IL31375A - Benzyl tetrazoles and processes for preparing same - Google Patents
Benzyl tetrazoles and processes for preparing sameInfo
- Publication number
- IL31375A IL31375A IL31375A IL3137569A IL31375A IL 31375 A IL31375 A IL 31375A IL 31375 A IL31375 A IL 31375A IL 3137569 A IL3137569 A IL 3137569A IL 31375 A IL31375 A IL 31375A
- Authority
- IL
- Israel
- Prior art keywords
- hydrogen
- chloro
- hydroxy
- tetrazole
- benzyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Novel benzyl tetrazolee and processes for preparing same MERCK ft C0tt INC.
C. 29404 31375/2 This invention relates to new benzyltetrazoleo, to processes for preparing them and to pharmaoeutical compositions containing said benzyltetrazoles. These compounds exhibit anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. They also possess a useful degree of antipyretic and analgesic activity* There has been much research carried on in the past two deoades for development of anti-inflammatory drugs. As a result, a great many new drugs have been synthesized. Most of these have been steroids of the 11-oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There has also been a concentrated effort in anti-inflammatory research in the indole series with the result of many useful drugs.
Vie have found that the 5-(p-cyclohexylbenzyl)-tetrazoles of this invention can etsily be prepared and are valuable anti-inflammatory agents.
The novel compounds according to the invention are represented by the structural formula wherein R and R' are hydrogen or lower alkyl, X is halogen or hydroxy, and Y is hydrogen or hydroxy. - - 31375/2 The more preferred compounds of this invention are 5-(p~cyclohexylbenzyl)-tetrazoles and salts thereof of formula I, wherein R is hydrogen; R' is hydrogen or alkylj X is halogen and Y is hydrogen or hydroxy.
Representative compounds of this invention are as follows: -[3-chloro-4-(4 '-hydroxycyolohexyl)-a-methylbenzyl]-tetrazole -(3-chloro-4-oyclohexyl-a-methylbenzyl)-tetrazole -(3-ohloro-4-cydohexylbenzyl)-tetrazole -[3-chloro-4-(4'-hydroxyeyelohexyl)benzyl]-tetrazole A further aspect of this invention embraces pharmaceutical compositions for the treatment of inflammation containing as active ingredient a compound of formula I above or a pharmaceutically acceptable salt thereof. ¾ 4 - 31375/2 Preferred active compounds of formula I above hydrogen are those in which R is hydrogen, R' is kydyexy or alkyl, X is halogen and T is hydrogen or hydroxy.
We have found that the 5-(p-cyclohexylbenzyl) - tetrazole compounds of this invention have a useful degree of anti-inflammatory activity and are effective in the treatment of arthritic and dermatological disorders and in like conditions which are responsive to treatment with anti-inflammatory agents. They also possess a useful > degree of anti-pyretic and analgesic activity. The instant p-cyclohexylbenzyl tetrazole compounds have con- siderable utility because of good solubility, few side effects and a favorable therapeutic index. These compounds are normally administered to patients orally in tablets or capsules, the optimum dosage depending of course, on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities of the compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated, oral dose levels to patients of preferred compounds in the range of .05-30 mg. /kg. per day (preferably in the range of 1-10 mg./kg. per day) are useful in control of arthritic conditions , depending on the activity of the specific compound and the reaction sensitivity of the patient.
Various tests in animals have been carried out to show the ability of compounds of this invention to exhibit reactions that can be correlated with anti-inflammatory activity in humans. One such test used is the Carrageenin testing method which is known to correlate well with anti- inflammatory activity in humans and is a standard test used to determine anti-inflammatory activities. This test shows n c 1 foot of a rat against non-inflammed controls. This is out- 2 lined in detail by C. A. Winter, Proc. Soc. Exptl. Biolog. 3 & Med., 1962, III, 51*1*. This correlation has been shown h by the activities of compounds known to be clinically active, including INDOCIN, ASPIRIN, BUTAZOLIDIN, TANDEARIL, 6 CORTONE, HYDROCORTONE and DECADRON. In view of the results 7 of this test, the instant compounds can be considered to be 8 active anti-inflammatory agents. Another test used to show 9 the ability of the instant compounds to inhibit edema is the Adjuvant arthritis test. This testing method is also 11 known to correlate with anti-inflammatory activity in 12 humans. The results of this test also show that the 13 instant compounds can be considered active anti-in lanunatory l1* agents.
The 5-(p-cyclohexylbenzyl) tetrazoles of this 16 invention are conveniently prepared by the following 17 method: 18 (a) The amidation of an available appropriately 19 substituted p-cyclohexylpheny'l acetic acid by any method well known in the art can be carried out. One such method 21 is the reaction of the acid with thionyl chloride, . tri 22 phosphorous oxychloride or phosphorous &pachloride which 23 may be carried out in an inert solvent (such as ether, benzene, toluene, etc.) to form the acid halide. This is followed by reacting with an excess of ammonia to form the 26 desired amides III. 27 (b) The substituted p-cyclohexylphenyl acet- 28 amides III are reacted with a suitable dehydrating agent 29 (such as phosphorous pentoxide, thionyl chloride or u conventional methods. This (c) These nitriles can then be treated with a azido compound (preferably sodium azide) to give the desired substituted 5-(p-cyclohexylbenzyl)-tetrazoles I.
The conversion of the nitriles to the tetrazoles can be carried out in a solvent (preferably a polar solvent such as dimethylformamide , acetic acid, butanol, etc.) in the presence of ammonium or substituted ammonium halide at an elevated temperature usually from about 50-150° C. (preferably in the range of 100-125°C.) for a period of time from a few hours to a few days depending on the substltuents present and the temperature of the reaction. The following equations illustrate this method of preparation: I wherein R, R' , X, and Y are as described above.
Appropriately desired end products having various X or Y substltuents can be prepared by using suitable reactions in order to convert one group to another. It Is often convenient in preparing the instant compounds to use a nitro substituent and convert this to 3 the desired group since by this route a great many substi-¾ uents can be prepared. This can be accomplished by the reduction of the nitro to the amino group, followed by use 6 of the Sandmeyer type reactions to introduce chlorine, or 7 bromine, xanthato , hydroxyl e**-e.44t-e*y4 groups. ·Φί*β- 0 -b-θ--o^rtrd-j&e^-t-θ·-a-.-ky-l—Bttlfifiyi- e-R-d--a-l-k-y-l--e i-i f>y-t-giH>we-. 1 The amino group can also be alkylated.-o*»--a^e-t>¾*-l€4e3k 2 These reactions may be carried out at any stage of the 3 synthesis.
*» The starting materials employed in the foregoing 5 method have previously been prepared. The various substitu- 6 ed p-cyclohexylphenyl acetamides can be prepared by 7 procedures outlined in Netherlands Patent Application 8 No. 66,11157 (Derwent 26,151), Netherlands Patent 6608098 9 No. 6-5Θ--5 5· (Derwent 24,299) or British Patent No. 1041691 (Derwent 22,687). Preparation of p-cyclohexylphenyl 21 acetyl nitriles can be found in French Patents, 22 Nos. 1483221 and 1463840. 23 The following are a group of detailed examples 4 which show the preparation of desired compounds of this invention. They are to be construed as illustrations of 26 the invention and not as limitations thereof. 27 EXAMPLE 1 28 To 3.1 g. (0.021 m.) of phosphorous pentoxide 29 is added 5.6 g. (0.02 m.) of a-( 3-chloro-H-cyclohexyl- 3 and the reaction vessel is heated in an oil bath to 200c'c, A slight streak of nitrogen is passed over the reaction mixture mixture* After 4 hours the reaction/is cooled and extracted four times with benzene. The benzene is then washed with water and evaporated to dryness and the a-(3-chloro-4-cyclohexylphenyl)propionitrile is distilled under reduced pressure.
When the procedure of Example 1 is followed but substituting for a-( 3-chloro-4-cyclohexylphenyl)propion~ amlde the corresponding known amides, then the nitrllea of Table 1 below are prepared.
Table I ct-(3-chloro-4-cyclohexylphenyl)acetonitrile a-(3-chloro-4-cyclohexylphenyl)propion trile a-(2-chloro-4-cyclohexylphenyl)acetonitrile a-( 2-chloro-4-cyclohexylphenyl)propionitrile a-(3-bromo-4~c clohexylphenyl) cetonitrile a-(3-bromo-4-cyclohexylphenyl)propionitrile a-( 3-bydroxy-4-cyclohexylphenyl)propionitrile a-[3-hydroxy-4-( '-acetoxycyclohexyl) henyl]propionitrile a-[3-chloro-4-(4'-acetoxycyclohexyl)phenyl]acetonitrile 31375/j? EXAMPLE 2 To 0,4 g of sodium hydroxide dissolved in 100 ml of 80$ ethanol is added 2.75 (0.01 m) of a-[3-chloro-4~ (4'-acetoxyeyclohexyl)phenyl]acetoni ile. This is then stirred at room temperature for 1 hour, neutralized with dilute hydrochloric acid and concentrated to dryness in vaouo. The residue is distributed between chloroform and water. When the chloroform is separated and dried over sodium sulfate and concentrated to dryness, the product is a-[3-ohloro-4-(4'~hydroxyoyclohexyl)phenyl]-acetohitrile.
