GB2072662A - Amidotetrazole compounds and process for their preparation - Google Patents
Amidotetrazole compounds and process for their preparation Download PDFInfo
- Publication number
- GB2072662A GB2072662A GB8107018A GB8107018A GB2072662A GB 2072662 A GB2072662 A GB 2072662A GB 8107018 A GB8107018 A GB 8107018A GB 8107018 A GB8107018 A GB 8107018A GB 2072662 A GB2072662 A GB 2072662A
- Authority
- GB
- United Kingdom
- Prior art keywords
- general formula
- compound
- formula
- hydrogen atom
- amino group
- 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.)
- Withdrawn
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Description
1
GB 2 072 662 A
1
SPECIFICATION
Amidotetrazole compounds and processes for their preparation
5 This invention relates to amidotetrazole compounds, to processes for their preparation and to pharmaceutical compositions containing them.
More particularly the invention relates to certain 1-phenyl-5-amidotetrazoles and processes for their preparation.
The present invention provides a compound of general formula (I):
10
N—N
CH3°^ ^,CH2—CONH—^ |
15
20
N—N
(I)
10
15
20
wherein R1 is a hydrogen atom or a nitro or amino group and R2 is a hydrogen atom or R1 and R2 are both 25 chlorine atoms.
A particularly preferred compound according to the invention is 1-phenyl-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido]tetrazole.
Compounds of general formula (I) may be prepared by condensing an activated derivative of general formula (II):
30
ch3o
35
40
,ch2cox ch3
c=o
(II)
25
30
35
40
wherein X is a leaving group 45 with a 1-phenyl-5-aminotetrazole of general formula I
45
50
55
N—N HzN-( || N—N
50
55
where R1 and R2 are as defined for formula (I) except that R1 is not an amino group, to give the desired compound of general formula (I) where R1 and R2are as defined for formula (III).
gQ The compound of formula (I) where R1 is an amino group may be prepared by reduction of the compound of formula (I) where R1 is a nitro group. The reduction may be performed, for example, by hydrogen in the presence of a catalyst, such as platinum, in a suitable solvent, such as a mixture oftetrahydrofuran and anhydrous ethanol.
The activated derivative of general formula (II) may be> for example, an acid halide such as the acid g5 chloride, an ester such as the p-nitrophenyl or pentachlorophenyi ester, an acid anhydride or a product of the
60
65
2
GB 2 072 662 A
2
reaction of the free acid of formula (IV):
,CH2COOH
15 with a coupling agent such as carbonyl diimidazole or dicyclohexylcarbodiimide.
The condensation reaction of the derivatives of general formula (II) with the 1-pheny-5-aminotetrazoles of formula (III) is generally performed in a solvent, optionally at an elevated temperature. The precise reaction conditions however, depend on the nature of the activated derivative used. Thus, for example, when an acid halide is used the reaction may be performed in a solvent such as tetrahydrofuran in the presence of an 20 organic base such as pyridine or triethylamine at a temperature such as the reflux temperature.
The activated derivatives of general formula (II) may be prepared from the acid of formula (IV) by known procedures.
For example, the acid chloride of formula (II) may be prepared by reaction of the acid of formula (IV) with thionyl chloride, phosphorus pentachloride or oxalyl chloride preferably in a solvent such as cyclohexane at 25 the reflux temperature. An ester of formula (II) may be prepared, for example, by reaction of the acid of formula (IV) with an alcohol preferably in the presence of an acid catalyst such as mineral acid, for example hydrochloric acid. An anhydride of formula (II) may be prepared, for example, by reaction of the acid of formula (IV) with an acid anhydride such as trifluoroacetic anhydride, an acid chloride such as acetyl chloride or an alkyl or aralkyl haloformate such as ethyl or benzyl chloroformate.
30 The acid of formula (IV) is a known compound which may be prepared, for example, by the method described in British Patent Specification No. 997638. The aminotetrazoles of formula (III) are also either known compounds or may be prepared by conventional methods from known starting materials for example, by the methods described in British Patent Specification No. 1,208,116 or by Garbretch eta! in Journal of Organic Chemistry, Volume 18, page 1020 (1953).
35 We have found that the compounds of general formula (I) exhibit both anti-inflammatory activity and analgesic activity in the rat. Moreover, the compounds have good therapeutic indices, the therepautic index of 1-phenyl-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido]tetrazole being particularly advantageous. The anti-inflammatory activity was determined by the Freund adjuvant arthritis test (Pearson, C.M. Proc. Soc. Exp. Biol. Med 91,951956) and analgesic activity was determined by applying an increasing 40 pressure to the inflamed paw (Randall, L.O. Selitto, J.J., Arch. Int. Pharmacodyn, ///, 409 1957) and recording pain threshold.
