AU763541B2 - Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers - Google Patents

Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers Download PDF

Info

Publication number
AU763541B2
AU763541B2 AU46410/99A AU4641099A AU763541B2 AU 763541 B2 AU763541 B2 AU 763541B2 AU 46410/99 A AU46410/99 A AU 46410/99A AU 4641099 A AU4641099 A AU 4641099A AU 763541 B2 AU763541 B2 AU 763541B2
Authority
AU
Australia
Prior art keywords
compound
propane
piperazin
hydrochloride salt
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU46410/99A
Other versions
AU4641099A (en
Inventor
Nitya Anand
Jang Bahadur Gupta
Sanjay Jain
Anita Mehta
Anil Kumar Saxena
Neelima Sinha
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/120,265 external-priority patent/US6083950A/en
Priority claimed from PCT/IB1999/000140 external-priority patent/WO2000005206A1/en
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of AU4641099A publication Critical patent/AU4641099A/en
Application granted granted Critical
Publication of AU763541B2 publication Critical patent/AU763541B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C07D207/408—Radicals containing only hydrogen and carbon atoms attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

WO 00/05205 PCT/IB99/01296 ARYLPIPERAZINE DERIVATIVES USEFUL AS UROSELECTIVE ALPHAI-ADRENOCEPTOR BLOCKERS 1. Field of the Invention The present invention relates to certain novel piperazine derivatives having protracted uro-selective ca,-adrenoceptor antagonistic activity exceeding those of previously described compounds. The compounds of the present invention hold promise for treating benign prostatic hyperplasia (BPH). This invention also relates to methods for making the novel compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hyperplasia using the compounds.
2. Description of the Related Art A review in J.Med.Chem., 1997, V.40, No.9, pp.
12 9 2 1 3 15, describes the most important pharmacological options available at present in the treatment of benign prostatic hyperplasia. The two most successful therapies are based on a-adrenergic receptor antagonism and androgen levels modulation by 5a-reductase inhibitors. 5a-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. a,-antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore the preferred modalities of treatment in the control of benign prostrate hypertrophy. c,-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure.
CONFIRMATION COPY a
C
WO 00/05205 PCT/IB99/01296 Thus, a,-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
The more important of the a,-adrenoceptor antagonists which are currently used in the management of BPH are shown below.
PRAZOSIN
TERAZOSIN
DOXAZOSIN
(RH-)-TAMSULOSIN
ALFUZOSIN
2 WO 00/05205 PCT/IB99/01296 However, most of these known drugs are associated with vascular side effects postural hypertension, syncope, dizziness, headaches, etc.) due to lack of selectivity of action between prostatic and vascular ca-adrenoceptors. Clearly, al-adrenoceptor antagonists which have inherently greater selectivity for prostatic ca-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective cr adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
Recently, it has been demonstrated that the prostate tissue of higher species like man and dog is overvalued by low affinity alA-adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel al-antagonists, namely, a new class of piperazine compounds, with greater selectivity of action against cIA adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.
There are many descriptions in the literature of the pharmacological activities associated with phenyl piperazines. Eur. J. Med. Chem.-Chimica Therapeutica 1977, V. 12, No. 2, pp.
173-176, describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below as anorectic agents with no CNS side effects.
2 0 N N-(CH 2 )n-
N
ORq)
R
WO 00/05205 WO 0005205PCTIIB99/01 296 The synthesis and pharmacology of some 2 3 -(4-aryl-l-piperazinyl)propyl]-IHbenz[de] isoquinolin-1I,3-(2TH-diones/2,5-pyrrolidinediones Indian Chem. Soc., 1986, V. DLII, pp.529-530), ofN-(N 4 -aryl-N'-piperozinylmethyl)-4-(4 '-methoxyphenyl)piperidine-2,6-diones Indian Chem. Soc., 1978, v. LV, pp.819-821), and of N-(N 4 -arylpiperazinylalkyl)- phthalirnides Indian Chem. Soc.. 1979, V. LVI, pp. 1002-1005), as shown below, have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals.
N N-(CH2)n--A n 1-3 o N 0 OJ1777O However, in those papers there is no mention of the adrenoceptor blocking activity of these compounds, and thus their usefulness in the treatment of benign prostate hyperplasia did not arise.
The earlier synthesis of various 1-(4-aryl-piperazin-l-yl)-3-(2-oxo-pyrrolidin-1yl/piperidin-1-yl) alkanes and their usefulness as hypotensive and antischemic agents is disclosed in unpublished Indian patent applications DEL 496/95 (March 3, 1995), DEL/500/95 (March 21, 1995) and DEL/96/96 (March 29, 1996) by the inventors herein.
These compounds had low al-adrenergic blocking activity (pKi 6 as compared to >8 of the known a -antagonists such as prazosin), and practically no adrenoceptor sub-class selectivity for alA vs. lB or alD adrenoceptors. It has now been discovered that structural modification of these compounds from lactam to dioxo compounds, from 2oxopyrrolidin to 2,5-dioxopyrrolidin and 2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for tlA in comparison to alBadrenoceptor blocking activity, an essential requirement for compounds to be good candidates for treatment of BPH.
3. Object of the Invention It is an object of the present invention to ameliorate at least some of the disadvantages of the prior art.
4. Summary of the Invention Accordingly the present invention provides a compound selected from the group consisting of 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopyrrolidin-1yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin-l-yl]-3-(2,6- S* dioxopiperidin- -yl)propane or its hydrochloride salt; 1-[4-(2-methylphenyl)piperazin-1- Syl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt; l-[4-(2-pyridyl)piperazin- S. 1-yl)-3-(2,6-dioxopyrrolidin-l-yl)propane or its hydrochloride salt; Methoxyphenyl)piperazin-1-yl]-3-[2,5-dioxo-3-phenyl-pyrolidin-l-yl]propane or its hydrochloride salt; or 1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin-l-yl] propane or its hydrochloride salt.
The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia; for the selective antagonising of al-adrenergic receptors in a mammal; or for the treatment of vascular disease, congestive heart failure or hypertension. These compositions comprise an effective amount of at least one of the above mentioned compounds with a pharmaceutically acceptable carrier.
That is the particular compounds of the invention is given below: 21/05/2003sw I812spa,5 Compound Chemical Name No.
1. 1- [4-(2-methoxyphenyl)piperazin- Il-yl]-3-(2,5-dioxopyrrolidin-1 -yl)propane 2. 1- [4-(2-methoxyphenyl)piperazin- l-yl]-3 -(2,6-dioxopiperidin- 1-yl)propane 3. 1-1 4-(4-fluorophenyl)piperazin- I-yl]-3 -(2,6-dioxopiperidin- 1 -yl)propane 4. 1- [4-(2-methylphenyl)piperazin- l-yl]-3-(2,6-dioxopiperidin- 1 -yl)propane 1-[4-(2-pyridyl)piperazin- l-yl)-3-(2,6-dioxopiperidin- 1-yl)propane 6. 1- [4-(2-methoxyphenyl)piperazin- I-yl]-3-[2,5 -dioxo-3 -phenyl-pyrolidin- yl]propane 7. 1 -[4-(phenyl)piperidin-l -yl]-3-[2,5-dioxopyrolidin- 1 -yl]propane The present invention further provides a method of selectively antagonising cc,-adrenergic receptors in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of methoxyphenyl)piperazin- l-yl] -3 -dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt; 1- [4-(2-methoxyphenyl)piperazin- l-yl]-3-(2,6-dioxopyrrolidin- 1-yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin- 1-yl]-3-(2,6-dioxopiperidin-l yl)propane or its hydrochloride salt; 1-[4-(2-methylphenyl)piperazin- 1-yl]-3-(2,6dioxopiperidin-1 -yl)propane or its hydrochloride salt; 1- [4-(2-pyridyl)piperazin- 1-yl)-3- (2,6-dioxopyrrolidin- 1-yl)propane or its hydrochloride salt; Methoxyphenyl)piperazin- 1 -yl] [2,5-dioxo-3-phenyl-pyrolidin- 1 -yl]propane or its hydrochloride salt; or l-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin-1-yl] propane or its hydrochloride salt, or of a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
The present invention also provides a method for treating benign prostatic hypertrophy in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of 1- [4-(2-methoxyphenyl)piperazin- 1 -yl]-3- 1-yl)propane or its hydrochloride salt; methoxyphenyl)piperazin- 1 -yl] -3 -(2,6-dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt; 1- [4-(2-methylphenyl)piperazin- 1-yl]-3-(2,6-dioxopiperidin- 1yl)propane or its hydrochloride salt; 1-[4-(2-pyridyl)piperazin-l-yl)-3-(2,6-
S
21/05/2003swI 1812spa,6 dioxopyrrolidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-Methoxyphenyl)piperazin- 1-yl]-3-[2,5-dioxo-3-phenyl-pyrolidin-1-yl]propane or its hydrochloride salt; or 1-[4- (Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin- I-yl] propane or its hydrochloride salt, or of a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
The present invention also provides a method for treating vascular disease, congestive heart failure, or hypertension in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of methoxyphenyl)piperazin- 1-yl]-3-(2,5-dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt; 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin- I1-yl]-3-(2,6-dioxopiperidin- yl)propane or its hydrochloride salt; 1-[4-(2-methylphenyl)piperazin-1-yl]-3-(2,6dioxopiperidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-pyridyl)piperazin-1-yl)-3- (2,6-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; Methoxyphenyl)piperazin- 1 -yl]-3-[2,5-dioxo-3-phenyl-pyrolidin- 1 -yl]propane or its hydrochloride salt; or 1-[4-(Phenyl)piperidin- 1 -yl]-3-[2,5-dioxopyrolidin-1-yl] propane or its hydrochloride salt, or of a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
The present invention further provides a method for making a compound having the structure of Formula I *R4
(CH
2 )m S-Y q Z' RIR (CH2)n-CH-CH2-N X 1 its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, or prodrugs, wherein Y is O or S; Q, X, Z and Z' are independently CH or N; m=0- 3; n= 0-4; R 1 R2 are independently selected from: H, F, Cl, Br, OCH 3
OC
2 Hs, OCH 2
CF
3
SCF
3
CH
3
C
2
H
5
CF
3 isopropyloxy, and cyclopropyl; R 3 is H, R 6 OH or OR 6 R6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R 4 R5, are H, C 1 .00 3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring, o.
7 21/05/2003swil1812spa,7 which comprises reacting a compound having the structure of Formula III' ~(CH2)mn with a compound having the structure of Formula IV Cl-(GH 2 )n--CH-CH 2
-N
Z R 2 thereby to produce the compound of Formula 1.
The present invention also provides a method for making a compound having the structure of Formula I (C11 2
)M
(CH
2 )n-CH-CHr---N
R
3
R
its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, or prodrugs, wherein Y is 0 or S; Q, Z and Z' are independently CHI; X is CH or N; m=0-3; n= 0-4; R 1 R2 are independently selected from: H, F, Cl, Br, OCH 3 0C 2
H
5
OCH
2
CF
3
SCF
3
CH
3
C
2 1- 5
CF
3 isopropyloxy, and cyclopropyl; and R 3
R
4 and R 5 are independently H, C 1 3 alkyl, substituted or unsubstituted phenyl, or a 5 -membered spiro ring, except when R, -R 5 are H; mis 0; nis 2; Qis CH; Xis N; Yis 0; Zand Z' are N, and :except when R, is H; R 2 is H; Cl or CH 3
R
3
-R
5 are H; mis 0; nis 1; Xis N; Yis0; Zand Z' are CH, 21/O5/2003sw18 182spa,8 which comprises reacting a compound having the structure of Formula VI' (CHz)m Y O with a compound having the structure of Formula V in pyridine at reflux temperature followed by reflux in the presence of acetic anhydride z'--R
H
2
N-(CH
2 )n--CH-CH 2 -N X- Z-R2 (v) thereby to produce the compound of Formula I.
The present invention also provides a method for making a compound having the (CH2)m
(CH
2 )n-CH-CH2-N X SZ-- yRI structure of Formula I its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, or prodrugs, wherein Y is O or S; Q, X, Z and Z' are independently CH or N; m=0-3; n= 0- 4; RI, R 2 are independently selected from: H, F, Cl, Br, OCH 3
OC
2 Hs, OCH 2
CF
3
SCF
3
CH
3
C
2
H
5
CF
3 isopropyloxy, and cyclopropyl; R 3 is H, R 6 OH or OR 6
R
6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R 4
R
5 are H, C 1 -3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring, 21/05/2003swl 1812spa,8 which comprises reacting a compound having the structure of Formula VIIP R(CH2)MR
(CH
2 )n-CH-CH 2 C1
R
3 with a compound having the structure of Formula VIII in the presence of a base and dimethylformamide solvent at a temperature from about 60-80'C for about 10- 18 hours (Vill) thereby to produce the compound of Formula I.
