WO2005105789A2 - Novel pyrrole derivatives with angiotensin ii antagonist activity - Google Patents
Novel pyrrole derivatives with angiotensin ii antagonist activity Download PDFInfo
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- WO2005105789A2 WO2005105789A2 PCT/EP2005/051911 EP2005051911W WO2005105789A2 WO 2005105789 A2 WO2005105789 A2 WO 2005105789A2 EP 2005051911 W EP2005051911 W EP 2005051911W WO 2005105789 A2 WO2005105789 A2 WO 2005105789A2
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- derivative
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- 0 C**1*=NC(c2ccccc2-c2ccc(*[n]3c(C=O)c(*)cc3*)cc2)=*1 Chemical compound C**1*=NC(c2ccccc2-c2ccc(*[n]3c(C=O)c(*)cc3*)cc2)=*1 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention provides novel pyrrole derivatives which may be represented by the general formula (I) shown below and in which:
- - Ri is a group independently selected from among: -CHO, -COOH, -CH 2 OH; R 2 is hydrogen or a linear or branched C ⁇ -C(s alkyl group; R 3 is hydrogen or a halogen group selected from among CI and Br; R is a linear or branched C 3 -C 5 alkyl group and the pharmaceutically acceptable salts thereof such as for example the sodium or potassium salt.
- the compounds of the present invention are proving to be potent angiotensin II (All) receptor antagonists by interacting with the specific ATi type receptors thereof on the surface of target cells.
- Ti receptors which play a central part in controlling arterial blood pressure, have mainly been identified in the adrenal cortex, in the kidneys and more recently also on the surface of platelets. Binding of All with the A i receptor brings about vasoconstriction, an increase in aldos- terone secretion, an increase in platelet aggregation and in arterial pressure. All is thus considered to be one of the principal aetiological factors in bringing about arterial hypertension and cardiovascular disorders.
- ATi antagonists have been subjected to preclinical and subsequently human pharmacological trials [see for example the monographs: "Antihypertensive agents; P.K. Chak- ravarty, -Exp. Opin. Ther. Patents (1996) 5 (5): 431-458 (Ashley Pub.)"; "Nonpeptide Angiotensin II Receptor Antagonists; The Next Generation Antihypertensive Therapy; R.R. Wexler et al., J. Med. Chem. (1996) 39 (3): 625-656; "Comparative pharmacology of the angiotensin II receptor antagonists; D.J. Dzielak, Exp. Opin. Invest. Drugs (1998) 1_ (5) : 741-751. (Ashley Pub. ) "] .
- the object of the present invention is to provide novel drugs for therapeutic use which exhibit potent and selective All antagonist activity for the treatment of any disorders in which elevated synthesis of All or overexpression of the ATi receptor may play a primary pathological role, as in the case of arterial hypertension, congestive cardiac insufficiency, platelet aggregation and disorders associated therewith such as for example myocardial and cerebral infarction, renal ischaemia, venous and arterial thrombosis, peripheral vasculopathy, pulmonary hypertension, diabetes mellitus, diabetic neuropathy, glaucoma and diabetic retinopathy.
- Dosage forms of the compounds provided by the invention may be prepared according to conventional methods such as for example tablets, capsules, suspensions, solutions, patches and may be administered orally, • parenterally, transdermally, transmucosally, ocularly or other appropriate manner to achieve the therapeutic effect, such as for example solid preparations for oral use with extended action which permit controlled release of the active substance over time.
- the active ingredient is usually administered to the patient in a reference dose which may range from 0.125 to 5 mg/kg body weight per dose.
- a water-soluble salt of the compounds provided, ⁇ such as the sodium or potassium salt or another non-toxic and pharmaceutically acceptable salt.
- Inactive ingredients which may be used are substances commonly used in pharmaceutical technology as excipients, binders, flavourings, disintegrants, transdermal and transmucosal absorption promoters, colorants, humectants etc. and, in the case of ocular administration, pharmaceutically acceptable preservatives may also be used.
