Claims
- 1. A substituted alkylamine derivative represented by the formula (I) ##STR23## wherein R.sup.1 is selected from the group consisting of
- a) a C.sub.2-6 alkenyl group, or a C.sub.2-6 alkenyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
- b) a C.sub.5-7 cycloalkenyl group, or a C.sub.5-7 cycloalkenyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
- c) a C.sub.2-6 alkynyl group, or a C.sub.2-6 alkynyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
- d) an aryl group, or an aryl group substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-2 halogenalkyl group, a C.sub.1-2 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group or a C.sub.3-5 alkenyloxy group,
- e) a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, primidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, osoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group, said heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group,
- f) a fused heterocyclic group selected from the group consisting of a benzo[b]furanyl, a benzo[b]thienyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group and an isoquinolyl group, said fused heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-2 halogenalkyl group a C.sub.1-2 hydroxyalkyl group,a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group, and
- g) the group represented by the formula ##STR24## wherein R.sup.11 is a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, primidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4=dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group; and
- R.sup.12 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
- p.sup.1 is 0 or 1;
- A.sup.1 is CH, N, O or S;
- B.sup.1 is CH, N, O or S;
- D.sup.1 is CH, N, O or S;
- E.sup.1 is CH, N, O or S;
- provided that no more than 2 of B.sup.1, D.sup.1 and E.sup.1 can be simultaneously N, O or S;
- R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group;
- R.sup.3 is a hydrogen atom, a C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, or a C.sub.3-6 cycloalkyl group;
- R.sup.4 and R.sup.5 may be the same or different and each is a hydrogen atom, or a halogen atom;
- R.sup.6 is selected from the group consisting of a) a C.sub.1-17 acyclic hydrocarbon group, or a C.sub.1-17 acyclic hydrocarbon group substituted by a hydroxy group, a halogen atom, a C.sub.3-6 cycloalkyl group, a C.sub.1-4 alkoxy group, a phenyl group, or a phenyl group substituted by a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group,
- in which said acyclic hydrocarbon group may contain 1 or 2 unsaturated bonds selected from the group consisting of double and triple bonds,
- b) a C.sub.3-6 cycloalkyl group, or a C.sub.3-6 cycloalkyl group substituted by a hydroxy group, a halogen atom, a C.sub.1-4 alkoxy group, a phenyl group, or a phenyl group substituted by a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group, and
- c) a phenyl group, or a phenyl group substituted by a hydroxyl group, a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
- R.sup.7 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
- p is 1;
- A is CH;
- B is CH;
- D is CH;
- E is CH;
- X and Y are independently O, S, CO, CHR.sup.a or NR.sup.b, or X--Y is --CH.dbd.CH-- or --C.tbd.C, in which
- R.sup.a is a hydrogen atom or a C.sub.1-6 alkyl group; and
- R.sup.b is a hydrogen atom or a C.sub.1-6 alkyl group;
- provided that, when one of X and Y is O, S or NR.sup.b, the other is CO or CHR.sup.a ;
- and, further, provided that the rings ##STR25## are aromatic rings, or a non-toxic salt thereof.
- 2. The substituted alkylamine derivative according to claim 1, wherein X--Y is OCH.sub.2, CH.sub.2 O, CH.sub.2 CH.sub.2, NHCH.sub.2, CH.sub.2 NH, SCH.sub.2, CH.sub.2 S, ##STR26## CH.dbd.CH or C.tbd.C.
- 3. The substituted alkylamine derivative according to claim 1, wherein R.sup.1 is the group represented by the formula ##STR27## wherein R.sup.11 is a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl groups;
- R.sup.12 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
- p.sup.1 is 0 or 1;
- A.sup.1 is CH, N, O or S;
- B.sup.1 is CH, N, O or S;
- D.sup.1 is CH, N, O or S;
- E.sup.1 is CH, N, O or S;
- provided that less than 2 of B.sup.1, D.sup.1 and E.sup.1 can be simultaneously N, O or S;
- R.sup.6 is the group represented by the formula ##STR28## wherein R.sup.8 and R.sup.9 are independently a C.sub.1-6 alkyl group, or they represent groups which when taken together, form a C.sub.3-6 cycloalkane together with the adjoining carbon atom;
- R.sup.10 is a hydrogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group.
- 4. The substituted alkylamine derivative according to claim 3, wherein X--Y is OCH.sub.2, CH.sub.2 O, CH.sub.2 CH.sub.2, NHCH.sub.2, CH.sub.2 NH, SCH.sub.2, CH.sub.2 S, ##STR29## CH.dbd.CH or C.tbd.C.
- 5. The substituted alkylamine derivative according to claim 3, wherein at least one of A.sup.1, B.sup.1, D.sup.1, and E.sup.1 is N, O or S; p is 0 or 1; and X--Y is OCH.sub.2, CH.sub.2 O, CH.sub.2 CH.sub.2, NHCH.sub.2, CH.sub.2 NH, SCH.sub.2, CH.sub.2 S, ##STR30## CH.dbd.CH or C.tbd.C.
- 6. The substituted alkylamine derivative according to claim 3, wherein ##STR31## forms a thiophene, oxazole, isoxazole, thiazole, pyridine or pyrimidine ring; and X--Y is OCH.sub.2, CH.sub.2 O, CH.sub.2 CH.sub.2, NHCH.sub.2, CH.sub.2 NH, SCH.sub.2, CH.sub.2 S, ##STR32## CH.dbd.CH, or C.tbd.C.
- 7. The substituted alkylamine derivative according to claim 3, wherein each or both of R.sup.7 and R.sup.12 are hydrogen atoms.
- 8. The substituted alkylamine derivative of claim 10, wherein ##STR33## represents a thiophene ring.
- 9. The substituted alkylamine derivative of claim 8, wherein X--Y represents CH.sub.2 O.
- 10. (E)-N-(6,6-dimethyl-2-heptene-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl-methyloxy]benzylamine, or a non-toxic salt thereof.
- 11. The compound of claim 10 in the form of its hydrochloride.
- 12. The substituted alkylamine derivative of claim 1, wherein R.sup.1 represents a thienyl moiety substituted by a hydroxyl group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyl alkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, a C.sub.3-5 alkynyloxy group, or a heterocyclic group, wherein said heterocyclic group is selected from the group consisting of
- a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group;
- with the proviso that when the thienyl group is substituted by said heterocyclic group, the heterocyclic group may also optionally be substituted by a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group, or a C.sub.1-4 alkoxy group.
- 13. The substituted alkylamine derivative of claim 12, wherein X--Y represents CH.dbd.CH, CH.tbd.C, CH.sub.2 O or CH.sub.2 NH, R.sup.2 represents a hydrogen atom, R.sup.3 represents methyl, ethyl, propyl, allyl, propargyl, or cyclopropyl, R.sup.4 and R.sup.5 each represent a hydrogen atom and R.sup.6 represents --CH.dbd.CH--R.sup.c or --C.tbd.C--R.sup.c, wherein R.sup.c represents a C.sub.3-6 alkyl group, a C.sub.3-6 alkenyl group, or C.sub.3-6 cycloalkyl group wherein the alkyl and alkenyl groups may be substituted by a lower alkoxy group having 1 to 4 carbon atoms, and the cycloalkyl group may be substituted by an alkyl group having 1 to 4 carbon atoms.
- 14. A pharmaceutical preparation comprising an effective amount of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
- 15. The pharmaceutical preparation of claim 14 comprising a squalene epoxidase inhibiting effective amount of the substituted alkylamine derivative of formula (I) wherein ##STR34## represents a thienyl group, or a pharmaceutically acceptable salt thereof.
- 16. The pharmaceutical preparation of claim 14 wherein the compound of general formula (I) is (E)--N-(6,6-dimethyl-2-heptene-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl-methyloxy]benzylamine, or a non-toxic salt thereof.
- 17. A method of treating hypercholesterolemia, hyperlipemia or arteriosclerosis in an individual in need of such treatment which comprises administering to said individual a therapeutically effective amount of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
- 18. The method of claim 17 wherein in said compound of general formula (I), ##STR35## represents a thienyl group.
- 19. The method of claim 17 wherein said compound of general formula (I) is (E)--N-(6,6-dimethyl-2-heptene-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl-methoxy]benzylamine, or a non-toxic salt thereof.
