Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-06
2004-04-27
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S256000, C514S269000, C514S304000, C544S295000, C544S298000, C544S335000, C544S362000, C546S125000
Reexamination Certificate
active
06727254
ABSTRACT:
BACKGROUND
The present invention relates to nociceptin receptor ORL-1 agonist 8-(bis-(halophenyl) methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]octan-3-ols and derivatives thereof useful in treating cough, pain, anxiety, asthma, alcohol abuse or depression. Pharmaceutical compositions comprising the compounds and combinations of the claimed compounds with other agents for treating cough, allergy or asthma symptoms are also disclosed.
8-(bis-(halophenyl)methyl)-3-heteroaryl-8-azabicyclo-[3.2.1]octan-3-ols were generically, but not specifically, disclosed in U.S. Pat. No. 6,262,066 B1 and WO 01/07050 as being useful in the treatment of cough, pain, anxiety, asthma, alcohol abuse or depression. Compounds of the present invention represent a selection invention over U.S. Pat. No. 6,262,066 B1 and WO 01/07050.
SUMMARY OF THE INVENTION
Compounds of the present invention are represented by formula I
or pharmaceutically acceptable salts thereof, wherein
R is R
4
-heteroaryl or
R
1
is H or C
1
-C
6
alkyl;
R
2
and R
3
are independently selected from the group consisting of —CH
3
, —OCH
3
, fluoro, chloro, bromo and iodo;
R
4
is 1 to 4 substituents independently selected from the group consisting of H, halo, (C
1
-C
6
) alkyl, —CN, —CF
3
, —OCF
3
, —(CH
2
)
n
—OR
5
, —(CH
2
)
n
—NR
5
R
6
, —(CH
2
)
n
—NHSO
2
R
5
, —(CH
2
)
n
—NH(CH
2
)
2
NR
5
R
6
, —(CH
2
)
n
—NHC(O)NR
5
R
7
, —(CH
2
)
n
—NH(CH
2
)
2
OR
5
and 1-piperazinyl;
n is 0, 1, 2 or 3;
R
5
and R
6
are independently selected from the group consisting of H and C
1
-C-
3
alkyl; and
R
7
is H, C
1
-C-
3
alkyl or amino(C
1
-C-
3
)alkyl.
In another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and a pharmaceutically acceptable carrier.
The compounds of the present invention are agonists of the ORL-1 receptor, and therefore, in another aspect, the invention relates to a method of treating pain, anxiety, cough, asthma, alcohol abuse or depression, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of formula I.
In another aspect, the invention relates to a method of treating cough, comprising administering to a mammal in need of such treatment: (a) an effective amount of at least one compound of formula I; and (b) an effective amount of one or more additional agents for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H
3
inhibitors, &bgr;-adrenergic receptor agonists, xanthine derivatives, &agr;-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK
1
, NK
2
and NK
3
tachykinin receptor antagonists, and GABA
B
agonists.
In still another aspect, the invention relates to a pharmaceutical composition comprising at least one compound of formula I and one or more additional agents selected from the group consisting of: antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H
3
inhibitors, &bgr;-adrenergic receptor agonists, xanthine derivatives, &agr;-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK
1
, NK
2
and NK
3
tachykinin receptor antagonists, and GABA
B
agonists.
DETAILED DESCRIPTION OF THE INVENTION
Referring to formula I, above, preferred compounds of the invention are those wherein R
2
and R
3
are in the 2-position on the phenyl rings. Also preferred are compounds wherein the same halo atom is selected for each of R
2
and R
3
. More preferred are compounds wherein R
2
is chloro and R
3
is chloro, with compounds wherein R
2
is 2-chloro and R
3
is 2-chloro being most preferred.
Also preferred are compounds wherein R is R
4
-heteroaryl wherein heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl or indolyl, in particular 2-pyridyl or 2-pyrimidinyl. Preferred definitions of R
4
are hydrogen, (C
1
-C
6
) alkyl, —OR
5
and 1-piperazinyl. More preferred definitions of R are 2-pyrimidinyl, 5-ethyl-2 pyrimidinyl, 4-(1-piperazinyl)-2-pyrimidinyl, 2-pyridyl and 6-methoxy-2-pyridyl.
R
1
is preferably H or —CH
3
, with H being more preferred.
The following individual compounds are especially preferred:
A preferred indication for compounds of formula I is for the treatment of cough.
As used herein, the following terms are used as defined below unless otherwise indicated:
halo represents fluoro, chloro, bromo and iodo;
heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 9 to 10 atoms having 1, 2 or 3 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl. The heteroaryl ring can be substituted with 1-4 R
4
groups, wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group may be optionally and independently substituted.
Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention can be prepared by known methods from starting materials either known in the art or prepared by methods known in the art.
A typical method for preparing the compounds of formula Ia wherein R
1
is H comprises reacting an 8-[bis-(halophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one of formula II with a lithium derivative of a heteroaryl:
The starting material of formula II can be prepared according
Ho Ginny D.
Ng Fay W.
Tulshian Deen
Magatti Anita W.
McKenzie Thomas
Schering Corporation
Shah Mukund J.
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