- the process for the preparation of the derivatives provided by the invention consists of a series of reactions which comprises : a) preparing the pyrrole derivatives le (see scheme 1) which consists in reacting a suitable R trimethylsilylalkyne, in which R has the above-stated meaning, with an R 2 acyl chloride in which R 2 has the above-stated meaning, in the presence of A1C1 3 (step 1) to yield the corresponding ketoalkyne la, which, by treatment with trimethylsilylcyanide under a nitrogen atmosphere, yields the corresponding CN addition derivative lb (step 2) , which, by reduction with LiAlH , yields the corresponding amine lc (step 3) and which, by, subsequent treatment with PdCl 2 and refluxing in an inert solvent such as acetonitrile, yields the corresponding pyrrole derivative Id (step 4) , which is finally subjected to Vilsmeier formyla- tion [Ber. (1927), 60 119
- the 2-formyl pyrrole derivatives of the general formula (I) obtained in this manner may be converted into the corresponding carboxylic acids or alcohols by treatment respectively with H2O2 or by reduction with NaBH in methanol under reflux- ing conditions (step 8, scheme 2) .
- the 2-formyl pyrrole derivatives of the general formula (I) in which Ri is CHO, R 2 is H, R 3 is H, Br or CI, R is C 3 -C 5 alkyl are prepared (see scheme 3) by reacting pyrrole with the appropriate N, -dimethylacylamide (DMP) in the presence of P0C1 3 and subsequent hydrolysis with sodium acetate to yield the corresponding 2-acylpyrrole which, by subsequent reduction with hydrazine and potash [according to Huang-Minion; J.A.C.S.
- Step 1 2 ⁇ Methyl -5-decyn-4-one (la).
- Step 2 4-Cyano-2-methyl-4-trimethylsilyloxy-5-decyne (lb) .
- LiAlH (0.167 moles) are suspended in 250 mL of anhydrous diethyl ether and the temperature is reduced to 0°C.
- 43 g of (lb) (0.162 moles) in 75 mL of anhydrous diethyl ether are added dropwise and the mixture is stirred for 20 h.
- LiAlH 4 is hydrolysed with water and 30% NaOH and the phases are separated.
- the aqueous phase is extracted repeatedly with diethyl ether, the organic phase is extracted with IN HC1, the aqueous phase is alkalised with 30% NaOH, extracted with diethyl ether, the combined organic phases are washed to neutrality, dried with Na2S0 4 and evaporated.
- Step 5 4-n-Butyl-3- [3- ( 2 -methyl )propyl] -2-pyrrolaldehyde (le).
- Step 6 5-n-Propyl -1- [2 ' - (1 -triphenylmethyl tetrazol -5- yl) biphenyl -4-yl-methyl] -2-pyrrolaldehyde (2a) .
- This compound was prepared using the same procedure as in Example 1. 3.9 g of 5-n-propyl-2-pyrrolaldehyde (0.031 moles) and 15 g of 4 ' -bromomethyl-2- (l-triphenylmethyltetrazol-5- yl) -biphenyl (0.031 moles) yield 15 g of product which are used in the subsequent step.
- Step 7 5-n-Propyl -1- [2 ' - (lH-tetrazol -5-yl ) biphenyl -4-yl- methyl] -2-pyrrolaldehyde (compound 2).
- Step 4 4-Bromo-5-n-propyl-2-pyrrolaldehyde .
- Step 6 4-Bromo-5-n-propyl-l- [2 '- (1-triphenylmethyltetrazol- 5-yl) biphenyl - 4-yl-methyl] -2-pyrrolaldehyde (2a) .
- Step 7 4-Bromo-5-n-propyl-l- [2 ' - (lH-tetra ⁇ ol -5-yl) biphenyl- 4 -yl -me thyl ] -2 -pyrrol al dehyde (compound 3) .
- Step 4 4-Chloro-5-n-propyl-2-pyrrolaldehyde .
- Step 6 4-Chloro-5-n-propyl-l- [2 ' - (1 -triphenylmethyltetrazol- 5-yl ) biphenyl -4-yl -methyl] -2-pyrrolaldehyde (2a) .
- Step 7 4-Chloro-5-n-propyl-l- [2 ' - (lH-tetrazol-5-yl)biphenyl- 4 -yl -me thyl ] -2 -pyrrolal dehyde (compound 4) .
- This compound was prepared using the same procedure as in Example 1. 12 g of 4-chloro-5-n-propyl-l- [2 '- (1- triphenylmethyltetrazol-5-yl) biphenyl-4-yl-methyl] -2- pyrrolaldehyde (0.019 moles) and 24 mL of 4N HCl (0.095 moles) yield 5.0 g of product.
