 7-hydroxy-furo- (3,4 - c) - pyridine This compound was prepared as described in
example 17 using, in step (i), p-fluorophenyl bromide
instead of phenyl bromide. Yield: 74% of a white crystalline product melting at 259 C (Tottoli),
elemental analysis of which showed good corres
pondence with the formula C20H15FNO2.HCl.The compound was insoluble in water at room temperature.
Example 20
1,3 - dihydro - 3 - (p - trifluoromethylphenyl) - 3 phenyl - 6 - methyl - 7- hydroxy - furo - (3,4 - c) pyridine
This compound was obtained as described in example 17 but replacing the phenyl bromide byp trifluoromethylphenyl bromide in step (i). Yield: 71% of a white crystalline product melting at 248 C with decomposition, elemental analysis of which showed good correspondence with the formula 021H16F3NO2.HCI. The compound was insoluble in water at room temperature.
Example 21 1,3 - dihydro - 3 - (p-ethoxyphenyl)-3-phenyl-6- methyl - 7- hydroxy- furo - (3,4-c5-pyridine This compound was obtained as described in example 17 but replacing the phenyl bromide by p ethoxyphenyl bromide in step (i). Yield: 58% of a white product melting at 230 C (Tottoli), elemental analysis of which showed good correspondence with the formula C22H21NO3.NCl.The compound was insoluble in water at room temperature.
Example 22 1,3 - dihydro - 3 - (p - diethylaminomethoxyphenyl) - 3 -phenyl-6-methyl-7-hydroxy-furo-(3,4-c)pyridine
This compound was obtained as described in example 16 but replacing, in step (iii), the phenyl bromide by p - diethylaminomethoxyphenyl bromide. Yield: 56% of a beige powder melting at 202 C (Tottoli), elemental analysis ofwhich showed good correspondence with the formula 025H28N2Os. The compound was insoluble in water at room temperature.
Example 23 1,3-dihydro-3-(p-[N-(α-methoxypyrrolidinyl)]- phenyl)-3-phenyl-6-methyl-7-hydroxy-furo (3,4-c)-pyridine This compound was obtained as described in
example 17 but replacing, in step (iii), the phenyl
bromide by p - [N - (o: - methoxypyrrolidinyl)] - phenyl
bromide. Yield: 73% of a white crystalline product
melting at 189 C (Tottoli), elemental analysis of which
showed good correspondence with the formula
C25H26N3O3.HCl. The compound was insoluble in
water at room temperature.
Example 24
1,3 - dihydro - 3,3 - di - (p - fluorophenyl) - 6 - methyl - 7
- hydroxy- furo - (3,4 - c) - pyridine This compound was obtained as described in
example 1 but replacing the methyl iodide by p
fluorophenyl bromide in steps (i) and (iii). Yield: 71%
of a white crystalline product melting at 236-239 C (Tottoli), elemental analysis of which showed good
correspondence with the formula 020H15F2NO2. The compound was insoluble in water at room tempera ture but soluble in dimethylsuiphoxide.
Example25 7,3- dihydro-3-(oc- furyl)-3-(p- (p-methylthio- phenyl) - 6- methyl - 7 - hydroxy- furo - (3,4 - c) - pyridine
This compound was obtained as described in example 13 but replacing the ethyl iodide, in step (iii), byp-thiomethylphenyl bromide. Yield 52% of a beige powder melting at 176 C (Tottoli), elemntal analysis of which howed good correspondence with the formula ClgH17NO3S.HCI. The compound was slightlysoluble in water at room temperature.
Example 26 1,3,-dihyro-3,3-di(α-furyl)-6-methyl-7- hydroxy-furo-(3,4-c)-pyridine
This compound was obtained as described in example 13 but replacing the ethyl iodide, in step (iii), by oc-furyl bromide. Yield 56% of a beige powder melting at 184"C (Tottoli), elemental analysis of which showed good correspondence with the formula C16H13NO4.HCl.The compound was slightly soluble in water at room temperature.
Example 27 1,3 - dihydro - 3 - cyclohexyl - 3 - (2,3 - dichlorophenyl) -6-methyl- 7-hydroxy-furo- (3,4-c)-pyridine
This compound was obtained as described in example 1 but replacing the methyl iodide by 2,3 dichlorophenyl bromide in step (i) and by cyclohexyl bromide in step (iii). Yield: 76% of a white crystalline
product melting with decomposition at 195-197 C
(Tottoli), elemental analysis of which showed good
correspondence with the formula C20H21CI2NO2. The
compound was insoluble in water at room tempera
ture but soluble in 0.1 N HCl.
