NZ530366A - Compounds useful for treatment or prevention of disease mediated by alpha-2B-adrenoceptor - Google Patents
Compounds useful for treatment or prevention of disease mediated by alpha-2B-adrenoceptorInfo
- Publication number
- NZ530366A NZ530366A NZ530366A NZ53036602A NZ530366A NZ 530366 A NZ530366 A NZ 530366A NZ 530366 A NZ530366 A NZ 530366A NZ 53036602 A NZ53036602 A NZ 53036602A NZ 530366 A NZ530366 A NZ 530366A
- Authority
- NZ
- New Zealand
- Prior art keywords
- carbon atoms
- group
- benzenesulfonamide
- dimethylpyrimidin
- straight chain
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
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- 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
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D403/12—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 chain containing hetero atoms as chain links
Abstract
Disclosed are compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, R4 and R5 are independently selected from the list consisting of H, a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen; X is H, a straight or branched alkyl group with 1 to 4 carbon atoms, phenyl or -OH; Z is H, acetyl, -CH2-Ph-O-CF3 or CH2-Ph-CF3; Y is a ring structure linked to formula (I) directly or with an alkyl chain having one or two carbon atoms. Further disclosed is the use of said compounds for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal. The pharmaceutical preparation containing this compound may be useful in treating a coronary heart disease, acute myocardial infarction, unstable angina pectoris, Prinzmetal's variant form of angina pectoris, other forms of chronic angina pectoris, essential hypertension, restenosis after coronary angioplasty or a vascular disease such as: vasoconstriction subsequent to subachnoid haemorrhage, hypoxic brain damage subsequent to subarachnoid haemorrhage, migraine, Raynaud's disease, cold intolerance, pre-eclampsia, male erectile dysfunction or obesity.
Description
New Zealand Paient Spedficaiion for Paient Number 530366
5303 66
WO 03/008387 PCT/FI02/00643
1
COMPOUNDS USEFUL FOR TREATMENT OR PREVENTION OF DISEASE MEDIATED BY ALPHA-2B-ADRENOCEPTOR
The present invention relates to the use of selective alpha-2B-adrenoceptor antagonists for the manufacture of a pharmaceutical preparation useful for the 5 treatment or prevention of diseases mediated by the alpha-2B-adrenoceptor in mammals.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the 10 practice, are incorporated by reference.
It is known that alpha-2B-adrenoceptors mediate vascular contractions. Therefore, alpha-2B-antagonists are useful in the treatment or prevention of diseases involving vascular contraction. It has also been found that certain individuals have a genetic polymorphism in the alpha-2B-adrenoceptor gene. It has been observed 15 that the alpha-2B-adrenoceptor protein in some subjects has a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide (WO 01/29082; Heinonen et al., 1999).
OBJECTS AND SUMMARY OF THE INVENTION
An object of this invention is to provide compounds useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal.
Thus this invention concerns a novel compound of formula (I)
(I)
or a pharmaceutically acceptable salt thereof.
Ri i R2 > R3 . R4 and Rs are independently of each other H , a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
X is H , a straight or branched alkyl chain with 1 to 4 carbon atoms, phenyl or -OH;
Z is H, acetyl, -CH2-Ph-0-CF3 or -CH2-Ph-CF3, where Ph is phenyl;
Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is
a) phenyl optionally mono- or disubstituted and each substituent is independently selected from the group consisting of a halogen, a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, a nitrile, an amide, amino, or a nitro group;
b) 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl, wherein one N
optionally has a substituent that is a straight or branched alkyl or alkoxy chain with 1 to 4 carbon atoms, or benzyl; and wherein the 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted and each substituent can independently be a straight or
branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
(c) pyridinyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen; or
3
(d) naphthyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen.
The following previously known compounds are excluded: 4-[(/ff-benzimidazol-5 2-ylmethyl)-amino]-/V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide
(Kumar & Reddy, 1985), A^-(4,6-dimethylpyriinidin-2-yl)-4- [(1 -methyl-1H-benzimidazol-2-ylmethyl)-amino] -benzenesulfonamide (No 653716, ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego CA 92127) and N-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -ethyl-1 #-benzimidazol-2-ylmethyl)-amino] -10 benzenesulfonamide (No AE-848/34956037, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 CP Rijswijk, The Netherlands) and iV-(4-methyl-2-pyrimidinyl)-4-[(l/f-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide (Farag & EI-Mouafi & Khalifa, 1991).
This invention further concerns use of compound of formula (I)
or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal wherein
Rl < I Rj » R4 and R5 are independently of each other H , a straight or 20 branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
X is H , a straight or branched alkyl chain with 1 to 4 carbon atoms, phenyl,
R41R5
(I)
-OH or =0 ;
Z is H, acetyl, -CH2-Ph-0-CF3 or -CH2-Ph-CF3, where Ph is phenyl;
4
Y is a ring structure optionally linked to formula (I) with an alkyl chain having one or two carbon atoms, wherein the ring structure is a) phenyl optionally mono- or disubstitued and each substituent is independently selected from the group consisting of a halogen, a straight or
branched alkyl or alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl or methoxy group, an acetyl, a nitrile, an amide, amino, or a nitro group;
b) 2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl, wherein one N optionally has a substituent that is a straight or branched alkyl or alkoxy
chain with 1 to 4 carbon atoms, or benzyl; and wherein the
2-benzimidazolyl, 2-imidazolyl, or 2- or 3-indolyl is optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen;
(c) pyridinyl optionally mono- or disubstituted and each substituent can 15 independently be a straight or branched alkyl or alkoxy group with 1 to 4
carbon atoms, or a halogen; or
(d) naphthyl optionally mono- or disubstituted and each substituent can independently be a straight or branched alkyl or alkoxy group with 1 to 4 carbon atoms, or a halogen.
The following compounds previously known to be selective alpha-2B-adrenoceptor antagonists are excluded: Ar-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -methyl-1 //-benzimidazol-2-ylmethyl)-amino] -benzenesulfonamide (No 653716, ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego CA 92127), 7V-(4,6-dimethylpyrimidin-2-yl)-4-[(1 -ethyl-1 -benzimidazol-2-yl-25 methyl)-amino] -benzenesulfonamide (No AE-848/34956037, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 CP Rijswijk, The Netherlands) and Af-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phenyl]-4-ethoxy-benzamide (No AF-
399/36012031, SPECS and BioSPECS B. V., Fleminglaan 16, 2289 CP Rijswijk, The Netherlands).
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are compounds of formula (I)
R,.R*
as defined in the preceding summary or pharmaceutically acceptable salts thereof wherein Ri and R3 are methyl and R2, R4 and R5 are H.
In some preferable compounds X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkoxy group and Z is H. Compounds fulfilling all of the aforementioned characteristics and wherein said phenyl is substituted and said alkoxy substituent is methoxy are 4-(2,4-dimethoxybenzylamino)-/V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfon-amide, Af-(4,6-dimethylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfon-amide, 4-(3,5-dimethoxybenzylamino)-AT-(4,6-dimethylpyrimidin-2-yl)-
benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-/V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and A^-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzyl-amino)-benzenesulfonamide.
In other preferred compounds X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkyl and/or a halogen and Z is H. These comprise compounds such as 4-benzylamino-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methylbenzyl-
(I):
6
amino)-benzenesulfonamide, 4-(2,4-dimethylbenzylamino)-Af-(4,6-dimethyl-
pyrimidin-2-yl)-benzenesulfonamide, //-(4,6-dimethylpyrimidin-2-yl)-4-(3-methyl-benzylamino)-benzenesulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-(4-methyl-
dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,6-dimethylbenzylamino)-A^-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(4-bromobenzylamino)-./V-
dichlorobenzylamino)-Ar-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide.
Further preferred compounds are A'-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -ethyl-1H-10 indol-3-ylmethyl)-amino] -benzenesulfonamide, A^-(4,6-dimethylpyrimidin-2-yl)-4-[(1 -isobutyl-1 //-benzimidazol-2-ylmethyl) -amino] -benzenesulfonamide, N-{4,6-dimethylpyrimidin-2-yl)-4-( 1 -phenylethylamino)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(2-methoxyphenyl)-ethylamino]-benzenesulfon-amide and A^-(4,6-dimethylpyrimidin-2-yl)-4-[(naphthalen-2-ylmethyl)-amino]-15 benzenesulfonamide.
According to one embodiment of the invention the compound is N-(4-methyl-2-pyrimidinyl)-4- [ [(1 -methyl-1 H-benzimidazol-2-yl)-methyl] amino] "benzenesulfonamide.
The invention also relates to the use of selective alpha-2B-adrenoceptor 20 antagonists of formula (I)
benzylamino)-benzenesulfonamide,
4-(2,5-dimethylbenzylamino)-iV-(4,6-
(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and
4-(2,6-
R4.R5
as defined in the preceding summary, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation.
In many preferable compounds to be used Ri and R3 are typically methyl and R2, R4and R5 are typically H.
In some compounds preferably used X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkoxy group and Z is H. Especially preferable for use are compounds in which said phenyl is substituted and said alkoxy substituent is methoxy. Such compound comprise 4-(2,4-dimethoxybenzylamino)-Ar-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-10 (4,6-dimethylpyrimidin-2-yI)-4-(3-methoxybenzylamino)-benzenesulfonamide, 4-(3,5-dimethoxybenzylamino)-iV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-Af-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzyl-amino)-benzenesulfonamide.
