Side-chain homologous vitamin D derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agents

• US 5,532,228 A
• Filed: 06/01/1993
• Issued: 07/02/1996
• Est. Priority Date: 02/06/1990
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Stein-Eyer, Andreas, Thieroff-Ekerdt, Ruth, Kirsch, Gerald, Neef, Gunter, Schwarz, Katica, Brautigam, Matthias, Rach, Petra
• Primary Examiner(s): PRIOR, KIMBERLY
• Application Number:
  US08/069,805
• Time in Patent Office: 1,127 Days
• Field of Search: 514/167, 552/653, 540/200, 540/202, 544/2, 544/3, 544/63, 544/224, 546/1, 548/100, 548/122, 548/123, 548/124, 548/125, 548/400, 549/1, 549/13, 549/29, 549/88, 549/90, 549/200, 549/356, 549/429, 549/549, 549/510, 549/512
• US Class Current: 514/167
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Abstract

The invention discloses side-chain homologous vitamin D derivatives of formula I ##STR1## in which R¹, R², R³, R⁴, R⁵, R⁶, B, and D have the meanings defined in the specification and either (1) A is a direct bond between carbon atoms 20 and 22 and X is an oxy alkylene radical, --(CH₂)_n O-- where n is 1 to 3; (2) A is a methylene bridge, --CH₂ --, between carbon atoms 20 and 22 and X is either an alkylene radical, --(CH₂)_n -- or an oxy alkylene radical, --(CH₂)_n O--, where n is 1 to 3; or (3) if A is a direct bond and B and D together form a second bond, then X(R⁵) (R⁶) is ##STR2## The compounds possess proliferation-inhibiting and cell-differentiating activity.

Claims

1. Side-chain homologous vitamin D derivatives of formula I ##STR12## in which R¹ means a hydrogen atom, a hydroxy or an acyloxy group with 1 to 9 carbon atoms,

R² means a hydrogen atom or an acyl group with 1 to 9 carbon atoms,

R³ or R⁴ means a hydroxy or acyloxy group with 1 to 9 carbon atoms, and the respective other substituent is a hydrogen atom or R³ or R⁴ together mean an oxygen atom,

R⁵ and R⁶, independently of one another, each mean a linear or branched alkyl radical with up to 5 carbon atoms, a trifluoromethyl group or together a saturated, unsaturated or aromatic carbocyclic 3-, 4-, 5- or 6-member ring formed with the tertiary carbon atom or with the inclusion of 1 or 2 N, O or S atoms a heterocyclic 3, 4, 5 or 6-member ring,

B and D either mean a hydrogen atom each or together a second bond (E-configured double bond) and either

A means a direct bond between carbon atoms 20 and 22 and

X means an oxy alkylene radical --(CH₂)_n O-- with n=1 to 3 or

A means a methylene bridge (--CH₂ --) between carbon atoms 20 and 22 and

X means an alkylene radical --(CH₂)_n -- or an oxy alkylene radical --(CH₂)_n O-- with n=1 to 3, or if A stands for a direct bond and B and D together stand for a second bond, ##STR13## means ##STR14##

2. Vitamin D derivatives according to claim 1, in which R¹ stands for a hydroxy group.

3. Vitamin D derivatives according to claim 1, in which R² stands for a hydrogen atom.

4. Vitamin D derivatives according to claim 1, in which R³ or R⁴ means a hydroxy group.

5. Vitamin D derivatives according to claim 1, in which n in X is 1 or 2.

6. Vitamin D derivatives according to claim 1, in which R⁵ and R⁶ stand for methyl groups.

7. Vitamin D derivatives according to claim 1, in which R⁵, R⁶ and the tertiary carbon atom together stand for a cyclopropyl ring.

9. A pharmaceutical preparation comprising at least one compound according to claim 1 and a pharmaceutically compatible vehicle.

10. A derivative according to claim 1, wherein A is --(CH₂)--.

8. 24-(1(R)-Hydroxy-4-methylpentyl),-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,

24-(1(S)-hydroxy-4-methylpentyl),-9,10-secochola-5Z, 7E,10(19),23E-tetraene-1(S),3(R)-diol,

24-(1(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,

24-(1(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol,

24-(1(R)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-1(S),3(R)-diol,

24(1(S)-hydroxy-3-methylbutyl)-9,10-secochola-5Z,7E,10(19)-triene-1(S),3(R)-diol,

24-(1(R)-hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10, (19),23E-tetraene-1(S),3(R)-diol,

24-(1(S)-hydroxy-3-isopropoxypropyl)-9,10-secochola-5Z,7E,10, (19),23E-tetraene-1(S),3(R)-diol,

24-isopropoxymethyl-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(R)-triol,

24-isopropoxymethyl-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(S)-triol,

24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(R)-triol,

24-(2-isopropoxyethyl)-9,10-secochola-5Z,7E,10(19),22E-tetraene-1(S),3(R),24(S)-triol,

26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S),3(R),24a(R)-triol, or

26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5Z,7E,10(19),23E-tetraene-1(S),3(R),24a(S)-triol.