1. An engine method, comprising:
pumping coolant from a pump output, in parallel, directly to a block and a head upper coolant jacket;
flowing coolant from the block directly to a head lower coolant jacket;
discharging coolant from the upper and lower jackets only to a control block;
selectively directing cooling from the control block to each of: a cabin heater; the radiator bypass; and the radiator.
2. The method of claim 1 wherein the engine is a direct injection engine with an integrated exhaust manifold.
3. The method of claim 2 wherein the engine includes an exhaust gas recirculation system.
4. An engine method, comprising:
pumping coolant from a pump output, in parallel, directly to an engine cylinder block and a cylinder head upper coolant jacket;
flowing coolant from the cylinder block directly to a cylinder head lower coolant jacket;
discharging coolant from the upper and lower jackets only to a control unit;
selectively directing cooling from the control unit to each of: 1) a cabin heater, and then to a radiator bypass, 2) the radiator bypass, and 3) the radiator.
5. The method of claim 4 wherein the coolant from the lower coolant jacket goes only to the radiator bypass and the radiator.
6. The method of claim 5 wherein the coolant from the upper coolant jacket goes only to the cabin heater.
7. The method of claim 4 wherein the cylinder head includes an integrated exhaust manifold having a combined exhaust gas output leading directly to a turbine of a turbocharger coupled to the engine.
8. The method of claim 6 further comprising adjusting a valve in the control unit via an electromechanical actuator controlled by a control system reading information from vehicle sensors, the actuator controlled responsive to code stored in non-transitory memory.
9. The method of claim 8 further comprising a coolant-operated vehicle interior heater upstream of a coolant-operated cooling device in a coolant line leading from the control unit and returning to the radiator bypass line.
10. A liquid-cooled internal combustion engine, comprising:
at least one cylinder head and one cylinder block, wherein
the at least one cylinder head is equipped with at least one integrated coolant jacket, said first coolant jacket having, at the inlet side, a first supply opening for the feed of coolant and, at the outlet side, a first discharge opening for the discharge of the coolant,
the cylinder block is equipped with at least one integrated coolant jacket, said coolant jacket, which is associated with the block, having, at the inlet side, a second supply opening for the feed of coolant and, at the outlet side, a second discharge opening being provided for the discharge of the coolant, and,
the discharge openings are connectable to the supply openings to form a coolant circuit,
wherein
the first discharge opening is connectable to the first supply opening via a heating circuit line in which there is arranged a coolant-operated vehicle interior heater,
the second discharge opening is connectable to the second supply opening via a recirculation line in which there is arranged a heat exchanger, and
the second discharge opening is connectable to the second supply opening via a bypass line.
11. The liquid-cooled internal combustion engine as claimed in claim 10, wherein the second discharge opening can be connected to the second supply opening via the heating circuit line.
12. The liquid-cooled internal combustion engine as claimed in claim 11, wherein the heating circuit line issues into the bypass line.
13. The liquid-cooled internal combustion engine as claimed claim 12, wherein a coolant-operated cooling device of an exhaust-gas recirculation system is provided in the heating circuit line upstream of the vehicle interior heater.
14. The liquid-cooled internal combustion engine as claimed in claim 10, wherein the second discharge opening, provided at the outlet side, for discharging the coolant is arranged in the cylinder block.
15. The liquid-cooled internal combustion engine as claimed in claim 13, wherein the at least one cylinder head is equipped with at least two integrated and mutually separate coolant jackets, wherein the second coolant jacket is connected, in order to be supplied with coolant, to the coolant jacket associated with the block, and the second discharge opening, provided at the outlet side, for the discharge of the coolant is arranged in the cylinder head.
16. The liquid-cooled internal combustion engine as claimed in claim 10, wherein a pump for delivering coolant is provided upstream of the supply openings.
17. The liquid-cooled internal combustion engine as claimed in claim 10, wherein, at the outlet side, there is provided a coolant control unit which has two inputs and at least three outputs, wherein a first input is connected to the first discharge opening, a second input is connected to the second discharge opening, a first output is connected to the heating circuit line, a second output is connected to the bypass line, and a third output is connected to the recirculation line.
18. The liquid-cooled internal combustion engine as claimed in claim 17, wherein the coolant control unit comprises a setting element which is adjustable.
19. The liquid-cooled internal combustion engine as claimed in claim 18, wherein the setting element, when in a rest position, separates the two inputs from the at least three outputs, such that the coolant circuit both through the cylinder head and also through the cylinder block is shut off.
