2-Ketoamidines
United States Patent 3884974
The present invention relates to amidino ketones of the formula ##SPC1## Wherein R1 is alkyl of 1 to 4 carbon atoms, phenyl or substituted phenyl, and R2 is alkyl of 1 to 4 carbon atoms, or R1 and R2 together are --(CH2)n --, wherein n is an integer from 2 to 7, And R3 is alkyl of 1 to 4 carbon atoms, or R1, r2 and R3 together with the carbon atom to which they are bound form the adamantyl radical, R4 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of 1 to 5 carbon atoms, or a group of formula ##SPC2## Wherein R7 and R8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or R7 and R8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and R5 and R6 are the same or different and each is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of 1 to 5 carbon atoms, or one of R4, R5 and R6 is phenyl or substituted phenyl and the others of R4, R5 and R6 are as defined above, useful as hypoglycaemic agents.
Application Number:
05/426714
Publication Date:
05/20/1975
Filing Date:
12/13/1973
View Patent Images:
Export Citation:
Assignee:
Sandoz Ltd. (Basle, CH)
Primary Class:
Other Classes:
558/430, 558/391, 544/160, 514/866, 546/235, 546/203, 544/162, 544/164, 564/244, 558/434, 544/163, 558/303, 546/246, 558/432, 544/159, 548/557, 558/5, 562/597, 548/215, 544/382, 564/30, 558/433, 564/245
International Classes:
C07D263/04; C07D295/28; C07D263/00; C07D295/00; C07C123/00
Field of Search:
260/564R,501.14
Other References:
chemical Abst. Vol. 73, Column 130,940(z), (1970)..
Primary Examiner:
Zitver, Leon
Assistant Examiner:
Schwartz, Gerald A.
Attorney, Agent or Firm:
Sharkin, Gerald Honor Robert Mcgovern Thomas D. J. O.
Parent Case Data:
IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
This application is a contination-in-part of our copending application Ser. No. 366,681 filed June 4, 1973.
Claims:
What is claimed is
1. A compound of the formula: ##SPC11##
2. A compound of the formula: ##SPC12##
3. A compound of claim 2, wherein R1, R2 and R3 are, independently alkyl and R4, R5 and R6 are, independently, alkenyl or alkyl.
4. The compound of claim 3, which is N1,N2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine.
5. The compound of claim 3, which is N2,N2 -di-isobutyl-N1,4,4-trimethyl-3-oxo-pentanamidine.
6. A compound of claim 2, wherein R1, R2 and R3 are methyl.
7. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is methyl.
8. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is ethyl.
9. The compound of claim 6, wherein R4 is methyl, R5 is ethyl and R6 is ethyl.
10. The compound of claim 6, wherein R4 is methyl, R5 is propyl and R6 is propyl.
11. The compound of claim 6, wherein R4 is methyl, R5 is isopropyl and R6 is isopropyl.
12. The compound of claim 6, wherein R4 is methyl, R5 is allyl and R6 is allyl.
13. The compound of claim 6, wherein R4 is methyl, R5 is butyl and R6 is butyl.
14. The compound of claim 6, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
15. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 methyl.
16. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 is ethyl.
17. The compound of claim 6, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
18. The compound of claim 6, wherein R4 is ethyl, R5 is isopropyl and R6 is isopropyl.
19. The compound of claim 6, wherein R4 is ethyl, R5 is butyl and R6 is butyl.
20. The compound of claim 6, wherein R4 is ethyl, R5 is isobutyl and R6 is isobutyl.
21. The compound of claim 6, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
22. The compound of claim 6, wherein R4 is propyl, R5 is methyl and R6 is methyl.
23. The compound of claim 6, wherein R4 is propyl, R5 is ethyl and R6 is ethyl.
24. The compound of claim 6, wherein R4 is propyl, R5 is propyl and R6 is propyl.
25. The compound of claim 6, wherein R4 is propyl, R5 is isopropyl and R6 is isopropyl.
26. The compound of claim 6, wherein R4 is propyl, R5 isobutyl and R6 is isobutyl.
27. The compound of claim 6, wherein R4 is propyl, R5 is allyl and R6 is allyl.
28. The compound of claim 6, wherein R4 is isopropyl, R5 is ethyl and R6 is ethyl.
29. The compound of claim 6, wherein R4 is isopropyl, R5 is propyl and R6 is propyl.
30. The compound of claim 6, wherein R4 is isopropyl, R5 is isopropyl and R6 is isopropyl.
31. The compound of claim 6, wherein R4 is isopropyl, R5 is allyl and R6 is allyl.
32. The compound of claim 6, wherein R4 is allyl, R5 is methyl and R6 is methyl.
33. The compound of claim 6, wherein R4 is allyl, R5 is ethyl and R6 is ethyl.
34. The compound of claim 6, wherein R4 is allyl, R5 is propyl and R6 is propyl.
35. The compound of claim 6, wherein R4 is allyl, R5 is isopropyl and R6 is isopropyl.
36. The compound of claim 6, wherein R4 is allyl, R5 is isobutyl and R6 is isobutyl.
37. The compound of claim 6, wherein R4 is allyl, R5 is allyl and R6 is allyl.
38. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is methyl.
39. The compound of claim 6, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
40. The compound of claim 6, wherein R4 is butyl, R5 is propyl and R6 is propyl.
41. The compound of claim 6, wherein R4 is butyl, R5 is isopropyl and R6 is isopropyl.
42. The compound of claim 6, wherein R4 is butyl, R5 is butyl and R6 is butyl.
43. The compound of claim 6, wherein R4 is butyl, R5 is allyl and R6 is allyl.
44. The compound of claim 6, wherein R4 is isobutyl, R5 is ethyl and R6 is ethyl.
45. The compound of claim 6, wherein R4 is isobutyl, R5 is propyl and R6 is propyl.
46. The compound of claim 6, wherein R4 is isobutyl, R5 is allyl and R6 is allyl.
47. The compound of claim 6, wherein R4 is sec-butyl, R5 is ethyl and R6 is ethyl.
48. The compound of claim 6, wherein R4 is sec-butyl, R5 is propyl and R6 is propyl.
49. The compound of claim 6, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
50. The compound of claim 6, wherein R4 is tert-butyl, R5 is ethyl and R6 is ethyl.
51. The compound of claim 6, wherein R4 is tert-butyl, R5 is isopropyl and R6 is isopropyl.
52. The compound of claim 6, wherein R4 is amyl, R5 is methyl and R6 is methyl.
53. The compound of claim 6, wherein R4 is amyl, R5 is ethyl and R6 is ethyl.
54. The compound of claim 6, wherein R4 is amyl, R5 is propyl and R6 is propyl.
55. The compound of claim 6, wherein R4 is amyl, R5 is allyl and R6 allyl.
56. The compound of claim 6, wherein R4 is isoamyl, R5 is ethyl and R6 is ethyl.
57. The compound of claim 6, wherein R4 is octyl, R5 is ethyl and R6 is ethyl.
58. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 phenyl.
59. The compound of claim 6, wherein R4 is ethyl, R5 is ethyl and R6 is phenyl.
60. The compound of claim 6, wherein R4 is phenyl, R5 is methyl and R6 is methyl.
61. The compound of claim 6, wherein R4 is phenyl, R5 is ethyl and R6 is ethyl.
62. The compound of claim 6, wherein R4 is phenyl, R5 is propyl and R6 is propyl.
63. The compound of claim 6, wherein R4 is phenyl, R5 is allyl and R6 is allyl.
64. The compound of claim 6, wherein R4 is p-Cl-phenyl, R5 is ethyl and R6 is ethyl.
65. The compound of claim 6, wherein R4 is p-CH3 -phenyl, R5 is ethyl and R6 is ethyl.
66. The compound of claim 6, wherein R4 is sec-butyl, R5 is isopropyl and R6 is isopropyl.
67. The compound of claim 6, wherein R4 is octyl, R5 is methyl and R6 is methyl.
68. The compound of claim 6, wherein R4 is β-methallyl, R5 is methyl and R6 is methyl.
69. The compound of claim 6, wherein R4 is β-methallyl, R5 is ethyl and R6 is ethyl.
70. The compound of claim 6, wherein R5 is β-methallyl, R5 is propyl and R6 is propyl.
71. The compound of claim 6, wherein R4 is hexyl, R5 is ethyl and R6 is ethyl.
72. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is ethyl.
