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Publication numberUS3725410 A
Publication typeGrant
Publication dateApr 3, 1973
Filing dateJul 15, 1970
Priority dateJul 15, 1970
Publication numberUS 3725410 A, US 3725410A, US-A-3725410, US3725410 A, US3725410A
InventorsM Freed, J Potoski
Original AssigneeAmerican Home Prod
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
3-aminomethyl-3-quinuclidinols
US 3725410 A
Abstract
This invention is concerned with new and novel derivatives of 3-aminomethyl-3-quinuclidinols which are pharmacologically active as CNS depressants useful in the calming of animals. Further, this invention is concerned with methods of producing the new and novel 3-aminomethyl-3-quinuclidinols. Still further, this invention is concerned with 3-methylenequinuclidine oxide which is a new and novel intermediate useful in the production of the new and novel 3-aminomethyl-3-quinuclidinol derivatives of the present invention.
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United States Patent 91 Potoski et al.

[1 1 3,725,410 [451. Apr. 3, 1973 I 3-AMINOMETHYL-3- QUINUCLIDINOLS [75] Inventors: John R. Potoski, Rosemont; Meier E. Freed, Paoli, both of Pa.

[73] Assigneer American Home Products Corporation, New York, NY.

[22] Filed: July 15, 1970 [21'] Appl. No.: 55,264

[51] Int. Cl. ..C07d 51/70, C07d 51/72 [58] Field of Search ..260/268 BC, 293.53

[56] References Cited UNITED STATES PATENTS 2,834,779 5/l958 Biel 1 ..260/268 BC 3,163,653 12/1964 Ochiai.. ..260/293.53

3,317,547 5/1967 Judd ..260/293.53

3,598,825 8/1971 Biel I1 ..260/268 BC FOREIGN PATENTS OR APPLICATIONS 865,973 9/1957 Great Britain ..260/293.53

4/1967 Japan ..260/268 BC OTHER PUBLICATIONS R. Mikhlina et al. Abst. SOV/79-29-7-50/83 of 2h. 0b. Khim. Vol. 29, p. 2337-73) (1959).

S. Hoffman-Laroche in Chem. Abstr. Vol. 65 C01.

Primary Examiner-Donald G. Daus Attorney-Andrew Kafko, Joseph Martin Weigman, Dwight J. Potter, Vito Victor Bellino and Robert Wiser [57] ABSTRACT This invention is concerned with new and novel derivatives of 3-aminomethyl-3-quinuclidinols which are pharmacologically active as CNS depressants useful in the calming of animals. Further, this invention is concerned with methods of producing the new and novel 3-aminomethy1-3-quinuclidinols. Still further, this invention is concerned with 3-methylenequinuclidine oxide which is a new and novel intermediate useful in the production of the new and novel 3- aminomethy1-3-quinuclidinol derivatives of the present invention.

3 Claims, No Drawings 3-AMINOMETHYL-B-QUINUCLIDINOLS This invention relates to new and novel 3-quinuclidinol derivatives. Particularly, this invention relates to new and novel 3-aminomethyl-3-quinuclidinol derivatives which in standard and accepted phar- 5 macological tests have demonstrated activity as CNS depressants useful in the calming of animals. Further, this invention is concerned with the production of the new and novel 3-aminomethyl-3-quinuclidinols and with the new and novel compound 3-methylenequinuclidine oxide useful as an intermediate in the production of the new and novel 3-aminomethyl-3-quinuclidinol derivatives as hereinafter set forth. Additionally, certain of the compounds of the present invenwherein R is selected from the group consisting of lower)alky1, hydroxy-(lower)alkyl,

Z i Z3 Z Z2 Z XIX x l o U l ll it wherein Q is (lower)alkylene, Q is a straight chain alkylene of from 2 to about 6 carbon atoms, 2 and Z are nonadjacent and selected from the group consisting of 7 hydrogen, hydroxy, trifluoromethyl, amino, halo, (lower)alkoxy and (lower)alkyl, and Z is selected from the group consisting of hydrogen, halo, (lower)alkoxy and (lower)alkyl, with the proviso that when Z, Z and Z are not hydrogen they are the same; and R and R are selected independently from the group consisting of hydrogen, (lower)alkyl,