Priority Claims (4)
| Number |
Date |
Country |
Kind |
| 62-299584 |
Nov 1987 |
JPX |
|
| 63-96286 |
Apr 1988 |
JPX |
|
| 63-113310 |
May 1988 |
JPX |
|
| 63-285381 |
Nov 1988 |
JPX |
|
Parent Case Info
This application is a continuation-in-part of copending applications Ser. No. 533,532, filed Jun. 5, 1990 which is CIP of Ser. No. 465,209, filed Mar. 8, 1990; and a CIP of Ser. No. 274,972 filed Nov. 22, 1988; all abandoned, and priority is claimed therefrom.
The disclosure of each of these application Ser. No. 533,532, Ser. No. 465,209, and Ser. No. 274,972, are incorporated herein, in their entirety, by reference thereto.
This invention relates to novel substituted alkylamine derivatives. More specifically, it relates to substituted alkylamine derivatives and their salts which are useful as pharmaceuticals, particularly for the treatment and prevention of hypercholesterolemia, hyperlipemia and arteriosclerosis, processes for production thereof, and their use.
Arteriosclerosis is a degenerative arterial disease which has closely to do with aging and diet, and is regarded as the cause of coronary and cerebral arterial diseases, the principal cause of death in the present day. Arteriosclerosis begins in early ages as deposition of lipid on the endothelia of large vessels, and with age, its degree increases. It will finally show clinical symptoms as ischemic heart diseases such as myocardial infarction and angina pectoris, cerebral arteriosclerosis such as cerebral infarction, and aneurism. It is known that the increase of various blood lipids is involved in this lipid deposition. In particular, the increase of blood cholesterol is the most prominent risk factor, and decreasing the blood cholesterol level to a normal value is the most effective therapeutic and prophylactic means against arteriosclerosis. It is said that in humans, more than 50% of cholesterol is derived from de novo biosynthesis. Nowadays, lovastatin and eptastatin which are inhibitors of enzymes in the process of de novo biosynthesis are clinically used as hypocholesterolemic agents (see, for example, A. W. Alberts et al., Proc. Natl. Acad. Sci., vol. 77, page 3957 (1980); and Tsujita et al., Biochim Biophs. Acta, vol. 877, page 50, 1986). However, since 3-hydroxy-3-methyl glutaryl-coenzyme A reductase, a target enzyme of these inhibitors, is positioned in the early stage of the cholesterol biosynthesis pathway, the administration of these drugs will also inhibit formation of dolichol and ubiquinone which are other biologically important metabolites. Furthermore, it was reported that triparanol, an inhibitor of the later stage of the cholesterol biosynthesis pathway, becomes the cause of cataract due to the accumulation of desmosterol. Since squalene epoxidase is positioned in the middle stage of the cholesterol biosynthesis pathway, an inhibitor of this enzyme is expected to solve these problems and serve as a hypocholesterolemic agent with high safety.
Some compounds have already been known as inhibitors of squalene epoxidase [see G. Petranyi et al., Science, vol. 224, page 1239 (1984)]. All of these, however, were developed as antimycotic agents which inhibit fungal squalene epoxidase selectively. No inhibitor has been known which inhibits mammalian enzyme and has utility as an hypocholesterolemic agent.
It is a primary object of this invention to provide an hypolipemic agent, and a therapeutic and prophylactic agent for arteriosclerosis which is safer and better than conventional hypolipemic agents.
The present inventors investigated squalene epoxidase inhibitors having hypocholesterolemic activity in order to develop a novel antiarteriosclerotic agent, and have found that substituted alkylamine derivatives of general formula [I] given below selectively inhibit squalene epoxidase of mammals, and have strong hypocholesterolemic activity.
Thus, the present invention provides substituted alkylamine derivatives represented by the general formula ##STR3## Wherein
R.sup.1 is selected from the group consisting of
a) a C.sub.2-6 alkenyl group, or a C.sub.2-6 alkenyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
b) a C.sub.5-7 cycloalkenyl group, or a C.sub.5-7 cycloalkenyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
c) a C.sub.2-6 alkynyl group, or a C.sub.2-6 alkynyl group substituted by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group,
d) an aryl group, or an aryl group substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group,
e) a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group, said heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group,
f) a fused heterocyclic group selected from the group consisting of a benzo [b] furanyl, a benzo [b] thienyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group and an isoquinolyl group, said fused heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group, and
g) a group represented by the formula ##STR4## wherein
R.sup.11 is a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group;
R.sup.12 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
p.sup.1 is 0 or 1;
A.sup.1 is CH, N, O or S;
B.sup.1 is CH, N, O or S;
D.sup.1 is CH, N, O or S;
E.sup.1 is CH, N, O or S;
provided that no more than 2 of B.sup.1, D.sup.1 and E.sup.1 can be simultaneously N, O or S;
R.sup.2 is a hydrogen atom or a C.sub.1-6 alkyl group;
R.sup.3 is a hydrogen atom, a C.sub.1-6 alkyl group, C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, or a C.sub.3-6 cycloalkyl group;
R.sup.4 and R.sup.5 may be the same or different and each is a hydrogen atom, or a halogen atom;
R.sup.6 is selected from the group consisting of
a) a C.sub.1-17 acyclic hydrocarbon group, or a C.sub.1-17 acyclic hydrocarbon group substituted by a hydroxy group, a halogen atom, a C.sub.3-6 cycloalkyl group, a C.sub.1-4 alkoxy group, a phenyl group, or a phenyl group substituted by a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group,
in which said acyclic hydrocarbon group may contain 1 or 2 unsaturated bonds selected from the group consisting of double and triple bonds,
b) a C.sub.3-6 cycloalkyl group, or a C.sub.3-6 cycloalkyl group substituted by a hydroxy group, a halogen atom, a C.sub.1-4 alkoxy group, a phenyl group, or a phenyl group substituted by a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group, and
c) a phenyl group, or a phenyl group substituted by a hydroxyl group, a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group;
R.sup.7 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C.sub.1-6 alkyl group or a
C.sub.1-4 alkoxy group;
p is 0 or 1;
A is CH, N, O or S;
B is CH, N, O or S;
D is CH, N, O or S;
E is CH, N, O or S;
provided that no more than 2 of B, D and E can be simultaneously N, O or S; and
X and Y are independently O, S, CO, CHR.sup.a or NR.sup.b, or X-Y is --CH.dbd.CH-- or --C.dbd.C--, in which
R.sup.a is a hydrogen atom or a C.sub.1-6 alkyl group; and
R.sup.b is a hydrogen atom or a C.sub.1-6 alkyl group;
provided that, when one of X and Y is O, S or NR.sup.b, the other is CO or CHR.sup.a ; and, further, provided that the rings ##STR5## are aromatic rings,
nontoxic salts of these, processes for production thereof, and the use thereof in the treatment of hypercholesterolemia, hyperlipemia and arteriosclerosis.
The invention will be described below in more detail.
It has previously been known that allylamine derivatives typified by naftifine and terbinafine represented by the following structural formulae ##STR6## show strong inhibiting activity on the fungal squalene epoxidase, and therefore are useful as an antifungal agent (see G. Petranyi et al., Science, vol. 224, page 1239 (1984). However, these compounds hardly show an inhibitory action on the mammalian squalene epoxidase including human squalene epoxidase, and cannot be inhibitors of cholesterol biosynthesis (see N. S. Ryder et al., Biochem J., vol. 230, page 765 (1985)
The present inventors extensively made investigations in order to develop a drug which selectively acts on the mammalian squalene epoxidase and shows anticholesterol activity, and have found that if a 1,3-substituted 5- or 6-membered aromatic ring of the formula ##STR7## wherein A, B, D, E, R.sup.7 and p are as defined above, in which its 3-position is substituted by a group of the formula R.sup.1 -X-Y- (R.sup.1, X and Y are as defined above) is substituted for the naphthalene ring moiety of the naftifine and terbinafine, a compound showing strong inhibitory activity on the mammalian squalene epoxidase can be obtained.
The inventors have also found that the squalene epoxidase inhibitory activity of the compounds of general formula [I] is very selective, and these compounds show little activity on the enzymes of fungi and are very valuable as drugs for treatment or prevention of hypercholesterolemia, hyperlipemia and arteriosclerosis.
Now, the definitions and specific examples of the various terms mentioned in the description of this specification will be explained.
The C.sub.1-6 alkyl group may be, for example, a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl groups. The C.sub.2-6 alkenyl group may be, for example, a linear or branched alkenyl group of 2 to 6 carbons containing 1 or 2 double bonds in the carbon chain, such as vinyl, 1-propenyl, isopropenyl, allyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1-butenyl, 3-methyl-1,3-butadienyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 3-methyl-2-pentenyl, 1-hexenyl and 2-hexenyl groups. The C.sub.2-6 alkynyl group may be, for example, a linear or branched alkynyl group of 2 to 6 carbon atoms containing 1 or 2 triple bonds in the carbon chain, such as ethynyl, 1-propynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl- 1-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1,3-pentadiynyl, 1-ethynyl-2-propynyl, 4-methyl-2-pentynyl and 2-hexynyl groups.
The C.sub.1-4 alkoxy group may be, for example, a linear or branched alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups. The lower alkenyloxy group includes linear or branched alkenyloxy groups having 3 to 6 carbon atoms such as 2-propenyloxy, 2-methyl-2-propenyloxy, 2-methyl-2-butenyloxy and 3-methyl-2-butenyloxy groups. Examples of the C.sub.3-6 cycloalkyl groups are cycloalkyl groups having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Examples of the cycloalkenyl groups are cycloalkenyl groups of 5 to 7 carbon atoms containing 1 or 2 double bonds in the ring, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 2,4-cyclopentadienyl, 1-cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and 1-cycloheptenyl groups.
Examples of the aryl group include monocyclic or polycyclic aromatic groups such as phenyl, naphthyl and tetrahydronaphthyl groups.
The halogen atoms may be, for example, fluorine, chlorine, bromine or iodine.
The C.sub.1-6 halogenoalkyl group may be, for example, a linear or branched halogenoalkyl group such as chloromethyl, 2-chloroethyl, 3-chloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-chlorobutyl, 2-chloropentyl and 3-chlorohexyl. The C.sub.1-6 hydroxyalkyl group may be, for example, a linear or branched hydroxyalkyl group such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-hydroxy-1-methyl propyl and 2-hydroxy-1-methylethyl.
The C.sub.1-17 acyclic hydrocarbon group which may contain 1 or 2 unsaturated bond selected from double and triple bonds may be, for example, a C.sub.1 -C.sub.17, preferably C.sub.3 -C.sub.12, linear or branched saturated hydrocarbon group, or a C.sub.1 -C.sub.17, preferably C.sub.3 -C.sub.12, linear or branched unsaturated hydrocarbon group having 1 or 2 double bonds and/or triple bonds. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 2,4,4-trimethylpentyl, heptyl, octyl, nonyl, decanyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, vinyl, ethynyl, allyl, isopentenyl, 1-pentenyl, propargyl, 1-propynyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-1-butenyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-1-butynyl, 4,4-dimethyl-1-pentenyl, 4,4-dimethyl-1-pentynyl, 3-ethyl-1-pentenyl, 3-ethyl-1-pentenyl, 4-ethyl-1-hexenyl, 4-ethyl-1-hexynyl, 1,1-dimethyl-2-hexenyl, 1,1,4,4-tetramethyl-2-pentenyl, 1,1,4,4-tetramethyl-2-pentynyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 1,3-pentadienyl, 4-penten-2-ynyl, 3-penten-2-ynyl, 3-methyl-3-buten-1-ynyl, 5,5-dimethyl-1,3-hexadienyl and 5,5-dimethyl-3-hexen-1-ynyl groups.
The C.sub.3-6 cycloalkane may be, for example, cyclopropane, cyclobutane, cyclopentane and cyclohexane.
In order to disclose the compounds of the invention represented by general formula [I] more specifically, the various symbols used in formula [I] will be explained in detail by citing preferred examples.
The C.sub.2-6 alkenyl group R.sup.1 which may be substituted is a linear or branched lower alkenyl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a C.sub.1-4 alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group. Preferably, it may be an unsubstituted lower alkenyl group such as vinyl, allyl, 1-propenyl, isopropenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-2-pentenyl, 1-hexenyl and 2-hexenyl groups; or a substituted lower alkenyl group such as 2-fluoro-2-propenyl, 2-chloro-2-propenyl, 2-bromo-2-propenyl, 2,3-dichloro-2-propenyl, 1,1-difluoro-2-propenyl, 3-fluoro-2-butenyl, 3-chloro-2-butenyl, 3-hydroxy-1-propenyl, 2-cyanoethenyl, 3-cyano-2-propenyl, 3-methoxy-1-propenyl, 3-methoxy-1-butenyl, 4-methoxy-2-butenyl, 4-methoxy-3-methyl-2-butenyl, 3-methoxy-1-vinyl-1-butenyl, 3-methoxy-2-methyl-1-vinyl-1-butenyl, styryl, cinnamyl, 2-(2-furyl)ethenyl, 2-(3-furyl)ethenyl, 3-(2-furyl)-2-propenyl, 4-phenyl-1,3-butadienyl, alpha-methylenecinnamyl, alpha-ethylidenecinnamyl, 1,1-dimethyl-3-phenyl2-propenyl, beta-methyl-alpha-methylenecinnamyl, 4-(2-furyl)- 1,2-butadienyl, 4-(3-furyl)-1,3-butadienyl, 3-(2-furyl)-1-methylene-2-propenyl, 3-(3-furyl)-1-methylene-2-propenyl, 2-(2-oxazolyl)ethenyl, 2-(5-oxazolyl)ethenyl, 2-(2-thiazolyl)ethenyl, 2-(4-thiazolyl)ethenyl and 2-(5-thiazolyl)ethenyl groups.
Examples of especially preferred lower substituted alkenyl groups R.sup.1 include unsubstituted alkenyl groups of 3 to 5 carbon atoms, such as 1-propenyl, isopropenyl, 1-methyl-1-propenyl, 2-methylpropenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-butenyl and 2-methyl-1-butenyl groups.
The C.sub.5-7 cycloalkenyl group R.sup.1 which may be substituted is a cycloalkenyl group which may be substituted by, for example, a hydroxyl group, a halogen atom, a cyano group, a lower alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group. Specific examples include 1-cyclopentenyl, 2-cyclohexenyl, 1,4-cyclohexadienyl, 2-methyl-1-cyclopentenyl, 2-methyl-1-cyclohexenyl, 3-hydroxy-1-cyclohexenyl, 3-methoxy-1-cyclohexenyl, 2-fluoro-1-cyclopentenyl, 2-chloro-1-cyclopentenyl, 2-fluoro-1-cyclohexenyl, 2-chloro-1-cyclohexenyl, 2-cyano-1-cyclohexenyl, 4-methoxy-1,3-cyclohexadienyl, 2-(2-furyl)-1-cyclohexenyl, 2-phenyl-1-cyclohexenyl, 3-(2-furyl)-2-cyclohexenyl, 3-phenyl-1-cyclohexenyl, 2-(5-oxazolyl)-1-cyclohexenyl, 2-(2-thiazolyl)-1-cyclohexenyl, and 2-(5-thiazolyl)-1-cyclohexenyl groups.
The C.sub.2-6 alkynyl group R.sup.1 which may be substituted may be a lower alkynyl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, an aryl group, a furyl group, an oxazolyl group or a thiazolyl group. Specific preferred examples include substituted or unsubstituted lower alkynyl groups such as ethynyl, 1-propynyl, propargyl, 1-butynyl, 2-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 1-pentynyl, 2-pentynyl, 2-phenylethynyl, 2-(2-furyl)ethynyl, 2-(5-oxazolyl)ethynyl, 2-(5-thiazolyl)ethynyl and 3-methoxy-3-methyl-1-butynyl.