Example 28 1,3- dihydro -3-cyclohexyl-3-(p - chlorophenyl) - 6 - methyl -7 - hydroxy - furo - (3,4 - c) - pyridine This compound was obtained as described in
example 27 but replacing 2,3 - dichlorophenyl bro
mide byp- chlorophenyl bromide in step (i). Yield:
79% ofa white crystalline product melting at 205-208 C (Tottoli), elemental analysis of which showed good correspondence with theformula
C20H22CI NO2. The compound was insoluble in water at room temperature but soluble in 0.1 N HCI.
Example 29
1,3- dihydro -3- cyclohexyl-3- (p -fluorophenyl) - 6 methyl - 7- hydroxy- furo - (3,4 - c) - pyridine This compound was obtained as described in example 28 but replacing p - chlorophenyl bromide byp-fluorophenyl bromide in step (i). Yield: 83% of a white crystalline product melting with decomposition at 208-21 00C (Tottoli), elemental analysis of which showed good correpondencewith the formula
C20H22F NO2. The compound was insoluble in water at
room temperature but soluble in 0.1 N- HCI.
Example 30
1,3- dihydro - 3,3 - dicyclohexyl - 6 - methyl - 7 - hydroxy-furo-(3,4-)-pyridine
This compound was obtained as described in
example 1 by using cyclohexyl bromide in both steps.
Yield: 69% of a white crystalline product melting with
decomposition at 187-190 C (Tottoli), elemental
analysis of which showed good correspondence with
the formula C20H29NO2. The compound was insoluble in water at room temperature but soluble in 0.1 N HCI.
TOXICITY Thetoxicityofthe compounds according to the invention has been determined on rats and mice by the oral route. No LD 50 could befoundforno death was noticed atthe does of 5 g/Kg for rats and of 2 g/Kg for mice.
A sub-acute toxicity study was undertaken on rats and dogs atthe doses of 10,60 and 360 mg/Kg for six weeks by oral route: no deaths occurred and no variation ofthe measurable factors was noticed.
PHARMACOLOGY
The interest ofthe compounds ofthe invention has been evidenced by various pharmacologictests.
1) Studyofthe urinary elimination in the rat.
This study has been conducted on Wistar male rats weighing 250-260 g.
Sixteen batches each of eight animals were used: one for control, one treated bytienilic acid as reference compound and fourteen batches by the compounds according to the invention, all animals of these lastfifteen batches atthesame does of 50 mg/kg/day.
Each animal was placed in a metabolic cage fitted forthe collection of urine and treated forthree days; neitherfood nor drink was given during the treatment in orderto avoid any contamination. The collected volumes of urine were measured after six hours and twenty four hours.f After six hours, each animal received 25 ml,kg of physiologic serum. On the fourth day, each animal received a lasttreatment and blood was taken off atthe retro orbital sinus under slight anaesthesia by diethyl ether. The results are reported in Table 1.
2) Action on blood pressure.
This study was conducted on rats suffering from induced high blood pressure, by the method of
GOLDBLATT in comparison with Indapamine. This method is not described in detail for it is well known.
The study showed, at the same therapeutic doses, that the compounds of the invention have on this test the same action forthe lowering of blood pressure on the rats.
3 Action on an experimentalhyperlipemia on rabbit
This study has been conducted according to the method of C.B. AMMERMAN and Coll,; Am. J. PHYS.
(1961) 200, 75-79.
In this method, the suppression of drinkforfive days induces in the rabbit a higher hepatic biosynthesis of cholesterol. Blood is taken off after the sixth day in the abdominal aorta forthe dosage of total lipids, triglycerids, total cholesterol, HDL cholesterol (enzymatic method after electrophoresis on cellulose acetate).
The livers are taken off and weighed. In all the cases the administration was done directlyintheoesopha- gus from the third to the fifth days. This experimentation has been conducted simultaneously on 15 batches each of six animals, two control batches (normal control and control without food), one
reference batch (animal without food buttreated by tienilic acid) and the last twelve batches by twelve of the compounds ofthe invention.Thesethirteen last
batches receive 50 mgikg/day. The results are re ported in Table 2 wherein the letters A to F represent:
A: Weight of livers in g,
B: Total lipids in g/l,
C: Triglycerids in g/l,
D: Total cholesterol in g/l,
E: HDL cholesterol in g/l (two columns),
F: LDL cholesterol in g/l.
TABLE I
Administration Volumes (ml0 per 06 of 50 mg/kg/day 0 - 6h 6 - 24h 0 - 24h Control 5.7 14.1 19.8 Tienilic 8.0 8.9 16.7 acid EX. 1 10.2 10.6 20.8 EX. 3 10.2 10.6 20.6 EX. 4 10.4 10.9 20.7 EX. 6 10.0 10.8 20.5 EX. 8 10.1 10.7 20.5 EX. 11 10.3 11.0 20.9 EX. 12 10.1 10.8 20.3 EX. 15 8.8 10.0 20.1 EX. 17 10.1 10.8 21.0 EX. 20 10.5 11.4 21.3 EX. 21 10.2 10.9 20.8 EX. 24 10.1 10.6 20.2 EX. 28 9.8 10.9 20.4 EX. 30 10.5 11.2 21.1 TABLE 2
Plasmatic valuet Cholesterol of Total the chnles lips 1 A B C D E F E Control 3.52 5.18 1.69 0.83 0.18 0.29 4.73 Control 2.52 11.10 1.23 2.66 0.41 2.12 6.81 food Tienilic 2.80 12.28 1.97 2.48 0.23 1.77 15.72 seid El. 1 2.63 11.05 1.46 2.51 0.31 1.70 8.01 EX. 3 2.79 11.67 1.53 2.47 0.30 1.62 7.93 EX. 6 2.72 11.44 1.57 2.50 0.24 1.65 8.17 EX. 8 2.72 12.04 1.47 2.48 0.27 1.67 8.31 EX. 11 2.65 11.56 1.61 2.50 0.28 1.67 7.79 Ex. 12 2.66 12.10 1.62 2.46 0.29 1.63 8.16 EX. 13 2.77 11.86 1.44 2.49 0.25 1.66 8.19 EX. 17 2.70 11.93 1.49 2.17 0.27 1.64 8.24 El. 20 2.69 11.79 1.44 2.51 0.26 1.64 8.12 EX. 24 2.78 11.97 1.48 2.46 0.27 1.70 7.85 Ex. 28 2.62 11.46 1.48 2.45 0.23 1.64 8.22 El. 30 2.65 11 8S 1.50 2.53 0.29 1.67 8.22 In conclusion of the various experimentations it can be noticed that the compounds of the invention have a regular diuretic action slightly betterthan the known diuretics ofthe same chemical family (thiazidic). In human therapy, they have also an action on the lowering of blood pressure which is rather common in diuretics but limited to the patients presenting an hypertension.An otherimportantfact is a significative lowering ofthe lipid rates in blood: this is a highly favorable action, for the patients treated by diuretics are generally suffering also from arteriosclerosis or other circulary insufficiencies wherein the lowering of the lipid rates is highly desired. Forthis reason, the compounds of the invention may be considered as diuretics offering a better protection of the patient.
CLINICAL EXPERIMENTATION Aclinical experimentation has been conducted on 127 patients with compounds of examples 3,4 and 5.
Each patientwastreated asfollows: on days 1,3,5 and 7, administration (double blind route) of a single dose of 100 mg or 200 mg or 400 mg of the selected compound or an equivalent presentation of placebo at 10.00 a.m. after a complete urination. Urines were collected forthefollowing 24 hours for determination ofthe diuresis. No treatment was given on days 2,4 and 6.
The diuresis was increased by 130 to 164% atthe dose of 100 mg, by 192 to 248% atthe dose of 200 mg and 288 to 371 % atthe dose of 400 mg (percentages given by reference to the action of placebo) with a better tolerance than with the compounds of patent application no. 2092586.
PRESENTATION
The preferred mode of administration includes tablets and gelatine capsules; fortabletsthe dosage units comprise 50 or 100 mg of active ingredient together with an appropriate carrier, such as starch.
POSOLOGY
In human therapy is is generally advisableto administer 100 to 400 mg per diem for at least one weekand, more generally, two orthreeweeks.