73. The compound of claim 6, wherein R4 is hexyl, R5 is methyl and R6 is methyl.
74. The compound of claim 6, wherein R4 is isobutyl, R5 is methyl and R6 is methyl.
75. The compound of claim 6, wherein R4 is sec-butyl, R5 is methyl and R6 is ethyl.
76. The compound of claim 6, wherein R4 is tert-butyl, R5 is methyl and R6 is ethyl.
77. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is methyl.
78. The compound of claim 6, wherein R4 is methyl, R5 is isoamyl and R6 is isoamyl.
79. The compound of claim 6, wherein R4 is isoamyl, R5 is allyl and R6 is allyl.
80. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is ethyl.
81. A compound of claim 2, wherein R1 and R2 are methyl and R3 is ethyl.
82. The compound of claim 81, wherein R4 is ethyl, R5 is ethyl and R6 is ethyl.
83. The compound of claim 81, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
84. The compound of claim 81, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
85. The compound of claim 81, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
86. The compound of claim 81, wherein R4 is sec-butyl, R5 is ethyl and R6 ethyl.
87. The compound of claim 81, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
88. The compound of claim 81, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
89. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are sec-butyl.
90. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are isobutyl.
91. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl and R4, R5 and R6 are ethyl.
92. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is tert-butyl and R5 and R6 are ethyl.
93. The compound of claim 2, wherein R1 to R6 are ethyl.
94. The compound of claim 2, wherein R1, R2, R3, R5 and R6 are ethyl and R4 is sec-butyl.
95. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are sec-butyl.
96. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is sec-butyl and R5 and R6 are ethyl.
97. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are isobutyl.
1. A compound of the formula: ##SPC11##
2. A compound of the formula: ##SPC12##
3. A compound of claim 2, wherein R1, R2 and R3 are, independently alkyl and R4, R5 and R6 are, independently, alkenyl or alkyl.
4. The compound of claim 3, which is N1,N2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine.
5. The compound of claim 3, which is N2,N2 -di-isobutyl-N1,4,4-trimethyl-3-oxo-pentanamidine.
6. A compound of claim 2, wherein R1, R2 and R3 are methyl.
7. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is methyl.
8. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 is ethyl.
9. The compound of claim 6, wherein R4 is methyl, R5 is ethyl and R6 is ethyl.
10. The compound of claim 6, wherein R4 is methyl, R5 is propyl and R6 is propyl.
11. The compound of claim 6, wherein R4 is methyl, R5 is isopropyl and R6 is isopropyl.
12. The compound of claim 6, wherein R4 is methyl, R5 is allyl and R6 is allyl.
13. The compound of claim 6, wherein R4 is methyl, R5 is butyl and R6 is butyl.
14. The compound of claim 6, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
15. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 methyl.
16. The compound of claim 6, wherein R4 is ethyl, R5 is methyl and R6 is ethyl.
17. The compound of claim 6, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
18. The compound of claim 6, wherein R4 is ethyl, R5 is isopropyl and R6 is isopropyl.
19. The compound of claim 6, wherein R4 is ethyl, R5 is butyl and R6 is butyl.
20. The compound of claim 6, wherein R4 is ethyl, R5 is isobutyl and R6 is isobutyl.
21. The compound of claim 6, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
22. The compound of claim 6, wherein R4 is propyl, R5 is methyl and R6 is methyl.
23. The compound of claim 6, wherein R4 is propyl, R5 is ethyl and R6 is ethyl.
24. The compound of claim 6, wherein R4 is propyl, R5 is propyl and R6 is propyl.
25. The compound of claim 6, wherein R4 is propyl, R5 is isopropyl and R6 is isopropyl.
26. The compound of claim 6, wherein R4 is propyl, R5 isobutyl and R6 is isobutyl.
27. The compound of claim 6, wherein R4 is propyl, R5 is allyl and R6 is allyl.
28. The compound of claim 6, wherein R4 is isopropyl, R5 is ethyl and R6 is ethyl.
29. The compound of claim 6, wherein R4 is isopropyl, R5 is propyl and R6 is propyl.
30. The compound of claim 6, wherein R4 is isopropyl, R5 is isopropyl and R6 is isopropyl.
31. The compound of claim 6, wherein R4 is isopropyl, R5 is allyl and R6 is allyl.
32. The compound of claim 6, wherein R4 is allyl, R5 is methyl and R6 is methyl.
33. The compound of claim 6, wherein R4 is allyl, R5 is ethyl and R6 is ethyl.
34. The compound of claim 6, wherein R4 is allyl, R5 is propyl and R6 is propyl.
35. The compound of claim 6, wherein R4 is allyl, R5 is isopropyl and R6 is isopropyl.
36. The compound of claim 6, wherein R4 is allyl, R5 is isobutyl and R6 is isobutyl.
37. The compound of claim 6, wherein R4 is allyl, R5 is allyl and R6 is allyl.
38. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is methyl.
39. The compound of claim 6, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
40. The compound of claim 6, wherein R4 is butyl, R5 is propyl and R6 is propyl.
41. The compound of claim 6, wherein R4 is butyl, R5 is isopropyl and R6 is isopropyl.
42. The compound of claim 6, wherein R4 is butyl, R5 is butyl and R6 is butyl.
43. The compound of claim 6, wherein R4 is butyl, R5 is allyl and R6 is allyl.
44. The compound of claim 6, wherein R4 is isobutyl, R5 is ethyl and R6 is ethyl.
45. The compound of claim 6, wherein R4 is isobutyl, R5 is propyl and R6 is propyl.
46. The compound of claim 6, wherein R4 is isobutyl, R5 is allyl and R6 is allyl.
47. The compound of claim 6, wherein R4 is sec-butyl, R5 is ethyl and R6 is ethyl.
48. The compound of claim 6, wherein R4 is sec-butyl, R5 is propyl and R6 is propyl.
49. The compound of claim 6, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
50. The compound of claim 6, wherein R4 is tert-butyl, R5 is ethyl and R6 is ethyl.
51. The compound of claim 6, wherein R4 is tert-butyl, R5 is isopropyl and R6 is isopropyl.
52. The compound of claim 6, wherein R4 is amyl, R5 is methyl and R6 is methyl.
53. The compound of claim 6, wherein R4 is amyl, R5 is ethyl and R6 is ethyl.
54. The compound of claim 6, wherein R4 is amyl, R5 is propyl and R6 is propyl.
55. The compound of claim 6, wherein R4 is amyl, R5 is allyl and R6 allyl.
56. The compound of claim 6, wherein R4 is isoamyl, R5 is ethyl and R6 is ethyl.
57. The compound of claim 6, wherein R4 is octyl, R5 is ethyl and R6 is ethyl.
58. The compound of claim 6, wherein R4 is methyl, R5 is methyl and R6 phenyl.
59. The compound of claim 6, wherein R4 is ethyl, R5 is ethyl and R6 is phenyl.
60. The compound of claim 6, wherein R4 is phenyl, R5 is methyl and R6 is methyl.
61. The compound of claim 6, wherein R4 is phenyl, R5 is ethyl and R6 is ethyl.
62. The compound of claim 6, wherein R4 is phenyl, R5 is propyl and R6 is propyl.
63. The compound of claim 6, wherein R4 is phenyl, R5 is allyl and R6 is allyl.
64. The compound of claim 6, wherein R4 is p-Cl-phenyl, R5 is ethyl and R6 is ethyl.
65. The compound of claim 6, wherein R4 is p-CH3 -phenyl, R5 is ethyl and R6 is ethyl.
66. The compound of claim 6, wherein R4 is sec-butyl, R5 is isopropyl and R6 is isopropyl.
67. The compound of claim 6, wherein R4 is octyl, R5 is methyl and R6 is methyl.
68. The compound of claim 6, wherein R4 is β-methallyl, R5 is methyl and R6 is methyl.
69. The compound of claim 6, wherein R4 is β-methallyl, R5 is ethyl and R6 is ethyl.
70. The compound of claim 6, wherein R5 is β-methallyl, R5 is propyl and R6 is propyl.
71. The compound of claim 6, wherein R4 is hexyl, R5 is ethyl and R6 is ethyl.
72. The compound of claim 6, wherein R4 is butyl, R5 is methyl and R6 is ethyl.
73. The compound of claim 6, wherein R4 is hexyl, R5 is methyl and R6 is methyl.
74. The compound of claim 6, wherein R4 is isobutyl, R5 is methyl and R6 is methyl.
75. The compound of claim 6, wherein R4 is sec-butyl, R5 is methyl and R6 is ethyl.
76. The compound of claim 6, wherein R4 is tert-butyl, R5 is methyl and R6 is ethyl.
77. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is methyl.