20. The liquid-cooled internal combustion engine as claimed in claim 19, wherein the setting element, when in a first working position, connects the first input to the first output such that a coolant circuit through the cylinder head is open via the heating circuit line. wherein the setting element, in a second working position, connects the first input to the first output such that a coolant circuit through the cylinder head is open via the heating circuit line, and connects the second input to the second output such that a coolant circuit through the cylinder block is open via the bypass line, and
wherein the setting element, in a third working position, connects the first input to the first output such that a coolant circuit through the cylinder head is open via the heating circuit line, and connects the second input to the third output such that a coolant circuit through the cylinder block is open via the recirculation line, and
wherein the setting element, when in a fourth working position, connects the first input and the second input to the first output such that a coolant circuit through the cylinder head and a coolant circuit through the cylinder block are open via the heating circuit line.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of the general formula (I)
in which
Z stands for C\u2550O, C\u2550S, or SO2;
U stands independently for CR5R6, NR7, O, S, SO, or SO2;
X stands independently for CR5R6, NR7, O, or S;
Y stands independently for CR5R6, NR7, O, or S;
A stands for CR8R9, C\u2550O, C\u2550S, NR10, O, S, or SO2;
b is 0 or 1;
n is 0 or 1;
m is 0 or 1;
provided that not more than one of U, X, and Y stands for NR7, O, or S; and X and Y do not stand for O or S, and X or Y only stands for NR7 in a position vicinal to U, when U stands for SO or SO2,
wherein, when at least one of n or m is not equal to zero, the bond between U and X or U and Y, respectively, or X and Y can be a C\u2550C or C\u2550N double bond;
Het is a ring system containing 1 or 2 rings, and at least one of the rings is aromatic and contains 5 or 6 ring atoms, of which at least one is nitrogen, and the other ring can be saturated or unsaturated and comprises from 5 to 7 ring atoms; while the ring system can contain additional 1 to 5 heteroatoms selected from the group consisting of N, S, and O, provided that not more than two heteroatoms are selected from the group consisting of S and O; and the ring system can be substituted by from one to four substituents R11,
with the following provisos:
when R1 and R2 do not together form part of a ring system,
1) 3-pyridyl has at position 6 no substituents other than H, when Het stands for 3-pyridyl; and
2) Het is not a substituted or unsubstituted pyridyl or pyrimidyl when Z stands for C\u2550O, n is 0, m is 1, and X stands for CR5R6, U stands for CR5R6, and R2 is not NO2;
R1 is selected from the group consisting of H; C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, C1-4 alkylcarbonyl, and C1-4 alkoxycarbonyl, each of which can be substituted by from one to three substituents Ra, wherein Ra is independently selected from the group consisting of optionally partially or completely halogenated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, and C1-4 alkylcarbonyl and also hydroxyl, nitro, and cyano, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkylsulfonyl, whose alkyl moieties may be partially or completely halogenated with independent halogen atoms, halogen, hydroxyl, nitro, cyano, \u2014NRc2, \u2014CONRc2, and SO2NRc2, wherein Rc is independently selected from the group consisting of H and C1-4 alkyl;
R2 is selected from the group consisting of H; C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, alkylsulfonyl, which in each case can be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; aryl C1-4 alkyl, aryl C0-4 alkylsulfonyl, heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb has the meanings stated above; halogen, hydroxyl, nitro, cyano, \u2014NRc2, \u2014CONRc2, and \u2014SO2NRc2, wherein Rc has the meanings stated above;
or
R1 and R2 form, together with the atoms to which they are bonded, an unsaturated nitrogen-containing five membered to seven membered ring comprising 1 or 2 unsaturated bonds and may, in addition to the nitrogen atom to which the R1 group is bonded, also contain a hetero atom or a heteroatom-containing group selected from the group consisting of O, S and NR7, and can be substituted by from one to four substituents R12;
R3 and R4 independently have the meanings stated for R2;
R5 and R6 are independently selected from the group consisting of H; C1-4 alkyl, C3-7 cycloalkyl, hydroxyl C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylthio, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms; halogen, hydroxyl, nitro, cyano, \u2014NRc2, and NRcCORd, wherein Rc has the meanings stated above and Rd is selected from the group consisting of C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, whose alkyl moieties can be partially or completely halogenated with independent halogen atoms, and wherein R5 or R6 may be bonded to a carbon atom forming part of a double bond,
R7 is selected from the group consisting of H; C1-4 alkyl, and C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; and aryl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb has the meanings stated above;
R8 and R9 are independently selected from the group consisting of H; C1-4 alkyl, C3-7 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, which can in each case be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; halogen, hydroxyl; aryl, aryl C1-4 alkyl, heterocyclyl, heterocyclyl C1-4 alkyl, which can be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb has the meanings stated above;
or
R8 and R9 form, together with the carbon atom to which they are bonded, a cyclopropane ring;
R10 is selected from the group consisting of H; C1-4 alkyl, C3-7 cycloalkyl, which in each case can be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; aryl, aryl C1-4 alkyl, heterocyclyl, and heterocyclyl C1-4 alkyl, each of which can be substituted on the or at least one ring by from one to four substituents Rb, wherein Rb has the meanings stated above;