Claims (35)
1. A1,3-dihydro-6-methyl-7-hydroxy-furo (3,4-c) - pyridine derivative ofthe general formula las defined herein or a therapeutically acceptable acid addition salt thereof.
2. 1,3 - dihydro - 3,3,6 -trimethyl - 7 - hydroxy furo - (3,4 - c) - pyridine.
3. 1,3-dihydro-3-(n-pentyl)-3,6-dimethyl-7hydroxy-furo-(3,4-c)-pyridine.
4. 1,3-dihydro-3- phenyl-3,6- dimethyl-7hydroxy-furo-(3,4-)-pyridine.
5. 1,3 - dihydro -3 - (p - chlorophenyl) - 3,6 dimethyl -7- hydroxy -furo - (3,4-c)- pyridine.
6. 1,3 - dihydro - 3 - (p-fluorophenyl) - 3,6 - dimethyl -7 - hydroxy -furo- (3,4-c) - pyridine.
7. 1,3-dihydro-3-(α-thienyl)-3,6-dimethyl-7- hydroxy-furo-(3,4-c)-pyridine.
8. 1,3-dihydro-3-[2- (3,4,5- trimethoxyphenyl)- ethyl]-3,6-dimethyl7-hydroxy-furo-(3,4-c)pyridine.
9. 1,3-dihydro-3-ethyl -3-(n-propyl)-6methyl -7- hydroxy-furo - (3,4-c) - pyridine.
10. 1,3-dihydro-3-ethyl -3-(n-butyl)-6methyl - 7 - hydroxy-furo - (3,4-c) - pyridine.
11. 1,3-dihydro-3-ethyl -3-phenyl-6-methyl- 7 - hydroxy-furo - (3,4-c) pyridine.
12. 1,3-dihydro -3-ethyl -3-(p-chlorophenyl)-6 -methyl-7-hydroxy-furo-(3,4-c)-pyrdine.
13. 1,3-dihydro-3-ethyl -3- (m-trifluoromethyl -phenyl)-6-methyl-7-hydroxy-furo-(3,4-c)
pyridine.
14. 1,3-dihydro-3-ethyl-3-(α-furyl)-6-methyl -7-hydroxy-furo-(3,4-c)-pyridine.
15. 1,3 - dihydro - 3-vinyl -3 - (p- methylthio - phenyl) - 6 - methyl -7 - hydroxy-furo- (3,4, c) pyridine.
16. 1,3-dihydro-3-propyl-3-(p-chlorophenyl)6 - methyl - 7 - hydroxy-furo - (3,4 - c) - pyridine.
17. 1,3-dihydro-3-dimethylaminopropyl-3-o
chlorohenyl-6-methyl-7-hydroxy-furo-(3,4-c)pyridine.
18. 1,3-dihydro-3,3-diphenyl-6-methyl-7hydroxy-furo-(3,4-c)-pyridine.
19. 1,3-dihydro-3-phenyl-3-(p-toluyl)-6methyl-7-hydroxy-furo-(3,4-c)-pyidine,
20. 1,3-dihydro-3-phenyl-3-(p-fluorophenyl)6 - methyl - 7 - hydroxy- furo - (3,4 - c) - pyridine.
21. 1,3-dihydro-3-(p-trifluoromethylphenyl)-3 -phenyl-6-methyl-7 -hydroxy-furo -(3,4-c) pyridine.
22. 1,3-dihydro-3-(p-ethoxyphenyl)-3-phenyl - 6 - methyl -7 - hydroxy -furo- (3,4 - c) - pyridine.
23. 1,3 - dihydro - 3 - (p- diethylaminomethoxy phenyl) - 3 - phenyl-6-methyl-7- hydroxy -furo - (3,4 -c)-pyridine.
24. 1,3- dihydro - 3. {p - [N-(α- methoxypyrroli
dinyl)]-phenyl}-3-phenyl-6-methyl-7-hydroxyfuro - (3,4 - c) - pyridine.
25. 1,3 - dihydro - 3,3 - di(p- fluorophenoyl) - 6 methyl -7- hydroxy-furo - (3,4-c) - pyridine.
26. 1,3-dihydro-3-(α-furyl)-3-(p-methylthio- phenyl) - 6-methyl-7- hydroxy - furo - (3,4 - c) pyridine.
27. 1,3 - dihydro -3,3- di(or-furyl) - 6- methyl -7 - hydroxy-furo-(3,4-c)-pyridine.