In other compounds preferably used X is H, Y is a phenyl optionally mono- or disubstituted with a straight or branched alkyl and/or a halogen and Z is H. Such compound comprise 4-benzylamino-AK4,6-dimethylpyrimidin-2-yl)-benzene-sulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4-(2-methylbenzylamino)-benzene-sulfonamide, 4-(2,4-dimethylbenzylamino)-iV-(4,6-dimethylpyrimidin-2-yl)-20 benzenesulfonamide, A^-(4,6-dimethylpyrimidin-2-yl)-4-(3-methylbenzylamino)-benzenesulfonamide, A^-(4,6-dimethylpyrimidin-2-yl)-4-(4-methylbenzylamino)-benzenesulfonamide, 4-(2,5-dimethylbenzylamino)-jV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,6-dimethylbenzylamino)-A^-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(4-bromobenzylamino)-iV-(4,6-dimethylpyrimidin-2-25 yl)-benzenesulfonamide and 4-(2,6-dichlorobenzylamino)-A/-(4,6-
dimethylpyrimidin-2-yl)-benzenesulfonamide.
8
Further preferred compounds to be used comprise 4- [(1 //-benzimidazol-2-ylmethyl)-amino]-JV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, N-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -ethyl-1 #-indol-3 -ylmethyl)-amino] -benzenesulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -isobutyl-1 Z/-benz-5 imidazol-2-ylmethyl)-amino] -benzenesulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-( 1 -phenylethylamino)-benzenesulfonamide, A^-(4,6-dimethylpyrimidin-2-yl)-4-[2-(2-methoxyphenyl)-ethylamino]-benzenesulfonamide and iV-(4,6-dimethyl-pyrimidin-2-yl)-4-[(naphthalen-2-ylmethyl)-amino]-benzenesulfonamide.
Alpha-2B-adrenoceptor antagonists are useful in the treatment and/or prevention 10 of many diseases.
Individuals having a deletion in the alpha-2B-adrenoceptor protein (WO 01/29082; Heinonen et al., 1999), particularly the deletion/deletion genotype (D/D genotype) is an important target group, which benefits from administration of selective alpha-2B-adrenoceptor antagonists. These individuals have a deletion of 3 15 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide.
It has been found that in a population-based cohort of Finnish middle-aged men that subjects with a D/D genotype of the alpha-2B-adrenoceptor gene have a 20 significantly elevated risk for acute myocardial infarction (AMI) in a five-year follow-up study. The risk for AMI was increased in subjects who had no previously diagnosed coronary heart disease (CHD) at the study outset. Therefore, it has been postulated that the D/D genotype is related to an impaired capacity to down-regulate alpha-2B-adrenoceptor function during sustained receptor 25 activation. Therefore, alpha-2B-adrenoceptors are believed to be involved in the pathogenesis of a significant fraction of all cases of AMI, especially in subjects
with the D/D genotype, but also in I/D and I/I subjects (I means "insertion" and stands for the "normal" allele).
The alpha-2B-adrenoceptor antagonists as disclosed in this invention would be particularly useful in the treatment or prevention of coronary heart diseases. As 5 examples can be mentioned a) Acute AMI
If alpha-2B-adrenoceptor dependent vasoconstriction is a causative factor in some cases of AMI, then antagonism of these receptors should restore coronary circulation and reduce the ischemic myocardial damage.
b) Unstable angina pectoris
An alpha-2B-adrenoceptor antagonist will relieve the vasoconstrictive component in the sustained ischemic episode, thus alleviating the symptoms and preventing AMI.
c) Prinzmetal's variant form of angina pectoris
Vasoconstriction is a key factor in the pathogenesis of Prinzmetal's angina,
and an alpha-2B- adrenoceptor antagonist may resolve and prevent attacks.
d) Other forms of chronic angina pectoris and CHD
An alpha-2B-adrenoceptor antagonist will help to alleviate the vasoconstrictive component in all types of CHD, providing both symptomatic 20 relief and protection from AMI. A general reduction in vascular tone will contribute to this by reducing venous return, cardiac workload and oxygen consumption (a nitrate-type effect; see below).
e) Prevention of restenosis after coronary angioplasty in cases where vasoconstriction plays a role in restenosis.
Furthermore, the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of essential hypertension, especially
in subjects with increased sympathetic activity and a hyperdynamic circulatory system.
In the study mentioned above, the D/D variant of the alpha-2B-adrenoceptor gene was not clearly associated with blood pressure. The inventors believe that this was 5 due to two main factors, 1) antihypertensive treatment, and 2) complex regulation of systemic blood pressure. In another study (Heinonen et al.), it was observed that the D/D genotype was associated with reduced basal metabolic rate and reduced heart rate. These associations probably reflect increased vascular resistance in these subjects.
In transgenic mice with targeted inactivation of the alpha-2B-adrenoceptor gene, intravenously administered alpha-2-adrenoceptor agonists fail to induce the characteristic blood pressure elevation, which is seen in normal animals and also in humans after large doses of such drugs (Link et al., 1996). The hypotensive effect of these drugs was markedly accentuated. This demonstrates that alpha-2B-15 adrenoceptors mediate vascular contraction. Thus, an antagonist should reduce blood pressure. This effect has not been seen with alpha-2B-non-selective alpha-2-adrenoceptor antagonists, because antagonism of alpha-2A-adrenoceptors increases sympathetic outflow, cardiac output and blood pressure. In mice with dysfunctional alpha-2A-adrenoceptors, alpha-2-adrenoceptor agonists caused an 20 accentuated hypertensive response and no hypotension (MacMillan et al., 1996).
An alpha-2B-adrenoceptor antagonist is postulated to have favourable effects in hypertensive subjects through their effects on renal function, muscle blood flow, and also on vascular resistance in other vascular beds. The anti-AMI effect of such a drug will be an additional benefit, as hypertension is a significant risk factor for 25 AMI. This protection is due to three factors: 1) a reduction in systemic blood pressure, 2) decreased risk of coronary vasoconstriction, and 3) a nitrate-like effect on venous return, myocardial workload and oxygen consumption.
WO 03/008387 PCT/FI02/00643
11
Moreover, the alpha-2B-adrenoceptor antagonists as disclosed in this invention would be useful in the treatment or prevention of other vascular diseases. Specifically, benefits can be expected in the treatment or prevention of
- vasoconstriction and hypoxic brain damage subsequent to subarachnoid 5 haemorrhage,
- migraine,
- Raynaud's disease and cold intolerance,
- pre-eclampsia,
- male erectile dysfunction, and
- obesity and the metabolic syndrome.
The last mentioned effect is due to the fact that reduced muscle blood flow and reduced basal metabolic rate contribute to the development of obesity and hypertension. An alpha-2B-adrenoceptor antagonist will, by increasing the muscle blood flow, increase energy expenditure and shift the caloric balance to a 15 favourable direction.
The alpha-2B-adrenoceptor antagonists disclosed in this invention are also useful in anaesthesia and analgesia to potentiate the clinical efficacy of alpha-2-adrenoceptor agonists, which are not selective for the alpha-2B-adrenoceptor subtype. By blocking the vasoconstriction induced by these agonists, a 20 simultaneously administered alpha-2B-adrenoceptor antagonist will allow the use of larger doses of said agonists, up to anaesthetic dose levels which have not previously been possible in man, only in veterinary anaesthetic practice.
12
EXPERIMENTAL SECTION
Human alpha-2-adrenoceptor binding affinity
The affinity of test compounds for the three human a2-adrenoceptor subtypes (0C2A, (X2B and 0C2c) was determined in competition binding assays with 3H-rauwolscine. 5 The biological material for these experiments consisted of membranes from Shionogi SI 15 cells stably transfected with any of the three human a2 subtypes (Maijamaki et al. 1992). Membrane (5-10 fig of total protein per sample) and 1-2 nM 3H-rauwolscine (specific activity 78 Ci/mmol) were incubated in 50 mM KH2PO4, pH 7.5 with 6 concentrations of the compounds. Each concentration was 10 run in duplicate. Non-specific binding was defined by 100 jiM oxymetazoline and corresponded to 5-15% of total binding. After 30 min at room temperature, incubations were terminated by rapid vacuum filtration through GF/B glass fiber filter and three 5 ml washes with ice-cold incubation buffer. The filters were then dried, impregnated with scintillate and their radioactivity was measured by 15 scintillation counting. The analysis of the experiments was carried out by nonlinear least square curve fitting. Experimentally determined IC50 values were converted to Ki's by making use of the Cheng-Prusoff equation (Cheng and Prusoff, 1973). Experiments were repeated a minimum of three times.
Table 1: Human oc2-adrenoceptor subtypes binding affinities. Data is presented as 20 Ki's in nM (Mean ± SEM).
Compound alpha-2A
alpha-2B
alpha-2C
A
>13000
160 ± 20
>30000
B
>4500
34 ±2
>10000
C
2000 ±400
±2
>10000
D
>10000
440 ±70
>10000
E
>5100
±4
>10000
WO 03/008387 PCT/FI02/00643
13
F
>4300
43 ±7
>10000
G
2200 ±600
32 ±5
>10000
H
>30000
8000 ±500
>30000
Results expressed in the form of " >" means that no numerical values for Ki's could be established due to lack of displacement or due to incomplete competition curves. However, the experimental data indicated that, at a minimum, the Ki's must be larger than the numbers given.
Antagonist activity on human alpha-2-adrenoceptor subtypes
Antagonist potencies were determined as the ability of test compounds to competitively inhibit epinephrine-stimulated 35S-GTPyS binding to G proteins (Tian et al., 1993; Wieland and Jakobs, 1994; Jasper et al., 1998) in membranes of CHO cells stably transfected with one of the three human 0C2 subtypes (Pohjanoksa 10 et al., 1997; Marjamaki et al., 1998). Membranes (2-6 jig of protein per sample) and 12 concentrations of test compound were preincubated for 30 min with a fixed concentration fo epinephrine (5 |iM for a2A„ 15 |iM for 0t2B> 5 |iM for 02c) in 50 mM Tris, 5 mM MgCl2, 150 mM NaCl, 1 mM DTT, 1 mM EDTA, 10 |iM GDP, 30 |iM ascorbic acid, pH 7.4 at room temperature. Binding of radiolabel was 15 started by the addition of trace amounts of 35S-GTPyS (0.08-0.15 nM, specific activity 1250 Ci/mmol) to the incubation mixture. After an additional 60 min at room temperature, the incubation was terminated by rapid vacuum filtration through glass fibre filter. Filters were washed three times with 5 ml ice cold wash buffer (20 mM Tris, 5 mM MgCl2, 1 mM EDTA pH 7.4 at room temperature), 20 dried and counted for radioactivity in a scintiallation counter. Analysis of experiments was carried out by non-linear least square fitting. Results are based on a minimum of three experiments.
14
Table 2: Antagonist effect on human (^-adrenoceptor subtypes. Data is presented as KB's in nM (Mean ± SEM).
Compound alpha-2A
alpha-2B
alpha-2C
B
14500 ±3600
75 ±9
5700 ± 700
C
5400 ±1400
17 ±5
6300 ±1400
E
7900 ±3100
29 ±5
7300 ±1100
F
8700 ±1100
240 ±60
12000 ± 2000
G
3200 ±500
86 ±64
4700 ±1800
For the purpose of the invention, the alpha-2B-adrenoceptor antagonist or its pharmaceutically acceptable salt can be administered by various routes. The 5 suitable administration forms include, for example, oral formulations; parenteral injections including intravenous, intramuscular, intradermal and subcutanous injections; transdermal or rectal administration forms. The required dosage of the compounds of the alpha-2B-adrenoceptor antagonist will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, 10 the administration route and the specific compound being employed. The suitable dose varies in the range 5 jJ.g to 100 mg per kg body weight and day for an adult person.
WO 03/008387 PCT/FI02/00643
EXAMPLES Example 1
N-f 4.6-Dimethylpvrimidin-2-vl)-4- \ (1 -ethyl-1 //-benzimidazol-2-vlmethyl)- amino] -benzenesulfonamide
Step I: Alkylation of 2-hydroxymethylbenzimidazole
99.2 mg (0.67 mmol) 2-hydroxymethylbenzimidazole was dissolved in 3 ml methanol. Potassium carbonate (103.1 g, 0.75 mmol) and diethylsulfate (442 |il 3.38 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness and purified on 10 silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals of l-ethyl-2-hydroxymethylbenzimidazole, 41 mg (32%).
Step II: Chlorination of l-ethyl-2-hydroxymethylbenzimidazole
mg (0.11 mmol) l-ethyl-2-hydroxymethylbenzimidazole was dissolved in 2 ml dichloromethane. Thionyl chloride (24 |il, 0.33 mmol) was diluted 20 times with 15 dichloromethane and the solution was added to the reaction mixture. Reaction mixture was stirred at room temperature for two hours, evaporated to dryness and washed with water to yield l-ethyl-2-chloromethylbenzimidazole as pale yellow crystals, 36 mg (95%).
Step III: Coupling reaction between l-ethyl-2-chloromethylbenzimidazole and 20 sulfamethazine
32.4 mg (0,12 mmol) sulfamethazine and 36 mg (0.18 mmol) l-ethyl-2-chloromethylbenzimidazole were dissolved in 4 ml methanol. 64 jil (0.44 mmol) triethylamine and catalytic amount of sodium iodide were added to the reaction
16
mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to provide white crystals of the title compound, 10 mg (20%). *H NMR (DMSO-d*, 500 MHz): 7.68 (2H, m), 7.60 (IH, 5 m), 7.52 (IH, m), 7.22 (IH, m), 7.17 (IH, m), 7.00 (IH, br, s), 6.78 (3H, m), 6.60 (IH, br, s), 4.60 (2H, m), 4.30 (2H, q, 7.2 Hz), 2.18 (6H, s), 1.28 (3H, t, 7.2 Hz); MS (ESI+): m/z 437 (M + H)+.
Example 2
4-r(li/-Benzimidazol-2-vlmethvlVamino1-jV"-(4.6-dimethvlpvrimidin-2-vlV 10 benzenesulfonamide
Following the procedure outlined in Step III of example 1, but without triethylamine and substituting l-ethyl-2-chloromethylbenzimidazole by 2-chloromethylbenzimidazole afforded the title compound with the yield of 51%. !H NMR (DMSO-dg, 500 MHz): 7.70 (2H, m), 7.48 (2H, br, m), 7.13 (2H, m), 15 7.11 (IH, t, 5.8 Hz), 6.70 (3H, m), 4.52 (2H, d, 5.8 Hz), 2.21 (6H, s); MS (ESI4): m/z 409 (M + H)+.
Example 3
Ar-(4.6-Dimethvlpvrimidin-2-vl)-4-r(Pvridin-4-vhnethvlVamino1-benzenesulfonamide
Following the procedure outlined in Step ID of example 1 without triethylamine and substituting l-ethyl-2-chloromethylbenzimidazole by 4-picolylchloride hydrochloride afforded the title compound with the yield of 54%. MS (ESI4): m/z 392 (M + Na)+, 370 (M + H)+.
RECTIFIED SHEET (RULE 91)
WO 03/008387 PCT/FI02/00643
17
Example 4
JV-(4.6-Dimethvlpvriimdiri-2-vl')-4-r (1 -isobutvl- li/-benzimidazol-2-vlmethvlV aminol -benzenesulfonamide (Compound A)
Following the procedure outlined in example 1, but substituting in step I ethyl 5 bromide for isobutyl iodide, afforded the tide compound with stepwise yields of 15%, 95% and 15%. 'H NMR (DMSO-dg, 500 MHz): 7.76 (2H, m), 7.70 (IH, m), 7.60 (IH, m), 7.27 (IH, m), 7.22 (IH, m), 7.15 (IH, br, t, 5.3 Hz), 6.86 (2H, m), 6.77 (IH, s), 4.65 (2H, d, 5.3 Hz), 4.13 (2H, d, 7.5 Hz), 2.27 (6H, s), 2.25 (IH, m), 0.91 (6H, d, 6.7 Hz); MS (ESI+): m/z 487 (M + Na)+, 465 (M + H)+.
Example 5
4-IY1 -Benzyl- l//-benzimidazol-2-vlmethvlVaminol-Ar-(4,6-dimethvlpvrimidin-2-vD- benzenesulfonamide
Following the procedure outlined in example 1, but substituting in step I ethyl bromide for benzyl bromide, afforded the title compound with stepwise yields of 15 23%, 90% and 18%. JH NMR (DMSO-d^, 500 MHz): 7.81 (2H, m), 7.52 (IH, m), 7.45 (IH, m), 7.30 (5H, m), 7.16 (2H, m), 6.75 (IH, s), 6.54 (2H, m), 6.02 (IH, br, s), 5.66 (2H, s), 5.63 (2H, s), 2.21 (6H, s); MS (ESI+): m/z 521 (M + Na)+, 499 (M + H)+.
Example 6
4-r( 1 -Ethvl- li/-benzimidazol-2-vlmethvl Vaminol -N-( 5-methoxvpvrimidin-2-vll-benzenesulfonamide
Following the procedure outlined in example 1 step III, but substituting sulfamethazine by 5-methoxysulfadiazine, afforded the title compound with the
RECTIFIED SHEET (RULE 91)
18
yield of 8%. Dimethylformamide was used as a solvent and additional silica gel chromatography purification with 2:1 petrol ether: ethyl acetate was needed. MS (ESI4): m/z 461 (M + Na)+, 439 (M + H)+.
Example 7
4-[('l//-Benzimidazol-2-ylmethvl')-aminol-/V-(,pvrimidin-2-vls)-benzenesulfonamide
628 mg (3.8 mmol) sulfadiazine and 728 mg (3.0 mmol) 2-chloro-methylbenzimidazole were dissolved in 10 ml 1 M NaOH. Solution was stirred and refluxed for four hours. Reaction mixture was neutralised with addition of 1 M acetic acid until product precipitated. Crystals were filtered and purified on silica 10 using gradient elution (chloroform to 5% methanol in chloroform) to obtain the title compound as white crystals with 38% yield. 'H NMR (DMSO-d6, 500 MHz): 8.46 (2H, m), 7.70 (2H, m) 7.49 (2H, br, m), 7.14 (IH, t, 5.7 Hz) 7.13 (2H, m), 6.98 (IH, m), 6.72 (2H, m), 4.53 (2H, 5.7 Hz); MS (ESI4): m/z 381 (M + H)+.