78. The compound of claim 6, wherein R4 is methyl, R5 is isoamyl and R6 is isoamyl.
79. The compound of claim 6, wherein R4 is isoamyl, R5 is allyl and R6 is allyl.
80. The compound of claim 6, wherein R4 is sec-hexyl, R5 is methyl and R6 is ethyl.
81. A compound of claim 2, wherein R1 and R2 are methyl and R3 is ethyl.
82. The compound of claim 81, wherein R4 is ethyl, R5 is ethyl and R6 is ethyl.
83. The compound of claim 81, wherein R4 is methyl, R5 is isobutyl and R6 is isobutyl.
84. The compound of claim 81, wherein R4 is ethyl, R5 is propyl and R6 is propyl.
85. The compound of claim 81, wherein R4 is ethyl, R5 is allyl and R6 is allyl.
86. The compound of claim 81, wherein R4 is sec-butyl, R5 is ethyl and R6 ethyl.
87. The compound of claim 81, wherein R4 is butyl, R5 is ethyl and R6 is ethyl.
88. The compound of claim 81, wherein R4 is sec-butyl, R5 is allyl and R6 is allyl.
89. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are sec-butyl.
90. The compound of claim 2, wherein R1, R3 and R4 are methyl, R2 is butyl and R5 and R6 are isobutyl.
91. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl and R4, R5 and R6 are ethyl.
92. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is tert-butyl and R5 and R6 are ethyl.
93. The compound of claim 2, wherein R1 to R6 are ethyl.
94. The compound of claim 2, wherein R1, R2, R3, R5 and R6 are ethyl and R4 is sec-butyl.
95. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are sec-butyl.
96. The compound of claim 2, wherein R1 and R3 are methyl, R2 is butyl, R4 is sec-butyl and R5 and R6 are ethyl.
97. The compound of claim 2, wherein R1 to R3 are ethyl, R4 is methyl and R5 and R6 are isobutyl.
Description:
This present invention relates to amidino ketones, especially 3-oxo-butanamidine derivatives.
The invention provides compounds of formula I, ##SPC3##
wherein
R 1 is alkyl of 1 to 4 carbon atoms, phenyl or substituted phenyl, and
R 2 is alkyl of 1 to 4 carbon atoms, or
R 1 and R 2 together are --(CH 2 ) n --, wherein n is an integer from 2 to 7,
And
R 3 is alkyl of 1 to 4 carbon atoms, or
R 1 , r 2 and R 3 together with the carbon atom to which they are bound form the adamantyl radical,
R 4 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of 1 to 5 carbon atoms, or a group of formula ##SPC4##
Wherein
R 7 and R 8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or
R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and
R 5 and R 6 are the same or different and each is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of 1 to 5 carbon atoms, or one of R 4 , R 5 and R 6 is phenyl or substituted phenyl and the others of R 4 , R 5 and R 6 are as defined above.
When in formula I R 1 or one of the substituents R 4 , R 5 and R 6 is a substituted phenyl group, the substituted phenyl group preferably is alkylphenyl, the alkyl radical having from 1 to 4 carbon atoms, especially methylphenyl, the alkyl substituent being preferably in the p position, or halophenyl, especially chlorophenyl, the halo substituent being preferably in the p position.
When R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, this is preferably a five or six membered heterocyclic ring, preferably saturated e.g., morpholine, pyrrolidine or piperazine.
Further, in accordance with the invention a compound of formula I may be obtained by a process comprising desulphurizing a compound of formula II, ##SPC5##
wherein R 1 to R 6 are as defined above.
The process according to the invention may be effected in the presence of a desulphurizing agent, preferably triaryl derivatives, trialkyl derivatives or mixed alkyl/triaryl derivatives wherein each of the alkyl groups preferably is of 1 to 4 carbon atoms, of phosphorous, arsenic, antimony or bismuth, especially, however, of phosphorus or arsenic. Especially preferred are the phosphorus derivatives. Preferred examples of desulphurizing agents are triphenylphosphine or arsine and triethyl-phosphite.
The process according to the invention may be effected in the absence of a solvent or in an inert organic solvent, e.g., dimethyl formamide, dioxane or dimethyl acetamide. However, the reaction is preferably effected in the absence of a solvent. The reaction temperature may be from 70° to 120°C. After the reaction is complete, the reaction mixture may be acidified, e.g., with an acid capable of forming a water-soluble acid addition salt form of the compound of formula I, e.g., hydrobromic acid, the residue is conveniently filtered off and the resulting acid addition salt form of the compound of formula I is conveniently isolated from the resulting reaction mixture in known manner, e.g., by concentrating by evaporation, and may be purified, e.g., by recrystallization.
Free base forms of compounds of formula I may be converted into acid addition salt form in conventional manner, and vice versa.
Examples of suitable acids for acid addition salt formation are the hydrohalic acids such as hydrochloric and hydrobromic acid, or perchloric acid, and organic acids such as oxalic acid and maleic acid.
The compounds of formula II, used as starting materials in the above process, may be obtained by reacting a reactive ester of an alcohol of formula III, ##SPC6##
wherein R 1 to R 3 are as defined above, with a compound of formula IV, ##SPC7##
wherein R 4 to R 6 are as defined above.
In the above reaction the compounds of formula IV react in their tautomeric form of formula IVa, ##SPC8##
wherein R 4 to R 6 are as defined above.
Suitable reactive esters of the alcohol of formula III, include esters of hydrohalic acids, e.g., hydrobromic or hydrochloric acid, or the tosylate. The reaction may be effected either in the absence of a solvent or in an inert organic solvent, e.g., a lower alcohol of 1 to 6 carbon atoms, acetone, or a cyclic or straight chain ether such as dioxane, tetrahydrofuran or diisopropyl ether. The reaction temperature conveniently is from 20° to 100°C. Free base forms of the resulting compounds of formula II are liberated from the acid addition salt forms in known manner, e.g., by treatment with an aqueous alkali metal hydroxide solution.
The compounds of formulae III and IV, used as starting materials in the above process, are either known or may be produced in known manner from known starting materials, for example a compound of formula IV wherein R 4 , R 5 and R 6 are alkyl may be obtained by reacting an alkylisothiocyanate with a dialkyl amine in conventional manner.
In so far as the production of the starting material is not particularly described, these compounds are known or may be produced and purified in accordance with standard procedures.
The compounds of formula I are useful because they possess pharmacological activity in animals. In particular the compounds are useful as hypoglycaemic agents as indicated by a lowering of the blood sugar content in the blood of rats on p.o. administration of from 100 to 300 mg/kg animal body weight, of the compounds, in accordance with the following test:
The compound to be tested is administered in increasing doses to groups of 5 to 10 animals. 2 hours after administration, a blood sample is taken from each animal, and the glucose content in the blood serum is established using the ferric cyanide test. The blood sugar lowering effect is determined by a comparison with a control group of 5 to 10 animals to which is administered a physiological common salt solution.