The aryl group R.sup.1 which may be substituted may be an aryl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a halogenoalkyl group having 1 or 2 carbon atoms such as a trifluoromethyl or 2,2,2-trifluoroethyl group, a hydroxyalkyl group having 1 or 2 carbon atoms such as a hydroxymethyl or 1-hydroxyethyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, a linear or branched C.sub.3-5 alkenyloxy group having 3 to 5 carbon atoms such as a 2-propenyloxy, 2-methyl-2-propenyloxy or 3-methyl-2-butenyloxy group. Examples of preferred aryl groups R.sup.1 include unsubstituted aryl groups such as phenyl, 1-naphthyl and 2-naphthyl groups; and substituted phenyl groups such as 2-hydroxyphenyl, 3-hydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2,6-difluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-formylphenyl, 3-formylphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 2-propylphenyl, 2,3-dimethylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 3-propoxyphenyl, 3-isopropoxyphenyl, 3-butoxyphenyl, 3-isobutoxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 2-trifluoromethylphenyl, 3-tri fluoromethylphenyl, 2-vinylphenyl, 3-vinylphenyl, 3-allylphenyl, 3-isopropenylphenyl, 3-(1-propenyl)phenyl, 3-(2-methyl-1-propenyl)phenyl, 3-(2-methyl-2-propenyl)phenyl, 3-(1-butenyl)phenyl, 3-(2-butenyl)phenyl, 3-(2-methyl-1-butenyl)phenyl, 3-(3-methyl-1-butenyl)phenyl, 3-(1-pentenyl)phenyl, 3-(2-pentenyl)phenyl, 3-(1,3-butadienyl)phenyl, 3-(1-vinyl-1-propenyl)phenyl, 2-allyloxyphenyl, 3-allyloxyphenyl, 3-(2-methyl-2-propenyloxy)phenyl, 3-(3-methyl-2-butenyloxy)phenyl.
The heterocyclic group R.sup.1 is a heterocyclic group selected from the group consisting of a pyrrolyl, furyl, thienyl, oxazoly, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl and thiomorpholinyl group, said heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group or a C.sub.3-5 alkenyloxy group.
Examples of preferred heterocyclic groups include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-oxazoly, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-2-furyl, 3-chloro-2-furyl, 2-chloro-3-furyl, 3-fluoro-2-furyl, 5-chloro-2-furyl, 4-cyano-2-furyl, 5-cyano-2-furyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 4-cyano-2thienyl, 5-cyano-2-thienyl, 4-methyl-2-oxazolyl, 5-methyl-2-oxazolyl, 5-methyl-4-oxazolyl, 4-methyl-5-oxazolyl, 5-cyano-2-oxazolyl, 2-cyano-5-oxazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 5-cyano-2-thiazolyl, 2-cyano-5-thazolyl, 5-methyl-3-isoxazolyl, 3-methyl-5-isoxazolyl, 5-cyano-3-isoxazolyl, 3-cyano-5-isoxazolyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 2-chloro-3-pyridyl, 4-chloro-3-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 2-chloro-4-pyridyl, 6-methoxy-2pyridyl, 2-methoxy-3-pyridyl, 4-methoxy-3-pyridyl, 2-methoxy-4-pyridyl, 4-cyano-2-pyridyl, 6-cyano-2-pyridyl, 2-cyano-4-pyridyl. Preferred among them are 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3- Cisoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl and 4-pyrimidinyl groups; and 5-membered substituted aromatic heterocyclic groups such as 5-chloro-2-furyl, 2-chloro-3-furyl, 3-methyl-2-furyl, 2-methyl-3-furyl, 4-methyl-3-furyl, 5-methyl-2-furyl, 5-cyano-2-furyl, 4-cyano-2-furyl, 3-methyl-2-thienyl, 2-methyl-3 -thienyl, 5-methyl-2-thienyl, 4-cyano-2-thienyl, 5-cyano-2-thienyl, 2-chloro-4-oxazolyl, 2-chloro-5-oxazolyl, 4-methyl-2-oxazolyl, 5-methyl-2-oxazolyl, 2-methyl-4-oxazolyl, 5-methyl-4-oxazolyl, 2-methyl-5-oxazolyl, 4-methyl-5-oxazolyl, 5-cyano-2-oxazolyl, 2-cyano-5-oxazolyl, 2-chloro-4-thiazolyl, 2-chloro-5-thiazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 5-cyano-2-thiazolyl, 2-cyano-5-thiazolyl, 5-methyl-3isoxazolyl, 3-methyl-5-isoxazolyl, 5-cyano-3-isoxazolyl and 3-cyano-5-isoxazolyl.
The fused heterocyclic group R.sup.1 is a fused heterocyclic group selected from the group consisting of a benzo [b] furanyl group, a benzo [b] thienyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group and an isoquinolyl group, said fused heterocyclic group being optionally substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group a C.sub.1-6 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group, or a C.sub.3-5 alkenyloxy group.
Examples of preferred fused heterocyclic group include 2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 2-benzo [b] thienyl, 4-benzo [b] thienyl, 2-benzoxazolyl, 4-benzoxazolyl, 7-benzoxazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 7-benzothiazolyl, 2-quinolyl, 8-quinolyl and 3-isoquinolyl groups.
The group represented by the formula ##STR8## is an aromatic group substituted by heterocyclic group R.sup.11, i.e., pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl or thiomorpholinyl group, in which said aromatic group is optionally substituted by R.sup.12, i.e., a halogen atom, a hydroxyl group, a cyano group, C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group.
Examples of the substituted aromatic group include 3-(2-furyl)phenyl, 3-(3-furyl)phenyl, 3-(2-furyl)-2-methylphenyl, 3-(3-furyl)-2-methylphenyl, 3-(2-furyl)-6methylphenyl, 3-(3-furyl)-6-methylphenyl, 3-(2-thienyl)phenyl, 3-(3-thienyl)phenyl, 2-methyl-3-(2-thienyl)phenyl, 6-methyl-3-(3-thienyl)phenyl, 3-(2-oxazolyl)phenyl, 3-(4-oxazolyl)phenyl, 3-(5-oxazolyl)-phenyl, 3-(2-thiazolyl)phenyl, 3-(4-thiazolyl)phenyl, 3-(5-thiazolyl)phenyl, 3-(3-isoxazolyl)phenyl, 3-(4-isoxazolyl)phenyl, 3-(5-isoxazolyl)phenyl, 3-(3-isothiazolyl)phenyl, 3-(4-isothiazolyl)phenyl, 3-(5-isothiazolyl)phenyl, 3-(1-pyrrolyl)phenyl, 3-(2-pyrrolyl)phenyl, 3-(3-pyrrolyl)phenyl, 3-(1-imidazolyl)phenyl, 3-(2-imidazolyl)phenyl, 3-(4-imidazolyl)phenyl, 3-(3-furazanyl)phenyl, 3-(2-pyridyl)phenyl, 3-(3-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 3-(2-pyrimidinyl)phenyl, 3-(4-pyrimidinyl)phenyl, 3-(2-pyrazinyl)phenyl, 3-(3-pyridazinyl)phenyl, 3-(4-pyridazinyl)phenyl, 3-(1-pyrazolyl)phenyl, 3-[2-(1,3,5-triazinyl)]phenyl, 3-[2-(1,3,4-oxadiazolyl)]phenyl, 3-[2-(1,3,4-thiadiazolyl)]phenyl, 4-(2-furyl)-2-furyl, 5-(2-furyl)-2-furyl, 5-(3-furyl)-2-furyl, 4-(2-thienyl)-2-thienyl, 4-(3-thienyl)-2-thienyl, 5-(3-thienyl)-2-thienyl, 5-(3-thienyl)- 3-thienyl, 5-(2-oxazolyl)-2-furyl, 5-(2-thiazolyl)-2-furyl, 4-(2-oxazolyl)-2-thienyl, 4-(4-oxazolyl)-2-thienyl, 5-phenyl-2-furyl, 2-(2-furyl)-4-oxazolyl, 2-(2-furyl)-5-oxazolyl, 4-(2-furyl)-2-oxazolyl, 5-(2-furyl)-2-oxazolyl, 4-(2-oxazolyl)-2-oxazolyl, 5-(2-oxazolyl)-2-oxazolyl, 2-(2-oxazolyl)-4-oxazolyl, 2-(5-oxazolyl)-4-oxazolyl, 2-(5-oxazolyl)-5-oxazolyl, 2-(2-oxazolyl)-5-oxazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl, 2-phenyl-4-oxazolyl, 2-phenyl-5-oxazolyl, 5-phenyl-3-isoxazolyl, 3-phenyl- 5-isoxazolyl, 2-(2-furyl)-4-thiazolyl, 2-(2-furyl)-5-thiazolyl, 4-(2-furyl)-2-thiazolyl, 5-(2-furyl)-2-thiazolyl, 5-phenyl-2-thiazolyl, 2-phenyl-4-thiazolyl, 2-phenyl-5-thiazolyl, 2-(3-thienyl)-4-thiazolyl, 2-(5-oxazolyl)-4-thiazolyl, 2-(3-thienyl)-5-thiazolyl, 2-(5-oxazolyl)-5-thiazolyl, 