Example 8
N-(li?-Benzimidazol-2-vlmethvl')-A|r-r4-(4.6-dimethvlpvrimidin-2-vlsulfamovD-phenvll-acetamide
18 mg (0.044 mmol) 4-[(lff-benzimidazol-2-ylmethyl)-amino]-jY-(4,6-dimethyl-pyrimidin-2-yl)-benzenesulfonamide was dissolved in 2 ml of 15% pyridine in dichloromethane. Acetyl chloride (31|_tl, 0.44 mmol) was diluted with 1 ml 20 dichloromethane and solution was added to the reaction mixture. After three hours reaction mixture was washed with acidic water and organic layer was evaporated to dryness. Crystals were purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals with 30% yield. ]H NMR (DMSO-ds, 500 MHz): 7.97 (2H, m), 7.60 (2H, m), 7.48 (2H, m), 7.14 (2H, m),
19
6.68 (IH, s), 5.08 (2H, s), 2.18 (6H, s), 1.93 (3H, s); MS (ESI+): m/z 473 (M + Na)+, 451 (M + H)+.
Example 9
A^-fl-Acetyl-l//-benzimidazol-2-vlmethvl)-A^-F4-f 4.6-dimethvlpvrimidin-2-5 vlsulfamovD-phenvll -acetamide
Title compound was purified from the reaction mixture produced according to example 8 with a yield of 14%. JH NMR (DMSO-d6, 500 MHz): 8.15 (2H, m), 7.80 (2H, m), 7.55 (2H, m), 7.48 (IH, s), 7.21 (3H, m), 5.17 (2H, s), 2.54 (6H, s), 2.03 (3H, s), 1.83 (3H, s); MS (ESr"): m/z 493 (M + H)+.
Example 10
4- f (1 -Acetvl-l//-benzimidazol-2-vlmethvD-amino1 -N-f4,6-dimethylpvrimidin-2-vD-benzenesulfonamide
Following the procedure of example 8, but instead of 15% pyridine in dichloromethane only few drops of pyridine in dichloromethane were used as a 15 solvent. Method afforded the title compound with a yield similar to that for N-(1H-benzimidazol-2-ylmethyl)-A^-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phenyl]-acetamide. MS (ESr1"): m/z 451 (M + H)+.
Example 11
4-Benzvlamino-A/r-(4,6-dimethvlpvrimidin-2-vl)-benzenesulfonamide
100 mg (0.36 mmol) sulfamethazine and 70.8 jil (0.60 mmol) benzyl bromide were dissolved in 4 ml methanol. Caesium carbonate (113.4 mg, 0.35 mmol) was added and solution was refluxed overnight with stirring. The reaction mixture was then
LUKUK. h-HIUNIHTII
evaporated to dryness, and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals in a yield similar to that described in example 1 for step IH. lH NMR (CDC13, 500 MHz): 7.93 (2H, m), 7.31 (5H, m). 6.58 (3H, m), 4.36 (2H, s), 2.34 (6H, s); MS (ESI1): m/z 369 (M +
Example 12
4-f4"BromobenzvlamigoV7\^4.6-dimethvlDVrimidin-2-vlVbenzenpgii1fn^aTmrfp-
Following the procedure outlined in example 11, but substituting benzyl bromide by 4-bromobenzyl bromide, afforded the title compound with a yield of 8%. lH 10 NMR (CDC13, 500 MH2): 7.91 (2H, m), 7.45 (2H, m), 7.19 (2H, m), 639 (IH, s) 6.55 (2H, m), 4.32 (2H, s), 2.34 (6H, s); MS (ESt): m/z 469 (M + Na)+, 447 (M + H)+.
Example 13 •
A/-fAifi-nitnffthYlP'Y"Tn^in-7-Y1)-A"^-methvlbeTirvlatninf>)^heTig«neCTilfnnarniH<>
rCompoundB>
Following the procedure outlined in example 11, but substituting benzyl bromide by 2-methylbenzyl bromide, afforded the title compound in a yield similar to that described in example l'for step IE. NMR (CDCI3, 500 MHz): 7.95 (2H, m), 7.22 (4H, m)„ 6.58 (3H, m), 4.30 (2H, s), 2.35 (3H, s), 2.34 (6H, s); MS (ESI*): 20 m/z 405 (M + Na)+.
H)+.
Intellectual Property Office of N.Z.
-9 DEC 2004
RECEIVED
RECTIFIED SHEET (RULE 91)
3.dez.2003 10:45
europ. pfitentrmt nr.823 s.ll-
21
Example 14
/V-f4.6-DimethvIpvrinn'f>in-^-v1V4-<'4-methvlbeiizvIaTninfi)-hpnzenesulfonamide
Following the procedure outlined in example 11, but substituting benzyl bromide by 4-methylbenzyl bromide, afforded the title compound in a yield similar to that 5 described in example 1 for step HI, 'H NMR (CDQ3, 500 MHz): 7.92 (2H, m), 7.20 (2H, m), 7.15 (2H, m), 6.58 (3a m). 4.31 (2H, s), 2.34 (3H, s), 2.33 (6H, s); MS (ESI*): m/z 405 (M+Na)+, 383 (M + H)+.
Example15
jy-f4.6-DimeriiYlpYn*TnTdin-^-Yn-4-fl-phetiy1ethv1amiTinVhen^enesti1finnainiHft
Following the procedure outlinedin example 11, but substituting benzyl bromide by (l-bromoethyl)-benzene, afforded die title compound with a yield of 12%. XH NMR (CDCI3,500 MHz): 7.84 (2H, m), 7.31 (5H, m), 6.57 (IH, s), 6.46 (2H, m), 4.53 (IH, q, 6.7 Hz), 2,30 (6H, s), 1.54 (3H, d, 6.7 Hz); MS (SSI4): m/z 405 (M + Na)+, 383 (M + H)+.
Example 16
A^4.6-Dimethv)pYH™1'ri™-3-vl^f2-mefa°^CT^Ta™nrO-hpn7pnpg1,1frmgTT'jMp
Following the procedure outlined in example 11, but substituting benzyl bromide by 2-methoxybenzyl bromide, afforded the title compound in a yield similar to that described in example 1 for step HI. NMR (CDCI3, 500 MHz): 7.92 (2H, m), 20 7.25 (2H, m), 6.90 (2H, m), 6.59 (3H, m), 4.36 (2H, s), 3.86 (3H, s), 2.32 (6H, s); MS (ESI*): m/z 421 (M + Na)+, 399 (M + H)"".
RECTIFIED SHEET (RULE 91)
3.dez.2003 10:45
europ. pptentfimt
22
Example 17
4-C2.4-Puneth\dbenzv^Tninr>t-A/,.rd|fUriimflhy1pyrimidili-2-vlV
benzenesulfnTiamidR
Following the procedure outlined in example 11, but substituting benzyl bromide
by 2,4-dimethylbenzyl bromide, afforded the title compound with a yield of 23%. *H NMR (CDCh, 500 MHz): 7.94 (2H, in), 7.14 (1H, m), 7.03 (1H, s), 6.98 (IH, f m), 6.58 (3H, m), 4.26 (2H, s), 2.34 (6H, s), 2.31 (3H, s), 2.30 (3H, s); MS (EST*):
m/z 419 (M + Na)+, 397 (M + H)+.
Example 18
Y-(diK-T>imethvlpvriTriidin-7-vl')-4-f3-mp-ftivl>vri7v1aminnVhenzenesulfonamide
Following the procedure outlined in example 11, but substituting benzyl bromide by 3-methylbenzyl bromide, afforded the title compound with a yield of 10%. *H NMR (CDa3l 500 MHz): 7,93 (2H, m), 7.23 (lH,m), 7.11 (3H, m), 6.62 (IH, s), 6.58 (2H, m), 4.31 (2H, s), 2.36 (6H, s), 2.34 (3H, s); MS (ESI*): m/z 405 (M + # 15 Na)+, 383 (M + H)+.
Example 19
by 2,6-dichlorobenzyl bromide, afforded the title compound with the yield of 10%. 'H NMR (CDC13,500 MHz): 7.96 (2H, m), 7.34 (2H, m), 7.20 (1H, m), 6.71 (2H, m), 6.59 (IH, s), 4.63 (2H, s), 2.34 (6H, s); MS (ESD: 437 (M + H)+.
4-f2.6-Dichlorobenzy1aTwiTir>VA/-r4.6-dimefHy1pyrimifliii-2-vlVbenzenesulfnnamidp (Compound O
Following the procedure outlined hi example 11, but substituting benzyl bromide
!
RECTIFIED SHEET (RULE 91)
3.dez.2003 10=46 europ. prtentrmt nr.b23 s.13
23
Example 20
Ar-f4.6-Dimp.fhv1pvrimidm-2-viy4-rfaaphthaien-2-vlme-ThvlVamirin]-baozenesulfonamide (Compound D1
Following the procedure outlined in example 11, but substituting benzyl bromide 5 by 2-bromomethylnaphtalene, afforded the title compound with the yield of 20%. NMR (DMSOdg, 500 MHz): 7.85 (4H, m), 7.68 (2H, m), 7.47 (3H, m), 7.19 (IH, t, 5.8 Hz), 6.70 (IE s), 6.66 (2H, m), 4.49 (2H, d, 5.8 Hz), 2.21 (6H, s); MS (ESI4): m/z 441 (M + H)+.
