Crystalline forms of a 3-carboxypropyl-aminotetralin compound
AssigneeTheravance, Inc.
InventorsSean M. Dalziel, Miroslav Rapta
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Abstract
The invention provides crystalline solid forms of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid. The invention also provides pharmaceutical compositions comprising such crystalline solid forms, methods of using such crystalline solid forms to treat diseases associated with mu opioid receptor activity, and processes useful for preparing such crystalline solid forms.
Claims24
A crystalline solid form of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid or a crystalline hydrochloride salt of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid.
A process for preparing crystalline (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid (compound 1), the process comprising deprotecting (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid benzyl ester by catalytic hydrogenolysis in the presence of a polar diluent comprising between about 10% and about 20% water to form crystalline compound 1.
A process for preparing crystalline (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid (compound 1), the process comprising:
- (a) reacting (S)-2-cyclohexylmethyl-4-oxo-butyric acid benzyl ester (4)
- with (6S,7S)-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid amide (3)
- to provide (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid benzyl ester (2)
- and
- (b) deprotecting the compound of formula 2 by catalytic hydrogenolysis in the presence of a polar diluent comprising between about 10% and about 20% water to provide crystalline compound 1.
A process for preparing crystalline (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid, the process comprising:
- (a) dispersing (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid in a polar diluent comprising between about 3% and about 20% water to form a mixture;
- (b) holding the mixture for at least about 12 hours;
- and
- (c) isolating the crystalline (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid from the mixture.
A compound of formula 4
- denoted by the chemical name (S)-2-cyclohexylmethyl-4-oxo-butyric acid benzyl ester;
- or
- a bisulfite adduct thereof of formula 5
- denoted by the chemical name sodium (S)-3-benzyloxycarbonyl-4-cyclohexyl-1-hydroxy-butane-1-sulfonate.
A compound of formula 2
- denoted by the chemical name (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid benzyl ester or a hydrochloride salt thereof.
A crystalline hydrochloride salt of (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid benzyl ester.
A process for preparing (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid, the process comprising:
- (a) reacting (S)-2-cyclohexylmethyl-4-oxo-butyric acid benzyl ester (4) with (6S,7S)-7-amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide (3) to provide (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid benzyl ester (2);
- and
- (b) deprotecting compound 2 by catalytic hydrogenolysis to provide (S)-4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)-2-cyclohexylmethyl-butyric acid.
Dependencies are inferred from the claim text.