CA1169069A

CA1169069A - Tetrahydronicotinamide derivative, a process for producing the same and a pharmaceutical composition comprising the same

Info

Publication number: CA1169069A
Application number: CA000393167A
Authority: CA
Inventors: Sakae Takaku; Takashi Mori; Fumiaki Matsuura; Yasushi Murakami; Shigeyuki Kataoka; Yasuhisa Takeda; Yasuhiro Yamashita; Takashi Matsuno; Yumiko Takeda; Shinichi Kaiho; Tamotsu Yamazaki; Koji Mizuno; Shigeru Takanashi; Shun-Ichi Hata
Original assignee: Chugai Pharmaceutical Co Ltd
Current assignee: Chugai Pharmaceutical Co Ltd
Priority date: 1981-12-23
Filing date: 1981-12-23
Publication date: 1984-06-12

Abstract

ABSTRACT OF THE DISCLOSURE

1,4,5,6-Tetrahydronicotinamide derivatives represented by the formula:

Description

~ ~ ~i9~9 This invention relates to 1,4,5,6 tetra-hydronicotinamide derivatives and their pxeparation.
In accordance with one aspect of the invention there is provided 1,4,5,6-tetrahydronicotinamide derivatives of formula (I) ~CONHR
~N ~ (I) H
wherein R is a phenyl group, unsubstituted or sub-stituted by 1 or 2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen or is pyridyl and pharmaceutically acceptable salts thereof.
In accordance with another aspect of the invention there is provided a process for preparing the derivatives of formula (I) which comprises partially reducing a nicotinamide derivative of the formula (II) CON~

N
wherein R is as defined above.
, When desired a derivative of formula (I) may be readily converted to a corresponding pharmaceutically acceptable salt, particularly an acid addition salt by reacting a free base of formula (I) with a pharmaco-logically compatible non-toxic, inorganic or organic acid- !
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~ ~ 6~069 The reduction is suitably performed by intro-ducing hydrogen gas in the presence of a catalyst in a solvent, for example, tetrahydrofuran, dioxane, alcohol, hydrous alcohol or acetic acid, preferably an alcoholic solvent. Suitably metal catalysts are used, and pal-ladium-on-carbon is particularly preferred. A Raney-nickel catalyst may also be used. The reaction temperature is suitably in the range of from O to 100C, preferably from 10 to 50C, and the reaction may be com-pleted by having the nicotinamide derivative absorbabout 2 mols-of hydrogen at a hydrogen pxessure of 1 to 50 atm., preferably 2 to 5 atm~
The 90 obtained compound of this invention is useful as a medicine since it has not only high ability to suppress aggregation of platelets but also antiin-flammatory, antipyretic and analgesic effects.
~` Experiments with animals have shown that many antiinflammatory agents have a~ ty to suppxess aggregation of platelets. But it has been pointed out that one defect of these antiinflammatory agents is that when administered to living organisms, they sup-press in prostaglandin I2 activity in the walls of the ` arteries and with extended administration, they accele-~; rate the aggregation of platelets on the arterial walls.
The compound of this lnvention is free from these defects and is used as an effective agent to prevent and cure thrombosis and is also effective as antiinflammatory and , antipyretic analgesic agents.
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~ 3 6 ~ 9 When used as a medicine, the compound of this invention is formulated by a conventional technique into a tablet, granule, powder, capsule or injection, and administered to patients either orally or parente-rally. A tablet, granule, powder or capsule is pre-pared by mixing the compound with a pharmaceutical carrier such as lactose, starch, dextrin, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc - or magnesium stearate. An injection is prepared by dissolving the compound in distilled water or a solu-tion of salt such as sodium chloride or potAssium chloride.
The dosage of the compound of this invention is 5 - 300 mg/Kg/day, preferably 10 - 150 mg/Kg/day, for oral administration, and is 0.5 - 100 mg/Kg/day, preferably 1 - 50 mg/Kg/day, for parenteral administration. The desired amount is administered in a single dose or in several doses daily.
This invention is now described in greater detail by reference to the following experiment and examples to which this invention is by no means limited.

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~ ~ 6~0~9 Experiment: Effect of ~reventing _cute pulmonarY
thromboembolic death in mice.
Six~week-old male ddY/SPF strain mice were administered orally with 200 mg/Kg of the compounds of Examples 9 and 10 and the ac-tive controls. Four hours later, the mice were intravenously administered with 325 mg/Kg of ADP and 140 mg/Kg of sodium arachi-donate. The number of the mice that were dead within 24 hours of the administration of ADP and sodium arachidonate was counted and the results are shown in the Table below. As a reference compound, 5-(o-chloro-benzyl)-433,5,6,7-tetrahydrothienoC3,2,C]-pyridine (ticlopldine) and 1,3-diphenyl-4-~2-(phenylsulfinyl)-ethyl]-3,5-pyrazolidinedione (sulfinpyrazone) were , used and their efficacy to prevent acute thrombosis was compared with that of the compound of this ~` invention.
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~ ~ s~g Example 1 Twenty-seven grams of N-nicotinoyl-2-methoxyaniline was dissolved in 800 ml of 10% hydrous ethanol. To the solution, 5 g of 10% palladium-on-carbon was added and the mixture was hydrogenated at 40 to 50C under atmospheric pressure. After 2 mols of hydrogen was introduced over a period of about 6 hours, the reaction was stopped and the catalyst was removed. The liquid reaction mixture was concentrated and the residual oil was purified with column chromatography on silica gel and recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-methoxyaniline having a melting point of 126-128C. Yield=60%
Elemental analysis:
Calculated for C13H16N2O2: C 67.2; H 6.9; N 12.1 (%~
Found : C 67.2; H,6.8; N 12.0 (%~
Example 2 ; By reducing and purifying N-nicotinoyl-3~methoxyaniline as in Example 1, N-(1,4,5,6-tetrahydronicotinoyl~-3-methoxy-aniline having a melting point of 173 to 176C was produced.
Yield=58%
Elemental analysis:

13 16 2 2 C 67-2; H 6.9; N 12,1 (~
Found: C 67.3; H 7.0; N 12.2 (%~
,~ Example 3 ~:
' 25 ~ As in Example 1, N-nicotinoyl-4-methoxyaniline was treated and recrystallized~from ethyl acetate/ether to give N- ( 1 t 4 r 5,6-tetrahydronicotinoyl~-4-methoxyaniline having a melting point of 112 to 115C. Yield=64%

~, Elemental analysis:
Calculated for Cl3H16N2O2: C 67.2; H 6.9; N 12.1 (%) Found : C 67.1; H 6.7; N 12.0 (%) Example _4 As in Example l, N-nicotinoyl-2,6-dimethylaniline was reduced at 45C and the crystal formed by concentration was recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2,6-dimethylaniline having a melting point of ll9 to 122C. Yield=62%
Elemental analysis:
Calculated for C14Hl8N2 C 73~0; H 7-~; N 12-2 (%) Found : C 72.9; H 7.8; N 12.1 (%~
Example 5 As in Example l, N-nictinoyl-2-methylaniline was reduced and purified, and recrystallized from me hanol/ether to give N-(1,4,5,6-tetrahydronicotinoyl~-2-methylaniline having a melting point of 141 to 144C. Yield=61%
Elemental analysis:
Calculated for C13Hl6N2 C 72-2; H 7-5; N 13-0 ~%) Found : C 72.1; H 7.6; N 13.1 (%) Example 6 , Fifty grams of N-nicotinoyl-2-fluoroaniline was ~ `dissolved in 700 ml of 10% hydrous ethanol. To the solution, ;`; S g of 10% palladium-on-carbon was added and the mlxture was -~25 reduced with hydrogen at room temperature and at atmospheric pressure. When a stoichiometric amount of hydrogen was absorbed, the reaction was stopped and the catalyst was removed.
The liquid reaction mixture was concentrated and the resulting ~; '.

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crystal was recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-fluoroaniline having a melting point of 137 to 140C. Yield=70%
Elemental analysis:
Calculated for C12H13N2OF: C 65.4; H 5.9; N 12.7 (%) Found : C 65.2; H 5.7; N 12.5 (%) Example 7 By reducing N-nicotinoylaniline as in Example 6 except that the hydrogen pressure was 4 atm., N-(1,4,5,6-tetrahydro-nicotinoyl)aniline having a melting point of 209 to 212C
was produced. Yield=63%
Elemental analysis:
12 14 2 C 71.3; H 7.0; N 14.0 (%) Found C 71.4; H 7.1; N 13.8 (%) 15 Example 8 As in Example 6, 2-nicotinamidopyridine was reduced and recrystallized from tetrahydrofuran ether to give 2-~ ~1,4,5,6-tetrahydronicotinamido)pyr`idine having a melting ; point of 156 to 159C. Yield=68%
Elemental analysis:
Calculated for CllH13N3O: C 65.0; H 6.5; N 20.7 t%) Found : C 64.9; H 6.4; N 20.6 (%) Example 9 As in Example 1, N-nicotinoyl-2,5-dimethoxyaniline was hydrogenated. After removing the catalyst, the solvent was concentrated and the resulting oil was purified by column chromatography on silica gel and recrystallized from methanol/
ether to gi~e N-(1,4,5,6-tetrahydronicotinoyl)-2,5-dimethoxy-.. ~

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1 ~ 6~0~g aniline having a melting point of 124 to 126C. Yield-60%
Elemental analysis:
Calculated for Cl~H18N2O3: C 64.1; H 6.9; N 10.7 (%) Found : C 64.0; H 6.8; N 10.8 (%) Example 10 As in Example 1, N-nicotinoyl-2-ethoxyaniline was hydrogenated~ After removal of the catalyst, the solvent was concentrated and the resulting crystal was recrystallized from methanol~water to give N-(1,4,5,6-tetrahydronicotinoyl)-2-ethoxyaniline having a melting point of 145 to 146C.
Yield-62%
Elemental analysis:
Calculated for C14H18N2O2: C 68~3; H 7O4~ N 11.4 (%~
Found: C 68.2; H 7.5; N 11,3 ~%) ~ ~ .
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Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for producing a 1,4,5,6-tetra-hydronicotinamide derivative of the formula:

wherein R is a phenyl group unsubstituted or sub-stituted by 1 or 2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halogen, or is a pyridyl group, or a pharmaceutically acceptable salt thereof comprising:
partially reducing a nicotinamide derivative of the formula:

wherein R is as defined above, and when desired converting the free base thus obtained to a corres-ponding pharmaceutically acceptable salt thereof.

2. A process according to claim 1, wherein the reducing is carried out with hydrogen gas in the pre-sence of a catalyst.

3. A process according to claim 2, wherein the catalyst is palladium-on-carbon or Raney-nickel.

4. A process according to claim 2, wherein the reducing is carried out at a temperature between 0 and 100°C.

5. A process according to claim 4, wherein the temperature is between 10 and 50°C.

6. A process according to claim 2, wherein the reducing is carried out at a hydrogen pressure between 1 and 50 atm.

7. A process according to claim 6, wherein the hydrogen pressure is between 2 and 5 atm.

8. A process according to claim 2, wherein the reducing is carried out in a solvent selected from the group consisting of tetrahydrofuran, dioxan, alcohol, hydrous alcohol and acetic acid.

9. A process according to claim 1, including a step of converting a free base obtained to a corres-ponding pharmaceutically acceptable salt.

10. A process according to claim 1, wherein R is phenyl substituted by 1 or 2 substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen.

11. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-2-methoxyaniline which comprises reducing N-nicotinoyl-2-methoxyaniline.

12. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-3-methloxyaniline which comprises reducing N-nicotinoyl-3-methoxyaniline.

13. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-4-methoxyaniline which comprises reducing N-nicotinoyl-4-methoxyaniline.

14. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-2,5-dimethoxy-aniline which comprises reducing N-nicotinoyl-2,5-dimethoxyaniline.

15. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-2-ethoxyaniline which comprises reducing N-nicotinoyl-2-ethoxyaniline,

16. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-2-methylaniline which comprises reducing N-nicotinoyl-2-methylaniline.

17. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)-2,6-dimethyl-aniline which comprises reducing N-nicotinoyl-2,6-dimethylaniline.

18. A process according to claim 1, for prepar-ing M-(1,4,5,6-tetrahydronicotinoyl)-2-fluoroaniline which comprises reducing N-nicotinoyl-2-fluoroaniline.

19. A process according to claim 1, for prepar-ing N-(1,4,5,6-tetrahydronicotinoyl)aniline which comprises reducing N-nicotinoylaniline.

20. A process according to claim 1, for prepar-ing 2-(1,4,5,6-tetrahydronicotinamido)pyridine which comprises reducing 2-nicotinamido pyridine.

21. A process according to claim 10, 11 or 12, wherein the reducing is carried out with hydrogen gas in the presence of a catalyst.

22. A process according to claim 13, 14 or 15, wherein the reducing is carried out with hydrogen gas in the presence of a catalyst.

23. A process according to claim 16, 17 or 18, wherein the reducing is carried out with hydrogen gas in the presence of a catalyst.

24. A process according to claim 19 or 20, wherein the reducing is carried out with hydrogen gas in the presence of a catalyst.

25. A 1,4,5,6-tetrahydronicotinamide derivative of formula (I) (I) wherein R is a phenyl group, unsubstituted or sub-stituted by 1 or 2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, is a pyridyl group, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 1, or by an obvious chemical equivalent.

26. A 1,4,5,6-tetrahydronicotinamide derivative of formula (I), as defined in claim 1, or a pharma-ceutically acceptable salt thereof, whenever prepared by the process of claim 2 or 3, or by an obvious chemical equivalent.

27. A 1,4,5,6-tetrahydronicotinamide derivative of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 4 or 5, or by an obvious chemical equivalent.

28. A 1,4,5,6-tetrahydronicotinamide derivative of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 6 or 7, or by an obvious chemical equivalent.

29. A 1,4,5,6-tetrahydronicotinamide derivative of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, whenever prepared by the process of claim 8, or by an obvious chemical equivalent.

30. A pharmaceutically acceptable salt of a derivative of formula (I), as defined in claim 1, whenever prepared by the process of claim 9, or by an obvious chemical equivalent.

31. A derivative of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R is phenyl substituted by 1 or 2 substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, whenever prepared by the process of claim 10, or by an obvious chemical equivalent.

32. N-(1,4,5,6-Tetrahydronicotinoyl)-2-methoxyaniline, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.

33. N-(1,4,5,6-Tetrahydronicotinoyl)-3-methoxyaniline, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.

34. N-(1,4,5,6-Tetrahydronicotinoyl)-4-methoxyaniline, whenever prepared by the process of claim 13, or by an obvious chemical equivalent.

35. N-(1,4,5,6-Tetrahydronicotinoyl)-2,5-dimethoxyaniline, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.

36. N-(1,4,5,6-Tetrahydronicotinoyl)-2-ethoxyaniline, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.

37. N-(1,4,5,6-Tetrahydronicotinoyl)-2-methylaniline, whenever prepared by the process of claim 16, or by an obvious chemical equivalent.

33. N-(1,4,5,6-Tetrahydronicotinoyl)-2,6-dimethylaniline, whenever prepared by the process of claim 17, or by an obvious chemical equivalent.

39. N-(1,4,5,6-Tetrahydronicotinoyl)-2-fluoro-aniline, whenever prepared by the process of claim 18, or by an obvious chemical equivalent.

40. N-(1,4,5,6-Tetrahydronicotinoyl)aniline, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.

41. 2-(1,4,5,6-Tetrahydronicotinamido)pyridine, whenever prepared by the process of claim 20, or by an obvious chemical equivalent.