Example 21
V-r4fi-DiTTip-rhY?pY"rri^tiin^2-vD-4-('3-mf>fhnTV>>gti7y1frrmTinVbeilzeiiesu1fnTiHTniHf>
(Compound E)
Following the procedure outlined in example 11, but substituting benzyl bromide by 3-methoxybenzyl bromide, afforded the title compound with the yield of 28%. NMR (CDC13, 500 MHz): 7.93 (2H, m), 6.86 (3H. m), 6.58 (3H, m), 4.33 (2H, 15 s), 3.78 (3H, s), 2.33 (6H, s); MS (ESI4): m/z 421 (M + Na)+, 399 (M + H)+.
Example 22
■V-(4.6"DDtiet^YlpYrimtdin-2-v1^-4-(4-nitrohfiTi^a^i>"VbenyeqeSUlfoHaniide
Following the procedure outlined in example 11, but substituting benzyl bromide by 4-nitrobenzyl bromide, afforded the title compound with a yield lower than 1 %. 20 MS (ESI4): m/z 414 (M + H)+.
I
RECTIFIED SHEET (RULE 91)
Xk3=4b LUKUH. hhi tlnihmi inr.823 s. 14
24
Example 23
A^-f4.6-Dimethvlpvrimidiii-2-vlV4-f4-trifluoromethvlhenzylflminr>)-benzenesul fan ami d e
Following the procedure outlined in example 11, bat substituting benzyl bromide 5 by 4-trifluoromethyIbenzyl bromide, afforded the title compound in a yield similar to that described in example 1 for step HI. MS (ESr): m/z 459 (M + Na)+, 437 (M
+ Hf.
Example 24
4-rBis-('4-trifluorometbvlben2YlVamirio1-V-r<i-6-diTnefhylpyninidiii-2-vlV
benzenesn1fan«Tnide
Title compound was purified from the reaction mixture produced according to example 23 with the yield of 20%. MS (EST*): 617 m/z (M + Na)+, 595 (M+H)"*.
Example 25
A/-{4 ^niTnethylpyrimi Hin-9-ylV4-r4-HifluoromethoXvben2VlamiTinV-15 benzenesulfnnamide
Following the procedure outlined in example 11, but substituting benzyl bromide by 4-trifluoromethoxybenzyl bromide, afforded the tide compound with a yield of 25%. MS (ESI*): m/z 475 (M + Na)+, 453 (M + H)+.
RECTIFIED SHEET (RULE 91)
cMWd lk) =4b europ. pfttentatit nr.823 • s.15
Example 26
4-rBis-f4-triflttarome1hoxvbeii7y1>aiTiin6l-jV,-(4.6-dime1hvlpvrimitiirt-2-vrV-benzenesulfonamide
Title compound was purified from the reaction mixture produced according to example 25 with a yield of 15%. MS (ESI4): m/z 649 (M + Naf, 627 (M + H)+.
Example 27
4-C?iS-r>irnethvlbenyvIaTTiiTin^>jV-/4.6-dimtf-rtTYlpY"rm*din-2-vlV benzenesulfonamide
Following the procedure outlined in example 11 without caesium carbonate and substituting benzyl bromide by 2,5-dimethylbenzyl bromide afforded the title compound with a yield of 35%. JH NMR (CDC13, 500 MHz): 7.93 (2H, m), 7.07 (3H, m), 6.59 (3H, m), 4.25 (2H, s), 2.33 (6H, s), 2.30 (3H, s), 2.28 (3H, s); MS (ESf): m/z 419 (M + Na)+.
Example 28
4-r2.6^DimethvlbenzYla™n")-V-(4.6-dimethvlovrimidin-2-'VD-benzenesulfonaTnide
Following the procedure outlined in example 11 without caesium carbonate and substituting benzyl bromide by 2,6-dimethylbenzyi bromide afforded the title compound with a yield of 25%. NMR (CDC13, 500 MHz): 7.99 (2H, m), 7.08 (3a m), 6.62 (3a m), 4.26 (2H, s), 2.37 (12H, m); MS (ESI4): m/z 419 (M + Na)V
RECTIFIED SHEET (RULE 91)
3.dez.2003 10:46 europ. patentfimt • nr.823 5.16
1 rifw-ri
26
Example 29
4-f3.5-DnnethoxvbeP^1atntnoVj^-f4.6-dimethyTpyrimTrjltn-^-y1V benzenesulfonamide
Following the procedure outlined in example 11 without caesium carbonate and 5 substituting benzyl bromide by 3,5-dimethoxybenzyl chloride afforded the title compound with a yield of 15%. lH NMR (CDC13, 500 MHz): 7.92 (2H, m), 6.60 ^ (IH, s), 6.58 (2H, m), 6.46 (2H, m), 6.38 (IH, m), 4.30 (2H, s), 3.76 (6H, s), 2.33
(6H, s); MS (ESI4): m/z 429 (M + H)+.
Example 30
4-f2.5-DimethoxyhenzvlaminoVM-(4.6-dimethv1pvrirrtHin-2-y1)-TTenTKnp_qi1fnnamirift
Following the procedure outlined in example 11 without caesium carbonate and substituting benzyl bromide by 2,5-methoxybenzyl chloride afforded the title compound with the yield of 13%. Reaction time was three days. *H NMR (CDC13, |£ 15 500 MHz): 7.91 (2H, m), 6.79 (3H. m), 6.58 (3H, m), 4.33 (2H, s). 3.81 (3H, s), 3.71 (3H, s), 2.33 (6R s); MS (EST*): m/z 429 (M + H)+.
Example 31
2.6-Dichlon>-Ar-r4-r4<v^imprbv1pvrimidiTi-9-yV<ni1faTiinv1)-phi>ny1l-heny^miHf»
Following the procedure outlined in example 11, but substituting benzyl bromide 20 by 2,6-dichlorobenzoyl chloride, afforded the title compound with almost quantitative yield. JH NMR (CDClj, 500 MHz): 8.11 (2H, m), 7.80 (2H» m), 7.33 (3H, m), 6.59 (ia s), 2.34 (6H, s};'MS. (EST): m/z 473 (M + H)+, 451 (M + H)+.
I
RECTIFIED SHEET (RULE 91)
.2003 10:47
europ. patentamt nr.b23 s.17
27
Example 32
4-f2-CvanobenzvlflminnV'V-(4fi-dirnerhvlpvrimidin-2-,vD-beiizenesuIfonaTnTrifi
Following the procedure outlined in example 11, but substituting benzyl bromide by a-bromo-o-tolunitrile, afforded the title compound with a yield of 21%. *H NMR (DMSO-dfi, 500 MHz): 7.83 (IH, m), 7.71 (2H, m), 7.65 (IH, in), 7.47 (2H, m), 7.15 (IH, br, t, 5.8 Hz), 6.73 (1H, m), 6.63 (2a m), 4.50 (2H, d, 5.8 Hz), 2.24 (6H, s); MS (ESI4): m/z 416 (M + Na)+, 394 (M + H)+.
Example 33
4-f2.4-Dimcthoxvbepyy1atr)inr>V-jvr-f4.6-dimethvlpvrimidin-^-Y1)-
benzenesu1fon«TTiide
62 mg (0.37 mmol) 2,4-dimethoxybenzylaldehyde and 100.9 mg (0.36 mmol) sulfamethazine were dissolved in 4 ml of 1,2-dichloroe thane. Acetic acid (168 fil, 2.8 mmol) was added to the reactipn mixture and solution was stizred with reflux overnight. Sodium triacetoxyborohydride (162.9 mg, 0.77 mmol) was dissolved to the reaction solution and refluxing was continued for three hours. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) and 2:1 petrol ether: ethylacetate to obtain the title compound as white crystals with a yield of
%. . !H NMR (CDCI3, 500 MHz): 7.91 (2H, m), 7.13 (IH, m), 6.58 (3H, m),. 6.47 (IH. m), 6.42 (IH, m), 4.53 (IH, t, 5.0 Hz), 4.30 (2H, d» 5.0 Hz), 3.82 (3H, s), 3.79 (3H, s), 2.33 (6H, s); MS (ESI4): m/z 429 (M + H)+.
RECTIFIED SHEET (RULE 91)
■ -Lia* 'Hr c.ur\wr. rMiLnmrn nr^-ot-^
28
Example 34
jy-(4.6-Ditttf*hYl pYrimidin-2-ylV4-rf 1-etfavl- l//-indol-3-vlmethvl)-aininol-benzenesu^rtn^mifif. fCompound F)
I-ethylindoIe-3-carboxaIdehyde was prepared from alkylation reaction of indole-3-5 carboxaldehyde. Indole-3-carboxaldehyde (900 mg, 6.2 mmol) was dissolved in 5 ml dimethylfonnanude, ethyl hcomide (918 (jlI, 12 mmol) and sodium hydride (282.8 mg, 12 mmol) were added to the reaction mixture. Solution was stirred and refluxed for three hours. The reaction mixture was then evaporated to dryness and washed with water. Pale brown crystals were obtained with 80% yield.