These tests indicate the potential use of the compounds of general formula (I) for the treatment of inflammatory diseases, in particular, chronic inflammatory diseases such as arthritis.
Thus, the present invention further provides a method for the treatment of a patient suffering from an 45 inflammatory disease which comprises administering to the patient an effective amount of a compound of general formula (I).
The invention also provides a pharmaceutical composition comprising a compound of general formula (I) together with a physiologically acceptable carrier or excipient.
The compounds may be formulated in conventional manner for administration by any convenient route 50 for example, for oral, rectal or parenteral administration.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, syrups or suspensions prepared by conventional means with physiologically acceptable excipients.
The compounds of general formula (I) may be formulated for rectal administration for example, in the 55 form of suppositories using a conventional suppository excipient. The compounds may also be formulated for parenteral administration in dry form for reconstitution before use, or as a sterile suspension.
A proposed daily dose for administration to man is 50 mg to 2500 mg total daily dose which may be conveniently administered in one to four doses per day.
The invention is further illustrated by the following Examples. The abbreviation THF is used to represent 00 tetrahydrofuran.
EXAMPLE 1
1-Phenyl-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido]tetrazole (a) 1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetyl chloride 05 A mixture of 1-(4-chlorobenzoyl)-5-methoxy-2- methylindol-3-yl acetic acid (16.0 g) and thionyl chloride
5
10
15
20
25
30
35
40
45
50
55
60
65
3
GB 2 072 662 A
3
(7.5 g) in cyclohexane (100 ml) was refluxed for 2 hours until a solid precipitated. The mixture was cooled and the precipitate was collected by filtration and washed with petroleum ether (b.p. 60-80°C). The washed precipitate was dried (40°C)to yield the title compound (16.1 g)m.p. 125-127°C.
5 (b) 1-Pheny/-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-y/acetamidoJtetrazole
The chloride of part (a) (19.0 g) in THF (150 ml) was added slowly with stirring to a solution of 1-phenyl-5-aminotetrazole (11.0 g) and pyridine (5 ml) in THF (100 ml). The mixture was refluxed for 5 hours then cooled and filtered. The filtrate was collected and the solvent distilled off under reduced pressure to leave a brown oily residue. The residue was added to methanol to precipitate a solid which was collected by 10 filtration and washed with hot menthanol to yield the title compound (15.5 g) m.p. 183-185°C I.R. 3200 (W), 1715 (m),1680 (s,sh), 755 (s) cm-1.
EXAMPLE 2
1-(3,4-Dichlorophenyl)-5-[1-(4-ch/orobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido]tetrazole 15 A solution of the product of Example 1 (a) (13.1 g) in THF (100 ml) was added dropwise to a mixture of 1-(3,4'-dichlorophenyl)-5-aminotetrazole.(10 g). triethylamine.(5 ml) and THF (200 ml). The mixture was refluxed for 2 h, cooled, filtered and the solvent was removed under reduced pressure to give a residue. A mixture of cyclohexane/ethyl acetate/acetone (4:4:2) was added, the mixture was filtered and the solvent removed under reduced pressure to give a yellow gum which crystallised from ethanol to yield the title 20 compound(2.15 g) m.p. 173-175°C.
Found: C% 54.74 (Calc. 54.80); H% 3.25 (3.36); N% 14.93 (14.74); Cl% 18.44 (18.66).
EXAMPLE 3
1-(4-Nitrophenyl)-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methyiindol-3-ylacetamidoJtetrazole 25 A solution of the product Example 1 (a) (95 g) in THF (500 ml) was added dropwise to a mixture of
1-(4-nitrophenyl)-5-aminotetrazole (62 g) triethylamine (30 ml) and THF (900 ml), refluxed for 13h, cooled and filtered. The solvent was removed under reduced pressure to give a solid gum which was dissolved in ethyl acetate (1000 ml) and washed with 10% hydrochloric acid and water. By partial evaporation of the solvent a precipitate was obtained which was filtered and crystallized from ethanol to yield the title compound (47 g) 30 m.p. 198-200°C.
Found: C% 53.42 (Calc. 57.19); H% 3.34 (3.69), N% 17.12 (17.96); Cl% 6.26 (6.49).
EXAMPLE 4
1-{4-Aminophenyl)-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido]tetrazole 35 The product of Example 3 (18 g) was dissolved in a mixture of THF and anhydrous ethanol (4:1) and reduced by catalytic hydrogenation (Pt02; 3 atm. of hydrogen). The catalyst was filtered off and the solvent was removed under reduced pressure to obtain a solid. The solid was treated with hot methanol, filtered, and the title compound (2 g) m.p. 185-187°C obtained by repeated chromatography on silica gel using a cyclohexane/ethyl acetate/acetone (4:4:2) mixture as eluent.