When the procedure of Example 3 is followed but substituting for a-[3-chloro-4-(4'-acetoxyeyclohexyl)-phenyl]acetonltrile the corresponding 4'-acetoxy compounds of Table I, Example 1, there are prepared the corresponding 4'-hydroxy products. :- 11 - ■ . · ' ' 31375/2 ί - ' ' EXAMPLE 3 ' ' ■ ' 1 - (3-Chloro-U-cyclohexyl-a-methylbenzyl)tetrazole A mixture of 3-1 έ'. ( P .013 m . ) of o.-( ?-chlo'ro- -cyclohexylphenyl)propionitrile , 1.1 (0.017 m) . of sodium azide and 0.9 ε· (O.lC m.) of ammonium chloride in 35 ml. of dry dimethylformamide is heated for 16 hours at 120° under nitrogen. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml. of 2.5 N sodium hydroxide and diluted with 100 ml. of water. The aqueous solution is washed With ether and then acidified (or neutralized when a 3-am.ino or 3-substituted amino compound is used). The acidified mixture is extracted with methylene chloride and the combined methylene chloride extracts are dried over sodium sulfate and concentrated. The residue is dissolved in boiling benzene, treated with . charcoal, filtered and the benzene solution concentrated. Recrystalllzatlon from benzene-petroleum ether gives 2.8 R. of, 5-(3-chloro-^-cyclohexyl-a-methylphenyl)tatrazole, m.p. l6l-l62°C; When the procedure of Example 3 is followed but substituting for a-( 3-chloro-i)-cyclohexylphenyl)propio- nitrile each of the nitriles of Table I·, Example 1, and the products of Example 2, there-is prepared the corresponding tetrazoles of Table II below. - 12 - 31375/2 Table II -(3-chloro-4-cyclohexylbenzyl)tetrazole -( 3-chloro-4-cyclohexyl-a-methylbenzyl)tetrazole -( 2-chloro-4-cyclohexylbenzyl)tetrazole -( 2-chloro-4-cyclohexyl-a-methylbenzyl) etrazole -( 3-bromo-4-cyclohexylbenzyl)tetrazole -( 3-bromo-4-cyclohexyl-a-methylbenzyl)tetrazole -( 3-hydroxy-4-cyclohexyl-a-methylbenzyl)tetrazole -[3-chloro-4-(4 '-acetoxycyclohexyl)-a-methylbenzyl]-tetrazole -[3-ohloro-4~(4 '-hydroxycyclohexyl)-a-methylbenzyl]-tetrazole -[3-hydroxy-4-(4 '-hydroxycyclohexyl)-a-methylbenzyl]- tetrazole -[3-chloro-4-(4 '-hydroxycyclohex l)benzyl]tetrazole - 13 - 31375/2 The following intermediates were obtained during the preparation of the compounds listed in Tables I and II: Table III cx-( 3-nitro-4-cyclohexylphenyl ) acetonitrile a-( 3-nitro-4-cyclohexylphenyl) propionitrile a-( 3-amin,o-4-cyclohexylphenyl ) propionitrile a-[ 3-nitro-4-(2' -acetoxycyclohexyl) phenyljacetonitrile oc—1 .3-nitro-4-(3' -acetoxycyclohexy1)phenyl]propionitrile -| .3-nitro-4-(2' -acetoxycyclohexyl)phenyl Jpropionitrile a-| .3-nitro-4-(3f -acetoxycyclohexyl )phenyl]acetonitrile oc- ^-nitro^- ' -acetoxycyclohexyl)phenyl jacetonitrile a ;3-nitro-4-( f -acetoxycyclohexyl)phenyl ]propionitrile a- ;2-nit'rp-4-(4' -acetoxycyclohexyl ) phenyl jacetoxynitrile a- ;2-nitro-4-(4' -acetoxycyclohexyl )phenyl ]propionitrile - ( 3-nitro-4-cyclohexylbenzyl ) tetrazole - ( 3-nitro-4-cyclohexyl-a-methylbenzylJtetrazole - t3-nitro-4-(2l -acetoxycyclohexyl)benzyl Jtetrazole - ;3-nitro-4-(3' -acetoxycyclohexyl)-a-methylbenzylj-tetrazole - ;3-'nitro-4-(2' -acetoxycyclohexyl )-a-methylbenzyl]-tetrazole - ;3-nitro-4-(3' -acetoxycyclohexyl)benzyl jtetrazole - ;3-nitro-4-(4' -acetoxycyclohex l)benzyl Jtetrazole - ;3-nitro-4-(4* -acetoxycyclohexyl )-a-methylbenzylJtetrazole - ;2-nitr'o-4-(4' -acetoxycyclohexyl)benzyl jtetrazole - ;2-nitro-4-(4' -acetoxycyclohexy1 )-ct-meth lbenzyl]tetrazole - ;3-nitro-4-(4' -hydroxycyclohexyl)-a-methylbens5yl]-tetrazole - 3-amino-4-(4' -hydroxycyclohexyl)-a-methylbenzyljtetrazole 14 31375/2 EXAMPLE ■¾ The following tablet composition is illustrative of the compositions of this invention: Five thousand tablets for oral use, each contain ing 10 mg. of 5-( -chloro- -cyclohexyl-a-methylbenzyl)-tetrazole are prepared from the following types and amounts of materials: -(3-chloro-i)-cyclohexyl-a-methylbenzyl) tetrazole 50 g.