Following the procedure outlined in example 33, but substituting 2,4-dimethoxybeiizylaldehyde by 1 -ethylindole-3-carboxaldehyde, afforded the title compound with a yield similar to that of 4-C2,4-dimethoxybenzylamiiio)-A-(4,6-dimethylpyrimidin-2-yl)-ben2enesulfonamide. Instead of sodium triacetoxyborohydride sodium borohydride was used to reduce the imine 15 intermediate. *H NMR (CDC13, 500 MHz): 7.88 (2H, m), 7.52 (1H, m), 7.29 (IH,. m), 7.18 (IH, m), 7-05 (1H, m), 7.03 (1H, s), 6.56 (2H, m), 6.52 (1H, s), 4,41 (2H, d, 4.7 Hz), 4.33 (IH, t, 4.7 Hz), 4.08 (2H, q, 73 Hz), 227 (6H, s), 1.38 (3H, t, 7.3 Hz); MS (ESr*): m/z 458 (M + Na)+.
Example 35
AT-f4-r4.6-Diniethvlpvriinidiii-2-vIsulfamovlVphenvn-2-f2-methoxvphenvlV acefamide
2-Methoxyphenylacetic add (33 mg, 0.20 mmol) and sulfamethazine (55 mg, 0.20 mmol) were dissolved in 4 ml of chloroform. Triethylamine (70 jil, 0.55 mmol) and diisopropylcarbodiimide (50 |al, 0.20 mmol) were added to the reaction 25 mixture. Solution was stirred and refluxed overnight. The reaction mixture was
I
RECTIFIED SHEET (RULE 91)
.2003 10:47
europ. pfttentrmt nr.s.is
29
then evaporated to dryness, washed with water and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals with the yield of 40%. JH NMR (CDC13, 500 MHz): 8.Q4 (2H, m), 7.54 (2H, m), 7.30 (2H, m), 6.98 (2H, m), 6.60 (IH, s), 3.95 (3H, s), 3.72 (2H, s), 2.33 (6H, s); MS (ESr*): m/z 449 (M + Na)+, 427 (M + H)+.
Example 36
2-Acetvl^-r4~('4.l<!i-HiTTiet1iYlpyrimidm-2-vlsu]famovD-phenvll-benzamide
Following the procedure outlined in example 35, but substituting 2-meth-oxyphenylaceric acid by 2-acetylbenzoic acid, afforded the title compound with a yield of 11%. MS (ESV): m/z 447 (M + Na)+, 425 (M + H)+.
Example 37
1 -Methvl-l//-mdolfe~2-carboxvlic acid r4-f4.6-dimfithvlpvriniidin-9--v1sulfiamr»viy phenyl!-amide
Following the procedure outlined in example 35, but substituting 2-methoxyphenylacetic acid by l-methylindole-2-caiboxylic acid and using dimethylformamide as a solvent afforded the title compound with a yield similar to that of iV-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phaciyl]-2-(2-methoxyphenyl)-acetamide. MS (ESO: m/z 458 (M + Na)*.
RECTIFIED SHEET (RULE 91)
■ l)L£.cCUk)3 l\a-4B
t.ukop. prtentflmt nr.823 s.20
Example 38
2-f3.S-Dimetfaoxvph&nvl)-A^-f4-r4.6-dimethvlpvriimdin-2~vlsulfamovlVphearivl1-acetamide
Following the procedure outlined in example 35, but substituting 2-meth-5 oxyphenylacetic acid by 3,5-dimethoxyphenyl acetic acid, afforded the title compound with a yield of 54%, MS (ESI*): m/z 457 (M + H)+.
Example 39
Ar-r4.6-DimethvlPVrmiidin-2-vlV4-r2--f2--methoxvpheiiv1Varhy1aTninn1-benzenesul-fnTiamiH^ (Compound
33 mg (0.08 mmol) A^4-(4,6-dimethylpyrimidin-2-ylsulfornoyl)-phenyl]-2-(2~ ro£thoxyphenyl)-acetamide was dissolved in 2 ml tetrahydrofurane. 340 fil of 1 M borane tetrahydrofurane complex was added to the reaction mixture under nitrogen atmosphere and solution was stirred overnight with reflux. Reaction was quenched with 6 M HCl and the reaction mixture was neutralised with 1 M NaOH. Product 15 was extracted with chloroform and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals with a yield of 20%. 'HNMRCGDCIg, 500 MHz): 7.92 (2H, m), 7.22 (lH,m), 7.12 (IH, m), 6.89 (2H, m), 6.60 (IH, br, s), 6.54 (2H, m), 3.85 (3H, s), 3.38 (2H, t, 6.9 Hz), 2.93 (2H, t, 6.9 Hz), 2.33 (6H, s); MS (EST*): m/z 435 (M + Na)+, 413 (M + H)+.
RECTIFIED SHEET (RULE 91)
3.dez.2003 10:48 europ. pfttentftmt nr.823 ' s.21
BBS (mmi algn
31
Example 40
4- T2-f 3.5-DimethoxvphenvD-eth vl ami nr>1~ fJ-tA, (wtimeth vl pYiimidin-2-vlV benzenesulfonamide
Following the procedure outlined in example 39, but substituting #-[4_(4,6-di-5 methylpyrimidin-2-ylsulfamoyI)-phenyI]-2-(2-methoxyphenyl)-acetamide by 2-(3,5-dime!h.oxyphenyl)-N-t4-(4J6-dimethylpyriinidin-2-ylsulfainoyl)-phenyl]-acetamide, afforded the title compound with a yield of 11%. lH NMR (CDCI3,500 MHz): 7.92 (2H, m), 6.58 (IH, s), 6.54 (2H, m), 6.34 (3H, s), 4.20 (IH, t, 5.8 Hz), 3.76 (6H, s), 3.42 (2H, m), 2.85 (2H, t, 6.9 Hz), 2.34 (6H, s); MS (ESI*): m/z 465 10 (M + Na)\443(M + H)+.
Example 41
A-men7.hydry1flminn)-Ar.(d1fi-dimetfavlpvriiniriin-?-ynt-benzenesnlfonamide (Compound BP
Sulfamethazine (105 mg, 0.38 mmol) and diphenylchlaromethane (77 ill, 0.38 15 mmol) were dissolved in 3 ml pyridine. Solution was stilted and refluxed overnight The reaction mixture was evaporated to dryness and dissolved to 1M NaOH. Product was precipitated with 1 M acetic acid. Precipitation cycle was repeated for three times to give white crystals of the tide compound with a yield of 8%. MS (ESI4): m/z 467(M + Na)+, 445 (M + H)+.
Example 42
4-(4-Aminoberavlammo>iV-f4.6-dimethvlpvrimidin-2-viybenzenesulfonamide
18 mg (0.04 mmol) of A^(4,6-dimethylpyrimidin-2-yl)-4-(4-nitrobenzylamino)-b enzenesulfonamlde was dissolved in 1 ml of tetrahydrofurane. Hydrazinium
Intellectual Property Office of N.Z.
- 9 DEC 2004
RECEIVED
RECTIFIED SHEET (RULE 91)
32
hydrate (50 |il, 1.5 mmol) and catalytic amount of palladium on charcoal were added to the reaction mixture. Solution was stirred overnight. The reaction mixture was evaporated to dryness and purified on silica using gradient elution (chloroform to 4% methanol in chloroform) to obtain with a yield of 59%. MS 5 (ESI*): m/z 406 (M + H)+, 384 (M + H)+.
Example 43
4- {f 4-(4.6-Dimethvlpvrimidin-2-vlsulfamovl Vphenvlaminol-methvl 1 -benzamide
4- {[4-(4,6-Dimethylpyrimidin-2-ylsulfamoyl)-phenylamino] -methyl} -benzoic acid methyl ester was prepared like described on example 11 and was treated with 25% 10 ammonia to obtain the title compound with a yield lower than 1%. ]H NMR (CDC13, 500 MHz): 7.81 (2H, m), 7.67 (2H, m), 7.37 (2H, m), 7.12 (IH, br, t, 6.0 Hz), 6.72 (IH, s), 6.60 (2H, m), 4.37 (2H, d, 6.0 Hz), 2.33 (6H, s); MS (ESI+): m/z 412 (M + H)+.
Example 44
4-(TC 2.6-Dichloro-phenvD-hvdroxv-methvll -amino 1 - jV-(4.6-dimethvlpvrimidin-2-vlVbenzenesulfonamide
11 mg (0.02 mmol) of 2,6-dichloro-Ar-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phenyl]-benzamide was dissolved in 2 ml tetrahydrofurane. Lithium aluminium hydride (6 mg, 0.16 mmol) was added to the reaction mixture under nitrogen 20 atmosphere and solution was stirred overnight. The reaction mixture was filtered, evaporated to dryness and purified by on silica using gradient elution (chloroform to 4% methanol in chloroform) to obtain the title compound with a yield of 18%. MS (ESI4): m/z 475 (M + Na)+.
33
It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the specialist in the field that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are 5 illustrative and should not be construed as restrictive.
