ZA200508082B - Five-membered heterocyclic derivative - Google Patents
Five-membered heterocyclic derivative Download PDFInfo
- Publication number
- ZA200508082B ZA200508082B ZA200508082A ZA200508082A ZA200508082B ZA 200508082 B ZA200508082 B ZA 200508082B ZA 200508082 A ZA200508082 A ZA 200508082A ZA 200508082 A ZA200508082 A ZA 200508082A ZA 200508082 B ZA200508082 B ZA 200508082B
- Authority
- ZA
- South Africa
- Prior art keywords
- group
- compound
- salt
- solvate
- formula
- Prior art date
Links
- 125000000623 heterocyclic group Chemical group 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 125
- 150000003839 salts Chemical class 0.000 claims description 80
- 239000012453 solvate Substances 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 208000023589 ischemic disease Diseases 0.000 claims description 10
- 229940127218 antiplatelet drug Drugs 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 9
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 8
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 230000003449 preventive effect Effects 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000000676 alkoxyimino group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 2
- -1 2,2-dimethyl-3- dimethylaminoazetidin-1-yl group Chemical group 0.000 claims 29
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 6
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims 3
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical compound C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 claims 3
- 125000005309 thioalkoxy group Chemical group 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 description 15
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 8
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 8
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 8
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 8
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 8
- 229960001138 acetylsalicylic acid Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 208000005189 Embolism Diseases 0.000 description 6
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 150000007979 thiazole derivatives Chemical class 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000000575 Arteriosclerosis Obliterans Diseases 0.000 description 1
- 206010008531 Chills Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Description
Five~Membered heterocyclic derivative
The present invention relates to 5-membered heterocyclic ring derivatives endowed with platelet coagulation-inhibiting activity.
Platelets play an important role in stopping hemorrhage caused by damage to blood vessel through aggregation to form thrombi. On the other hand, it has been known that, when vascular endothelium is injured or the blood vessel is narrowed as in the case of arteriosclerosis, platelets aggregate and trigger thrombus or embolus formation, causing ischemic diseases such as myocardial infarction, angina pectoris, ischemic cerebrovascular disorder, and peripheral vascular disease. Therefore, platelet aggregation inhibitors are administered for prevention and treatment of such ischemic diseases. Among them, aspirin has long been used as one of such platelet coagulation inhibitors, and their effects were demonstrated by APT (Antiplatelet Trialists'
Collaboration) in which clinical test results obtained by administering aspirin to 1,000,000 patients had been subjected to metaanalysis (BMJ, vol.308, pages 81-106, 1994).
Aspirin, however, is known to cause side effects such as
ES!
® hemorrhage in gastrointestine or like organs, namely, the so- called "aspirin-induced ulcer," and the side effect occurs at a rate of about 1 per 100 patients independently of its dose (BMJ, vol.321, pages 1183-1187, 2000).
The inhibitory effect of aspirin on platelet aggregation is known to be based on the activity to inhibit the activity of cyclooxygenase. Cyclooxygenases include cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and aspirin specifically inhibits COX-1 at a low dose, resulting in inhibition of platelet aggregation. The inhibition of
COX-1 also causes the aspirin-induced ulcer (Neurology, vol.57, Suppl.2, pages S5-S7, 2001 and Drugs Today, vol.35, pages 251-265, 1999). In addition, nonsteroidal antiinflammatory drugs are known to exhibit antiinflammatory action by selectively inhibiting COX-2.
As described above, although aspirin is useful as a platelet aggregation inhibitor, its use could lead to a side effect of gastrointestinal dysfunction attributable to the
COX-1-inhibiting activity, which is mechanism of an action for platelet aggregation inhibition, and there is a strong demand for new platelet coagulation inhibitors having no COX- l1-inhibiting activity.
Meanwhile, there have been compounds known as pyrazole derivatives having antithrombotic activity, such as compound (A) (Japanese Patent No. 2586713 and Chem. Pharm. Bull., vol.45, pages 987-995, 1997) and compound (B) (WO9729774).
F=20 lo 0 57 3 roo “7 080g; 0 0
NY
3 MeO
F — —
CN Ne CHF,
F’ | H,NO,S
Compound (A), however, exhibits an ICs value of 5.3 x 10" M against collagen-induced platelet aggregation, with even stronger inhibitory activity against COX-2 (ICso, 2.4 X 1077 M). Similarly, the platelet aggregation inhibitory activity of compound (B) is not so strong compared with its inhibitory activity against COX-2.