7,1 Z1 Z1 7. z z 2 z Z XIX l U i Y and i l Q o l I o I wherein 0, Z, Z and Z are as herein-above set forth;

iii. at

[CH2] --1C \R'LQ: 1'2 11 wherein m is l, 2 or 3, R, R and R are hydrogen and R is selected from the group consisting of hydrogen,

(lower)alkyl, and

wherein Z, Z and Z are as hereinabove set forth; m is l or 2, R and R are hydrogen and R and R are concatenated to form with the carbon atom to which they are attached a carbocyclic structure of from about 5 to about 8 carbon atoms; and m is 2 and R and R are concatenated to form with R R and the carbon atoms to which they are attached a benzene ring or a benzene ring substituted with l to 3 members selected from the group consisting of halo, (lower)alkoxy and (lower)alkyl or substituted with l or 2 nonadjacent members selected from the group consisting of hydroxy, trifluoromethyl and amino; and

wherein R is selected from the group consisting of hydrogen, (lower)alkyl,

-Q I :-Z1, and Q 0- Z wherein Q, Q, Z, Z and Z are as hereinabove set forth; and R is selected from the group consisting of R",

wherein Q is (lower)alkyl and Z, Z and Z are as hereinabove set forth, and

wherein R is alkylene of from 2 to about 4 carbon atoms and R and R are each (lower)alkyl or are con catenated to form with the nitrogen atom .to which they are attached a nitrogen containing heterocyclic ring containing from about 4 to about 8 carbon atoms; and

non-toxic pharmaceutically acceptable acid addition salts thereof.

Of particular interest are the new and novel compounds of the present invention which are represented by the class of those having the following structural formula:

whereinR, R and R are as set forth in Formula l, and non-toxic pharmaceutically acceptable acid addition salts thereof. Typical compounds of Formula II are: 3- (4-phenylpiperazinomethyl)-3-quinuclidinol; and 3- 3,3-diphenylpiperazinomethyl)-3-quinuclidinol; and

wherein m, R, R, R and R are as set forth in Formula I, and non-toxic pharmaceutically acceptable acid addition salts thereof, including compounds having the structural formula:

wherein n is 1, 2 or 3 and R is selected from the group consisting of hydrogen, (lower)alkyl and Z X2 1 X22 wherein Z, Z and Z are as set forth in Formula (I), and non-toxic pharmaceutically acceptable acid addition salts thereof and compounds having the structural formula:

wherein n is l, 2 or 3 and q is a number from about 4 to about 7, and the non-toxic pharmaceutically acceptable acid addition salts thereof. A typical compound of Formula (V) is 3-[(3-azaspiro[5,5]undecino)methyl]- 3-quinuclidinol; and compounds of Formula III having the structural formula:

wherein Z, Z and Z are set forth in Formula I, and non-toxic pharmaceutically acceptable acid addition salts thereof. A typical compound of Formula VI is: 3- (l,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol; and compounds having the structural formula:

OII

L/ W s R (VII) wherein R and R are as set forth in Formula (I), and non-toxic pharmaceutically acceptable acid addition salts thereof, particularly, compounds having the formula:

AOH

(VIII) wherein R is as set forth in Formula I and R is selected from the group consisting of R and wherein 0 Z, Z and Z are as set forth in Formula I and non-toxic pharmaceutically acceptable acid addition salts thereof, and compounds of Formula VII having the structural formula:

on A R1 ut I N--R"N is R wherein X is as previously set forth, R is (lower)alkyl,

Hal. is a halogen such as fluorine, bromine, iodine or chlorine, and LAH is lithium aluminum hydride.