40 Found: C% 60.49 (Calc. 60.52); H% 4.27 (4.29); N% 19.14 (19); Cl%7.02 (6.87).
4
GB 2 072 662 A
4
EXAMPLE 5
The following are examples of different types of pharmaceutical compositions according to the invention.
10
15
20
25
30
Capsules
Active ingredient Microcrystailine cellulose Magnesium stearate
Tablets Film coated
Core
Active ingredient Microcrystailine cellulose Magnesium stearate
Film coating
Hydroxypropyl methylcel I u lose Titanium dioxide
Suppositories
Active ingredient Suppository base*
35
40
*Any conventional base may be used.
Claims (1)
1. A compound of general formula (I):
ch3o mg/capsule
100.0 97.0 3.0
Fili weight 200.0
mg/tablet
100.0 97.0 3.0
4.5 1.2
Weight 205.7
mg/suppository
200.0 2500.0
Weight 2700.0
45
50
ch2—conh—^
N—N
(I)
10
15
20
25
30
35
40
45
50
wherein R1 is a hydrogen atom or a nitro or amino group and R2 is a hydrogen atom or R1 and R2 both ' represent chlorine atoms.
2. 1-Phenyl-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-ylacetamido] tetrazole.
55 3. A method of preparing a compound of general formula (I), wherein R1 and R2 are as defined in claim 1 55 except that R1 is not an amino group, which comprises condensing an activated derivative of general formula (II):
5
GB 2 072 662 A 5
ch3o
.ch2cox ch3
(II)
5
5
c=o
10
10
where X is a leaving group 15 with a 1-phenyl-5-aminotetrazo!e of general formula (III):
15
25
20
(iii)
25
20
where R1 is a hydrogen atom or a nitro group and R2 is a hydrogen atom or R1 and R2 both represent chlorine atoms and recovering the desired compound of general formula (I).
30 4. A method of preparing a compound of formula (I) as defined in claim 1 wherein R1 is an amino group 30 which comprises reducing a compound of formula (I) where R1 is a nitro group and recovering the desired compound of formula (I), where R1 is an amino group.
5. A pharmaceutical composition which comprises, as active ingredient at least one compound of general formula (I) as defined in claim 1 together with a physiologically acceptable carrier or excipient
35 therefor. 35
6. A pharmaceutical composition which comprises as active ingredient 1-phenyl-5-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindoi-3-ylacetamido] tetrazole.
7. A method according to claim 3, substantially as herein described with reference to any of the specific Examples 1 to 3.
40 8. A method according to claim 4, substantially as herein described with reference to Example 4. 40
9. A pharmaceutical composition according to claim 5 substantially as herein described with reference to Example 5.
10. Use of a compound of general formula (I) as defined in claim 1 as an anti-inflammatory and/or analgesic agent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8007546 | 1980-03-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2072662A true GB2072662A (en) | 1981-10-07 |
Family
ID=10511901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8107018A Withdrawn GB2072662A (en) | 1980-03-05 | 1981-03-05 | Amidotetrazole compounds and process for their preparation |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0035412A1 (en) |
| JP (1) | JPS56133284A (en) |
| AU (1) | AU6810281A (en) |
| ES (1) | ES500139A0 (en) |
| GB (1) | GB2072662A (en) |
| ZA (1) | ZA811492B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1343827A (en) * | 1971-06-15 | 1974-01-16 | Science Union & Cie | Acylaminotetrazoles and process for preparing them |
| GB1383088A (en) * | 1972-07-03 | 1975-02-05 | Allen & Hanburys Ltd | Pharmacologically active quinaldamide derivatives |
-
1981
- 1981-03-05 JP JP3059981A patent/JPS56133284A/en active Pending
- 1981-03-05 GB GB8107018A patent/GB2072662A/en not_active Withdrawn
- 1981-03-05 ZA ZA00811492A patent/ZA811492B/en unknown
- 1981-03-05 ES ES500139A patent/ES500139A0/en active Granted
- 1981-03-05 EP EP81300916A patent/EP0035412A1/en not_active Withdrawn
- 1981-03-05 AU AU68102/81A patent/AU6810281A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| ES8301230A1 (en) | 1982-12-01 |
| JPS56133284A (en) | 1981-10-19 |
| EP0035412A1 (en) | 1981-09-09 |
| AU6810281A (en) | 1981-09-10 |
| ES500139A0 (en) | 1982-12-01 |
| ZA811492B (en) | 1982-10-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |