1,2-Disubstituted cyclopropanes

Details 1,2-Disubstituted cyclopropanes 1,2-Disubstituted cyclopropanes

1999-10-13

2001-01-09

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S427000, C514S438000, C514S649000, C546S329000, C548S566000, C549S074000, C564S161000, C564S192000, C564S336000

Reexamination Certificate

active

06172091

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel cyclopropane derivatives, pharmaceutical compositions containing them and methods of using them. The compounds of the invention bind to the calcium-sensing receptor and thus, are useful in treating diseases related to calcium imbalance and metabolism.
BACKGROUND OF THE INVENTION
Known cyclopropane derivatives include secondary and tertiary cyclopropyl methylamines described in Teotino, U. M.; Della Bella, D.; Gandini, A.; Benelli, G.,
J. Med. Chem.
1967, Vol. 10, p. 1091 as monoamine oxidase inhibitors; and cyclopropyl-methylguanidines described in Borne, R. F.; Forrester, M. L.; Waters, I. W.,
J. Med Chem
, Vol. 20, p. 771 (1977) as useful in treating hypertension. GB 1,086,191 discloses certain phenyl cyclopropane derivatives.
Extracellular calcium can exert effects on different cell functions as discussed in Nemeth et al., 11 Cell Calcium 319,1990. The role of extracellular calcium in parafollicular and parathyroid cells is discussed in Nemeth, et al., 11 Cell Calcium 323,1990.
PCT/US93/01642 (WO 94/18959); PCT/US95/13704 (WO 96/12697) and PCT/US92/07175 (WO 93/04373) disclose compounds which are described as modulators of inorganic ion receptor activity, such as mimicing or blocking the effect of extracellular calcium on a cell surface calcireceptor.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula I
wherein
R
1
is unsubstituted aryl; or aryl substituted with at least one substituent selected from the group consisting of C
1
-C
6
alkyl, cycloalkyl, halogen, haloalkyl, nitro, and C
1
-C
6
alkoxy;
R
2
is phenyl substituted with at least one substituent selected from C
1
-C
6
alkyl, cycloalkyl, haloalkyl, chloro, fluoro, iodo, C
1
-C
6
alkoxy, alkylthio, arylthio, alkylsulfone, arylsulfone, hydroxy, hydroxy alkyl, —COOR
7
and CON(R
8
)
2
; unsubstituted heteroaryl or heteroaryl substituted with at least one substituent selected from C
1
-C
6
alkyl, cycloalkyl, haloalkyl, chloro, fluoro and iodo;
R
3
is hydrogen, C
1
-C
6
alkyl or C
1
-C
6
geminal dialkyl;
R
4
is hydrogen, CON(R
9
)
2
, SO
2
N(R
10
)
2
, COR
11
or COOR
12
;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
are independently selected from hydrogen or alkyl; and
n is 1;
or a pharmaceutically acceptable salt or stereochemically isomeric form thereof.
The compounds of formula I bind to the calcium-sensing receptor and thus are useful in treating diseases related to calcium imbalance and metabolism. Such diseases include hyperparathyroidism, osteoporosis, Paget's disease, hypercalcemia malignancy, hypertension and renal osteodystrophy.
The present invention also relates to pharmaceutical compositions containing one or more of the compounds of formula I and methods for the treatment of disorders related to calcium imbalance, such as, hyperparathyroidism, osteoporosis, and the like.
In another aspect, the claimed invention relates to intermediates of formula
wherein R
1
, R
2
and R
3
are as described above, and one of R
5
and R
6
is alkyl and the other is hydrogen or both R
5
and R
6
are alkyl.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term alkyl, alone or in combination, refers to straight, cyclic and branched-chain alkyl groups. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like, preferably C
1
-C
6
alkyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups, C
1
-C
6