28. 1,3 - dihydro - 3- cyclohexyl - 3 - (2,3 dichlorophenyl) - 6 - methyl -7 - hydroxy-furo - (3,4- c) - pyridine.
29. 1,3-dihydro -3-cyclohexyl-3-(pchlorophenyl) -6 - methyl -7 - hydroxy-furo - (3,4-c) pyridine.
30, 1,3-dihydro-3-cyclohexyl-3-(pfluorophenyl)-6- methyl -7 - hydroxy -furo - (3,4-c) - pyridine.
31. 1,3-dihydro-3,3-dicyclohexyl-6-methyl-7hydroxy-furo-(3,4-c)-pyridine.
32. A processforthe preparation of a 1,3 - dihydro -6-methyl-7-hydroxy-furo-(3,4-c)-pyridine derivative ofthe general formula las defined herein, the process comprising oxidizing a secondary alcohol ofthe general formula Il as defined herein, reacting the resultant ketone with a compound of the general formula XA2 as defined herein in the presence of magnesium in diethyl ether at the boil and treating the resultant tertiary alcohol with an acidic agent to provoke breaking ofthe isopropylidene ring and 3,4 cyclisation.
33. A process according to claim 32 in which the oxidation is effected with manganese dioxide.
34. A process for the preparation of a 1,3-dihydro -6-methyl-7-hydroxy-furo-(3,4-c)-pyridine derivative ofthe general formula las defined herein being substantially as described herein with reference to any of the Examples.
35. A pharmaceutical composition comprising a 1,3-dihdyro-6-methyl-7-hydroxy-fuor-(3,4-c)pyridine derivative ofthe general formula las defined herein or a therapeutically acceptable acid addition saltthereof in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08407082A GB2137618B (en) | 1983-04-05 | 1984-03-19 | Furo-(3,4-c)-pyridine derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8309165 | 1983-04-05 | ||
| GB838327815A GB8327815D0 (en) | 1983-10-18 | 1983-10-18 | Furo-(3 4-c)-pyridine derivatives |
| GB08407082A GB2137618B (en) | 1983-04-05 | 1984-03-19 | Furo-(3,4-c)-pyridine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8407082D0 GB8407082D0 (en) | 1984-04-26 |
| GB2137618A true GB2137618A (en) | 1984-10-10 |
| GB2137618B GB2137618B (en) | 1986-05-08 |
Family
ID=27262039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08407082A Expired GB2137618B (en) | 1983-04-05 | 1984-03-19 | Furo-(3,4-c)-pyridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2137618B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2572405A1 (en) * | 1984-10-27 | 1986-05-02 | Scras | NOVEL DERIVATIVES OF 6-PHENETHYLAMINOALCOYL FURO- (3,4-C) -PYRIDINE AND PROCESS FOR THEIR PREPARATION |
| FR2629820A1 (en) * | 1988-04-06 | 1989-10-13 | Scras | DRUGS WITH FURO (3,4-C) PYRIDINE ENANTIOMERS |
-
1984
- 1984-03-19 GB GB08407082A patent/GB2137618B/en not_active Expired
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2572405A1 (en) * | 1984-10-27 | 1986-05-02 | Scras | NOVEL DERIVATIVES OF 6-PHENETHYLAMINOALCOYL FURO- (3,4-C) -PYRIDINE AND PROCESS FOR THEIR PREPARATION |
| FR2572285A1 (en) * | 1984-10-27 | 1986-05-02 | Scras | MEDICINES BASED ON NEW PHENETHYLAMINOALCOYL-6 FURO- (3,4-C) -PYRIDINE DERIVATIVES |
| FR2629820A1 (en) * | 1988-04-06 | 1989-10-13 | Scras | DRUGS WITH FURO (3,4-C) PYRIDINE ENANTIOMERS |
| FR2629821A1 (en) * | 1988-04-06 | 1989-10-13 | Scras | STEREOSPECIFIC PROCESS FOR THE PREPARATION OF ENANTIOMERS OF FURO (3,4-C) PYRIDINE AND COMPOUNDS THUS OBTAINED |
| EP0337858A1 (en) * | 1988-04-06 | 1989-10-18 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Stereo-specific process for the preparation of enantiomers of furo[3,4-c]pyridine, compounds thus obtained and therapeutical compositions based on these compounds |