00* 21/O5/2003sw181S2spa,8 WO 00/05205 PCT/IB99/01296 Detailed Description of the Invention Sa. Synthesis of the compounds of the invention The compounds of the present invention may be prepared by one of the reaction sequences (Schemes I, II III) shown below to yield compounds of Formula II with the Rt, R2, R3, R, 5R, R6, m, n, Z, Q and Y groups as defined above. The starting materials for Schemes I, II and III may be suitably adapted to produce the more general compounds of Formula I.
Scheme I Scheme-I shows the synthesis of compounds of the Formula II in which RI, R2, R3, R4,
R
5 R6, n, Z, Q, X, and Y are as defined earlier. The preparation comprises condensing a,co-dicarboximides of Formula III with 1-(4-arylpiperazin-1-yl)-oa-chloroalkanes of Formula IV, in the presence of a base and an organic solvent at a temperature ranging from 80-150 0 C for a period varying between 8-24 hours to produce the corresponding 1-(4-arylpiperazin-1-yl)-(a-[N- (ot,c-dicarboximido)]alkanes of the Formula II where RI and R 2 have the meanings given above.
Phase transfer catalysts, preferably tetrabutylanmmoniumn bromide, are particularly useful in catalysing the reaction.
WO 00/05205 WO 0005205PCTIIB99/01296
(CH
2
)M'
O-/O
H
(01)
R
1 C1-(H 2 )ri---CH-CH 2 -N X I Z R 2
R
3 Scheme-I WO 00/05205 WO 0005205PCTIIB99/01296 Scheme 11 The compounds of Formula 11 can also be prepared by condensation of the piperazines of the Formula V with the anhydrides of Formula VI wherein Rl, R 2
R
3 Y, Z, X, and mn' are as defined above.
(CH2)m' 0 0
(VI)
H
2
N-(CH
2 )n--CH-C11 2 -N I R 2
R
3 (CH)n-CHCHrN
X
I z ]R2 Scheme-fl ~4 WO 00/05205 PCTIIB99/01296 Scheme-III The compounds of Formula 11 can also be prepared by alkylation of the ct,codicarboximide moiety with a,co-dihaloalkanes followed by condensation of I -(o0haloalkyl)dicarboximide thus obtained (Formula VII) with I -arylpiperazines (Formula VIII) as shown below, wherein RI, R 2
R
3 Y, Z, X, m' and n are as defined above. The reaction is preferably carried out in the presence of a base and an organic solvent at a temperature ranging from 60-1 00 aC for a period varying between 10-24 hours to produce the corresponding 1 arylpiperazin-1-yl)-o-[N-(a,o-.dicarboximido)alanes of Formula 11. Phase transfer catalysts, more preferably tetrabutylanimonium bromide and potassium iodide, are useful in catalysing the reaction.
(CH
2 )m' o\\N (cH 2 )-cH--cH 2 -a
X
3
(VII)
H-N
X/
(VII)
-CH-C1 2 N
X-<
I
3 Z}-R2 Scheme-DIl WO 00/05205 PCT/IB99/01296 In the above Schemes, where specific bases, acids, solvents, phase transfer catalysts, etc., are mentioned, it is to be understood that other acids, bases, solvents, phase transfer catalysts, etc., known to those skilled in the art may also be used. Similarly, the reaction temperature and duration of the reactions may be adjusted according to the desired needs.
The starting piperazines of the Formulas IV, V and VIII are known in the art and may be synthesized by the procedures described in Kiritzy, et al., J. Med. Chem., 1978, V. 21, p. 1301 U.S. Patent No. 3,637,705 (Abbott, 1972); FR 2,179,491 (1973); Aggarwal et al., Ind. J. Chem., 1982, V.21B, pp. 435-439; and U.S. Patent No. 2,922,788 (Parcell, 1960).
5b. Pharmacological Testing Results The affinity of the compounds of the invention for each subtype of oa-adrenoceptor can be assessed by receptor binding assays (RBA's) described in the examples given below. It should be noted that the identification and characterization of the foregoing receptors is still in progress and that their types and subtypes are subject to review and refinement.
Receptor binding and in vitro functional assay studies described below indicated that the compounds of the present invention possess selective and potent a1, adrenoceptor antagonistic activity over the and aD adrenoceptors. The present invention also provides a method to demonstrate the selective affinity of the compounds for prostatic tissues over vascular tissues.
Further, the examples presented below describe a method to treat BPH in mammals wherein the test compounds alleviated pressure at dosages which did not result in significant change in blood WO 00/05205 PCT/IB99/01296 pressure. Several of the compounds of present invention demonstrated manifest selectivity for prostatic tissues in comparison to known compounds, such as terazosin, doxazosin, etc. The compounds of the present invention also lowered the blood pressure with prolonged duration of action. The compounds of the present invention have been demonstrated to be useful for treating warm blooded animals and mammals. These compounds can be administered orally or parenterally in suitable pharmaceutical compositions.
Preferred compounds of the invention are 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5dioxopyrrolidin- 1-yl)propane (Compound No. 1-[4-(2-methoxyphenyl)piperazin- 1-yl]-4-(2,5dioxopyrrolidin-l-yl)butane (Compound No. and l-[4-(2-methoxyphenyl)piperazin-l-yl]-3- 2 ,6-dioxopiperidin-l-yl)propane (Compound No. 13).
Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention having the utility of the free bases of Formulas I and II may be formed with inorganic or organic acids, by methods well known in the art and may be used in place of the free bases.
Representative examples of suitable acids for formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric and nitric acids.
The present invention also includes within its scope prodrugs of the compounds of Formulas I and II. In general, such prodrugs will be functional derivatives of these compounds which are readily converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
WO 00/05205 PCT/IB99/01296 The invention also includes the enantiomers, diastereomers, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites having the same type of activity. The invention further includes pharmaceutical compositions comprising the molecules of Formula I and II, or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
In yet another aspect, the invention is directed to methods for selectively blocking aA receptors by delivering in the environment of said receptors, to the extracellular medium (or by administering to a mammal possessing said receptors), an effective amount of the compounds of the invention.
The invention will now be illustrated by the following non-limiting examples.
