1. A compound of formula I,
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, C1-6 aliphatic, C5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused 7-10 membered bicyclic saturated, partially unsaturated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of RA; or R1 is \u2014OR, \u2014SR, \u2014CN, \u2014NO2, \u2014SO2R, \u2014SOR, \u2014C(O)R, \u2014CO2R, \u2014C(O)N(R)2, \u2014NRC(O)R, \u2014NRC(O)N(R)2, \u2014NRSO2R, or \u2014N(R)2;
each RA is independently \u2014R, halogen, -haloalkyl, -hydroxyalkyl, \u2014OR, \u2014SR, \u2014CN, \u2014NO2, \u2014SO2R, \u2014SOR, \u2014C(O)R, \u2014CO2R, \u2014C(O)N(R)2, \u2014NRC(O)R, \u2014NRC(O)N(R)2, \u2014NRSO2R, or \u2014N(R)2;
wherein when R1 is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, then RA is \u2014R, halogen, -haloalkyl, -hydroxyalkyl, \u2014SR, \u2014CN, \u2014NO2, \u2014SO2R, \u2014SOR, \u2014C(O)R, \u2014CO2R, \u2014C(O)N(R)2, \u2014NRC(O)R, \u2014NRC(O)N(R)2, \u2014NRSO2R, or \u2014N(R)2;
wherein when R1 is a 3-7 membered heterocylic ring having 1-4 nitrogen, wherein one nitrogen is attached to the quinoline ring, and RA is \u2014OR, then at least one R2 is halogen;
Z is O, S, SO2, SO, C(O), CO2, C(O)N(R), NRC(O), NRC(O)N(R), NRSO2, or N(R);
Ring A is a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R2 is independently \u2014R, halogen, -haloalkyl, \u2014OR, \u2014SR, \u2014CN, \u2014NO2, \u2014SO2R, \u2014SOR, \u2014C(O)R, \u2014CO2R, \u2014C(O)N(R)2, \u2014NRC(O)R, \u2014NRC(O)N(R)2, \u2014NRSO2R, or \u2014N(R)2; or two R2 groups on the same atom are taken together with the atom to which they are attached to form a C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
m is 0, 1, or 2; and
n is 1, 2, 3, 4, or 5;
wherein, at least one of RA or R2 is halogen or haloalkyl, or at least one R2 is \u2014OR; and
wherein, the following compounds are excluded:
6-chloro-N-{(1S,3S)-1-hydroxy-3-methylcyclohexylmethyl}-2-(3S)-3-hydroxypyrrolidin-1-ylquinoline-5-carboxamide;
6-chloro-N-{(1S,3S)-1-hydroxy-3-methylcyclohexylmethyl}-2-(3R)-3-hydroxypyrrolidin-1-ylquinoline-5-carboxamide;
6-chloro-N-{(1S,3S)-1-hydroxy-3-methylcyclohexylmethyl}-2-(4-hydroxypiperidin-1-ylquinoline-5-carboxamide; and
6-chloro-N-{(1S,3S)-1-hydroxy-3-methylcyclohexylmethyl}-2-(3-hydroxy-3-methylpyrrolidin-1-ylquinoline-5-carboxamide.
2. The compound of claim 1, wherein at least one of RA or R2 is F, or at least one of R2 is OH.
3. The compound of claim 1, wherein R1 is hydrogen.
4. The compound of claim 1, wherein R1 is
5. The compound of claim 1, wherein R1 is C5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused 7-10 membered bicyclic saturated, partially unsaturated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of RA.
6. The compound of claim 1, wherein R1 is \u2014OR, \u2014SR, \u2014SO2R, \u2014SOR, \u2014NRC(O)R, \u2014NRC(O)N(R)2, \u2014NRSO2R, or \u2014N(R)2.
7. The compound of claim 1, wherein Z is C(O)N(R).
8. The compound of claim 1, wherein Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, oxetanyl, or azetidinyl.
9. The compound of claim 1, wherein Ring A is cyclohexyl or cycloheptyl.
10. The compound of claim 1, wherein each R2 is independently H.
11. The compound of claim 1, wherein each R2 is independently methyl, F, CF3, or OH.
12. The compound of claim 1, of formula II,
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1, of formula III:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1, selected from Table 1.
15. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
16. A method for modulating P2X7 activity in a subject or in a biological sample, comprising the step of administering to said subject or contacting said biological sample with a compound of claim 1 or a physiologically acceptable salt thereof.
17. A method for treating a P2X7-mediated disease or disorder in a subject in need thereof, comprising the step of administering to said subject a compound of claim 1.
