Tramadol analogs and uses thereof

Details Tramadol analogs and uses thereof Tramadol analogs and uses thereof

2002-12-02

2004-08-24

Davis, Brian (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S305000, C564S339000, C564S440000

Reexamination Certificate

active

06780891

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to tramadol analogs that are useful for the treatment of CNS-related disorders including pain, anxiety, depression and attention deficit disorder.
BACKGROUND OF THE INVENTION
Opioids such as morphine are very effective for the treatment of pain, but can result in very serious adverse effects, including respiratory depression, and addiction and dependency. Less serious side effects include gastrointestinal inhibition effects and obstipation. As a result, the use of such drugs is limited by the possibility of adverse effects. There is, therefore, a need for effective analgesics, which are not associated with these adverse effects.
U.S. Pat. No. 3,652,589, to Flick, discloses a genus of phenol ethers, which are described as having analgesic properties. The genus includes 2-((dimethylamino)methyl)-1-(3-methoxyphenyl)-cyclohexanol), which has been given the name tramadol. The patent also discloses 3-benzyloxyphenyl analogues of tramadol. U.S. Pat. No. 5.733,936 discloses tramadol analogs substituted at the 4-position of the cyclohexane ring.
Tramadol is commercially available from Ortho-McNeil Pharmaceuticals as a racemic mixture of the (R,R)- and (S,S)-enantiomers under the trademark ULTRAM®. It is approved by the United States Food and Drug Administration for treatment of pain, and reportedly does not produce the side effects generally associated with opioids. However, because tramadol is less effective in relieving pain than the opioid drugs, there remains a need for alternative analgesic compounds.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to compounds of formula I:
wherein
R
1
is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl;
R
2
is selected from hydrogen, hydroxy, cyano, haloalkyl, glycosyl, SO
2
R
5
, and OR
5
;
R
3
and R
4
are independently selected from hydrogen and lower alkyl, or R
3
and R
4
taken together with nitrogen form a five- or six-membered heterocyclic or substituted heterocyclic ring; and
R
5
is selected from alkyl, aryl, alkylaryl, substituted alkyl, substituted aryl, and substituted alkylaryl.
It has been unexpectedly discovered that compounds of formula I possess unique pharmacological characteristics with respect to stimulation of opiate receptors and increasing monoamine levels, particularly by inhibition of norepinephrine transport. Therefore, these compounds are effective in treating disorders, including CNS-related disorders, modulated by opiate receptor activity and/or monoamine activity, with diminished side effects compared to administration of the current standards of treatment. These disorders include, but are not limited to, acute and chronic pain, affective disorders, including anxiety and depression, and attention deficit disorders.
In the context of the present invention, alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl. Preferred alkyl groups are those of C
20
or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, and norbornyl
Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Lower alkoxy refers to groups containing one to four carbons.
Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxy-carbonyl, and benzyloxycarbonyl. Lower-acyl refers to groups containing one to four carbons.
Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; each of which rings is optionally substituted with 1-3 lower alkyl, substituted alkyl, substituted alkynyl, ═O, —NO
2
, halogen, hydroxy, alkoxy, OCH(COOH)
2
, cyano, —NR
1
R
2
, acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, or heteroaryloxy; each of said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with 1-3 substituents selected from lower alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, phenyl, benzyl, benzyloxy, carboxamido, heteroaryl, heteroaryloxy, —NO
2
or —NRR (wherein R is independently H, lower alkyl or cycloalkyl, and —RR may be fused to form a cyclic ring with nitrogen); The aromatic 6- to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, and fluorene; and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl and phenethyl.
Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, and pyrimidinylethyl.
Heterocycle or heterocyclic means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, and tetrahydrofuran.
Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with alkyl, aryl, haloalkyl, halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, nitro, amino (primary, secondary or tertiary), alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy, or substituted aryl, wherein up to three H atoms in each residue are replaced with alkyl, aryl, haloalkyl, halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, nitro, amino (primary, secondary or tertiary), alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
Haloalkyl refers to an alkyl residue, wherein one or more H atoms are replaced by halogen atoms; the term haloalkyl includes perhaloalkyl. Examples of haloalkyl groups that fall within the scope of the invention include CH
2
F, CHF
2
, and CF
3
Glycosyl means a sugar residue, attached through an ether linkage. Examples of glycosyl groups include glycosyl, fructosyl, mannosyl, and lactosyl.
Any numerical values recited herein include all values from the lower value to the upper value in increments of one unit provided that there is a separation of at least 2 units between any lower value and any higher value. As an example, if it is stated that the amount of a component or a value of a process variable such as, for example, temperature, pressure, time and the like is, for example, from 1 to 90, preferably from 20 to 80, more preferably fro

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