alkoxy is preferred. The term “aryl” as used herein, alone or in combination with other terms, indicates aromatic hydrocarbon groups such as phenyl or naphthyl, more particularly preferred is phenyl and heteroaromatic cyclic groups (“heteroaryls”) such as furan, pyridine, thiophene and pyrrole, preferably the heteroaromatic cyclic group is a 5 or 6 membered ring wherein the hetero atom is at least one of N, S or O, more preferred is one hetero atom. With reference to substituents, the term independently means that when more than one of such substituent is possible, such substituents may be the same or different from each other. The term halogen defines fluoro, chloro, bromo and iodo.
When compounds of formula I contain a basic moiety, acid addition salts may be prepared. Examples of suitable acids to form such salts include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclo hexanesulfamic, salicylic, 2-phenoxybenzoic or 2-acetoxybenzoic, and the like. Such salts can be made by known methods of reacting the free base of compounds of formula I with the acid and isolating the salt.
Stereochemistry of the cyclopropane is cis or trans, preferably trans, and absolute stereochemistry at the stereogenic center identified in formula I by an asterisk is R or S, preferably R.
The term stereochemically isomeric forms as used herein defines the different isomeric forms which the compounds of formula I may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and/or enantiomers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula I both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention can be obtained using conventional means.
The present invention is directed to compounds of Formula I
wherein
R
1
is unsubstituted aryl; or aryl substituted with at least one substituent selected from the group consisting of C
1
-C
6
alkyl, cycloalkyl, halogen, haloalkyl, nitro, and alkoxy;
R
2
is phenyl substituted with at least one substituent selected from C
1
-C
6
alkyl, cycloalkyl, haloalkyl, chloro, fluoro, iodo, C
1
-C
6
alkoxy, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, —COOR
7
and CON(R
8
)
2
;
R
3
is hydrogen, C
1
-C
6
alkyl or C
1
-C
6
geminal dialkyl;
R
4
is hydrogen, CON(R
9
)
2
, SO
2
N(R
10
)
2
, COR
11
or COOR
12
;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, and R
12
are independently selected from hydrogen or alkyl; and
n is 1;
or a pharmaceutically acceptable salt or stereochemically isomeric form thereof.
Of particular interest are those compounds wherein R
1
is unsubstituted aryl or aryl substituted with halogen or C
1
-C
6
alkyl; R
2
is unsubstituted pyridyl, pyridyl substituted with at least one of C
1
-C
6
alkyl, cycloalkyl, haloalkyl, chloro, fluoro or iodo, or phenyl substituted with at least one substituent selected from C
1
-C
6
alkyl, cycloalkyl, haloalkyl, chloro, fluoro, iodo, C
1
-C
6
alkoxy, alkylthio, alkylsulfone, arylsulfone, hydroxy, hydroxyalkyl, —COOR
7
and CON(R
8
)
2
; stereochemistry at the cyclopropane is trans, preferably R,R absolute configuration; R
3
is alkyl, preferably methyl and R
4
is hydrogen, CON(R
9
)
2
, COR
11
or COOR
12
, preferably hydrogen.
More preferred are compounds of formula I wherein R
1
is unsubstituted phenyl or thiophene or phenyl or thiophene substituted with halogen or C
1
-C
6
alkyl; R
3
is phenyl substituted with C
1
-C
6
alkyl, chloro, fluoro, iodo or C
1
-C
6
alkoxy.
In particularly preferred compounds, R
1
is unsubstituted phenyl or thiophene and R
2
is phenyl substituted with C
1
-C
6
alkoxy.
The absolute stereochemistry is most preferably RRR.
In a particularly preferred embodiment, the compound of formula I is N-((R,R)-2-phenylcyclopropanylmethyl)-1-(R)-(3-methoxyphenyl)ethylamine, represented by formula IA.
The compounds of formula I are prepared as outlined in Schemes 1-6.
wherein R
1
, R
3
, R
5
and R
6
are as described above and R
2′
is as described above for R
2
except that R
2′
is not phenyl substituted with at least one substituent selected from alkylsulfone, arylsulfone, —COOR
7
and —CON(R
8
)
2
.
wherein R

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