2-(4-thiazolyl)-4-thiazolyl, 2-(4-thiazolyl)-5-thiazolyl, 2-(5-thiazolyl)-4-thiazolyl, 2-(5-thiazolyl)-5-thiazolyl, 4-(5-thiazolyl)-2-thiazolyl, 5-(5-thiazolyl)-2-thiazolyl, 4-(2-thiazolyl)-2-thiazolyl, 2-(2-thiazolyl)-5-thiazolyl, 5-phenyl-2-thienyl, 2-(3-thienyl)-4-pyridyl, 4-(3-thienyl)-2-pyridyl, 5-(3-thienyl)-3-pyridyl, 4-phenyl-2-pyridyl, 2-phenyl-4-pyridyl, 4-phenyl-2-pyrimidyl and 2-phenyl-4-pyrimidyl groups. Preferred among them are 3-(2-furyl)phenyl, 3-(3-furyl)phenyl, 3-(2-thienyl)-phenyl, 3-(3-thienyl)-phenyl, 3-(1-pyrrolyl)phenyl, 3-(1-imidazolyl)phenyl, 3-(2-oxazolyl)phenyl, 3-(4-oxazolyl)-phenyl, 3-(5-oxazolyl)phenyl, 3-(2-thiazolyl)phenyl, 3-(4-thiazolyl)phenyl, 3-(5-thiazolyl)phenyl, 3-(3-isoxazolyl)phenyl, 3-(4-isoxazolyl)phenyl, 3-(5-isoxazolyl)phenyl, and 3-(1-pyrazolyl)phenyl groups. The 2-methylphenyl, 2-(2-furyl)phenyl, 3-(3-furyl)phenyl, 3-(1-pyrrolyl)phenyl, 3-(4-oxazolyl)-phenyl, 3-(5-oxazolyl)phenyl, 3-(1-imidazolyl)phenyl, 3-(4-thiazolyl)phenyl, 3-(5-thiazolyl)phenyl, 5-(2-furyl)-2-furyl, 4-phenyl-2-furyl, 5-phenyl-2-furyl, 4-phenyl-2-thienyl, 5-phenyl-2-thienyl, 2-phenyl-5-oxazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl, 2-(2-furyl)-4-oxazolyl, 2-(2-furyl)-5-oxazolyl, 2-(2-thienyl)-4-oxazolyl, 2-(2-thienyl)-5-oxazolyl, 2-(5-oxazolyl)-4-oxazolyl, 2-(5-oxazolyl)-5-oxazolyl, 2-phenyl-5-thiazolyl, 4-phenyl-2-thiazolyl, 5-phenyl-2-thiazolyl, 2-(2-furyl)-4-thiazolyl, 2-(2-furyl)-5-thiazolyl, 2-(4-thiazolyl)-4-thiazolyl, 2-(5-thiazolyl)-4-thiazolyl, 2-(4-thiazolyl)-5-thiazolyl and 2-(5-thiazolyl)-5-thiazolyl groups are especially preferred.
X and Y are identical or different and each represents an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula --CHR.sup.a -- in which R.sup.a represents a hydrogen atom or a lower alkyl group, or a group of the formula --NR.sup.b -- in which R.sup.b represents a hydrogen atom or a lower alkyl group; or taken together, X and Y represent a vinylene or ethynylene group. If either one of X and Y represents an oxygen atom, a sulfur atom or the group --NR.sup.b --, the other represents a carbonyl group or the group --CHR.sup.a --. Examples of groups represented by the formula --X--Y-- include --(CHR.sup.a).sub.2 --, --CHR.sup.a O--, --OCHR.sup.a --, --CHR.sup.a S, --SCHR.sup.a --, --CHR.sup.a NR.sup.b --, --NR.sup.b CHR.sup.a --, --CHR.sup.a CO--, --COCHR.sup.a --, --COO--, --OCO--, --COS--, --SCO--, --CONR.sup.b, --NR.sup.b CO--, --CH.dbd.CH--, and --C.tbd.C-- (in these formulae, R.sup.a and R.sup.b are as defined hereinabove). Of these, the ethylene group, (E)-vinylene group, the group --CH.sub.2 O--, and the group --CH.sub.2 NH-- are preferred.
R.sup.2 is preferably a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl, propyl or isopropyl group. The hydrogen atom is preferred.
R.sup.3 represents a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkyl group or a C.sub.3-6 cycloalkyl group, for example linear or branched lower alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups, linear or branched lower alkenyl groups having 3 to 5 carbon atoms such as allyl, 2-butenyl, 2-pentenyl, 2-methyl-2-propenyl and 3-methyl-2-butenyl groups, linear or branched lower alkynyl groups having 3 to 5 carbon atoms such as propargyl, 2-butynyl and 2-pentynyl groups, and cycloalkyl groups having 3 to 5 carbon atoms such as cyclopropyl, cyclobutyl and cyclopentyl groups. Methyl, ethyl, propyl, allyl, propargyl and cyclopropyl groups are preferred, and the methyl, ethyl and propyl groups are most preferred.
R.sup.4 and R.sup.5 represent a hydrogen atom or a halogen atom, preferably a hydrogen atom, a fluorine atom or a chlorine atom. The hydrogen atom is especially preferred.
A trans-form (E-form) geometric isomer and a cis-form (Z-form) geometric isomer exist at the double bond formed by the two carbon atoms to which R.sup.4 and R.sup.5 are bonded respectively. The trans-form geometric isomer is preferred.
The acyclic hydrocarbon group R.sup.6 which may be substituted (the acyclic hydrocarbon groups may contain 1 or 2 unsaturated bonds selected from the group consisting of double and triple bonds) means a linear or branched acyclic hydrocarbon group having 1 to 17, preferably 3 to 12, carbon atoms which may be substituted, for example, by a hydroxyl group, a halogen atom, a C.sub.3-6 cycloalkyl group, a C.sub.1-4 alkoxy group, or a phenyl group which may be substituted by a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group and in which the carbon chain may contain 1 or 2 unsaturated bonds selected from the group consisting of double and triple bonds Examples of preferred acyclic hydrocarbon groups include substituted or unsubstituted saturated hydrocarbons such as isopropyl, tert-butyl, isopentyl, tert-pentyl, neopentyl, isopropoxymethyl, tert-butoxymethyl, 2-(isopropoxy)ethyl, 2-(tert-butoxy)ethyl, 2-methoxy-2-methylpropyl, p-(tert-butyl)benzyl, phenethyl, alpha-methylbenzyl, alpha,-alpha-dimethylbenzyl, 3-phenylpropyl, 2-(p-fluorophenyl)ethyl, 2-[p-(tert-butyl)phenyl]ethyl, alpha,alpha-dimethyl-p-fluorobenzyl and alpha,alpha-dimethyl-p-(tert-butyl)benzyl group; groups represented by the formula --CH.dbd.CH--R.sup.g (in which R.sup.g represents a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a cycloalkyl group which may be substituted, or a phenyl group which may be substituted), such as 2-cyclopropylvinyl, 2-(1-methylcyclopropyl)vinyl, 1-propenyl, 1-butenyl, 3-methyl-1-butenyl, 3,3-dimethyl-1 -butenyl, 3-methoxy-3-methyl-1-butenyl, 1-pentenyl, 3-methyl-1pentenyl, 3,3-dimethyl-1-pentenyl, 3-ethyl-1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, styryl, 2-(p-fluorophenyl)vinyl, 2-[p-(tert-butyl)phenyl]vinyl, 3-methyl-3-phenyl-1-butenyl, 3-methyl-3-(p-fluorophenyl)-1-butenyl, 3-methyl-3-[p-(tert-butyl)phenyl]-1-butenyl, 1,3-butadienyl, 3-methyl-1,3-butadienyl, 1,3-pentadienyl, 3-methyl-1,3-pentadienyl, 4-methyl-1,3-pentadienyl, 3,4-dimethyl-1,3-pentadienyl, 1,3-hexadienyl and 5,5-dimethyl-1,3-hexadienyl groups; and groups represented by the formula --C.tbd.