For the above mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and condition to be treated. However, in general, satisfactory results are obtained when administered at a daily dosage of from 1.5 mg to about 300 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range from about 100 to about 1,000 mg, and dosage forms suitable for oral administration comprise from about 25 mg to about 500 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
Specific Examples of daily dosages, at which satisfactory results are obtained on p.o. administration are:
i. Compound of Example 46 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.
ii. Compound of Example 14 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg; and
iii. Compound of Example 68 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.
As the free base forms of the compounds of formula I are usually oily at room temperature, the compounds are conveniently administered in pharmaceutically acceptable acid addition salt forms which have the same order of activity as the free base forms, and which are readily prepared in conventional manner. Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate. A pharmacetical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration. Aside from the usual pharmaceutical diluents or carriers, e.g., water, alcohols, natural or hardened oils and waxes, these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.
An example of a tablet composition comprises 136 mg of N 1 -butyl-N 2 ,N 2 -diallyl-4,4-dimethyl-3-oxo-pentanamidine hydrobromide, 1 mg of magnesium stearate, 4 mg of polyvinyl pyrrolidone, 0.5 mg of dimethyl silicone oil, 5 mg of talc, 10 mg of maize starch, 137.8 mg of lactose and 1.5 mg of polyethylene glycol - 6,000.
The tablets are produced in conventional manner and are provided with a double slit.
In a preferred class of compounds, R 1 , R 2 and R 3 are independently alkyl, R 4 is alkyl, alkenyl, phenyl, or substituted phenyl and R 5 and R 6 are, independently, alkyl, alkenyl, alkoxyalkyl or cyanoalkyl. More especially R 1 , R 2 and R 3 are alkyl, especially methyl, and R 4 , R 5 and R 6 are independently alkenyl especially of 3 to 4 carbon atoms or especially alkyl of 1 to 4 carbon atoms.
In another preferred class of compounds R 5 and R 6 are identical.
In another class of compounds R 1 is phenyl or substituted phenyl and R 2 is alkyl, or R 1 and R 2 together are --(CH 2 ) n -- and R 3 is alkyl, or R 1 , R 2 and R 3 together with the carbon atom to which they are bound form the adamantyl radical, R 4 is a group of formula; ##SPC9##
wherein
R 7 and R 8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or
R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and
R 5 and R 6 are phenyl or substituted phenyl.
In the following non-limitative Examples the temperatures are indicated in degrees Centigrade, room temperature is between 20° and 30°C, unless otherwise indicated. The commonly used vacuum is between 8 and 20 mm of Hg, unless otherwise indicated.
EXAMPLE 1 N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine
a. N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine
A mixture of 14.3 g of bromopinacoline, 12.8 g of N 1 ,N 2 ,N 2 -triethyl thiourea and 120 cc of acetone is heated to the boil at reflux for 8 hours. The reaction mixture is subsequently concentrated by evaporation in a vacuum. 80 cc of an aqueous 1 N sodium hydroxide solution are added to the resulting residue, and the resulting mixture is extracted with diethyl ether. The ethereal solution is dried with potassium carbonate and is subsequently concentrated by evaporation. N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine is obtained as oily residue.
b. N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine
13.5 g of the oily N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine obtained in section (a) are mixed with 13.5 g of triphenyl phosphine, and the mixture is heated in an oil bath to 120° for 6 hours in a flask provided with an upright tube. The reaction mixture is subsequently cooled and triturated with 1 N hydrobromic acid until the acid reaction is maintained. The undissolved triphenyl phosphine sulphide is filtered off and washed with water. The aqueous filtrate is extracted with diethyl ether and purified with charcoal. After the charcoal is filtered off, the aqueous filtrate is evaporated to dryness in a vacuum. After recrystallization from 2 parts by volume of isopropanol/g of compound, or from 4.5 parts by volume of acetone/g of compound, the resulting N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine hydrobromide has a M.P. of 138°-140°.
Treatment of the hydrobromide with an aqueous 2 N sodium hydroxide solution, extraction of the alkaline solution with diethyl ether and concentration by evaporation of the ethereal mixture yields oily N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine.
EXAMPLE 2 N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentanamidine.
a. N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea
A solution of 7.3 g of methyl isothiocyanate in 20 cc of benzene is added to a solution of 12.9 g of di-isobutylamine in 50 cc of benzene, and the resulting mixture is allowed to stand at 20° for 4 days. The mixture is subsequently concentrated by evaporation, and N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea, having a M.P. of 98°-100°, is obtained as residue.
b. N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethylhexanamidine hydrobromide
19.5 g of N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea are dissolved in 100 cc of acetone, and 17.3 g of bromopinacoline are added to the solution. The resulting mixture is allowed to stand at 20° for 12 hours. The mixture is subsequently heated to the boil for 4 hours, is subsequently cooled, and the resulting precipitate is filtered off. The N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethylhexanamidine hydrobromide, obtained as filter residue, has a M.P. of 202°-204°.
c. N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentanamidine
11.8 g of N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethyl-hexanamidine (obtained from the hydrobromide by treatment with caustic soda solution and extraction of the liberated base with ether) are heated to 120° for 8 hours together with 12.5 g of triphenyl arsine. The resulting melted material is neutralized with 1 N hydrobromic acid (about 28 cc). The aqueous solution is poured off and cold alcohol is added to the smeary crystalline product until the solid components are filterable. Filtration is subsequently effected. The filter residue contains about 11.6 g of a mixture of triphenyl arsine and triphenyl arsine sulphide. The filtrate is extracted with 100 cc of diethyl ether, and the aqueous solution is concentrated by evaporation in a vacuum. The evaporation residue is heated to 80° together with 150 cc of ethyl acetate, whereby after initial solution crystals are formed. Cooling is then effected to 0°, and the residue N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentamidine hydrobromide (M.P. 151°-156°) is filtered off.
The compounds of formula I, indicated in the following Tables, are obtained by using the processes exemplified in the above Examples 1 and 2 and the corresponding starting materials. The indicated melting points refer to the corresponding salt forms. The free base forms of the compounds of formula I are obtained from the salt forms in known manner, e.g., by treatment with caustic soda solution and extraction with ether.
The substituents are in the ω-position except where otherwise stated.