REFERENCES
Cheng, Y., and Prusoff, W.H., 1973. Biochem. Pharmacol. 22: 3099
Jasper, J.R., Lesnick, J.D., Chang, L.K., Yamanashi, S.S., Chang, T.C., Hsu, S.A.O., Daunt, D.A., Bonhaus, D.W., and Egen, R.M., 1998. Biochem. Pharmacol. 10 55:1035
Marjamaki, A., Ala-Uotila, S., Luomala, K., Perala, M., Jansson, C., Jalkanen, M., Regan, J.W., and Scheinin, M., 1992. Biochem. Biophys. Acta 1134:169
Marjamaki, A., Pihlavisto, M., Cockcroft, V., Heinonen, P., Savola, J.-M., and Scheinin, M., 1998. Mol. Pharmacol. 53: 370
Pohjanoksa, K., Jansson, C.C., Luomala, K., Marjamaki, A., Savola, J.-M., and Scheinin, M., 1997. Eur. J. Pharmacol. 35: 53
Tian, W.-N., Duzic, E., Lanier, S.M., and Deth, R.C., 1993. Mol. Pharmacol. 45: 524
Kumar, V.B., Reddy, M.V., Indian J. Chem., Sect. B (1985), 24B(12), 1298-1301
Farag, A.M., El-Mouafi, H.M., Khalifa, M., 1991. Egypt. J. Pharm. Sci. 32 (3-4), 951-9
Wieland, T., and Jakobs, K.H., 1994. Meth. Enzymol. 237: 3
Claims (22)
1. A compound of formula (I) R4.R5 (I) or a pharmaceutically acceptable salt thereof wherein Ri, R2, R3, R4 and R5 are independently selected from the list consisting of H, a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched alkoxy group with 1 to 4 carbon atoms and a halogen; X is selected from the group consisting of H , a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, phenyl and -OH; Z is selected from the group consisting of H , acetyl, -CH2-Ph-0-CF3 and -CH2-Ph-CF3, where Ph is phenyl; Y is a ring structure linked to formula (I) directly or with an alkyl chain having one or two carbon atoms, wherein the ring structure is selected from the group consisting of a, b, c and d; a) is selected from the group consisting of phenyl, monosubstituted phenyl and disubstituted phenyl where each substituent is independently selected from the group consisting of a halogen, a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy chain with 1 to 4 carbon atoms, a halogen substituted 36 methyl, a halogen substituted methoxy group, a nitrile, an amide, amino, and a nitro group; b) is selected from the group consisting of 2-benzimidazolyl, 2-imidazolyl, 2-indolyl, 3-indolyl, mono substituted 2-benzimidazolyl, mono substituted 2-imidazolyl, mono substituted 2-indolyl, mono substituted 3-indolyl, disubstituted 2-benzimidazolyl, disubstituted 2-imidazolyl, disubstituted 2-indolyl and disubstituted 3-indolyl, wherein in the substituted species the substituents are independently chosen from the list consisting of a straight chain alkyl with from 1 to 4 carbon atoms, a branched chain alkyl with from 1 to 4 carbon atoms, a straight chain alkoxy with from 1 to 4 carbon atoms, a branched chain alkoxy with from 1 to 4 carbon atoms, and a halogen; further, in any of the species, one N has zero or one substituent that is selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy chain with 1 to 4 carbon atoms and benzyl; (c) is selected from the group consisting of pyridinyl, mono substituted pyridinyl and disubstituted pyridinyl where each substituent is independently selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy group with 1 to 4 carbon atoms, and a halogen; (d) is selected from the group consisting of naphthyl, mono substituted naphthyl and disubstituted naphthyl where each substituent is independently selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy group with 1 to 4 carbon atoms, and a halogen; 37 excluding 4-[(l//-benzimidazol-2-ylmethyl)-amino]-iV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4- [(1 -methyl-1H-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide, 7V-(4,6-dimethyl pyrimidin-2-yl)-4- [(1 -ethyl- l//-benzimidazol-2-ylmethyl)-amino]-benzene sulfonamide, Af-(4-methyl-2-pyrimidinyl)-4-[(li/-benzimidazol-2-ylmethyl)-amino]-benzenesulfonamide and N-(4-methyl-2-pyrimidinyl)-4-[[(1 -methyl-1H-benzimidazol-2-yl)-methyl]-amino]-benzenesulfonamide.
2. A compound of formula (I) according to claim 1 wherein Ri and R3 are methyl and R2, R4 and R5 are H.
3. A compound of formula (I) according to claim 1 or 2 wherein X is H , Y is selected from the group consisting of phenyl, mono substituted phenyl and disubstituted phenyl where in the substituted species the substituents are independently chosen straight chain alkoxy groups or branched chain alkoxy groups and Z is H .
4. A compound of formula (I) according to claim 1, wherein said compound is selected from the list consisting of 4-(2,4-dimethoxybenzylamino)-AL(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfonamide, 4-(3,5-dimethoxybenzylamino)-AL(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-Af-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and A/-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzyl-amino)-benzenesulfonamide.
5. A compound of formula (I) according to claim 1 or 2 wherein X is H , Y is selected from the group consisting of a phenyl, mono substituted phenyl and disubstituted phenyl, where in the substituted species the substituents are independently chosen from the group consisting of a branched chain alkyl, a straight chain alkyl and a halogen and Z is H . Intellectual Property Office of N.Z. 17 NOV 2004 RECEIVED 38
6. A compound of formula (I) according to claim 1, wherein said compound is selected from the group consisting of 4-benzylamino-iV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, yV-(4,6-dimethylpyrimidin-2-yl)-4-(2-methylbenzylamino)-benzenesulfonamide, 4-(2,4-dimethylbenzylamino)-AL (4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, A^-(4,6-dimethylpyrimidin-2-yl)-4-(3-methylbenzylamino)-benzenesulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4-(4-methylbenzylamino)-benzenesulfonamide, 4-(2,5-dimethylben-zylamino)-7V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,6-di-methylbenzylamino)-7V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(4-bromobenzylamino)-7V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide and 4-(2,6-dichlorobenzylamino)-jV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide.
7. A compound of formula (I) according to claim 2 selected from the group consisting of A^-(4,6-dimethylpyrimidin-2-yl)-4-[(l-ethyl-l//-indol-3-ylmethyl)-amino]-benzenesulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4-[(l-isobutyl-l//-benzimidazol-2-ylmethyl)-amino] -benzenesulfonamide, Af-(4,6-dimeth-ylpyrimidin-2-yl)-4-( 1 -phenylethylamino)-benzenesulfonamide, 7V-(4,6-dimeth-ylpyrimidin-2-yl)-4-[2-(2-methoxyphenyl)-ethylamino]-benzenesulfonamide and A^-(4,6-dimethylpyrimidin-2-yl)-4-[(naphthalen-2-ylmethyl)-amino]-benzene-sulfonamide.
8. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation useful for the treatment or prevention of a disease mediated by the alpha-2B-adrenoceptor in a mammal wherein R4,R5 (I) liiteliiotiml Property Office of MX 1 7 NOV Mk 39 Rl . ^2 > R3 ) R( and R5 are independently selected from the list consisting of H, a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched alkoxy group with 1 to 4 carbon atoms and a halogen; X is selected from the group consisting of H , a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, phenyl, or -OH and =0 ; Z is selected from the group consisting of H, acetyl, -CH2-Ph-0-CF3 and -CH2-Ph-CF3, where Ph is phenyl; Y is a ring structure linked to formula (I) directly or with an alkyl chain having one or two carbon atoms, wherein the ring structure is selected from the group consisting of a, b, c and d; a) is selected from the group consisting of phenyl, mono substituted phenyl and disubstituted phenyl where each substituent is independently selected from the group consisting of a halogen, a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy chain with 1 to 4 carbon atoms, a halogen substituted methyl, a halogen substituted methoxy group, an acetyl, a nitrile, an amide, amino, and a nitro group; b) 2-benzimidazolyl, 2-imidazolyl, 2-indolyl, 3-indolyl, directly or with wherein in the substituted species the substituents are independently chosen from the list consisting of a straight chain alkyl with from 1 to 4 carbon atoms, a branched chain alkyl with from 1 to 4 carbon atoms, a straight chain alkoxy with from 1 to 4 carbon atoms, a branched chain alkoxy with from 1 to 4 carbon atoms, and a halogen; further, in any of the species, one N has zero or one substituent that is selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy " {nleFikusl Property Qni-V- O* MX \ 7 m 2004 40 group with 1 to 4 carbon atoms, a branched chain alkoxy chain with 1 to 4 carbon atom and benzyl; (c) is selected from the group consisting of pyridinyl, mono substituted pyridinyl and disubstituted pyridinyl where each substituent is independently selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy group with 1 to 4 carbon atoms, and a halogen; (d) is selected from the group consisting of naphthyl, mono substituted naphthyl and disubstituted naphthyl where each substituent is independently selected from the group consisting of a straight chain alkyl group with 1 to 4 carbon atoms, a branched alkyl group with 1 to 4 carbon atoms, a straight chain alkoxy group with 1 to 4 carbon atoms, a branched chain alkoxy group with 1 to 4 carbon atoms, and a halogen; excluding A^-(4,6-dimethylpyrimidin-2-yl)-4-[( 1-methyl-l//-benzimidazol-2-ylmethyl)-amino] -benzenesulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4-[(1 -ethyl-l//-benzimidazol-2-ylmethyl)-amino] -benzenesulfonamide and N-[4-(4,6-dimethylpyrimidin-2-ylsulfamoyl)-phenyl]-4-ethoxy-benzamide.