| WO1989009772A1 (en) * | 1988-04-06 | 1989-10-19 | Societe De Conseils De Recherches Et D'application | STEREOSPECIFIC METHOD FOR PREPARING ENANTIOMERS OF FURO[3,4-c]PYRIDINE, COMPOUNDS SO OBTAINED AND THERAPEUTIC COMPOSITIONS BASED ON SAID COMPOUNDS |
| GB2235194A (en) * | 1988-04-06 | 1991-02-27 | Scras | Stereospecific method for preparing enantiomers of furo[3,4-c]pyridine,compounds so obtained and therapeutic compositions based on said compounds |
| US5026855A (en) * | 1988-04-06 | 1991-06-25 | Societe De Consels De Recherches Et D'applications Scientifiques | Stereospecific process for the preparation of furo[3,4-c]pyridine, enantiomer, compounds thus obtained and therapeutical compositions thereof |
| AU616753B2 (en) * | 1988-04-06 | 1991-11-07 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Stereospecific method for preparing enantiomers of furo(3,4-c)pyridine, compounds so obtained and therapeutic compositions based on said compounds |
| GB2235194B (en) * | 1988-04-06 | 1992-01-29 | Scras | Stereospecific process for the preparation of furo[3,4-c] pyridine enantiomers, compounds thus obtained and therapeutical compositions thereof |
| BE1003843A4 (en) * | 1988-04-06 | 1992-06-30 | Sod Conseils Rech Applic | Stereospecific PROCESS FOR PREPARATION OF THE FURO ENANTIOMERS (3,4-C) PYRIDINE COMPOUNDS AND THEREBY. |
| AT397093B (en) * | 1988-04-06 | 1994-01-25 | Sod Conseils Rech Applic | STEREO-SPECIFIC PROCESS FOR THE PRODUCTION OF ENANTIOMERS OF THE 3-SUBSTITUTED FURO (3,4-C) PYRIDINE, ENANTIOMERS OR MIXTURES THEREOF AND THEIR CONTAINED THERAPEUTIC AGENTS |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8407082D0 (en) | 1984-04-26 |
| GB2137618B (en) | 1986-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4383998A (en) | Furo-(3,4-c)-pyridine derivatives and their pharmaceutical use | |
| US4581363A (en) | Furo-(3,4-C)-pyridine derivatives and therapeutic compositions containing the same | |
| US4735950A (en) | Furo-(3,4-C)-pyridine derivatives and therapeutic composition containing the same | |
| US4569939A (en) | Diuretic 6-vinyl-furo-(3,4-c)-pyridine derivatives | |
| US4110460A (en) | 2,3-Dihydro-imidazo[2,1-b]-thiazole derivatives and applications thereof | |
| US4914104A (en) | Imidazo [1,5-a]pyrimidine derivatives and process for their preparation | |
| GB2137618A (en) | Furo-(3,4-c)-pyridine derivatives | |
| US4585776A (en) | 4-chloro-furo-(3,4-c)-pyridine derivatives process for their preparation and therapeutical compositions containing them | |
| GB2154583A (en) | pyrimidobenzthiazoles | |
| CA1132562A (en) | Halogeno derivatives of isopropylamino pyrimidine, their preparation and therapeutic use | |
| CA1182397A (en) | 2,6-diaryl-pyridinecarboxylic acids | |
| EP0058009A1 (en) | Novel benzanilide derivatives and pharmaceutical compositions containing them | |
| NO161102B (en) | LURGET FOOD FOR RODGANTS INCLUDING FOOD AND A POISON. | |
| JPS6168490A (en) | 1,3-dihydro-6-aminomethyl-7-hydroxy-furo-(3,4-c)-pyridine derivative, manufacture and medicinal composition | |
| US4273940A (en) | Bis-(2-benzylaminoethyl)-disulfides | |
| US3733418A (en) | Method of treating hyperlipemia using bis(substituted phenyl) acetals | |
| JPS61151177A (en) | Novel hydrazide derivative and drug containing same as active ingredient | |
| JPH085884B2 (en) | 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives | |
| HU201330B (en) | Process for producing new thieno (3',4'-4,5)imidazo(2,1-b)thiazole derivatives | |
| CS256398B2 (en) | Method of phenylnona tetronic acids' derivatives production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19990319 |