18. The method of claim 17, wherein the disease or disorder is Parkinson’s disease, multiple sclerosis (MS); Alzheimer’s disease, traumatic brain injury, encephalitis; depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders, cognition disorders; epilepsy, seizure disorders; urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy, inflammatory bowel disease; allergic rhinitis, asthma, reactive airway disease, chronic obstructive pulmonary disease; rheumatoid arthritis, osteoarthritis, myocardial infarction, uveitis, atherosclerosis; or psoriasis.
19. A method for treating multiple sclerosis in a subject, comprising the step of administering to said subject a compound of claim 1 or a physiologically acceptable salt thereof.
20. A process for manufacturing a compound of formula I, comprising the steps of:
reacting a compound of formula A:
wherein Z, Ring A, R2, n, and m are as defined in claim 1;
with a compound of formula H\u2014R1;
wherein R1 is as defined in claim 1;
to yield a compound of formula I.
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. Method for manufacturing a dental model for being applied in dentistry by means of a layer-wise additive manufacturing method, said method including the following steps:
modifying a three-dimensional CAD model of the dental model wherein at least one gap-like recess is generated, so that the CAD model is cut into segments by this at least one gap-like recess,
manufacturing the dental model by means of a layer-wise additive manufacturing method on the basis of the modified three-dimensional CAD model,
characterized in that
in said step of modifying the three-dimensional CAD model at least one connection bridge is generated at at least one of the gap-like recesses, which at least one connection bridge connects the segments abutting said gap-like recess to one another,
wherein said at least one connection bridge is adapted to fix the orientation and position of the segments abutting the gap-like recess with respect to each other.
2. Method according to claim 1, in which at least one connection bridge is generated in a gap-like recess.
3. Method according to claim 1, in which the dental model is a jaw model that corresponds to at least a part of a human jaw and wherein a segment consists of a partial section of the jaw model that comprises one or several teeth.
4. Method according to claim 1, in which the connection bridges are cut through after the manufacture of the dental model.
5. Method according to claim 4, in which reference connections between the dental model and the mounting plate are established before cutting through the connection bridges.
6. Method according to claim 5, in which the reference connections are established such that pins protruding from the mounting plate engage with holes in the bottom of the dental model when the dental model is put onto the mounting plate.
7. Method according to claim 1, in which:
in said step of modifying the three-dimensional CAD model a layer is integrated at the bottom of the CAD model of the dental model as connection bridge in each of the gap-like recesses, which layer connects the segments abutting the gap-like recess with each other,
in said step of modifying the three-dimensional CAD model holes are integrated into the bottom of the CAD model of the dental model,
after the manufacture of said dental model pins are inserted into the holes, wherein the pins protrude by a certain amount from the dental model after having been inserted into the holes,
said pins protruding from said dental model are pressed into a liquid bed of plaster,
after the pressing of the pins it is waited until a mounting plate of plaster has been formed by a solidification of the bed of plaster and
the dental model is removed from the mounting plate, wherein the pins remain either in the dental model or the mounting plate and serve as reference connection between the dental model and the mounting plate.
8. Method according to claim 1, in which between each two neighbouring segments there are provided at least three connection bridges.
9. Method according to claim 1, in which the connection bridges in a gap-like recess are designed such that their total volume is 20% of the volume of the gap-like recess at maximum.
10. Dental model that represents at least a partial section of a human jaw, wherein the dental model has at least one gap-like recess at which at least one connection bridge is arranged that connects both sides of the gap-like recess with each other so that the dental model is cut into two segments by the gap-like recess and the only connection between both segments exists via said at least one connection bridge, wherein said at least one connection bridge is adapted to fix the orientation and position of the segments abutting the gap-like recess with respect to each other
wherein said at least one connection bridge has been made of the same material as the whole rest of the dental model.
11. Dental model according to claim 10, in which between each two neighbouring tooth positions in the jaw a gap-like recess is placed.
12. Dental model according to claim 10, in which at least one connection bridge is positioned in a gap-like recess.
13. Dental model according to claim 12, in which the total volume of said at least one connection bridge in a gap-like recess is 20% of the volume of the gap-like recess at maximum.
14. Dental model according to claim 12, in which in each gap-like recess at least two connection bridges are arranged.
15. Dental model according to claim 12, in which in each gap-like recess a layer exists at the bottom of the dental model.
16. Dental model according to claim 10, in which holes from below exist in the bottom of the dental model corresponding to each tooth position.
17. Dental model according to claim 16, in which by the number andor arrangement of the holes in the bottom at a tooth position the position of this tooth in the dental model is coded.
18. Dental model according to claim 12, in which a connection bridge in at least one of the gap-like recesses consists of a layer at the edge of the gap-like recess.
19. Dental model according to claim 18, in which the layer captures the whole edge of the gap-like recess.