--C--R.sup.g in which R.sup.g is as defined hereinabove, such as 2-cyclopropylethynyl, 2-(1-methylcyclopropyl)ethynyl, 1-propynyl, 1-butynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-methoxy-3-methyl- 1-butynyl, 1-pentynyl, 3-methyl-1-pentynyl, 3,3-dimethyl-1-pentynyl, 3-ethyl-1-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, 2-phenylethynyl, 2-(p-fluorophenyl)ethynyl, 2-p-(tert-butyl)phenyl)ethynyl, 3-methyl-3-phenyl-1-butynyl, 3-methyl-3-(p-fluorophenyl)-1-butynyl, 3-methyl-3-p-(tert-butyl)phenyl]-1-butynyl, 3-buten-1-ynyl, 3-methyl-3-buten-1-ynyl, 3-penten-1-ynyl, 3-methyl-3-penten-1-ynyl, 4-methyl-3-penten-1-ynyl, 3,4-dimethyl-3-penten-1-ynyl, 3-hexen-1-ynyl and 5,5-dimethyl-3-hexen-1-ynyl groups. Preferred among them are groups of the formula --CH.dbd.CH--R.sup.c (in which R.sup.c represents an alkyl or alkenyl group having 3 to 6 carbon atoms which may be substituted by one lower alkoxy group having 1 to 4 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms which may be substituted by an alkyl group having 1 to 4 carbon atoms, such as 3,3-dimethyl-1-butenyl, 3-methoxy-3-methyl-1-butenyl, 1-pentenyl, 3,3-dimethyl-1-pentenyl, 3-ethyl-1- pentenyl, 1-hexenyl, 3,3-dimethyl-1-hexenyl, 1-heptenyl, 1-octenyl, 3-methyl-1,3-butadienyl, 1,3-pentadienyl, 4-methyl-1,3-pentadienyl, 1,3-hexadienyl, 5,5-dimethyl-1,3-hexadienyl, 2-cyclopropylvinyl, 2-(1-methylcyclopropyl)vinyl, 2-cyclopentylvinyl and 2-cyclohexylvinyl groups; and groups of the formula --C.tbd.C--R.sup.c in which R.sup.c is as defined above, such as 3,3-dimethyl-1-butynyl, 3-methoxy-3-methyl-1-butynyl, 1-pentynyl, 3,3-dimethyl-1-pentynyl, 3-ethyl-1-pentynyl, 1-hexynyl, 3,3-dimethyl-1-hexynyl, 1-heptynyl, 1-octynyl, 3-methyl-3-butyn-1-ynyl, 3-penten-1-ynyl, 4-methyl-3-penten-1-ynyl, 3-hexen-1-ynyl, 5,5-dimethyl-3-hexen-1-ynyl, 2-cyclopropylethynyl, 2-(1-methylcyclopropyl)ethynyl, 2-cyclopentylethynyl and 2-cyclohexylethynyl groups. More preferred are groups of the following formula ##STR9## in which R.sup.d represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R.sup.e and R.sup.f are identical or different and each represents a methyl group or an ethyl group or taken together represents a cyclopropyl group, such as 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-methoxy-3-methyl-1-butynyl, 3-methyl-1-pentynyl, 3-ethyl-1-pentynyl, 3-methyl-1-hexynyl, 2-cyclopropylethynyl and 2-(1-methylcyclopropyl)ethynyl groups. Of these, the 3,3-dimethyl-1-butynyl and 3-methoxy-3-methyl-1-butynyl groups are most preferred.
The C.sub.3-6 cycloalkyl group R.sup.6 which may be substituted may be, for example, a cycloalkyl group which may be substituted by, for example, a hydroxyl group, a halogen atom, a C.sub.1-4 alkoxy group or a phenyl group which may be substituted by a halogen atom, a C.sub.1-6 alkyl group, or a C.sub.1-4 alkoxy group. Examples of preferred cycloalkyl groups include 1-cyclopropyl, 1-methyl-cyclopropyl, 1-ethylcyclopropyl, 1-methoxycyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, 1-methylcyclopentyl, 1-methoxycyclopentyl, 1-cyclohexyl and 1-methoxycyclohexyl, groups. The phenyl group R.sup.6 which may be substituted may be, for example, a phenyl group which may be substituted by a hydroxyl group, a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-4 alkoxy group. Examples of preferred phenyl groups include phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-isobutylphenyl, 4-(tert-butyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 2,6-dichlorophenyl.
Examples of preferred 5- or 6-membered aromatic rings represented by the formula ##STR10## in which A, B, D, E and p are as defined, include benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine rings The benzene, furan, thiophene, oxazole, isoxazole, thiazole, pyridine and pyrimidine rings are preferred, and the benzene ring is most preferred.
Most preferably, the aromatic ring is unsubstituted. As required, it may have one substituent, or two identical or different substituents, selected from the group consisting of halogen atoms, a hydroxyl group, cyano group, C.sub.1-6 alkyl groups and C.sub.1-4 alkoxy groups. Of these, the hydroxyl group, fluorine and chlorine atoms, the methyl group and the ethyl group are preferred.
A preferred group of the compounds provided by this invention are substituted alkylamines of general formula [I] in which R.sup.1 represents an aryl or heterocyclic group which may be substituted by a hydroxy group, a halogen atom, a cyano group, a formyl group, a C.sub.1-6 alkyl group, a C.sub.1-6 halogenoalkyl group, a C.sub.1-2 hydroxyalkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-4 alkoxy group or a C.sub.2-5 alkenyl group, or a group represented by the formula ##STR11## wherein R.sup.11 is a pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, 1,2-dithiolanyl, 1,3-dithiolanyl, 1,2-dithiolyl, 1,3-dithiolyl, dihydrothiopyranyl, tetrahydrothiopyranyl, 1,4-dithianyl, 1,4-dithiinyl, 1,4-oxathiinyl or thiomorpholinyl group, and the ring of the formula ##STR12## is a benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, 1,3,4oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring; X represents a methylene group and Y represents an oxygen atom or an imino group, or X and Y, taken together, represent an ethylene group or an (E)-vinylene group; the aromatic ring of the formula ##STR13## is a benzene, furan, thiophene, oxazole, isoxazole, thiazole, pyridine, isothiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridazine, triazole or pyrimidine ring; R.sup.2 represents a hydrogen atom; R.sup.3 represents an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, an alkynyl group having 3 to 5 carbon atoms, or a cycloalkyl group having 3 to 5 carbon atoms; R.sup.4 and R.sup.5 each represent a hydrogen atom, and the double bond formed by the two carbon atoms to which they are bonded is of a trans-form (E-form); and R.sup.6 is a group of the formula --CH.dbd.CH--R.sup.c in which R.sup.c represents an alkyl or alkenyl group having 3 to 6 carbon atoms which may be substituted by one alkoxy group having 1 to 4 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms which may be substituted by 1 or 2 alkyl groups having 1 to 4 carbon atoms, or a group of the formula --C.tbd.C--R.sup.c in which R.sup.c is as defined. In this group, more preferably, R.sup.1 is a phenyl, naphthyl, furyl, thienyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl or benzofurazanyl group which may have one substituent, or two identical or different substituents, selected from the class consisting of halogen atoms and hydroxyl, cyano, formyl, hydroxymethyl, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 alkenyl, C.sub.3 -C.sub.5 alkynyl, C.sub.1 -C.sub.3 alkoxy and C.sub.3 -C.sub.5 alkenyloxy groups, or a group represented by the formula ##STR14## wherein R.sup.11 is a furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, phenyl, pyridyl, tetrahydrothienyl or dihydrothienyl group, and the ring of the formula ##STR15## is a benzene, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.
Especially preferred substituted alkylamines of general formula [I] are those in which R.sup.1 is a 2-methylphenyl, 2-fluorophenyl or 3-cyanophenyl group, and those in which R.sup.1 is the aromatic ring of the formula ##STR16## wherein R.sup.11 is a thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, tetrahydrothienyl or dihydrothienyl group, and the ring of the formula ##STR17## is a benzene or thiophene ring.
A further preferred group of the formula ##STR18## is those in which R.sup.11 is a 3-thienyl, 1-pyrrolyl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, tetrahydrothienyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl group; the aromatic ring represented by the formula ##STR19## is a benzene or thiophene ring.