R11 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylsulfonyl, which can in each case be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; aryl, heterocyclyl, aryl C0-4 alkylsulfonyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb has the meanings stated above, halogen, hydroxyl, nitro, cyano, \u2014NRc2, \u2014CONRc2, and \u2014SO2NRc2, wherein Rc has the meanings stated above; and
R12 is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, which can in each case be substituted by from one to three substituents Ra, wherein Ra has the meanings stated above, or can be partially or completely halogenated with independent halogen atoms; aryl, heterocyclyl, aryl C1-4 alkyl, and heterocyclyl C1-4 alkyl, which can in each case be substituted on the ring or at least on one ring by from one to four substituents Rb, wherein Rb has the meanings stated above, and is also selected from the group consisting of optionally partially or completely halogenated C1-4 alkoxy, hydroxyl, halogen, nitro, cyano, and NRc2 when R12 is bonded to a carbon atom, wherein Rc has the meanings stated above;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein the bond between U and X and U and Y, respectively, or X and Y, is a single bond, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1, wherein Z stands for C\u2550O, or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1, wherein R1 stands for H or C1-4 alkyl, or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1, wherein R1 and R2 together with the atoms, to which they are bound, form an unsaturated nitrogen-containing five to seven membered ring having 1 or 2 unsaturated bond(s) and, in addition to the nitrogen atom, to which R1 is bound, may contain a heteroatom or a heteroatom-containing group selected from the group consisting of O, S and NR7 and may be substituted with one to four substituents R12, wherein R12 is as defined in claim 1, or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1, wherein the unsaturated nitrogen containing ring is an unsubstituted five or six membered ring having one or two unsaturated bond(s) and no further heteroatom, or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1, wherein U stands for S or CR5R6, wherein R5 and R6 are independently selected from H and C1-4 alkyl, X stands for CH2, and n=0, or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1, wherein A stands for C\u2550O or CR8R9, wherein R8 and R9 independently stand for H or C1-4 alkyl or A is absent (i.e. b=0), or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1, wherein Het stands for pyridyl, isoquinolinyl, pyrimidyl or imidazolyl, optionally substituted with a substituent R11, wherein R11 is defined as in claim 1, or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 selected from
5-Pyridin-3-yl-1,3-dihydroindol-2-one
6-Isoquinolin-4-yl-3,4-dihydro-1H-quinolin-2-one
6-Isoquinolin-4-yl-1-methyl-3,4-dihydro-1H-quinolin-2-one
6-Pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-Nitro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one
7-Pyridin-3-yl-4H-benzo1,4thiazin-3-one
8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-thione
9-Pyridin-3-yl-1,2,6,7-tetrahydro-5H-pyrido3,2,1-ijquinolin-3-one
8-(5-Methoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-Isoquinolin-4-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
9-(5-Methoxypyridin-3-yl)-1,2,6,7-tetrahydro-5H-pyrido3,2,1-ijquinolin-3-one
9-Isoquinolin-4-yl-1,2,6,7-tetrahydro-5H-pyrido3,2,1-ijquinolin-3-one
8-Pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinoline-4-thione
6,6-Dimethyl-8-pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(5-Ethoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(5-Trifluoromethylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(5-Fluoropyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-Imidazol-1-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one.
8-Pyridin-4-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-Pyrimidin-5-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(Pyridin-4-carbonyl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(Pyridin-3-carbonyl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(5-Phenylpyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1quinolin-4-one
8-(5-Isopropoxypyridin-3-yl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-(1-Imidazol-1-yl-ethyl)-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(4-Fluorophenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(3-Fluorophenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(4-Methoxyphenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(3-Methoxyphenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(2-Fluorophenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(3-Trifluoromethylphenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(3,4-Difluorophenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(3-Trifluoromethoxyphenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
8-5-(2-Methoxyphenyl)pyridin-3-yl-1,2,5,6-tetrahydropyrrolo3,2,1-ijquinolin-4-one
or a pharmaceutically acceptable salt thereof.
11. (canceled)
12. Pharmaceutical composition, containing a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
13. (canceled)
14. (canceled)
15. (canceled)
16. A composition comprising a compound according to claim 1 and at least one other active ingredient selected from active ingredients to counteract obesity, loop diuretics, angiotensine converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), \u25a1-receptor blockers, renin inhibitors, calcium channel blockers, and 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.
17. A method of treating hyperaldosteronism in a mammal wherein a pharmaceutically effective amount of a compound according to claim 1 is administered to a patient in need thereof.
18. The method according to claim 17, wherein the treating of hyperaldosteronism includes the treating of hypokalaemia, hypertension, congestive heart failure, ventricular fibrillation, renal failure, including chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, postmyocardial infarction syndrome, coronary cardiac diseases, inflammation, increased collagen formation, vasculitis, fibrosis, including cardiac or myocardial fibrosis, remodeling following hypertension, endothelial dysfunction andor edema.
19. (canceled)