2-hydroxy-3—(4-hydroxy-3-sulfonamidophenyl)—prop...

Details 2-hydroxy-3—(4-hydroxy-3-sulfonamidophenyl)—prop... 2-hydroxy-3—(4-hydroxy-3-sulfonamidophenyl)—prop...

2001-07-25

2002-08-20

Richter, Johann (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S456000, C514S466000, C514S524000, C514S604000, C549S366000, C549S351000, C549S357000, C549S443000, C564S099000

Reexamination Certificate

active

06436914

ABSTRACT:

BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the formula I
and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:
R
1
is lower alkyl, aryl or arylalkyl;
A is hydrogen or
B is hydrogen, alkyl, alkenyl, or
but when A is hydrogen, B may only be
R
2
, R
2′
, R
2″
, R
3
, R
3′
and R
3
″ are independently hydrogen, hydroxy, alkoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, aryloxy, arylalkoxy, hydroxyalkoxy, lower alkyl, trifluoromethyl, halogen, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, —(CH
2
)
n
NR
4
COR
5
, —CONR
4
R
4′
, —CO
2
R
5
, —NR
4
SO
2
R
1
, —NR
4
R
4′
, —OCH
2
CH
2
NR
4
R
4′
, —OCH
2
CONR
4
R
4′
, —OCH
2
CO
2
R
4
, —PO
3
R
4
R
4′
or aryl; or R
2
and R
2′
or R
3
and R
3′
may together form a carbocycle or heterocycle;
m is 0−3;
n=0−3;
R
4
and R
4′
are independently hydrogen or lower alkyl; and
R
5
is lower alkyl.
The compounds of formula I possess activity at the beta 3 adrenergic receptor in mammals and are useful in the treatment of diabetes, obesity, depression, achalasia and intestinal hypermotility disorders.
DESCRIPTION OF THE INVENTION
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term “alkyl” refers to both straight and branched chain groups having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl. The term “alkyl” also includes cycloalkyl groups having 1 to 12 carbon atoms, such as cyclopentyl and cyclohexyl.
The term “lower alkyl” as employed herein includes such alkyl groups as described above containing 1 to 6 carbon atoms.
The term “alkoxy” refers to any of the above alkyl groups linked to an oxygen atom.
The term “lower alkoxy” refers to any of the above lower alkyl groups linked to an oxygen atom.
The term “alkenyl” refers to monounsaturated straight and branched chain groups having 1 to 12 carbon atoms, such as ethenyl, allyl, 3-butenyl, or 2-methylallyl where the point of attachment may be at a saturated or unsaturated carbon atom.
The term “aryl” refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be 1, 2 or 3 lower alkyl groups, halogens or lower alkoxy groups. Phenyl and substituted phenyl are preferred.
The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine.
The term “carbocycle” refers to fully saturated or unsaturated rings of five or six carbon atoms, such as cyclopentane, cyclohexene or benzene.
The term “heterocycle” refers to fully saturated or unsaturated rings of five to fifteen atoms containing one to five oxygen and/or sulfur atoms and/or one to four nitrogen atoms provided that the total number of hetero atoms in the ring is five or less.
The compounds of formula I can be converted to salts, in particular pharmaceutically acceptable salts using art recognized procedures. The compounds of formula I have at least one basic center, and they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids for example sulfuric acid, phosphoric acid or a hydrohalic acid, or with organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as alkane- (of 1 to 4 carbon atoms) or arylsulfonic acids, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
It should be understood that the present invention includes prodrug forms of the compounds of formula I.
The compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.
Compounds of formula I can be prepared by reduction of a compound of formula II (which is a novel intermediate)
with a reducing agent such as borane or lithium aluminum hydride in a solvent such as tetrahydrofuran at a temperature of 0° to 65° C.
Compounds of formula II can be prepared by coupling compounds of formula III
with compounds of formula IV
using standard protocols for amide bond formation, such as stirring at a temperature of 0° to 65° C. a 1:1 mixture of compounds of formulae III and IV in a solvent such as N,N-dimethylformamide to which is added a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a catalyst such as 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole hydrate.
The compounds of formula IV are commercially available or are prepared by the methods described in U.S. patent application Ser. No. 08/346,543 filed Dec. 2, 1994, PCT Application WO 95/29159 and EP 611003, Wu and Pridgen, J. Org. Chem. 1991, 56, 1340-1344, and Pridgen Advances in Asymmetric Synthesis, Vol. 2, pp. 55-117 (1997).
Compounds of formula III can be prepared by sulfonylation of the compound of formula V
with a sulfonylating agent such as methanesulfonyl chloride in a solvent such as pyridine at a temperature of −30° to 30° C.
The compound of formula V can be prepared by reduction of the compound of formula VI
with hydrogen gas at a pressure of one to six atmospheres in an alcohol solvent such as methanol or ethanol containing a catalyst such as 10% palladium on carbon. The compound of formula V is susceptible to air oxidation, should be protected from atmospheric oxygen, and should not be purified prior to conversion to the compound of formula III.
The compound of formula VI can be prepared by diazotization of the commercially available compound of formula VII
by treatment at about 0° in a solvent such as water with a nitrite such as sodium nitrite and a strong mineral acid such as sulfuric acid.
Compounds of formula I having S hydroxyl stereochemistry are prepared from the compound of formula VII that is 3-nitro-L-tyrosine.
For compounds of formula I having R hydroxyl stereochemistry the compound of formula VII

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