- Step 8 5-n-Propyl -l- [2 r - (lH-tetrazol -5-yl ) biphenyl -4-yl - methyl] -2-pyrrolecarboxylic acid (compound 10).
- Step 8 2 -Methyl -5-n-propyl -3-isopropyl -1- [2 ' - (lH-tetrazol -5- yl)biphenyl-4-yl-methyl] pyrrole (compound 15)
- Scheme 2 (step 8)
- Step 1 4 ' -Aminomethyl-2- (lH-tetrazol-5-yl) biphenyl (4a).
- Table 1 shows some of the compounds obtained in this manner with some physico-chemical properties which identify them, without this in any way limiting the spirit and scope of the present invention.
- Antagonist activity at the ATi receptor on the part of compounds provided by the invention was assessed as the capacity to inhibit binding of the specific All agonist to rat liver membranes.
- the method described by R.S.L. Chang et al., [JPET (1992), 262, 133-38] and M.J. Robertson et al., [Br. J. Pharmacol. (1992), 107, 1173-1180] was used with slight modifications.
- the concentration of radioligand [ 125 I]-Sar ⁇ , Ile 8 - angiotensin II used was 25 pM with a membrane content corresponding to a protein concentration of approx. 25 ⁇ g of protein per sample; the incubation time was 180 minutes at 25°C.
- compound 1 is approx. 200 times more potent than the BPT-pyrrole derivative stated by way of example in the cited patent, EP-0323841 (8.9 nM of compound 1 vs . 1.6 ⁇ M of compound 277 of EP 0 323 841, table 5, page 81) ; in fact, in order to obtain truly potent compounds (i.e. with at least submicromolar activity) in this pyrrole series, it was necessary to introduce into R2 an alkyl group with specific steric bulk features, such as for example the isobutyl group in compound 1 or the isopropyl group in compound 6 and a C 3 -Cs alkyl in R instead of just methyl.
- the comparison drugs used were some of the most widely therapeutically used compounds from this class such as losartan, valsartan and eprosartan.
- the compounds were administered in- traperitoneally (I.P.) dissolved in a physiological solution as sodium salts in a volume of 5 mL/kg using various doses in the range from 5-20 mg/kg so as to be able to calculate an ED 15 , i.e. the dose in mg/kg which brings about a 15% reduc- tion in average basal systolic pressure within a period of 0- 120 minutes of administration.
- Table 3 Reduction in systolic arterial pressure in the SHR and RHR rat brought about by (I. P.) administration of the stated compounds provided by the invention in comparison with some All antagonists in therapeutic use.
- A->B permeability was thus assessed, namely the apparent permeability coefficient (Papp) , of the compounds under investigation, tested at a concentration of 50 ⁇ M with an incubation time of 60 minutes, in the apical-to-basolateral direction.
- B->A permeability is reversely assessed, i.e. in a baso- lateral-to-apical direction, with an incubation time of 40 minutes. The results obtained are shown in Table 4 below.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES05747406T ES2370401T3 (en) | 2004-04-28 | 2005-04-27 | NEW PIRROL DERIVATIVES WITH ANTIGONIST ACTIVITY OF ANGIOTENSIN II. |
JP2007510037A JP4898661B2 (en) | 2004-04-28 | 2005-04-27 | Novel pyrrole derivatives having angiotensin II antagonist activity |
AT05747406T ATE517889T1 (en) | 2004-04-28 | 2005-04-27 | NEW PYRROLE DERIVATIVES WITH ANGIOTENSIN II ANTAGONISTIC EFFECT |
CA002564303A CA2564303A1 (en) | 2004-04-28 | 2005-04-27 | Novel pyrrole derivatives with angiotensin ii antagonist activity |
EP05747406A EP1753746B8 (en) | 2004-04-28 | 2005-04-27 | Novel pyrrole derivatives with angiotensin ii antagonist activity |