9. Use of compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 wherein Rx and R3 are methyl and R2, R4 and R5 are H.
10. Use of compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 or 9 wherein X is H , Y is selected from the group consisting of phenyl, mono substituted phenyl and disubstituted phenyl where in the substituted species the substituents are independently chosen straight chain alkoxy groups or branched chain alkoxy groups and Z is H . Intellectual Property Office of N.2. 1 7 NOV 2004 41
11. Use of compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 wherein said phenyl is substituted and said alkoxy substituent is methoxy, said compound is selected from the group consisting of 4-(2,4-dimethoxybenzylamino)-Af-(4,6-dimethylpyrimidin-2-yl)-benzene sulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-(3-methoxybenzylamino)-benzenesulfonamide, 4-(3,5-dimethoxybenzylamino)-7V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,5-dimethoxybenzylamino)-7V-(4,6-dimethyl pyrimidin-2-yl)-benzenesulfonamide and Ar-(4,6-dimethylpyrimidin-2-yl)-4-(2-methoxybenzylamino)-benzenesulfonamide.
12. Use of compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 or 9 wherein X is H, Y is selected from the group consisting of a phenyl, mono substituted phenyl and disubstituted phenyl, where in the substituted species the substituents are independently chosen from the group consisting of a branched chain alkyl, a straight chain alkyl and a halogen, and Z is H .
13. Use of compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 wherein said compound is selected from the group consisting of 4-benzylamino-A^-(4,6-dimethylpyrimidin-2-yl)-benzene sulfonamide, J¥-(4,6-dimethylpyrimidin-2-yl)-4-(2-methylbenzylamino)-benzene sulfonamide, 4-(2,4-dimethylbenzylamino)-iV-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, iV-(4,6-dimethylpyrimidin-2-yl)-4-(3-methylbenzylamino)-benzenesulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4-(4-methylbenzylamino)-benzenesulfonamide, 4-(2,5-dimethylbenzylamino)-7V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide, 4-(2,6-dimethylbenzylamino)-7V-(4,6-dimethyl pyrimidin-2-yl)-benzenesulfonamide, 4-(4-bromobenzylamino)-7V-(4,6-dimethyl pyrimidin-2-yl)-benzenesulfonamide and 4-(2,6-dichlorobenzylamino)-J/V-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide. Intellectual Property Office o? N.Z. 1 7 KSV 2004 42
14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 9 wherein said compound is selected from the group consisting of 4-[( l//-benzimidazol-2-ylmethyl)-amino]-7V-(4,6-dimethyl pyrimidin-2-yl)-benzenesulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-[(l-ethyl-l//-indol-3-ylmethyl)-amino]-benzenesulfonamide, 7V-(4,6-dimethyl pyrimidin-2-yl)-4-[(1 -isobutyl- l//-benzimidazol-2-ylmethyl)-amino] -benzene sulfonamide, Ar-(4,6-dimethylpyrimidin-2-yl)-4-( 1 -phenylethylamino)-benzene sulfonamide, 7V-(4,6-dimethylpyrimidin-2-yl)-4-[2-(2-methoxyphenyl)-ethyl amino]-benzenesulfonamide and A^-(4,6-dimethylpyrimidin-2-yl)-4-[(naphthalen-2-ylmethyl)-amino]-benzenesulfonamide.
15. The use according to any one of claims 8 to 14, wherein the disease is a coronary heart disease (CHD).
16. The use according to any one of claims 8 to 14, wherein the disease is selected from the group consisting of acute myocardial infarction (AMI), unstable angina pectoris, Prinzmetal's variant form of angina pectoris, other forms of chronic angina pectoris, CHD, and restenosis after coronary angioplasty.
17. The use according to any one of claims 8 to 14, wherein the disease is essential hypertension.
18. The use according to any one of claims 8 to 14, wherein the disease is a vascular disesase, which is selected from the group consisting of vasoconstriction subsequent to subarachnoid haemorrhage, hypoxic brain damage subsequent to subarachnoid haemorrhage, migraine, Raynaud's disease, cold intolerance, pre-eclampsia, male erectile dysfunction and obesity. intellectual Prooerty Oifico of M2. 1 7 MOY 2004 .Received 43
19. The use according to any one of claims 8 to 14, wherein said alpha-2B-adrenoceptor antagonist is administered to a mammal to potentiate the clinical efficacy of an anaesthetic and/or analgetic alpha-2-adrenoceptor agonist, said agonist not being selective for the alpha-2B-adrenoceptor subtype.
20. The use according to any one of claims 8 to 14, wherein said alpha-2B-adrenoceptor antagonist is administered to an individual having a deletion of 3 glutamates from the glutamic acid repeat element of 12 glutamates (amino acids 297-309), in an acid stretch of 17 amino acids, located in the third intracellular loop of the receptor polypeptide.
21. The use according to claim 20 wherein said individual is a deletion/deletion genotype.
22. The compound as claimed in claim 1 and substantially as hereinbefore described with reference to any one of the forgoing Examples. intellectual Property Ofrice of I'vi.Z. 17 NOV 2GM
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30644901P | 2001-07-20 | 2001-07-20 | |
| FI20011560A FI116940B (en) | 2001-07-20 | 2001-07-20 | New N-pyrimidinyl para-aminobenzenesulfonamide derivatives as Alpha-2B adrenoceptor antagonists, useful for treating e.g. coronary heart disease, myocardial infarction, angina, restenosis and hypertension |
| PCT/FI2002/000643 WO2003008387A1 (en) | 2001-07-20 | 2002-07-22 | Compounds useful for treatment or prevention of disease mediated by alpha-2b-adrenoceptor |
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| EP (1) | EP1417182A1 (en) |
| JP (1) | JP2004535467A (en) |
| CA (1) | CA2454187A1 (en) |
| HU (1) | HUP0401076A2 (en) |
| IL (1) | IL159511A0 (en) |
| MX (1) | MXPA04000615A (en) |
| NZ (1) | NZ530366A (en) |
| PL (1) | PL367040A1 (en) |
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| FI118265B (en) * | 2004-01-15 | 2007-09-14 | Jurilab Ltd Oy | A method for detecting the risk of acute myocardial infarction and coronary heart disease |
| PL1861101T3 (en) | 2005-03-23 | 2013-06-28 | Klat Pharma Animal Health Gmbh | Use of amides of sulfadimidine for the treatment of intestinal diseases in veterinary science |
| EA202091020A1 (en) | 2017-10-24 | 2020-07-24 | Байер Акциенгезельшафт | SUBSTITUTED IMIDAZOPYRIDINAMIDES AND THEIR APPLICATION |
| WO2020216669A1 (en) | 2019-04-23 | 2020-10-29 | Bayer Aktiengesellschaft | Phenyl-substituted imidazopyridine amides and use thereof |
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| RU2086544C1 (en) * | 1991-06-13 | 1997-08-10 | Хоффманн-Ля Рош АГ | Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity |
| US6150389A (en) * | 1994-07-11 | 2000-11-21 | Allergan Sales, Inc. | Comformationally rigid bicyclic and adamantane derivatives useful as α2 -adrenergic blocking agents |
| BR0108221A (en) * | 2000-02-11 | 2003-03-05 | Juvantia Pharma Ltd Oy | Use of a selective alpha-2b-adrenoceptor antagonist for the manufacture of a pharmaceutical preparation and method for treating or preventing an alpha-2b-adrenoceptor-mediated disease in a mammal |
| MXPA02010651A (en) * | 2000-04-28 | 2003-03-10 | Sankyo Co | PPARggr; MODULATORS. |
-
2002
- 2002-07-22 EP EP02748902A patent/EP1417182A1/en not_active Withdrawn
- 2002-07-22 NZ NZ530366A patent/NZ530366A/en unknown
- 2002-07-22 PL PL02367040A patent/PL367040A1/en not_active Application Discontinuation
- 2002-07-22 CA CA002454187A patent/CA2454187A1/en not_active Abandoned
- 2002-07-22 JP JP2003513947A patent/JP2004535467A/en not_active Withdrawn
- 2002-07-22 RU RU2004105035/04A patent/RU2004105035A/en not_active Application Discontinuation
- 2002-07-22 MX MXPA04000615A patent/MXPA04000615A/en unknown
- 2002-07-22 HU HU0401076A patent/HUP0401076A2/en unknown
- 2002-07-22 WO PCT/FI2002/000643 patent/WO2003008387A1/en not_active Application Discontinuation
- 2002-07-22 IL IL15951102A patent/IL159511A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003008387A1 (en) | 2003-01-30 |
| EP1417182A1 (en) | 2004-05-12 |
| JP2004535467A (en) | 2004-11-25 |
| PL367040A1 (en) | 2005-02-21 |
| RU2004105035A (en) | 2005-06-27 |
| IL159511A0 (en) | 2004-06-01 |
| MXPA04000615A (en) | 2004-04-20 |
| HUP0401076A2 (en) | 2004-09-28 |
| CA2454187A1 (en) | 2003-01-30 |
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| Date | Code | Title | Description |
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| PSEA | Patent sealed | ||
| RENW | Renewal (renewal fees accepted) |