. (A) in the preferred synthesis,X A1 l,3-qumuclidone is reacted by heating at about 50C. for about 1 hour in a mixture of a 50 percent dispersion of sodium hydride in nujol, dimethylsulfoxide and trime thylsulfoxonium iodide. The mixture is cooled and extracted with a suitable inert organic solvent such as dichloromethane which is washed with an aqueous salt solution (NaCl) and dried (over MgSO Removal of the drying agent provides 3-methylenequinuclidine oxide (XI). The compound (XI) is then reacted with an appropriate compound of the formula HN-X by heating at a temperature ranging from about 150C. to about 220C. for a time period ranging from about minutes to about 1 hour. Upon cooling, the reaction mixture is extracted with an appropriate inert organic solvent (i.e. dichloromethane, ether, ethylacetate, hexane) followed by routine recovery procedures, such as filtering and recrystallization.

When used herein and in the appended terms (lower)alkoxy", (lower)alkyl", (lower)alkylene" and the like contemplates hydrocarbon containing radicals, straight and branched chain, containing from about 1 to about 6 carbon atoms, and includes groupings such as methyl, ethyl, n-propyl, i-propyl, n-

claims, the

butyl, t-butyl, n-pentyl, n-hexyl, 2-methylpentyl, and

. the like. The terms halo or halogen when used alone or in association with groups such as (lower)alkyl or phenyl contemplates the halogens, and includes fluorine, chlorine, bromine and iodineq The starting material 3-quinuclidinone is well-known and commercially available. The starting materials of Formula HN- X are readily available or are prepared by methods known to those skilled in the art.

In accord with the present invention, the compounds I of the present invention have been found to possess interesting pharmacological properties. More particularly, these compounds, in standard pharmacological tests, have exhibited utility as central nervous system (CNS) depressant agents which are useful in producing .s !miQsEEtEEQBE WB- In the, pharmacological evaluation the central nerdecreased respiration) and autonomic activity (i.e. miosis, mydriasis, diarrhea) are noted. The animals are tested for changes in reflexes (i.e. flexor, extensor) and are rated by use of a pole climb and inclined screen for the presence of sedation'ataxia. The Eddy Hot-Plate Method [Nathan B. Eddy and Dorothy Leimbach, J. Pharmacol. Exper. Therap. 107, 385 (1953 )1 is used to test for analgesia. The experiment is terminated by subjecting each animal to a maximal electroshock to test for anti-convulsant activity.

The compounds of this invention when administered orally in the above test procedure, induce decreased motor activity (Central Nervous System depressant activity useful in the calming of animals) at a dosage level of from 4.00 mg./kg. to 400 mg./kg. There were no deaths in the test animals at the highest dose used, 400 mg./kg., intraperitoneally.

In the pharmacological evaluation of the anti-inflammatory activity of the compounds of the present invention, the in vivo effects of these compounds are tested by a modification of procedures described by Winter et al., Proc. Soc. Exp. Biol. and Med., lll:544 (I962) and Buttle et al., Nature, 179:629 (1957), which is as follows:

Male Sprague-Dawley rats 120-160 grams are used. The compound is administered orally as a solution or suspension in distilled water, (plus two drops Tween 80) in a volume of 10 ml/kg. Each compound is given to six rats and vehicle alone is administered to six more rats as a control. Sixty minutes after drug administration, edema is induced by an injection of 0.05 ml. of a 1 percent carrageenin solution in saline into the subplantar tissue of the rats right hind paw. Paw volume is then immediately measured volumetrically plethysmograph and again 3 hours later. The mean volume of swelling for the control group is calculated and compared to the test groups. Compounds that inhibit swelling 23 percent as compared to controls are considered active. Inhibition is calculated by the formula:

Mean vol. swelling of control mean vol. swelling of test Inhibition: X 100 with a and flufenamic and mefanamic acids. The clinical correlation is excellent.

Certain compounds of this invention, when tested as described above, exhibit anti-inflammatory activity. Special notice is directed to 3-(4-phenylpiperazinomethyl)-3-quinuclidinol which demonstrated a 28 percent inhibitory activity as compared to the control compounds.