Example R 1 R 2 R 3 R 4 R 5 R 6 M.P. Salt ____________________________________________________________ ______________ form 3 Methyl Methyl Methyl Methyl Methyl Methyl 197-199° Bromide 4 Methyl Methyl Methyl Methyl Methyl Ethyl 174-175° Bromide 5 Methyl Methyl Methyl Methyl Ethyl Ethyl 165-167° Bromide 6 Methyl Methyl Methyl Methyl β-CH 3 O-ethyl β-CH 3 O-ethyl 130-131° Bromide 7 Methyl Methyl Methyl Methyl Propyl Propyl 175-177° Bromide 8 Methyl Methyl Methyl Methyl Isopropyl Isopropyl 160-161° Bromide 9 Methyl Methyl Methyl Methyl Allyl Allyl 88-90° Bromide 10 Methyl Methyl Methyl Methyl Butyl Butyl 119-120° Bromide 11 Methyl Methyl Methyl Methyl Isobutyl Isobutyl 155-157° Bromide 12 Methyl Methyl Methyl Ethyl MEthyl Methyl 190-192° Bromide 13 Methyl Methyl Methyl Ethyl Methyl Ethyl 144-145° Bromide 14 Methyl Methyl Methyl Ethyl β-CH 3 O-ethyl β-CH 3 O-ethyl 91-93° Oxalate 15 Methyl Methyl Methyl Ethyl Propyl Propyl 143-145° Bromide 16 Methyl Methyl Methyl Ethyl Isopropyl Isopropyl 132-134° Bromide 17 Methyl Methyl Methyl Ethyl Butyl Butyl 121-122° Bromide 18 Methyl Methyl Methyl Ethyl Isobutyl Isobutyl 160-162° Bromide 19 Methyl Methyl Methyl Ethyl Allyl Allyl 119-121° Bromide 20 Methyl Methyl Methyl Propyl Methyl Methyl 125-127° Bromide 21 Methyl Methyl Methyl Propyl Ethyl Ethyl 125-127° Bromide 22 Methyl Methyl Methyl Propyl β-CH 3 O-ethyl β-CH 3 O-ethyl 54-56° Bromide 23 Methyl Methyl Methyl Propyl Propyl Propyl 101-102° Bromide 24 Methyl Methyl Methyl Propyl Isopropyl Isopropyl 137-138° Bromide -25 Methyl Methyl Methy l Propyl Isobutyl Isobu tyl 169-170° Bro mide 26 Methyl Methyl Methyl Propyl Allyl Allyl 102-104° Oxalate 27 Methyl Methyl Methyl Isopropyl Ethyl Ethyl 151-152° Bromide 28 Methyl Methyl Methyl Isopropyl Propyl Propyl 119-120° Bromide 29 Methyl Methyl Methyl Isopropyl Isopropyl Isopropyl 171-172° Bromide 30 Methyl Methyl Methyl Isopropyl Allyl Allyl 126-128° Oxalate 31 Methyl Methyl Methyl Allyl Methyl Methyl 140-142° Bromide 32 Methyl Methyl Methyl Allyl Ethyl Ethyl 136-137° Bromide 33 Methyl Methyl Methyl Allyl Propyl Propyl 140-141° Bromide 34 Methyl Methyl Methyl Allyl Isopropyl Isopropyl 140-142° Bromide 35 Methyl Methyl Methyl Allyl Isobutyl Isobutyl 148-149° Bromide 36 Methyl Methyl Methyl Allyl Allyl Allyl 93-94° Oxalate 37 Methyl Methyl Methyl Butyl Methyl Methyl 113-114° Bromide 38 Methyl Methyl Methyl Butyl Ethyl Ethyl 117-118° Bromide 39 Methyl Methyl Methyl Butyl Propyl Propyl 79-80° Bromide 40 Methyl Methyl Methyl Butyl Isopropyl Isopropyl 130-132° Bromide 41 Methyl Methyl Methyl Butyl Butyl Butyl 78-82° Bromide 42 Methyl Methyl Methyl Butyl Allyl Allyl 80-81° Bromide 43 Methyl Methyl Methyl Isobutyl Ethyl Ethyl 192-194° Bromide 44 Methyl Methyl Methyl Isobutyl Propyl Propyl 103-104° Bromide 45 Methyl Methyl Methyl Isobutyl Allyl Allyl 96-98° Bromide 46 Methyl Methyl Methyl sec-Butyl Ethyl Ethyl 128-131° Bromide 47 Methyl Methyl Methyl sec-Butyl CH 3 O-ethyl CH 3 O-ethyl 83-84° Oxalate 48 Methyl Methyl Methyl sec-Butyl Propyl Propyl 113-114° Oxalate 49 Methyl Methyl Methyl sec-Butyl Allyl Allyl 104-105° Oxalate 50 Methyl Methyl Methyl tert-Butyl Ethyl Ethyl 138-139° Bromide 51 Methyl Methyl Methyl tert-Butyl Isopropyl Isopropyl 134-135° Bromide 52 Methyl Methyl Methyl Amyl Methyl Methyl 128-130° Bromide 53 Methyl Methyl Methyl Amyl Ethyl Ethyl 74-76° Oxalate
54 Methyl Methyl Methyl Amyl Propyl Propyl 60-61° Bromide 55 Methyl Methyl Methyl Amyl Allyl Allyl 82-84° Oxalate 56 Methyl Methyl Methyl Isoamyl Ethyl Ethyl 119-120° Bromide 57 Methyl Methyl Methyl Octyl Ethyl Ethyl 84-85° Bromide 58 Methyl Methyl Ethyl Ethyl Ethyl Ethyl 107-109° Bromide 59 Methyl Methyl Ethyl Methyl Isobutyl Isobutyl 143-145° Bromide 60 Methyl Methyl Ethyl Ethyl Propyl Propyl 125-126° Oxalate 61 Methyl Methyl Ethyl Ethyl Allyl Allyl 87-88° Oxalate 62 Methyl Methyl Ethyl sec-Butyl Ethyl Ethyl 100-102° Bromide 63 Methyl Methyl Methyl Methyl Methyl Phenyl 189-192° Bromide 64 Methyl Methyl Methyl Ethyl Ethyl Phenyl 213-216° Bromide -65 Methyl Methyl Methy l Phenyl Methyl Methyl 179-182° Bromide N 66 Methyl Methyl Methyl Phenyl Ethyl Ethyl 169-172° Bromide 67 Methyl Methyl Methyl Phenyl Propyl Propyl 181-182° Bromide 68 Methyl Methyl Methyl Phenyl Allyl Allyl 113-115° Bromide 69 Methyl Methyl Methyl p-Cl-phenyl Ethyl Ethyl 181-183° Bromide 70 Methyl Methyl Methyl p-CH 3 -phenyl Ethyl Ethyl 162-163° Bromide 71 Methyl Methyl Phenyl Ethyl Ethyl Ethyl 143-144° Bromide 72 Methyl Methyl Ethyl Butyl Ethyl Ethyl 113-114° Bromide 73 Methyl Methyl Ethyl sec-Butyl Allyl Allyl 92-93° Oxalate 74 Methyl Methyl Methyl sec-Butyl Isopropyl Isopropyl 163-164° Bromide 75 Methyl Methyl Methyl Octyl Methyl Methyl 127-128° Bromide 76 Methyl Methyl Methyl β-Methallyl Methyl Methyl 135-137° Bromide 77 Methyl Methyl Methyl β-Methallyl Ethyl Ethyl 153-155° Bromide 78 Methyl Methyl Methyl β-Methallyl Propyl Propyl 142-143° Bromide 79 Methyl Methyl Methyl Hexyl Ethyl Ethyl 90-91° Oxalate 80 Methyl Methyl Methyl Butyl Methyl Ethyl 108-109° Bromide 81 Methyl Methyl Methyl Hexyl Methyl Methyl 128-129° Bromide 82 Methyl Methyl Methyl Isobutyl Methyl Methyl 185-186° Bromide 83 Methyl Methyl Methyl sec-Butyl Methyl Ethyl 98-100° Bromide 84 Methyl Methyl Methyl tert-Butyl Methyl Ethyl 163-164° Bromide 85 Methyl Methyl Methyl sec-Hexyl Methyl Methyl 81-82° Oxalate 86 Methyl Methyl Methyl Methyl Isoamyl Isoamyl 164-165° Bromide 87 Methyl Methyl Methyl Isoamyl Allyl Allyl 74-75° Oxalate 88 Methyl Methyl Methyl sec-Hexyl Methyl Ethyl 108-110° Oxalate 89 Methyl Methyl Methyl Ethyl 2-Cyanoethyl 2-cyanoethyl 167-168° Bromide 90 Methyl Methyl Methyl sec-Butyl Methyl 2-cyanoethyl 95-96° Oxalate 90A p-CH 3 -phenyl Methyl Methyl β-CH 3 O-ethyl Ethyl Ethyl 90 B p-CH 3 -phenyl Methyl Methyl 1-piperazine Alkyl Ethyl 90 C p-CH 3 -phenyl Methyl Methyl Methyl p-CH 3 -phenyl Ethyl 90 D p-CH 3 -phenyl Methyl Methyl Methyl p-Cl-phenyl Ethyl 90 E pentamethylene Methyl sec-Butyl Methyl Methyl 90 F tetramethylene Methyl sec-Butyl Methyl Methyl 91 Methyl Methyl Methyl Dimethylamino Ethyl Ethyl 193-195° Bromide 92 Methyl Methyl Methyl Methyl sec-Butyl sec-Butyl 107-108° Oxalate 93 Methyl Butyl Methyl Methyl sec-Butyl sec-Butyl 85-86° Oxalate 94 Methyl Butyl Methyl Methyl Isobutyl Isobutyl 131-132° Oxalate 95 Methyl Butyl Methyl Ethyl Ethyl Ethyl 91-93° Bromide 96 Methyl Butyl Methyl tert.-Butyl Ethyl Ethyl 113-114° Oxalate 97 Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl 155-156° Oxalate 98 Ethyl Ethyl Ethyl sec-Butyl Ethyl Ethyl 168-170° Oxalate 99 Ethyl Ethyl Ethyl Methyl sec-Butyl sec-Butyl 151-152° Oxalate 100 Methyl Butyl
Methyl sec-Butyl Ethyl Ethyl 120° Oxalate 101 Ethyl Ethyl Ethyl Methyl Isobutyl Isobutyl 138-139° Bromide 102 Adamantyl Methyl Isobutyl Isobutyl 187-189° Bromide 103 Adamantyl Ethyl Ethyl Ethyl 240-242° Bromide ____________________________________________________________ ______________
Using the process exemplified in Example 1 or 2 and the appropriate starting materials, there are obtained the following compounds ##SPC10##
The invention provides compounds of formula I, ##SPC3##
wherein
R 1 is alkyl of 1 to 4 carbon atoms, phenyl or substituted phenyl, and
R 2 is alkyl of 1 to 4 carbon atoms, or
R 1 and R 2 together are --(CH 2 ) n --, wherein n is an integer from 2 to 7,
And
R 3 is alkyl of 1 to 4 carbon atoms, or
R 1 , r 2 and R 3 together with the carbon atom to which they are bound form the adamantyl radical,
R 4 is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof, cyanoalkyl wherein the alkyl radical is of 1 to 5 carbon atoms, or a group of formula ##SPC4##
Wherein
R 7 and R 8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or
R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and
R 5 and R 6 are the same or different and each is alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms in the aggregate thereof or cyanoalkyl wherein the alkyl is of 1 to 5 carbon atoms, or one of R 4 , R 5 and R 6 is phenyl or substituted phenyl and the others of R 4 , R 5 and R 6 are as defined above.