There has been known, as a compound endowed with anti- platelet activity, a thiazole derivative (C) (J. Med. Chemn.,
Vol. 37, pages 1189-1199, 1994).
NeO g NE an ne
J
Mel (C)
However, the thiazole derivative (C) also inhibits COX inhibiting effect, and the platelet aggregation inhibiting action of the derivative (C) is based on this COX inhibiting effect.
In view of the above, an object of the present invention is to provide a strong platelet coagulation inhibitor without inhibiting COX-1 or COX-2.
The present inventors have made an extensive study in search of such a platelet aggregation inhibitor, and found that S5-membered heterocyclic ring derivatives represented by the following formulas (I) and (II) exhibit strong platelet coagulation inhibitory activity without inhibiting COX-1 or
COX-2, thereby completing the invention.
Accordingly, the present invention provides a compound represented by formula (I):
Ary
Ary wherein the group represented by formula (1):
Ary
Ary is any of the groups represented by formula (a) to (c):
Ar; 0 Ar; _N Ar _N
X — pos
Ar N Ar” Ar” ~N 2 2 2 2
R
(a) (b) (ec) (wherein Ar; and Ar; each independently represent a 6- membered aromatic heterocyclic group which may have a substituent or a phenyl group which may have a substituent;
® and R® represents a group selected from among a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, and a lower alkyl group which may have a substituent);
X represents a carbonyl group or a thiocarbonyl group; and
Y represents a group represented by formula (2):
R' (wherein the ring structure A represents a 4- to 7-membered ring which may have, in addition to N shown in formula (2), one hetero atom selected from among N, O, and S; and the ring structure A may have a substituent represented by R}, wherein
R' represents 1 to 4 groups, which are identical to or different from one another, selected from among a hydroxyl group, a cyano group, an oxo group, a halogeno group, a lower alkyl group which may have a substituent, a lower alkoxy group, an aralkyloxy group, a lower thicalkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower acyl group, a carboxyl group, a hydroxyiminocarbonyl group, an alkoxyimino group, a lower alkylsulfonyl group, an amino group which may have a substituent, a carbamoyl group which may be a substituted by a lower alkyl group, an aminosulfonyl group which may be substituted by a lower alkyl group, a 3- to 6~-membered spiro-alicyclic alkyl group which may have a substituent, and a 4- to 7-membered alicyclic heterocyclic group which may have a substituent), a salt of the compound, or a solvate of the compound or the salt.
®
The present invention also provides a drug containing a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt.
The present invention also provides a preventive and/or therapeutic agent for an ischemic disease, containing a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt.
The present invention also provides a platelet aggregation inhibitor, containing a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt.
The present invention also provides a drug composition containing a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt and a pharmacologically acceptable carrier therefor.
The present invention also provides use of a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt in production of a drug.
The present invention also provides use of a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt in production of a preventive and/or therapeutic agent for an ischemic disease.
The present invention also provides use of a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt in production of a platelet aggregation inhibitor.
The present invention also provides a method for
® treating an ischemic disease, characterized by comprising administering an effective amount of a compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt.
The compound (I) of the present invention, salts of the compound, and solvates of the compounds or the salts potently inhibit platelet aggregation, and accordingly, also inhibit thrombogenesis without inhibiting COX-1 or COX-2. Therefore, they are useful as preventive and/or therapeutic agents for ischemic diseases caused by thrombus or embolus such as myocardial infarction, angina pectoris (chronic stable angina, unstable angina, etc.), ischemic cerebrovascular disorder (transient ischemic attack (TIA), cerebral infarction, etc.), peripheral vascular disease, embolism after replacement with an artificial vessel, thrombotic embolism after coronary artery intervention (coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), stent placement, etc.), diabetic: retinopathy and nephropathy, and embolism after replacement with an artificial heart valve, and are also useful as preventive and/or therapeutic agents for thrombus and embolus associated with vascular operation, blood extracorporeal circulation, and the like.
Moreover, the compound (I) of the present invention, salts thereof, and solvates of the compounds or the salts are useful for ameliorating ischemic conditions such as ulcer, pain, and chill, which accompany chronic arteriosclerosis obliterans.
