Claims
- 1. A racemic or optically active compound of formula I, ##STR14## wherein R is alkyl of 3 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubstituted by alkyl of 1 to 4 carbon atoms, .alpha.-dialkylpropynyl of 5 to 9 carbon atoms or .alpha.-dialkyl-allyl of 5 to 9 carbon atoms, hydroxyalkyl of 2 to 7 carbon atoms or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the last two radicals being separated by at least two carbon atoms from the nitrogen atom to which R is bound,
- R.sub.1 is
- i. hydrogen or alkyl of 1 to 4 carbon atoms, in the 2,3,6 or 7 position, or
- ii. chlorine or bromine, in the 2, 3 or 7 position,
- iii. nitro or-NHA wherein A is alkanoyl of 1 to 4 carbon atoms, in the 2, 3 or 7 position, or
- iv. fluorine, cyano or COOB, wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, and
- R.sub.2 is
- i. hydrogen or alkyl of 1 to 4 carbon atoms in the 2, 3, 6 or 7 position,
- ii. chlorine or bromine, in the 2, 3 or 7 position, or
- iii. fluorine in the 2 or 3 position, or a pharmaceutically acceptable acid addition salt thereof.
- 2. A method of treating Angina pectoris, hyperkinetic heart syndrome and conditions resulting from muscular hypertrophic subvalvular aortic stenosis in animals which comprises administering to an anima in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 3. A method of treating heart rhythm disorders in animals which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 4. A method of treating hyperlipoidemiaor hyperglycemia in animals under stress which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 5. A compound of claim 1 wherein R.sub.2 is H.
- 6. A compound of claim where R is other than phenoxy-alkyl, R.sub.1 is hydrogen or alkyl in the 2, 3, 6 or 7 position, or chlorine or bromine in the 2, 3 or 7 position, or fluorine, cyano or COOB wherein B is alkyl of 1 to 4 carbon atoms, in the 2 or 3 position, or nitro in the 7 position.
- 7. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in association with a pharmaceutical carrier or diluent.
- 8. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, isopropyl, H and H.
- 9. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, isopropyl, 2-methyl and H.
- 10. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, isopropyl, 6-methyl and H.
- 11. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, tert.butyl, H and H.
- 12. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, tert.butyl, 2-methyl and H.
- 13. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, tert.butyl, 7-chloro and H.
- 14. The compound of claim 1 where R, R.sub.1 and R.sub.2 are, respectively, tert.butyl, 3-carbethoxy and 2-methyl.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 4432/75 |
Apr 1975 |
CH |
|
Parent Case Info
This is a continuation-in-part of our copending application Ser. No. 605,972 filed Aug. 20, 1975 now U.S. Pat. No. 3,998,835, dated Dec. 21, 1976.
The present invention relates to new organic compounds.
In accordance with the invention there are provided new compounds of formula I, ##STR2## wherein R is alkyl of 3 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms monosubstituted by alkyl of 1 to 4 carbon atoms, .alpha.-dialkylpropyinyl of 5 to 9 carbon atoms or .alpha.-dialkyl-allyl of 5 to 9 carbon atoms, hydroxyalkyl of 2 to 7 carbon atoms or phenoxyalkyl of 8 to 11 carbon atoms, the oxygen atom of the last two radicals being separated by at least two carbon atoms from the nitrogen atom to which R is bound,
When R is alkyl or hydroxyalkyl the alkyl moiety thereof preferably is branched, especially in an .alpha.-position to the nitrogen atom to which it is bound. Especially preferred alkyl radicals are isopropyl, tert. butyl, 3-pentyl and tert. pentyl (.alpha.-dimethylpropyl). The preferred hydroxyalkyl radicals are, for example, the .alpha.-dimethylhydroxyethyl and .alpha.-dimethylhydroxypropyl groups.
When R contains cycloalkyl, this especially signifies cyclopropyl, cyclopentyl or cyclohexyl.
When R is cycloalkyl monosubstituted by alkyl, the alkyl substituent thereof especially signifies methyl. The alkyl substituent is conveniently in the .alpha.-position. A preferred alkylcycloalkyl group is 1-methylcyclohexyl.
When R is the .alpha.-dialkylpropinyl or .alpha.-dialkylallyl defined above, the alkyl groups thereof preferably are identical and specially signify methyl.
When R is the phenoxyalkyl radical defined above, this especially signifies phenoxyethyl.
R especially signifies the phenoxyalkyl, .alpha.-dialkylpropynyl or alkyl group defined above; the two latter significances are specially preferred.
When R.sub.1 and/or R.sub.2 is alkyl of 1 to 4 carbon atoms, these radicals especially contain 1 or 2, preferably 1 carbon atom.
R.sub.1 preferably signifies hydrogen, bromine, chlorine, cyano or the alkyl group defined above; the two latter substituents are especially preferred.
R.sub.2 specially signifies hydrogen or the alkyl group defined above.
A preferably signifies formyl or acetyl.
B preferably signifies methyl, ethyl or tert.butyl.
R.sub.1 preferably is in the 2 or 3 position, especially the 2 position. R.sub.2 preferably is in the 7 position.