Preparation of 1-[4-(4-Fluorophenyl)piperazin--yl]-3-[2,5-dioxopyrrolidin-l-ylpropane (Compound No. 1) Scheme-I: A mixture of 2 ,5-dioxopyrrolidine (0.500 g, 5 mmol), l-[4-(4-fluorophenyl)piperazin-l-yl]-3-chloropropane (1.28 g, 5 mmol), potassium carbonate (0.502 g, 3.75 mmol) and tetrabutylammonium bromide (0.322 g, 1 mmol) in acetone (25 ml) was refluxed for 16 hours at 800C with stirring. The solvent was evaporated off in vacuo and the residue was suspended in water (80 ml). The aqueous solution was extracted with chloroform (3x50 ml), and the WO 00/05205 PCT/IB99/01296 organic layers combined, washed with water (2x50 ml), dried over Na 2
SO
4 and evaporated i vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as eluent; yield 1.00 g oil.
Scheme-11: l-amino-3-[4-(4-fluorophenyl)piperazin-l-yl]propane (0.700 g, 2.95 mmol) and succinic anhydride (0.295 g, 2.95 mmol) were refluxed in pyridine (10 ml) for 10 hours.
Acetic anhydride (2 ml, excess) was added and the mixture was further refluxed for 5 hours.
Solvent was removed in vacuo and the residue was suspended in water and extracted with chloroform (2x25 ml). Organic layers were combined, washed with water (2x25 ml), dried over Na 2
SO
4 and concentrated. The compound was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as eluent; yield 0.436 g oil.
Scheme-II: A mixture of l-chloro-3-(2,5-dioxopyrrolidin-l-yl) propane (1.54 g, 8.80 mmol), l-( 4 -fluorophenyl)piperazine (1.58 g, 8.80 mmol), potassium carbonate (1.21 g, 8.80 mmol) and potassium iodide (0.146g, 0.88 mmol) in N,N-dimethylformamide (25 ml) was heated at 100 C for 18 hours. Solvent was evaporated under reduced pressure. Residue was shaken with water (25 ml), extracted with chloroform (2x25 ml), and the organic layers combined, washed with water (2x20 ml), dried over Na 2
SO
4 and concentrated to give an oil which was purified by column chromatography over flash silica gel using chloroform-methanol 98:2) as eluent; yield 2.00g oil.
WO 00/05205 PCT/IB99/01296 The hydrochloride salt of 1-[4-(4-fluorophenyl)piperazin-l-yl]-3-(2,5-dioxopyrrolidin-1yl)-propane (Compound No. 1) was formed in quantitative yield by the addition of ethereal hydrogen chloride solution to a methanolic solution of the free base and the resultant precipitate was collected by filtration, m.p 246-2470C.
Preparation of 1-[4-(2-methoxyphenyl)piperazin-l-yl]-3-[2,5-dioxopyrrolidin-l-yl]propane (Compound No. 2) Scheme-I: A mixture of 2,5-dioxopyrrolidine (3.68 g, 37.24 mmol), 1-[4-(2-methoxyphenyl)piperazin-l-yl]-3-chloropropane (10.0 g, 37.24 mmol), potassium carbonate (7.70 g, 55.8 mmol) and tetrabutylammonium bromide (2.38 g, 7.4 mmol) in acetone (100 ml) was refluxed for 12 hours at 80 0 C with stirring. The solvent was evaporated off in vacuo and the residue was taken up in water (80 ml). The aqueous solution was extracted with chloroform (3 x 50 ml) and the organic layers combined, washed with water (2 x 50 ml), dried over Na 2
SO
4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (99:1) as eluent; yield 8.00 g in oil. The hydrochloride salt was prepared by the method described above; mp 199-202 0
C.
WO 00/05205 PCT/IB99/01296 Scheme-II: A mixture of l-chloro-3-(2,5-dioxopyrrolidin-l-yl) propane (28.00 gm, 159.5 mmol), l-(2-methoxyphenyl)piperazin hydrochloride (36.45 g, 159.5 mmol), potassium carbonate (44.03 g, 319.0 mmol) and potassium iodide (1.58 g, 9.57 mmol) in N,N-dimethylformamide (115 ml) was heated at 80°C for 17 hours and the solvent was evaporated under reduced pressure. Residue was suspended in ethyl acetate (600 ml), washed with water (5 x 100 ml.) and dried over Na 2
SO
4 and concentrated to give an oil which was purified by column chromatography over silica gel (100- 200 mesh) using chloroform-methanol (99:2) as eluent; yield 55.1 g, oil. The hydrochloride salt of this product was formed in the manner described above; mp 199-202°C.
1-Chloro-3-(2,5-dioxopyrrolidin-1-yl)propane can be prepared by the reaction of dioxopyrrolidine and 1-bromo-3-chloropropane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
Preparation of 1-[4-(2-methoxyphenyl)piperazin-1-yl]-4-[2,5-dioxopyrrolidin-l-yl]butane (Compound No. 9) Scheme-EI: A mixture of 1-chloro-4-(2,5-dioxopyrrolidin-l-yl)butane (11.0 g, 58.04 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (12.99 g, 56.85 mmol), potassium carbonate (16.02 g, 116.09 mmol) and potassium iodide (0.577 g, 3.48 mmol) in N,N-dimethylformamide (45 ml) was stirred at 100"C for 18 hours. N,N-dimethylformamide was evaporated at reduced pressure and the residue was taken up in water (100 ml) and extracted with chloroform (2x100 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1- WO 00/05205 PCT/IB99/01296 [4-(2-methoxyphenyl)piperazin-l-yl]-4-(2,5-dioxopyrrolidin-l-yl)butane as an oil which was purified by column chromatography over silica gel (230-400 mesh) using chloroform-methanol (98:2) as eluent; yield 18.00 g, oil. Hydrochloride salt was prepared by the method described above; mp 218-220°C.
1-Chloro-4-(2,5-dioxopyrrolidin-1-yl)butane can be prepared by the reaction of dioxopyrrolidine and 1-bromo-3-chlorobutane in the presence of potassium carbonate and tetrabutylammonium bromide in acetone.
Preparation of 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-[2,6-dioxopiperidin-1-yl)propane (Compound No. 13) Scheme-I: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol), 1-[4-(2-methoxyphenyl)piperazin-l-yl]-3-chloropropane (6.18 g, 23.02 mmol), potassium carbonate (2.38 g, 17.27 mmol) and tetrabutylammonium bromide (1.48 g, 4.60 mmol) in acetone (80 ml) was refluxed for 16 hours at 80°C with stirring. The solvent was evaporated off in vacuo and the residue suspended in water (60 ml), extracted with chloroform (3x40 mmol) and the organic layers combined, washed with water (2.40 ml), dried over anhydrous NazSO4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel (230-400 mesh) using chloroform-methanol (98:1) as eluent; yield 3.58 g oil.
WO 00/05205 PCT/IB99/01296 The hydrochloride salt was prepared in the quantitative yield by the method described above; m.p.
206-210°C.
Scheme-III: A mixture of 1-chloro-3-(2,6-dioxopiperidin- -yl)propane (22.06 gm, 116.40 mmol), l-(2-methoxyphenyl)piperazine (21.90 g, 114.06 mmol), potassium carbonate (16.06g, 116.40 mmol) and potassium iodide (1.16g, 6.98 mmol) in N,N-dimethylformamide ml), was heated at 80 0 C for 17 hrs. and the solvent was evaporated under reduced pressure.
Residue was dissolved in ethyl acetate (400 ml), washed with water (5 x 100 ml) and dried over Na 2
SO