On the other hand, in the preferred groups of compounds of general formula [I], R.sup.3 desirably represents an alkyl group having 1 to 3 carbon atoms, an allyl group, a propargyl group or a cyclopropyl group; and R.sup.6 represents a group of the formula ##STR20## in which R.sup.d represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; Re and R.sup.f may be identical or different and each represents a methyl or ethyl group, or taken together, may represent a cyclopropyl group. Particularly, R.sup.3 is preferably a methyl, ethyl or propyl group.
The above substituted alkylamine derivatives may exist in the form of an acid addition salt. Examples of the acid addition salts are inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, perchlorates and phosphates; and organic acid salts such as p-toluenesulfonates, benzenesulfonates, methanesulfonates, oxalates, succinates, tartarates, citrates, fumarates and maleates. Preferably, they are nontoxic salts which are pharmaceutically acceptable. Furthermore, depending upon the embodiments of the substituents, the compounds of formula [I] provided by this invention may contain stereoisomers such as geometric isomers and optical isomers. The compounds [I] of this invention include all of these stereoisomers and their mixtures.
General processes for producing the compounds of this invention will now be described.
The compounds [I] of this invention may be produced by any one of the following processes A, B, C, D and E. ##STR21##
In the above formulae, Z represents a leaving group; R.sup.3' represents a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.6 alkenyl group, a C.sub.2 -C.sub.6 alkynyl group or a C.sub.3 -C.sub.6 cycloalkyl group, X.sup.a and Y.sup.b represent a carbonyl group or a group of the formula --CHR.sup.a -- in which R.sup.a is as defined above; X.sup.b and Y.sup.a represent an oxygen atom, a sulfur atom or a group of the formula --NR.sup.b --in which R.sup.b is as defined above; and A, Q, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above.
The above processes A, B and C are alkylation of amines which are well known in the field of organic syntheses, and can therefore be carried out by using ordinary means known per se. These processes are carried out by using a solvent which does not adversely affect the reactions, and reacting compounds [II] and [III] in process A, compounds [IV] and [V] in process B and com( pounds [I.sup.a ] and [VI] in process C in nearly equimolar proportions or using one of them in a slightly excessive proportion. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; alcohols such as ethanol and isopropanol; dimethylformamide, acetonitrile and dimethyl sulfoxides; and mixtures of these. The reaction temperature is generally -20 .degree. C. to 150 .degree. C., preferably from room temperature to the boiling point of the solvent used. The reaction time may be usually 5 minutes to 10 days, preferably 1 to 24 hours. Advantageously, the reactions are carrried out in the presence of a base in order to carry them out smoothly. Examples of the base are alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and organic amines such as triethylamine and pyridine. The amount of the base used is not critical, and can be varied over a broad range. Generally, it is nearly 1 mole, or slightly more, preferably 1 to 2 moles, per mole of the starting materials.
Processes D and E are for the production of compounds I.sup.c ] or [I.sup.d ] corresponding to the compounds of general formula [I] in which the group of the formula --X--Y--is --COO--, --OCO--, --CONR.sup.b --, --NR.sup.b CO--, CHR.sup.a O--, --OCHR.sup.a --, --CHR.sup.a S--, or --SCHR.sup.a --(in which R.sup.a and R.sup.b are as defined). Processes D and E are usually carried out in a solvent which does not adversely affect the reaction (such as tetrahydrofuran, dioxane, chloroform, benzene, acetone, dimethylformamide or dimethyl sulfoxide) by reacting compounds [VII] and [VIII] in process D and compounds [IX] and [X] in process E in nearly equimolar proportions or using one of them in a slightly excessive molar proportion. The reaction conditions used at this time vary depending upon the starting compounds used. Generally, the reaction temperature is in the range of -70 .degree. C. to 100.degree. C., preferably -20 .degree. C. to 50 .degree. C., and the reaction time is 1 minute to 24 hours, preferably 30 minutes to 5 hours. Preferably, the reaction is carried out in the presence of a base so as to perform the action smoothly. Examples of the base used at this time are inorganic bases such as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate and organic bases such as pyridine, triethylamine and dimethylaminopyridine. The amount of the base used is not critical, and can be varied over a broad range. Generally, it is nearly 1 mole, or slightly more, preferably 1 to 2 moles, per mole of the starting materials.
Process F is for the production of compounds of formula [I.sup.c ] corresponding to compounds of formula [I] in which the group --X--Y-- is --CH.sub.2 NH--.
Process F can be carried out by condensing compound [XI] with compound [XII] in benzene or alcohol to form an imine and thereafter, reducing the product. The reagent used in the reduction may be, for example, sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride. The reaction is carried out, for example, in methanol, ethanol or tetrahydrofuran at 0.degree. C. to room temperature for 1 to 6 hours.
If the starting compounds [I.sup.a ], [II], [III], [IV], [V], [VII], [VIII], [IX], [X], [XI] and [XII] contain reactive functional groups such as a hydroxyl or amino group in addition to the amino groups which are involved in the reaction, these reactive functional groups may, as required, be protected prior to the reaction, and the protected groups may be removed after the reaction. Protective groups which can be easily eliminated by hydrolysis under acidic or alkaline conditions may be used for this purpose. Examples of the protective groups are methoxymethyl, tetrahydropyranyl, trityl, dimethyl-(tert-butyl)silyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl groups.
The desired compound of formula [I] obtained by the above processes in accordance with this invention can be isolated and purified by, for example, column chromatography, solvent extraction, precipitation and recrystallization, either alone or in combination. As required, the compound [I] of the invention as a free base may be converted to its acid addition salt, or vice versa. The step of converting the free base of the compound [I] into its acid addition salt or the step of converting the acid addition salt to its free base can be carried out easily by ordinary methods using the corresponding acids or bases.
The leaving group represented by Z may be, for example, a halogen atom such as a chlorine, bromine or iodine atom, or an organic sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group.
The starting compounds [I.sup.a ] to [XII] used in processes A to F can be purchased as commercial goods, or may be produced and obtained by the methods described in the literature (see, for example, J. Med. Chem., vol. 27, page 1539, 1984; J. Med. Chem., vol. 29, page 112, 1086; and Japanese Laid-Open Patent Publications Nos. 32440/-1981, 123177/1982, 208252/1983, 45/1986, 201850/1987 and 5059/1988), the general processes shown below, or processes substantially in accordance with them.
For example, the starting compounds used in this invention may be produced by the following synthesizing methods. ##STR22##
In the above formulae, X.sup.c and Y.sup.c are identical or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, a group of the formula --CHR.sup.a -- in which R.sup.a is as defined above or a group of the formula --NR.sup.b -- in which R.sup.b is as defined above; each of R.sup.20 and R.sup.21 represents a hydrogen atom, a lower alkyl group or a lower alkoxy group; B represents a hydrogen atom or a protective group; and A, Q, X, Y, X.sup.a, X.sup.b, Y.sup.a, Y.sup.b, Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined above. When either one of X.sup.c and Y.sup.c represents an oxygen atom, a sulfur atom or the group --NR.sup.b --, the other represents a carbonyl group or the group --CHR.sup.a --.
Production Route (a)
The step of reacting compound [XI] with compound [VII] to produce compound [XIII] is carried out in the presence of a base such as sodium hydride, sodium hydroxide or potassium carbonate in a solvent, for example tetrahydrofuran, ethanol or dimethylformamide, at a temperature of -20 .degree. C. to 100 .degree. C. for 2 to 3 hours using the compounds [XI] and [VII] in nearly equimolar proportions. The step of reacting compound [XII] with compound [IX] to produce compound [XIII] can be performed in the same way as the step of reacting compound [XI] with compound [VII].
The step of reacting compound [XIII] with compound [XV] to produce compound [II.sup.a ] can be performed by condensing compound [XIII] with compound [XV] in benzene or an alcohol to form an imine or amide and reducing it, or by reacting an excessive amount of compound [XV] with compound [XIII] and simultaneously performing reduction. Reagents used for reduction at this time are, for example, sodium borohydride, sodium cyanoborohydride and aluminum lithium hydride. The reaction may be carried out, for example, in methanol, etanol or tetrahydrofuran at 0 .degree. C. to room temperature for 1 to 6 hours.