Lacto^U.S.P. 600 g.
Sucrose, powdered, U.S. P. 600 g.
Corn starch, U.S. P. 150 g.
The finely powdered materials are mixed well and the mixture is granulated with 10¾ starch paste. The wet mass is forced through an 8-mesh screen, dried at 1»5°C. - ΪΪ- In a forced-air oven and then put through a 12-mesh screen. As lubricant, 15 grams of magnesium stearate is added before compressing into tablets.
In a similar manner, the 5-(p-cyclohexylbenzyl)- 3 tetrazoles of Example -2-, Table II, can be compounded as useful tablets.
Claims (17)
1. A process for the preparation of benzyl tetrazole of the formula R wherein R and R' are hydrogen or lower allsyl, X Is halogen or hydroxy, and Y is hydrogen or hydroxy, which comprises reacting a correspondin nitrlle of the formula R where R, R* , X and Y have the same meaning as above with an azido compound.
2. A process according to Olalm 1 wherein the nitrlle is reacted with sodium azide in a polar solvent at a temperature between 50° - 150°C.
3. · prooess for the preparation of compounds according to Olalm 1 where R is hydrogen, R' is hydrogen or alk l, X is halogen and Y is hydrogen or hydroxy.
4. · A process for the preparation of a compound according to Claim 1, where R is hydrogen, R' is hydrogen, X is 3-chloro and Y is hydrogen. - -18- - 31375/2
5. A process for the preparation of a compound according to Claim 1, where R is hydrogen, R' is methyl, is 3-chloro and Y is hydrogen.
6. A prooess or the preparation of a compound according to Olaim 1, where R is hydrogen, R* is methyl, X is 3-chloro and Y is 4'-hydroxy.
7. A process for the preparation of a compound according to Claim 1, where R is hydrogen, R' is hydrogen, X is 3-chloro and Y is 4'-hydroxy.
8. · Benayl tetrazoles of formula I in Claim 1, wherein R and R* are hydrogen, or lower alkyl, X is halogen, or hydroxy, and Y is hydrogen,or hydroxy, and pharmaceutically acceptable salts thereof.
9. · A compound according to Claim 8, wherein R is hydrogen, R' is hydrogen, or lower alkyl, X is halogen, and Y is hydrogen or hydroxy.
10. 5-(3-Chloro-4-cyclohexylbenzy1) etrazole.
11. · 5-(3-Chloro-4-oyclohexyl-a-methylbenzyl)tetrazole.
12. 5-[ (3-Chloro-4-(4 '-hydrox cyclohexy1)-a-methy1-benzyl) ]tetrazole.
13. · 5-[ (3-Chloro-4(4 '-hydroxycyclohexyl)benzyl}] -tetrazole.
14. · Benzyl tetrazole compounds according to Claim 8, substantially as described herein with reference to the Examples* V 18 - 19· - 313715/3
15. · Pharmaceutical compositions for the relief of inflammation comprising as an active ingredient a compound according to Claim 8 or a pharmaceutically acceptable salt thereof„
16. Compositions according to Claim 15» comprising as an active Ingredient a compound according to any of Claims 9 to 14 or a pharmaceutically acceptable salt thereof.