4 and concentrated to given an oil which was purified by column chromatography over silica gel (100-200 mesh) using chloroform-methanol (99:1) as eluent; yield 33.8 g, oil. The hydrochloride salt was prepared in the quantitative yield by the addition of excess ethereal hydrogen chloride solution to a methanolic solution of the free base and collected by filtration of the resultant precipitate; m.p. 206-210 0
C.
An illustrative list of the compounds of the invention which were synthesized by one or more of the above described methods is now given.
l-[ 4 4 -Fluorophenyl)piperazin-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane hydrochloride; m.p.
246-247 0
C.
1-[ 4 -(2-Methoxyphenyl)piperazin-l-yl]-3-(2,5-dioxopyrrolidin-l-yl)propane hydrochloride; m.p. 199-202*C.
WO 00/05205 WO 0005205PCT/1B99/01296 1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane hydrochloride; m.p. 218-2200C.
1-[4-(2-Pyridyl)piperazin-1-yll-3-(2,5-dioxopyrrolidin-1-yl)propane hydrochloride; m.p.
261-262 0
C.
1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane hydrochloride; m.p.
230-2310C.
1-[4-(2-Pyrimidyl)piperazin-1-yI]-3-(2,5-dioxopyrrolidin-1-yI)propane hydrochloride; m.p.
196-1980C.
1-[4-(3,4-Dinethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin41-y) propane hydrochloride; m.p. 244-2460C.
1-[4-(Phenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yI) propane hydrochloride; m.p. 258- 259 0
C.
1-[4-(2-Methoxyphenyl)piperazin-1-ylI-4-(2,5-dioxopyrrolidin-1-yobutame hydrochloride; m.p.
218-220 0
C.
WO 00/05205 PT19/19 PCT/IB99/01296 1-[4-(2-Methoxyphenyl)piper-azin-1-ylJ-2-(2,5-dioxopyrrolidin-1-yI)ethane hydrochloride; m.p. 232-234*C.
1-[4-(3-Methoxyphenyl)piperazin-1-ylJ-3-(2,5-dioxopyrrolidin-l-yl)propane hydrochloride; m.p. 199-201*C.
1-[4-(4-Methoxyphenyl)piperazin-1-ylI-3-(2,5-dioxopyrrolidin-1-yl)propane hydrochloride; m.p. 240-242*C.
1-[4-(2-Methoxyphenyl)piperazin-1-ylJ-3-(2,6-dioxopiperidin-1-yl)-propane hydrochloride; m.p. 206-210*C.
1-[4-(4-Fluorophenyl)piperazin-1-yII-3-(2,6-dioxopiperidin-1-y)propane; 200-202 0
C.
1-f4-(4-Chlorophenyl)piperazin-1-ylJ-3-(2,6-dioxopiperidin-1-yl)propane hydrochloride; m.p. 206-208*C.
1-[4-(3-Trifluoromethylphenyl)piperazin-1-ylj-3-(2,6-dioxopiperidin-1 -yl)propane hydrochloride; m.p. 228-229*C.
1-[4-(2-FiuorophenyI)piperazin-1-yI-3-(2,6-dioxopiperidin-1-yl)propane hydrochloride; m.p. 215-216 0
C.
WO 00/05205 WO 0005205PCTIIB99/01296 l-[ 4 2 -MethylphenY)piperain1y1-3-(2,6-dioxopiperidin-1.y~propane hydrochloride; m.p.
206-207 0
C.
1-[ 4 2 -Pyridyl)piperazin-1byl).3..(2,6-dioxopiperidin.1.yl) propane hydrochloride; m.p. 244-245*C.
l-[ 4 3 -Chlorophenyl)piperazin -l-ylJ-3 6-dioxopiperidin -l-yl)propane hydrochloride; m.p. 214-215*C.
l-[ 4 3 4 -Dimethylphenyl)piperazin-1-yJ 3 2 6 -dioxopiperidin-l-yI)propane hydrochloride; low melting hygroscopic.
l-[ 4 2 -Pyrimidyl)piperazin.1yI..3.(2,6..dioxopipetidin-1..yl)propafle hydrochloride; m.p. 195-196 0
C.
1-4(-ehxpey~ieai--ll3(,-ixpprdn1y~rpn hydrochloride; m.p. 196-197*C.
1-4(-ehxpey~ieai--ll3(,-ixpprdn1y~rpn hydrochloride; m.p. 218-220*C.
WO 00/05205 PCT/IB99/01296 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,6-dioxopiperidin--yl)butane hydrochloride; m.p. 190-192 0
C.
1-[4-(2-Methoxyphenyl)piperazin-l-ylxo-(2,-dioxo-3-phenylpyrrolidin--yl]propane hydrochloride; m.p. 171-172°C.
1-f 4 -(Phenyl)piperadin-1-yl]-3-(2,5-dioxopyrrolidin-l-yl]propane hydrochloride; m.p.
208-209 0
C.
All the melting points reported above are uncorrected and measured by an open capillary method using Buchi 535.
Receptor Binding Assay In vitro receptor binding Receptor binding assays (RBA's) were performed for native al-adrenoceptors. Rat submaxillary and rat liver membrane preparations were used to assess the affinity for IA^ and as subtypes, respectively. Aliquots of membrane protein (100 200 mg) were incubated in a final volume of 250 ml assay buffer (50 mM Tris, 0.5 mM EDTA at pH 7.4) with 0.5 nM [3H] prazosin for 60 mins at 28 0 C. Reaction was stopped by rapid filtration on Millipore filters. Filters were dried and bound radioactivity counted. Non-specific binding was determined in the presence WO 00/05205 WO 0005205PCT[IB99/01296 of 0.3 mM prazosin. Protein was assayed according to the method of protein estimation by Lowry, O.H. et al., J. Biol. Chem., V. 193, pp. 265-275 (1951). Results are listed in Table I.- Table I Compound No.
7BA In Vitro Functional Assay (pKB) In Vivo BP nM) alA a1B alA aIB aID Fall in Duration in mmiHg mini.
Compound 1 >2500 1000 7.1 7.0 6.8 5.0 15.0 Compound 2 19 244 8.7 7.6 7.3 25 120.0 Compound 3 1500 1000 7.2 5.0 !Compound 4 1660 2100 5.6 Compound 5 106 175 5.3 5.3 7.0 Compound 6 1140 >250 4.7 5.3 6.5 0 Compound 7 450 282 6.4 6.7 6.5 Compound 8 57 590 7.5 6.6 Compound 9 1 35 9.0 8.0 8.3 46 >180 Compound 10 1600 2350 6.9 6.7 6.9 Compound 11 >2500 >250 0 WO 00/05205 WO 0005205PCTfIB99/01296 Compound 12 >2500 >250 0 Compound 13 3 168 8.6 8.0 7.9 50.0 >180 Compound 14 67 1192 8.4 7.4 7.1 20.0 60.0 Compound 15 520 201 6.7 6.0 6.2 Compound 16 345 765 6.5 6.9 Compound 17 21 396 8.0 7.1 17.9 50.0 120.0 Compound 18 9 1267 8.2 5.5 8.5 40.0 >150 Compound 19 164 >250 6.4 6.7 0 Compound 20 22 113 7.5 7.6 Compound 21 2130 176 6.5 6.7 6.5 Compound 22 >2500 >250 6.4 7.0 0 Compound 23 2170 940 Compound 24 z2500 >250 Compound 25 1.6 7.5 Compound 26 30 600 Compound 27 1300 2000 WO 00/05205 PCT/IB99/01296 In vitro Functional Studies In vitro al-Adrenoceptor selectivity In order to study selectivity of action of the present compounds towards different a-adrenoceptor subtypes, the ability of these compounds to antagonize cl-adrenoceptor agonist induced contractile response of aorta (aID), prostate (alA) and spleen was studied. Aorta, prostate and spleen tissues were isolated from urethane anaesthetized (1.5 gm/kg) male wistar rats.
Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition NaCI 118; KCI 4.7; CaCI, 2.5; MgSO 4 7H20 1.2; NaHCO 3 25; KHPO 1.2; glucose 11.5. Buffer was maintained at 37 0 C and aerated with a mixture of 95% 02 and 5% C02.
A resting tension of 2g (aorta) or 1 g (spleen and prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders.
Tissues were allowed to equilibrate for 2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylephrine (spleen and prostate) were obtained in the absence and presence of the tested compound (at concentrations of 0.1, 1 and 10 iM).
Antagonist affinity was calculated and expressed as pKB values in Table 1.