US11/568,362 US7906501B2 (en) | 2004-04-28 | 2005-04-27 | Pyrrole derivatives with angiotensin II antagonist activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITTO2004A000264 | 2004-04-28 | ||
IT000264A ITTO20040264A1 (en) | 2004-04-28 | 2004-04-28 | NEW PYROLIC DERIVATIVES WITH ANGIOTENSIN-II ANTAGONIST ACTIVITY |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005105789A2 true WO2005105789A2 (en) | 2005-11-10 |
WO2005105789A3 WO2005105789A3 (en) | 2006-02-02 |
Family
ID=34968865
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/051911 WO2005105789A2 (en) | 2004-04-28 | 2005-04-27 | Novel pyrrole derivatives with angiotensin ii antagonist activity |
Country Status (9)
Country | Link |
---|---|
US (1) | US7906501B2 (en) |
EP (1) | EP1753746B8 (en) |
JP (1) | JP4898661B2 (en) |
AT (1) | ATE517889T1 (en) |
CA (1) | CA2564303A1 (en) |
ES (1) | ES2370401T3 (en) |
IT (1) | ITTO20040264A1 (en) |
PT (1) | PT1753746E (en) |
WO (1) | WO2005105789A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012114285A1 (en) | 2011-02-23 | 2012-08-30 | Lupin Limited | Heteroaryl derivatives as alpha7 nachr modulators |
US9388196B2 (en) | 2012-03-06 | 2016-07-12 | Lupin Limited | Thiazole derivatives as alpha 7 nAChR modulators |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4036706A1 (en) * | 1990-11-17 | 1992-05-21 | Hoechst Ag | METHOD FOR THE TREATMENT OF CARDIALS AND VASCULAR HYPERTROPHY AND HYPERPLASIA |
-
2004
- 2004-04-28 IT IT000264A patent/ITTO20040264A1/en unknown
-
2005
- 2005-04-27 ES ES05747406T patent/ES2370401T3/en active Active
- 2005-04-27 CA CA002564303A patent/CA2564303A1/en not_active Abandoned
- 2005-04-27 AT AT05747406T patent/ATE517889T1/en active
- 2005-04-27 EP EP05747406A patent/EP1753746B8/en not_active Not-in-force
- 2005-04-27 US US11/568,362 patent/US7906501B2/en not_active Expired - Fee Related
- 2005-04-27 PT PT05747406T patent/PT1753746E/en unknown
- 2005-04-27 JP JP2007510037A patent/JP4898661B2/en not_active Expired - Fee Related
- 2005-04-27 WO PCT/EP2005/051911 patent/WO2005105789A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0253310A2 (en) * | 1986-07-11 | 1988-01-20 | E.I. Du Pont De Nemours And Company | Angiotensin II receptor blocking imidazoles |
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
Non-Patent Citations (1)
Title |
---|
PRASUN K CHAKRAVARTY: "ANTIHYPERTENSIVE AGENTS" EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 5, no. 5, 1 May 1995 (1995-05-01), pages 431-458, XP000567227 ISSN: 1354-3776 cited in the application * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012114285A1 (en) | 2011-02-23 | 2012-08-30 | Lupin Limited | Heteroaryl derivatives as alpha7 nachr modulators |
US9072731B2 (en) | 2011-02-23 | 2015-07-07 | Lupin Limited | Heteroaryl derivatives as alpha7 nAChR modulators |
US9393247B2 (en) | 2011-02-23 | 2016-07-19 | Lupin Limited | Heteroaryl derivatives as alpha7 nAChR modulators |
US9388196B2 (en) | 2012-03-06 | 2016-07-12 | Lupin Limited | Thiazole derivatives as alpha 7 nAChR modulators |
Also Published As
Publication number | Publication date |
---|---|
US20070244170A1 (en) | 2007-10-18 |
EP1753746A2 (en) | 2007-02-21 |
ITTO20040264A1 (en) | 2004-07-28 |
EP1753746B8 (en) | 2012-02-15 |
WO2005105789A3 (en) | 2006-02-02 |
EP1753746B1 (en) | 2011-07-27 |
ES2370401T3 (en) | 2011-12-15 |
PT1753746E (en) | 2011-08-25 |
JP2007534724A (en) | 2007-11-29 |
ATE517889T1 (en) | 2011-08-15 |
ES2370401T8 (en) | 2012-04-09 |
JP4898661B2 (en) | 2012-03-21 |
CA2564303A1 (en) | 2005-11-10 |
US7906501B2 (en) | 2011-03-15 |
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