Claims (29)
1. A compound represented by formula (I), a salt of the compound, or a solvate of the compound or the salt: Ary Ary wherein the group represented by formula (1): Ary Q Ars is any of the groups represented by formula (a) to (c): Ar; 0 Ar; _N Ar; _N O- - r- - Ar N Ary” AN 2 2 Re 2 (a) (b) (ec) (wherein Ar; and Ar, each independently represent a 6- membered aromatic heterocyclic group which may have a substituent or a phenyl group which may have a substituent; and R? represents a group selected from among a hydrogen atom, a halogeno group, a hydroxyl group, a lower alkoxy group, and a lower alkyl group which may have a substituent); X represents a carbonyl group or a thiocarbonyl group; and Y represents a group represented by formula (2):
© R' (wherein the ring structure A represents a 4- to 7-membered ring which may have, in addition to N shown in formula (2), one hetero atom selected from among N, O, and S; and the ring structure A may have a substituent represented by R', wherein R! represents 1 to 4 groups, which are identical to or different from one another, selected from among a hydroxyl group, a cyano group, an oxo group, a halogeno group, a lower alkyl group which may have a substituent, a lower alkoxy group, an aralkyloxy group, a lower thioalkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower acyl group, a carboxyl group, a hydroxyiminocarbonyl group, an alkoxyimino group, a lower alkylsulfonyl group, an amino group which may have a substituent, a carbamoyl group which may be a substituted by a lower alkyl group, an aminosulfonyl group which may be substituted by a lower alkyl group, a 3- to 6-membered spiro-alicyclic alkyl group which may have a substituent, and a 4- to 7-membered alicyclic heterocyclic group which may have a substituent).
2. A compound as described in claim 1, a salt of the compound, or a solvate of the compound or the salt, wherein the group represented by formula (1) is a group represented py formula (b), and R' in formula (2) represents 1 to 4 groups, which are identical to or different from one another, selected from among a cyano group, an Oxo group, a halogeno group, a lower alkyl group which has been substituted by a halogeno group, a lower alkoxy group, an aralkyloxy group, a lower thioalkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower acyl group, a carboxyl group, a hydroxyiminocarbonyl group, an alkoxyimino group, a lower alkylsulfonyl group, an amino group which may have a substituent, a carbamoyl group which may be substituted by a lower alkyl group, an aminosulfonyl group which may be substituted by a lower alkyl group, a 3- to 6-membered spiro- alicyclic alkyl group which may have a substituent, and a 4- to 7-membered alicyclic heterocyclic group which may have a substituent.
3. A compound as described in claim 1, a salt of the compound, or a solvate of the compound or the salt, wherein when the group represented by formula (1) is a group represented by formula (b), the group represented by formula (2) is any one of the following groups: (1) a pyperidyl group which may be substituted by one to four groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group and halogen-lower alkyl group, (ii) a pyperazinyl group which may be substituted by one or two groups selected from an oxo group and a lower alkyl group, and (iii) a pyrrolidinyl group which may be substituted by a halogen atom, a carbamoyl group and a halogeno-lower alkyl group. 236 Amended sheet: 24 July 2007
4. A compound as described in any one of claims 1 to 3, a salt of the compound, or a solvate of the compound or the salt, wherein X is a carbonyl group.
5. A compound as described in any one of claims 1 to 4, a salt of the compound, or a solvate of the compound or the salt, wherein Ar; in formula (I) is a pyridyl group which may have a substituent or a pyridazinyl group which may have a substituent.
6. A compound as described in any one of claims 1 to 4, a salt of the compound, or a solvate of the compound or the salt, wherein Ar; in formula (I) is a phenyl group which may have a substituent.
7. A compound as described in any one of claims 1 to 6, a salt of the compound, or a solvate of the compound or the salt, wherein Ar; in formula (I) is a pyridyl group which may have a substituent.
8. A compound as described in any one of claims 1 to 6, a salt of the compound, or a solvate of the compound or the salt, wherein Ar, in formula (I) is a phenyl group which may have a substituent.
9. A compound as described in any one of claims 1, 2 and 4 to 8, a salt of the compound, or a solvate of the compound or the salt, wherein the group represented by formula (1) is a group represented by formula (a): Ari 0 To Ar, N (a) 237 Amended sheet: 24 July 2007 wherein Ar; and Ar; have the same meanings as described in claim 1.
10. A compound as described in any one of claims 1, 2 and 4 to 8, a salt of the compound, or a solvate of the compound or the salt, wherein the group represented by formula (1) is a group represented by formula (b): Ares _N Ar re R (b) wherein Ar,, Ar,, and R?’ have the same meanings as described in claim 1.