The step of reducing compound [XIII] to produce compound [XIV] may be performed by, for example, treating the compound [XIII] with sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride in a solvent such as methanol, ethanol or tetrahydrofuran at 0.degree. C. to room temperature for 1 to 5 hours.
The step of converting compound [XIV] to compound [IV.sup.a ] may be performed by, for example, treating the compound [XIV] with halogenation reagents such as thionyl chloride or phosphorus tribromide or with sulfonation reagents such as methane sulfonyl chloride in the presence of triethylamine in a solvent such as chloroform or methylene chloride at -20.degree. C. to room temperature for 1 to 5 hours.
Production Route (b)
The step of reacting compound [XVI] with compound [XVII] to produce compound [XIII.sup.a ] may be performed, for example, by treating the compounds with a base such as butyl lithium or sodium hydride in a solvent such as tetrahydrofuran at 0.degree. C. to room temperature for 1 to 6 hours.
The step of reacting compound [XVIII] with compound [XIX] may be carried out in the same way as the step of reacting compound [XVI] with compound [XVII].
The step of producing compound [XIII.sup.b ] by reducing compound [XIII.sup.a ] may be carried out, for example, by catalytically reducing compound [XIII.sup.a ] in a solvent such as methanol or ethanol, at room temperature and atmospheric pressure for 1 to 10 hours in the presence of a catalyst such as palladium-carbon.
The step of producing compounds [II.sup.b ] or compound [II.sup.c ] by reacting compound [XIII.sup.a ] or compound [XIII.sup.b ] with compound [XV] may be carried out in the same way as in the above step of reacting compound [XIII] with compound [XV] to produce compound [II.sup.a ]. Furthermore, the step of reducing compound [XIII.sup.a ] or compound [XIII.sup.b ] to form compound [XIV.sup.a ] or compound [XIV.sup.b ], and then converting the compound [XIV.sup.a ] or compound [XIV.sup.b ] into compound [IV.sup.b ] or compound [IV.sup.c ] may be carried out in the same way as a series of steps of producing compound [IV.sup.a ] from compound [XIII] via compound [XIV] described above.
Production Route (c)
The step of producing compound [XIV.sup.c ] by reacting compound [XX] with compound [XIX] or reacting compound [XXI] with compound [XVII] may be carried out in the same way as in the above-described step of producing compound [XIII.sup.a ] by reacting compound [XVI] with compound [XVII].
The step of converting compound [XIV.sup.c ] into compound [XIV.sup.d ] may be performed by reacting compound [XIV.sup.c ], either as such or after protection by a suitable protecting group, with bromine in an organic solvent such as methylene chloride, chloroform or ethyl ether at 0.degree. to 60.degree. C. for 0.5 to 3 hours, concentrating the reaction mixture to dryness, and then treating the residue in the presence of a base such as sodium hydroxide or potassium hydroxide in an alcohol solution such as methanol, ethanol or isopropanol at the boiling point of the solvent for 1 to 10 hours.
The step of converting compound [XIV.sup.d ] into compound [IV.sup.d ] may be carried out in the same way as in the step of converting compound [XIV] into compound [IV.sup.a ].
Production Route (d)
the step of producing compound [I.sup.a ] by reacting compound [XIII.sup.c ] with compound [V.sup.a ] may be performed in the same way as in the production of compound [II.sup.a ] by reacting compound [XIII] with compound [XV].
The compound [V.sup.a ] used at this time can be produced by the so-called Gabriel method which comprises reacting compound [III] with phthalimide at 10.degree. to 100.degree. C. in the presence of a base such as sodium hydroxide or potassium carbonate in a solvent such as tetrahydrofuran or dimethylformamide to produce compound [XXII] and then reacting this compound with hydrazine in ethanol or dimethylformamide to produce compound [V.sup.a ].
Production Route (e)
The step of producing compound [XXV] by reacting compound [XI.sup.a ] with compound [XV] may be performed in the same way as in the step of producing compound [II.sup.a ] by reacting compound [XIII] with compound [XV], the step of reducing compound [XI.sup.a ] to produce compound [XXIII] and then converting it into compound [XXIV] may be performed in the same way as the step of reducing compound [XIII] to produce compound [XIV] and converting it into compound [IV.sup.a ]. The step of reacting compound [XXIV] with compound V or reacting compound [XXV] with compound [III] to produce compound [XXVI], and then, as required, deprotecting this compound to obtain compound [VIII] may be carried out by the same method as in process A or B described above.
In the starting compound of formula [XI.sup.a ] in Production Route (e), the protecting group B may be any of various protective groups normally used in organic syntheses as protective groups for the hydroxyl group, mercapto group or amino group. Specific examples are methoxymethyl, tetrahydropyranyl, trityl, tert-butoxycarbonyl and dimethyl-tert-butylsilyl groups.
Production Route (f)
The step of producing compound [XXVIII] by reducing compound [XXVII] is the partial reduction utilizing the difference in reactivity in the reduction of the coexisting carbonyl groups, and can be carried out, for example, by reducing compound [XXVII] with 1 to 2 equivalents, based on compound [XXVII], of a reducing agent such as sodium borohydride at -20.degree. C. to room temperature for 1 to 5 hours in a solvent such as ethanol or tetrahydrofuran, or catalytically reducing compound [XXVII] in the presence of a catalyst such as palladium-carbon for 1 to 5 hours. The step of producing compound [XXX] by converting compound [XXVIII] into compound [XXIX], and then reacting it with compound [V] may be carried out in the same way as in the step of producing compound [XXVI] by converting compound [XXIII] into compound [XXIV] and reacting the resulting compound with compound [V].
The step of producing compound [XXXI] by converting compound [XXX] may be carried out by reduction when the product is an alcohol product in which Y.sup.b is a group of the formula --CHR.sup.a -- in which R.sup.a is as defined above, or by hydrolysis when the product is a carboxylic acid product in which Y.sup.b is a carbonyl group.
The step of producing the corresponding alcohol [XXXI] by reducing the compound [XXX] can be carried out in the same way as in the step of producing compound [XIV] by reducing the compound [XIII]. The step of hydrolyzing compound [XXX] to produce the corresponding carboxylic acid compound [XXXI] can be carried out, for example, by dissolving the compound [XXX] in a solvent such as hydrous ethanol or hydrous tetrahydrofuran in which an equimolar proportion or an excessive molar proportion of a base such as sodium hydroxide is present, and hydrolyzing it at room temperature to 100.degree. C. for 1 to 10 hours.
The step of producing compound [X] by converting compound [XXXI] can be performed, for example, by treating it with a halogenation reagent such as thionyl chloride or phosphorus tribromide in the absence of a solvent or in a solvent such as chloroform or methylene chloride at -20.degree. C. to room temperature for 1 to 5 hours.
The products obtained by the above steps may, as required, be purified or isolated by known purifying methods such as chromatography, recrystallization, solvent extraction, precipitation and distillation either singly or in combination.
Starting compounds for these starting intermediates can be purchased as commercial goods or can be easily obtained by the known methods of organic syntheses described in the literature (see, for example, J. Med. Chem., vol. 27, page 1539, 1984; J. Med. Chem., vol. 29, page 112, 1086; and Japanese Laid-Open Patent Publications Nos. 32440/1981, 123177/1982, 208252/1983, 45/1986, 01850/1987 and 5059/1988).
The compounds of this invention represented by general formula I] inhibit the mammalian squalene epoxidase very selectively and strongly, and are expected to be useful as an hypolipemic agent or an antiarterio sclerotic agent.
US Referenced Citations (8)
Foreign Referenced Citations (3)
| Number |
Date |
Country |
| 0051196 |
Oct 1981 |
EPX |
| 0066628 |
Dec 1981 |
EPX |
| 2185980 |
Jan 1987 |
GBX |
Non-Patent Literature Citations (4)
| Entry |
| Stuetz, A. Chem. Abs., No. 85436c, (1983), 100. |
| Stuetz, A. Chem. Abs., No. 169006d, (1981), 95. |
| Stuetz, A. Chem. Abs., No. 217260, (1987), 107. |
| Maeda, et al., Chem. Abs., No. 6950, (1981), 107. |
Continuation in Parts (3)
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Number |
Date |
Country |
| Parent |
533532 |
Jun 1990 |
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| Parent |
465209 |
Mar 1990 |
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| Parent |
274972 |
Nov 1988 |
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Patent Grant
5234946