When the compounds of this invention are employed pharmaceutically; i.e. as CNS depressants in calming animals or as anti-inflammatory agents, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar and so forth. They may be administered orally in the form of solution or they may be injected parenterally, e.g. intra-muscularly. For parenteral administration, they may be used in the form of a sterile solution or suspensions containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present pharmacologically active agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the com-. position is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof. All temperatures used herein and in the appended claims are in degrees Celsius unless otherwise indicated.

EXAMPLE I 3-Methylenequinuclidine oxide Sodium hydride (4.0 g., 50 percent dispersion in nujol) is dissolved in 50 ml. of dry dimethylsulfoxide, under a dry nitrogen atmosphere, at to and with stirring. The resulting solution is cooled to 15 and to it is added trimethylsulfoxonium iodide (16.0 g., 0.073 mole). The mixture is stirred for 20 minutes. To the mixture is then added 9.0 g. (0.070 mole) of 3-quinuclidinone. The quinuclidinone is rinsed in with an additional 10 ml. of dimethylsulfoxide. After the initial reaction subsides, the mixture is heated at 50 for 1 hour, cooled and diluted with ml. of water. The

aqueous-solution is extracted with 4 X 50 ml. of dichloromethane. The dichloromethane is back washed with 25 ml. of a saturated aqueous sodium chloride and dried (MgSO Removal of the drying agent and concentration of the dichloromethane solution gives a yellow oil. Distillation of the oil gives a colorless liquid with hp. 6878 at 6.0 mm. and weight of 7.5 g. The distilled liquid is shown by spectroscopy to be a mixture of oxide product and dimethylsulfoxide in a ratio of approximately 2:1. Hereafter, this mixture will be designated as 1.

EXAMPLE ll 3-(4-Phenylpiperazinomethyl)-3-quinuclidinol A mixture of 4.5 g. of l and 3.2 g of N-phenylpiperazine is heated at to 200 for 20 minutes and allowed to stand overnight at room temperature. The

3-[4-( 3,4,S-trich1or0phenyl)piperidinomethyl]-3- quinuclidinol.

EXAMPLE V 3-[(3-azaspiro[5 ,5 ]undecino)methyl]-3-quinuclidinol A mixture of I (2.8 g.) and 4,4-spiropentamethylenepiperidine (1.8 g.) is heated at 200 for minutes. On cooling, crystallization occurs. Recrystallization of the solid from hexane gives 2.6 g. of white solid with m.p. 1081 14. Recrystallization of the solid from ethanol-water gives 1.8 g. of white solid with m.p. l20l23. Finally, recrystallization of the solid from hexane gives 1.6 g. of product with m.p. 121123.

Anal. Calcd for C H N O: C, 73.92; H, 11.03; N, 9.58. Found: C, 74.29; H, 11.26; N, 9.91.

In a similar manner, using the appropriate starting materials, the following compounds are provided:

3-[(2-azaspiro[4,4]nonino)methyl]-3-quinuclidinol;

3-[(2-azaspiro[4,5]decino)methyl]3-quinuclidinol; 3-[(2-azaspiro[4,6]undecino)methyll-3-quinuclidinol; 3-[(2-azaspiro[4,7]dodecino)methyl]-3-quinuclidinol; 3-[(3-azaspiro[5,4]decino)methyl]-3-quinuclidinol; 3-[(3-azaspiro[5,6]dodecino)methyl]-3-quinuclidinol; 3-[(3-azaspiro[5,7]tridecino)methyl]-3-quinuclidinol; 3-[(3-azaspiro[6,4]undecino)methyl]-3-quinuclidinol; 3-[ 3-azaspiro[6,5 ]dodecino )methylJ-B-quinuclidinol; 3-[(3-azaspiro[6,6]tridecino)methyl]-3quinuclidinol; 3-[(3-azaspiro[6,7]tetradecino)methyl]-3-quinuclidinol.