When in formula I R 1 or one of the substituents R 4 , R 5 and R 6 is a substituted phenyl group, the substituted phenyl group preferably is alkylphenyl, the alkyl radical having from 1 to 4 carbon atoms, especially methylphenyl, the alkyl substituent being preferably in the p position, or halophenyl, especially chlorophenyl, the halo substituent being preferably in the p position.
When R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, this is preferably a five or six membered heterocyclic ring, preferably saturated e.g., morpholine, pyrrolidine or piperazine.
Further, in accordance with the invention a compound of formula I may be obtained by a process comprising desulphurizing a compound of formula II, ##SPC5##
wherein R 1 to R 6 are as defined above.
The process according to the invention may be effected in the presence of a desulphurizing agent, preferably triaryl derivatives, trialkyl derivatives or mixed alkyl/triaryl derivatives wherein each of the alkyl groups preferably is of 1 to 4 carbon atoms, of phosphorous, arsenic, antimony or bismuth, especially, however, of phosphorus or arsenic. Especially preferred are the phosphorus derivatives. Preferred examples of desulphurizing agents are triphenylphosphine or arsine and triethyl-phosphite.
The process according to the invention may be effected in the absence of a solvent or in an inert organic solvent, e.g., dimethyl formamide, dioxane or dimethyl acetamide. However, the reaction is preferably effected in the absence of a solvent. The reaction temperature may be from 70° to 120°C. After the reaction is complete, the reaction mixture may be acidified, e.g., with an acid capable of forming a water-soluble acid addition salt form of the compound of formula I, e.g., hydrobromic acid, the residue is conveniently filtered off and the resulting acid addition salt form of the compound of formula I is conveniently isolated from the resulting reaction mixture in known manner, e.g., by concentrating by evaporation, and may be purified, e.g., by recrystallization.
Free base forms of compounds of formula I may be converted into acid addition salt form in conventional manner, and vice versa.
Examples of suitable acids for acid addition salt formation are the hydrohalic acids such as hydrochloric and hydrobromic acid, or perchloric acid, and organic acids such as oxalic acid and maleic acid.
The compounds of formula II, used as starting materials in the above process, may be obtained by reacting a reactive ester of an alcohol of formula III, ##SPC6##
wherein R 1 to R 3 are as defined above, with a compound of formula IV, ##SPC7##
wherein R 4 to R 6 are as defined above.
In the above reaction the compounds of formula IV react in their tautomeric form of formula IVa, ##SPC8##
wherein R 4 to R 6 are as defined above.
Suitable reactive esters of the alcohol of formula III, include esters of hydrohalic acids, e.g., hydrobromic or hydrochloric acid, or the tosylate. The reaction may be effected either in the absence of a solvent or in an inert organic solvent, e.g., a lower alcohol of 1 to 6 carbon atoms, acetone, or a cyclic or straight chain ether such as dioxane, tetrahydrofuran or diisopropyl ether. The reaction temperature conveniently is from 20° to 100°C. Free base forms of the resulting compounds of formula II are liberated from the acid addition salt forms in known manner, e.g., by treatment with an aqueous alkali metal hydroxide solution.
The compounds of formulae III and IV, used as starting materials in the above process, are either known or may be produced in known manner from known starting materials, for example a compound of formula IV wherein R 4 , R 5 and R 6 are alkyl may be obtained by reacting an alkylisothiocyanate with a dialkyl amine in conventional manner.
In so far as the production of the starting material is not particularly described, these compounds are known or may be produced and purified in accordance with standard procedures.
The compounds of formula I are useful because they possess pharmacological activity in animals. In particular the compounds are useful as hypoglycaemic agents as indicated by a lowering of the blood sugar content in the blood of rats on p.o. administration of from 100 to 300 mg/kg animal body weight, of the compounds, in accordance with the following test:
The compound to be tested is administered in increasing doses to groups of 5 to 10 animals. 2 hours after administration, a blood sample is taken from each animal, and the glucose content in the blood serum is established using the ferric cyanide test. The blood sugar lowering effect is determined by a comparison with a control group of 5 to 10 animals to which is administered a physiological common salt solution.
For the above mentioned use the dosage will, of course, vary depending on the compound employed, mode of administration and condition to be treated. However, in general, satisfactory results are obtained when administered at a daily dosage of from 1.5 mg to about 300 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammals, the total daily dosage is in the range from about 100 to about 1,000 mg, and dosage forms suitable for oral administration comprise from about 25 mg to about 500 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
Specific Examples of daily dosages, at which satisfactory results are obtained on p.o. administration are:
i. Compound of Example 46 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.
ii. Compound of Example 14 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg; and
iii. Compound of Example 68 from 30 to 100 mg/kg animal body weight for rats, and for the larger mammals from about 100 mg to about 1,000 mg.
As the free base forms of the compounds of formula I are usually oily at room temperature, the compounds are conveniently administered in pharmaceutically acceptable acid addition salt forms which have the same order of activity as the free base forms, and which are readily prepared in conventional manner. Representative acid addition salt forms include organic acid salt forms such as the hydrogen maleate, fumarate, tartrate and methane sulphonate and mineral acid salt forms such as the hydrochloride, hydrobromide and sulphate. A pharmacetical composition may comprise a compound of formula I, in free base form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in the form of, for example, capsules, tablets, suppositories, suspensions or solutions, for enteral or parenteral administration. Aside from the usual pharmaceutical diluents or carriers, e.g., water, alcohols, natural or hardened oils and waxes, these pharmaceutical compositions may contain suitable preserving, stabilizing, wetting, solubilizing, sweetening, flavouring or colouring agents.
An example of a tablet composition comprises 136 mg of N 1 -butyl-N 2 ,N 2 -diallyl-4,4-dimethyl-3-oxo-pentanamidine hydrobromide, 1 mg of magnesium stearate, 4 mg of polyvinyl pyrrolidone, 0.5 mg of dimethyl silicone oil, 5 mg of talc, 10 mg of maize starch, 137.8 mg of lactose and 1.5 mg of polyethylene glycol - 6,000.
The tablets are produced in conventional manner and are provided with a double slit.