In vitro Receptor Selectivity Selectivity of action of the present componds was tested against a range of different receptors, 1B- and ;o-adrenergic, muscarinic cholinergic, serotoninergic histaminergic angiotensin II, endothelin (ET, and as well as calcium and potassium thannels. Rat aorta was used to study the effect of the compounds on 5-HT2A,-ETA, calcium WO 00/05205 PCT/IB99/01296 and potassium channels. Angiotensin II receptor antagonistic activity was studied in rabbit aorta.
Muscarinic cholinergic receptor and ETB receptor antagonistic activity was studied in rat trachea, while guinea pig trachea was used to study H 1 receptor antagonistic activity. Electrically stimulated rat vas deferens was used to investigate the effect of c2-adrenoceptors, while 1,adrenoceptor antagonistic activity was studied using electrically stimulated rat ventricular strips.
Results of this selectivity study is shown in (Table 2).
Table 2 Selectivity Study Receptor Type pK, ac-adrenergic B-adrenergic Muscarinic HI-Histaminergic 5-HT2A
ETA
ETB
Angiotensin II Calcium Channel Potassium Channel NE No effect Not tested.
Compound 2
NE
4.2 5.0 5.3 7.6
NE
NE
Compound 9
NE
5.0 5.4 7.9 4.3 5.4 5.6
NE
NE
Compound 13
NE
5.1 5.7 4.3 4.9 5.3
NE
WO 00/05205 PCT/IB99/01296 In vivo Antihypertensive Effect Antihypertensive effect of selected compounds according to the invention were studied for their ability to lower blood pressure in anaesthetized and conscious normotensive and spontaneously hypertensive rats via intravenous, oral and intraduodenal routes. Results are shown in Tables I and 3.
Anaesthetized Normotensive Rats Intravenous Route Male wistar rats were anaesthetized with urethane (2.5 g/kg). Femoral vein and carotid artery were cannulated. Blood pressure and heart rate were recorded using Statham pressure transducer. Data was recorded on Grass polygraph as well as using online data acquisition system (Buxco AT). Intravenously administered compounds of the invention were initially tested at 0.3 mg/kg over a period of 3 hours for their effect on blood pressure and the results are shown in Table 1. For a select few of the compounds, the blood pressure lowering effect upon intravenous administration was also studied at dosages of 0.03, 0.1, 0.3, and 1 mg/kg.
Intraduodenal Route Male wistar rats were fasted for 18 hours. Rats were anaesthetized with urethane. Femoral vein and carotid artery were cannulated. A catheter was placed in the duodenum following lapratomy. The compounds of the present invention (at dosages of 0.3, 1, 3 and 10 mg/kg) were administered in the duodenum and blood pressure was monitored for 3 hours. Results are recorded in Table 3.
WO 00/05205 PCT/IB99/01296 Table 3 Effect on mean arterial pressure in anaesthetized normotensive rats.
Compound Dose Mean Arterial Pressure Duration No. (mg/kg) Change from basal) of Action Compound 2 1 -19 2.5 hr 3 -43 2.5 hr -42 2.5 hr Compound 9 1 -19 3.0 hr 3 -53 3.0 hr -57 3.0 hr Compound 13 1 -32 3.0 hr 3 -40 3.0 hr -42 3.0 hr Conscious Normotensive Rats Femoral artery of normotensive male wistar rats, maintained on an overnight light diet, were catheterized under pentobarbitone anaesthesia (35 mg/kg). Femoral artery catheter was exteriorized through the neck region for blood pressure recording. Compounds of the present invention (at dosages of 0.1, 0.3 and 1 mg/kg) were administered 24 hours following surgery through oral route in the form of gavage to overnight fasted rats. Blood pressure and heart rate were recorded with the help of Statham pressure transducer on a Grass polygraph and the results are shown in Table 4.
WO 00/05205 PCT/IB99/01296 Table 4 Effect on systolic blood pressure in conscious spontaneously hypertensive rats Compound No. Dose Systolic Pressure (mg/kg) Change from basal) (at 6 hours) 0 Compound 2 Compound 9 12.0 13.0 17.0 0.4 -24.0 -25.0 18.0 19.0 14.0 Compound 13 Conscious Spontaneously Hypertensive Rats Spontaneously hypertensive rats weighing between 250 300 g were used in this study.
Rats were fasted overnight. Blood pressure was monitored from tail artery using semi-automatic noninvasive blood pressure monitoring apparatus. Compounds of the present invention (at dosages of 1, 3, 10, and 30 mg/kg) were administered orally. Blood pressure was monitored prior to and 1.5, 4, 6 and 24 hours after drug administration. Results are shown in Table WO 00/05205 PCT/IB99/01296 Table Effect on mean arterial blood pressure in conscious freely moving normotensive rats.
Compound No. Dose Mean Arterial Pressure (mg/kg) Change from basal) Compound 2 3 -14 Compound 9 1 -4 -11 Compound 13 1 3 In Vivo Selectivity Study Male mongrel dogs (12 20 Kg) were anaesthetized with pentobarbitone sodium mg/kg, iv). Trachea was intubated for artificial respiration. Femoral artery and femoral vein were cannulated for recording blood pressure and for administration of drug solutions, respectively. Blood pressure was recorded on a polygraph through a pressure transducer. A paramedian incision was made lateral to the penis and the bladder was exposed. Urine was drained through a cannula put directly into the bladder and it was guided into the urethra gently and was placed at the prostatic urethra. Balloon was inflated with 2 cc air and its placement was confirmed by digital pressure. Intraurethral pressure was recorded on the polygraph through a pressure transducer. Graded dose response relationship of phenylephrine (1-16 Vtg/kg, iv) was obtained on prostatic pressure and blood pressure, prior to administration of the compounds of WO 00/05205 PCT/IB99/01296 the present invention. Compounds 2, 9, and 13 (at dosages of 0.01, 0.03, 0.1, and 0.3 mg/kg) were administered intravenously 10 min before obtaining phenylephrine dose response curves.
Results were analyzed and pseudo pKB values were calculated as described in Kenny et al (1996). Results are shown in Table 6.
Table 6 Effect on blood pressure and intraurethral pressure in anaesthetized dogs pseudo pK, Blood Pressure Intraurethral Pressure Compound 2 6.9 7.60 Compound 9 7.4 7.9 Compound 13 7.1 8.1 While the invention has been described by reference to specific embodiments, this was for purposes of illustration only. Numerous alternative embodiments will be apparent to those skilled in the art and are deemed to be within the scope of the invention.
33a Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.
16/01/01,td11812.com.doc,33