EXAMPLE V1 3-( 1 ,2,3,4-Tetrahydroisoquinolinomethyl)-3- quinuclidinol A mixture of l (2.0 g.) and 1.4 of tetrahydroisoquinoline is heated at 170 i 5 for 30 minutes. On cooling, crystallization occurs. The crystals are triturated with ether and filtered to give 1.35 g. of white solid product with m.p. 113-1l8. Recrystallization of the solid from cyclohexane gives 1.2 g. of product with m.p. 117-l 19.

Anal. Calcd for C H N O: C, 74.96; H, 8.88; N, 10.29. Found: C, 74.67; H, 8.88; N, 10.27.

In a similar manner, using the appropriate starting materials, the following compounds are provided:

3-(6-chloro-1,2,3,4-tetrahydroisoquinolinomethyl)- 3-quinuclidinol;

3-(1,2,3 ,4-tetrahydro-7-methoxyisoquindinomethyl)-3-quinuclidinol;

3-(5-hexyl-l ,2,3 ,4-tetrahydroisoquinolinomethyl)-3- quinuclidinol;

3-( l ,2,3,4-tetrahydro-5,7-dimethylisoquinolinomethyl)-3-quinuclidinol;

3-(6-bromo-8-ethyl-l ,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol;

3-(5,7-diamino-1,2,3 ,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol;

3-(1,2,3,4-tetrahydro-7-iodoisoquinolinomethyl)-3- quinuclidinol;

3-(6-trifluoromethyl-1,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol;

3-( 1,2,3 ,4-tetrahydro-5,6,7-trimethylisoquinolinomethyl)-3-quinuclidinol;

3-(1,2,3,4-tetrahydro-7,8-diiodorsoquinolinomethyl)-3-quinuclidinol;

3-(6,8-diamino-1,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol;

3-( 1,2,3 ,4-tetrahydro-7-hydroxyisoquinolinomethyl)-3-quinuclidinol;

3-(1,2,3,4-tetrahydro-7-methylisoquinolinomethyl)- B-quinuclidinol;

3-(5 ,6,7-trichlorol ,2,3,4-tetrahydroisoquinolinomethyl )-3-quinuclidinol;

3-( l ,2,3,4-tetrahydro-5,6,7-trimethoxyisoquinolinomethyl)-3-quinuclidinol;

3-(6-fluoro-l ,2,3,4-tetrahydroisoquinolinomethyl)- 3-quinuclidinol;

3-( 5-chloro l ,2,3,4-tetrahydro-7-methylisoquinolinomethyl)-3-quinuclidinol;

3-( l ,2,3,4-tetrahydro-6,7-dihydroxyisoquinolinomethyl)-3-quinuclidinol;

3-(7-ethoxy-1,2,3,4-tetrahydroisoquinolinomethyl)- 3-quinuclidinol;

3-(6-amino-l ,2,3,4-tetrahydroisoquinolinomethyl)- I i-quinuclidinol;

3-[6,8-di(trifluoromethyl)-1,2,3,4-

tetrahydroisoquinolinomethyl]I i-quinuclidinol;

3-(6-bromo-1,2,3,4-tetrahyroisoquinolinomethyl)-3- quinuclidinol;

3-(7-ethyl-1,2,3 ,4-tetrahydroisoquinolinomethyl)-3- quinuclidinol;

3-(6,7-dibromo-1,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidino1;

3-( 7 ,8-diethoxyl ,2,3 ,4-tetrahydroisoquinolinomethyl)-3-quinuclidino1;

3-(7,8-diethyl-1,2,3,4-tetrahydroisoquinolinomethyl)-3-quinuclidinol;

3-(6-ethy1)-1,2,3 ,4-tetrahydro-7-hydroxyisoquinolinomethyl )-3-quinuclidinol.