In a preferred class of compounds, R 1 , R 2 and R 3 are independently alkyl, R 4 is alkyl, alkenyl, phenyl, or substituted phenyl and R 5 and R 6 are, independently, alkyl, alkenyl, alkoxyalkyl or cyanoalkyl. More especially R 1 , R 2 and R 3 are alkyl, especially methyl, and R 4 , R 5 and R 6 are independently alkenyl especially of 3 to 4 carbon atoms or especially alkyl of 1 to 4 carbon atoms.
In another preferred class of compounds R 5 and R 6 are identical.
In another class of compounds R 1 is phenyl or substituted phenyl and R 2 is alkyl, or R 1 and R 2 together are --(CH 2 ) n -- and R 3 is alkyl, or R 1 , R 2 and R 3 together with the carbon atom to which they are bound form the adamantyl radical, R 4 is a group of formula; ##SPC9##
wherein
R 7 and R 8 are the same or different and each is alkyl of 1 to 4 carbon atoms, or
R 7 and R 8 together with the nitrogen atom are a heterocyclic ring, or a heterocyclic ring having a ring oxygen atom, and
R 5 and R 6 are phenyl or substituted phenyl.
In the following non-limitative Examples the temperatures are indicated in degrees Centigrade, room temperature is between 20° and 30°C, unless otherwise indicated. The commonly used vacuum is between 8 and 20 mm of Hg, unless otherwise indicated.
EXAMPLE 1 N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine
a. N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine
A mixture of 14.3 g of bromopinacoline, 12.8 g of N 1 ,N 2 ,N 2 -triethyl thiourea and 120 cc of acetone is heated to the boil at reflux for 8 hours. The reaction mixture is subsequently concentrated by evaporation in a vacuum. 80 cc of an aqueous 1 N sodium hydroxide solution are added to the resulting residue, and the resulting mixture is extracted with diethyl ether. The ethereal solution is dried with potassium carbonate and is subsequently concentrated by evaporation. N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine is obtained as oily residue.
b. N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine
13.5 g of the oily N 1 ,N 2 ,N 2 -triethyl-5,5-dimethyl-4-oxo-2-thiahexanamidine obtained in section (a) are mixed with 13.5 g of triphenyl phosphine, and the mixture is heated in an oil bath to 120° for 6 hours in a flask provided with an upright tube. The reaction mixture is subsequently cooled and triturated with 1 N hydrobromic acid until the acid reaction is maintained. The undissolved triphenyl phosphine sulphide is filtered off and washed with water. The aqueous filtrate is extracted with diethyl ether and purified with charcoal. After the charcoal is filtered off, the aqueous filtrate is evaporated to dryness in a vacuum. After recrystallization from 2 parts by volume of isopropanol/g of compound, or from 4.5 parts by volume of acetone/g of compound, the resulting N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine hydrobromide has a M.P. of 138°-140°.
Treatment of the hydrobromide with an aqueous 2 N sodium hydroxide solution, extraction of the alkaline solution with diethyl ether and concentration by evaporation of the ethereal mixture yields oily N 1 ,N 2 ,N 2 -triethyl-4,4-dimethyl-3-oxo-pentanamidine.
EXAMPLE 2 N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentanamidine.
a. N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea
A solution of 7.3 g of methyl isothiocyanate in 20 cc of benzene is added to a solution of 12.9 g of di-isobutylamine in 50 cc of benzene, and the resulting mixture is allowed to stand at 20° for 4 days. The mixture is subsequently concentrated by evaporation, and N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea, having a M.P. of 98°-100°, is obtained as residue.
b. N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethylhexanamidine hydrobromide
19.5 g of N 2 ,N 2 -di-isobutyl-N 1 -methyl thiourea are dissolved in 100 cc of acetone, and 17.3 g of bromopinacoline are added to the solution. The resulting mixture is allowed to stand at 20° for 12 hours. The mixture is subsequently heated to the boil for 4 hours, is subsequently cooled, and the resulting precipitate is filtered off. The N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethylhexanamidine hydrobromide, obtained as filter residue, has a M.P. of 202°-204°.
c. N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentanamidine
11.8 g of N 2 ,N 2 -di-isobutyl-4-oxo-2-thia-N 1 ,5,5-trimethyl-hexanamidine (obtained from the hydrobromide by treatment with caustic soda solution and extraction of the liberated base with ether) are heated to 120° for 8 hours together with 12.5 g of triphenyl arsine. The resulting melted material is neutralized with 1 N hydrobromic acid (about 28 cc). The aqueous solution is poured off and cold alcohol is added to the smeary crystalline product until the solid components are filterable. Filtration is subsequently effected. The filter residue contains about 11.6 g of a mixture of triphenyl arsine and triphenyl arsine sulphide. The filtrate is extracted with 100 cc of diethyl ether, and the aqueous solution is concentrated by evaporation in a vacuum. The evaporation residue is heated to 80° together with 150 cc of ethyl acetate, whereby after initial solution crystals are formed. Cooling is then effected to 0°, and the residue N 2 ,N 2 -di-isobutyl-N 1 ,4,4-trimethyl-3-oxo-pentamidine hydrobromide (M.P. 151°-156°) is filtered off.
The compounds of formula I, indicated in the following Tables, are obtained by using the processes exemplified in the above Examples 1 and 2 and the corresponding starting materials. The indicated melting points refer to the corresponding salt forms. The free base forms of the compounds of formula I are obtained from the salt forms in known manner, e.g., by treatment with caustic soda solution and extraction with ether.
The substituents are in the ω-position except where otherwise stated.