Further, in accordance with the invention a compound of formula I may be obtained by a process comprising
a. hydrolyzing the oxazolidine group in a compound of formula II, ##STR3## wherein R, R.sub.1 and R.sub.2 are as defined above, and ##STR4## is a radical capable of being split off hydrolytically, or b. substituting in the 4 position a compound of formula III, ##STR5## wherein R.sub.1 and R.sub.2 are as defined above, and W is an anionic leaving group, by reaction with a compound of formula V, ##STR6## wherein R is as defined above.
The processes of the invention may be carried out in accordance with known methods.
Process variant a) is a hydrolysis of an oxazolidine. Oxazolidines are readily hydrolyzable (see Chemical Reviews 53, 315-317 [1953]). Therefore, Z and Z.sup.I in the compounds of formula II may signify the radical of any desired aliphatic or aromatic aldehyde or ketone ##STR7## , e.g. of propionaldehyde, benzaldehyde, acetaldehyde or acetone. The hydrolysis of compounds of formula II is conveniently effected under acid conditions. A dilute acid, especially a mineral acid, e.g. 0.5 N to 3 N hydrochloric acid or 1 N sulphuric acid, is preferably chosen as suitable acid. The reaction may be effected in the presence of water. It is possible to use a water-miscible organic solvent, e.g. a lower alkanol such as ethanol, but this is not essential. The reaction temperature may vary, e.g., between 0.degree. and about 80.degree. C, and is preferably effected at an elevated temperature, e.g. 60.degree. to 80.degree. C.
Process variant b) is a substitution reaction on an aromatic, nitrogen-containing heterocycle which contains an anionic leaving group on a carbon atom adjacent to the nitrogen. W preferably signifies chlorine, bromine or a lower alkylthio group such as methylthio; W especially signifies chlorine. The substitution is readily effected, e.g. by allowing to stand a solution of a compound of formula III and a compound of formula V. This is effected in an inert organic solvent, e.g. a lower alkanol such as tert. butanol. The reaction is preferably effected in the presence of a base, e.g. an alkali metal alcoholate such as potassium tert.butylate. The reaction temperature may vary between about 0.degree. and approximately 80.degree. C, and is preferably effected at room temperature. The reaction may be accelerated by stirring.
Acid addition salt forms of compound of formula I, e.g. the hydrochloride, hydrogen malonate, fumarate, hydrogen fumarae, hydrogen maleate, or naphthalene-1,5-disulphonate may be produced in known manner from the free base forms, and vice versa.
Some of the compounds of formula III are known (F. Eloy and A. Deryckere, Helv.chem.Acta 53, 645-647 [1970]; and E. Bisagni et al., Bull.Soc.Chim.France 1974, 515-518).
The compounds of formula IIIa, ##STR8## wherein R.sub.2 is as defined above,
wherein B is as defined above, in the 2 or 3 position, are obtained, for example, by treating a compound of formula IV, ##STR9## wherein R.sub.1.sup.I and R.sub.2 are as defined above, with phosphorus oxychloride or phosphorus oxybromide.
In one convenient method of producing nitro compounds of formula III a corresponding compound of formula III wherein positions 2 and 3 are unsubstituted is nitrated in conventional manner. It is expected that any conventional nitrating agent will attack position 2 rather than position 3 so the resulting compound of formula III would be expected to be the 2-nitro derivative.
Any nitro group in the compounds of formula III may be converted into amino or an NHA group. A 4-chloro substituent may be converted into an alkylthio group in conventional manner.
The compounds of formula IVa, ##STR10## wherein R.sub.1.sup.II and R.sub.2.sup.I are independently hydrogen, alkyl of 1 to 4 carbon atoms in the 2, 3, 6 or 7 position, or a member of the series fluorine, chlorine or bromine in the 2 or 3 position,
If desired, in the compounds of formula IVa a chlorine, bromine or nitro substituent in the 7 position may be introduced by chlorination, bromination or nitration. A bromine atom in the 2 or 3 position may be substituted by a cyano group and this cyano group may be converted by alcoholysis into a COOB group, wherein B is as defined above.
These measures may be carried out in accordance with known methods, have been described in the literature and are partially described in the experimental part.
Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.
Individual optical isomer forms may be obtained from racemic forms in conventional manner. In one convenient preparation a compound of formula I is obtained in optically active form starting from optically pure R or S glyceraldehyde.
In the following non limitative Examples all temperatures are indicated in degrees Centrigrade and are uncorrected.
The nitro or acetamido substituent of the compounds of formula I can be either in the 2 or 3 position of the nucleus; is probably in the 2 position; it is in the same position as the nitro substituent in the mono-nitro derivative obtained by nitrating 4-chloro-furo-[3,2-c]-pyridine in the presence of nitric and sulphuric acids.
US Referenced Citations (3)
| Number |
Name |
Date |
Kind |
| 3705907 |
Troxler |
Dec 1972 |
|
| 3751429 |
Seemann et al. |
Aug 1973 |
|
| 3845065 |
Shen et al. |
Oct 1974 |
|
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
605972 |
Aug 1975 |
|
Patent Grant
4071630