11. A compound as described in any one of claims 1, 2 and 4 to 8, a salt of the compound, or a solvate of the compound or the salt, wherein the group represented by formula (1) is a group represented by formula (c): Ar Th Ary” N {c) wherein Ar, and Ar; have the same meanings as described in claim 1.
12. A compound as described in any one of claims 1, 2 and 4 to 11, a salt of the compound, or a solvate of the compound or the salt, wherein the ring structure A in formula (2) is a ring selected from among azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperazine, and oxazepane, and R' represents 1 to 4 groups, which are identical to or different from one another, selected from 238 Amended sheet: 24 July 2007 among a hydroxyl group, a cyano group, an oxo group, a halogeno group, a lower alkyl group which may have a substituent, a lower alkoxy group, an aralkyloxy group, a lower thiocalkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower acyl group, a carboxyl group, a hydroxyiminocarbonyl group, an alkoxyimino group, a lower alkylsulfonyl group, an amino group which may have a substituent, a carbamoyl group which may be substituted by a lower alkyl group, an aminosulfonyl group which may be substituted by a lower alkyl group, a 3- to 6-membered spiro- alicyclic alkyl group which may have a substituent, and a 4- to 7-membered alicyclic heterocyclic group which may have a substituent.
13. A compound as described in any one of claims 1, 2 and 4 to 11, a salt of the compound, or a solvate of the compound or the salt, wherein the ring structure A in formula (2) is a ring selected from among azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperazine, and oxazepane, and R! represents 1 to 4 groups, which are identical to or different from one another, selected from among a cyano group, an oxo group, a halogenoc group, a lower alkyl group which has been substituted by a halogeno group, a lower alkoxy group, an aralkyloxy group, a lower thioalkoxy group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a lower acyl group, a carboxyl group, a hydroxyiminocarbonyl group, an alkoxyimino group, a lower alkylsulfonyl group, an amino group which may have a 239 Amended sheet: 24 July 2007 substituent, a carbamoyl group which may be substituted by a lower alkyl group, an aminosulfonyl group which may be substituted by a lower alkyl group, a 3- to 6-membered spiro- alicyclic alkyl group which may have a substituent, and a 4- to 7-membered alicyclic heterocyclic group which may have a substituent.
14. A compound as described in any one of claims 1, 2 and 4 to 11, a salt of the compound, or a solvate of the compound or the salt, wherein the ring structure A in formula (2) is a ring selected from among azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperazine, and oxazepane, and R' represents 1 to 4 groups, which are identical to or different from one another, of halogeno groups or lower alkyl groups which have been substituted by a halogeno group.
15. A compound as described in any one of claims 1, 2 and 4 to 11, a salt of the compound, or a solvate of the compound or the salt, wherein the group represented by formula (2) is a group selected from among a 3- dimethylaminocazetidin-1l-yl group, a 2,2-dimethyl-3- dimethylaminoazetidin-1-yl group, a 2-hydroxymethylazetidin- l1-yl group, a 2-carbamoylazetidin-1l-yl group, a 2- oxopyrrolidino group, a 2-hydroxymethylpyrrolidino group, a 2-carbamoylpyrrolidino group, a 2-fluoromethylpyrrolidino group, a 3-fluoropyrrolidino group, a 2- hydroxymethylpiperidino group, a 2-carbamoylpiperidino group, a 2-methylcarbamoylpiperidino group, a 2- 240 Amended sheet: 24 July 2007 dimethylcarbamoylpiperidino group, a 3-fluoropiperidino group, a 4-fluoropiperidino group, a 4,4-difluoropiperidino group, a 4-fluoromethylpiperidino group, a 4-methoxypiperidino group, a 3-oxo-4-methylpiperazino group, a 4-methylpiperazino group, a 4-ethylpiperazino group, a 4-isopropylpiperazino group, a 4-cyclopropylpiperazino group, a 2,4-dimethylpiperazino group, a 3,4-dimethylpiperazino group, a 3-cyclopropyl-4- methylpiperazino group, a 3,4,5-trimethylpiperazino group, a 2,2,4-trimethylpiperazino group, a 3,3,4-trimethylpiperazino group, a 2-cyclopropanespiro-4-methylpiperazino group, a morpholino group, a 3-carbamoylmorpholino group, a 1,1- dioxothiomorpholino group, a 3-oxo-4-methylhomopiperazino group, a 5-oxo-4-methylhomopiperazino group, a 4- methylhomopiperazino group, a 4-ethylhomopiperazino group, a 4-cyclopropylhomopiperazino group, and a 1,4-oxazepan-4-yl group.