Example R 1 R 2 R 3 R 4 R 5 R 6 M.P. Salt ____________________________________________________________ ______________ form 3 Methyl Methyl Methyl Methyl Methyl Methyl 197-199° Bromide 4 Methyl Methyl Methyl Methyl Methyl Ethyl 174-175° Bromide 5 Methyl Methyl Methyl Methyl Ethyl Ethyl 165-167° Bromide 6 Methyl Methyl Methyl Methyl β-CH 3 O-ethyl β-CH 3 O-ethyl 130-131° Bromide 7 Methyl Methyl Methyl Methyl Propyl Propyl 175-177° Bromide 8 Methyl Methyl Methyl Methyl Isopropyl Isopropyl 160-161° Bromide 9 Methyl Methyl Methyl Methyl Allyl Allyl 88-90° Bromide 10 Methyl Methyl Methyl Methyl Butyl Butyl 119-120° Bromide 11 Methyl Methyl Methyl Methyl Isobutyl Isobutyl 155-157° Bromide 12 Methyl Methyl Methyl Ethyl MEthyl Methyl 190-192° Bromide 13 Methyl Methyl Methyl Ethyl Methyl Ethyl 144-145° Bromide 14 Methyl Methyl Methyl Ethyl β-CH 3 O-ethyl β-CH 3 O-ethyl 91-93° Oxalate 15 Methyl Methyl Methyl Ethyl Propyl Propyl 143-145° Bromide 16 Methyl Methyl Methyl Ethyl Isopropyl Isopropyl 132-134° Bromide 17 Methyl Methyl Methyl Ethyl Butyl Butyl 121-122° Bromide 18 Methyl Methyl Methyl Ethyl Isobutyl Isobutyl 160-162° Bromide 19 Methyl Methyl Methyl Ethyl Allyl Allyl 119-121° Bromide 20 Methyl Methyl Methyl Propyl Methyl Methyl 125-127° Bromide 21 Methyl Methyl Methyl Propyl Ethyl Ethyl 125-127° Bromide 22 Methyl Methyl Methyl Propyl β-CH 3 O-ethyl β-CH 3 O-ethyl 54-56° Bromide 23 Methyl Methyl Methyl Propyl Propyl Propyl 101-102° Bromide 24 Methyl Methyl Methyl Propyl Isopropyl Isopropyl 137-138° Bromide -25 Methyl Methyl Methy l Propyl Isobutyl Isobu tyl 169-170° Bro mide 26 Methyl Methyl Methyl Propyl Allyl Allyl 102-104° Oxalate 27 Methyl Methyl Methyl Isopropyl Ethyl Ethyl 151-152° Bromide 28 Methyl Methyl Methyl Isopropyl Propyl Propyl 119-120° Bromide 29 Methyl Methyl Methyl Isopropyl Isopropyl Isopropyl 171-172° Bromide 30 Methyl Methyl Methyl Isopropyl Allyl Allyl 126-128° Oxalate 31 Methyl Methyl Methyl Allyl Methyl Methyl 140-142° Bromide 32 Methyl Methyl Methyl Allyl Ethyl Ethyl 136-137° Bromide 33 Methyl Methyl Methyl Allyl Propyl Propyl 140-141° Bromide 34 Methyl Methyl Methyl Allyl Isopropyl Isopropyl 140-142° Bromide 35 Methyl Methyl Methyl Allyl Isobutyl Isobutyl 148-149° Bromide 36 Methyl Methyl Methyl Allyl Allyl Allyl 93-94° Oxalate 37 Methyl Methyl Methyl Butyl Methyl Methyl 113-114° Bromide 38 Methyl Methyl Methyl Butyl Ethyl Ethyl 117-118° Bromide 39 Methyl Methyl Methyl Butyl Propyl Propyl 79-80° Bromide 40 Methyl Methyl Methyl Butyl Isopropyl Isopropyl 130-132° Bromide 41 Methyl Methyl Methyl Butyl Butyl Butyl 78-82° Bromide 42 Methyl Methyl Methyl Butyl Allyl Allyl 80-81° Bromide 43 Methyl Methyl Methyl Isobutyl Ethyl Ethyl 192-194° Bromide 44 Methyl Methyl Methyl Isobutyl Propyl Propyl 103-104° Bromide 45 Methyl Methyl Methyl Isobutyl Allyl Allyl 96-98° Bromide 46 Methyl Methyl Methyl sec-Butyl Ethyl Ethyl 128-131° Bromide 47 Methyl Methyl Methyl sec-Butyl CH 3 O-ethyl CH 3 O-ethyl 83-84° Oxalate 48 Methyl Methyl Methyl sec-Butyl Propyl Propyl 113-114° Oxalate 49 Methyl Methyl Methyl sec-Butyl Allyl Allyl 104-105° Oxalate 50 Methyl Methyl Methyl tert-Butyl Ethyl Ethyl 138-139° Bromide 51 Methyl Methyl Methyl tert-Butyl Isopropyl Isopropyl 134-135° Bromide 52 Methyl Methyl Methyl Amyl Methyl Methyl 128-130° Bromide 53 Methyl Methyl Methyl Amyl Ethyl Ethyl 74-76° Oxalate
54 Methyl Methyl Methyl Amyl Propyl Propyl 60-61° Bromide 55 Methyl Methyl Methyl Amyl Allyl Allyl 82-84° Oxalate 56 Methyl Methyl Methyl Isoamyl Ethyl Ethyl 119-120° Bromide 57 Methyl Methyl Methyl Octyl Ethyl Ethyl 84-85° Bromide 58 Methyl Methyl Ethyl Ethyl Ethyl Ethyl 107-109° Bromide 59 Methyl Methyl Ethyl Methyl Isobutyl Isobutyl 143-145° Bromide 60 Methyl Methyl Ethyl Ethyl Propyl Propyl 125-126° Oxalate 61 Methyl Methyl Ethyl Ethyl Allyl Allyl 87-88° Oxalate 62 Methyl Methyl Ethyl sec-Butyl Ethyl Ethyl 100-102° Bromide 63 Methyl Methyl Methyl Methyl Methyl Phenyl 189-192° Bromide 64 Methyl Methyl Methyl Ethyl Ethyl Phenyl 213-216° Bromide -65 Methyl Methyl Methy l Phenyl Methyl Methyl 179-182° Bromide N 66 Methyl Methyl Methyl Phenyl Ethyl Ethyl 169-172° Bromide 67 Methyl Methyl Methyl Phenyl Propyl Propyl 181-182° Bromide 68 Methyl Methyl Methyl Phenyl Allyl Allyl 113-115° Bromide 69 Methyl Methyl Methyl p-Cl-phenyl Ethyl Ethyl 181-183° Bromide 70 Methyl Methyl Methyl p-CH 3 -phenyl Ethyl Ethyl 162-163° Bromide 71 Methyl Methyl Phenyl Ethyl Ethyl Ethyl 143-144° Bromide 72 Methyl Methyl Ethyl Butyl Ethyl Ethyl 113-114° Bromide 73 Methyl Methyl Ethyl sec-Butyl Allyl Allyl 92-93° Oxalate 74 Methyl Methyl Methyl sec-Butyl Isopropyl Isopropyl 163-164° Bromide 75 Methyl Methyl Methyl Octyl Methyl Methyl 127-128° Bromide 76 Methyl Methyl Methyl β-Methallyl Methyl Methyl 135-137° Bromide 77 Methyl Methyl Methyl β-Methallyl Ethyl Ethyl 153-155° Bromide 78 Methyl Methyl Methyl β-Methallyl Propyl Propyl 142-143° Bromide 79 Methyl Methyl Methyl Hexyl Ethyl Ethyl 90-91° Oxalate 80 Methyl Methyl Methyl Butyl Methyl Ethyl 108-109° Bromide 81 Methyl Methyl Methyl Hexyl Methyl Methyl 128-129° Bromide 82 Methyl Methyl Methyl Isobutyl Methyl Methyl 185-186° Bromide 83 Methyl Methyl Methyl sec-Butyl Methyl Ethyl 98-100° Bromide 84 Methyl Methyl Methyl tert-Butyl Methyl Ethyl 163-164° Bromide 85 Methyl Methyl Methyl sec-Hexyl Methyl Methyl 81-82° Oxalate 86 Methyl Methyl Methyl Methyl Isoamyl Isoamyl 164-165° Bromide 87 Methyl Methyl Methyl Isoamyl Allyl Allyl 74-75° Oxalate 88 Methyl Methyl Methyl sec-Hexyl Methyl Ethyl 108-110° Oxalate 89 Methyl Methyl Methyl Ethyl 2-Cyanoethyl 2-cyanoethyl 167-168° Bromide 90 Methyl Methyl Methyl sec-Butyl Methyl 2-cyanoethyl 95-96° Oxalate 90A p-CH 3 -phenyl Methyl Methyl β-CH 3 O-ethyl Ethyl Ethyl 90 B p-CH 3 -phenyl Methyl Methyl 1-piperazine Alkyl Ethyl 90 C p-CH 3 -phenyl Methyl Methyl Methyl p-CH 3 -phenyl Ethyl 90 D p-CH 3 -phenyl Methyl Methyl Methyl p-Cl-phenyl Ethyl 90 E pentamethylene Methyl sec-Butyl Methyl Methyl 90 F tetramethylene Methyl sec-Butyl Methyl Methyl 91 Methyl Methyl Methyl Dimethylamino Ethyl Ethyl 193-195° Bromide 92 Methyl Methyl Methyl Methyl sec-Butyl sec-Butyl 107-108° Oxalate 93 Methyl Butyl Methyl Methyl sec-Butyl sec-Butyl 85-86° Oxalate 94 Methyl Butyl Methyl Methyl Isobutyl Isobutyl 131-132° Oxalate 95 Methyl Butyl Methyl Ethyl Ethyl Ethyl 91-93° Bromide 96 Methyl Butyl Methyl tert.-Butyl Ethyl Ethyl 113-114° Oxalate 97 Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl 155-156° Oxalate 98 Ethyl Ethyl Ethyl sec-Butyl Ethyl Ethyl 168-170° Oxalate 99 Ethyl Ethyl Ethyl Methyl sec-Butyl sec-Butyl 151-152° Oxalate 100 Methyl Butyl
Methyl sec-Butyl Ethyl Ethyl 120° Oxalate 101 Ethyl Ethyl Ethyl Methyl Isobutyl Isobutyl 138-139° Bromide 102 Adamantyl Methyl Isobutyl Isobutyl 187-189° Bromide 103 Adamantyl Ethyl Ethyl Ethyl 240-242° Bromide ____________________________________________________________ ______________
Using the process exemplified in Example 1 or 2 and the appropriate starting materials, there are obtained the following compounds ##SPC10##