Claims (23)

1. The compound which is 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5- dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt.
2. The compound which is 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6- dioxopyrrolidin-1-yl)propane or its hydrochloride salt.
3. The compound which is 1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6- dioxopiperidin-l-yl)propane or its hydrochloride salt.
4. The compound which is 1-[4-(2-methylphenyl)piperazin-1-yl]-3-(2,6- dioxopiperidin- 1 -yl)propane or its hydrochloride salt. The compound which is 1-[4-(2-pyridyl)piperazin- 1-yl]-3-(2,6-dioxopyrrolidin- 1- yl)propane or its hydrochloride salt.
6. The compound which is 1- [4-(2-Methoxyphenyl)piperazin-1-yl]-3- [2,5-dioxo- 3- phenyl-pyrolidin- 1 -yl]propane or its hydrochloride salt.
7. The compound which is 1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin- 1- yl] propane or its hydrochloride salt.
8. A pharmaceutical composition comprising a compound of any one of the preceding claims together with a pharmaceutically acceptable carrier.
9. A method of selectively antagonising cL-adrenergic receptors in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of methoxyphenyl)piperazin- 1-yl]-3-(2,5 -dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt; 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6- dioxopyrrolidin-l1-yl)propane or its hydrochloride salt; fluorophenyl)piperazin- 1-yl]-3-(2,6-dioxopiperidin- 1 -yl)propane or its hydrochloride salt; 1-[4-(2-methylphenyl)piperazin-1l-yl]-3-(2,6-dioxopiperidin- ~1-yl)propane or its hydrochloride salt; 1-[4-(2-pyridyl)piperazin-1-yl)-3-(2,6- dioxopyrrolidin-1-yl)propane or its hydrochloride salt; Methoxyphenyl)piperazin- 1-yl]-3-[2,5 -dioxo-3 -phenyl-pyrolidin- 1 -yl]propane or its hydrochloride salt; or 1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin- 1- yl]propane or its hydrochloride salt, or of a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
10. The method of claim 9 wherein said compound is l-[4-(2-methoxy- phenyl)piperazin- l-yl]-3-(2,5 -dioxopyrrolidin- 1 -yl) propane or its hydrochloride salt. S.i 21/05/2003swi l812spa,34
11. The method of claim 9, wherein said compound is methoxphenyl)piperazin- 1 -yl]4-(2,5-dioxopyrrolidin-1-yl)butane) or its hydrochloride salt.
12. The method of claim 9, wherein said compound is methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt.
13. A method for treating benign prostatic hypertrophy in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3- (2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; methoxyphenyl)piperazin- 1-yl]-3-(2,6-dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin- 1- yl)propane or its hydrochloride salt; 1-[4-(2-methylphenyl)piperazin-1-yl]-3-(2,6- dioxopiperidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-pyridyl)piperazin- 1- yl)-3-(2,6-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; Methoxyphenyl)piperazin- 1-yl]-3-[2,5-dioxo-3 -phenyl-pyrolidin- 1 -yl]propane or its hydrochloride salt; or 1-[4-(Phenyl)piperidin-1l-yl]-3-[2,5-dioxopyrolidin- 1- yl]propane or its hydrochloride salt, or a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
14. The method of claim 13, wherein said compound is 1-[4-(2-methoxyphenyl) piperazin-1-yl]-3-(2,5-dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt. The method of claim 13, wherein said compound is methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane or its hydrochloride salt.
16. The method of claim 13, wherein said compound is methoxyphenyl)piperazin- 1 -yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt.
17. A method for treating vascular disease, congestive heart failure, or hypertension in a mammal comprising administering to said mammal an effective amount of at least one compound selected from the group consisting of methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopyrrolidin- 1-yl)propane or its hydrochloride salt; 1-[4-(2-fluorophenyl)piperazin-1-yl]-3-(2,6- dioxopiperidin-1-yl)propane or its hydrochloride salt; 21/05/2 0 03swl 1812spa,35 methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt; 1-[4-(2-pyridyl)piperazin-1-yl)-3-(2,6-dioxopyrrolidin-1- yl)propane or its hydrochloride salt; 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3- [2,5-dioxo-3-phenyl-pyrolidin-1l-yl]propane or its hydrochloride salt; or 1-[4- (Phenyl)piperidin-1-yl]-3 [2,5-dioxopyrolidin- l-yl] propane or its hydrochloride salt, or of a composition comprising said at least one compound together with a pharmaceutically acceptable carrier.
18. The method of claim 17, wherein said compound is 1-[4-(2-methoxyphenyl) piperazin- l-yl]-3 -dioxopyrrolidin- 1 -yl)propane or its hydrochloride salt.
19. The method of claim 17, wherein said compound is minethoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane or its hydrochloride salt. The method of claim 17, wherein said compound is methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane or its hydrochloride salt.
21. A method for making a compound having the structure of Formula I (CH 2 )m R Z' -R (CHn-CHHf-N X R K 3 its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, amides, or prodrugs, wherein Y is O or S; Q, X, Z and Z' are independently CH or N; m=0-3; n= 0-4; R 1 R 2 are independently selected from: H, F, Cl, Br, OCH 3 OC 2 H 5 OCH 2 CF 3 SCF 3 CH 3 C 2 Hs, CF 3 isopropyloxy, and cyclopropyl; R 3 is H, R 6 OH or OR 6 R 6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R4, R 5 are H, C, 1 3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring, S* which comprises reacting a compound having the structure of Formula III' 21/05/2003swl 812spa,36 ~(CH2)MR H with a compound having the structure of Formula IV C1-(CH 2 )n--CH-CH 2 N- thereby to produce the compound of Formula I.
22. The method of claim 21 for producing a compound having the structure of Formula 11 (CH2Wn V (CH2n-CH-CHf-N I R 2 wherein n, X, Z, R 1 R 2 and R 3 are as defined for Formula I and mn' =1-4, which comprises reacting a compound having the structure of Formula III 21105/2003sw1l8I2spa,37 H (MI) with said compound of Formula IV.
23. A method for making a compound having the structure of Formula I (CH 2 )M (CH 2 )n-CH-CHf-N X-K/j R 3 its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, or prodrugs, wherein Y is 0 or S; Q, Z and T'are independently CH; X is CH or N; m=0-3; n= 0-4; R 1 R 2 are independently selected from: H, F, Cl, Br, OCH 3 0C 2 H- 5 OCH 2 CF 3 SCF 3 CH 3 C 2 H 5 CF 3 isopropyloxy, and cyclopropyl; and R 3 R 4 and R 5 are independently H, C 13 alkyl, substituted or unsubstituted 0000 phenyl, or a 5-membered spiro ring, except when R 1 -R 5 are H; m is 0; n is 2; Q is dO969: CH; X is N; Y is 0; Z and Z' are N, and except when R, is H; R 2 is H; Cl or CH- 3 R 3 -R 5 are H; m is 0; n is 1; X is N; Y is 0; Z and Z' are CH, which comprises reacting a compound having the structure of Formula VI R4 *see sea* *a S 21/05/2 00 3sw I l8l2spa,38 with a compound having the structure of Formula V in pyridine at reflux temperature followed by reflux in the presence of acetic anhydride /te\ th'-R H 2 N-(CH 2 )n--CH-CH 2 -N X-- V. R 2 (V) thereby to produce the compound of Formula I.
24. The method of claim 23 for producing a compound having the structure of Formula II o wherein n, X, Z, RI, R 2 and R 3 are as defined for Formula I and 1-4, which comprises reacting a compound having the structure of Formula VI (CH2)mi (VI) with said compound of Formula V. 21/05/2003swl 1812spa,39 A method for making a compound having the structure of Formula I its pharmaceutically acceptable salts, esters, amides, enantiomers, diastereomers, N-oxides, or prodrugs, wherein Y is O or S; Q, X, Z and Z' are independently CH or N; m=0-3; n= 0-4; RI, R 2 are independently selected from: H, F, Cl, Br, OCH 3 OC 2 H 5 OCH 2 CF 3 SCF 3 CH 3 C 2 H 5 CF 3 isopropyloxy, and cyclopropyl; R 3 is H, R 6 OH or OR 6 R 6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R 4 R 5 are H, C 1 -3 alkyl, substituted or unsubstituted phenyl, or a spiro ring, which comprises reacting a compound having the structure of Formula VII' (CH2)m R4 MI (CH 2 )n-CH--CH 2 CL with a compound having the structure of Formula VIII in the presence of a base and dimethylformamide solvent at a temperature from about 60-80 0 C for about 10-18 hours :H-N X .*cm R 21/05/20 0 3swl 1812spa,40 thereby to produce the compound of Formula I.
26. The method of claim 25 for producing a compound having the structure of Formula II (CH 2 O R (CH 2 )n-CH-CH 2 -N X R3 Z: R2 wherein n, X, Z, RI, R 2 and R 3 are as defined for Formula I and 1-4, which comprises reacting a compound having the structure of Formula VII. r (CH2)m'- 0^ 0 (CH 2 )n-CH-CH 2 -CI R 3 (VII) with said compound of Formula VIII. 27 A compound of any one of claims 1 to 7, substantially as herein described with reference to any one of the Examples. 28 A pharmaceutical composition of claim 8, substantially as herein described with reference to any one of the Examples. 29 A method of any one of claims 9 to 12 of selectively antagonising al-adrenergic receptors in a mammal which method is substantially as herein described with reference to any one of the Examples. 21/05/200 3 sw I 812spa,41 A method of any one of claims 13 to 16 of treating benign prostatic hypertrophy in a mammal which method is substantially as herein described with reference to any one of the Examples. 31 A method of any one of claims 17 to 20 for treating vascular disease, congestive heart failure, or hypertension in a mammal which method is substantially as herein described with reference to any one of the Examples. 32 A method of any one of claims 21 to 26 for making a compound having the structure of Formula I which method is substantially as herein described with reference to any one of the Examples. 33 A compound whenever made by the method of any one of claims 21 to 26 or claim
32. 34 Use of a compound of any one of claims 1 to 7 in the preparation of a medicament to selectively antagonise ai-adrenergic receptors in a mammal; to treat benign prostatic hypertrophy in a mammal; or to treat vascular disease, congestive heart failure or hypertension in a mammal. Use of claim 34, substantially as herein described with reference to any one of the Examples. DATED this 21st day of May, 2003 RANBAXY LABORATORIES LIMITED By their Patent Attorneys: CALLINAN LAWRIE *o 21/05/2003sw 1812spa,42
AU46410/99A 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers Ceased AU763541B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US09/120,265 US6083950A (en) 1997-11-13 1998-07-21 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers
US09/120265 1998-07-21
PCT/IB1999/000140 WO2000005206A1 (en) 1998-07-21 1999-01-26 Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers
AU19797/99 1999-01-26
PCT/IB1999/001296 WO2000005205A1 (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers

Publications (2)

Publication Number Publication Date
AU4641099A AU4641099A (en) 2000-02-14
AU763541B2 true AU763541B2 (en) 2003-07-24

Family

ID=26318738

Family Applications (1)

Application Number Title Priority Date Filing Date
AU46410/99A Ceased AU763541B2 (en) 1998-07-21 1999-07-16 Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers

Country Status (10)

Country Link
EP (1) EP1097134A1 (en)
AU (1) AU763541B2 (en)
BR (1) BR9912318A (en)
CA (1) CA2338317A1 (en)
HU (1) HUP0102980A3 (en)
MX (1) MXPA01000637A (en)
NZ (1) NZ509388A (en)
PL (1) PL345562A1 (en)
SK (1) SK932001A3 (en)
WO (1) WO2000005205A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100906102B1 (en) 2001-03-27 2009-07-07 사무엘 보고치 Replikin Peptide and Uses thereof
WO2005113498A1 (en) * 2004-05-19 2005-12-01 Ranbaxy Laboratories Limited Adrenergic receptor antagonists
EP1758583A2 (en) * 2004-05-31 2007-03-07 Ranbaxy Laboratories Limited Arylpiperazine derivatives useful as adrenergic receptor antagonists

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (en) * 1971-09-04 1973-03-15 Pfizer NEW PIPERAZINE COMPOUNDS
EP0103357A2 (en) * 1982-06-22 1984-03-21 Warner-Lambert Company Substituted phenylpiperazine compounds suitable as antihypertensive agents, and processes for their production

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2727469A1 (en) * 1977-06-18 1978-12-21 Hoechst Ag NEW HEXAHYDROPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
JPS57197265A (en) * 1981-05-29 1982-12-03 Eisai Co Ltd Carboxylic acid imide derivative, its preparation and medicament containing the same
US4675403A (en) * 1985-10-16 1987-06-23 American Home Products Corporation 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity
ES2094690B1 (en) * 1994-11-22 1997-08-01 Univ Madrid Complutense NEW DERIVATIVES OF IMIDA-PIPERAZINES.
ATE201016T1 (en) * 1995-06-09 2001-05-15 Hoffmann La Roche PYRIMIDINDIONE, PYRIMIDINDRION, TRIAZINDIONE DERIVATIVES AS ALPHA-1 ADRENERGIC RECEPTOR ANTAGONISTS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (en) * 1971-09-04 1973-03-15 Pfizer NEW PIPERAZINE COMPOUNDS
EP0103357A2 (en) * 1982-06-22 1984-03-21 Warner-Lambert Company Substituted phenylpiperazine compounds suitable as antihypertensive agents, and processes for their production

Also Published As

Publication number Publication date
NZ509388A (en) 2003-12-19
AU4641099A (en) 2000-02-14
WO2000005205A1 (en) 2000-02-03
CA2338317A1 (en) 2000-02-03
PL345562A1 (en) 2001-12-17
EP1097134A1 (en) 2001-05-09
HUP0102980A2 (en) 2001-12-28
BR9912318A (en) 2001-05-02
SK932001A3 (en) 2001-08-06
HUP0102980A3 (en) 2003-02-28
MXPA01000637A (en) 2002-04-08

Similar Documents

Publication Publication Date Title
US6410735B1 (en) 1-(4-arylpiperazin-1-y1)-ω-[N-(α,ω-dicarboximido)]-alkanes useful as uro-selective α1-adrenoceptor blockers
US3976776A (en) Tranquilizer process employing N-(heteroarcyclic)piperazinylalkylazaspiroalkanediones
DE60217147T2 (en) LACTAM DERIVATIVES FOR USE AS HUMANE 11CBY RECEPTOR ANTAGONISTS
JP3262333B2 (en) Piperazine derivatives as 5-HT1A antagonists
KR920005742B1 (en) Process for the preparation of pharmaceutically useful dihydropyridinyl dicanboxylate amide and esters
US6914064B2 (en) 1,4-Disubstituted piperazine derivatives useful as uro-selective α1-adrenoceptor blockers
US20030045525A1 (en) Quinoline and quinazoline compounds useful in therapy
AU2002222315A1 (en) 1,4-disubstituted piperazine derivatives useful as uro-selective alpha1-adrenoceptor blockers
WO2000005206A1 (en) Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers
AU763541B2 (en) Arylpiperazine derivatives useful as uroselective alpha1-adrenoceptor blockers
US4826845A (en) 3(2H)-pyridazinones and pharmaceutical compositions thereof
AU604756B2 (en) Isoindoline derivatives and preparation thereof
US20030229070A1 (en) Pyrrolothiazine and pyrrolothiazepine compounds having serotonin-2 receptor antagonist and alpha-1-blocking action
IE45423B1 (en) Process for hypotensive 2-(4-substituted piperazin-1-yl)-4-aminoquinazolines
US4677108A (en) 4-oxo-pyrido[2,3-d]pyrimidinone derivatives
FR2643373A1 (en) NOVEL BISARYLALKENES DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
US3970663A (en) Certain amino-nicotinamide derivatives
KR20090011376A (en) Novel Compounds Antagonistic to 5-HT7 Receptors
TW562798B (en) 1-(4-arylpiperazin-1-yl)-omega-[N-(alpha,omega-dicarboximido)]-alkanes useful as uroselective alpha1-adrenoceptor blockers and pharmaceutical compositions for treating benign prostatic hypertrophy in a mammal
JPH0641071A (en) Indole acetate derivative
JP2002521362A (en) Allylpiperazine derivatives useful as uroselective α1-adrenoceptor blockers
KR880001735B1 (en) Isoindole derivatives and preparation method thereof

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)