16. A drug containing a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt.
17. A preventive and/or therapeutic agent for ischemic diseases, containing a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt.
18. A platelet aggregation inhibitor containing a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt. 241 Amended sheet: 24 July 2007
19. A pharmaceutical composition containing a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt, and a pharmacologically acceptable carrier therefor.
20. Use, for production of a drug, of a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt.
21. Use, for production of a preventive and/or therapeutic agent for ischemic diseases, of a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt.
22. Use, for production of a platelet aggregation inhibitor, of a compound as recited in any one of claims 1, 2 and 4 to 15, a salt of the compound, or a solvate of the compound or the salt.
23. A drug containing a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt.
24. A preventive and/or therapeutic agent for ischemic diseases, containing a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt.
25. A platelet aggregation inhibitor containing a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt.
26. A pharmaceutical composition containing a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt, and a pharmacologically 242 Amended sheet: 24 July 2007 acceptable carrier therefor.
27. Use, for production of a drug, of a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt.
28. Use, for production of a preventive and/or therapeutic agent for ischemic disease, of a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt.
29. Use, for production of a platelet aggregation inhibitor, of a compound as recited in claim 3, a salt of the compound, or a solvate of the compound or the salt. 243 Amended sheet: 24 July 2007
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003115204 | 2003-04-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200508082B true ZA200508082B (en) | 2007-07-25 |
Family
ID=36760909
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200508082A ZA200508082B (en) | 2003-04-21 | 2004-04-20 | Five-membered heterocyclic derivative |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1774435A (en) |
| ZA (1) | ZA200508082B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180099916A (en) | 2007-02-09 | 2018-09-05 | 메타베이시스 테라퓨틱스, 인크. | Novel antagonists of the glucagon receptor |
| CN115745953A (en) * | 2022-06-29 | 2023-03-07 | 上海凌凯医药科技有限公司 | Hydroxyl fluorination reagent and hydroxyl fluorination method |
-
2004
- 2004-04-20 CN CN 200480010326 patent/CN1774435A/en active Pending
- 2004-04-20 ZA ZA200508082A patent/ZA200508082B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1774435A (en) | 2006-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5227805B2 (en) | Combination of IAP inhibitor and taxane 7 | |
| US6596744B2 (en) | Method for treating fibrotic diseases or other indications IIC | |
| RU2209813C2 (en) | Derivatives of pyridazine, medicinal agents based on thereof and method for treatment of arthritis | |
| US7166625B2 (en) | Method for treating fibrotic diseases and other indications | |
| EP2098231A1 (en) | Use of NAD formation inhibitors for the treatment of ischemia-reperfusion injury | |
| RU2005127873A (en) | Pyrazole derivatives | |
| US5480888A (en) | Inhibitor for restenosis after percutaneous coronary arterioplasty | |
| JP2010536846A (en) | Indole and indazole compounds as cell necrosis inhibitors | |
| US20020107245A1 (en) | Method for treating fibrotic diseases or other indications IVC | |
| AR051780A1 (en) | FUSIONED RING COMPOUNDS CONTAINING NITROGEN AND USING THEMSELVES | |
| KR970001322A (en) | Substituted N- [indole-2-carbonyl] -glycineamides and derivatives as diabetes inhibitors | |
| RU2007103831A (en) | Pyrazole derivatives | |
| RU2008142600A (en) | ORGANIC COMPOUND | |
| WO2006137510A1 (en) | Agent for reduction of bleeding in cerebrovascular disorder | |
| NO20054854L (en) | Five-ring heterocyclic derivatives | |
| DE4442116A1 (en) | 2-amino-1,3-thiazines as inhibitors of nitric oxide synthase | |
| JP2020533345A5 (en) | ||
| JP2010043132A (en) | Drug of combination of antithrombotic agent and pyrazolone derivative | |
| ZA200508082B (en) | Five-membered heterocyclic derivative | |
| JPH03215426A (en) | Agent for suppressing increase of blood sugar | |
| WO2005074938A1 (en) | Drug for inhibiting vascular intimal hyperplasia | |
| ZA200505734B (en) | Pyrazole Derivative | |
| BRPI0612582A2 (en) | combination of organic compounds | |
| JP4175887B2 (en) | Novel vascular stenosis treatment or prevention agent | |
| RU2008149917A (en) | DERIVATIVES OF PHENYLPENTADIENOIL AND THEIR APPLICATION AS ANTAGONISTS PAR 1 |