EXAMPLE Vll 3-Diethylaminomethyl-3-quinuclidinol U 11 A Girl-c113 A mixture of 5.0 g. of l and 4.0 g. of diethylamine An etherial solution of 2.0 g. of 3-(4-phenyl- 3-[N-ethyl-2-(diethylamino)ethylaminomethyl1-3- piperazinomethyl)-3quinuclidinol, prepared as in Exquinuclidinol, maleate; I ample II, is treated with excess isopropanolic hydrogen 3-m0rpholinomethyl-3-quinuclidinol, benzoate. chloride and the resulting solid is washed with ether What is claimed:

and with acetone. The title salt is recrystallized from 1. A compound having the formula: isopropanol.

In a similar manner, using the appropriate starting A CHzX materials, the following salts are provided:

3-( 3 ,3-diphenylpiperazinomethyl )-3-quinuclidinol, {f

hydrochloride; I O 3'(4'phenylplperidinomethyl)'3'qinuclidi"l' wherein X is 4-phenylpiperazino and 3,3-diphenylhydrochloride; i erazino 3-[(3-azas iro[5 5]undecino)meth 11-3- pp P i Y q 2. A compound as set forth in claim 1, WhlCh is: 3-(4- uchdmol, sulfate; phenylpiperazinomethyl)-3-quinuclidinol. l*2?,4tgtfahydro'soqumolmomethyl)'3'qum' 15 3. A compound as set forth in claim 1, which is: 3-

uFhdmolPltratei (3,3-diphenylpiperazinomethyl)-3-quinuclidinol. 3-d1ethylam1nomethyl-3-qu1nucl1dmol, phosphate; I It It g

Patent Citations
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US2834779 *Dec 11, 1956May 13, 1958Lakeside Lab IncDisubstituted aminoalkyl quinuclidinium derivatives
US3163653 *Sep 21, 1962Dec 29, 1964 -nhsoz-r
US3317547 *Jun 24, 1965May 2, 1967Colgate Palmolive CoQuinuclidyl ethers of dibenzocycloheptadiene
US3598825 *Dec 13, 1967Aug 10, 1971Aldrich Chem Co Inc2(4 phenyl piperazino methyl)3 quinuclidinones
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JP42016312A * Title not available
Non-Patent Citations
Reference
1 *R. Mikhlina et al. Abst. SOV/79 29 7 50/83 of 2h. Ob. Khim. Vol. 29, p. 2337 73) (1959).
2 *S. Hoffman Laroche in Chem. Abstr. Vol. 65 Col. 3847 d (1966).
Referenced by
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US5554613 *Jun 2, 1993Sep 10, 1996Zeneca LimitedHeterocyclic derivatives
US5612352 *Apr 8, 1993Mar 18, 1997Zeneca LimitedHeterocyclic compounds
US5654315 *Dec 16, 1992Aug 5, 1997Imperial Chemical Industries PlcQuinuclidine compounds useful in treating diseases
US5691349 *Aug 4, 1993Nov 25, 1997Zeneca LimitedQuinclidine derivatives as squalene synthase inhibitors
US5714496 *Aug 25, 1993Feb 3, 1998Zeneca LimitedQuinuclidine derivatives as squalene synthase inhibitors
US5731323 *Dec 21, 1993Mar 24, 1998Zeneca LimitedQuinuclidine derivatives as squalene synthase inhibitors
US5770608 *Feb 24, 1997Jun 23, 1998Imperial Chemical Industries PlcHeterocyclic derivatives
US5792777 *Oct 27, 1992Aug 11, 1998Zeneca LimitedBiphenyl quinuclidines
US6433168Jul 21, 2000Aug 13, 2002Sumika Fine Chemicals Co., Ltd.Highly pure phenothiazine compound, production method thereof, production method of intermediate therefor, and hydrate and novel crystal as starting materials for the intermediate
US20030143757 *Oct 25, 2002Jul 31, 2003Jonathan MooreMethods for identifying drug cores
Classifications
U.S. Classification544/362, 540/481, 540/543, 544/127, 546/137, 546/135, 540/597
International ClassificationC07D453/00, C07D453/02
Cooperative ClassificationC07D453/02
European ClassificationC07D453/02