17. Compositions according to Claim 15 or 16 in dosage unit form permittin (bhe administration of from 0.03-30 mg/kg and preferably 1-10 mg/kg of body weight per day. PC/rb
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US69905268A | 1968-01-19 | 1968-01-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
IL31375A0 IL31375A0 (en) | 1969-03-27 |
IL31375A true IL31375A (en) | 1973-05-31 |
Family
ID=24807734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL31375A IL31375A (en) | 1968-01-19 | 1969-01-07 | Benzyl tetrazoles and processes for preparing same |
Country Status (7)
Country | Link |
---|---|
BE (2) | BE727012A (en) |
CH (1) | CH506542A (en) |
DE (1) | DE1902304A1 (en) |
FR (2) | FR2000467B1 (en) |
GB (1) | GB1214102A (en) |
IL (1) | IL31375A (en) |
NL (1) | NL6900204A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8318889D0 (en) * | 1983-07-13 | 1983-08-17 | Lilly Industries Ltd | Pharmaceutical compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1483221A (en) * | 1965-06-15 | 1967-06-02 | Merck & Co Inc | Alpha-lower alkyl- (3-halo-4-cyclohexylphenyl) acetic acids and processes for their manufacture |
-
0
- BE BE642636D patent/BE642636A/xx unknown
-
1969
- 1969-01-06 NL NL6900204A patent/NL6900204A/xx unknown
- 1969-01-07 IL IL31375A patent/IL31375A/en unknown
- 1969-01-13 GB GB0815/69A patent/GB1214102A/en not_active Expired
- 1969-01-17 CH CH66269A patent/CH506542A/en not_active IP Right Cessation
- 1969-01-17 BE BE727012D patent/BE727012A/xx unknown
- 1969-01-17 DE DE19691902304 patent/DE1902304A1/en active Pending
- 1969-01-20 FR FR6900945A patent/FR2000467B1/fr not_active Expired
-
1970
- 1970-04-06 FR FR7012353A patent/FR2070046B1/fr not_active Expired
Also Published As
Publication number | Publication date |
---|---|
FR2000467B1 (en) | 1974-05-24 |
CH506542A (en) | 1971-04-30 |
FR2000467A1 (en) | 1969-09-05 |
GB1214102A (en) | 1970-12-02 |
NL6900204A (en) | 1969-07-22 |
BE642636A (en) | |
BE727012A (en) | 1969-07-17 |
DE1902304A1 (en) | 1969-09-04 |
FR2070046B1 (en) | 1974-10-11 |
IL31375A0 (en) | 1969-03-27 |
FR2070046A1 (en) | 1971-09-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4351841A (en) | Pharmaceutical preparation and method of treatment | |
US3923910A (en) | Ethynylbenzene compounds and derivatives thereof | |
JPH0223537B2 (en) | ||
JPH03128343A (en) | Novel zinc derivative of anti-inflammatory drug having improved therapeutic characteristics | |
JPS58113142A (en) | Manufacture of novel naphthalene derivative | |
JPH059424B2 (en) | ||
DE2031227A1 (en) | New substituted Sahcylsauren and process for their production | |
JPH0222271A (en) | Conjugated gamma-oxybutenolide compound and antitumor agent containing said compound as active component | |
JPS60193973A (en) | Isoxazole derivatives, manufacture and drug | |
IL31375A (en) | Benzyl tetrazoles and processes for preparing same | |
JPS5879950A (en) | Novel derivatives of 4-phenyl-4-oxo-2-butenoic acid and their salts, manufacture, use as drug and composition containing them | |
JPH0234951B2 (en) | ||
US3631167A (en) | 3-indenylmethyltetrazoles | |
US4116972A (en) | Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation | |
US3958012A (en) | D 2-(6-Substituted-2-naphthyl)-propanals | |
US4105786A (en) | Ethynylbenzene compounds and derivatives thereof | |
US3987116A (en) | Ethynylaryl compounds and derivatives thereof | |
CS216206B2 (en) | Method of making the derivatives of the diphenylpyrazole | |
US4256760A (en) | Methods of treating mammals suffering from inflammation and pain | |
JPS60142959A (en) | Quinoline derivative | |
GB2027022A (en) | Pyridoxine derivatives and their use | |
US4288596A (en) | Furoindoles | |
US4539331A (en) | Imidazole carboxamide derivatives and pharmaceutical compositions thereof | |
JP2989059B2 (en) | Substituted anilide | |
US3985790A (en) | Phenoxyalkane carboxylic acid derivative |